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NEW YORK ACADEMY OF MEDICINE. STATED MEETING DEC, 4th, 1867, DR. ALFRED C. POST, President, in the Chair. ON BLOOD-LETTING. Dr. Post, by previous arrangement, opened the discussion upon the subject of blood-letting. After attending to the of the practice it having been in vogue among the Egyptians, Assyrians, and other nations, and resorted to by Polydorus soon after the seige of Troy, endorsed by , and its rank as a remedial agent all through the period of Roman civilization, he remarked as follows : Notwithstanding its loss of reputation, partly caused by the abuse of its power, he contended.that venesection was a remedy of great value, and in many cases it was indispensable; in other words, that it shortened the period of disease, and increased the prospect of cure. Its effect upon the circulation was well marked, as evidenced by a decrease in the frequency of the pulse, a lowering of the animal heat, and a diminution in the volume of the artery. To use a conventional phrase, "fhe pulse rises," it becomes fuller, and the patient very often feels immediate relief. The effect of opening a vein is beautifully illustrated in peritoneal , for here the pulse being " small," an increase in force is more readily detected. In acute inflammation, and in active determination of blood to important organs, the blood-letting plan of treatment was of substantial value. It relieved local pain. Among the other effects the Doctor alluded to free and copious perspiration, a tendency to syncope, nausea, emesis, and sometimes . It may be judiciously employed from infancy to old age, in the first mentioned stage of life, its application, for no very cogent reasons, was limited to the use of leeches. In advanced age great caution is required, but for the benefit of the over-timid, he cited two recorded cases. One that of a man aged 87, bled twice in one day; another aged 80, bled nine times for pneumonia. These in proof that even under this adverse condition, it was not so destructive to life after all. The case of the late Dr. Cheesman, (who died in 1862, aged 75 years,) as related by Dr. Alonzo Clark, was also to be in this connection, since he was evidently benefited by a copious bleeding. Dr. Post then related several cases to fortify his position, one or two of which are here given. A woman aet. 40, small and slender, with a pulse of force, but not remarkably compressible, being seized with a severe cephalalgia referable to the frontal region, sent for him. He administered the usual remedies, revulsive, , etc., but without effect. The patient then suggested bleeding, which Dr. P. had not before entertained, owing to its apparent contraindication. Her solicitation was backed by the assurance that previous bleedings in similar attacks had afforded relief. The loss of something over a pint of blood from her arm verified her statement. He was subsequently called at long intervals, and bled the patient each time with the same result. After several years also, he was summoned at night to her bedside; she was in state of stupor, had a wild look, was unable to speak, but significantly pointed to her elbow. A full bleeding brought relief, and since then she has enjoyed comparative immunity from attack. Case 2. A young clergyman, in the course of a platform speech, reeled and fell. Having a flushed face, full pulse, and great confusion of mind, he was bled, with marked and relief. Dr. Post, in concluding his remarks, cited the case of strangulated hernia at the New York Hospital, upon which he had called the usual consultation of his colleagues, preliminary to an operation. In the interim, however, he directed the hard, tender, and tense tumor to be covered with leeches, when spontaneous reduction took place. He also referred to the benefits of the local abstraction of blood by leeches in the case of pneumonia in the very young subject, and in pneumonia generally, when no depressing influence is at work. Dr. Anderson referred to the change in professional opinion regarding this matter, which would be more obvious by a period 25 years ago with the present time. He having read the work of Dr. Armstrong on fevers, in which venesection lvas much praised, and it had occurred to him that following up the bleeding, with anodynes, would be philosophical. While of this way of thinking, a , "a full, hearty liver," sent for him. The patient had great respiratory oppression, but no pneumonia; bleeding at once relieved him. In the case of Dr. Cheesman it would be proper to note, that more blood was lost than was originally intended, since the slipping of the bandage allowed the bed to become quite well ensanguined before the discovery was made. Remarks were made by Drs. Woodhull, Foster, and Garish. Dr. Van Buren said, at the beginning of his professional career it was thought impossible to initiate the treatment of pleurisy without a resort to blood-letting. In such cases the respiration did certainly become quite free. He also alluded to the benefit accruing from venesection in two cases of convulsions, before the days of chloroform. Dr. Wooster gave in his testimony regarding the application of leeches between the shoulder blades, especially in the case of young children suffering from pneumonia of a grave type. He was in every sense well pleased with the result. Dr. Sayre was cognizant of a case where leeches were between the shoulders, and the child died in consequence. This had made a strong impression on him. Oiled silk jackets, poultices, etc., he regarded as much safer, and more . Cases requiring prompt bleeding he regarded as quite rare. He did not wish to be understood as saying they never , since he had himself carried a lancet in his vest pocket for 15 years, and had used it three times. The change in our modes of treatment were due, he , not to popular prejudice, but to the increased of medical men. The starvation and the lancet plan had gone out of date; all were beginning to believe more in good food and good air. Dr. Woodhull would hesitate to bleed, except in cases of sudden apoplexy. Dr. Richards, after a few remarks by Dr. Van Buren a change of type in disease, asked whether it might not be a change of opinion, and for the purpose of giving the junior members of the Academy an opportunity of expressing their views, he moved that the discussion be resumed at the first opportunity. The motion prevailed, and the Academy adjourned. Stated Meeting, Feb. 5th, 1868. Dr. Alfred C. Post , in the Chair. After the usual routine, business was transacted. Dr. D. B. St. John Roosa read a paper upon Congenital Deaf Mutism. A short discussion ensued, when the President declared the continuation of the discussion on blood-letting to be in order. BLOOD-LETTING. Dr. O'Sullivan made the following remarks on the effects of blood-letting: Mr. President: The discussion on blood-letting, and the elicited on that subject at a former meeting of the Academy, has been one of the most interesting and instructive to me as one of the Junior Fellows. The earliest lessons which I have learned in the study of medicine, have been intimately connected with the ideas prevailing at the time as regards blood-letting, and which governed the practice some years since. When I commenced practice, I determined with all the zeal of a young practitioner, to test the merits of blood-letting thoroughly. In the neighborhood where I have resided for the past 11 years, there are several large founderies and machine shops, where hundreds of stalwart men are constantly . Here was a wide field for investigation, and so was I to give the subject a fair trial, that for several years I never went without a lancet in my pocket. I, however, began to perceive very soon that among this class of patients, who were apparently well able to stand depletion, I had to alter my views materially, and finally to abandon almost the use of the lancet, especially in diseases affecting the respiratory organs. Now, sir, whether this is owing to the fact that this class of patients reside in ill-ventilated and crowded apartments, or that in their daily avocations they are constantly breathing a vitiated and poisoned atmosphere, or else to climatic reasons, I am not at present prepared to say. The fact however remains, that a certain degree of enervation exists among this class of patients, and that we must be very careful how we deplete them. In acute diseases of children I have never pursued the practice. I can say with a clear , that I have never even applied a single leech, but on the contrary, endeavored to sustain my little patients from the beginning, in every possible way, locally; the oil silk jacket and poultices sufficiently fulfil the indications for depletion. In this connection I will briefly mention the history of an case which occurred in my practice some eight years ago, and which I think strongly sustains my views on the . In January, I860, I received a telegram urgently calling me to Baltimore, to see a relative, who was a student at the seminary in that city. I left immediately by the Night Express train, arriving at five A.M. I at once proceeded to the seminary, and found the patient in a very debilitated , in the second stage of pneumonia; and, as I was by the nurse, and later by the medical attendant, that he had had no sleep for three days and nights. It was evident to me at a single glance, that if sleep was not speedily procured, delirium must ensue, and with necessarily a fatal result. I was further informed by both the physician and nurse, that at the onset of the disease the patient had been bled very freely (a large basin full of blood being taken from him) and that debility had followed the venesection, and from which he had but imperfectly rallied when I saw him. The state of affairs can be readily imagined, when it is known that the was a mere anaemic youth of 19 years of age; of course, I need hardly say that the antiphlogistic regimen was also . On auscultation, I found he had a very extensive , involving both the lower and middle lobes of the lung, there had been applied extensive counter-irritation on the theory of its furthering resolution, a mode of treatment which the best clinical observers of the day have so fully . In relating particulars, the attending physician expressed his surprise, that notwithstanding he had administered large doses of opium in a concentrated form, no sleep had been , and that in his opinion the case was very serious, and an immediate fatal result was highly probable. He asked my views of the case, and what I would suggest in the present emergency. I said I very much regretted the treatment he had pursued in the earlier stages of the disease, that in so young and weak a patient, instead of depletion, sustaining treatment of a decided character should have been pursued from the very beginning, that had such a course been adopted, the solidification would not be so extensive, nor the debility be so extreme. I suggested at once the most heroic sustaining treatment; beef-tea, tonics, stimulants, etc. Being then with any of the profession in Baltimore, I telegraphed to a distinguished Fellow of this Academy, who kindly sent me the names of some prominent physicians in Baltimore, with one of whom an immediate consultation was had, and who fully my views of the treatment of the case; and on the first night on a few grains of Dover's powder the patient enjoyed three hours of most refreshing sleep, resting as placidly as an infant. I, with the nurse, watched him the whole night. Now for the sequel: the pneumonia was cured, but the patient was lost, as he died of phthisis some six months later. The I have drawn is, that the immediate and predisposing cause of the fatal result in this case, is attributable to excessive on the one hand, and defective nutrition on the other. I would mention further, that the young man inherited no to the disease of which he died his relatives on both sides were not tainted with the disease, many of them living to an extreme old age. During the collegiate course of the in New York city, he was under my constant supervision, and was never to my knowledge sick for a single day. No further remarks having been offered, the meeting . Phila. Medical ft Surgical Reporter. |
ARTICLE XII. THE VALEDICTORY LECTURE TO THE CLINICAL COURSE ON OPHTHALMOLOGY AND AURAL SURGERY IN COOK COUNTY HOSPITAL. By J. 8. HILDRETH, M.D., Surgeon to Hospital. Gentlemen: Our thirty-first lecture, and last of the course, is concluded. Many of you will soon leave for fields of practical effort. To get into practice, is the aim with you all. To those about to make the essay, it has become an all-absorbing and anxious thought. Some remarks, bearing upon this subject, seem pertinent to the waning hour. Practice is the exercise of the comprehension of a subject. Compreheneion may be defined, as taking hold of in the mind; the power of the understanding. Results will correspond to this faculty, other things being equal. When large, its are powerful; as in the orator, whose polemic eloquence sways the multitude. If refined, the effect will be subtile and delicate; as with the prima donna, whose chant plays upon the heart of her audience. Let the comprehension be selfish and wicked, actions become ugly and brutal; pirates and scoundrels generally, illustrate this. Now, the understanding, or grasp of anything, may be diversely acquired: 1st. By trial; as a mason tempers mortar a manipulation of chemistry, though he may not know the meaning of the word; or, as a laborer learns the use of the lever, in raising heavy bodies yet ignorant of its mechanical principle. 2d. Philosophically, or by induction and deduction, as grasped the law sustaining the universe; Columbus America. 3d. Accidentally, without forethought, as gold was found in California; Gasthold Schwartz is said to have stumbled upon gunpowder. 4th. From the minds of others, as shown in the moulding influence of association a man is known by the company he keeps; in the use of books they are sacks of food for the understanding. There are still other methods. But, acquire it as one may, comprehension, or knowledge, is the measure of capacity for usefulness and everything else. Manifold causes and conditions make it exceedingly varied in different persons. Let us a few: Take capability. How many have fiddled catgut for a , with no other result than to fiddle away their time; yet, Ole Bull is celebrated throughout Christendom, for his execution on the violin. One artist will produce a portrait that speaks to you; while another, with the same kind of paints, brushes, and canvas, makes a picture nobody recognizes, the name be written beneath. Sometimes this quality is intuitive, as with a celebrated mathematician of this city. Next, see the effect of education. Take two men of equal capacity and bent for a particular calling. Educate one , and let.the other come to it, as best he may. Then note the difference, as shown in the career of certain officers in our late war. Innumerable other striking illustrations of this might be cited, but one amply proves the point. Extraordinary ability, alone, can compensate for a lack of systematic training; and, even then, the individual must needs train himself. Quality of mind, good or bad, a love of truth, or the reverse, wields a potent influence over the intelligence. Minds are found, so small in goodness, it seems as if they dreaded that some truth should penetrate their littleness. Some are ugly enough to refuse to investigate what they fear to be true; thinking, thereby, to extinguish scientific light. Others are so mean as not to admit what they know to be true, lest it benefit somebody beside themselves. And there are still others, too stingy to either learn or let anybody else, if they can help it, .spending their time trying to make believe the world has come to a stand-still; that there is no advance in anything, because they, themselves, are incapable of any. Verily, they have their reward. Let us never forget, however, to do justice to a large and excellent class, who aim to do right, but are enslaved by others, or thwarted by circumstances beyond their control. Such , and must have, a better fate. Comprehension also varies in kind. There are those who have peculiar knowledge of designing, modeling, or projecting; and, then, there are those specially fitted to grasp the of a design, model, or plan. Constantine the Great could found St. Peter's, at Rome; but it took other minds to work it up. An architect models a ship he cannot build; carpenters, blacksfniths, ropemakers, and numerous other workers, must construct the craft. An engineer projects a railway across a chain of mountains; the manufacturer of gunpowder, smelter of iron, rude bosses, driving ruder gangs, with manifold agencies besides, must carry out the plan, or the parallel bars of iron can never unite States, mingle society, and so hold a nation together. In manufactures and the arts, we frequently see a certain form of comprehension, called aptitude; shown in turning out glassware, compounding silk and woolen dyes, making , etc. Another, and very important form of this faculty, is a trait of men who lead the world: a quality of mind which seeks out, brings together, arranges, and sets to work the requisite materials and forces for a certain result. All persons, in anything, possess more or less of this influence. How it preponderates in the life of Washington, Martin Luther, John Jacob Astor, or Stephenson. Great and important often search long and hard to find a master, with enough of this quality to bring them out. There were competent hands ready to make submarine cable, men to cast it into the Ocean's depths, nautical skill to guide them with their charge, astute electricians to locate break and find defect, vigilant operators, shrewd capitalists, and all other means for the of the Atlantic cable. This scattered material and had, however, to wait until Cyrus W. Field came to marshal them together, and tie the knot between the old and new continents. During the late rebellion, what gigantic armies were in the field; what fleets upon the seas. Monitors crowded the rivers; innumerable munitions, which made the world , were brought to bear on every side. The nation quaked, to its very foundation, in the struggle for life and liberty. But years, centuries long, were spent before the man was found who could lead our country through the wilderness. This tact may be termed the power of coordination, or of of means to a given end. It is by no means always to strength of intellect, inventive genius, artistic or scientific ability. On the contrary, men of transcending talent have totally failed to make it felt, for the lack of a certain something to bring themselves before the world. It was said of a gigantic intellect, that, in politics, he put to sea on an ebb tide, and was stranded going out. What a museum of valuable inventions, scientific discoveries, artistic productions, poetry, music, and the like, is lost to the world, because its light is hid and nobody dares take the bushel off. Let us now make an application of the principle we have been illustrating, to the physician. The practice of medicine is one thing; to huckster drugs, look owlish, wheedle, drive fast, pull teeth, and slaver in reach with unfledged advice is another thing though frequently supposed by aspirants for public confidence, to be a good imitation. Probably, attached to no other vocation are there more inconsistent notions, weird fancies, and empty ideas mixed up with unsuitable counsel and mistaken effort. Some think anatomy the keynote of success, and the fuller you sound it the better practice must be. Its importance is too evident to be questioned. But this department teaches the structure of the house you live in, not how to live. Another says, physiology should be the guide of your efforts. It teaches only the uses of parts. Nobody can live by knowing that are made to look out of, chimnies to smoke, and the 's function is to digest, and so on through every part of the structure. A third, suggests pathology for the basis of action. Men and women are not wanting who know the of our present system of paper currency. But where is the doctor to cure it? Mathematics, botany, chemistry, and other branches, have their special advocates in this regard. Mathematics aid to tax and appraise, not augment assimilation. Botany will germinate ideas, and big ones too; yet they must have animal heat to thrive, about which chemistry can tell you. Thus, we might go on, piling citation upon citation; but enough has been adduced to substantiate our point. Medicine is a concatenation of sciences and an epitome of arts. To practise it successfully, one must marshal and lead these manifold elements, so as to cast in the depths of a telegraphic cable between health and disease, to the end that the ailment of the patient may be known and relief dispatched to the suffering organs. In other words, the better you can yoke up medical science and art and then hitch them on to your team, the more weight you will carry through the world as a doctor; whether you attempt to handle the whole system, or concentrate your energies on a part. Earnest, honest counsel, often fired with eloquence, is to graduating classes. Sometimes, however, I have heard curious advice given to young men, and some not young, as they sat, diploma in hand, to receive the last lecture instalment. I have particularly noticed the suggestion, variously worded, for the newly plumed doctor, "to get on the right side of the women." As if women had any wrong side. Better let them take heed, lest there be so much wrong side to their ability that nobody can tell which the right side is. Believe me, that intuitive sense peculiar to women will esteem you, not as a medicine man, but as a man in medicine. Another occasional injunction to graduates is to avoid . The best of advice, but not always understood. knows what is commonly meant by quackery; but does not know when and where it occurs. Is it not quackery, when a doctor pretends to understand a case, and knows he does not? Is it not quackery, when he treats a case without counsel, and at the same time knows there is somebody within reach of the patient's means, who understands it better than he does ? Is it not quackery, for a doctor to send a to a drugstore run by men of indifferent talent, bad habits laziness, especially and where whiskey is dispensed behind the counter, or somewhere else, yes, and in the free lunch at 11 o'clock style? Is it not quackery, when the plays upon a patient's hopes by rote, because he cannot read his or her condition by note? Is it not fearful quackery, to become a denominational bigot in sectarian medicine? I will not continue this strain longer, lest it fill the hour. We have seen how upon one's comprehension of a subject depends his practice. That this comprehension, or taking hold of in the mind power of the understanding may be diversely acquired; how exceedingly varied it is in quantity and quality among individuals; and, also, that it comprises a faculty "knowing no obstacle," by which it is allied to practical effort. All this applies with equal force to the acquisition of medical knowledge. Inasmuch as the latter pertains to the welfare of humanity, its study should be governed by a care, delicacy, and patience commensurate with the magnitude of the subject. The true practitioner of medicine is a cosmopolitan student. He searches truth everywhere, that he may embrace it; and he also searches for error, that he may tread it down. He is a bookish man, and reads all sorts of books relating to his regular, irregular, and defective and as many more as he can. Like a searching man, he investigates all sorts of systems of medicine: allopathic, homoeopathic, eclectic, , electropathic, and nothingopathic, in order that he may develope discriminating talent. He is a man of observation, and allows nothing to escape attention, which may enlarge the understanding. His receptive mind always opens the door to entertain knowledge, come from whom or where it may. care to learn but one thing at a time, it is correctly , and will be retained. Knowing the importance of ability to make knowledge available to the world, he aims to cultivate business talent, etiquette, economy, and politics; that he may know how to live among men. To these, still higher qualities should be added. On a snowy night, millions upon millions of the white flakes descend from the heavens, though the darkness comprehends them not. Like birds, weary in flight, they lodge in the trees; palisade and stake are crowned as with opal; crystal tops out, even the smoke stack; the farmer's soil is shielded from icy blasts; neither pauper-house nor jail is forgotten; for, with philanthropic zeal, these light-winged messengers strive to send them from the face of nature. How earnestly they cling to the charlatan's window, as if fain to repent him of his wickedness. Sidewalks and streets are paved with more than jasper gems. But dawn scarce comes, ere the chimney's new crest is ; morning's breath shakes free the branches; horses, tired at early call, nose off1 the posts; the unwholesome mist from the quack doctor's office despoils the purity of these harbingers of health; they are trodden down by man and beast. Soon this great fleecy mantle will have passed from before our eyes. Yet, ere long, it will again come, to gladden us anew. the graceful willow shall spin its slender blossoms; the trees weave their wedding garments; and earth shall spread her velvet carpet to receive the bridal train. What came tiny and gauze-clad, will turn the miller's wheel, bear great ships on its back, and dredge out the river's bed; it will fill the springs, where the cattle slake their thirst in summer's heat; shower gently down, set the bow in the clouds, and enter into myriad forms beside, in nature's great temple. Gentlemen, the moments of life are snowflakes of eternity. Silently ever-coming, though comprehended not. Like the dove, they bring the olive-branch of peace; infancy and old age are crowned by their radiance; in their strength youth becomes invigorated, and manhood stately; with lavish hand they sustain us in wintry storms of trial; from their fulness, the poor hope for support, and the outcast for justice. These invisible missionaries ever work for the weal of mankind; , they search out the heathen in their blindness wherever they may be to enlighten them. Scattered for all, are the priceless jewels of time. But these visions unceasingly change: full vigor brings ; the baby's smile turns to wailing; patients pass away; the olive-branch, green and fruitful, fades and withers; waves of adversity sweep away the sands of life; poverty slopes into penury; the exiled and downtrodden look for equity beyond the grave; reformers are ostracized, and barbarians smite ; opportunities, pregnant with success, are wasted; the barque of life, though launched amid balmy breezes, may go down in a tempest's billow. Yet, out of the incessant roll of the unfathomable mutations of our being, is the living built. Though bitter grief come, hopes fade, plans break, effort upon effort fail, friends prove false, society frown, and everything seem to oppose, there is, somehow, a hidden strength in the moments, the finite cannot trace, which may rear the fairest and noblest structure a well-spent life. Aim to comprehend and to so practise, that your living shall become the pride of the rich and the hope of the poor. |
O i t n r hi I. Medical College Commencements in Chicago. Several weeks since, Rush Medical College closed its regular annual college term, by conferring the degree of M.D. upon 120 for graduation. The degrees were conferred by the President of the College, Prof. J. V. Z. Blaney, and the valedictory address was delivered by Prof. R. L. Rea. The exact number of students in attendance during the past winter we have not seen stated, but think it was not far from 275. The Chicago Medical College celebrated its ninth annual commencement on the 3d of March. The afternoon of the day had been spent in the reading of theses by their authors, and the public examination of the candidates for . At the commencement proper, the President of the Faculty first delivered the certificates to such members of the Junior Class as had passed satisfactory examinations in the Junior Series of branches, accompanying the same by a brief exhortation in relation to the further prosecution of their studies. Certificates were next given by the Professor of Surgery, to those members of the class who had served a specified time as dressers in the surgical wards of Mercy Hospital. Dr. J. S. Hildreth, Surgeon to the Eye and Ear Department of the County Hospital, conferred special certificates on seven of the candidates for graduation, who had not only attended his clinics in the Hospital, but had also passed a satisfactory by him, on the subject of Ophthalmology. He the certificates by a short and very appropriate address. The Committee of the Faculty, appointed for that purpose, awarded the prize for the best thesis to Nicholas Senn, and for the second best to D. W. Nolan. The President then conferred the degree of Doctor of on 45 regular candidates for graduation, and 5 ad-eundum and honorary degrees on practitioners who had been properly recommended for that purpose. The delivery of the diplomas was accompanied by a brief and impressive charge to the , concerning the nature and importance of the duties and responsibilities they assumed in entering upon the active of the profession of medicine. E. S. Cleveland, in behalf of the class, responded to the charge of the President in a very neat and appropriate address. The exercises were closed by a valedictory address by Prof. E. Andrews, on the Recreations of the Physician; a subject which was treated in a most interesting and instructive manner. It will be seen by this brief statement, that the Chicago Medical College, though organized, from its first establishment, on the basis of a long lecture-term; consecutive order of studies (the branches being divided into junior and senior series), examinations; and hospital clinical instruction as an part; with higher lecture-fees than any other school in this region; has advanced with steadiness and rapidity to a high degree of prosperity. Indeed, the City of Chicago has not advanced more rapidly in her commercial or material interests than she has in the growth of her medical schools. Ten years since, she had but one medical college and one hospital. The number of medical students in attendance was about 130, and the number of conferred about 40. Now we have 2 colleges, 4 hospitals, 400 students, and 170 graduates, making her rank next to New York and Philadelphia, as a great centre of medical college and hospital instruction. Alumni Association of the Chicago Medical College. The first anniversary meeting of this association was held in the College Hall, immediately after the close of the exercises. The President of the Association, Professor Jewell, delivered an address on the subject of Medical . He advocated the immediate adoption of all the of the Cincinnati Convention, and presented the wdiole subject in a style so clear and interesting as to fix the attention and elicit the approval of his audience. -Illinois State Medical Society. The next Annual of the Illinois State Medical Society will be held in the City of Quincy, commencing on the Third Tuesday in May, 1868. It is very desirable that the profession throughout the State should be well represented. N. S. DAVIS, March 26tli, 1868. Permanent Secy. AMERICAN MEDICAL ASSOCIATION. Office of Permanent Secretary, Wm. B. Atkinson, M.D., $.- W. Cor. Broad and Pine Sts., Phila. The Nineteenth Annual Meeting of the American Medical Association will be held in Washington, on Tuesday, May 5th, 1868, at 11 o'clock A.M. The following Committees are expected to report: On Ophthalmology, Dr. Jos. S. Hildreth, Illinois, Chairman. On Cultivation of the Cinchona Tree, Dr. J. M. Toner, D.C., Chairman. On Surgical Diseases of Women, Dr. Theophilus Parvin, Ind., Chairman. \ On Rank of Medical Men in the Navy, Dr. N. S. Davis, Ill., Chairman. On Insanity, Dr. C. A. Lee, N.Y., Chairman. On American Medical Necrology, Dr. C. C. Cox, Md., Chair'n. On Leakage of Gas-Pipes, Dr. J. C. Draper, N.Y., Chairman. On Medical Ethics, Chairman. On Plan of Organization, Dr. C. C. Cox, M.D., Chairman. On Provision for the Insane, Dr. C. A. Lee, N.Y., Chairman. On the Climatology and Epidemics of Maine, Dr. J. C. Weston; of New Hampshire, Dr. P. A. Stackpole; Vermont, Dr. Henry Janes; Massachusetts, Dr. Alfred C. Garratt; Rhode Island, Dr. C. W. Parsons; Connecticut, Dr. E. K. Hunt; New York, Dr. W. F. Thoms; New Jersey, Dr. Ezra M. Hunt; Pennsylvania, Dr. D. F. Condie; Maryland, Dr. 0. S. Mahon; Georgia, Dr. Juriah Harriss; Missouri, Dr. Geo. Engelman; Alabama, Dr. R. Miller; Texas, Dr. T. J. Heard; Illinois, Dr. R. C. Hamil; Indiana, Dr. J. F. Hibberd; of Columbia, Dr. T. Antisell; Iowa, Dr. J. W. H. ; Michigan, Dr. Ab'm Sager; Ohio, Dr. W. Russell; , Dr. F. W. Hatch; Tennessee, Dr. Joseph Jones; W. Virginia, Dr. E. A. Hildreth; Minnesota, Dr. Sam'l Willey. On Clinical Thermometry in Diphtheria, Dr. Jos. G. , N.Y., Chairman. On the Treatment of Disease by Atomized Substance, Dr. A. G. Field, Iowa, Chairman. On the Ligation of Arteries, Dr. Benj. Howard, N.Y., Ch'n. On the Treatment of Club-Foot without Tenotomy, Dr. L. A. Sayre, N.Y., Chairman. On the Radical Cure of Hernia, Dr. G. C. Blackman, Ohio, Chairman. On Operations for Harelip, Dr. Hammer, Mo., Chairman. On Errors of Diagnosis in Abdominal Tumors, Dr. G. C. E. Weber, Ohio, Chairman. On Prize Essays, Dr. Chas. Woodward, Ohio, Chairman. On Medical Education, Dr. A. B. Palmer, Mich., Chairman. On Medical Literature, Dr. Geo. Mendenhall, Ohio, Chairman. Secretaries of all medical organizations are requested to lists of their delegates, as soon as elected, to the Secretary. W. B. ATKINSON. JUST PUBLISHED. A Complete List of the Muscles of the Human Body, by William Little, M.D., Chicago. A Chart, size 24x38, the name, origin, insertion, and use of all the muscles in the Human Body. Price 50 cents; mounted on rollers, $1.50. Also, the Cranial Nerves, Twelve Pairs, giving the name, origin, foramen of exit, distribution, and function. Price 20 cents. Address, WILLIAM LITTLE, M.D., 220 Indiana St., Chicago. Mortality Report for the Month of February: CAUSES OF DEATH. Accidents 6 xApoplexy 6 Bowels, Brain, congestion of 6 Brain, disease of 2 Brain, inflammation _ 5 Birth, premature 9 " still 36 " tedious 1 Bronchitis____________ 7 Bronchitis, capillary _ 4 Cerebritis 2 Childbirth 3 Cholera infantum 21 Convulsions 41 Croup 12 Debility____________12 Diphtheria 1 6 Dropsy 3 Dysentery 4 Encephalites 2 Fever, puerperal 5 Fever, scarlet________ 5 Fever, typhoid_______ 7 Heart, disease of___ 7 Hydrocephalus________ 8 Inanition 8 Lungs, hemorrhage of 2 Lungs, congestion of _ 5 Measles_______________24 Measles, following the 3 Meningitis___________ 5 Paralysis____________ 2 Peritonitis__________ 4 Phthisis Pneumonia___________ 52 Pneumonia, typhoid 2 Scrofula 2 Small-pox___________ 33 Tabes mesenterica____ 9 Teething_____________ 5 Varioloid____________ 2 Unknown______________ 2 Total___________423 Deaths in Feb'y, 1868, 423 | Deaths in Feb'y, 1867, 265 | Decrease, 158 Deaths in January, 1868, 438 | Increase, 15 AGES. Under 5_____________254 5 to 10______________ 25 10 to 20_____________ 15 20 to 30____________ 42 30 to 40_____________ 38 Males,___________221 Single,__________335 White____________420 40 to 50____________ 22 50 to 60_____________ 3 60 to 70____________ 12 70 to 80_____________ 8 80 to 90_____________ 4 Females, 202 Married,___________ 88 Colored,_____________3 90 to 100___________ O 100 to 110__________ 0 Unknown_____________ 0 Total_________ 423 Total, 423 Total, 423 Total,__________423 NATIVITY. Chicago 198 Other parts U. S. 104 Australia _________ 0 Belgium____________ 0 Bohemia 1 Canada 3 Denmark 0 England____________ 7 F rance____________ 1 Germany 41 Holland 9 Ireland 30 Isle of Man 1 Norway_____________ 10 Nova Scotia 1 Prussia 5 Poland 0 Prince Edward Isla. 1 Russia______________ 0 Scotland____________ 4 Sandwich Islands 0 Sweden_____________ 10 Switzerland 0 Wales 0 Unknown_____________ 0 Total_________ 423 MORTALITY BY WARDS FOR THE MONTH. Ward. Mortality. Pop. in 1866. Ono death in Ward. Mortality. Pop. in 1866. One death in 1 10 9,668 1,208 1-2 14 25 12,108 448 12-27 2 21 12,985 811 9-16 15 47 15,766 404 1-4 3 18 15,738 655 9-12 16 35 14,912 573 7-13 4 19 10,884 380 1-8 County hosp.10 5 30 9,610 536 1-9 HosWom.Chi.3 6 18 10,680 391 7-9 Soldier's Ho. 1 7 43 18,755 538 5-35 Home of the 8___ 17 10,429 453 10-23 Friendl's, 2 9 20 13,940 42214-33 Marinehos., 0 10 17 11,416 634 2-9 Mercy hos., 1 11 32 12,924 359 St.Luke'shos.O 12 28 12,695 396 2-3 St.Jose. asyl. 6 13 16 8,188 629 11-13 Lake Hosp., 4 Total,________________________________________423 DEATHS BY SMALL-POX. For the Month of February, 1868. 1st Ward 2 3d Ward 1 4th Ward________________1 5th Ward________________4 6th Ward_______________ 1 7th Ward________________6 8th Ward 2 9th Ward________________4 10th Ward_______________ 1 11th Ward________________________2 12th Ward________________________1 15th Ward________________________4 Lake Hospital___________________4 Total, ______________________33 January, 1868,_________________27 Varioloid, 2d Ward,_____________2 CITY physician's report. It appears from the Report of the City Physician, that The whole number of patients remaining in Hospital, February 1, was 45 Admitted during the month,_______________________________________ 68 Total,_____________________________________________________ 113 Discharged cured, 61; Died, 6; Remaining at Hospital, 46; The complaints of those who were discharged cured were: Variola confluens, 20; Variola coherens, 15; Variola discreta, 21; Rubeola, 4; Scarlatina, 1. Five persons died of variola confluens and one of phthisis teberculosis. Of the above five, three had never been vaccinated, and the other two had been vaccinated, but it had not taken. The diseases of those now in the hospital are as follows: Variola confluens, 18; Variola coherens, 12; Variola discreta, 16. Money Receipts to March 27th. Drs. S. P. Breed, $3; A. W. Gray, 3; Geo. Fredigke, 3; J. F. Kelsey, 3; D. B. Trimble, 3; John P. Seebold, 3; Jas. M. Barlow, 3; W. A. Fox, 3; G. L. Henderson, 3; A. H. DePuy, 3; Asher Goslin, 3; Carter & Frazey, 3; R. C. Moore, 6; H. A. Chase, 3; J. B. Cloud, 3; W. W. Duncan, 3; John D. Wood, 3; W. H. Lyford, 3; J. H. Reynolds, 3; C. G. Reim, 3; A. A. Dunn, 3; G. Bradley, 1.50; John Walker, 3; F. B. , 6. Average Duration of Life in Italy. The director of the Italian Life Assurance Society, M. W. Rey, has published some interesting statistics showing the average duration of life in Italy as compared with that in other countries, from which it appears that the mortality of Italians is exceptionally great. He shows that in Italy, 22J per cent, of the infant population die yearly, and that, even in the healthiest districts, the average duration of life is 33.43 years only, while in France it is 38.33, at Geneva, 42.02, and in England, 39.31. The number of births, too, is relatively much smaller in Italy than in England and France. Lamentable Death from Chloroform. A young lady, the wife of a lieutenant-colonel in the Confederate army, died at Gallatin under very painful circumstances. Being near confinement, and suffering during the night with great pain, she inhaled some chloroform on her own account. She laid the handkerchief upon her chin and fell asleep. In the morning she was found dead. This circumstance goes to prove how dangerous a plaything chloroform is. - |
THE CHICAGO MEDICAL EXAMINER. N. S. DAVIS, M.D., Editor. VOL. IX. NOVEMBER, 1868. NO. 11. ThhihoI phjsntrxBuitJspg. ARTICLE XLIV. INTRODUCTORY LECTURE TO THE TENTH COURSE OF INSTRUCTION IN THE CHICAGO MEDICAL COLLEGE, October 5th, 1868. By N. S. DAVIS, M.D., Professor of Principles and Practice of Medicine in Chicago Medical College, and of Clinical Medicine in Mercy Hospital. Gentlemen: It has become my duty, in behalf of the , to extend to you the customary greeting at the of this, the Tenth Annual Course of Instruction in this Institution. The occasion, though of annual recurrence, is nevertheless one of marked interest to each one of you. Each period of human life has its pains and its pleasures; its toils, its , and its rewards. But none of these periods is more pregnant with importance than that which is more especially devoted to a preparation for the active duties of Life, usually called the period of pupilage. It is during this period that the young man not only acquires the knowledge which is to enable him to take his place among the active workers in society, but he also forms and fixes those habits, and develops those mental activities, that determine with much certainty both the position he shall attain in his calling, and the degree of his usefulness in society. Hence, whatever relates to your habits, your discipline, and your acquisition of knowledge, now, is of vital importance in its bearing upon all the future of your lives. If you spend this time in the mere passive reception of such facts and items of knowledge as may be presented to you, critically examining each item and measuring its relations to all others, you may close your nominal period of pupilage with a show of knowledge, but without the mental discipline to apply it accurately, or the mental activity that continually an increase of acquisition. Your mental growth will, consequently, stop at the threshold of your professional career; and though such career should be extended over thirty or forty years, yet at the end you would be found still working on the same scanty collection of materials that supplied you the first year, and following out the same monotonous routine of in which you started. These simple truths cannot be too strongly impressed on the mind of every young man entering upon the study of medicine with the intention of engaging in the active duties of practice. The extent of the field of medical sciences to be mastered; the number and variety of the conditions influencing human life and health, and the intricate nature of the questions involved in the diagnosis and treatment of disease, all demand of the medical student who would do justice, either to his calling or his conscience, a capacious, well-stored mind, disciplined to the highest degree of activity and exactness. Yet it requires but a casual acquaintance with the great body of practitioners in our country, to perceive that their most prominent deficiencies, and most frequent embarrassments, arise directly from the defective development of the' mental qualities just named. And this, again, is easily traceable to the of the system of medical education which has prevailed in this country since our existence as ah independent nation. Theoretically, that system has its basis in a course of three years of quiet study in the office of a private preceptor, aided by a short annual review of the several branches in the medical colleges. And if it was true, that every practitioner who students into his office, faithfully acted the part of a preceptor or teacher, by judiciously directing which branches should be studied first, and by daily systematic examinations and instructions of the student in those branches; and if the organization of the colleges was such that each student was to confine his attention to the reviews and in the branches corresponding with his period of in study, there would be little fault to find with the . For while it lvould make good students, on one hand, on the other it would contribute largely to keep up the habits of reading and close observation by the practitioner acting as . Practically, however, it has long since become the custom for students to enroll their names in the office of some practitioner, and spend the period of private pupilage in the desultory of medical books, without an hour of instruction from their so-called preceptors once a month; while the colleges are so organized that no classification of the pupils is allowed, the new beginner and the advanced student being mixed in the same lecture-room, and subjected alike to the hearing of a review of all the branches of medicine, heterogeneously, within the period of sixteen or eighteen weeks. The young man, who thirty or sixty days since left the plough, the , or the schoolroom, and who does not yet know enough of the elements of medical science to tell the number of bones in his own cranium, and the student of two and three years, are placed side by side, and made to listen daily, at alternate hours, to lectures on the elements of anatomy and practical medicine, physiology and the details of practical surgery, chemistry, and obstetrics, etc., at such a rate that in the short period of four or five months they have had poured into their ears instruction in anatomy, physiology, chemistry (organic and inorganic), materia medica, histology, microscopy, general pathology, anatomy, hygiene, medical jurisprudence, practical , surgery, obstetrics, and clinical observations at the . When we remember that the careful reading of a creditable text-book on any three of these branches of medical science would occupy a good student more than the eighteen weeks by most of the colleges for an entire lecture term, we shall realize how absurd the present system appears in actual practice. Indeed, it is doubtful whether human ingenuity could devise, by the most careful deliberation, a scheme of education better calculated to prevent the acquisition of extensive knowledge, thoroughness of mental discipline, or quickness and accuracy of observation; or one more directly favorable to superficial and imperfect acquirements, hasty and illogical reasoning, and the abrogation of all distinction the elementary and the practical the foundation and the superstructure. So glaring were the defects in our system of medical , and so prominent the evils resulting, both to the and the community, that more than thirty years since, it began to be most severely criticised by such men as Nathaniel Chapman, Daniel Drake, Samuel Jackson, Alexander H. , and many others of high standing in the profession. From 1835 to 1846, the subject not only engaged the attention of many of the most eminent men connected with the medical colleges, but elicited earnest discussion in most of the State Medical Societies then existing. These discussions resulted in the assembling of the first National Medical Convention, held in the city of New York, in May, 1846; and from which the American Medical Association. Since the of that Association, not an annual session has passed which there was not a general admission on the part of its members from every part of the country, that our system of medical college instruction is most lamentably defective. And even in the Convention of delegates from medical colleges alone, held in Cincinnati, May, 1867, not a single member was found willing to attempt a defence of the present system. Yet such has been the force of self-interest, and such the overpowering influence of the desire on the part of each college to swell the size of its classes and the number of its alumni, coupled with a want of confidence in the faithful cooperation of competing colleges, that no essential changes in the system have been effected. It is true that new branches have been added to the college curriculum; a few additional have, been created; from two to four weeks have been added to the annual lecture terms in most of the colleges; and additional clinical facilities have been provided in many places; but the same ignoring of preliminary education; the same of all classification of students or successive order of ; and the same repetitional, heterogeneous, intermingling of instruction on all branches of medical science and art, to all grades of students in one class, in the short space of four or five months, still exists in all but one or two of the medical colleges in our country. Within the last few years the faculties of many of the , in different parts of the country, have officially signified their readiness to adopt such specified changes as would remedy all the important defects of the present system, provided such changes can be adopted simultaneously by all, or a large , of the colleges in all parts of the country. But the of many others remain silent, while the organs a few, let no opportunity pass unimproved, to ridicule earnestly advocates improvements demanded alike by the interests of humanity and the honor of our noble calling. They are careful never to attempt a defence of the present defective system of education, or manfully to criticise proposed plans for improvement. But they are ever ready to sneeringly apply the epithet " Pseudo-Reformers f and to talk facetiously of " of Reform," and "Phantoms in BlackP This small class of small men always remind us of one of the finny tribes, which, incapable of any other defence, when attacked expels from its ink-bag a mass of black fluid by which the water is rendered so turbid that its own body is hidden from the view of its . I need not remind you, gentlemen, that the members of the Faculty of this College are among the most earnest advocates of such changes in the general system of medical college , as are almost universally admitted to be necessary, for they have demonstrated this in the organization of the itself. So early as 1857, while three of the present Faculty of this College held prominent chairs in the Faculty of the Rush College of this city, chiefly through the active advocacy of Professor Byford and myself, a plan was devised for extending the annual college term of that institution to six or eight months, classifying the students, and arranging the order of teaching into junior and senior departments, which received the sanction of a large majority of the, then existing, faculty, and was finally prevented from practical adoption solely by the of the late Professor Brainard, who was President of the College. Two years later, namely, in the spring of 1859, a very favorable opportunity occurred for the establishment of a new medical college in this city, under the auspices of the Board of Trustees of what was then called "Lind University." Professor H. A. Johnson, who had previously resigned his in the Rush Medical College, and Professor E. Andrews, acting more or less in concert with Professor R. N. Isham and the late Dr. David Rutter, ascertaining that the said Board of Trustees were desirous of establishing a Medical Department of their University, and were willing to sanction such an as the interests of the profession and the community required, without regard to effete customs or the mere number of students, entered into a contract with the Board, by which they were authorized to nominate a Faculty, and adopt such plan of organization as the faculty so nominated might deem proper. Having thus taken the initiatory steps for the organization of a new medical school, Professor Johnson, in behalf of the parties just named, communicated the fact to my colleague in the chair of Obstetrics, and to myself, together with an for us to join them, and aid in the completion of the . Having fully satisfied ourselves that no important changes could be effected in the plan of instruction in the Rush Medical College, and regarding such changes as of far more importance to the profession than any mere personal interests of our own, we cheerfully resigned our places and entered upon the new work. A plan of organization for the new school was speedily matured, embracing thirteen professorships; the of progressive study and teaching, by dividing the various branches into junior and senior groups or departments, and classifying the students accordingly; the requirement of annual examinations; the adoption of hospital clinical instruction as an essential part of the course; and the extension of the term. To demonstrate to all the profession, that those engaging in the organization of the new college were not actuated by any petty personal rivalry, or desire to establish a new school merely to compete with those previously existing for numbers of students, regardless of the great principles of education, the lecture term adopted was five calendar months, and the annual lecture fees fifty dollars cash and no credit, while at that time the Rush Medical College, in our own city, had a lecture term of only sixteen weeks, and an annual lecture fee of only dollars, and our next nearest neighbor, the Medical of the University of Michigan, charged only an fee of ten dollars. Having completed the plan of organization and nominated competent men to fill the several chairs, the same received the sanction of the Trustees of the University. Rooms for occupancy were fitted up in what was called Lind's Block, on Market Street, and on the first Monday in October, 1859, the first course of lectures in this institution was commenced, with a class of about thirty students. With the Mercy as an ample field for daily clinical instruction, the entire course was completed with regularity and great satisfaction. At the first public commencement, on the first Monday in March, I860, the degree of M.D. was conferred on nine students. ' Three years subsequently, the ground was purchased, and the building in which we are now assembled wras erected, and dedicated as a temple for the advancement of medical science and art. About the same time, Mr. Sylvester Lind, after whom the University had been named, having failed, from pecuniary , to endow the Theological Department, as he had agreed to do, the Board of Trustees procured a change of name to that of Lake Forest University. This change in the name, together with the failure of the Board to furnish the money for the new college building in accordance with the agreement, led to the organization of a new Board of Trustees under the laws of the State in which the title to the Medical College property was vested, and the new corporation took the name of the Chicago Medical College. From the first year of our organization to the present time, the prosperity of the College has been remarkably uniform and satisfactory. Commencing with thirty-three students and twelve graduates (including three ad eUndems') the first year, we closed our last and ninth course with 113 students and fifty graduates (including two ad eundem and three honorary degrees). In pecuniary matters our condition is equally satisfactory. Instead of a load of indebtedness taxing the pockets of every member of the Faculty annually to pay the interest; or a concern, in which every chair is encumbered with one or more shares of the stock, the Trustees are the absolute owners of the College building and grounds, and completely secured from all encumbrances. In addition, we have accumulated an admirable museum for illustration of the various branches; a library of several hundred volumes; and a complete laboratory for instruction in elementary, organic, and practical . Having, in the short period of nine years, secured all these results, and fully demonstrated the success and permanency of our College, the Trustees and Faculty have unanimously agreed to extend our annual lecture term to six months; to complete the classification of studies and students, by making three corresponding with the three years of study; to three annual courses of lectures before graduating, with a thorough examination at the close of each; and to exact at least a moderate standard of preliminary education at the . At the same time, they have increased the facilities for instruction, added a separate chair on Public Hygiene, special courses on Ophthalmology, Orthopaedic , physical and instrumental diagnosis, and Comparative Anatomy; with the most perfect arrangements for detailed in practical and analytical chemistry. And at the opening of this, the tenth annual course of instruction, it is with unfeigned pleasure and gratitude that I welcome you, , to the halls of the first American Medical College whose organization is in accordance with those principles of everywhere acknowledged to be correct; whose system of instruction, both in regard to length of term and systematic order of studies, is commensurate with the field of medical and the demands of the profession; and whose material appliances are complete in every part. I acknowledge a of pride that I am identified with an institution whose Trustees and Faculty have risen so far above the mere of pecuniary gain and petty competition for numbers of students, as to demonstrate to the whole profession of our country the practicability of establishing and maintaining colleges on a basis commensurate with the wants, the , and the honor of the profession. And I am sure there is not one of you, who cooperate with us by submitting as students to a patient, systematic, and course of professional study, who will not, in after years, feel an equal, nay! a greater pride in your Alma Mater. Her successful example must and will be followed, sooner or later, by other colleges in every part of the country. Many of those now existing may cling to their idols, namely, jealousy of each other and an overweening desire for large classes, of quality; but if so, they will some day wake up to find themselves supplanted by new ones on a more rational basis. The change may be slow. Indeed, all great improvements in human institutions are of slow growth. The revolution may destroy the work of centuries in a day; but, like the whirlwind, it leaves only wrecks and debris in its path, which often require generations to remove and replace with improved organizations. But, fellow-students, having indulged in this brief glance at the past history of the Chicago Medical College, and welcomed you to its halls, I must not close without a few words to you the duties and responsibilities devolving upon every student of medicine. If there are any established truths in the various departments of medical science; if there is any real efficacy in the action of medicines on the human system; if their intelligent administration is capable of mitigating human suffering and prolonging human life; if the surgical art, applied, is capable of rectifying deformities, removing obstructions and tumors, staying the flow of blood, and healing wounds; in few words, if the medical profession is a necessary part of every civilized society, its members the conservators of public health and the welcome guests at every bedside of the sick, then is there a responsibility resting upon every student which he cannot appreciate too early or too clearly. You are preparing to enter upon the practice of a profession where every step you take is in relation to the two most sacred interests of your fellow-men namely, life and health. On the extent and accuracy of your knowledge, the quickness of your perceptions, the coolness of your judgment, and the skill of your manipulations, may depend the life of the first mother or child with whom you have to do. Medical science is constituted of such facts, principles, and materials from all other sciences, as relate to the human system, in all its varying conditions of health and disease. Medical art the application of this vast aggregation of facts, principles, and appliances, to the and treatment of all the diseases, accidents, and to which the human family are liable. The field open for cultivation by the medical student is broad; the three years' time allotted for improvement is comparatively short; and he who expects to reap a harvest of either usefulness or honor, will find no time to loiter by the way. He cannot afford to lull his senses with the fumes of , or poison his blood and pervert his passions with alcohol. He cannot recline on the alluring sofa of sensual pleasures, nor w'aste time in the lecture-room listening to the facetious or vulgar stories of his pretended teachers. His work is an earnest and responsible one. And all the more so, a large majority of those with whom he has to do, are incapable of judging whether he does them justice or not. At every step, he requires accuracy of knowledge, quickness of perception, purity of thought, correctness of deduction, and promptness of action. My hearers, these are qualities that are neither born with us, nor furnished ready made by any institution; nor can they be purchased with any quantity of money or good wishes. They are, however, within the reach of all of you. Patient, , systematic study, animated by the noble aspiration to be useful in your day and generation, and associated with a daily life of unbending virtue, will develop every one of them in their fulness. It should be the aim of every student of to so qualify himself, both in the acquisition of knowledge and in the development and discipline of his mental faculties, that he can give to every patient committed to his charge, all the benefit that the science and art of medicine is capable of affording. Gentlemen, if you will treasure up, and faithfully act, through life, on these brief and hastily-expressed hints, you may not all gather an abundance of that wealth which is measured either by gold or greenbacks, but you will surely gather what is far better, a consciousness of having made the world better and happier for your having lived in it, and a conscience void of offence towards God and man. Chloride of Ammonium and Tincture of Aconite in Ovarian Neuralgia. Dr. J. Waring-Curran states that this combination seems to have a magical influence in the treatment of ovarian neuralgia. He reports six cases in which various sedatives and anodynes had been tried in vain. He prescribed an eight-ounce mixture, containing two drachms of muriate of ammonia, with five-drop doses of tincture of aconite, and found that before the mixture was finished by the patient the pains had entirely ceased. Medical Press and Circular, August 19, 1868. |
11 PS r 11 a n s. ON THE TREATMENT OF WHOOPING-COUGH. By JOHN C. PETERS, M.D., of New York. Is there any additional experience in the use of the decoction of chestnut leaves (castanea visca) in whooping-cough? Some time ago, Dr. Unzieker, of Cincinnati, gave it a fair trial in 30 cases, and felt satisfied that he had at last found a remedy to cope with this disease. It always gave decided relief in the first two weeks. First the cough was lessened and the patient rested easier at night, then the decline of all the symptoms very rapid. He used three or four drachms of the leaves in boiling water, to be drank ad libitum, either hot or cold, and with or without sugar. Children do not dislike it. The remedy is so simple, safe, and pleasant, that if this is not another instance of those tremendous exaggerations which so often make their way into the records of medicine, it should receive careful attention, especially as the remedy is so easily procured. In the mild cases of whooping-cough, which generally last only two or three weeks, very little treatment is required. The suggestion of Dr. Snow, of Providence, to place small of carbolate of lime in saucers about the room, where the child lives and sleeps, deserves attention as a prophylactic and disinfecting agent. It not only prevents others from the disease, and destroys the contagion of the disorder on the spot, but also helps the patient. For Dr. Snow says, in all cases in which he tried it, a marked effect in diminishing the frequency and severity of the cough was quickly noticed. The carbolate of lime is almost as cheap as the chloride, and need not be made unpleasant, for only sufficient should be put in the saucers to render its odor barely perceptible. Some should also be put in the spit-cups, slop-jars, etc., in which the expectorate or vomit. For it is not only the breath of the child, but its secretions and excretions, which convey the to others. Thus Dr. Aitken says the disorder was first into St. Helena by the captain of a ship, who sent the clothes of some children with whooping-cough on shore to be washed. We have known the disease to be conveyed miles in the winter-time by the mother of a nursing infant. The child nursed just before its mother left the house; she at once put on her cloak and furs, and thus shut in the infection; then went to see her sister's children, whom she took on her lap and fondled. They contracted the disease at the usual time. It is very probable, that there would be many more cases of pertussis mitior than gravior, if the hygienic management of the little sufferers were better attended to, than it generally is. Mild cases, which often last two or three weeks, may easily be converted into severe ones, by shutting the patient up in close rooms, or even heated houses, until these become filled with poisonous emanations, which probably unite with other effete matters and increase the malaria many fold. It is especially in these cases that change of air does so much good. The is benefited even by removal to so short a distance as half a mile; a sail across a river is also beneficial, although the distance be short, especially if the house be well ventilated while the patient is absent. This is all the mystery in those cases in which children recover from an almost hopeless state, even in a few hours after they have been sent away from home. From the very commencement the child should be well clad, and kept in the open air as much as the weather will permit. Next to bad air, the most injurious agent is improper food, consisting of rich, sweet, indigestible, or greasy articles. These things not only irritate the stomach, but cause risings of acrid gases and fluids, which almost excoriate the pharynx and larynx and superinduce a stomach or throat-cough in addition to the specific disorder. And each aggravates the other. A light but nourishing diet of bread and milk, hominy, rice, corn-starch, farina, etc., with meat once a day, consisting of plain soup, the inside cuts of beef or mutton, chicken and fish without the skins; no fried potatoes, made gravies, or rich fricassees, etc., etc., will keep up the strength of the child and prevent all of the stomach. Some bland or mucilaginous drink may be partaken of freely, like barley, or gum-Arabic water, flax-seed, or slippery-elm tea, etc. These will soothe and moisten the throat, and whole oesophageal and gastric mucous membrane. It is not sufficiently known that in severe cases of , the stomach is singularly red and injected; and when it becomes inflamed, this is denoted not only by pain in the , but also by the suppression of the glairy fluid, which should be thrown up by vomiting. In these cases, the little often lies in a state of complete exhaustion at the of the paroxysm of coughing, unable to discharge anything, either from the stomach or lungs, or even to whoop (Aitken). Counter-irritation to the epigastrium, with or without aconite in soap or weak hartshorn liniment to the back, are the most useful remedies in these cases. Even a few leeches to the stomach and a flax-seed poultice are not amiss. It is probably in these gastric cases, before they have advanced to far, that ipecac., has gained its great reputation. The first or catarrhal stage of ordinary whooping-cough is like that of a feverish cold, and it is not until the fever remits and is about to pass away, that the cough which has previously distressed the patient, is followed by the characteristic whoop. The first stage may last from six or eight days to two or three weeks; but an experienced and observant physician will suspect the disease he has to deal with from the peculiar paroxysmal character of the coughs, which are divided by long intervals of comparative ease. Small doses of acetate of ammonia and ., are useful in this stage: liquor ammoniae acetatis SSiss, syrupi ipecac., gss. Dose: quarter, half, or whole teaspoonful in water several times a day, according to the age of the child; or ipecac., and spirits of nitre: spts. nit. dulce, 5ij; syrupi ., 5ij; aq. cinnamomi SSiss. Dose: quarter, half, or whole teaspoonful in a little water. Those who prefer it may give one or two drops of aconite; or two or three drops of digitalis; or one or two drops of gelsiminium, or quarter, half, or whole drops of tinct. of veratrum viride. When the second or spasomodic stage sets in, the patient has a series of fits or paroxysms of severe coughing, occurring at irregular, but rather long intervals, and so rapid is the action of the diaphragm, that the air is almost instantly expelled from the lungs, and the patient half suffocated, turns black in the face. At length the crisis approaches, the diaphragm relaxes, and a violent inspiration follows, accompanied by the whoop. This sound remits, but soon returns, and thus inspiration and expiration continue, till the patient is at length relieved by a copious expectoration, or vomiting, or both. The matters expectorated are frequently thick, viscid, and muciform. Those vomited are thick and glairy, of much tenacity, semi-transparent, and often very copious (Aitken). It is in this stage that alkalies are so very beneficial. Sub. carbonate of potash 20 grains; cochineal 10 grains; sugar, oz.; water four oz.: rub together and strain. Dose: quarter teaspoonful four times a day for a child one year .old; half a teaspoonful for one of two years; and a teaspoonful for one of four years. The .cochineal is supposed by some to be an anti-spasmodic of some power, but it is more than probable that the alkali is the only efficient part of the prescription. Dr. Hawley found the bromide of ammonium useful on of its peculiar anaesthetic effect on the nerves of the and pharynx: Dose: one or two grains thrice a day for infants; up to twelve grains for much older children. The infusion of wild thyme slightly sweetened is said to *effect great improvement of the spasmodic cough. Aitken thinks it is not very important which of the more decided or antispasmodics is selected, but thinks hyoscyamus and syrup of poppies are the safest and best. Still, there is no doubt that eonium malcolatum is milder and better than , belladonna, prussic acid, or opium. Potassae sub. carb, gr. 20; aq. foeniculi three and a half ounces; tinct. conii . half ounce. Dose: quarter, half, or whole teaspoonful, to the age of the child. In severe cases: substitute 1 drachm of tinct. belladonna, for the half ounce of eonium; or ten minims of dilute hydrocyanic acid. Vollant and others prefer the powdered root of belladonna alone, giving one-fifth of a grain, first once, then twice, and finally four times a day, until the paroxysms begin to subside, which will certainly be on the third or fourth day. Then it is to be given at much longer intervals. Others prefer prussic acid alone. Acid, hydrocyan, dilut. m. iv; syrupi simplicis, vel misturae amygdalae one drachm; aq. pur. seven drachms. Dose: half or one teaspoonful for a child nine months old. Or pulv. ipecac, compos, half to one and a half grain; ext. conii maculat. one gr.; pulv. cinnamomi gr. ij; sacch. alb. gr. iv; make a powder to be given at night, for children two years of age, when there is but little wheezing or vomiting, but a very troublesome night-cough. The most frequent complication of this disease is acute , when the mucus not only becomes deficient in quantity, but thick and viscid, teasing the patient with fruitless efforts to free it from the lungs, thus causing a frequent recurrence of the paroxysm. The alkaline treatment is the best here, with the addition of a few drops of aconite or digitalis. Or equal parts of aquae laurocerasi, tinct. digitalis, and wine of antimony may be given in three, five, ten, or more drop doses. When the bronchitis becomes more chronic and assumes the form of purulent inflammation, the pus secreted being formed into sputa and moderate in quantity, give: Misturae ammoniaci one and a half ounce; aquae cinnamomi, one and a half ounce; syrupi tolutani, half oz.; tinct. castorei, two drachms; tinct. opii camph., two drachms. Dose: one, two, or three , according to the age of the child, frequently (Paris). When the pus is thrown up pure as from an abscess and in large quantities, astringents are required. Aluminis, gr. 24; acidi sulph. diluti m. 12; syrupi rheados (poppies) half an oz.; aq. pur. two and a half oz. Dose: one to three teaspoonfuls every six hours (West). Or: aluminis gr. 25; extracti conii maculat. gr. 12; syrupi rheados two drachms; aquae anethi three oz. Dose: one or two teaspoonfuls every three or six hours, for a child two or three years old (Golding Bird). Acidi nitrici diluti twelve drachms; tinct. cardamomi comp, three drachms; aquae three and a half oz.; syrupi one oz. (Gl3Bs). One or two teaspoonfuls every two or three hours will cure in from two to fourteen days. Zinci sulphatis gr. eight; extracti belladonna, gr. two to five; aquae four oz. Dose: one to four teaspoonfuls, two, four, or six times a day, for a child three years old. If inflammation of the lungs set in, the treatment is nearly the same as for acute bronchitis. Or vini antimonii , m. 30; vini ipecac., m. 10; tinct. aconit. rad. m. 5; tinct. camphorae compos, m. 20; mucilag. acaciae seven drachms. Dose: one or two teaspoonfuls every four hours, for a child four years of age (West). But the most distressing accident is when the pleura becomes inflamed, for then the patient's sufferings are fearfully during the paroxysms of the cough. Then a roller bandage should be put on the chest to limit the movements of the ribs as much as possible. This may be moistened with an infusion of digitalis, or aconite, or opium; and the ordinary internal treatment well followed up. But the results of nineteen post mortem examinations made by Graily Hewitt during a recent epidemic, showed that the most frequent and fatal lesion of the lungs, in children from one month to four years of age, was of the lung substance, or a return to the foetal condition, or atelectasis. This calls for the free employment of stimulants and as strong liquid nourishment as can be digested. Tinct. nucis vomica, quarter, half, or one drop every few hours; or, tinct. cantharidis dr. j;>> tinct. camphorae compos. 5j ; tinct. compos, dr. 10. Dose: quarter or half teaspoonful every two or four hours. Or three to five, or ten drops of spirits of ammonia. In the third stage a number of remedies have been . Assafoetida is much esteemed, and is considered by some physicians to be a specific not only in this, but in every other stage of the disease. Aitken says, it should be given in an emulsion, in the dose of one or two grains to a child two years old, repeated three or four times a day, or even as often as every two or three hours. Tinct. assafoetida dr. j; tinct. opii m. 10; ipecacuanhae pulv. gr. 10; aquae two oz. Dose: one teaspoonful every three or four hours (Reece). purae dr. j; olei amygdalae dulc. gutt. 20; rub together, and add mucilag. acaciae two oz.; syrupi altheae one oz. Dose: one teaspoonful every two hours for a child two years old (Kopp). Ext. lactucae viros gr. iv; assafoetidae depur. gr. viij; sacch. lact. vel. alb. gr. 40. Make eight powders; one every two or four hours. Musk and castor have been largely used in severely cases. Tinct. castorei half oz.; spts. lavend. compos, two dr.; aq. camphorae ad. two oz. Dose: quarter or half in sweetened water. Ext. pulsatillae gr. j; pulv. rad. valerian minor gr. three to six; elaeosacchar, foenicul, half drachm. Make twelve powders; one from two to four times a day. Herb, ledi palustris (wild rosemary) fol. sennae dr. j; pulv. ipecac, gr. four; aquae fervent four ozs.; sacch. alb. half to one oz.; liquor ammon. anisat. one drachm. Dose: one to four teaspoonfuls every two to four hours. Highly by Buttner. Ext. dulcamarae gr. 20; kali tartar depur gr. 40; aq. foenicul one oz.; vini stibiat. half drachm. Dose: five to twenty drops in water, every two, four, or six hours. The external treatment has received great attention. Olei succini dr. 2; liniment saponis compos, dr. 10; mix for a similar to Roche's. Rub one drachm upon the back and chest, two or three times a day (Hooper). Spirit, camphorae half oz.; tinct. opii. dr. 2; olei succini dr. 2; olei amygdalae half oz. Mix for a liniment to be rubbed on the chest, night and morning (Savory). Tanner prefers tinct. aconite dr. 2: soap liniment dr. 12; or a mixture of equal parts of tinct. belladonnas, glycerine, and camphor liniment, to be rubbed on the back every night. Such is the abundance of good and useful remedies, that all new suggestions should be received with great caution. Gazette. |
ARTICLE XLVI. THE OXYGEN MIXTURE, A NEW ANaeSTHETIC COMBINATION. By E. ANDREWS, M.D., Prof, of Principles and Practice of Surgery, Chicago Medical College. Every surgeon who has seen the prompt and pleasant action of the nitrous oxide gas, so much used by dentists, has wished that in some way it might be made available in surgery. The patient usually goes under the influence in 30 or 40 seconds, and wakes with equal promptness, without vomiting or other unpleasant symptoms, all of which is in contrast with the slowness, the nausea, and the discomforts of chloroform and ether. There have been, however, great obstacles to the use of the gas, owing to its evanescent action. The oxygen contained in it is in a state of chemical , so that it is not available for oxygenation of the blood; hence if any attempt is made to continue its action, the patient becomes purple in the face, showing all the signs of asphyxia; subsultus tendinum then supervenes, and shortly after he ceases to breathe, and, if allowed nothing but pure nitrous oxide, would doubtless die in a few minutes. I have for some time been experimenting, to see whether by the addition of free oxygen to the nitrous oxide, a mixture would not be obtained, by which a. patient might be anaesthetized for an indefinite period without danger of asphyxia, and thus render gas available for the most prolonged operations of . These experiments are not yet finished, but they have advanced far enough to show that the preparation, which I have named the Oxygen Mixture, is certainly available for a large part of our operations, and that for pleasantness, and probable safety, it is infinitely superior to chloroform, ether, or unmixed nitrous oxide. The following facts and experiments show the present state of our knowledge on the subject: In the first place, pure nitrous oxide, when given for brief operations, appears to be the safest anaesthetic known. , in American and European hospitals, kills one out of about every 3600 patients who take it; but the Colton Dental Association, a company with branches in all our principal cities, established for the sole purpose of extracting teeth, has on its books over sixty thousand cases of anaesthesia by nitrous oxide, without a single death caused by the anaesthetic. Now, it cannot be supposed that the addition of a moderate amount of free oxygen, in mechanical mixture, to nitrous oxide can produce any new danger; on the contrary, by removing all possibility of asphyxia, it must be eminently an element of safety. To test this question, the following experiments were : Exp. 1. A large rat was placed in a glass jar on a perforated floor, beneath which was a stratum of lime-water to absorb the carbonic acid produced by its breathing. To make more sure of this result, a jet of lime-water spray was thrown into the jar at frequent intervals during the experiment. I then turned on a small stream of pure nitrous oxide gas, which, being fifty per cent, heavier than atmospheric air, settled to the bottom, and expelled the atmospheric air by displacement. In two minutes the animal fell over upon its side, breathing slowly with inspirations. The respirations continued to become slower, until, at the end of ten minutes, they ceased entirely, and life was found to be extinct. The death was doubtless from asphyxia. Exp. 2. Another fat was placed in the jar under the same conditions, and exposed to an oxygen mixture consisting of about one-fourth of free oxygen to three-fourths of nitrous . In two and a half minutes he was so completely that he could not be made to respond to pinching or pushing. There was no panting, or laboring for breath, as when pure nitrous oxide was used, but the respiration was rather slow, and very gentle. He was kept in the mixture half an hour, and then removed, still perfectly anaesthetized. In five minutes he began efforts at walking, and in ten seemed to be perfectly to his natural condition. Exp. 3. A rat was placed in the jar and given the oxygen mixture, containing 25 per cent, pure oxygen. This being more than is contained in the atmosphere, diluted the nitrous oxide too much, which, together with the fact that the animal was less susceptible than the former, prevented full anaesthesia. He fell into a sort of intoxicated condition, without appearing to be fully unconscious, and continued thus throughout the . At the end of 30 minutes the gas was shut off, and the animal shortly recovered his sobriety. Exp. 4. The same animal was again exposed to the oxygen mixture for half an hour, with precisely the same results as . Exp. 5. To test the relative safety of the oxygen mixture as compared with ether, my friend Dr. Sherman took the same rat, after his recovery from experiment No. 4, and dropped into the jar a little sulphuric ether. In a short time he was unconscious, and in two minutes was dead. Exp. 6. A lady had an anchylosed knee, to which I wished to restore motion by forcible flexion. Having a dread of ether and chloroform, she inhaled the oxygen mixture in the of one-third free oxygen to two-thirds nitrous oxide. In forty seconds she was perfectly anaesthetized, without any of the countenance, or laboring for breath. There was a little pallor about the lips. I broke up the adhesions of the joint by flexing and extending it forcibly. She probably inhaled the gas about two minutes, felt no pain, and awaked without nausea. Exp. 7. A young woman took in my presence the mixture as prepared by Dr. Rogers, dentist, for the extraction of a tooth. There was, as before, a slight pallor of the prolabia, but no purpling of the face. The tooth was extracted pain, and the patient awoke without nausea. Exp. 8. A woman, aged 42, had anchylosis of the right hip, with contraction of the flexors of both knees, fixing those joints at a right angle. I desired to cut all the hamstring tendons of both limbs, and to break up by force the adhesions of the hip. The gas was given from a 30-gallon elastic bag, with an imperfect inhaler. The mixture contained one-third free oxygen. Owing to the imperfection of the inhaler, it was found impossible to prevent the patient getting considerable air with the gas, so that the anaesthesia was less , and slower than in the former instance. After inhaling it for nine minutes, she became unconscious, and I severed all the hamstrings. I then endeavored to break the adhesions of the head of the femur, but found they were too firm, and I desisted. The operations lasted about three minutes, when she was to recover, which she did without nausea, though she had a meal in the stomach. Twice during the inhalation there was a sort of pallor of the face, with very faint duskiness, which induced me to suspend the administration of the gas a few . Exp. 9. Mrs. R. had ingrowing, painful nails on both feet. Ten months ago she took ether for the extraction of one of them. She was of a very nervous temperament, was slow in coming under the influence of the ether, and after partially awaking remained delirious, and distressed a considerable time. Three months afterwards she took pure nitrous oxide for the extraction of a tooth. She was anaesthetized in about one , and felt no pain, but the countenance was blue with , and she was delirious a good while after waking. She felt uncomfortable for several days. Six months afterwards she was again anaesthetized by Dr. Reber, a dentist, who had prepared the oxygen mixture at the suggestion of Dr. Sherman. The gas contained one-third free oxygen. She was in one and three-quarter minutes, and in that condition Dr. Sherman split the offending toe-nail and tore out the proper half of it without causing any pain. She inhaled the gas for three minutes in all. On awaking, she was as usual delirious, which state, however, continued only fifteen minutes, a much shorter time than after ether or pure nitrous oxide. There was no blueness nor pallor of the lips during inhalation, and on her waking she was much more comfortable than after anaesthesia with the other articles. Dr. Reber has given the oxygen mixture to several patients for the extraction of teeth, and states that it uniformly acts more agreeably than unmixed nitrous oxide. Dr. Rogers, a dentist of this city, states that he has used a mixture containing one-third free oxygen for several years, and that in his opinion it is far pleasanter than unmixed nitrous oxide. Some months ago some such mixture was proposed in , but was overthrown, I think, by the influence of Dr. Richardson, who argued, on theoretical grounds merely, that it would not be successful, nor safe. I cannot learn that it was ever actually tried in Europe. Prof. Watt, of the Dental College in Cincinnati, has been experimenting, I understand, on what involves partly the same principle. I am informed that he gives alternately inspirations of nitrous oxide and atmospheric air, and thus both avoids the asphyxia, and is able to continue the inhalation a long time. I have written to him inquiring about his results, but have received no answer. The above experiments are by no means sufficient to settle the value of the oxygen mixture, but they give strong reason to think that it will prove the safest, and by far the pleasantest, anaesthetic known. As to its safety, it is highly significant, that a rat which had been twice immersed in the mixture for half an hour without injury, was killed in two minutes by ether; and yet ether is far safer than chloroform. It is my impression that the best proportion of oxygen will be found to be one-fifth by volume, which is the same as in the atmospheric air. There are some points requiring care in the management, in order to insure success. As the oxygen dilutes the nitrous oxide, it is necessary to be very careful to exclude all atmospheric air, or else the anaesthesia will be imperfect. The inhaler must be taken into the mouth, the lips very closed around it, and the nares compressed by the person administering the anaesthetic. Eor the same reason, great care should be taken to secure purity of the gases, otherwise the mixture will be too weak to control some patients. I have found, by introducing phosphorus into a bell glass of what was supposed to be very pure nitrous oxide, that it contained free oxygen, which doubtless was from included air; and therefore four times the bulk of free, inert nitrogen must have been present also, to weaken the power of the article. The oxygen is best prepared by taking pure chlorate of mixed with a little black oxide of manganese, and placing them in a copper retort and applying heat. The gas should pass through four washing-bottles, just as the nitrous oxide does. The same bottles will answer. As the nitrous oxide is fifty per cent, heavier than oxygen, it is better to pass it into the gasometer first. The oxygen coming afterwards, passes up through it, and hastens the mixing. It is better to let them stand a day or two, if possible, before using, to complete the mixture, but this is not essential. Dr. Evans, the well-known American dentist in Paris, asserts that the ordinary nitrous oxide is very far from pure, even when well made. He states that he has been in the habit of his gas by mechanically condensing it to a liquid under high pressure. This liquid, being absolutely pure nitrous oxide, is then allowed to reassume the gaseous form in a bag, or a . He finds that gas thus purified, only requires about half the usual quantity to anaesthetize a patient. It seems probable, therefore, that the oxygen mixture will enable us to anaesthetize a patient for the longest as well as for the shortest surgical operations, and that it is safer and than any anaesthetie known. There are, however, some inconveniences about it, on account of its great bulk. For office use, and also in hospitals, this is no objection, as it can be kept in a gasometer; but for outside patients it can only be carried in a large rubber bag. In city practice, among the higher classes, however, this is no obstacle, as the bag can always be taken in a carriage, without attracting observation. I shall continue my experiments, and report the results at a future time. |
tu u 11 v r ui i American Medical Association. In the present number of the Examiner, we devote a large amount of space to the record of proceedings of the recent annual meeting of the , in Washington. It is copied from the National Intelligencer of that city. The meeting was a very pleasant and profitable one, in all respects. The representation was more general from all parts of the country than for several years past; the Committee of Arrangements had provided accommodations, both for the general meetings and those of the several sections; the reports and volunteer papers were more thoroughly considered in the sections; and the social entertainments were abundant and excellent, without intruding on any of the time required for the transaction of business. The spirit manifested throughout was earnest, affable, and harmonious; vindicating the truly national character of the organization, and affording another demonstration that, in of science and humanity, there are no sectional lines. We trust the next meeting, which is to be held in New Orleans, will embrace a still larger delegation, and be actuated by the same spirit. Annual Meeting of the Illinois State Medical Society. The annual meeting of this Society was commenced in Quincy, May 19th, 1868, and continued two days. About sixty were in attendance, and the time was devoted wholly to the transaction of appropriate business. Many of the , as usual, failed to report. Yet, there was a goodly of reports and papers presented; they were more carefully prepared, and received a more full and satisfactory than for several years past. Dr. S. T. Trowbridge, of Decatur, was elected President, and Chicago chosen for the next place of meeting. A full record of the proceedings will be found in the next number of the Examiner. San Francisco Medical Society. The physicians of San Francisco have organized a medical society, and have elected the following named officers for the ensuing year: President, Dr. J. P. Whitney; First Vice-President, Dr. S. R. Harris; Second Vice-President, Dr. J. B. Pigne Dupuytren; Recording Secretary, Dr. Henry Gibbons, Jr.; Corresponding Secretary, Dr. T. M. Logan; Treasurer, Dr. A. G. Soule; Librarian, Dr. Wm. T. Garwood; Committee on Admissions, Drs. J. Haine, H. Gibbons, Senior, Thos. Bennett, W. P. Tilden, G. Hewston. The Committee on Admissions have held a meeting in the Twelfth District Court room, for the purpose of examining the credentials of those who desire to be enrolled as members of the society. Already between sixty and seventy physicians have given in their names, and there is little doubt that many more will come forward when the objects of the society are more fully known. Vienna, May 6, 1868. The Medical School of Vienna, although less known in our country than that of Paris or London, undoubtedly ranks first in Europe, as regards its course of instruction and its means of illustration. The term of study is five years, the first two devoted to the elementary branches of medicine and , embracing, also, botany, geology, and comparative ; the remaining three to the practical branches and clinics. For the study of morbid anatomy, the pathological museum of Prof. Rokitansky is open. Post mortem examinations are also performed in the presence of the class. The department devoted to diseases of the skin, and under the direction of Prof. Hebra, is especially interesting. These wards furnished the originals for his series of lithographed plates, illustrating skin diseases. Arrangements for bathing and steaming are , so that, when circumstances demand it, patients can be put through more courses than are required in a Turkish bath. The hospital is built in the form of a square, enclosing a large court which, being laid out in graveled walks and with fountains, trees, and shrubbery, forms a beautiful park -where patients may enjoy and exercise themselves in the open air. The entire hospital is capable of accommodating 2500 patients without crowding. Ventilation is most carefully provided for, and, on entering the wards, no odor whatever is perceived. Exit for the light gases is obtained by flues passing out from the ceiling, at the ends of the ward. A similar provision below, carries off the heavy gases. Double windows, situated six feet apart, admit fresh air from both sides, and opening somewhat above the beds, prevent a direct current of air from striking the patient. The beds are placed in single rows oh either side, while the centre is free and open. All parts of the building are whitewashed several times a year. Erysipelas and are strangers in this hospital, and the healthy condition of wounds, and ready union after surgical operations, speak plainer than words of the purity and cleanliness of its wards. Upon the wall, at the head of each patient, is hung a card, giving his name, age, diagnosis, and treatment of his disease, also, the diet he is receiving. The latter is as carefully to by the physician as the more direct medication. A complete record of treatment from day to day is thus preserved, for the observation of the student. Few men are emploped in the hospital as nurses, that duty being performed almost by females; they are well trained, and attend to their duties in a manner that cannot be excelled. Medical clinics are held in the wards, at the bedside, and the students required to diagnose and treat the cases, under the professor. Amputations and all surgical operations, not great skill, are performed by the student, under the direction of the surgeon. This is a practical teaching obtained in but very few schools. For the study of surgery, diseases of women, laryngoscopy, and dermatology, the student will find Vienna offering very great advantages. The galvano-caustic is much used. Combining the principles of the ecraseur and actual cautery, it is valuable in operating where hemorrhage is difficult to control. Besides the General Hospital, Vienna has a large Foundling Hospital, where infants of uncertain parentage are received at any hour, day or night, and, as in the return of stolen property, no questions are asked. The moral influence of such an cannot be overestimated. It does not diminish or the number of illegitimate children, but it does prevent the destruction of hundreds. I do not think that all the preaching and legislating on the subject of infanticide has yet saved a single young one's life. Here, where provision is made for the reception and care of foundlings, the crime is seldom committed. It is not so much the destruction of the child that the mother desires, as the concealment of her own guilt, When we cannot abolish crime, it is our duty to prevent, as much as possible, its evil results. Experience, in this country, has shown that the foundling hospital is the only successful means of abating infanticide. Yours, truly, J. S. SHERMAN. The undersigned beg leave to state that they are no longer connected with the institution called "Hotel for Invalids," on account of its departure from its original plan. Jos. W. Freer, M.D. E. C. Rogers, M.D. Wm. C. Lyman, M.D. Money Receipts to May 27th. Drs. Henry Biroth, $3; B. F, Rolfe, 5; F. K. Bailey,x3; R. M. Boyer, 3; D. A. Sheffield, 3; H. C. Hutchinson, 3; Duncan, 6; Joseph Tefft, 5; Lyman Ware, 3; H. L. Smith, 3; D. S. Jenks, 3; T. Nichols, 3; B. F. Brown, 3; J. A. W. Hostetler, 3; A. Niles, 3; G. R. Bibb, 3; J. T. Frazer, 3; A. M. Maxwell, 3; E. Robbins, 3; R. D. Cogswell, 3. Mortality Report for the Month of April: CATTSTTS nr TOP. ATM Accident, drowned,___1 burns,_____ 4 " fright,bruises 2 fall of floor, 1 railroad, 1 " scalded,____ 2 " machinery, 1 Anaesarca 1 Angina pectoris, 1 Aorta, aneurism of___ 1 Apoplexy 4 Atrophy 1 Birth, premature 8 " still____________23 " tedious__________ 1 Bowels, ulceration of, with abdom'l tumor, 1 Brain, inflammation _ 2 " disease of 1 " congestion, of 2 " oedema of, pneumo. 1 " softening of,__1 Bronchitis 3 Carries, of spine, 1 Cancer of breast_____ 1 " of liver_______ 1 " of bowels, 1 " of mouth,______ 1 " of uterus, 2 Cancer, of stomach 2 Canker sore mouth 1 Catarrh______________ 1 Convulsions__________29 Croup 5 membranous, 1 Debility_____________ 5 Diphtheria___________ 6 Diarrhoea 1 " chronic,_______ 2 Dropsy_______________ 1 " chest 1 " complica'd with cardiac rbeu'sm 1 " of spinal cord, 2 " from heart dise. 1 Drowning_____________ 1 Dysentery, 1 Enteritis 1 " acute,_________ 1 Encephalites__________ 1 Erysipelas,___________ 2 " neck and face foil, sm.-pox, 1 Fever, congestive____ 1 " puerperal______ 5 " remittent 1 " scarlet 3 " typhus 1 " typhoid_________ 7 Fungus hemadotes_____ 1 3-astromalacia,______ 1 Hemorrhage, secondary 1 Heart, disease of_______ 1 dropsy of, 1 " " pneumonia 1 " malformation of 1 " valvular disease 3 Hepatitis 1 Hydrothorax, 1 Hydrocephalus 2 " acute, 2 Inanition 9 indigestion_____________ 1 intemperance 2 Laryngitis 3 Liver, tumor of 1 " induration of 2 Lungs, congestion of _ 3 " emphysema of_ 1 " inflammation of 1 " paralysis of 1 Manslaughter, 1 Measles_______________ 7 Metritis, 1 Meningitis 5 " cerebro-spinal, 3 " complic'd with scarlet fever, 1 " tuberculosis, 1 Mitral valves, disease, 1 Nephritis 1 Slicrosis o f inferior mallary bone, 1 did Age 5 " and pneumonia, 1 " chronic stomach, 1 Ovaritis,____________ 1 Paraphlegia__________ 1 Paralysis of lungs and heart following , _____________ 1 Pericarditis complicated with pneumonia, 1 " " effusion,__v 1 Peritonitis 1 " metro__________ 2 Pharyngitis__________ 1 Phthisis pulmonalisis_ 30 Poisoned 1 Pneumonia____________ 17 " complicated with measles, 4 " " teething, 1 Prostatic calculus and inflam'n of bladder, 1 Pyaemia_______________ 3 Scurvy and encepaloid cancer of kidneys, _ 1 Scrofula . 1 Small-pox___________ 11 " complicated with pneumonia 1 Skull, fracture of, 1 Suicide 6 Spine, disease of 1 " fracture of______ 1 Syncope from heart . disease, 1 Tabes mesenterica,___ 5 Tetanus traumaticus,- 1 " " idiopathic 1 Tedious labor, 1 Teething______________ 6 Tumor, abdominal, 2 " " and phthisis pulmonalis, 1 Uraemia of scarlet fever 1 Varioloid______. 1 Whooping-cough 4 Total___________305 Deaths m April, l>>b>>, b'Jo | Deaths m April, lob/, z/o | increase, z/ Deaths in March, 1868, 380 | Decrease, 75 AGES. Under 0____________laa 5 to 10_____________ 20 10 to 20____________ 14 20 to 30____________ 30 30 to 40____________ 30 40 to 50____________ 21 50 to 60____________ 18 60 to 70____________ 11 70 to 80____________ 11 80 to 90_____________ 3 90 to 100__________ 0 100 to 110_________ 0 Unknown 3 Total 305 Males,____________163 Single,___________204 White,____________301 Females,___________142 Married,___________ 101 | Colored, 4 I Total, 305 Total,______________305 Total, 305 NATIVITY. Chicago 126 Other parts U. S._ 52 Bavaria 1 Bohemia 5 Canada 8 Denmark 2 England_____________ 9 Grermany 42 Holland 1 Ireland____________ 39 Isle of Man_________ 1 Norway 6 Prussia___________* 0 Scotland 5 Sweden 5 Unknown 3 Total_________ 305 DEATHS BY SMALL-POX. For the Month of April. 1868. 4th Ward 1 5th Ward 3 6th IV ard_________________ 1 7th Ward 1 9th Ward Varioloid,____1 12th Ward________________________ 1 15th Ward________________________ 3 Lake Hospital 2 Total,_______________________35 MORTALITY BY WARDS FOR THE MONTH. Ward. Mortality. Pop. in 1866. One death in Ward. Mortality. Pop. in 1866. One death in 1 5 9,668 1,927 3-5 2 15 12,985 865 2-3 3 15 15,738 1,049 1-5 4 18 10,884 604 3-4 5 19 9,610 495 1-4 6 13 10,680 81311-13 7 43 18,755 436 1-6 8 14 10,429 745 0-0 9 19 13,940 733 4-7 10 9 11,416 1,267 1-3 11 16 12,924 807 3-4 12 21 12,695 604 1-2 13 13 8,188 629 11-13 Total, 14___ 15 12,108 807 1-5 15. 35 15,766 449 1-35 16 18 14,912 828 4-9 bounty hosp. 3 Dhica. River, 1 Bridewell, 1 Home of the Friendl's, 2 Marine hos., 1 Mercy hos., 3 St.Luke's hos.l St.Jose. asyl. 3 Lake Hosp., 2 _________________________________305 |
ARTICLE XIX. MEDICAL EDUCATION. AN ADDRESS DELIVERED BEFORE THE ALUMNI ASSOCIATION OF CHICAGO MEDICAL COLLEGE. By J. S. JEWELL, M.D., of Chicago, Pres't of the Association. Delivered at the Annual Meeting of the Association, held at Chicago Medical College, March 3d, 1368. Gentlemen of the Alumni Association of Chicago College: The institution of which we are members, has just closed the ninth year of its existence. Beginning under external not the most auspicious, it has passed evenly and along, to the surprise, even of many of its friends, not to mention those who looked upon it, if not wTith enmity, yet as a spasmodic or Utopian scheme. In spite of adverse , unfriendly and often unbecoming criticisms, it has, from the first, enjoyed a real, healthy growth, and to-day has an acknowledged and a permanent place among the institutions of our city and country; one, we may be permitted to say, in which is found only cause for congratulation. From a without means, it has advanced to a position where its foundation has been, we trust, enduringly , laid. To whatever other causes this success has been due (and there are other causes), it is in great measure due to the men' who first founded it, to give practical form to their well-grounded views in to medical education, and to which practical effort they have consecrated no small portion of their time, means, and influence, without any corresponding material equivalent as a return. To no one of that number can these remarks be so fully applied as to the worthy and respected President of our Alma Mater. By many of us was it thought to be a fitting time to call the children, who have been scattered abroad, back to the old ground, for mutual advice, encouragement, and . With nine years of our institution committed to history; with a band of faithful and generous alumni; and with the prospect and determination, if practicable, of taking new and important steps in relation to medical education; and in view of the necessity of harmony of purpose and effort, so far as the alumni are concerned, you have been called together. We had hoped to have seen a greater number present from the classes of former years; but to such as are with us, and to the new members, in behalf of the faculty, trustees, and resident alumni, I extend you a welcome, which lacks language corresponding to its cordiality. This coming together is not for purposes of self-glorification, though we may in all propriety congratulate each other and the institution, on the success it has achieved. It is rather for the purpose, as I view it, of renewing old and forming new ; rekindling our zeal; perfecting our organization, in view of its ends; and of considering, at this juncture, what are the present relations of the institution, in the welfare of which we have so deep an interest to the profession and medical and what should or will be its policy in the future, and in what way, if any, we, as its members, may aid its efforts in the worthy cause to which it is committed. Never, in its , could a meeting of its graduates and friends, with such purposes, take place with more propriety. Then, in the first place, it is only necessary to remind you, I hope, how much an institution, especially one like this, is on its graduates. They are its living, acting, practical testimonies; epistles known and read of all men. If we are progressive, liberal, and practical in spirit, comparatively and extensive in professional learning, and faithful in the discharge of professional and other duties, the result cannot but be to reflect honor back on the institution from which we have issued. Conversely, if we display opposite qualities, the institution, by an inevitable consequence, shares our failure or disgrace. Thus, in some important respects, our interests are one the relations reciprocal. You know not with what and satisfaction the institution, represented in its faculty, looks out after those it has fostered and upon whom it has set the seal of its approbation. How they watch with a just pride their good deeds, and with what pain they learn of any act inconsistent with a true manhood. They cannot but feel , since the responsibility is recognized and accepted, which rests on them, in sending out members to assume responsible places in the communities of our land. The impressions of various kinds made on the mind of the student, while passing through the prescribed course, cannot be devoid of influence on his subsequent professional career. He #will have, as a general thing, a broad, manly, and liberal, or a narrow, low, and sordid view of his profession; much in with the spell cast about him by the institution to the of which he has committed himself. These relations should never be forgotten, and I hope they are remembered by all congregated here to-day. In the second place, let us not forget the relations our sustains to medical education and the profession in this country, to-day, not less than through its entire history. That we may understand the relation just mentioned, let us glance briefly at its two terms. But first, the state of medical education in general, and the needs of the profession. Some of you will be surprised to learn, that just one hundred years ago, almost to a day, the first medical school was in this country. This was in 1768, in the city of , and now we meet here on the threshold of a new ! That school and others, called into existence sooner or later, were evidently intended to meet, temporarily, an felt in a new country. It does not seem to have entered the thought of these pioneers in medical education that their primitive schools were adequate to the real wants of the . Men still returned to the old world, to acquire what the imperfect schools of the new could not afford. But so pressing were the needs of the new communities, and so great the inducements to enter practice, that, in connexion with the difficulty and expense of visiting the old world, it soon came to pass that the profession, as a whole, had only such as the imperfect home schools could afford. The character of a people devoted, necessarily, at that early period, to the development of the material resources of the country, was soon communicated to the profession, with the effect to render men careful only of securing a mere practical acquaintance with the simple diseases prevalent in the early settlements. Then, the absence of the legal restrictions which, from time immemorial, were in force in the old world, by which communities were in some measure protected from quacks and pretenders, permitted all persons whom inclination, a sordid interest, or accident led to practice, to do so without let or . This opening the professional arena to a host of and quackish persons; this practical obliteration of all well-marked distinctions in the popular mind, or even in the profession, between incompetent professionals and the educated physician was striven against, but with indifferent success. Those who took this stand, gradually abandoned the unequal contest and soon came to tolerate, if not to fall in with, the adverse tide. The final result was, a majority of the practicing physicians in the country had never beheld the inside of a college, even such as the country afforded, and among the remainder, the majority had attended but one course of lectures before becoming involved in the toils of practice; while the few only, as rare exceptions, had a diploma from an indigenous college. The rarest professional phenomenon was to see, or even hear of a man who had graduated at one of the renowned schools of the old world. This state of things, true to the , led to several results. Among them, we notice: 1. A miserably low standard of attainment among those popularly accounted as members of the profession. The result in fact, was to abolish any valid standard for comparison and judgment. 2. A continuance, as a permanent system, with occasional unimportant changes for better or worse, of the temporary scheme adopted in the beginning, in relation to course, time, and range of study in the medical colleges. 3. A most overwhelming admiration for the men, institutions, and boohs of the old world. This latter is, even now, only to relict to something like just proportions. These, in brief, were the main results reached almost a century ago. The one hundred years which have elapsed since the of the first medical college, have witnessed in this fail' land of a development and progress in the material, scientific, educational, moral, and religious aspects of life, such as must be, and is, matter for unfeigned astonishment to every reflecting mind. Everywhere, forgetting the things that are behind, has marked progress been made toward perfection. But one exception, however, must be made to this statement, and only one. It relates to our profession. We do not make this as a general statement. We do not refer to the progress of medical knowledge, because that has kept pace at least with other progressive forms of knowledge. do we refer to the state of the professional mind as to in medical education, because there has been decided advance in this respect. While all forms of science, and those tributary to medicine, have been widening their fields and multiplying their objects an hundred fold, medical schools have, almost without an exception, stood absolutely still. Generally speaking, they have revolved within the same limits and on much the same ground they did one hundred years ago. There has been no advance, in any sense, corresponding to what has been observed in other departments of education, or commensurate with the growing state of medicine. This has not existed because the profession was unaware of it, or had not protested against it. Protestations were often made, and the more so as time passed on. There has been a progressively increasing demand on the colleges for higher education; but the demand, practically speaking, has been unheeded. But what has been actually the practice of the schools in this , and what is the practice now? It is so well known as almost to weary one to hear it stated. The colleges have almost uniformly laid down two courses of four calendar months each, or sixteen weeks; in all, something like three years is supposed to be spent in study before taking a degree. It is really amazing to look over the details of the curriculum and see how much must be crowded in the brief space of three years. But in some cases, there has been ever a letting down from the positions assumed just one hundred years ago. The candidate was then obliged, as he is not now, to submit to examinations in latin and mathematics, and present and defend a latin thesis, besides pursuing and submitting to examinations in all medical subjects, properly so-called. Though there has been such a rapid extension of the domain of medicine, there has been no corresponding extension of terms. As they were one hundred years ago, so are they, generally speaking, now. This remarkable brevity in number and length of college terms is not compensated for by any and accurate preliminary culture, as a rule, in attaining which, valuable habits of study are formed and acquirements made. As often as any other way, students come from the farm, or some other sphere in which they seldom possess any of the above prerequisites. But, perhaps, these defects in the system are counterbalanced by the adoption of a happy logical order among the various studies, so as to economize the time? It would surprise any disinterested but intelligent observer to be told, as he must be in truth, that faulty as the system is in other respects, it is most so here. There has been, as a rule, no kind of attention paid to a logical order among the various branches taught. Order is said to be the first law of heaven. I do not know about that; but this I do know, it is likely to prove the last in medical college instruction. This cannot be set aside, as of small consequence. Everywhere else, in all kinds of business, in learning all other professions, in all other forms of teaching or education a progressive order is considered, and justly so, as an indispensable, almost a paramount feature. But in medicine, instead of this, its various branches have been presented in the veriest medley. We cannot plead that medical is an exception to other kinds of teaching; neither can we plead custom, or authority, or respectability, such will not do. It will be no offset to this to say, our institutions have turned out men who have become eminent. This is but the transparent logical fallacy of "post hoc, ergo propter hoed' It is a mortifying, indisputable fact that, in this respect, the medical colleges in this country are behind the times. There is but one course open which should be entertained. That is, enlightened, liberal reform. This should be pushed, in spite of the harmless sneers of a halting conservatism. The time has been, when it was best to wait and consider, perhaps, but that time has passed. There is no longer any valid excuse for delay. But what effect on the profession and on the progress of medicine has this unfortunate attitude of the colleges ? As to the former, certainly not good. No one will but if the colleges had exacted three terms instead of two, of six months each instead of four, medical men, as a whole, would have been better educated. No one will contend that the colleges have no responsibility in this matter. As water will not rise above its fountain head, neither will the profession, as a body, transcend its fountains of instruction and intelligence. This is true, if there is any force in personal influence and in the affairs of men. As to the latter the progress of medicine the same may be said. It savors of a truism, to say that medicine would have been advanced more than it has been, if the profession had been more learned, capable, and , as it would have been under a different.course of . These effects on the profession and the progress of medicine, have not been passing unperceived. Whenever the profession has been brought to reflect, as it often has, and when the opportunity has been offered for expression, almost invariably the call has been for higher education. The reports of societies and medical journals have often been fairly with unmistakable expressions, that the colleges must adopt a more elevated and rational system of instruction. It is almost painful to think in what estimation our system is held abroad. To our complacent, minutely furnished, and highly favored brethren in Europe, we are little better than gentiles or barbarians, in a scientific point of view. Every one knows how lightly the title of doctor is held in popular esteem in this country, and how narrow, for reasons at once obvious, is the line between quacks and the regular profession. Is it any wonder to the frank and intelligent outsider, that mistakes should be made by the people as to where that line is, if it exists? Having glanced briefly at the relations of medical in general in this country to medical education, let us notice, in a few words, what are and have been, from its , the relations of this institution to the same. The establishment of this school took place under the , in the minds of its founders, that there was no longer any excuse for not making some change in the right direction. While the true conception required to satisfy it a sweeping and radical reform, yet the practical difficulties in the way of the enterprise made it necessary to lower the conception for the time, without, however, losing sight of it. The three of importance the design included, were: 1. To lengthen the term to five instead of four months. 2. Multiply the chairs, by dividing some of the leading ones, as anatomy, chemistry, surgery, practical medicine, etc., that each teacher might have a narrower field, and more time to occupy it; and the student more time and less for study. 3. To arrange the various branches embraced in the , so that the most primary, as determined by the real wants of the student, should come first, while others should in a strictly natural or logical order; so that the studies of this day, week, or session would not be alone for themselves, but preparatory to ulterior studies, and so on to the end of the curriculum. The student was to be restrained from entering on that part of his course to-day, which, to be comprehended, would remand him to-morrow to some prior study he had , or, worse still, which it had been arranged to lead him into at some subsequent period. You are all familiar with the division of studies and course, in conformity with the above, which has, from the beginning, prevailed in this school. While it was felt that the^ma/ step could not be taken; that the contemplated change must be gradual; yet that the extension of time from four to five months, and the division of the chairs adopted, and the attempt to the course were important advances in a normal , none will deny. The ground at first taken has not since been abandoned. So far from any disposition to this being manifested, the faculty, or various members of it, have had under consideration various schemes for attaining higher ground in relation to medical education. Time passed on, and it began to be known that a medical college planted on these principles could be sustained, and was actually receiving sympathy and encouragement from the profession, so far as it became known. At each meeting of the American Medical Association, education received thoughtful attention, until at last, at the meeting of 1866, held in Baltimore, it culminated in the appointment of a committee, which was empowered to call a convention of colleges, to consider the whole matter of medical college instruction, with a view to reform. In obedience to the call of the committee, a convention assembled at Cincinnati, beginning on the 3d of May, 1867, Prof. Alfred Stills, of , presiding. That convention continued its sessions for three days, and was made up of delegates from most of the prominent colleges in the United States. This institution was worthily represented by Professors Davis and Byford. On the first day of the convention, the former presented propositions for its action, and, during its continuance, ably supported them. The meeting seems to have been conspicuous for its harmony and good feeling, and the propositions were thoroughly, , and temperately discussed. The final result, was the adoption of the propositions at first submitted, without any fundamental change, and without a dissenting voice. They read, omitting the last of the series, as follows: "Resolved: "1st. That every student applying for matriculation in a Medical College, shall be required to show, either by certificate, or by a direct examination by a Committee of the Faculty, that he possesses a thorough knowledge of the common English branches of education, including the first of mathematics, the elements of natural sciences, and a knowledge of Latin and Greek to understand the terms of the profession; and that the certificate presented, or the result of the examinations thus required, be regularly filed as a part of the records of each Medical College. "2d. That every Medical Student shall be required to study four full years, including three regular annual courses of College instruction, before being admitted to an examination for the degree of Doctor of Medicine. "3d. That the minimum duration of a regular annual term, or course of Medical College instruction, shall be six calendar months. "4th. That every Medical College shall embrace in its the following branches, to be taught by not less than nine Professors, namely: Descriptive anatomy, including ; physiology and histology; inorganic chemistry, medica, organic chemistry, and toxicology; general , therapeutics, pathological anatomy, and public hygiene; surgical anatomy and operations of surgery; medical and medical ethics; practice of medicine, practice of surgery, obstetrics, and diseases of women and children; medicine and clinical surgery. And that these several branches shall be divided into three groups or series, with the three courses of Medical College instruction required. "The first, or Freshman Series, shall embrace descriptive anatomy and practical dissections; physiology and histology; inorganic chemistry and materia medica. To these, the of the student shall be mainly restricted during his first course of Medical College instruction, and in these he shall submit to a thorough examination, by the proper members of the Faculty, at its close, and receive a certificate indicating the degree of his progress. "The second, or Junior Series, shall embrace organic and toxicology; general pathology, pathological anatomy, therapeutics, and public hygiene; surgical anatomy and of surgery; medical jurisprudence and medical ethics. To these the attention of the medical student shall be directed during his second course of Medical College instruction, and in them he shall be examined, at the close of his second course, in the same manner as after the first. "The third, or Senior Series, shall embrace practical ; practical surgery; obstetrics, and diseases peculiar to women and children; with clinical medicine and clinical surgery in a hospital. These shall occupy the attention of the student during his third course of College instruction, and at its close he shall be eligible to a general examination for the degree of Doctor of Medicine. "The instruction in the three series is to be given , and to continue throughout the whole of each annual College term; each student attending the lectures on such branches as belong to his period of progress in study, in the same manner as the sophomore, junior, and senior classes, each pursue their studies simultaneously throughout the collegiate year, in all our Literary Colleges. " 5th. That every Medical College should immediately adopt some effectual method of ascertaining the actual attendance of students, upon its lectures and other exercises, and at the close of each session, of the attendance of the student, a certificate, specifying the time and the courses of instruction actually attended, should be given, and such certificate only should be received by other Colleges as evidence of such attendance." Immediately following the convention, the American Medical Association convened on the 7th, at the same place, and on the second day Dr. Sayre, of New York, offered the following: "Resolved, That this Association, most heartily approving the whole action of the Convention of Medical Colleges, urge its practical adoption on all the Medical Colleges in the country." This resolution was adopted. It will be observed by you all, that the course, finally agreed on in the Convention and by the Association, differs only in measure, not in kind, from that adopted in this College from the beginning, and which has been urged for years past, on all occasions, by the worthy President of this faculty, to whose action, more than that of any single man, the movement now under consideration may be fairly attributed. It is on the eve of this grand advance determined on among the colleges, and upon which the profession has set the seal of its approbation, and which is to open the new century dawning on American medical colleges; it is to catch the spirit and feel the spell of this medical college centennary; to approve and urge, in our proper capacity, the adoption of the propositions agreed on; to exchange congratulations; renew old associations and form new; rekindle our zeal, and consecrate ourselves anew and intelligently to the best interests of the profession; it is for such purposes we have come together to-day. To these calls may we all respond. Let us not leave here, faltering as to our personal duty, however humble, nor devoid of hope or interest in this cause. Let us try and be worthy of, and display a truly filial affection for, our Alma Mater, acquitting ourselves in whatever sphere as men, and ever ready to come up and lend what assistance and encouragement we may in forwarding the noble cause our Institution is so honorably identified with. |
O i t a r ial. Medical Colleges in this City. The next Annual Lecture Term in Rush Medical College commences on the 30th of . The introductory lecture will be given by Prof. E. Powell. The next Annual Lecture Term in Chicago Medical College will commence on the 5th of October. The introductory lecture will be given by Prof. N. S. Davis. The laboratory for analytical and practical chemistry in this College is now ready for the reception of students, and Prof. Wheeler informs us that a class is now entering upon its work in that . The arrangements are very complete, and the in practical chemistry will be as thorough as in the best schools in France and Germany. Correction. University of Nashville. In a previous number of the Examiner, it was stated that "an effort seems to have been made to remove Professors Jennings, Eve, and Jones from their chairs in the Medical Department of the . They denied the right of the rest of the Faculty to remove them, and appealed to the proper court. A decision has been recently rendered, sustaining their appeal, and the rest of the Faculty from interfering with them in the performance of their duties in the College." We made the statement from what purported to be the decision of the Judge or Chancellor having the case in charge, and, consequently, had no reason to doubt its correctness. In the August number of the Nashville Journal of Medicine and Surgery its correctness is denied, and the alleged facts in the case set forth. After stating the facts, however, the editor of that journal adds: "We know that Dr. Davis thought he had authority for his statement, but he knew it was one-sided, and a flat contradiction of its truth was before him which he saw proper to set aside, and he has thus constituted himself an agent for placing before the public a statement false in every particular." Perhaps Dr. Bowling, in his sanctum in Nashville, may know better than we do what we have before us at any given moment of time here in Chicago; but we doubt it. Now, the truth is, we did make our statement on the authority of what purported to be. the written decision of a Judge or Chancellor in . We did not know that any such decision was "one-sided." And we did not have before us, at that time, any contradiction of its truth, either flat or round. Such contradiction may have existed in a previous number of the Nashville Journal, or ; but if so, we had overlooked it. From the statements in the August number of the Nashville Journal, it appears that certain differences had arisen in the Faculty, by which it was claimed that Professors Jennings, Eve, and Jones had, by their ow'n acts, vacated their chairs, and other men were appointed to fill them. The three named appealed to Chancellor for an injunction, and it was granted, as we stated in the paragraph to which exceptions have been taken. But Judge Milligan, of the Supreme Court of Tennessee, issued a , overruling the decision of the Chancellor: This latter part was unknown to us when we penned the former paragraph. And we are happy to end the matter by quoting the following, which is the last authoritative announcement in the Nashville Journal: "Just as we are going to press, we are happy to that all suits against the new Faculty are withdrawn, and that there will be no further disturbance." So may it be! The Medical Gazette of New York. This sprightly little sheet had. ceased to visit its readers until some of our exchanges had suggested its death. But its publication has been resumed, and the number for August 22d makes a better appearance than those preceding it. Honors. The Royal Medical and Chirurgical Society of London recently conferred the title of Foreign Honorary Fellow on Dr. Samuel D. Gross, of Philadelphia. Dr. William Marsden, of Quebec, was recently made the recipient of a handsome present, from the citizens of that city, as a testimonial for his services in reference to the cholera. Bennett Eclectic Medical College. We have received a circular announcing that a new college with the above title had been organized in this city. The ridiculous manner in which it prostitutes the name of Dr. Bennett, and the slanders upon the regular profession, show plainly the character of those engaged in the organization. Eclectic have been tried in Cincinnati and other cities, but with no very flattering degree of success. Nebraska State Medical Society. The profession in have recently organized a State Medical Society, with the following officers: President, G. C. Monell, M.D.; , N. C. Larsh, M.D.; Corresponding Secretary, G. C. Danise, M.D.; Permanent Secretary, S. D. Mercer, M.D.; Treasurer, D. Whittington, M.D. The next annual meeting is to be held in Nebraska City, on the first Tuesday in June, 1869. Medical College Changes. It is said that the Medical Department of Bowdoin College is to be removed to Portland, Maine. William Warren Greene, M.D., late Professor of Surgery in the Michigan University, has taken up his residence in , Maine. Profs. Austin Flint, Senior and Junior, and Foster Swift, have resigned their places in the Long Island College Hospital. New Sydenham Society's Publications. Messrs. Lindsay & Blakiston, of Philadelphia, are the agents in this country for the sale of the publications of this Society. The subscription price for 1868 is ten dollars in currency. Medical Department of University of Michigan. The troubles in the Medical Department of this University are said to have been fully and satisfactorily settled. Money Receipts to Aug. 28th. Drs. Aug. Rhoads, $3: A. E. Van , 3; Wm. B. Hart, 3; John Sharp, 3; J: Guinan, 3; J. W. Duncan, 3; C. R. Parke, 3; P. S. Macdonald, 3; Griffen, 1.50; L. T. Hewins, 5; R. S. Addison, 3. COOK COUNTY HOSPITAL, CITY OF CHICAGO. WINTER TERM OF CLINICAL INSTRUCTION, 1868-69. The regular course of clinical lectures in this institution will commence on Friday, Oct. 2d, and continue for nine months. The prosperity of this great public hospital, liberally supplied with the most adequate means for clinical and practical , affords an extensive field for the study of every form of medical, surgical, and special disease. During the year ending July 31st, 1868, over 1100 patients were treated in this hospital, and upwards of 100 important surgical operations were performed. In the Lying-in , there were 98 births. The large number of autopsies usually made in presence of the class together with the pathological museum, gives an excellent opportunity for the study of morbid anatomy. The Dispensary, for out-patients, is organized to so classify diseases that every patient shall receive the most thorough attention. This, alone, furnishes a large number of interesting cases. Lectures will be delivered as follows: Surgical Clinics, with operations, and Medical Clinics, with examinations at the , on Tuesdays and Fridays; Eye and Ear Clinics, with operations, and Clinic on Diseases of Women and Children, on Saturdays. Commencing invariably at o'clock P.M., and continuing two hours. It is the purpose of the medical staff to use and develop the immense resources of this institution, for the promotion of education; and to add whatever is possible to the means and facilities for medical study attainable in Chicago the for which they will labor being an exalted standard of knowledge among the students and such junior as may seek our city for this purpose. Fee for admission to the Hospital, $5. Graduate free. LECTURES ON THE EYE AND EAR. In addition to the course of lectures and operations on the Eye and Ear, embraced in the regular term of clinical at the County Hospital, Chicago, Dr. Hildreth will also deliver a Special Course on these organs. The theory of the ophthalmoscope; the analysis and of "accommodation," astigmatism, and other optical and mechanical defects of the eye, will be fully dwelt upon. The methods of exploring the ear will be fully demonstrated. The number of interesting cases in the Eye and Ear Wards of the hospital insures abundant opportunity for becoming with ophthalmic and aural disease. THE CHARITABLE EYE AND EAR CLINIC, A Free Dispensary, established by prominent citizens of Chicago, is likewise accessible to students. The Hospital Ticket admits, without further charge, to all of the above. Treatment of Diseases of the Heart. Dr. S. 0. , Physician to Guy's Hospital (Guy's Hospital Reports, 1867), lays down seven principles of treatment for diseases of the heart: 1st, to lessen its work ; 2d, to insure regularity of action in avoiding all excitement; 3rd, to lessen the distention of the right heart by purgatives, diuretics, etc.; 4th, to prevent syncope attendant upon exhaustion; 5th, to strengthen the fibres of the heart by suitable out-door exercise ; 6th, to prevent fibrillation of the blood by suitable remedies, for instance, of ammonia ; and 7th, to prevent secondary , such as pneumonia, pleuritic effusion, etc. Mortality Report for the Month of July: CAUSES OF DEATH. Abscess, 1 Accident, drowned 16 " by engine, _ 1. " fall,__________ 2 " horse kick,- 1 " poisoning, _ 1 " railroad, 2 " revolver, 1 " scalding, 1 Anaesarca, 1 " and diarrhoea 1 Apoplexy, 10 Apthia and diarrhoea, 1 Apoplexy, from and heat, 1 Ascitis, abdominal, 1 Atelectasis pulmonium, 1 Births, premature, 11 " still_____________37 tedious,______ 2 Bowels, congestion of, and abortion, 1 " inflammation, 8 " perforation , 1 " uleeration of,_ 1 Brain, congestion of, _ 6 " disease of, 2 " inflammation 9 " tubercular disease 1 Catarrh, 2 Cholera infantum,_____273 " convulsions, 8 " dysentery, 1 " foil, measles, 1 Cholerine, 1 Cholera infantum and phrenitis, 1 Childbirth, hemorrhage from,__________________ 1 Cholera morbus, 7 Childbirth__________, 1 Convulsions, 74 " puerperal, 2 " sunstroke, 1 " urasmic, 1 " teething, _ 15 Croup, 3 Cyanosis, 1 Debility, 8 " and old age, 1 Delirium tremens,_____ 6 Diphtheria,____________ 2 Diabetes milletus,____ 1 Diarrhoea,_____________34 " chronic, 6 " & convulsions 5 Dropsy, 2 Dysentery, 17 " chronic, 1 " complicated with pneumonia, 1 " & teething,- 1 Endocarditis, 1 Enteritis, 4 " complicated with meningitis, 2 Enteritis, complicated cholera infantum,- 1 Encephatitis, 5 Enterocolites 3 Epistaxis, 1 Epilepsy 2 " superinduced by heat,____________ 1 Erysipelas,___________ 1 " foil, measles, 1 " traumatic, _ 1 Exhaustion from , 2 Fever, congestive,___ 2 " " and , 1 " puerperal, _ 4 " scarlet, 11 " " and , 1 " typhoid, 9 " , 1 Gastritis_____________ 1 " and , 1 Gastroenteritis,______ 1 Hepatitis,____________ 1 Heart, disease of 2 " dropsy of 1 " organic disease 2 " hypertrophy of 1 " valvular disease 2 Hemorrhage, internal, 1 Hernia, strangulated _ 2 Hydrocephalus 10 " acute 7 Intemperance and , 2 Idigestion,___________ 1 Inanition,_____________ 9 Ileus,________________ 1 Intestines, of_______________1 " injuries of 1 laundice,_____________ 1 Kidneys, Rright's of 1 Leg, tumor of 1 Lightning, struck by_ 3 Liver and kidneys fatty degeneration of 1 Liver, cirrhosis of 1 " inflammation of 1 Lungs, congestion " " of at childbirth, 1 " congestion of and measles, 1 Meningitis 15 " acute, 1 " foil, diarrhoea *, cerebro , _____________ 8 " tubercular, 4 Mania, puerperal 1 Manslaughter, 1 Measles, 7 Mthtrophibitis, , 1 Miliaria puperanum, retroception of 1. Mouth, canker sore of 1 Myetitis, acute 1 Nutrition, defective 1 CEdema glottde, 1 Old age, 4 " and debility,- 3 " " paralysis, 1 Palate, fissure of, _ 1 Paralysis, 3 Parotitis, 1 Paralysis and old age, 1 Pericarditis 1 Periostitis of inferior maxillary, 1 Pistolshot through ,_________________ 1 PJeuritis, double, and emboli in heart,_______ 1 Poisoned wound from snake bite, ___________ 1 Phthisis, acute,_______ 1 " pulmonalis,______32 " " a abortion, 1 Pyaemia, 1 Pneumonia, 17 " complicated with measles, 3 " typhoid, 3 " and of bowels,____ 1 Rheumatism, , 1 Scrofula, 2 Septaemia, 1 Suicide,_____________ 4 Sunstroke,____________19 Small-pox, 2 Stomach, congestion of 1 Stomatitis,___________ 2 Tabes mesenterica,___19 Tetanous traumaticus, 1 Teething,_____________27 " and diarrhoea,- 5 " and meningitis, 1 Tumor, abdominal, 1 " ovarian,_________ 3 Uraemia,_____________ 2 Uterus, cancer of,__ 1 " hemorrhage of, 1 Whooping cough,_____ 6 " " & , 3 Whooping cough and diarrhoea,_________ 4 Unknown,____________ 1 Total__________896 COMPARISON. Deaths in July, 1868, 896 | Deaths in July, 1867, 597 | Increase, 299 Deaths in June, 1868, 305 | Increase, 591 AGES. Under 5____________654 5 to 10_____________ 27 10 to 20____________ 24 20 to 30___________ 45 30 to 40____________ 54 40 to 50____________ 40 50 to 60____________ 24 60 to 70____________ 15 70 to 80_____________11 80 to 90_____________ 0 90 to 100__________ 0 100 to 110_________ 0 Unknown 2 Total________ 896 Males,____________510 Single,___________765 White,____________891 Females, o85 Married,___________ 131 | Colored,____________ 5 Total,______________896 Total,_______________896 Total,______________896 NATIVITY. Chicago___________555 Other parts U. S. 92 Austria, 2 Bohemia 5 Canada_____________ 8 Denmark 1 France, 1 England___________ 13 Germany 110 Holland 2 Ireland___________ 49 Norway____________ 16 Poland_____________ 4 Atlantic Ocean,___ 1 Scotland___________ 5 Sweden 26 Switzerland 1 Unknown 5 Total 896 MORTALITY BY WARDS FOR THE MONTH. Ward. Mortality. Pop. in 1868. One death in Ward. Mortality. Pop. in 1868. One death in 1___ 10 11,991 1,199 1-10 14 63 14,168 224 6-7 2 19 13,739 723 1-9 15 65 20,429 314 2-7 3 43 16,620 386 1-2 16 31 16,011 519 2-3 16,499 392 4-5 Bridewell, 2 5 36 13,434 373 1-6 County hosp.19 6 50 12,507 250 1-7 Chi. River, 3 7_________ 88 21,957 249 1-9 Mercy Hosp. 2 8 59 14,003 237 1-3 Yard of R. I. 9___ 57 18,050 234 1-5 Railroad, 1 10 _______ 28 13,644 487 2-5 Soldier'shom.l St.Joseph's Orph.As. 6 11 _______ 50 13,317 266 1-3 Marine hos. 1 HomeforFriendless, 2 12 ______ 105 14,739 141 1-3 Orphan asyl. 1 Immigrants, 56 13 ______ 4.9 11,113 226 4-5 Lake Michi. 7 Police Stat. 12 St., 1 Total,____________________________'1 896 Druggists Renewing Prescriptions. The Academy of Medicine, New York, after a long and impartial discussion of the various points at issue, adopted unanimously the following preamble and resolution, and referred them to the State Society: Whereas, The attention of this Academy has been called to the repetition of prescriptions, containing active ingredients, by druggists, without the written order of physicians; and whereas, serious consequences to patients are liable to ensue; therefore, Resolved, That we respectfully request the druggists of this city not to repeat such a prescription without the written order of the physician, he being the only competent judge of the or necessity of such renewal. Uterine Injections. At a recent meeting of the Imperial Academy of Medicine, the subject of uterine injections, which of late has occupied the attention of that learned body, was again briefly discussed, and MM. Gosselin, Depaul, and Ricord condemned this method of therapeutics, which, despite the of the instruments adopted, may determine an attack of metro-peritonitis, which, according to the declaration of M. Gosselin, has already occurred in the service of M. Jobert. L' Evenement Medicale. Musical Bullet Probe. At the Paris Exposition there was exhibited a probe for announcing audibly the presence of a bullet in a wound. If the points of the instrument came in contact with a metallic body, an electrical circuit was made and a small bell rang. An ozone generator was also exhibited, made of flat plates of glass coated with tin foil and electrified by a Ruhmkoff coil. A stream of air driven through the apparatus came out so charged with ozone as to be irrespirable, and possessing the power of bleaching paper, linen, soiled engravings, and so forth. This discovery is spoken of as likely to be of much practical value in the arts. Pacific Medical and Surgical Journal. Gossypium as an Emmenagogue and Parturifacient. Dr. Bellamy, of Columbus, Ga., says of the common , gossypium {Atlanta Med. and Surg. Journal): "I am fully satisfied, from the experiments and impartial tests I have given the remedy, that it is fully equal, if not superior, to ergot in promoting the various functions of the uterine organs. I look upon it as a sure, speedy, and safe remedy, not only for difficult, painful, contracted labors, but also to control all the irregularities of females, and to alleviate their peculiar monthly sufferings. It is very certain that its effects are so powerful upon the uterine system as to produce miscarriage, if during pregnancy. I feel that its merits cannot be too highly extolled, and deem it too valuable a remedy to remain hidden in the depths of obscurity. I consider it preferable to ergot. The proper time to gather the root is when it is as old as possible, without being injured by the severe frosts: , it is best when gathered during the months of October and November." Deaths from Sunstroke. An examination of the statistics of death from sunstroke in the city of New York, gives the following exhibit: In August, 1853, 224 persons died from ; in 1863, there were 135 deaths from sunstroke, and during the present year up to Saturday, the 18th ult., there were no less than 883 deaths from heat alone, as reported by the papers. Ex. An Alleged Preservative against the Cattle Plague. Chloride of copper is now extensively used in Germany against the cattle plague, or rather as a preservative. The modus eperandi is as follows: * Take green crystallized chloride of copper, eight gram., spirits of wine, two kilog., and dissolve. With this solution impregnate a pad of cotton, lay it on a plate, and set fire to it in the centre of the stable, turning the animals' heads towards the flame, so as to make them breathe the fumes. This is performed morning and evening, burning one pad for every three heads of cattle. At night, a spirit-lamp filled with this solution is lighted in the stable. To prevent accidents, the flame is surrounded with wire gauze. The liquid is also internally, with the addition of fifteen gram, of chloroform for the above quantity. A teaspoonful of this is put into the animals' drink three times a day. As a further precaution, the litters are watered with the same solution. Effect of Digitalis on the Mind. It is a popular that digitalis acts injuriously upon the memory, and that it hastens childishness in elderly persons. Undoubtedly it has a peculiar and specific influence on the mind, probably through its remarkable power over the circulatory system. It has been used in Germany with success in the treatment of hallucinations. In the Allg. Ztschr. fur Psycliatrie a case of a^woman is reported, aged 38 years, who was constantly with the appearance of devils and imps, brandishing flames and'threatening to strangle her. She wtas placed on digitalis (9ss., aquae SSv., 5j-1. d.), and in two or three months was quite restored. The real effects of the drug on mental action should be studied. |
ARTICLE XXXI. REPORT ON THE PATHOLOGY AND TREATMENT OF EPIDEMIC CHOLERA. By N. S. DAVIS, M.D., Professor of Practical and-Clinical Medicine, in Chicago Medical College. Presented to the Illinois State Medical Society, May, 1868. At the annual meeting of the Illinois State Medical Society for 1867, the writer was appointed a Special Committee to at this meeting on the causes, pathology, and treatment of that much dreaded scourge called, variously, Epidemic, , and Asiatic Cholera. But few subjects could be selected from the whole field of Therapeutics and Practical Medicine concerning which a greater diversity of views have been and acted upon, or concerning which the professional mind is more unsettled, than the one now under consideration. In the following report no attempt will be made to criticise the views of others, or to reconcile the apparently conflicting found in our medical literature. On the contrary, it will be limited mostly to a plain statement of the writer's own views of the treatment of cholera, as derived from direct observation at the bedside of cholera patients. My opportunities for observation commenced in the summer of 1849, during the severe epidemic which prevailed at that time in the city of New York, and were continued in Chicago during the epidemics of 1850-51-52-54 and '66. To occupy the whole field of investigation assigned to me by the Society would require the writing of a volume rather than a report suitable for reading to a Society like this. And, inasmuch as the causes of cholera are still a subject of active investigation, they will be alluded to simply in this paper. The essential cause of cholera, or the specific cholera poison (if such an agent exists), is still involved in mystery. The most popular theory at the present time is, that it consists of a highly poisonous organic body, developed in the gastric and intestinal evacuations of patients laboring under cholera, and capable of being transported from place to place by such , either freshly voided, or by adhering to clothing, or by diffusion in the soil (Pettenhoffer), when there is a water-bearing stratum near the surface. Some observers have claimed to discover the specific poison in the cholera dejections, by the aid of the microscope. That such dejections contain an abundance of animalcules when voided, and that an abundant crop of fungi or sporules appear in the same discharges when allowed to stand from two to five days in a temperature above 60deg Fahrenheit, is unquestionably true. I have made quite a number of microscopic examinations of the discharges from the bowels, both from patients laboring under ordinary serous diarrhoea and epidemic cholera. In all of them, when examined soon after having been voided, were abundant, especially those called vibriones ; and in the samples taken from two well-marked cases of cholera, the ordinary vibriones, there appeared two or three of larger size, more caudate, and moving across the field with great activity. After the discharges had been allowed to stand from two to five days, fungoid growths appeared in abundance, that were not present when first voided. These are not presented as specimens of the specific cholera poison. On the contrary, so far as my examinations have been extended, they lead rather to the conclusion that these products may be found in all serous discharges from the alimentary membrane, whether in cholera, cholera morbus, or simple diarrhoea. But if the untiring scientific researches of the have not yet fully identified some materies morbi as the specific cause and propagation of epidemic cholera, they have done what is of equal or greater practical value, namely, pointed out the meteorological and sanitary conditions favorable to its development and fatality. Meteorologically, these conditions are, a warm, damp, still atmosphere, with deficiency in free electricity and ozone. But with -these must coexist such local sanitary conditions as are capable of furnishing either animal or vegetable miasms, or both combined. Hence the disease has always been most prevalent and fatal where human beings were most crowded together, with the least attention to ventilation and cleanliness, whether in caravans of pilgrims, in emigrant ships, or the low and uncleanly parts of cities. And, whenever invading country districts, it has chosen the alluvial valleys and malarial districts, and wholly passed by the more rugged and primitive geological districts. The truth and value of these observations are both illustrated by a close study of the rise, progress, and decline of an epidemic of cholera in any of our populous cities. Foi' instance, here are two maps, one of and the other of New York, on which are indicated the districts most infected with cholera in the summer of 1866. 1866. In 7th Ward, 1 case to 100 population. 14th " 1 " 95 " 1st, 2d, 8th, 9th " 1 " 250 " PS of whole number of cases in 7th, 14th, and 16th Wards. 1867. August and September. 1st, 2d, 3d, 9th, 10th Wards, 63,000, 1 death in 335. 5th, 6th, 7th, 13th, 14th " 69,000, 1 " 125. Pathology. My views of the pathology of cholera can be stated in a few words, as follows: A direct diminution of that elementary property of living, organized matter, which I call vital affinity, coupled with contractility, or partial paralysis of the capillary vascular system, or, more properly, of the arterioles, and special morbid sensibility of the mucous membrane of the alimentary canal. The coexistence of these pathological conditions causes, first, diminution of organic changes, and consequent diminution of secretion and calorification, with a sense of weakness and , accompanied by pallor, intestinal commotion, and thin stools, constituting what has been called cholerine, or the first stage of epidemic cholera. Second: Still further diminution of secretion and calorification, with complete , or paralysis of the arterioles, which, cooperating with the morbid sensibility of the mucous tissues, causes a rapid exudation or exosmose of the serous and saline elements of the blood from their capillaries, and their rapid ejection by vomiting and , constituting the second or active stage of the disease. Third: The entire suspension of organic changes, including secretion and calorification, with such exhaustion of the watery and saline elements of the blood, as leaves the whole mass viscid and unoxygenated, constituting the stage of collapse. After much clinical study and observation, during repeated epidemics of cholera, it has seemed to me that the foregoing essential pathological conditions most fully explain both the symptoms during life, and the post mortem appearance after death. Whether they arise from the introduction into the blood of some specific materies morbi capable of propagation and transportation, or from the influence of some special of atmospheric and sanitary conditions, remains for future investigations to determine. Treatment. The pathological conditions stated, not only afford a satisfactory explanation of the symptoms and results of cholera, but they equally afford clear indications for a rational mode of treatment. These indications are; 1st. To increase vital affinity and vascular contractility, and diminish the morbid sensibility of the stomach and bowels, thereby preventing the development of the second stage of the disease. 2d. To add to the first indication such measures as will most speedily arrest the rapidly exhausting discharges that characterize the second stage; and 3d. To add to both the foregoing such means as will be most efficient in supplying the lost elements of the blood, renewing the sensibility of that portion of the organic nervous system called vaso-motor, and promoting the of the blood. If we were certain that the disease was produced by the introduction into the system of some specific wzaterzes morbi, of course there would be an indication for , of prior and paramount importance to all those just enumerated, namely, to administer some remedy which would be capable of directly neutralizing or expelling the specific poison. But as we neither know the nature of the supposed poison nor its antidotes, we must pass this item by for the , and confine our attention to the consideration of such means as we deem best calculated to fulfil the several previously stated. In doing this, we shall adhere rigidly to the purpose at the commencement of this article. To fulfil the indications presented in the first stage of cholera, three things are of paramount importance, viz.: rest, pure air, and such medicine as will produce a decided tonic and mildly anodyne influence. By tonics here I do not mean nervous exhilarants, or what are popularly styled diffusible stimulants, but such medicines as produce an increase of vital affinity and tonicity of the tissues. I require the patient to maintain the recumbent position, restrict his diet mostly to milk porridge (boiled milk and wheaten flour), ventilate the room freely, and if the air is damp and impure, increase the ozone by either sprinkling a solution of permanganate of potash or allowing the slow oxidation of phosphorus in it, and give some one of the mineral acids, with a small proportion of an opiate. A that I use more frequently than any other is as follows: 1^. Aromat. Sulph. Acid, 3iij. Sulph. Magnesia, 5iij. Tinct. Opii, 3iij. Aqua Menth., liij. Mix, and give a teaspoonful, in sweetened water, every two, three or four hours, according to the severity of the symptoms, until all intestinal commotion ceases, and the evacuations consistent and natural. A dozen combinations might be named, all calculated to produce similar results, but it would be a waste of your time. In the second stage, I require the same attention to the of the room, and the same position of the patient, with the addition of dry warmth to the extremities and strong mustard sinapisms over the abdomen and nearly the whole length of the spine. But now the whole mucous surface, of continuing its natural function of absorption, has its action, and is rapidly discharging the serum and salts of the blood, with more or less detachment of its own epithelium, as shown by the copious and frequent discharges up and down. To arrest this process I rely mainly on the following: 1^. Sulph. Morph., 3grs. Calomel, 12grs. White Sugar, 5j<< Mix, and divide into 12 powders, one of which is given after every turn of vomiting, whether it be once in five or forty minutes. The craving for drink is satisfied as much as possible by small pieces of ice. After every evacuation from the bowels, I direct to be thrown into the rectum an enema of two ounces of cold water, containing half a grain of sulphate morphia, and 10 grains of acetate of lead. If the cramps are very severe, a moderate dose of morphia may be injected with advantage. But sufficient caution should be used to avoid the patient. In using the powders and enemas just mentioned, it is of very great importance to note the manner of theii* administration. They should be given immediately after every evacuation. The act of vomiting is one that cannot be performed continuously; and medicine just as soon as the effort ceases, and the patient inclines to turn his head down to rest, will remain in contact with the mucous membrane long enough to make some impression before the muscular structures have regained the powrer to renew the act of vomiting. But if the physician yield to the inclinations of the patient and nurse to let him rest &ferv minutes, or, as they often express it, "to let his stomach get settled a little," a fresh supply of serous fluid will have accumulated in the stomach, and the fibres are again ready to act, and now the medicine is no sooner swallowed than it is returned by vomiting, and no is gained. The rule to which I call your attention so strongly is applicable to the administration of all medicines or restoratives during the active stage of vomiting. When the vomiting is so far checked as to admit of half or three-quarters of an hour between the paroxysms, I begin to administer in the form of animal broth, well salted either with salt or chlorate potassa, and strong coffee; the first to nourish and supply the lost elements of the blood, and the , to sustain the wakefulness and activity of the nervous centres. They must be given at first in only dessert-spoonful doses, but may be increased, if found to be retained by the . If the active progress of the disease is arrested during the early part of the second stage, before great exhaustion has been induced, the remainder of the treatment may be such as we have indicated as applicable to the first stage. But if the discharges have continued until the surface is much shrunken, the pulse very feeble, the urine and other secretions suspended, so soon as the discharges are slightly checked we must not only resort to the cautious but diligent use of the restoratives already , but remedies to sustain the sensibility of the vaso-nervous system, and consequently secretion, must be resorted to. Of these, probably strychnia is the most reliable. A sugar-coated granule, containing of a grain, may be given every half hour or hour, according to the urgency of symptoms, until some effect is induced. Or, if the stomach will retain it, a teaspoonful of the following formula may be given, in a tablespoonful of water, just as often, viz. : II. Tinct. Cinnamon, Nitrous Ether, gij. Tinct. Nux Vom., 3j. Mix. This has the advantage of being more diuretic, but its greater bulk and pungency renders it more liable to be rejected. If the patient passes into full collapse, the judicious administration of dilute mucilaginous solutions of non-purgative salts, milk, animal broth, and strychnia, with a continuance of dry warmth and free ventilation, will afford the best chance of ; but the majority of patients in this stage prove insensible to any and every kind of treatment. If the cholera attack is arrested at any stage, and the patient passes into a slow fever, it must be treated on the same principles as the ordinary enteric typhoid fever. I have thus endeavored to give you, in the shortest possible space, the principles which govern my treatment of epidemic cholera, and some of the medicines and formulae on which I most rely. I have used a great variety of remedies in the second or stage of this disease. I have seen a few cases by the internal use of chloroform, in doses of 10 drops every 20 minutes, and a larger number by the combination of chloroform, Cannabis Indica and morphine, called chlorodyne. I have treated some with salines some with salt and mustard emetics have bled some from the arm, and cupped others both over the spine and epigastrium; and have seen several treated with purgatives, mercurial, saline, and oleaginous. And I have seen some patients recover under all these kinds of treatment, and have seen a larger number recover under no treatment at all, except rest and diluent drinks. The special mode of cholera recommended in this paper I was led to adopt during the epidemics of 1849 and 1850, and through all my subsequent experience it has been with me far more successful than any other plan that I have tried, or seen tried by others. I think the most fatal of all the methods of treating cholera that have yet been practised is that which relies mainly on opiates and alcoholic inebriants. In conclusion, I would make one suggestion. It is now very generally considered that of iron and permanganate of potassa are the most reliable disinfectants for rendering innoxious the dejections of cholera. If there is any truth in the theory that cholera is caused by a specific poison, derived from cholera dejections, would not the early and persistent internal administration of sulphate of iron neutralize the poison in the system, and arrest the disease? Has it or the sulphites been tried? A few pages might be added on paphylaxis, but I have already trespassed on your patience too far. |
St Hhm. CLINICAL LECTURE ON A CASE OF EPILEPSY AND VERTIGO, IN WHICH BLOODLETTING WAS EMPLOYED WITH ADVANTAGE. By C. HANDFIELD JONES, M.D., Physician to St. Mary's Plospital. Gentlemen: "Medio tutissimus ibis" is a wise old saw, but one which it seems not easy to act upon. The pendulum of opinion commonly deviates to one side or other of the true line. It appears to me, that at present there is some tendency to error of this kind in the case of epilepsy, which seems to be by some too much as if it were invariably associated with deficient blood-supply to the brain. Very often this is the case; but that the encephalon is by no means unfrequently hyperaemic in epileptic states, and that this hyperaemia may even materially contribute to the production of the order, I think I shall be able to prove. Let me ask your attention to the following history: W. F., aged 49, stableman, was seen on Aug. 15th, 1865. He was sent to me by my friend Dr. Palmer, from whom I the following statement: "Eleven years ago, he had a severe epileptic fit for the first time; he continued vertiginous, weak, and unable to work for several days; his pulse feeble and small; his skin cool and moist. Leeches, cold to the head, free purging, and iodide of potassium, failed to relieve him. He was then admitted into St. Mary's. On coming out, he told me that he was cupped and had various remedies, but all failed to do him good until he was bled, after which he rapidly and completely recovered. Since then he had several attacks of severe vertigo, with such muscular weakness as to compel him to give up work; the second was accompanied with an approach to coma. Since then they have rather diminished in severity. On each occasion, his tongue has been moderately clean; pulse between 60 and 70 decidedly soft, and not filling out the artery, without any jerk; skin pale, cool, and moist; eyes not injected; no heat of head; no thirst; appetite diminished. Each time I have tried all I could to avoid venesection, have purged freely, applied cold to the head, once cupped him, forbidden (which he says make him worse), but have each time been compelled to bleed. The last time (April 19th), I am certain that his pulse was stronger and fuller two days after the than it had been for days before. The day after giving the iodide of potassium, he was decidedly more vertiginous." Dr. Palmer describes the patient as usually of slow, hesitating speech, and having the puzzled, hebete look of an epileptic, with a small forehead and brain-case. Such is the account given me by a most able and intelligent observer. I subjoin the account I received from the patient's wife. She states that her husband was taken with a fit one morning at 4.45 A.M., while in bed. He was as well as ever he was in his life when he went to rest. The fit did not last long. He went to his work the same morning; but in about two hours, while at work in the mews, he was taken with another, and had seven that day, at about two hours' interval. The next day he had three fits, and continued to have them more or less for three weeks until he went into St. Mary's Hospital. During this time, he lost his speech when the attacks were coming on; but, in the intervals, he was conscious and able to speak. He was leeched before he went to the hospital; but when there he was cupped and bled from the arm several times with great relief. He was there several weeks. If he got too much beer it affected his head, and made him stupid; he used to take a great deal. He had had no attack lately (Dec. 1865). So far the wife. At my interview, I observed that his lips were pallid; his pulse 75, of good size and force; his head cool, not tender, but it felt as if it did not belong to him; his appetite was good; the tongue clean. The rhythm and sounds of the heart were ; but the organ was rather displaced towards the . He felt no great weakness. The giddiness he as coming on him all at once, and lasting (till he was bled) for weeks, with intervals of comparative amendment. When the giddiness was on him he was unable to lie down, but could at other times. He had no nausea or sickness. He never passed worms, as far as he was aware. He had typhus fever when he was young; but no other illnesses, except falls once from the roof of a house about eighty-four feet high, when he "cracked his head a bit" and was stunned for a few minutes; once also he was knocked down by a cart and struck his head. In fact, he seems to have hurt his head a good many times. The bone was indented notably at the upper and fore part of his head towards the right side; but there was no tenderness in this situation. He had been bled at least six times, and been cupped and leeched besides. Hot weather did not try him at all, nor did cold; he could expose his bare head to the sun without any discomfort. He denied having had syphilis; and presented no outward indication of it. He was obliged to be careful in what he drank; he could not take much beer. August 17. He was more giddy to-day "just the same as a drunken man." The forehead was not hot; the eyes were dull, but not injected. Pulse quite quiet, steady, and regular. Bowels well open. Ears cool, and cheeks and prolabia actually anaemic. Pressure on the carotids caused the veins of the to fill, and made the giddiness much more severe. There was no undue pulsation of the cervical or temporal arteries. The pupils were lively. His manner was very tranquil, free from nervous fussiness. He was not apt to have cold feet. I could see no rational indication for bloodletting; but, as he did not mend without, and as former experience was in its favor, I could say nothing against it. He was bled to sixteen ounces, and came to see me the next day, when he stated that he felt better in one hour after the bleeding, and was nearly well, to work the day after. The pulse and general aspect, and condition of pupils, were just as before. I did not see him again till September 15th, when he came to see me at St. Mary's Hospital, complaining of a return of the giddiness during the last five days; it was very severe, and had not been relieved by calomel and mistura alba or by nitromuriatic acid. I ordered for him five grains of powder of colchicum thrice daily; of this he took a few doses, and got rid of his disorder completely. His pulse, I am informed, was fuller and stronger after he had taken the colchicum than it had ever been before. January 3. 1866. He had been well since last date, with the exception of one attack, which was brought on by drinking, and ceased after purgation. December 5, 1867. He remained quite well up to the present time. His urine was examined and found to be non-albuminous. That the bleeding in this instance was really advantageous can, I think, hardly be questioned, regard being had not only to the immediate results, but to the subsequent condition of the patient. The attacks have not been rendered more frequent, but the reverse; in fact, for some considerable time he has been quite free from any disorder. The vertigo must, I think, be regarded as a manifestation of epilepsy, as it succeeded the latter directly in time, and was by the same measures, and by those alone, which the convulsive disorder. That it depended on increased pressure can, I think, hardly be doubted, although the exterior of the head certainly exhibited no signs at all of hyperaemia. The effect of pressure on the neck, which must have told chiefly on the jugular veins as it caused distention of the frontal, was to aggravate the giddiness; and this result not only confirms the opinion above expressed, but goes to show that the blood-flow a tergo was free, that there was no in the arteries. The greater fulness and strength of the pulse after the bloodletting and the colchicum resulted, I , from the cessation of the depressing effect which the exercised on the heart itself. Although the disorder was a neurosis, it is evident that the nerve-force in this man must have been of a very different quality from that which it has manifested in sundry instances, one of which I have related in my work, p. 61, where bloodletting appeared to be the cause of most severe and prolonged epilepsy. It is probable that the injuries to the head had rendered the brain less tolerant of any undue amount of even its natural , the blood; as they had also of a less natural one, the beer. If this abnormal state of excitability increased, we can well understand that depletion might be a necessary means to relieve it. The condition just referred to implies some from the type of healthy nutrition; and it is far from uncommon to find hyperaemia ensuing under such circumstances. It appears to me that the smaller arteries which are most in hyperaemia and in like conditions go very often along with the tissue they supply in regard to their vital activity. Certainly, they are often relaxed while a tissue is vigorously performing its function; but this activity can only last for a time; and, if the hyperaemia be prolonged, the functional power of the tissue soon declines, and then the hyperaemia solely injurious, and, as I wrote many years ago, " of supplying a want, imposes a burden." Again, if the vital power of the tissue be lowered ab initio, that of the arteries is very apt to be lowered along with it, and then, without any previous manifestation of functional activity, we have at once injurious hyperaemia. Of this, frost-bite and chilblains, and probably many common catarrhal inflammations, afford good examples. If we suppose this man's brain to have failed now and then in its due mode of nutrition, its nerve-nower to have declined, as was not unlikely, after having been a good deal knocked about and "bemused with beer," the smaller cerebral arteries would readily fall into a like state of paresis, and thus the blood-supply would become excessive, and the nerve-power be thereby still further lowered and deranged. Bloodletting, by lessening the amount of blood, might contribute materially to enable the brain-tissue and its arteries to regain their condition. As the pulse became fuller and stronger after the and colchicum, it might have been expected that the pressure would be increased, and therewith the . Very possibly the pressure was increased in the radial and some other arteries; but there is no necessity that it should have been so in the carotids and vertebrals, or their smaller branches, which are the chief regulators of the blood-flow. Moreover, the very circumstance that the smaller arteries were more contracted than before, would, by lessening the facility of the escape of blood from the larger tend to produce greater fulness of the pulse, and excite the heart to stronger action. Let me now produce to you some evidence which I have brought together from various sources, which appears to me tolerably conclusive, that active hyperaemia, determination of blood to the brain, may be the efficient cause of epileptic attacks. C. II. Parry states that a patient, "Miss F., who has twenty or thirty epileptic fits annually, for two or three days before a fit constantly finds a constitutional enlargement of the thyroid gland increase to a very great degree; in a day or two after the fit, it returns always to its natural state, the accumulation of excitement in her subsiding at the same time." That this evident local turgescence of an organ, fed by arteries given off near those supplying the encephalon, did not cause anaemia of the latter, is tolerably clear, from its being mentioned that the head was unduly hot, the feet being cold. The same author to a very striking case, by which, he says, "it has been demonstrated that convulsions may depend on excessive impetus of blood in the vessels of the brain, since in that case they were removed by interrupting or diminishing the'flow of blood through the carotid arteries to that organ, in consequence of which a state of sopor often ensued." In another case, by him in the same place {Elements of Pathology [and Therapeutics, p. 254), a constant twitching of certain fibres of the flexor muscles of the forearm was uniformly suspended by compression of the carotid artery on the opposite side, while it was not diminished by compression of the artery on the same side. Trousseau corroborates Parry's statements. He says that he has practised and recommended compression of the carotids for more than twenty years, and that he has found it highly . He makes special reference to this procedure when speaking of the convulsions attending on scarlatina dropsy; but employs it equally in other similar conditions not resulting from uraemia. He directs the artery to be compressed upon the side opposite to that on which the convulsions are most marked, and gives particular directions for the . He states that, when an artery is thus effectually , the red flush of the face is sometimes suddenly by pallor, and that in some instances the eclamptic immediately ceases and gives place to perfect relaxation. I do not understand him to affirm that the proceeding is always successful; but, I think, none can doubt that his testimony strongly supports the position above stated. Other evidence can be cited to the same effect. In a case observed by Reimer, and alluded to by Schroeder van der Kolk (Sydenham Society's edition, p. 228), compression of the carotids succeeded times in cutting the fit short, the patient experiencing great relief and improvement in his memory and mental condition. Labalbury (Gazette des Hopitaux, I860, Sept. 15th) relates a case of puerperal eclampsia which was cured by compression of the carotids. Parry gives the following case as a proof that epilepsy may be cured by bleeding and low diet. About thirty years ago, he states, he was sent for to see a nobleman, who had been a gross feeder but not intemperate, and had been subject to epileptic fits. He found him insensible and stertorous, after having repeated paroxysms of the disorder. His face was flushed, and his pulse strong, full, and laboring. His bowels had been duly open without relief. After bloodletting to fourteen or sixteen ounces, the insensibility, which had many hours, very quickly ceased. The bleeding was more than once repeated. Purgative and saline medicines were given. A low diet, as well as much bodily exercise, was . The patient soon recovered his health, and never any return of his malady. Had not the bloodletting been a right remedy in such a case as this, it is most probable it would have been injurious, and would being (repeated) have induced the speedy recurrence of the disorder, as it did in a case recorded by Dr. Copland. (Vide note, p. 799, art. Epilepsy.) / Dr. Parry mentions another case, which exemplifies the . An old man, who had lived freely, had a chronic of one of his legs accompanied by oedema. Both these affections were greatly relieved by the application of a tight bandage. In a few days he was, for the first time in his life, seized with violent epilepsy. Graves, relating the successful treatment of a boy, aged nine, for uraemic convulsions occurring after scarlatina, by cold on the head, states that, as he was sitting by the bedside of the patient, he was more than once able to predict the approach of the fit, by means of watching the pulsation of the carotids, which then became much more frequent and stronger. This observation (he says), taken in connection with the fact that the pulse at the wrist became weaker and more indistinct at that very moment, suggests many interesting concerning local determinations of blood. Though the uraemia was doubtless the prime cause in this instance in inducing that state of brain which gave rise to the convulsions, the peculiar hyperaesthesia of the excitable districts, yet the success of the cold affusion, leeches to the head, and purgatives, render it also, I think, clear that this perilous symptom was mainly staved off by lessening the blood-flow towards the head. So also in the convulsions which are apt to occur in the early stage of the exanthemata, there can be, I conceive, no doubt at all that the brain is, as Dr. West describes it, in a state of active congestion, true hyperaemia. Exposure to the heat of the sun may, as he says, disturb the circulation and favor of the brain, and so induce convulsions or other of an overloaded state of brain, which may all subside as soon as the excited circulation has recovered its wonted balance. He gives a good case in point, very similar to one respecting which I was consulted last year, in which, after exposure to a hot sun, actual and very severe meningitis occurred. The eclamptic attacks which occur in puerperal females are undoubtedly sometimes greatly relieved by bloodletting and , and consequently can scarcely be regarded as of undue intravascular pressure affecting the . Of this the following case (vide Lancet, 1866, Nov. 3) may be cited as an example. Mary D., aged nineteen, a well-developed, robust, plethoric woman, had always lived well, and never had a day's illness. She had one sister, aged fourteen, who some years ago was to occasional epileptic seizures. In her first labor, she had two fits of convulsions, in which she foamed at the mouth and bit her tongue, her features being much distorted. Mr. Draper was sent for by the midwife in attendance, and found the patient recovering from the second attack. She was in a semi-conscious condition; face flushed; skin hot, but moist; tongue large and red, and lacerated by the teeth; head hot; pupils rather contracted; pulse 120, full, and with difficulty compressible; occasional slight muscular spasm. The child's head being at the pelvic outlet, where the midwife said it had been for about two hours and a half, the forceps were applied, and a male child delivered. It was slightly asphyxiated, but was quickly restored. After the expulsion of the placenta the patient appeared quiet and comfortable. In three-quarters of an hour the convulsions returned, the paroxysms being more severe than before. Sinapisms were applied to the nucha and the calves, and cold to the head; and a dose of calomel and jalap was given, besides the following draught every hour: 1^. Ammon, potassio-tartrat. gr. |; potassae nitratis gr. x; sodae potassio-tartrat. gr. xx; aquae 3j. Most of the powder was rejected by vomiting. After this treatment the patient remained tolerably quiet about two hours, when she had another relapse, the first being more violent and recurring more rapidly than hitherto; and she remained between the paroxysms. The face, as before, was flushed; respiration hurried and short; pulse 120 to 130, hard. As there was no albumen of consequence in the urine, about twenty-five ounces of blood were taken in a full stream from the arm. The pulse then became soft and compressible, and the patient shortly became conscious. She was ordered five grains of calomel and a minim of croton oil, and the above saline to be continued. After this, the patient had no return of the fits, slept moderately well during the night, and made a good recovery. In contrast to this case, it would be easy to cite numerous others where not depletory, but sedative treatment has been , and found highly beneficial. No doubt can exist that, in puerperal eclampsia, the quality of the disorder may be in different individuals; and, if so, why may it not be the same in epilepsy ? If any should object to the instances I have cited of uraemic, puerperal, and exanthematic convulsions being considered truly comparable to the attacks of essential epilepsy, I reply that Trousseau expressly recognizes their identity with those of as regards the morbid phenomena, and says that they only differ in the attacks being multiple, and in the under which they occur. Neither of these features seems to me to establish any material distinction between the two classes. Multiple attacks are, we well know, met with every now and then in chronic epilepsy. As to the attendant and originating circumstances, when the visible result is so similar, it seems to me very much like begging the question at issue to affirm that the condition of brain they produce is unlike that which prevails in all cases of essential epilepsy. It is fully conceded that, among the cases of epilepsy occurring in our large towns, it is rare to meet with one where the morbid is not one of anaemia and weakness and undue mobility, rather than of sthenic excitement and plethora; yet I can by no means admit that the latter condition is to be excluded from our list of causes, and I believe the case I narrated at the of this lecture to afford a fair instance in point. To the above evidence must be added that of Schroeder van der Kolk, to whom we are much indebted for his minute into the changes produced in the nervous centres by this disease. He entirely dissents from the view that suddenly anaemia is the essential precursory condition of the attack. Among other observations, he says: "Equally little does this view find support from the fact that, before an attack, epileptic patients are usually more excited, more lively, and more irritable, and their face and their head manifest a greater degree of congestion. In one case I was able to this with precision. In a young man aged nineteen, who, under the use of digitalis, had continued for a considerable time free from attacks, I found the heat of the head excessively great in comparison with that of the cheek," the temperature of the forehead and vertex exceeding that of the cheek by 13deg Fahr. Scarcely fifteen minutes after this observation had been made, a violent attack came on. (Sydenham Society's translation, p. 299.) He has found positive advantage from the use of , issues, and setons or cupping to the neck; not only the epilepsy, but the consecutive dementia, being removed oi' amended thereby. I have often spoken to you of the varying quality of disease; and I hope, from this review, you will be to agree with me, that the same holds true of convulsive disorder. Brit. Med. Journ., Feb. 8, 1868. The oldest Doctor in the world, Professor F. Verdugo, , Spain, died, lately, aged 105 years. Ele had practised medicine for eighty years. |
PERISCOPE. OULACHAN OIL AS A SUBSTITUTE FOR COD-LIVER OIL. The following valuable article has been recently published in the Pharmaceutical Journal and Transactions, (London, June, 1868,) by the distinguished botanist and zoologist, Robert Brown. As our possessions have lately been extended on the north-west coast, it has peculiar commercial and therapeutical interest, and we copy it therefore at length: "The fish which forms the subject of this communication may, if we consider its importance to the Indians, or the still more useful purposes to which both the fish itself and its oil might be applied, without fear of contradiction be ranked as one of the most valuable products of the western shores of America. Many of the earlier fur-traders and adventurers refer to it in enthusiastic terms under its Chinook name of Oulachan or Eulachon,* and give accounts of its abundance in the Columbia River early in this century. All readers of Washington Irving's charming 'Astoria,' cannot fail to remember his of it. It belongs to the family Salmonidoe, and is usually classed in Gerard's genus Thaleicthys, but as I believe that that genus is separated from the older one of Osmerus on very insufficient grounds, I have preferred to designate it as Osmerus pacificus, The synonymy and specific characters will therefore stand as follows: *Ross Cox calls it "the sweet little anchovy" ('The Columbia River,' etc., vol. i. p. 105.) It is also spelt hoolakan and Ulichan. Alexander Ross calls it the "fathom fish," because strung on threads in their dried condition, they were sold by the fathom (' Adventures of Firstf Settlers on the Columbia River,' p. 94). Osmerus pacificus (Salmo (Mallotus') pacificus), Richardson Fauna Boreali-Americana; Thaleicthys Steven si, Gerard, Gen. Rep. on Fishes; Thaleicthys pacificus, "Grd." Cooper and Suckley Natural History of Washington Territory, Plate LXXV. figs. 1-4; Osmerus pacificus, (Rich.) Ayres, Cal. Acad. Nat. Science, ii. 64. Head subconical and pointed. Mouth large; posterior extremity of maxiliar bone extending to a vertical line drawn posteriorly to the orbit. Eye rather small. Adipose fin placed opposite the posterior portion of the anal, which is rather elongated. The insertion of the ventral fins is situated considerably in advance of the anterior margin of the dorsal. Scales moderate, subelliptical. Dorsal region grayish-olive; middle of flank yellowish-orange, dotted with black; belly yellowish, unicolor; upper sides and surface of head grayish; fins unicolor. 2. The Oulachan or Eulachon is a small, delicate-looking fish, about the size of a smelt, and not unlike it, semipellucid, and with fine scales. On or about the 24th of March, at nearly the same time each year, it enters the northern rivers, and the southern ones a little later. It was once abundant in the Columbia, but that stream being now disturbed by the of steamers, it is only now in exceptional years that they are caught there in any quantity. In Fraser River, and in most of the rivers on the coast of British Columbia, they are still found at that season (March) in greater or smaller quantities; but it is in the Naas River, falling into the Pacific, in lat. 54deg 40' N., that the Eulachon is found in the greatest quantities, and it is to its capture in that stream that these notes chiefly relate. The fish comes up from the sea into the fresh water for the of spawning, but, unlike most of its allies, the salmon proper, on the coast, returns to the sea again, and is not seen until the following year. During that season they swarm in inconceivable shoals, and I can well believe that the Indians in no hyperbole when I have heard them say that their canoes have been lifted in the water by the countless swarms of fishes. Their arrival is at once heralded by flocks of Laridae and other marine birds swooping down to seize upon them, and during the whole of the fishing season the screams of the gulls vie with the shouts of the Indian fishers. 3. By long custom made and provided for, northern tribes have a vested right of fishing the Eulachon on the banks of the Naas, and certain other equally numerous and powerful tribes are prohibited from enjoying this privilege, and are compelled to buy their oil from their more fortunate neighbors'. , some days before the expected advent of the fish in the river, the Indians assemble from far and near to the number of several thousands, in order that they may take up their proper camping-grounds on the banks. Men, women, and children come, it is the herring-fishing of the Indians, and all can be employed. A general holiday prevails, and tribes vie with tribes, families with families, in dress and feasting, and show their joyousness in a thousand different ways. Families who have not met for twelve months now meet, and the Eulachon, or Yghuh (almost unspellable and certainly unpronounceable), fishing is looked forward to from one year's end to the other as a time for gossiping, courting, and general merrymaking. In a few days, however, the fish begin to make their , and now all are on the alert, and all idling is at an end. The first shoal, as I have said, come into the river, from the 24th to the 27th of March, and stay three days. These are so exceedingly fat that they cannot be cooked in a pan, for they will "blaze up" like a mass of oil. Out of these the best portion of the oil is made. In about three days these begin to disappear, and are succeeded by a second shoal, not so large or so fat, and these again in a day or two by the third and last shoal, which is poorer, and are dried for winter use, being free from oil to permit of this. So fat are these last even, that if lighted during the dry state, they will burn like a candle, and are often used as such by the natives, hence they are sometimes called the "candle-fish." The river during the time of fishing presents a busy scene, covered with canoes sweeping the fish in, while others filled are landing and being unloaded by the women and children, again wildly to rush back to share in the harvest. Ashore the scene is not less vivid. Fires are blazing and pots boiling, and boxes being filled with the oil, while in and around and all over, prevails an amount of unctuousness indescribable, a greasiness of which it is to conjure up the faintest idea! The fish are chiefly taken by nets (in the Naas), but myriads get washed ashore and are caught by the old women and children and kept as their . In Fraser River they are principally captured by means of a flattened cedar pole, the edges of which for a couple of feet or so near the end being set with sharp teeth or nails, which act like so many spear-points. The Indian, standing in his canoe, sweeps this through the water, and so numerous are they that there is no fear but that a number will be impaled on the points. These are swept behind him into the canoe as a mower uses a scythe, until the canoe is full. Herrings and shoals of all other small fishes are caught likewise in this mode. Besides those kept for drying or from which the oil is made, vast quantities are used in the fresh state for food, and the sudden arrival of fish, occurring generally just at a time when the Indians' winter stores are nearly finished and they are rather pressed for food, the plethora often proves fatal by producing surfeit. 4. The oil is obtained by putting the fish into wtater in boxes generally hollowed out of a solid block of cedar (Thug a gigantea, Nutt., T. Menziesii, Dough), or so closely made as to be water-tight and then throwing in red-hot stones. This method of boiling is practised by all the Indians on the north-west coast of America. The oil is then skimmed off' the surface and set aside to cool. The oil is never made by iron vessels (after the more familiar manner of the whites) over the fire, for in that case the fishes would be , and it would be difficult to separate the broken fragments from the oil. The quality, however, greatly depends upon the care employed, and the amount of heat used to extract the oil from the fatty tissues of the fish. An inferior description is also made by squeezing the fishes out of which the finer oil has already been extracted in the method described, in a cloth against a board.* Properly prepared, the oil is at a of 60deg Fahr., amber-colored and liquid. At a lower it becomes thick and opaque, increasing in solidity to the degree of cold; in this state it is whitish in color, and resembles soft lard. The northern tribe keep it in boxes of,their own making, but the more southern Indians such as the Quakwolths, at Fort Rupert (lat. 50deg 42' 36" N., long. 127deg 25' 07" W.) preserve it in bottles, made out of the stem of the giant seaweed, Macrocystis pyrifera, Ag., squeezing out a little, when required, as a painter does his colors out of the tinfoil tubes. * I have given the general rationale of the process of manufacture. There are, however, various superstitions connected with the oulachan (as with else the Indian has to do with), which entail various minute ceremonies. Mr. William Duncan, the excellent missionary at Metlakatah, thus refers to it in a letter addressed to the Church Missionary Society: "...The process (of extraction) is as follows: Make a large fire; place three or four heaps of stones as big as your hand in it; while these are heating, fill a few baskets with rather stale fish, and get a tub of water into the house. When the stones are red-hot, bring a deep box, about eighteen inches square, near the fire, and put about half a gallon of the fish into it and as much fresh water, then three or four hot stones, using wooden tongs. Repeat the doses again, then stir up the whole. Repeat them again, stir again; take out the cold stones and place them in the fire. Proceed in this way till the box is nearly full, then let the whole cool, and commence skimming off the grease. While this is cooking prepare box in the same way. In doing the third, use, instead of fresh water, the liquid from the first box. On coming to the refuse of the boiled fish in the box, which is still pretty warm, let it be put into a rough willow basket, then let an old woman, for the purpose of squeezing the liquid from it, lay it on a wooden grate, sufficiently elevated to let a wooden box stand under; then let her lay her naked chest on it, and press with all her weight. On no account must a male undertake to do this. . Cast what remains in the basket, anywhere near the house, but take the liquid just saved and use it over again instead of fresh water. The refuse must be allowed to accumulate, and though it will soon become putrid and change into a heap of maggots, and give out a smell almost unendurable, it must not be removed. The filth contracted by those engaged in the work, must not be washed off until all is over; that is, till all the fish are boiled, and this will take about two or three weeks. All these plans must be carried out without any addition or change, otherwise the fish will be ashamed (the Indians think), and perhaps never come back again." 5. The fish, cooked fresh, is most delicious, and, when salted, is also a very palatable article of food, and held in much among the Hudson Bay Company's traders and other old residents on the coast. The Indians dry vast numbers for *winter use, and carry them with them in strings, during their annual migrations south, and for sale to other tribes who come to purchase them as well as oil. The Tsimpsheans say that the Naas river clothes them and the Skeena river feeds them, the Hydahs, from the Queen Charlotte Islands, and other tribes who are prohibited from fishing for the Oulachan in the Naas, come and purchase the oil from them, paying blankets for it, while the salmon of the Skeena supplies them with supplies of food. I cannot but think that these fish would form a most valuable and lucrative article of commerce either in the salt or dried condition, and that in either of these forms, or preserved in ice, or in their own olive oil, like sardines, they would command a ready market, especially in the Roman countries along the Pacific coast, in China, and even in Europe, and the Atlantic States of America. A small joint stock company was indeed formed in Victoria, in 1864, for that purpose, but failed for want of capital and in ignorance of the habits of the fish. Before they could get their affairs settled to start north, the season was past, and nothing further was ever done. The Indians, no doubt, declare that no white man shall ever cast a net into the Naas, but independently of this somewhat futile threat, supplies could be purchased from the Indians to almost any amount, and, if sufficient inducement were held out to them, the present catch could very easily be increased tenfold. 6. The oil is of even greater value than the fish itself, as usually seen in the opaque lard-like condition, and after having undergone no. other preparation than the rough trying out just described, its taste is not unpleasant, and the odor by no means disagreeable. Even in this condition, it has been used by the whites for culinary purposes, and the Indians use it in all their meals, much after the same way as we do butter, using it also as a sauce to their dried salmon. So fond are they of it, and so essential to their health is it (as I shall presently refer to), that the Hydahs and other tribes, as I have already said, come over to purchase it eagerly, and the Hydahs, Stekins, , and other northern tribes that winter in Victoria and Puget Sound, will come on board the Metlakathlah mission schooner to purchase it. They complain of the price, but still cannot do without it. An old Tsimpshean once said to me, "I can buy beef and bread cheaper, but my heart never feels good until I have got this grease. There are just two sweet things in food rum and oulachan oil!" However much we may be inclined, from a civilized stand-point of view, to doubt the of this summation of a lifetime's experience, there is no doubt that this oil, both in an edible and medicinal light, is of the utmost value. It is the latter property which the readers of the present article will be most interested in, and which I desire most earnestly to press upon their attention. Its effects on phthisical patients are most wonderful, and, from the moist climate of the northern portions of the Pacific coast, the natives are very subject to phthisis, haemoptysis, and other forms of pulmonary disease. As it is, many die annually of these , and I believe that I only speak the opinion of all who know these people, or lvIio have thought over the subject, that were it not for this oulachan oil, these northern tribes, once so powerful, and still so courageous, intelligent, and physically fine, would be decimated, and already enfeebled in constitution through vices learnt from the whites, their extermination would soon be un fait accompli. It relieves violent coughs in a most remarkable manner, and equally conduces to the accumulation of flesh. In a word, it has all the properties of cod-liver oil and other fish oils in an intensified degree, without their taste a taste which is found even in the best and most carefully prepared oils, and prohibits many availing themselves of their valuable qualities. I have known delicate ladies who would have vomited at the smell of the ordinary cod-liver oil, put the bottle of oulachan oil (slightly heated, in order to liquefy it) to their mouths, and drink it without the smallest nausea! If the oil thus rudely prepared by the natives be so little , I doubt not but that if it underwent the usual processes of the chemist, that it might be produced tasteless. The old fur traders on the coast everywhere use it in pulmonary diseases, and even send supplies of it into the interior, for the use of friends residing there. It is looked upon almost as a specific, and the few boxes which the Hudson Bay Company's trading vessel brings down on her annual spring voyage (not as an article of commerce, but for the of friends,) are generally bespoke long before. The officers of the Company have long preferred prescribing it to cod-liver oil, both in their own families and in general . One of these gentlemen, whose great intelligence and long experience entitle his opinions to every respect,* enter * I believe I am at liberty to mention his name. The Honorable John Sebastian Holmecken, Chief Trader and Surgeon H. B. C., Member of the Legislative Council of British Columbia, and formerly Speaker of the Assembly of Vancouver Island. tains very similar views to those I have advocated, and I have, moreover, heard him attribute the health and even the existance of the Indians during their exposed life in a hyperpluviose climate like that of Fort Simpson and north to Sitka, to the use of oulachan oil. In the course of my journeys into the of Oregon and elsewhere, I had occasion to recommend and procure some for friends troubled with phthisical complaints, and in every instance I have heard its merits extolled to the highest degree. 7. The object of this paper has been to draw the attention of pharmaceutists to this oil, and with a view to its being tried in a medicinal and commercial way. In 1864, some specimens were sent to England, and became rancid before arriving, though even in that condition they were valued at the rate of PS40 per ton; but I am not aware that it has ever yet been tried in European medicinal practice. I have no doubt that if efforts were made to procure a sufficient quantity to give it a proper trial at the hands of physicians, whose opinions would carry weight with them, the Oleum Osmeri would prove a useful to our animal Materia Medica, as auxiliary to, or for, the better known and justly esteemed Oleum Jecoris Aselli of the Pharmacopoeia." |
Nutrients Nutrients nutrients Nutrients 2072-6643 MDPI 10.3390/nu15051150 nutrients-15-01150 Editorial The Perspectives of Plant Natural Products for Mitigation of Obesity Li Daotong Chen Fang * National Engineering Research Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, College of Food Science and Nutritional Engineering, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China * Correspondence: [email protected]; Tel.: +86-10-6273-7645 24 2 2023 3 2023 15 5 115020 2 2023 23 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). This research received no external funding. pmcObesity is a metabolic disease caused by an imbalance between energy intake and consumption, which leads to excessive fat accumulation in adipose tissues. The prevalence of obesity is increasing worldwide and its associated metabolic disorders have alarmingly become a global public health issue that severely affects the health and quality of life of people . It is estimated that two billion people (nearly one-third of the world's population) have been classified as obese . The obesity-associated hypertension, hyperglycemia and dyslipidemia are also risk factors that are closely linked to multiple diseases such as diabetes mellitus, cardiovascular disease, and cancer, which are major causes of death worldwide . The rapid increase in the prevalence of obesity and the associated metabolic dysfunction highlights the urgent need for managing the detrimental health effects. Weight loss by surgical treatment is effective in reducing the risk of morbidity and mortality, while it may cause negative emotions in people. Some anti-obesity drugs have been available and approved for the treatment of obesity, whereas their use may trigger certain side effects . Exploring and developing risk-free and efficient weight management treatments to prevent and treat obesity is still an unmet clinical need. Recently, plant-derived natural compounds have attracted much attention due to their relatively high safety profile with fewer side effects. In our Special Issue entitled "The Perspectives of Plant Natural Products for Mitigation of Obesity", several articles have been published that focus on the crucial role of plant natural products in mitigating obesity. Flavonols are a group of flavonoids that include quercetin, kaempferol, myricetin, and isorhamnetin. Onions, tea, apples, kale, lettuce, tomatoes, broccoli, and grape skins are important foods of dietary flavonols. By investigating the relationship between dietary flavonols intake and obesity parameters (fat mass, waist circumference, and body mass index) in 40 obese and 40 healthy volunteers, the study by Joanna Popiolek-Kalisz provided evidence that consumption of flavonol-enriched foods may play a protective role in obesity development. Kochujang is a Korean fermented, soybean-based red pepper paste that has been reported to have obesity-reducing effects in rats. In a randomized, double-blind clinical trial, the study of Han et al. compared the anti-obesity effects of traditional Kochujang and commercially available Kochujang in overweight and obese patients. The results showed that the traditional Kochujang is superior to the commercial Kochujang in reducing body fat content and improving blood lipid profiles. These two human studies suggest that long-term consumption of functional foods enriched in natural dietary phytochemicals is effective to reduce the risk of obesity and metabolic syndrome. The development of obesity is closely associated with adipogenesis, which is characterized by an increased number and size of adipocytes in adipose tissues. The differentiation of preadipocytes into mature adipocytes is a key step for cellular lipid metabolism and accumulation . Inhibition of adipogenesis and lipid accumulation in adipocytes may be an effective strategy for regulating obesity. Warinhomhoun et al. isolated the natural metabolites from an orchid species in Thailand and evaluated their biological impact on the growth and differentiation of mouse embryonic 3T3-L1 pre-adipocytes. They found that a bibenzyl compound could suppress adipogenesis by inhibiting adipocyte differentiation and lipid accumulation. The underlying molecular mechanisms were linked to the downregulation of adipogenic regulators such as peroxisome proliferators activated receptor g (PPARg) and CCAAT/enhancer-binding protein a (C/EBPa) and the suppression of mitogen-activated protein kinase (MAPK) pathway. Of note, the plant natural compounds can be used as a mixture to exert synergistic effects for the prevention and treatment of obesity. The study by Lee et al. reported that a combination of p-synephrine, p-octopamine HCl, and hispidulin effectively reduced the expression of adipogenic marker proteins (PPARg, C/EBPa, and C/EBPb) in 3T3-L1 adipocytes and mitigated the body weight gain in high-fat diet (HFD)-fed mice. Xu et al. explored the anti-obesity effect and mechanism of nuciferine, a main aporphine alkaloid component in lotus leaf, in HFD-fed mice. They found that treatment of nuciferine prevented body weight gain, improved glycolipid metabolism, and promoted energy expenditure in obese mice. Nuciferine suppressed lipogenesis and promoted fatty acid oxidation by activating the AMP-activated protein kinase (AMPK) pathway in hepatocytes and adipocytes. Liquiritigenin is a natural flavonoid isolated from the herb Glycyrrhiza uralensis Fisch. Qin et al. studied the effects of liquiritigenin on lipogenesis in adipocytes and the results showed that liquiritigenin was able to inhibit lipid accumulation in 3T3-L1 cells via a mammalian target of rapamycin (mTOR)-mediated autophagy mechanism. Polymethoxyflavones are flavonoids found in citrus fruits with bioactive properties. Jin et al. reported that the polymethoxyflavones isolated from citrus leaves effectively improved HFD-induced insulin resistance and dyslipidemia in obese mice. The polymethoxyflavones exert the anti-obesity effect via the modulation of fatty-acid oxidation and lipolysis. Fennel is a herbaceous and perennial plant cultivated in China and fennel essential oil contains volatile natural compounds including p-anisaldehyde, limonene, estragole, anethole, and trans-anethole. The study by Hong et al. reported that inhalation of fennel essential oil exerted a protective effect against lipid and metabolic dysfunction in HFD-induced obese rats. Overall, this Special Issue provides compelling evidence of the role of plant-derived natural compounds in the treatment and prevention of obesity. Studies are required to further explore the potential pharmacological and physiological activities of bioactive phytochemicals and understand their underlying mechanisms of action. Author Contributions Conceptualization, F.C.; writing-original draft preparation, D.L.; Writing review and editing, F.C. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare that they have no competing interests. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Seidell J.C. Halberstadt J. The global burden of obesity and the challenges of prevention Ann. Nutr. Metab. 2015 66 (Suppl. S2) 7 12 10.1159/000375143 26045323 2. Chooi Y.C. Ding C. Magkos F. The epidemiology of obesity Metabolism 2019 92 6 10 10.1016/j.metabol.2018.09.005 30253139 3. Apovian C.M. Obesity: Definition, comorbidities, causes, and burden Am. J. Manag. Care 2016 22 s176 s185 27356115 4. Srivastava G. Apovian C.M. Current pharmacotherapy for obesity Nat. Rev. Endocrinol. 2018 14 12 24 10.1038/nrendo.2017.122 29027993 5. Popiolek-Kalisz J. The Impact of Dietary Flavonols on Central Obesity Parameters in Polish Adults Nutrients 2022 14 5051 10.3390/nu14235051 36501081 6. Han A.L. Jeong S.J. Ryu M.S. Yang H.J. Jeong D.Y. Park D.S. Lee H.K. Anti-Obesity Effects of Traditional and Commercial Kochujang in Overweight and Obese Adults: A Randomized Controlled Trial Nutrients 2022 14 2783 10.3390/nu14142783 35889740 7. Hausman D.B. DiGirolamo M. Bartness T.J. Hausman G.J. Martin R.J. The biology of white adipocyte proliferation Obes. Rev. 2001 2 239 254 10.1046/j.1467-789X.2001.00042.x 12119995 8. Warinhomhoun S. Khine H.E.E. Sritularak B. Likhitwitayawuid K. Miyamoto T. Tanaka C. Punsawad C. Punpreuk Y. Sungthong R. Chaotham C. Secondary Metabolites in the Dendrobium heterocarpum Methanolic Extract and Their Impacts on Viability and Lipid Storage of 3T3-L1 Pre-Adipocytes Nutrients 2022 14 2886 10.3390/nu14142886 35889842 9. Lee D. Lee J.H. Kim B.H. Lee S. Kim D.W. Kang K.S. Phytochemical Combination (p-Synephrine, p-Octopamine Hydrochloride, and Hispidulin) for Improving Obesity in Obese Mice Induced by High-Fat Diet Nutrients 2022 14 2164 10.3390/nu14102164 35631305 10. Xu H. Lyu X. Guo X. Yang H. Duan L. Zhu H. Pan H. Gong F. Wang L. Distinct AMPK-Mediated FAS/HSL Pathway Is Implicated in the Alleviating Effect of Nuciferine on Obesity and Hepatic Steatosis in HFD-Fed Mice Nutrients 2022 14 1898 10.3390/nu14091898 35565866 11. Qin H. Song Z. Zhao C. Yang J. Xia F. Wang L. Ali A. Zheng W. Liquiritigenin Inhibits Lipid Accumulation in 3T3-L1 Cells via mTOR-Mediated Regulation of the Autophagy Mechanism Nutrients 2022 14 1287 10.3390/nu14061287 35334944 12. Jin Y.J. Jang M.G. Kim J.W. Baek S. Ko H.C. Hur S.P. Kim S.J. Anti-Obesity Effects of Polymethoxyflavone-Rich Fraction from Jinkyool (Citrus sunki Hort. ex Tanaka) Leaf on Obese Mice Induced by High-Fat Diet Nutrients 2022 14 865 10.3390/nu14040865 35215514 13. Hong S.J. Yoon S. Jo S.M. Jeong H. Youn M.Y. Kim Y.J. Kim J.K. Shin E.C. Olfactory Stimulation by Fennel (Foeniculum vulgare Mill.) Essential Oil Improves Lipid Metabolism and Metabolic Disorders in High Fat-Induced Obese Rats Nutrients 2022 14 741 10.3390/nu14040741 35215391 |
Nutrients Nutrients nutrients Nutrients 2072-6643 MDPI 10.3390/nu15051094 nutrients-15-01094 Reply Reply to Lee, S.Y. Comment on "Sung et al. Body Fat Reduction Effect of Bifidobacterium breve B-3: A Randomized, Double-Blind, Placebo Comparative Clinical Trial. Nutrients 2023, 15, 28" Sung Hyun Kyung 1+ Youn Sang Jun 2 Choi Yong 2 Eun Sang Won 3 Shin Seon Mi 4*+ Suzuki Toshikazu Academic Editor 1 Department of Pediatrics, College of Korean Medicine, Semyung University, Jecheon-si 27136, Republic of Korea 2 RnBS Corp., Seoul 06032, Republic of Korea 3 Daehan Chemtech Co., Ltd., Seoul 01811, Republic of Korea 4 Department of Internal Medicine, College of Korean Medicine, Semyung University, Jecheon-si 27136, Republic of Korea * Correspondence: [email protected]; Tel.: +82-43-649-1873 + These authors contributed equally to this work. 22 2 2023 3 2023 15 5 109423 1 2023 16 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). DAEHAN CHEMTECHThis research was funded by DAEHAN CHEMTECH. pmcThank you kindly for your interest in and opinion on our research . In this clinical trial, the intake of probiotics and lactic acid bacteria was prohibited during the study period, and participants who used them were excluded. Additionally, if changes in intestinal flora were analysed, the mechanism of body fat reduction could have been elucidated; however, the research team agreed that the intestinal microbiome test would not be conducted. Bilsborough et al. assessed reliability using a test-retest methodology to compare the precision of two dual-energy X-ray absorptiometry (DEXA) devices in highly trained Australian football players. They found a reliability of 0.3% (coefficient of variation) for lean body mass and 2.5% (coefficient of variation) for body fat mass and body fat percentage after performing two scans on each DEXA device. To assess test-retest reliability, the athletes were instructed to follow standard protocols of food and fluid intake to ensure optimal hydration before each scan. Therefore, it can be said that reliability was assessed in the same physical conditions as far as possible, without changes in body fat mass and lean body mass caused by other interventions. This trial aimed to confirm the effect of reducing body fat mass after taking investigational foods in overweight or obese adults. For test-retest reliability, repeated DEXA measurements should be conducted under similar conditions. However, in this study, measurements were conducted before and after intervention; therefore, it is meaningless to report reliability using the coefficient of variation, which represents DEXA precision, because the subjects' body fat mass and lean body mass had changed due to investigational food intake. The intake determination data are as follows. Five-week-old male C7BL/6J mice were fed approximately 166 g of a high-fat diet mixed with 108 or 109 CFU/d of Bifidobacterium breve B-3 for an 8-week study period. Anti-obesity efficacy was confirmed, and there was no report of toxicity . Furthermore, at Tokyo Medical and Health University in Japan, individuals with a high body mass index were given food containing B. brev B-3 (5.0 x 109 CFU/d), and the effect on body weight, body fat, and blood parameters was assessed. A decrease in body fat mass was confirmed in the B. brev B-3 intake group . Accordingly, the daily intake of the test substance B. brev B-3 was set at 5 billion CFU/d considering the human application test results of similar raw materials and subject safety. Despite some studies reporting that vaccination can affect weight, there are more reports on weight gain related to social distancing which was more common than vaccination due to COVID-19 . Rather, the possibility of weight gain is higher in a pandemic situation; hence, the fact that there was weight loss in this study conducted during this period can be considered a remarkable achievement. In this study, as per the protocol, per-protocol (PP) analysis was performed for efficacy evaluation as the purpose was to estimate the true efficacy of the intervention on subjects who have completed the trial. More research is needed on the mechanism of body fat reduction. Moreover, this study was conducted by dividing subjects into two groups through random assignment, and there was no difference between the groups in terms of dietary habits or amount of exercise performed at the beginning of the study (Table 1). The limitations to this study were mentioned in the published paper . Author Contributions Conceptualization, S.J.Y. and Y.C.; methodology, S.J.Y. and Y.C.; software, S.J.Y. and Y.C.; validation, H.K.S.; formal analysis, S.J.Y. and Y.C.; investigation, S.M.S.; data curation, writ-ing original draft preparation, writing review and editing, S.M.S. and H.K.S.; visualization, H.K.S.; supervision, S.W.E.; project administration, S.W.E.; funding acquisition, S.W.E. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. nutrients-15-01094-t001_Table 1 Table 1 Changes in physical activity and dietary habits (PPS). BB-3 Group (N = 42) Placebo Group (N = 41) p-Value * IPAQ Total Physical activity (MET-min/week) V2 2401.50 +- 1955.78 2848.59 +- 3562.14 0.6819 1 V5 4151.02 +- 5655.05 2808.20 +- 3294.04 0.3164 1 V5 - V2 1749.52 +- 4582.37 -40.39 +- 2645.99 0.3412 1 IPAQ Total Energy expenditure (kcal/week) V2 3065.91 +- 2694.03 3653.76 +- 4955.91 0.7327 1 V5 5257.72 +- 7531.41 3509.73 +- 4546.55 0.3275 1 V5 - V2 2191.81 +- 5915.85 -144.02 +- 3317.14 0.3458 1 Dietary survey (kcal) V2 1883.56 +- 573.85 1827.53 +- 657.96 0.5447 1 V5 1811.72 +- 440.19 1721.49 +- 545.25 0.2006 1 V5 - V2 -71.84 +- 579.75 -106.03 +- 704.08 0.8734 1 * Compared between group; 1 p-value for the Wilcoxon rank sum test; The International Physical Activity Questionnaire (IPAQ) was used to assess physical activity, while the 24 h dietary recall method was used to assess dietary habits. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Lee S.Y. Comment on Sung et al. Body Fat Reduction Effect of Bifidobacterium breve B-3: A Randomized, Double-Blind, Placebo Comparative Clinical Trial. Nutrients 2023, 15, 28 Nutrients 2023 15 1093 10.3390/nu15051093 2. Sung H.K. Youn S.J. Choi Y. Eun S.W. Shin S.M. Body fat reduction effect of Bifidobacterium breve B-3: A randomized, double-blind, placebo comparative clinical trial Nutrients 2023 15 28 10.3390/nu15010028 36615686 3. Bilsborough J.C. Greenway K. Opar D. Livingstone S. Cordy J. Coutts A.J. The accuracy and precision of DXA for assessing body composition in team sport athletes J. Sports Sci. 2014 32 1821 1828 10.1080/02640414.2014.926380 24914773 4. Kondo S. Xiao J.Z. Satoh T. Odamaki T. Takahashi S. Sugahara H. Yaeshima T. Iwatsuki K. Kamei A. Abe K. Antiobesity effects of Bifidobacterium breve strain B-3 supplementation in a mouse model with high-fat diet-induced obesity Biosci. Biotechnol. Biochem. 2010 74 1656 1661 10.1271/bbb.100267 20699581 5. Minami J.I. Kondo S. Yanagisawa N. Odamaki T. Xiao J.Z. Abe F. Nakajima S. Hamamoto Y. Saitoh S. Shimoda T. Oral administration of Bifidobacterium breve B-3 modifies metabolic functions in adults with obese tendencies in a randomised controlled trial J. Nutr. Sci. 2015 4 e17 10.1017/jns.2015.5 26090097 6. Sanchez E. Lecube A. Bellido D. Monereo S. Malagon M.M. Tinahones F.J. Spanish Society for the Study of Obesity Leading factors for weight gain during COVID-19 lockdown in a Spanish population: A cross-sectional study Nutrients 2021 13 894 10.3390/nu13030894 33801989 7. Park J.-H. Yoo E. Kim Y. Lee J.-M. What Happened during COVID-19 in South Korea? Comparing Physical Activity, Sleep Time, and Body Weight Status Int. J. Environ. Res. Public Health 2021 18 5863 10.3390/ijerph18115863 34072563 8. Lee M.N. Choi Y.S. Kim S.D. The leading factors of obesity and severe obesity in Korean adults during the COVID-19 pandemic Int. J. Environ. Res. Public Health 2022 19 12214 10.3390/ijerph191912214 36231516 |
Sao Paulo Med J Sao Paulo Med J spmj Sao Paulo Medical Journal 1516-3180 1806-9460 Associacao Paulista de Medicina - APM 36043675 10.1590/1516-3180.2021.0952.R2.11052022 1516-3180.2021.0952.R2.11052022 Original Article The impact of bariatric and metabolic surgery on the morbidity and mortality of patients infected during the COVID-19 pandemic: a retrospective cohort study Costa Luiz Henrique Sala de Melo I Costa Luiz Filipe Sala de Melo II Kachan Gabriela Rezende III Gentile Joao Kleber de Almeida IV Mendonca Raul Andrade Filho V Costa Marcela Ralin de Carvalho Deda VI Ribas Jurandir Marcondes Filho VII I MD. Physician and General Surgeon, Postgraduate Program in Digestive Tract Surgery, Colegio Brasileiro de Cirurgia Digestiva (CBCD), Aracaju (SE), Brazil II Undergraduate Student of Medical Sciences, Faculdade de Medicina-Universidade Cidade de Sao Paulo (FM-UNICID), Sao Paulo (SP), Brazil. III MD. Physician, Department of Medicine, Faculdade de Medicina-Universidade Cidade de Sao Paulo (FM-UNICID), Sao Paulo (SP), Brazil. IV MD. Gastrosurgeon, General Surgeon, Doctoral Student, and Assistant Professor, Department of Surgery, Faculdade de Medicina-Universidade Cidade de Sao Paulo (FM-UNICID), Sao Paulo (SP), Brazil. V MD. Gastrosurgeon and General Surgeon, Department of Urgency of Hospital de Urgencias de Aracaju, Aracaju (SE), Brazil. VI PhD. Professor, Department of Physiotherapy, Universidade Federal de Sergipe (UFS), Lagarto (SE), Brazil. VII PhD. Physician and General Surgeon, Department of Digestive Surgery, Universidade Federal do Parana (UFRP), Curitina (PR), Brazil. Address for correspondence: Joao Kleber de Almeida Gentile Secao Tecnica de Cirurgia do Aparelho Digestivo, Hospital do Servidor Publico Municipal R. Castro Alves, 60 Aclimacao Sao Paulo (SP) Brasil CEP 01532-000 Tel. (+55 11) 98268-8090 E-mail: [email protected] Author's contributions: Melo Costa LHS, Melo Costa LFS, Kachan GR, Almeida Gentile JK, Mendonca Filho RA, Deda Costa MRC, and Ribas Filho JM: Substantial contributions to the conception or design of the work; acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Conflicts of interest: The authors declare no conflicts of interest 29 8 2022 2023 141 2 120124 14 2 2022 04 5 2022 11 5 2022 This is an open-access article distributed under the terms of the Creative Commons Attribution License ABSTRACT BACKGROUND: Since the impact of the coronavirus disease 2019 (COVID-19) pandemic in March 2020, several studies have shown a strong relationship between obesity and severe cases of COVID-19. It is imperative to assess whether bariatric surgery exerts a protective effect in such cases. OBJECTIVE: This study aimed to assess the impact of bariatric surgery on the morbidity and mortality in obese patients during the COVID-19 pandemic. A comprehensive search was performed using the PubMed and Cochrane Library databases. DESIGN AND SETTING: Retrospective cohort studies conducted in the Faculdade de Medicina da Universidade Cidade de Sao Paulo, Sao Paulo (SP), Brazil. METHODS: The search comprised the following descriptors: "bariatric, surgery, COVID-19". Current retrospective cohort studies that examined the influence of bariatric surgery on the morbidity and mortality of obese patients during the COVID-19 pandemic were considered eligible. RESULTS: After removing duplicates, 184 studies were obtained from the databases. Of these, 181 were excluded from the analysis as they did not meet the eligibility criteria. Patients undergoing postoperative follow-up of bariatric surgery had a similar probability of SARS-CoV-2 infection compared to the general population, and persistent comorbidities were associated with an increased risk and severity of infection. CONCLUSION: Bariatric surgery has a protective effect against severe COVID-19 in the obese population, bringing the prevalence of severe disease cases to levels equivalent to those of the nonobese general population, with a positive impact on morbidity and mortality. KEYWORDS (MeSH terms): Bariatric surgery Obesity COVID-19 Body mass index AUTHOR'S KEYWORDS: Comorbidities Protective factor Hospitalization rate Infection rate pmcINTRODUCTION In March 2020, the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) a pandemic. Since then, the impact of this infection on the public and private health systems of many countries has become evident. 1 The overcrowding of intensive care beds has led to the cancellation of elective surgeries, as there has been an increasing demand for professionals and and resources to treat infected patients. 2,3 In this context, Hussain et al. 4 presented a flowchart scaling priority among candidates for elective and revision procedures during the pandemic. Patients with severe obesity, comorbidities, or surgical complications should be prioritized when performing procedures. Outpatient activities began to be performed through tele-medicine, and only urgent procedures such as early and late surgical complications remained in the usual routine. Studies indicate obesity as an isolated risk factor for severe cases of COVID-19. 4-6 In addition, biochemical and endocrine factors related to obesity, such as type 2 diabetes and insulin resistance, are worse prognostic factors in infected patients. 7,8 Therefore, it has become imperative to evaluate whether bariatric surgery exerts a protective effect against severe covid-19 conditions. Retrospective studies have evaluated outcomes in patients with previous bariatric surgery infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) regarding the severity of the disease, need for intensive care and impact on mortality. 6,9,10 However, there remains a lack of controlled clinical trials or other prospective studies evaluating such parameters. OBJECTIVE The present study aimed to evaluate, through a literature review, the impact of bariatric surgery on the morbidity and mortality of obese patients during the COVID-19 pandemic in reference centers inside and outside Brazil. METHODS Data sources and surveys A comprehensive search was conducted using the PubMed and Cochrane Library databases. The search strategies comprised the following descriptors: "bariatric, surgery, COVID-19". These have been adapted for use in various databases. The access routes to the descriptions of the studies used in this article are presented in Table 1. Table 1 Comprehensive search strategy for research on bariatric and metabolic surgery during the coronavirus-2019 pandemic using harvesting information retrieval framework Author (year) Date searched Article title Journal Search terms Databases Aminian et al. 9 (2020) September 15, 2021 Association of prior metabolic and bariatric surgery with severity of coronavirus disease 2019 (COVID-19) in patients with obesity Official Journal of the American Society for Bariatric Surgery Bariatric surgery; Obesity; COVID-19; Body mass index PubMed Bel Lassen et al. 10 (2021) September 15, 2021 COVID-19 and its Severity in Bariatric Surgery-Operated Patients Obesity (Silver Spring) Bariatric surgery; Obesity; COVID-19; Body mass index PubMed Uccelli et al. 6 (2020) September 15, 2021 COVID-19 and Obesity: Is Bariatric Surgery Protective? Retrospective Analysis on 2,145 Patients Undergone Bariatric-Metabolic Surgery from High Volume Center in Italy (Lombardy) Obesity Surgery Bariatric surgery; Obesity; COVID-19; Body mass index; PubMed Current retrospective cohort studies that examined the influence of bariatric surgery on the morbidity and mortality of obese patients during the COVID-19 pandemic were eligible for this review without restrictions on dates and languages. Further inclusion criteria included studies that evaluated adult patients over 18 and under 65 years of age, obese patients who underwent bariatric surgery, and those infected by SARS-CoV-2, in reference centers inside and outside Brazil. Studies with patients outside the age group of 18 to 65 years, those that did not deal with bariatric surgery, and those performed outside the pandemic period were excluded. Data extraction Data extraction was performed using a standardized data extraction form. The data extracted from all studies included study details, demographic data of participants, and available information on the interventions used. RESULTS Search results A total of 186 studies were obtained from the surveyed databases. After removing duplicates, 184 studies were retained for the analysis. Of these, 181 were excluded after analyzing titles, abstracts, and full texts because they did not meet the eligibility criteria. Only three studies were included in this review . The characterization of the participants included in the studies is shown in Table 2. Figure 1 Flow diagram of the results. Table 2 Characterization of the participants included in the study Study n Average age (years) Sex Diagnosis Aminian et al. 9 4,365 46 Male and female Obesity Bel Lassen et al. 10 738 50 Male and female Obesity Uccelli et al. 6 2,145 44 Male and female Obesity A description of studies evaluating the impact of bariatric surgery on the morbidity and mortality of obese patients during the COVID-19 pandemic is shown in Table 3. Table 3 Description of studies evaluating the impact of bariatric surgery on morbidity and mortality of obese patients during the coronavirus disease 2019 (COVID-19) pandemic Study Aminian et al. 9 Bel Lassen et al. 10 Uccelli et al. 6 Participants n = 363 tested positive for COVID-19 Group with previous surgery: 33; Group of non-operated: 330 n = 738; All underwent bariatric surgery Group "probably infected": 62; Group "probably not infected": 676 n = 2,145; All underwent bariatric surgery Goals Investigate the relationship between previous metabolic surgery and the severity of COVID-19 in patients with severe obesity. Estimate the prevalence of COVID-19 and evaluate factors associated with the incidence and severity of the disease in patients who underwent bariatric surgery. Investigate the incidence of SARS-CoV-2 infection and its severity in patients who underwent bariatric surgery. Collection procedures A search was performed in medical records of the institution that conducted the study for patients who tested positive in RT-PCR for COVID-19, evaluating the rate and time of hospitalization, need for ICU, mechanical ventilation, dialysis, and mortality in patients who tested positive in RT-PCR for COVID-19, evaluating the rate and time of hospitalization, need for ICU, mechanical ventilation, dialysis and mortality. A standardized questionnaire was conducted through telephone calls in which probable symptoms of COVID-19 were questioned, such as anosmia, fever, rhinorrhea, odynophagia, or patients who tested positive for the disease. In addition, a medical record search was performed for anthropometric and laboratory data before and after the patients. A questionnaire was sent to patients previously submitted to bariatric surgery in which age, gender, BMI, origin, comorbidities, and type of surgery were questioned, and they were asked about the main symptoms of COVID-19, and occurrence of hospitalization and ICU admission. Main findings The mean preoperative BMI in the group with previous surgery was 49.1 +- 8.8kg/m2, decreasing to 37.2 +- 7.1 kg/m2 at the time of testing for COVID-19. The mean BMI of the non-operated group was 46.7 +- 6.4 kg/m2. Six patients (18.2%) from the group submitted to surgery, and 139 patients (42.1%) from the non-operated group were admitted to the hospital (P = 0.013). 43 patients (13%) from the non-operated group required ICU admission (P = 0.021). 22 patients (6.7%) required mechanical ventilation. Five patients (1.5%) underwent dialysis. Eight patients (2.4%) died. In the group with previous surgery, none of these four outcomes were identified. Patients had a mean age of 50 +- 12.3 years, with most being female (78.3%) and 44% having type 2 diabetes before surgery. The most used surgical technique was gastric bypass (54.4%), followed by sleeve gastrectomy (45.0%). The mean postoperative time at collection was 3.7 +- 2.7 years. There was no difference in the surgical technique outcomes between the groups. The mean postoperative time was significantly longer in the "probably infected" group, with a considerably higher proportion of persistently diabetic patients than in the "probably not infected" group. All patients underwent elective bariatric surgery. The mean preoperative BMI was 44 +- 6.8 kg/m2 with a reduction to 29.3 +- 5.5 kg/m2 in the postoperative period. The main technique used was laparoscopic sleeve gastrectomy (82.4%). The reduction in the number of comorbidities was almost entirely statistically significant. A total of 181 patients (8.4%) reported at least one symptom related to COVID-19. Nevertheless, only 26 cases (1.2%) were tested, and only 13 individuals (0.6%) tested positive. Six patients (0.3%) were admitted to hospital units; two patients (0.1%) required ICU with mechanical ventilation. The mean length of hospital stay was 23 +- 13 days. Conclusions The study identified that previous bariatric surgery is associated with lower hospitalization rates and the need for ICU for patients infected with SARS-CoV-2. Patients under postoperative follow-up of bariatric surgery presented a probability of SARS-CoV-2infection similar to that of the general population. The persistence of type 2 diabetes and the presence of lower BMI are associated with increased risk and severity of SARS-CoV-2 infection. Because the rate of hospitalization and need for ICU of the patients evaluated was equivalent to those of the general nonobese population, the study concludes that bariatric surgery can be considered a protective factor for severe acute respiratory syndrome caused by SARS-CoV-2 infection RT-PCR = reverse transcription polymerase chain reaction; ICU = intensive care unit; BMI = body mass index; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus 2. DISCUSSION Studies indicate obesity as an isolated risk factor for severe cases of COVID-19. 4-6 In addition, biochemical and endocrine factors related to obesity, such as type 2 diabetes and insulin resistance, are associated with a worse prognosis in infected patients. 7,8,11 In this context, the publications evaluated in this study explore bariatric surgery as an intervention capable of serving as a protective factor against severe cases of COVID-19. 6,9,10 There is great heterogeneity between the methodology of the studies since the situation of social isolation itself made it impossible to conduct controlled clinical trials. The publication by Uccelli et al., 6 whose data collection was carried out from March to May 2020, presented many participants from several different areas of Italy, which allowed a global analysis of the involved population. However, there was a population bias as only patients who had already undergone surgery answered the questionnaire, and there was no control group of non-surgical patients. There was also a low testing rate with reverse transcription polymerase chain reaction (RT-PCR) (1.2%), which may have underestimated the number of infected patients. Moreover, as the questionnaire was self-applicable online, seeking the most common symptoms of COVID-19, there was bias in the collection not being performed by an examiner trained to perform the necessary anamnesis. The study conducted by Aminian et al., 9 whose data collection was carried out between March and July 2020, analyzed patients who tested positive for COVID-19 through RT-PCR and anthropometric data extracted from the institution's medical records confirmed the reliability of the research. However, the major limitation of this study was the small number of patients with a history of previous bariatric surgery, which resulted in a longer confidence interval and may have influenced the statistical analysis of the results. Moreover, as only six operated patients were hospitalized for COVID-19, laboratory, radiological, and oxygenation data were unavailable for most patients in this group; therefore, they were not included in the statistical analysis. Bel Lassen et al. 10 performed data collection between March and May 2020. Similar to the study by Aminian et al., 9 this study used anthropometric data collected from medical records with good reliability. Additionally, a large number of participants were included in the study. However, the postoperative time among the patients was extremely heterogeneous, with an interval of up to 16 years. This introduced a population bias that may have interfered with the results. Similar to the study by Uccelli et al., 6 a self-administered questionnaire was made available, which may have been subject to different interpretations by individuals regarding the symptoms of COVID-19. Despite the heterogeneity in the methodology employed by the different authors and the complicating factors between data collection and statistical analysis of results, the three publications concluded that the prevalence of severe COVID-19 conditions in patients in the postoperative period of bariatric and metabolic surgery does not differ from the prevalence in the general nonobese population. From the perspective of countries' health systems that have managed COVID-19 in the long term, it is necessary to develop controlled clinical trials with a good methodology to assess whether such results are reproducible and whether there are other clinical implications in carrying out such procedures. CONCLUSION Based on the results of the analyzed studies, even with the reservations described regarding the methodological limitations employed, it can be concluded that bariatric surgery exerts a protective effect against severe cases of COVID-19 in the obese population, with a positive impact on morbidity and mortality. Faculdade de Medicina-Universidade Cidade de Sao Paulo (FM-UNICID), Sao Paulo (SP), Brazil Sources of funding: This research received no specific grants from any public, commercial, or not-for-profit funding agency REFERENCES 1 World Health Organization Coronavirus disease 2019 (COVID-19): Situation Report - 52 Available from: Accessed in 2022 (May 4) 2 Spinelli A Pellino G COVID-19 pandemic: perspectives on an unfolding crisis Br J Surg 2020 107 7 785 787 10.1002/bjs.11627 32191340 3 Iacobucci G Covid-19: all non-urgent elective surgery is suspended for at least three months in England BMJ 2020 368 m1106 10.1136/bmj.m1106 32188602 4 Hussain A Mahawar K El-Hasani S The Impact of COVID-19 Pandemic on Obesity and Bariatric Surgery Obes Surg 2020 30 8 3222 3223 10.1007/s11695-020-04637-7 32388706 5 Nakeshbandi M Maini R Daniel P The impact of obesity on COVID-19 complications: a restrospective cohort study Int J Obes (Lond) 2020 44 9 1832 1837 10.1038/s41366-020-0648-x 32712623 6 Uccelli M Ceasana GC De Carli SM Covid-19 and Obesity: Is Bariatric Surgery Protective? Retrospective Analysis on 2145 Patients Undergone Bariatric-Metabolic Surgery from High Volume Center in Italy (Lombardy) Obes Surg 2021 31 3 942 948 10.1007/s11695-020-05085-z 33128218 7 Vas P Hopkins D Feher M Rubino F B Whyte M Diabetes, obesity and COVID-19: A complex interplay Diabets Obes Metab 2020 22 10 1892 1896 10.111/dom.14134 32627299 8 Finucane F Davenport C Coronavirus and Obesity: Could Insulin Resistance Mediate the Severity of Covid-19 Infection? Front Public Health 2020 8 184 184 10.3389/fpubh.2020.00184 32574288 9 Aminian A Fathalizadeh A Tu C Association of prior metabolic and bariatric surgery with severity os coronavirus disease 2019 (COVID-19) in patients with obesity Surg Obes Relat Dis 2021 17 1 208 214 10.1016/j.soard.2020.10.026 33243670 10 Bel Lassen P Poitou C Genser L COVID-19 and its Severity in Bariatric Surgery-Operated Patients Obesity (Silver Spring) 2021 29 1 24 28 10.1002/oby.23026 32875723 11 Lockhart S O'Rahilly S When Two Pandemics Meet: Why Is Obesity Associated with Increased COVID-19 Mortality? Med (N Y) 2020 1 1 33 42 10.1016/j.medj.2020.06.005 32838359 |
Summary The positional Burrows-Wheeler transform (PBWT) data structure allows for efficient haplotype data matching and compression. Its performance makes it a powerful tool for bioinformatics. However, existing algorithms do not exploit parallelism due to inner dependencies. We introduce a new method to break the dependencies and show how to fully exploit modern multi-core processors. Availability and implementation Source code and applications are available at Supplementary information Supplementary data are available at Bioinformatics Advances online. Swiss National Science Foundation 10.13039/501100001711 SNSF-PP00P3_176977 pmc1 Introduction The positional Burrows-Wheeler transform (PBWT) data structure allows for the development of efficient matching algorithms between haplotypes (Durbin, 2014). That is, the PBWT allows matching in linear time relative to the number of haplotypes instead of the quadratic time of a naive all-versus-all approach. Another advantage is the impressive data compression rate made possible by this data structure. This makes the PBWT, and associated algorithms, a core component of bioinformatics tools, such as Beagle, EagleImp, GLIMPSE or XSI (Browning et al., 2021; Rubinacci et al., 2021; Wertenbroek et al., 2022; Wienbrandt and Ellinghaus, 2022), and bioinformatics courses (Gagie et al., 2022). However, algorithms relying on the PBWT for processing haplotypes over a genomic region exhibit a positional dependency, i.e. the state of the structure at a given position (genomic locus) depends on the previous position. This makes it hard to parallelize. Others (Sanaullah et al., 2021; Shakya et al., 2022; Wang et al., 2023) have proposed methods to make PBWT algorithms more efficient but are still sequential. In this article, we introduce a method to manage the dependency and split the problem for parallel execution. We show that with this new method haplotype matching algorithms can achieve a speed-up of up to 8x on a modern 12-core processor. 2 Methods The algorithms presented in Durbin (2014) for haplotype matching and compression rely on two key internal data structures: the positional prefix array ak which represents the ordering of haplotypes at position k and the divergence array dk which stores the position where a haplotype differs from the previous one in the current ordering. (For definitions (see Durbin, 2014), the same nomenclature is used here). The ak and dk arrays for a position k are built from the arrays of the previous position ak-1 and dk-1. This dependency propagates back until the initial arrays a0 and d0 which are given. The positional prefix array a0 represents the arbitrary order the haplotypes come in from the input data, at each position the haplotypes are reordered given the genotype they carry at that position, either a 0 (reference genotype) or a 1 (alternative genotype). So when generating a1 all haplotypes with the reference genotype (0) at the first position (k = 0) come before those that have an alternate genotype (1) at position k = 0. This is equivalent to a radix sort (also known as digital sort or bucket sort). Therefore, at each position k, the k previous genotypes (reverse prefix) dictate the position of that haplotype. The divergence array dk is generated at the same time by keeping track of at which position k, previously matching haplotypes stop matching (do not share the same genotype anymore). These two arrays are key in PBWT-based algorithms for matching or compression. To start processing at an arbitrary position k the arrays ak and dk must be known (iteratively computed from the starting position 0 up to k). This dependency makes it difficult to split a genomic region with N loci, k[0,N[ between separate threads for parallel processing. 2.1 Splitting the genomic region and breaking the dependency A key observation is that if we generate ak and dk from a previous position k - b (over a chunk of b previous loci, b < k) with initial arrays a0 and d'k-b (an array filled with the value k - b) instead of the actual arrays ak-b and dk-b, then for all haplotypes, except the ones that are identical over k - b to k, the computed values in the ak and dk arrays will be correct. That is, as if computed from the start, i.e. starting at k = 0 with a0 and d0 and iterating over k loci instead of only b loci. This means we have an approximated version of ak and dk that can only have wrong values for groups of identical haplotypes over the chunk of b loci. For a because they cannot be ordered given the b observed loci and for d because they differ at a loci before k - b. Because d'k-b was initialized with k - b the condition dk[i]=k-b lets us know for which indices i the values of ak and dk might be wrong. Keypoint: The correction of arrays ak and dk computed from position k - b (b steps) with a0 and d'k-b instead of ak-b and dk-b can be done in a single step if the correct ak-b and dk-b are known. Strategy: It is possible split the genomic region of N loci into t chunks of b=N/t loci for t threads to handle in parallel. Each thread can compute the approximated ak and dk arrays (end of the chunk) from the position k - b (start of the chunk), with a0 and d'k-b instead of the actual arrays for the start of each chunk. The ak and dk arrays at the end of the first chunk will be correct because the first chunk is supposed to start with a0 and d0 (note, d'0=d0). Then, we can use the keypoint above to correct the remaining t - 1 a and d arrays in t - 1 sequential steps. Because t will typically be small (e.g. 2-64 threads), the number of steps executed sequentially is small compared to the total number of steps N (e.g. in the millions). Also, the bigger the chunk the smaller the chance to have identical haplotypes, the less time will be required to correct the a and d arrays. Once the t arrays are generated the heavier algorithms (matching, compression, etc.) can be launched in parallel with t threads. The process is illustrated in the Supplementary Figures SP1-SP4. 2.2 Algorithms to correct approximated a and d arrays The method to correct a and d is decomposed into two algorithms; Algorithm 1 shows how to fix ak and dk, between a start and stop index, given the arrays at k - b. The start and stop indices represent a group of identical haplotypes over loci k - b to k. To rearrange the haplotypes in ak between start and stop, they require to follow the order given in ak-b. To do so, the positions of the haplotypes in the previous chunk are looked up in ak-b-1, which is the inverse of the positional prefix array ak-b (see Algorithm 2). These positions are then sorted in incremental order and finally the correct order is set in ak by referring to the haplotype number in ak-b given the incrementally sorted indices. Now that the group of identical haplotypes are ordered correctly (correct values in ak), we need to fix the divergence values, the first value at position start will already be correct because it refers to the previous non-matching haplotype. For the other values, they now need to be updated to reflect the divergences in the previous chunk given the corrected ordering. Although the haplotypes are grouped together in the current chunk, they might have other haplotypes in between them in the previous chunk. This requires to scan for the biggest value of d between the previous haplotype and the current one referring to the ordering in the previous chunk, similarly to what is done with p, q of Algorithm 2 presented in Durbin (2014). Algorithm 1: Correction of positional prefix and divergence arrays ak, dk between start and stop given previous arrays ak-b, dk-b Initialization, create array arr[stop-start] fori:=startto stop - 1 do arr[i-start]:=ak-b-1[ak[i]] end sort (arr) fori:=startto stop - 1 do ak[i]:=ak-b[arr[i-start]] end fori:=start+1to stop - 1 do scan_start:=arr[i-start-1]+1 scan_stop:=arr[i-start]+1 dk[i]=max_element(dk-b[scan_start:scan_stop]) end Algorithm 2 allows to determine groups of matching haplotypes over k - b to k and calls Algorithm 1 to fix the values in ak and dk. To do so Algorithm 2 has to generate the array ak-b-1, which is required for Algorithm 1. This is done by looping through all entries of ak-b which are haplotype identifiers, so if ak-b =idx it means the first haplotype is idx, therefore ak-b-1[idx]=0. So a maps positions to identifiers and a-1 maps identifiers to positions. Then Algorithm 2 iterates over the d array keeping track of haplotype groups matching over k - b to k, for each of such groups it will call Algorithm 1 to correct the a and d arrays. Algorithm 2 is used to sequentially correct the approximate a and d arrays generated in parallel with the strategy proposed in Section 2.1 (see Algorithm P in Section 2.3). A step-by-step example of the execution of Algorithms 1 and 2 is provided in the Supplementary Materials and illustrated with Supplementary Figures S1 and S2. Algorithm 2: Correction of positional prefix and divergence arrays ak, dk given correct previous arrays ak-b, dk-b initialization, create array ak-b-1[M], group_index: = 0 // Fill ak-b-1 array, reciprocal of ak-b array for i:=0 to M - 1 do ak-b-1[ak-b[i]]:=i end // Iterate over the divergence array to find and fix matching groups fori:=0to M - 1 do ifdk[i]pthen ifi-group_index>1then Algorithm 1 with start := group_index and stop :=i end group_index: = i end end if M-group_index>1 then Algorithm 1 with start := group_index and stop :=M end 2.3 From sequential to parallel algorithm The sequential PBWT-based algorithms can be summarized with Algorithm S which loops over all N genotype loci and alternates between updating the a and d arrays and running the matching algorithm or compression step. Algorithm S: Sequential PBWT-based algorithm Constants: N: #genotype loci, M: #haplotypes Initialization, create array a0=[0,1,2,...,M-1] and d0=[0,...,0] fork:=0to N do Run matching [e.g. Algorithm 3 or 4 from Durbin (2014)] or compression step Generate ak+1 and dk+1 from ak and dk end Our parallel implementation is described in Algorithm P. The algorithm relies on the keypoint and strategy presented above. The algorithm starts by a parallel step to generate the approximate a and d arrays, then runs a small sequential loop to correct these arrays with Algorithm 2 presented above. Finally, it launches T threads that will each run Algorithm S with the heavier matching or compression algorithms. Each thread handles a chunk of the genomic region starting at positions k{0,b,2b,3b,...,(T-1)*b} with the now available and correct ak, dk arrays (instead of a single thread running Algorithm S over the whole genomic region starting at k = 0 with a0 and d0 and finishing at N). Algorithm P: Parallel PBWT-based algorithm Constants: N: #genotype loci, M: #haplotypes, T: #threads b=N/T //Chunk size // A: Parallel generation of approximate a and d arrays Launch T - 1 threads with Algorithm 2 from Durbin (2014) for b steps starting from positions k{0,b,2b,3b,...,(T-2)*b} with arbitrary ak=[0,1,2,...,M-1] and dk=[k,...,k] that will generate the approximate ai and di arrays (with i{b,2b,3b,...,(T-1)*b}) // B: Sequential correction of the approximate arrays ai, di for t:=1 to T - 1 do join(thread t) if t > 1 // (Note: ab, db are already correct) then Algorithm 2: correct at*b and dt*b with a(t-1)*b and d(t-1)*b end end // C: Parallel run of matching Algorithm 3 or 4 Launch T threads running Algorithm S with e.g. Algorithm 3 or 4 from Durbin (2014) for b steps starting from positions k{0,b,2b,3b,...,(T-1)*b} with the now available and correct ak, dk arrays 2.4 Time and space complexity analysis The worst case time complexity of Algorithm 1 relative to M input haplotypes (if all haplotypes match from k - b to k, with a and d that require to be corrected) is quasilinear, O(M log M). Algorithm 1 can be split in four steps, three loops and one sorting algorithm: The first two loops iterate over the matching haplotypes so they are O(M). The sort is O(M log M) because it is implemented with a merge sort (Knuth, 1975). The last loop may look like it could have quadratic complexity because of the inner max element look-up, but it has not. The number of look-ups for the combined max elements is bounded by the number of haplotypes, because the array arr is comprised of sorted positions we have 0<=scan_start<scan_stop<=M and i(scan_stop-scan_start) is bounded by M, therefore the number of look-ups in this loop is O(M). The worst case time complexity of Algorithm 2 relative to M input haplotypes is quasilinear O(M log M). Algorithm 2 has two main parts: first, it generates ak-b-1 which is done in M steps, therefore it is O(M). Second, it has to apply Algorithm 1 to a number of matching haplotype groups. The time complexity of Algorithm 1 is dominated by the sorting step which is O(M log M). The worst case time complexity of the second part of Algorithm 2 is also O(M log M), because either all haplotypes match and we have a single group of size M to sort (apply Algorithm 1), or we have a given number of smaller groups to sort. Because the sum of the group sizes is bounded by M, running a number of smaller sorts will require a lower or equal asymptotic number of steps than sorting all the haplotypes (e.g. apply Algorithm 1 to M groups of size 1). Therefore, the worst case time complexity of running Algorithm 2 is O(M log M). The space complexity is O(M) because a constant number of arrays of size M is required and the merge sort also has linear space complexity (Knuth, 1975). The PBWT algorithms for matching and compression have a worst case time complexity of O(NM) where N is the number of genotype loci and M the number of haplotypes. Our parallel version will have a worst case time complexity of O(NM/T+TM log M) where T is the number of threads. The added O(TM log M) quasilinear complexity is negligible compared to the gains we have by dividing NM by T. For example, with data from (1000 Genomes Project Consortium and others, 2015): N>=88,000,000, M = 5008, and T will typically be small (e.g. 2-64 threads). 3 Results We applied the strategy above on two haplotype matching algorithms from Durbin (2014) and implemented them as the parallel implementation shown in Algorithm P: Algorithm 3 which reports all matches between haplotypes above a given length and Algorithm 4 which reports all set-maximal matches between haplotypes. Figure 1 shows the runtime of the original single-threaded algorithm (Algorithm S) and its multi-threaded counterparts (Algorithm P) for different number of threads t on data from (1000 Genomes Project Consortium and others, 2015). With an AMD 3900X processor. The multi-threaded implementations achieve a speed-up of 7x and 8.37x on Algorithms 3 and 4 respectively running with 12 threads. Results on the Human Reference Consortium data (McCarthy et al., 2016) are available in the Supplementary Materials (with a similar speed-up of 7.04x and 8.16x for 12 threads), as well as an example application that implements the matching algorithms and reports the results to a file to allow a direct comparison to the original software from Durbin (2014). The Supplementary Materials also provide a comparison between generating the a and d arrays sequentially with Algorithm 2 from Durbin (2014) against our parallel implementation with sequential correction (Algorithms 1 and 2) presented here (Sections A and B of Algorithm P) for different number of threads. Supplementary Figure SP5 shows that the parallel version followed by the sequential correction can provide a speed-up of up to 10.94x when generating the a and d arrays. Fig. 1. Runtime and speed-up of Algorithms 3 and 4 from Durbin (2014) and their parallel implementations running on a 12-core AMD 3900X processor (each run 10 times). Algorithm 3 reports all matches longer than 2000 genotypes (loci) between all haplotypes, Algorithm 4 reports the set maximal matches between all haplotypes. Data are chromosome 20 from (1000 Genomes Project Consortium and others, 2015) 5008 haplotypes, 1 822 268 genotype loci 4 Discussion In this article, we have presented a method and two algorithms that allow parallel execution of PBWT-based haplotype matching algorithms. The method allows to exploit modern multi-core processors and has shown a 7x-8.37x reduction in execution time with 12 threads compared to the single-threaded version. For PBWT-based compression, some methods break the per loci dependency by design for better random access performance (e.g. Wertenbroek et al., 2022). Therefore, these algorithms can be multi-threaded directly. However, compression methods that do not break this dependency (e.g. Deorowicz and Danek, 2019; Durbin, 2014; LeFaive et al., 2021; Li, 2016) could be accelerated by the presented methods. Beside these results, the a and d arrays could be saved to a file so that subsequent runs of the algorithms could be launched in parallel directly and now these arrays can be generated efficiently in parallel thanks to Algorithms 1 and 2 presented here, with up to a 10.94x reduction in time. Algorithm 2 also exhibits another interesting property: it provides the indices of groups of haplotypes that are identical over a large genomic chunk. This information could be leveraged to speed up PBWT-based methods, e.g. (Hofmeister et al., 2022), by treating the whole group as a single haplotype block and avoid redundant computations. Supplementary Material vbad021_Supplementary_Data Click here for additional data file. Acknowledgements The authors would like to thank Dr Simone Rubinacci for his insights. Funding This work was supported by the School of Engineering and Management Vaud (HEIG-VD). O.D. was supported by the Swiss National Science Foundation (SNSF), grant number [SNSF-PP00P3_176977]. Conflict of Interest: none declared. |
Plants (Basel) Plants (Basel) plants Plants 2223-7747 MDPI 10.3390/plants12051063 plants-12-01063 Editorial Advances in Forest Ecophysiology: Stress Response and Ecophysiological Indicators of Tree Vitality Potocic Nenad Croatian Forest Research Institute, Division of Forest Ecology, Cvjetno naselje 41, 10450 Jastrebarsko, Croatia; [email protected] 27 2 2023 3 2023 12 5 106303 2 2023 21 2 2023 22 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcBack in the beginning of the year 2021, when the work on this Special Issue started, it was quite clear that the topics of tree stress response and the ecophysiological indicators of tree vitality were both current and important, but the attitude of the scientific community towards the idea of a Special Issue on the subject was yet to be determined. Now that we are closing the first, and already preparing the second volume, I am very happy to definitely confirm your high interest. Air pollution and the changing climate are some of the greatest threats to the health and functioning of forest ecosystems, strongly jeopardizing their ecological and economic functions as well as services. The impact of increasing temperatures and extreme weather events (droughts, storms, temperature and precipitation extremes) on the vitality of forest trees is often difficult to separate from the impact of pollution, such as nitrogen deposition and tropospheric ozone, as they can exhibit synergistic effects. For example, forest soil acidification, atmospheric N deposition, and climate change are all partly responsible for the continuous decrease in foliar P concentrations in Europe, causing reduced tree growth . The use of indicators is elementary in modern forest ecophysiological research, as they help us to disentangle complex interactions between trees and various stress-inducing factors as well as better estimate the level of damage to trees and forest ecosystems. The initial Special Issue framework, as defined by the title and suggested topics of interest, has been broadened in the process thanks to your valuable submissions, adding terms such as heavy metals, carbon isotopes, water use efficiency, polyamines, antioxidants, or plant hormones to the list of subjects which already included photosynthetic activity and other biochemical stress indicators; nutrients in different tree compartments; tree growth; tree leaf loss and mortality; visible symptoms of stress in foliage; and microscopical markers of stress. All of these terms share one common trait: they have an important role in measuring and assessing tree stress in the context of the great ecological challenges of today. Eleven papers are included in this Special Issue, with wide-ranging topics from various disciplines but centered around tree response to environmental stress. In line with the current trends in environmental research, climate takes clear precedence over pollution, and as many as nine of the articles discuss climate effects; tree anatomy, growth, nutrition, foliar injury, the level of antioxidants, and defoliation are used as response variables. Three papers, by Levanic and Straus , Sensula and Wilczynski , and Popa et al. , discuss the effects of climate on tree growth, and the paper by Sensula and Wilczynski also includes the effects on water use efficiency and carbon isotopes' composition. Two papers, one by Ognjenovic et al. and another by Cesljar et al. , focus on climate effects on tree crown defoliation. While the first paper tests the differences between defoliation and defoliation change as long-term and short-term indicators, respectively, of tree vitality, the second paper discusses the links between crown defoliation and tree mortality. Defoliation is again featured in the paper by Ognjenovic et al. , where its effect on the nutritional response of beech trees to climate and stand factors is discussed. Soheili et al. investigate how cell anatomical structure is affected by drought stress. Nutrition, oxidative stress, and defoliation in four Mediterranean tree species are the focus of the paper by Lovreskov et al. , while Kebert et al. discuss species-level differences in osmoprotectants and antioxidants under water deficit and high temperatures. Despite the prevalence of interest in climate effects, pollution-oriented papers are not less exciting: tree responses to heavy-metal-induced stress are the subject of a paper by Kebert et al. , and the effects of ozone and drought on oak seedlings are discussed by Baesso Moura et al. . The latter paper also nicely underlines the fact that climate and pollution effects on trees, although often investigated separately, are in practice often related and intertwined. In conclusion, the task of this Special Issue is twofold: one, to remind us that a better understanding of the physiological processes influencing tree vitality under the changing climate and air pollution pressures requires considerable research efforts and constant advancements in research methods and approaches; two, to highlight the fact that the environmental pressures instigating the use of tree stress response indicators are more present than ever, and will likely continue to affect tree vitality in the foreseeable future. As the Guest Editor of this Special Issue, I would like to use the opportunity to thank all of the authors for their valuable submissions, their dedicated and hard work, and the continuous exchange of thoughts and ideas that form the backbone of current scientific research, pushing it ever further. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Jonard M. Furst A. Verstraeten A. Thimonier A. Timmermann V. Potocic N. Waldner P. Benham S. Hansen K. Merila P. Tree Mineral Nutrition Is Deteriorating in Europe Glob. Chang. Biol. 2015 21 418 430 10.1111/gcb.12657 24920268 2. Talkner U. Meiwes K.J. Potocic N. Seletkovic I. Cools N. De Vos B. Rautio P. Phosphorus Nutrition of Beech (Fagus sylvatica L.) Is Decreasing in Europe Ann. For. Sci. 2015 72 919 928 10.1007/s13595-015-0459-8 3. Levanic T. Straus H. Effects of Climate on Douglas-Fir (Pseudotsuga Menziesii (Mirb.) 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, Introduction, Results, Discussion, Materials and methods, and Figure legends sections), equivalent to approximately four pages of typed text. Line 72: "Myp2 plays a subtle non-essential role for cytokinesis during unperturbed growth." Note that Ref 14 shows that Myp2 contributes as much as Myo2 to contractile ring constriction. Agree. The sentence has been changed in the revised manuscript to read: "Myo2 is essential for viability and cytokinesis during unperturbed growth, whereas Myp2 plays a non-essential but important role during CAR constriction, and in response to salt stress [14-16]." Line 81: Consider a separate paragraph for the sentence "Remarkably, in response..." The modified version now includes a separate paragraph, as suggested by the reviewer. Line 96: What is the meaning of myo2 motility in "Myo2 motility is reduced in fission yeast cells expressing an rlc1-S35A S36A mutant version." This refers to a previous work by Matthew Lord's group (Reference number 31: Sladewski TE, et al. Mol Biol Cell. 2009;20(17):3941-52), which showed that the average rate of in vitro motility for purified Myo2 bound to the Rlc1-S35A S36A mutant is reduced by ~25% compared to that of Myo2 bound to Rlc1-S35D S36D or wild-type Rlc1. As the reviewer notes, this is not clearly described in the original manuscript, so new text has been added in the revised version to read: "However, another study described that the average in vitro motility rate of purified Myo2 bound to the Rlc1-S35A S36A mutant is reduced by ~25% compared to that of the myosin bound to wild-type Rlc1, and that phosphorylation at both sites is positive for CAR constriction dynamics ." Lines 124 and 141. Start new paragraphs. Two new paragraphs have been started in the revised manuscript as recommended. Line 158: "The cytokinetic delay was mainly observed during the stage of ring constriction and disassembly." Might Myo5 be covering for Myo2 during ring assembly as shown in Ref 14? In response to the possibility raised by the reviewer, we have investigated this. As shown in the new Figure 1 figure supplement 2 in the revised manuscript, we found that the delayed CAR assembly of myo51D cells was aggravated in the presence of an rlc1-S35A allele during growth with glycerol, suggesting that Myo51 cooperates with Myo2 in this process as proposed. The corresponding Results section in the revised manuscript now reads: "Myo51 is a type V myosin that plays an important role in S. pombe during ring assembly, as myo51 cells complete this process later than normal . Myo51 deletion further and specifically increased the CAR assembly time in rlc1-S35A cells during glycerol growth , suggesting that Myo51 cooperates with Myo2 in this process." Line 163: extra "with" at the end of the line. The extra "with" has been eliminated in the revised version. Line 186: "relative expression of Pak2 was always very low compared to Pak1 and could only be detected after long exposure times of immunoblots." How do you know that the low signal is due to low numbers of molecules or an insensitive antibody? Both possibilities are in our opinion highly unlikely since the Pak2-GFP fusion can be easily detected when expressed in glycerol-growing cells under the control of the Pak1 promoter instead of its own promoter . Thus, despite being de-repressed, Pak2 expression is low during respiration. Line 215: I would rephrase for clarity: "did not display defects in cytokinesis, septation or growth." Also, "the average times for CAR assembly and disassembly were longer in the Pak1-M460G pak2D double mutant cells." Both sentences have been rephrased in the revised manuscript as suggested. Line 257: "engrossed" is a poor choice of words. Engrossed means something else than intended. This is truly a poor choice of words. The term has been changed to "thickened" in the revised manuscript. Line 259: Is for3-DAD the same as For3(DAD)? Yes, it is the same allele, whereas For3(DAD)-2GFP refers to the protein fusion. The for3-DAD allele lacks the intra-molecular interaction between the autoregulatory (DAD) and inhibitory (DID) domains, and is therefore constitutively active (Martin SG,et al.. Mol Biol Cell. 2007;18(10):4155-67; reference 43 in the revised manuscript). To avoid confusion, for3-DAD has been used in the revised text. A short phrase in the main text explaining the mutated protein structure would avoid having to look up the reference. Text describing the main mutations in the constitutively active for3-DAD allele has been included in the revised manuscript as follows: "In contrast to wild-type cells , total levels of the constitutively active For3 allele for3-DAD fused to GFP, which lacks the intramolecular interaction between the autoregulatory (DAD) and inhibitory (DID) domains to adopt an open and constitutively active conformation , were not reduced upon Sty1 activation by glycerol ." Line 322: reword "this was accompanied by recovery of total For3 levels." This line has been rewritten with the whole paragraph in the revised manuscript by following the reviewer s advice in Major point 1 above. Line 873: I do not understand what you mean by "ring assembly and disassembly" vs. "ring constriction and disassembly." Why is disassembly included with assembly? Figure 3F has the same problem. Taking into account the reviewer's opinion, which is also shared by reviewer #1 (please see major point A above), the terms "CAR assembly and disassembly" have been changed to "CAR assembly and contraction" throughout the revised manuscript, including all the Figures and the corresponding Figure legends. Throughout: myosin, myo2 (gene), glucose and glycerol are not proper nouns. OK. They are now written in lowercase throughout the revised manuscript, including figures and figure legends. Reviewer #3 (Recommendations for the authors): To address the points of weakness, the authors may consider the following. (1) Use available phosphomimetic Rlc1 alleles (e.g., Sladewski et al., MBoC 2009) to provide orthogonal evidence for the authors' conclusions. Following the reviewer's suggestion, we have performed a series of new experiments with cells expressing a phosphomimetic a rlc1-S35D allele, as shown in Figure 1 of the original manuscript. These new experiments include quantifying CAR dynamics and ring constriction rates during growth on glucose (fermentation) and glycerol (respiration). As can be seen in the revised Figure 1C, and confirming previous observations with the rlc1-S35D S36D allele by Sladewsky et al., CAR dynamics and ring constriction rates were identical between wild-type and rlc1-S35D cells. Similarly, the phosphomimetic rlc1-S35D allele did not alter CAR dynamics and constriction rate during glycerol-growth, which were identical to those of wild-type cells . We have included explanatory text on this issue in several places within the Results section of the revised manuscript: "Cells expressing a dual phospho-mimicking form of Rlc1 (Rlc1-S35D S36D) exhibit normal CAR dynamics and support cytokinesis like wild-type cells . Similarly, CAR dynamics and ring constriction rates were identical between wild-type and Rlc1(S35D)-GFP cells ." "Strikingly, the unphosphorylated mutants rlc1-S35A and rlc1-S35A S36A, but not rlc1-S36A or the phosphomimetic versions rlc1-S35D and rlc1-S35D S36D, also grew very slowly in this medium ." "Conversely, expression of the phosphomimetic rlc1-S35D allele did not alter CAR dynamics and constriction rate when grown with glycerol ." (2) As far as I could tell, all data concerning the interplay between the two pathways (SAPK-For3 and PAK-Rlc1) are based on the rescue of the latter by expression of For3-DAD. In a simple scheme, this would put SAPK-For3 downstream of PAK-Rlc1; however, normal degradation of For3 in Rlc1-S35A cells rejects this model. I believe this point deserves to be emphasized in the manuscript. This leaves two other models: two independent pathways , or PAK1-Rlc1 being activated in response to reduced For3. These can be dissected by testing if For3-DAD expression suppresses Rlc1 phosphorylation. Following the reviewer's suggestion, we have used Phos-tag followed by Western blot analysis to explore whether Rlc1 in vivo phosphorylation at Ser35 is negatively affected by the for3-DAD allele. As shown in the new Figure 4 figure supplement 1E, Rlc1 Ser35 phosphorylation remained unchanged in cells expressing the for3-DAD allele compared to those expressing the wild-type allele, either during fermentation or respiration. As suggested, we have included a new paragraph in the Results section of the revised manuscript describing the epistatic relationships between the SAPK-For3 and PAK-Rlc1 pathways during respiratory control of fission yeast cytokinesis: "SAPK-For3 may act downstream of the PAK-Rlc1 cascade, as the cytokinesis and growth defects of rlc1-S35A and pak1-M460G pak2 mutants are suppressed by for3-DAD. However, normal For3 degradation of For3 during respiration in rlc1-S35A cells excludes this possibility. Moreover, for3-DAD expression did not reduce Rlc1 phosphorylation at Ser35 in the presence of glucose or glycerol , suggesting that Pak1/2-Rlc1 is not activated by changes in For3 levels. Thus, both the SAPK-For3 and PAK-Rlc1 pathways act independently and are critical for the successful completion of cytokinesis during respiration." (3) As stated in the above section, I strongly suggest that the effects of ROS and antioxidants in sty1 be examined. We could not analyze CAR dynamics or the effect of antioxidants in a sty1 background, because, unlike mutants lacking the upstream Wis1 (MAPK) or Wak1/Win1 (MAPKKs), sty1 and atf1 mutants (lacking the Sty1 downstream transcription factor Atf1) cannot grow on this carbon source (Reference 45: Zuin A et al. PLoS One. 2008;3(7):e2842). This phenotype is also shown in the new Figure 4 figure supplement 1C in the revised manuscript. The respiration-defective phenotype of sty1 cells suggests that Sty1 may acts as a scaffold for recruiting the transcriptional machinery during respiration, independently of its activation status, similar to Hog1, the MAPK ortholog in S. cerevisiae. In any case, wis1 cells show identical phenotypes to those of the sty1 mutant related to the negative control of For3 function, including the presence of thickened actin cables, increased actin cable-to-patch ratio during growth with glycerol . Most importantly, Wis1 deletion increased the actin cable to patch ratio in rlc1-S35A cells , suppressed their delayed cytokinesis and reduced constriction rate , multiseptation , and was able to restore cell growth in glycerol . All this evidence confirms that the downregulation of For3 during respiration is strictly dependent on Sty1 activation. We have included new explanatory text in the Results section of revised manuscript as follows: "In agreement with previous observations , For3 levels increased in glucose-grown wild-type or rlc1-S35A cells lacking Sty1 activity by deletion of Wis1, the only MAPKK of the SAPK , and also in the presence of glycerol . We could not analyze the cytokinetic and growth defects of rlc1-S35A cells during respiration in the absence of Sty1, because, unlike mutants lacking Wis1 or Wak1/Win1 (MAPKKs), sty1 and atf1 cells (lacking the Sty1 downstream transcription factor Atf1) are growth defective on this carbon source . Nevertheless, similar to the sty1 mutant , wis1 cells exhibited thickened actin cables and an increased actin cable-to-patch ratio during growth on glycerol . Furthermore, Wis1 deletion increased the actin -patch ratio in rlc1-S35A cells , suppressed their delayed cytokinesis and reduced constriction rate , multiseptation , and restored cell growth in glycerol ." In addition, the revised Figure 4A shows a simplified scheme to assist readers unfamiliar with the details of For3 down-regulation by the SAPK pathway. Finally, and as suggested by the reviewer, the revised Figures 6B and 6C now include quantitative data showing that, as expected, CAR dynamics and constriction rates for wis1 cells during respiration were not affected by the presence or absence of antioxidants (GSH). This is described in the Results section to read: "Remarkably, 0.16 mM of the antioxidant tripeptide reduced glutathione (GSH) in the growth medium counteracted many effects of oxidative stress in rlc1-S35A and myo2-E1 cells grown in glycerol. Changes included recovery of For3 levels , the cable-to-patch ratio , the timing of CAR assembly/contraction and constriction rate , septation and growth . Normal growth depended on For3 . In contrast, in wis1 cells GSH had no significant effect on the above-mentioned characteristics . Hence, respiration-induced oxidative stress reduces the nucleation of actin cables by formins and renders the execution of cytokinesis dependent on the phosphorylation of the Myo2 light chain Rlc1." No competing interests declared. No competing interests declared. Data curation, Software, Formal analysis, Investigation, Visualization, Methodology, Writing - review and editing. Resources, Formal analysis, Validation, Investigation, Methodology. Resources, Data curation, Formal analysis, Investigation, Methodology. Formal analysis, Investigation, Methodology. Resources, Formal analysis, Validation, Investigation, Methodology, Project administration, Writing - review and editing. Formal analysis, Investigation, Methodology. Data curation, Validation, Investigation, Methodology. Conceptualization, Resources, Supervision, Funding acquisition, Validation, Visualization, Writing - review and editing. Conceptualization, Data curation, Supervision, Validation, Investigation, Visualization, Writing - review and editing. Conceptualization, Supervision, Funding acquisition, Validation, Writing - original draft, Writing - review and editing. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34775 Cardiology Internal Medicine Epidemiology/Public Health A Study on Acute Myocardial Infarction and Its Prognostic Predictors Muacevic Alexander Adler John R Sathvik Manduri 1 Kalva Eswar Chand Satyendra Sai 1 Suma Gonji 2 1 Department of Internal Medicine, NRI Medical College and General Hospital, Guntur, IND 2 Department of Community Medicine, Katuri Medical College and Hospital, Guntur, IND Eswar Chand Satyendra Sai Kalva [email protected] 8 2 2023 2 2023 15 2 e347757 2 2023 Copyright (c) 2023, Sathvik et al. 2023 Sathvik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Introduction Acute Myocardial Infarction (AMI) is a serious cardiac event characterized by the sudden death of heart muscle tissue due to the obstruction of blood flow to the heart. It is a leading cause of death and disability worldwide. The relationship between AMI and serum uric acid levels is an area of ongoing research. Serum uric acid is a byproduct of purine metabolism and is typically present in the blood at low levels. Elevated levels of uric acid have been linked to several cardiovascular risk factors, including hypertension, diabetes, and hyperlipidemia. This has led to the investigation of the relationship between uric acid levels and AMI. Materials and Methods In this study, 100 individuals who were presented with acute myocardial infarction were included. All patients were categorized into four Killip's classes based on history, clinical examination, and lab investigation. Subsequently, the four Killip's classes were co-related with the serum uric acid of the patient. Results Serum uric acid levels were high in males compared to females. serum uric acid levels were high in Killip's class III (7.24) and IV (7.57) compared to class I (4.48) and II (5.26). There was no significant correlation between serum uric acid and the co-morbidities like diabetes and hypertension, with a p-value of 0.48. Conclusion An increase in Killip Class is positively correlated with an increase in blood uric acid levels. Uric acid can therefore be utilized as a prognostic indicator in individuals who present with myocardial infarction. nstemi stemi prognosis serum uric acid myocardial infarction killip's class The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Non-communicable diseases are becoming more significant since they have displaced infectious diseases as the leading cause of disability, morbidity, and premature mortality, demonstrating the epidemiological shift . In India, cardiovascular disease (CVD) is a silent epidemic, and the prevalence of heart diseases has increased fourfold during the past 40 years. The number of CVD patients increased dramatically from 271 million in 1990 to 523 million in 2019, as did mortality, which increased from 12.1 million in 1990 to 18.6 million in 2019 . Rapid urbanization and lifestyle modifications such as inactivity, an unwholesome diet, obesity, dyslipidemia, smoking, increased blood pressure, and diabetes has increased the prevalence of coronary heart disease during the past 20 years . In conclusion, acute coronary syndrome (ACS) is a kind of CVD, and cardiovascular disease (CVD) is an umbrella term that covers a variety of illnesses that affect the heart and blood vessels. The term "acute coronary syndrome" (ACS) refers to a variety of conditions. Acute Myocardial Infarction (AMI) can present as Non-ST Elevation Myocardial Infarction (NSTEMI), ST Elevation MI (STEMI), or unstable angina (UA) . Notably, all of these illnesses may have a similar clinical appearance and symptoms. In ACS, relieving or limiting ischemia, preventing reinfarction, and improving outcome and well-being are the main therapy objectives. AMI risk stratification is carried out using several clinical evaluations and scores; Killip's classification is one of them . Killip classified AMI patients into four groups to detect the severity of left ventricular dysfunction and predict mortality. Class I: No signs of LV failure Class II: Presence of S3 heart sound on auscultation and basal crepitation Class III: Pulmonary edema Class IV: Cardiogenic shock The predicted mortality rates for the four classes are 6%, 17%, 38%, and 81%, respectively . A significant risk factor and reliable predictor of cardiovascular illnesses is arterial stiffness . Age and other medical conditions exacerbate arterial stiffness, which indicates vascular flexibility and function. According to some studies, uric acid can cause vascular endothelial dysfunction by inducing oxidative stress and inhibiting endothelial nitric oxide synthase, as well as by encouraging the growth of vascular smooth muscle cells and amplifying the vasoconstrictive effects of angiotensin II, endothelin, and thromboxane, which lead to subclinical changes in arterial structure . Additionally, there is a strong relationship between uric acid and markers of arterial stiffness. Uric acid is a significant risk factor and predictor of cardiovascular events, such as acute myocardial infarction, atherosclerosis, and stroke . With this knowledge, this study aims to investigate the association between Killip's class and serum uric acid levels in acute myocardial infarction. Materials and methods A descriptive study was conducted in a tertiary care hospital in Guntur from April 2021 to September 2022 among 100 patients who were admitted to the emergency room with resting chest pain lasting more than 30 minutes after gaining ethics committee approval. Patients or their families were asked for their informed consent. Until a sample size of 100 was reached, a convenience sampling technique was utilized. Inclusion and exclusion criteria Patients with STEMI or NSTEMI with resting chest pain lasting more than 30 minutes, new ST/T changes or new left bundle branch block, or presence of pathological Q waves on ECG or ECHO showing regional wall motion abnormality and raised cardiac enzymes (CK-MB, troponins) more than 99th percentile for the upper reference value, were all included in the study. Patients with other illnesses and drugs which are known to raise SUA levels were excluded from the study. A semi-structured questionnaire was used to collect patients' socio-demographic details, presenting complaints, risk factors, and other pertinent clinical data. Blood pressure, random blood sugar, ECG or ECHO, chest X-ray, Killip's classification, and COBRA INTEGRA/COBAS C SYSTEM, which uses the uricase method to determine the quantity of uric acid in serum, were utilized as study tools. According to a study by Kuwabara M., the reference range for uric acid was 3 to 5 mg/dl in males and 2 to 4 mg/dl in females. Clinical examination, auscultatory findings for class II, chest X-ray findings for class III, and vital signs, clinical condition, and ECG of the patient for class IV were used to classify patients into Killip's classes. The pertinent data is subsequently entered into a Microsoft Excel master chart (Redmond, USA) and statistically assessed by IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. Results The 100 patients in the current study had either STEMI or NSTEMI, and their ages ranged from 53.76 +- 8.056. Sixty-five percent of the study subjects were males, and out of them, 52 were smokers. Additionally, a large majority of persons, 66% and 72% of them, respectively, have a history of hypertension and diabetes mellitus. The distribution of sociodemographic profiles and risk factors were shown in Table 1. Table 1 Distribution of socio-demographic profile, and risk factors among study subjects (n=100). Variables Percentage (%) Age in years 35-39 8.0 40-44 6.0 45-49 14.0 50-54 28.0 55-59 18.0 60-64 17.0 >65 9.0 Gender Male 65.0 Female 35.0 History of smoking 47.0 Smokers 53.0 Distribution of diabetes 34.0 Diabetics 66.0 Distribution of hypertension 30.0 Hypertensives 70.0 Out of the 100 individuals, 47% had anterior wall MI, 12% had anterior wall MI and lateral wall MI, 34% had inferior wall MI, and 7% had non-ST elevation MI (Table 2). Table 2 Distribution of types of AMI in the study population (n=100). AWMI: Anterior wall MI, LWMI: Lateral wall MI, IWMI: Inferior wall MI, NSTEMI: Non-ST elevation MI Region of the AMI Percentage (%) AWMI 47.0 AWMI/LWMI 12.0 IWMI 34.0 NSTEMI 7.0 Total 100.0 KILLIP classes I and II made up around 80% of the 100 patients in our study, whereas classes III and IV (20%) . Figure 1 Distribution of study population based on KILLIP'S class. Males have higher mean uric acid levels compared to females . Figure 2 Distribution of mean uric acid levels among males and females. In the present study, SUA levels were substantially higher in class IV and class III patients. By using the Kruskal-Wallis test, the mean variance was statistically significant (p=0.000), as shown in Table 3 and Figure 3. Table 3 Relationship between SUA levels and Killip class. Killip class SUA Mean Mean Rank P I 4.48 25.05 0.000 II 5.26 38.32 III 7.24 62.05 IV 7.57 64.32 Figure 3 Relationship between SUA levels and Killip class. By using the Kruskal-Wallis test, it was shown that there was no statistically significant correlation between mean SUA levels and the presence of diabetes or hypertension (p=0.484) (Table 4). Table 4 Association between SUA and hypertension and/or diabetics. Adjustable Mean SUA SD P-value and diabetes 5.545 1.547 0.484 Either diabetes or hypertension seen 5.029 1.3445 Don't have hypertension/diabetes 4.781 .4163 Total 5.223 1.418 Discussion In this study, blood uric acid levels in AMI were measured and correlated with Killip class among 100 study subjects. Our investigation showed that SUA levels are higher in Killip's classes III and IV, with a mean of 7.57 and 7.24, respectively. Similarly, a study by Nadkar MY et al. revealed that SUA levels were higher in classes III and IV compared to classes I and II. Another study by Bos MJ et al. showed that SUA is the strongest risk factor for AMI. To contradict these studies, a study by Chen L et al. stated that SUA levels were positively correlated with serum triglyceride levels but not with the severity of coronary artery disease. Whereas a study by Xue T et al. revealed that only a stable high level of SUA was associated with an increased risk of MI, while a change in SUA in any direction was not associated with the risk of MI. A study by Kojima S et al. stated that the combination of SUA and Killip's class is a good predictor of mortality in patients with MI. A study conducted by Maryam M et al. showed that patients with heart failure (the cases group), as compared to the control group, demonstrated a noticeably higher amount of uric acid. Additionally, individuals with STEMI had uric acid levels that were significantly greater than those with heart failure who did not have a STEMI. A study by Tsai TH showed that even in patients undergoing primary percutaneous coronary intervention, Killip III continues to be a highly and independently reliable predictor of 30-day and one-year death in ST-segment elevation myocardial infarction patients. According to our study and also stated by Taniguchi Y et al. , there was no significant relationship between hypertension and diabetes and SUA levels in our study. . To contradict this, many studies proved a positive relationship between diabetes and SUA . However, it was unclear why earlier research discovered a positive relationship between uric acid and diabetes. Limitations To find out the results of the interaction between SUA and Killip's class, we did not follow up with the patients. We conducted our study with 100 participants; a larger sample size could produce more conclusive results. Conclusions Based on the above findings, we conclude that the SUA levels are directly proportional to Killip's class. Therefore, the risk of mortality due to AMI increases as uric acid levels rise. So, we can use serum uric acid levels as a predictor of cardiovascular disease. Human Ethics Animal Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. Institutional Ethics Committe, NRI Medical Collage and General Hospital issued approval IEC/NRIMC/277. The Institutional Ethics Committee, NRIMC has reviewed and discussed your protocol on 12/04/2021 to conduct the Research Project entitled A STUDY ON ACUTE MYOCARDIAL INFARCTION AND ITS PROGNOSTIC PREDICTORS. After consideration, the committee has decided to approve the study under the protocol the following condition * It is understood that the study is being conducted at NRI Medical College & General Hospital Guntur * Any serious adverse event that occurs during the conduct of the study at NRI Medical College & General Hospital, Guntur should be reported to the Ethics Committee immediately * The Study will be conducted after informed consent from patient/guardian Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. 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J Am Acad Orthop Surg Glob Res Rev J Am Acad Orthop Surg Glob Res Rev JAAOS Glob Res Rev JAAOS Glob Res Rev JAAOS Global Research & Reviews 2474-7661 Wolters Kluwer Philadelphia, PA 36893168 JAAOSGlobal-D-22-00156 10.5435/JAAOSGlobal-D-22-00156 00006 3 Case Report Parsonage-Turner Syndrome After COVID-19 Vaccination in a Child Cassart Elisa Masnou MD, PhD Vilas Dolores Rolan MD, PhD Abe Ryo PT Cavanilles-Walker J. M. MD, PhD, FEBOT From the Department of Orthopaedic Surgery and Traumatology. Hospital Germans Trias i Pujol, Badalona (Dr. Cassart, and Dr. Cavanilles-Walker); the Neurology Service, Department of Neuroscience, Hospital Germans Trias i Pujol, Badalona (Dr. Vilas); and the Centro de Rehabilitacion Funcional Montigala, Badalona, Barcelona, Spain (Abe). Correspondence to Dr. Cassart: [email protected] 3 2023 09 3 2023 7 3 e22.0015601 6 2022 23 1 2023 28 1 2023 Copyright (c) 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons. 2023 American Academy of Orthopaedic Surgeons This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Parsonage-Turner syndrome (PTS) is a peripheral neuropathy involving the brachial plexus very rare in childhood. To date, no cases of PTS after COVID-19 vaccination have been reported in children. We report a case of a 15-year-old boy affected by PTS after the second dose of the BNT162b2 (Comirnaty, Pfizer-BioNTech) COVID-19 vaccine. OPEN-ACCESSTRUE pmcParsonage-Turner syndrome (PTS) is a rare peripheral neuropathy involving the brachial plexus characterized by sudden onset pain affecting the upper extremity associated with muscle weakness. With an estimated incidence of 1.64 cases per 100,000 people,1 PTS usually develops in people aged between 20 and 60 years, being very rare in children. The diagnosis is based on clinical history, physical examination, electrophysiological study, and exclusion of other pathologies. The clinical picture of PTS is very diverse because a large variety of nerves can be affected. Muscle paresis commonly manifests as scapula alata, secondary to paresis of the muscles involved in scapular fixation.2 Pain is the first symptom in 90% of patients, being the location of pain variable, but in most cases radiated from the cervical spine or shoulder region into the arm.1 Electrodiagnostic testing is widely used to diagnose PTS. Abnormal sensory potentials, lack of denervation potentials, and abnormal conduction velocities are the most frequent findings. The etiology and pathophysiology of PTS still remain unclear.3 Recent viral infections, such as herpes simplex virus, Epstein-Barr virus, cytomegalovirus, HIV, hepatitis B virus, and parvovirus B19 infections, have been reported as the probable trigger in 25% of patients with PTS.4-6 Vaccination has been described to precede PTS in 4.3% to 15.5% of cases.1,5 To date, only a few cases of PTS after COVID-19 vaccination have been reported, none of them in the childhood.7-15 In this study, we report a case of a child affected by PTS after the second dose of COVID-19 vaccination. Case A 15-year-old boy presented to the clinic because of acute pain and functional impotence in his left shoulder that started 1 week before. Physical examination revealed reduced range of motion for shoulder flexion and abduction because of weakness and pain. He had full flexion and extension of the wrist and fingers as well as hand interosseous muscles. Four weeks earlier, he had received the second dose of the BNT162b2 (Comirnaty, Pfizer-BioNTech) coronavirus disease (COVID-19) vaccine. Since the administration of the first dose, 3 weeks before the second one, he suffered from hypoesthesia in his left shoulder. His medical history was normal. No previous vaccine reactions were recorded. The pain was partially controlled after placing the arm in a sling together with oral nonsteroid anti-inflammatory drugs. After 2 weeks of treatment, the pain improved, but severe paresis in the left shoulder, mainly in the elevation and abduction involving the deltoid, and also in the infraspinatus muscle, along with hypoesthesia in the lateral aspect of the shoulder, after the distribution of the axillary nerve, still persisted. Cervical spine and left shoulder MRI performed 2 weeks after the onset of symptoms were normal. The electrophysiological study, performed 4 weeks after the onset of symptoms, showed a severe axonal loss of the left axillar nerve with fibrillation and positive spontaneous waves in the deltoid muscle, suggesting a severe acute denervation. The clinical features, the recent vaccination, and the electrophysiological findings lead us to the diagnosis of a PTS. The patient began an intensive rehabilitation program, 1 hour every day, consistent in ultrasonography and electrical stimulation therapy for 20 minutes, along with passive range of movement and active exercises. At the beginning, passive scapular mobilization and pectoralis stretching as well as isometric lower trapezius and external rotation were done. Progressively, shoulder elevation with pulley and active scapular recentering were introduced. Finally, eccentric exercise proprioception and strength exercises with rubber bands were implemented. After 6 months, the patient recovered a full shoulder range of movement but still was showing persistent atrophy in the anterior deltoid muscle and partial weakness of the deltoid 4+/5, infraspinatus 3+/5, and supraspinatus 4/5, with persistent hypoesthesia in the lateral aspect of the upper arm. A new electrophysiological study revealed a slight spontaneous electrical activity with polyphasic elements, along with focal axonal loss in the deltoid muscle. The presence of abundant polyphasic elements of reinnervation stood out. The neurography of the left suprascapular and axillary nerves exhibited severely altered responses in the left axillary nerve with focal and axonal blockade. At the 1-year follow-up, the patient recovered full range of motion and strength as well as axillary nerve sensitivity. Discussion In this study, we report the first case of a child-onset PTS after COVID-19 vaccination. Although the etiology of PTS is still unclear, an immune-mediated inflammatory reaction against the affected nerve in genetically predisposed patients triggered by multiple factors has been suggested. SARS-CoV-2 infection has been described as a possible initiating event for PTS.16-21 Regarding vaccination as a possible initiating factor, PTS has been linked most recurrently to the administration of tetanus, human papilloma virus, influenza, and encephalitis vaccines.1,4,5 In children, it has also been described after immunization for diphtheria, tetanus, and pertussis.5 To date, few cases have been described after COVID-19 vaccination,7-15 none of them in the children. The time from vaccination until the onset of PTS symptoms has been described around 28 days.22 Specifically, after COVID-19 vaccination, it has been reported to be between 13 hours and 8 weeks.10,13 Our patient reported the onset of symptoms 4 weeks after vaccine administration suggesting a correlation between PTS and the vaccine administration in the absence of other related factors. The diagnosis of PTS is mainly based on the clinical presentation and the electrophysiological findings. A rapid onset of severe pain in the shoulder and arm, followed by weakness of the muscles in the affected areas should make us to suspect this entity. Neurophysiologic studies are the best modality to confirm the diagnosis. Abnormal sensory potentials, lack of denervation potentials, and abnormal conduction velocities are the most frequent findings. In general, neurophysiologic studies should be done 2 to 3 weeks after the onset of symptoms because there is no degenerative action potential in the acute stage. In our case, although different shoulder muscles were paretic, we could only observe EMG abnormalities in the axillar nerve. This could be explained, at least partly, because the deltoid muscle was the most affected one. In addition, other possible pathologies which could explained the clinical picture of our patient, such as cervical spine radiculopathy or entrapment neuropathy, were ruled out. The MRI could be useful to rule out other etiologies and to depict the sequelae of skeletal muscle denervation. Intramuscular edema usually appears after a few weeks, and in advanced stages, muscle atrophy and fatty infiltration might be seen. The current treatment recommendations for PTS include a combination of analgesics, nonsteroid anti-inflammatory drugs, corticosteroids, and anticonvulsants. Physical therapy must be done early to achieve better final functional results.1,23 About 70% of adult patients may present residual paresis,1 while 63% of children achieve full recovery.23 Other post vaccine-related inflammatory responses apart from PTS are well known. Shoulder injury related to vaccine administration (SIRVA) is a recognized complication presenting with significant shoulder pain and stiffness. It is thought to occur because of improper administration of the vaccine into the subdeltoid bursa or shoulder joint leading to an inflammatory cascade leading to conditions such as adhesive capsulitis, subacromial bursitis, rotator cuff tendinitis or tears, or even subcortical bone osteitis.4 Although it has been reported more frequently with influenza tetanus, pneumococcus, and papillomavirus vaccinations, the first case of SIRVA after COVID-19 vaccination was reported in April 2021 by Cantarelli et al.24 Although our patient initially had pain, the fact that the symptoms progressed in the form of painless paresis along with the absence of remarkable findings around the shoulder on the MRI makes it possible for us to reasonably rule out SIRVA. Although the exact cause of PTS is still unknown and is not possible to establish a causative connection between this case of PTS and the administration of the COVID-19 vaccine, the close association between the two events in the absence of other potential causes makes our diagnosis feasible. A total of 11000.3 million vaccine doses have been administrated in the world by April 1, 2022, with more than 58% of the world population fully vaccinated.25 Considering these data, additional cases of PTS after COVID-19 vaccination are to be expected in the near future calling attention on its early diagnosis, which is essential for a suitable management and prognosis. None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Cassart, Dr. Vilas, Dr. Cavanilles-Walker, and Abe. References 1. van Alfen N van Engelen BGM : The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 2006;129 :438-450.16371410 2. Gstoettner C Mayer JA Rassam S : Neuralgic amyotrophy: A paradigm shift in diagnosis and treatment. J Neurol Neurosurg Psychiatry 2020;91 :879-888.32487526 3. van Eijk JJJ Groothuis JT van Alfen N : Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment. Muscle Nerve 2016;53 :337-350.26662794 4. Shaikh MF Baqai TJ Tahir H : Acute brachial neuritis following influenza vaccination. BMJ Case Rep 2012;2012 :bcr2012007673. 5. Hamati-Haddad A Fenichel GM : Brachial neuritis following routine childhood immunization for diphtheria, tetanus, and pertussis (DTP): Report of two cases and review of the literature. Pediatrics 1997;99 :602-603.9093307 6. Scanvion Q Perez T Cassim F : Neuralgic amyotrophy triggered by hepatitis E virus: A particular phenotype. J Neurol 2017;264 :770-780.28247042 7. Mahajan S Zhang F Mahajan A Zimnowodzki S : Parsonage Turner syndrome after COVID-19 vaccination. Muscle Nerve 2021;64 :e1-e4.33851437 8. Diaz-Segarra N Edmond A Gilbert C Mckay O Kloepping C Yonclas P : Painless idiopathic neuralgic amyotrophy after COVID-19 vaccination: A case report. PM R 2021;14 :889-891.33886164 9. Crespo Burillo JA Loriente Martinez C Garcia Arguedas C Mora Pueyo FJ : Amyotrophic neuralgia secondary to Vaxzevria (AstraZeneca) COVID-19 vaccine. Neurologia (Engl Ed) 2021;36 :571-572.34330677 10. Queler SC Towbin AJ Milani C Whang J Sneag DB : Parsonage-Turner syndrome following COVID-19 vaccination: MR neurography. Radiology 2022;302 :84-87.34402669 11. Vitturi BK Grandis M Beltramini S : Parsonage-Turner syndrome following coronavirus disease 2019 immunization with ChAdOx1-S vaccine: A case report and review of the literature. J Med Case Rep 2021;15 :589.34903275 12. Flikkema K Brossy K : Parsonage-Turner syndrome after COVID-19 vaccination: A case report. JBJS Case Connect 2021;11 :e21.00577. 13. Shields LBE Iyer VG Zhang YP Burger JT Shields CB : Parsonage-Turner syndrome following COVID-19 vaccination: Clinical and electromyographic findings in 6 patients. Case Rep Neurol 2022;14 :58-67.35350287 14. Min YG Kim JE Hwang JY Shin JY Sung JJ Hong YH : Parsonage-Turner syndrome following COVID-19 vaccination. J Neurol Neurosurg Psychiatry 2022;93 :1231-1232.35387865 15. Koh JS Goh Y Tan BYQ : Neuralgic amyotrophy following COVID-19 mRNA vaccination. QJM 2021;114 :503-505.34347105 16. Voss TG Stewart CM : Parsonage-Turner syndrome after COVID-19 infection. JSES Rev Rep Tech 2022;2 :182-185.35039808 17. Cabrera Pivaral CE Rincon Sanchez AR Davalos Rodriguez NO Ramirez Garcia SA : Parsonage Turner syndrome associated with COVID-19: About two family cases. Neurologia (Engl Ed) 2023;38 :59-60.36462623 18. Zazzara MB Modoni A Bizzarro A : COVID-19 atypical parsonage-turner syndrome: A case report. BMC Neurol 2022;22 :96.35296278 19. Fortanier E le Corroller T Hocquart M Delmont E Attarian S : Shoulder palsy following SARS-CoV-2 infection: Two cases of typical parsonage-turner syndrome. Eur J Neurol 2022;29 :2548-2550.35429214 20. Mitry MA Collins LK Kazam JJ Kaicker S Kovanlikaya A : Parsonage-turner syndrome associated with SARS-CoV2 (COVID-19) infection. Clin Imaging 2021;72 :8-10.33190028 21. Finsterer J Scorza FA Vandendries C Seror P : SARS-CoV-2 or SARS-CoV-2 vaccination associated parsonage-turner syndrome. Comment on: "Neuralgic amyotrophy and COVID-19 infection: 2 cases of spinal accessory nerve palsy" by coll et al. Joint Bone Spine 2021;88:105196. Joint Bone Spine 2021;88 :105239.34139321 22. Tsairis P Dyck PJ Mulder DW : Natural history of brachial plexus neuropathy. Report on 99 patients. Arch Neurol 1972;27 :109-117.4339239 23. Host C Skov L : Idiopathic neuralgic amyotrophy in children. Case report, 4 year follow up and review of the literature. Eur J Paediatric Neurol 2010;14 :467-473. 24. Cantarelli Rodrigues T Hidalgo PF Skaf AY Serfaty A : Subacromial-subdeltoid bursitis following COVID-19 vaccination: A case of shoulder injury related to vaccine administration (SIRVA). Skeletal Radiol 2021;50 :2293-2297.33944967 25. Our World in Data: Coronavirus (Covid 19) Vaccinations. http//ourworldindata.org/covid-vaccinations. Accessed April 1, 2022. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34777 General Surgery Oncology Post-esophagectomy Anastomosis Leak: A 10-Year Experience at a Specialized Center for Cancer Surgeries in Pakistan Muacevic Alexander Adler John R Shafiq Ahsan 1 Azad Junaid 1 Batool Shan-e-Zahra 1 Butt Usman Ismat 2 Umar Muhammad 2 Syed Aamir 1 Khattak Shahid 1 1 Surgical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK 2 Surgery, Services Hospital Lahore, Lahore, PAK Ahsan Shafiq [email protected] 8 2 2023 2 2023 15 2 e347772 2 2023 Copyright (c) 2023, Shafiq et al. 2023 Shafiq et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Esophageal cancer has been reported to be the seventh most common cancer and the sixth most common cause of mortality. Use of advanced diagnostic techniques has increased the detection of preoperative metastases and resulted in better patient selection for further management by curative surgery. We carried out a study to evaluate the outcome of esophagectomy at our institute in terms of acute leak, mortality and hospital stay. We also looked at various preoperative, intraoperative and postoperative risk factors contributing to leak after esophagectomy. We evaluated 589 patients during the period from January 2009 to December 2019. All these patients underwent elective esophagectomy for esophageal cancer at our hospital. Out of these, leak was seen in 30 patients (5.1%). We found no statistically significant difference when evaluating patient and tumour characteristics of patients who developed leak against those who did not. We also didn't find any significant difference in intraoperative or postoperative factors between the two groups. Proper preoperative evaluation and optimization are necessary to overcome various patient co-morbidities. On the basis of our study we conclude that when performed in high-volume centers with an adequately trained multi-disciplinary team approach, esophagectomy for carcinoma has a good outcome. oesophageal cancer specialized-services cancer transthoracic esophagectomy the: transhiatal esophagectomy The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Esophageal cancer has been reported to be the seventh most common cancer. It is reported to be the sixth most common cause of mortality . Risk factors for esophageal carcinoma include gastroesophageal reflux disease (GERD), smoking, achalasia, obesity, infection by virus, poverty, and genetic factors . Use of advanced diagnostic techniques has increased the detection of preoperative metastases and therefore resulted in better patient selection for further management by curative management. Other developments in endoscopic field have also advanced not only diagnostic but therapeutic capabilities as well. Advances in surgical technique and intensive care have resulted in improvement in survival in resectable cases . The reported morbidity of esophagectomy despite improvements is still reported to be as high as 30%. However five-year survival of these patients is only 20% . The main surgical treatment option for resectable esophageal cancer is esophagectomy. It is a complex undertaking having considerable morbidity and mortality. The incidence of esophageal cancer is increasing worldwide. Despite multidisciplinary care and improvements in treatment modalities, the outcome remains poor. Neoadjuvant chemoradiation prior to surgical resection is the current approach. It has resulted in improved survival in patients with early disease. Different approaches are used to perform this procedure. Trans-hiatal, Ivor Lewis and McKeown are types of primary open surgery. Minimal access laparoscopy and thoracoscopic approach are also used while lymphadenectomy may be one-, two-, or three-field depending upon the nature of the disease. Because of the invasiveness of the procedure it is associated with many complications which result in reduction of survival . In this study we have evaluated the outcome of esophagectomy at our institute in terms of acute leak, mortality and hospital stay which were carried out over a 10-year period from January 2009 to December 2019. We also looked at various preoperative, intraoperative and postoperative risk factors contributing to leak after esophagectomy. Materials and methods We included patients who underwent esophagectomy at Shaukat Khanum Memorial Cancer Hospital (IRB approval ex-11-01-23-01). Cases carried out between January 2009 and December 2019 were reviewed. American Joint Committee on Cancer (AJCC) 8th edition classification was used to stage the patients. A multi-disciplinary team meeting was done to discuss management of all patients. Neoadjuvant chemo-radiotherapy was done for patients having locally advanced disease (patients with T3 or above and/or N1 disease). External beam radiation between 45 and 55Gy with cisplatin and 5FU for given to patients as part of neoadjuvant therapy. Four weeks after the completion of the neoadjuvant, restaging scan was done. Patients found to have resectable disease then underwent elective esophagectomy. Intraoperative and postoperative records were maintained on a computerized data system. All relevant data were recorded and 90-day mortality was noted. For gastroesophageal junction tumours, esophagectomy was performed via a transhiatal approach while for mid/lower esophageal tumours a transthoracic approach (three-stage or Ivor Lewis esophagectomy) approach was used. During surgery, the tumour and its adjacent lymph nodes were removed en bloc. We noted the age of the patient, their gender, endoscopic level of tumor, differentiation of tumor, type of tumor, tumor T and N stage and operative approach used. We made use of SPSS(r) version 22.0 for WindowsTM (IBM Corp., Armonk, NY, USA) for data analysis. Frequencies and percentages were used for description of categorical variables. Quantitative variables were described as median with range. To compare categorical data chi-square test was used for binominal variables and one-way analysis of variance for tri and tetra nominal variables. A value of p less than 0.05 was taken as significant. Results We evaluated patients undergoing esophagectomy during the period from January 2009 to December 2019. All these patients underwent elective esophagectomy for esophageal cancer at our hospital. Out of these, leak was seen in 30 (5.1%). We found no statistically significant difference when evaluating patient and tumour characteristics of patients who developed leak or not. We also didn't find any significant difference in intraoperative or postoperative factors between the two groups (Table 1). Table 1 Baseline patient and tumour characteristics Variable Leak= yes Leak = no Gender Male 18 311 0.640 Female 12 248 Type of cancer Squamous cell carcinoma 24 442 0.944 Adeno carcinoma 5 109 Other 1 8 Site of cancer Upper 0 11 0.499 Mid 5 109 Lower 25 439 Tumour stage T1 0 30 0.519 T2 1 459 T3 26 25 T4 3 45 Node stage N0 6 176 0.126 N1 18 314 N2 6 69 Neoadjuvant therapy Yes 30 535 0.247 No 0 24 Type of surgery 3 stage 23 360 0.254 2 stage 1 173 Trans Hiatal 6 26 Pre-operative Haemoglobin Less than 10 g / dl 1 49 0.299 More than 10 g / dl 29 510 Intra-operative pressor Yes 8 101 0.232 No 22 458 intra-operative Bleeding Less than 250 ml 29 478 0.086 More than 250 ml 1 81 90 day mortality Yes 4 10 0.0038 No 26 549 The average age of patients undergoing surgery at our hospital was 49.53 years (SD+-11.029 years). A little more than half (55.9%) of the patients were male. Tumours of the lower esophagus were the most commonly seen (77.9%). The most common type was however squamous cell carcinoma (79.1%). The most commonly performed surgery at our set up was three-stage esophagectomy (65%). The average hospital stay was 13.82+-5.45 days. Our 90-day mortality was 2.4%. Of the 30 patients who developed postoperative leak all were explored. Almost half the patients underwent re-anastomosis (Table 2). There were four mortalities in the patients who developed leak. Table 2 Breakdown of post leak intervention and mortality by type of procedure done Intervention Number of cases Mortalities Exploration and re-anastomosis 14 3 Exploration and drainage 16 1 Total 30 4 Discussion In this retrospective study of patients undergoing esophagectomy at our institute from January 2009 to December 2019, 30 patients developed postoperative leak (5.1%). These patients were analyzed and compared to evaluate the potential risk factors. Incidence of leakage reported in our study is similar to that reported in international literature. Famiglietti et al. in their article published in 2020 have quoted rates of anastomotic leak ranging from 2-17% . The purpose of our study was to evaluate the data of our patients who had undergone surgery for esophageal carcinoma to evaluate postoperative mortality and evaluate various factors influencing the outcome in these patients. We evaluated various patient-, surgery-related factors influencing the outcomes. We analyzed the probable risk factors of patients developing leak post esophagectomy. However our results failed to show any statistically significant correlation between leak and factors (Table 1). Acute leak is one of the commonest and most dreaded complications faced after esophagectomy. A number of researchers have worked to identify factors associated with increased risk of leak. A number of factors have been thought to be associated with this risk including patient and surgery related such as history of smoking, adverse pulmonary or cardiac events, three-stage approach, advance tumour stage and nutritional status. It has been documented that leak is associated with worse outcome including increased postoperative mortality, longer need to keep patient nil per oral, and longer hospital and ICU stays . In our study we found that patient-associated or tumour-associated characteristics such as gender, TNM stage, type of tumour or site of tumour had no co-relation with postoperative outcome. Gockel in his risk analysis noted that only site of tumour was significantly related to postoperative morbidity while none of the other preoperative patient or tumor characteristics had any significant correlation . The number of leaks that were seen were more in transthoracic three-stage esophagectomy as compared to transhiatal dissection but this difference was not found to be statistically significant. Schroder in his review found no significant difference in outcome when comparing types of surgeries . Similarly, no significant correlation was seen in patients receiving neoadjuvant therapy as compared to those for whom upfront surgery was performed . When we evaluated for the difference between cases using the blood lost during the procedure (keeping a value of 250ml) we found no statistical difference between the two groups. Boshier et al., in a systematic review and meta-analysis, showed that perioperative blood transfusion was associated with significantly worse long-term survival in esophageal cancer patients undergoing esophagectomy . However our study failed to show similar findings. Similarly, intraoperative pressor use also had no significant effect on the postoperative risk of leak. Walsh et al. in their cohort study showed that intraoperative vasopressor use was not significantly associated with increased odds of postoperative anastomotic leak following open Ivor Lewis esophagectomy . Our results however showed that developing leak was significantly related to 90-day mortality. Fabbi et al. in a review of articles from 1995 to 2019 noted that leakage was associated with significant morbidity and mortality . Our study has a number of limitations. First, our study is a single-center study. Although our center is a specialized center for management of cancer patients, the patients presenting to our center are limited and not representative of the whole population. Second, we evaluated a limited number of variables. Perhaps a more elaborated study might yield some clinically significant relations. Conclusions On the basis of our study we conclude that when performed in high-volume centers with an adequately trained multi-disciplinary team approach, esophagectomy for carcinoma has a good outcome in terms of postoperative leakage. Proper preoperative evaluation and optimization are necessary to overcome various patient co-morbidities. Human Ethics Animal Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. Shaukat Khanum Memorial Cancer Hospital and Research Centre Institutional Review Board issued approval ex-11-01-23-01 Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. References 1 Global burden, risk factors, and trends of esophageal cancer: an analysis of cancer registries from 48 countries Cancers (Basel) Huang J Koulaouzidis A Marlicz W 13 2021 2 Etiology and prevention of esophageal cancer Gastrointest Tumors Yang CS Chen X Tu S 3 16 3 2016 27722152 3 Recent advances in treating oesophageal cancer F1000Res Harada K Rogers JE Iwatsuki M Yamashita K Baba H Ajani JA 9 2020 4 Prognostic factors and survival analysis in esophageal carcinoma Arq Bras Cir Dig Tustumi F Kimura CM Takeda FR Uema RH Salum RA Ribeiro-Junior U Cecconello I 138 141 29 2016 27759773 5 Surgical treatment of esophageal cancer in the era of multimodality management Ann N Y Acad Sci Borggreve AS Kingma BF Domrachev SA 192 209 1434 2018 29761863 6 Management of anastomotic leaks after esophagectomy and gastric pull-up J Thorac Dis Famiglietti A Lazar JF Henderson H 1022 1030 12 2020 32274171 7 Morbidity and mortality after esophagectomy for esophageal carcinoma: a risk analysis World J Surg Oncol Gockel I Exner C Junginger T 37 3 2005 15969746 8 Comparative outcomes of transthoracic versus transhiatal esophagectomy Surgery Takahashi C Shridhar R Huston J Blinn P Maramara T Meredith K 263 270 170 2021 33894983 9 Surgery and adjuvant therapy after esophagectomy Ann Esophagus Matsuda S Kawakubo H Mayanagi S Irino T Kitagawa Y 17 4 2021 10 Effect of perioperative blood transfusion on the long-term survival of patients undergoing esophagectomy for esophageal cancer: a systematic review and meta-analysis Dis Esophagus Boshier PR Ziff C Adam ME Fehervari M Markar SR Hanna GB 31 2018 11 Use of vasopressors during esophagectomy is not associated with increased risk of anastomotic leak Dis Esophagus Walsh KJ Zhang H Tan KS 34 2021 12 Anastomotic leakage after esophagectomy for esophageal cancer: definitions, diagnostics, and treatment Dis Esophagus Fabbi M Hagens ER van Berge Henegouwen MI Gisbertz SS 34 2021 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34757 Emergency Medicine Internal Medicine Hematology A Case of Acute Intermittent Porphyria Leading to Severe Disability in a Young 21-Year-Old Female Muacevic Alexander Adler John R Ramzan Adil 12 Cao Jenny Jia Ling 3 Frazer John S 4 Stein Penelope 5 Ahmad Shakeel 6 1 Stroke Medicine, Whipps Cross Hospital, London, GBR 2 Endocrinology and Diabetes, Peterborough City Hospital, Peterborough, GBR 3 Cardiac Care Unit, Peterborough City Hospital, Peterborough, GBR 4 Intensive Care Unit, Peterborough City Hospital, Peterborough, GBR 5 Hematology, King's College Hospital NHS Foundation Trust, London, GBR 6 Acute/Internal Medicine, Peterborough City Hospital, Peterborough, GBR Adil Ramzan [email protected] 8 2 2023 2 2023 15 2 e347577 2 2023 Copyright (c) 2023, Ramzan et al. 2023 Ramzan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Acute intermittent porphyria (AIP) is a rare metabolic disorder that is challenging to diagnose and treat. Symptoms are nonspecific and severe acute attacks may be life-threatening. This is a case of a previously healthy 21-year-old woman diagnosed with an acute attack of AIP following recurrent hospitalizations with undiagnosed abdominal pain over a 12-month period with gradual onset of motor neuropathy which resulted in complete paralysis and respiratory failure. Through our case, we will highlight the challenges in AIP diagnosis and management, its potential severity, and how an early diagnosis could have prevented severe disability. porphyria and disability aip delay in diagnoses and disability aip and disability aip acute intermittent porphyria The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Heme binds to four globin chains to form hemoglobin, an important component of red blood cells. Heme is derived from porphyrins and several enzymes play a key role in the synthesis of heme . If any of the enzymes is defective the precursors start to accumulate and result in an acute attack . The type of porphyria depends on the type of affected enzyme. There are several types of porphyria, including acute intermittent porphyria (AIP), hereditary coproporphyria, variegate porphyria, and aminolevulinic acid dehydratase deficiency (ALAD) porphyria. In addition to these types, porphyria cutanea tarda is the most common type of cutaneous porphyria. Cutaneous porphyrias, variegate porphyria, and ALAD porphyria present with blistering and scarring of the skin in addition to the other symptoms. Porphyria symptoms are nonspecific and severe acute attacks may be life-threatening. AIP is the most common type of all porphyrias and is caused by an autosomal dominant variant in the gene coding for hydroxymethylbilane synthase (HMBS), also known as porphobilinogen synthase (PBG synthase), a key enzyme in heme synthesis. The consequent build-up of toxic heme precursors, especially alpha-aminolevulinic acid (ALA) and PBG, clinically manifests in a wide spectrum of neurovisceral signs and symptoms due to their toxic effects on nerve fibers. Delays in recognizing and treating attacks may lead to serious complications including predominantly motor axonal neuropathy, seizures, psychosis, or hyponatremia . Due to the rarity and non-specific presentation of this condition, diagnoses can be challenging. This case illustrates a young lady who was previously well and had no co-morbidities and presented to hospitals recurrently with abdominal pain. She was seen in two different hospitals which added to the time to diagnosis. This case also demonstrates how severe AIP can be if treatment is delayed. With the help of this case, it is highlighted how important it is to keep this condition in mind in young patients especially females, with unexplainable severe abdominal pain as there is a risk of severe disability. Case presentation A 21-year-old woman presented with a one-week history of severe, constant abdominal pain with dysuria. She was evaluated at the emergency department of her local hospital eight times over the previous 12 months with abdominal pain. In addition, she was also admitted to a different hospital where she had specialized scans, including computed tomography (CT) abdomen and pelvis, which were normal. Previous blood tests, including complete blood count, C-reactive protein, liver and renal function tests, and electrolytes, were all unremarkable. Physical examination and routine blood tests including C-reactive protein, full blood count, electrolytes, liver, and renal function tests were consistently unremarkable. She also underwent esophagogastroduodenoscopy , which showed gastritis. She was discharged with analgesics, a proton pump inhibitor, and sometimes antibiotics including nitrofurantoin for urinary tract infections (UTIs). Her social history was significant for smoking and cannabis use. She had been referred to the mental health team for a possible eating disorder, having had reduced oral intake for the past six months, weight loss of 10kg in two months with a body mass index (BMI) of only 14.5. Figure 1 Oesophagogastroduodenoscopy The figure shows gastritis. There is no evidence of peptic ulcer disease as a cause of her recurrent abdominal pain. Two months before the hospital admission, which led to the diagnosis, she developed upper and lower limb weakness with recurrent falls leading to bruising of upper and lower limbs. Her family history was negative, as well as her past medical history. She was tachycardic on initial observations and hypertensive during her hospital stay. Her abdomen was soft and non-tender. She had weakness in the right upper arm, consistent with motor neuropathy, she had decreased strength against resistance in the right arm. There was no sensory deficit. Glasgow Coma Scale (GCS) score was 15/15. On admission, routine blood tests showed hyponatremia with sodium of 121 mmol/L but were otherwise unremarkable with normal inflammatory markers, renal function, cortisol, and thyroid-stimulating hormone (TSH). Urine culture was negative. Sodium fell to 114 after commencing intravenous (IV) 0.9% NaCl. Her plasma and urine osmolalities were 249 and 660 mOsmol/kg, respectively. Her urinary sodium was 165 mmol/L. Plasma osmolality, urine osmolality, and urinary electrolytes suggested the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). At this point, considering a young female with a history of recurrent abdominal pain associated with hyponatremia, neuropathy, and neuropsychiatric symptoms a possible diagnosis of AIP was considered . The urine PBG screen was positive, and the sample was sent to a reference center for quantification. Her magnetic resonance imaging (MRI) head excluded intra-cranial pathology and a CT abdomen and pelvis with contrast was unremarkable as well . Due to tachycardia , prolonged corrected QT interval (QTc) with chest pain and hyponatremia, she was transferred to the cardiac care unit (CCU), and these changes resolved after the correction of electrolyte imbalance. Figure 2 MRI brain MRI brain of the patient is negative for any evidence of infarction, hemorrhage, or tumor as a cause of her motor weakness. MRI: magnetic resonance imaging Figure 3 CT abdomen and pelvis with contrast CT abdomen and pelvis were negative for any evidence of acute pancreatitis, ascites, or inflammatory bowel disease as a cause of her abdominal pain. CT: computed tomography Figure 4 ECG ECG demonstrates sinus tachycardia with 135 beats per minute. The corrected QT interval (QTc) for tachycardia is 543 ms which is prolonged (normal range 360-460 ms). ECG: electrocardiogram On the sixth day of admission, PBG quantification confirmed a very high level of 86 mmol/mmol creatinine (reference range 0-1.5 mmol/mmol creatinine), and she was subsequently managed in collaboration with a porphyria specialist. Unfortunately, she had already deteriorated with reduced GCS of 7/15, type 1 respiratory failure , upper and lower limb weakness, and acute kidney injury. She was moved to the intensive therapy unit (ITU) where she was intubated and put on a ventilator under sedation. She also required vasopressor support. Haem arginate treatment was started to suppress her porphyrin levels. An initial weaning attempt in the ITU revealed that she had persistent bilateral motor neuropathy, more on the right side, with respiratory compromise. She was not able to move her legs and arms as well as had lost her head control. She was re-intubated, and later on, a tracheostomy was done. In addition to her peripheral motor neuropathy, she also developed swallowing difficulties which were later confirmed with the help of videofluoroscopy. She was commenced on total parenteral nutrition. She had recurrent acute attacks over the next four weeks, and these were managed with four-day courses of haem arginate. Her recurrent porphyria attacks were felt to be delaying her neurological recovery, and she started monthly treatment with subcutaneous givosiran at the recommendation of a porphyria specialist. She continued to have supportive management, including intensive physiotherapy sessions, and after 37 days of ITU stay, she was finally stepped down to a respiratory ward with a tracheostomy in situ. At this point, the patient had regained her head control and shoulders control and was able to flex her hips against gravity. She could communicate verbally but remained bed-bound as she was unable to bear weight. She had no further porphyria attacks, and her abdominal pain had settled. After almost three months of acute inpatient care, the patient's tracheostomy was reversed, and she was transferred for inpatient neurorehabilitation. Her proximal strength of both upper and lower limbs muscles was 3/5, however, it was 2/5 distally at the time of discharge from the acute hospital. Discussion Our case describes how easy it is to miss the diagnosis of AIP because it is rare and symptoms and signs are nonspecific. In the absence of obvious pathology, patients may be believed or thought to be exaggerating or even fabricating their pain. Missing or delaying the diagnosis of acute porphyria may result in catastrophic consequences. Acute attacks may occur in any of the subtypes of porphyria, including AIP, variegate porphyria, coproporphyria, and ALAD porphyria among others. AIP is difficult to diagnose due to the combination of its low prevalence and clinical heterogeneity. Figure 5 illustrates the heme synthesis pathway and different types of porphyria depending upon the affected enzyme. Alpha-ALA is derived from glycine and succinyl co-A in the presence of an enzyme called ALA synthetase which is then reduced to PBG by the action of another enzyme called ALA dehydratase. PBG is then converted to hydroxymethylbiline. PBG deaminase is required to catalyze this reaction and this enzyme is affected in AIP which results in the accumulation of the precursors including PBG and ALA which can be detected in urine and blood samples to help in making the diagnosis. Figure 5 Heme synthesis pathway Image credit: Dr. Adil Ramzan AIP is more common in females and typically presents in the late teens to early 30s. Symptomatic AIP has a prevalence of 5.4 per million in Europe . The prevalence of pathogenic AIP gene variants is as high as one in 2000, but over 90% of people with a gene-variant will never have an acute attack which is due to a combination of genetic and environmental factors . Penetrance is estimated at 20-50% in families with AIP but about 1% in the general population. Indeed, our patient did not have any family history of porphyria, but she had several possible attack triggers including caloric restriction, exposure to porphyrinogenic medications (she was given nitrofurantoin to treat UTI), smoking, recreational drug use, infection, and hormonal factors. Importantly our patient was under investigation for an eating disorder. She had lost weight, and her BMI was only 14.5 at presentation, which suggests that possibly she was avoiding eating because of her abdominal pains and that might have contributed to her severe attack. How avoiding eating can contribute to an acute attack is poorly understood . When attacks do occur, the nonspecific presentation compounds the diagnostic challenge. However, the combination of abdominal pain (particularly when recurrent) with hyponatremia and neurological manifestations in a young adult is strongly suggestive of acute porphyria . Abdominal pain occurs in nearly all attacks . Pain is severe and poorly localized and may also be felt in the back, legs, and chest. Other common clinical features include nausea, vomiting, constipation, hypertension, tachycardia, psychiatric symptoms, seizures (which may be associated with hyponatremia), peripheral motor neuropathy (sensory neuropathy is less common), encephalopathy, hyponatremia, and dark orange or red colored urine. It is essential to identify any precipitating factors and try to remove them. These include drugs. Many commonly prescribed drugs are porphyrinogenic and may trigger or potentiate an attack. The safety of medications in porphyria can be checked at Other triggers include hormonal factors in women (including the luteal phase of the menstrual cycle), alcohol, stress, reduction in calorie intake, and smoking. Triggering elements present in our patient included nitrofurantoin prescribed for a possible urine infection, severe calorie restriction, smoking, recreational drug use, and stress. Routine investigations should include a complete blood count, C-reactive protein, renal and liver function tests, and urine and plasma osmolarities (if hyponatremia). Depending upon presentation, electroencephalography (EEG) and MRI head can be considered. The essential investigation to diagnose or exclude an acute attack of porphyria is a urine PBG concentration which requires a random light-protected sample. Further specific investigations, including urine, plasma, and fecal samples (all light protected) should be sent for porphyrin biochemistry to diagnose and differentiate between the four types of acute hepatic porphyrias . Genetic studies provide confirmation. An attack of AIP may be life-threatening if not treated promptly. In general management of an acute attack involves supportive and specific treatments. Mild attacks may resolve with supportive management, but careful observation is needed as attacks can progress from mild to severe very quickly. A high carbohydrate diet may be helpful if patients tolerate oral intake however IV dextrose in water solutions may precipitate or aggravate hyponatremia and should be avoided. Haem arginate remains the treatment of choice for all severe porphyria attacks, Haem arginate works by reducing the synthesis of d-ALA, but in patients with recurrent episodes causing significant disability and requiring repeated courses of haem arginate, then givosiran may be indicated [10-12]. Givosiran is a new gene-silencing therapy, which works by reducing the levels of 5-ALA synthase, an enzyme required for the production of d-ALA. In our patient, givosiran was highly effective at preventing further attacks that would have delayed neurological recovery . Along with these, pain management, respiratory support, intensive physiotherapy, nutritional support, medication review for safety in porphyria, mental health support , and patient and caregiver education should be continued in parallel. Organizations support groups such as the National Acute Porphyria Service, National Organization for Rare Disorders, and the British Porphyria Association provide valuable resources . Our case is a clear example of how severely AIP can affect a patient's mental and physical status and emphasizes how important is to make early diagnoses that could effectively have prevented significant disability. Conclusions In conclusion, AIP can lead to severe disability if diagnoses or treatment is delayed. The most common presentation is non-specific abdominal pain and initial investigations are usually negative. Young females of post-pubertal age are more commonly affected. Patients may present with weight loss due to a decrease in oral intake in an attempt to avoid abdominal pains. In suspected cases, light-protected samples of urine, blood, and feces should be sent for qualitative and quantitative analysis. If there is a suspicion of AIP, medications should be reviewed for their safety profile in porphyrias. Haem arginate is the first-line treatment and it should be commenced as soon as possible. Givosiran, a novel agent, can be considered in severe and refractory attacks after consultation with a porphyria specialist. Early diagnosis and commencement of treatment may prevent severe complications. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. Not applicable issued approval not applicable. This is a case report and consent of the patient was taken, this is not a prospective clinical study. References 1 Physiology of haemoglobin Continuing Education in Anaesth Crit Care Pain Thomas C Lumb AB 251 256 12 2012 2 Acute hepatic porphyria: pathophysiological basis of neuromuscular manifestations Front Neurosci de Souza PV Badia BM Farias IB Pinto WB Oliveira AS 715523 15 2021 34646118 3 Acute intermittent porphyria associated with respiratory failure: a multidisciplinary approach Crit Care Res Pract Menegueti MG Gil Cezar AT Casarini KA Muniz Cordeiro KS Basile-Filho A Martins-Filho OA Auxiliadora-Martins M 283690 2011 2011 21687623 4 Acute hepatic porphyrias: recommendations for evaluation and long-term management Hepatology Balwani M Wang B Anderson KE 1314 1322 66 2017 28605040 5 Acute intermittent porphyria: analgesia can be dangerous BMJ Case Rep Silva CD Mateus JE Teles C Vaio T 0 12 2019 6 Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP Hematology Am Soc Hematol Educ Program Linenberger M Fertrin KY 400 410 2020 2020 33275677 7 Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha Cell Handschin C Lin J Rhee J 505 515 122 2005 16122419 8 EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks Hepatology Gouya L Ventura P Balwani M 1546 1558 71 2020 31512765 9 Urinary excretion of porphyrins, porphobilinogen and d-aminolaevulinic acid following an attack of acute intermittent porphyria J Clin Pathol Marsden JT Rees DC 60 65 67 2014 23908454 10 Acute intermittent porphyria: an overview of therapy developments and future perspectives focusing on stabilisation of HMBS and proteostasis regulators Int J Mol Sci Bustad HJ Kallio JP Vorland M 675 22 2021 33445488 11 Prophylactic heme arginate infusion for acute intermittent porphyria Front Pharmacol Kuo HC Lin CN Tang YF 712305 12 2021 34690757 12 Phase 1 trial of an RNA interference therapy for acute intermittent porphyria N Engl J Med Sardh E Harper P Balwani M 549 558 380 2019 30726693 13 Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria N Engl J Med Balwani M Sardh E Ventura P 2289 2301 382 2020 32521132 14 RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria J Intern Med Sardh E Harper P 593 610 291 2022 35067977 15 Psychiatric manifestations of treatable hereditary metabolic disorders in adults Ann Gen Psychiatry Demily C Sedel F 27 13 2014 25478001 16 Patient and caregiver experiences of living with acute hepatic porphyria in the UK: a mixed-methods study Orphanet J Rare Dis Gill L Burrell S Chamberlayne J 187 16 2021 33902669 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34763 Internal Medicine Neurology Dramatic Responses to Low-Dose Pramipexole in Painful Legs and Moving Toes Syndrome Muacevic Alexander Adler John R Umezawa Gakusuke 1 Hasegawa Takafumi 1 Ikeda Kensuke 1 Saito Genichi 2 Aoki Masashi 1 1 Department of Neurology, Tohoku University School of Medicine, Sendai, JPN 2 Department of Neurology, Jinmei Saito Hospital, Ishinomaki, JPN Takafumi Hasegawa [email protected] 8 2 2023 2 2023 15 2 e347638 2 2023 Copyright (c) 2023, Umezawa et al. 2023 Umezawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Painful legs and moving toes syndrome (PLMTS) is a rare movement disorder characterized by spontaneous abnormal, involuntary toe movements and unilateral or bilateral lower extremity pain that predominantly affects women in middle age or later. The background etiology of PLMTS includes peripheral neuropathy, a history of trauma, and nerve root damage, but the cause of the disease is often undetermined. The pain usually occurs first and is often more distressing to the patient than abnormal toe movement. Spontaneous resolution is rare, and symptomatic therapies include the oral administration of anticonvulsants, antidepressants, and various pain relievers, as well as other therapeutic interventions, including botulinum toxin injection and epidural block, but their effectiveness is uncertain. We report a case of PMLTS in which low doses of pramipexole, a non-ergot dopamine agonist, dramatically improved both abnormal toe movement and leg pain, which are documented by videography. plmts pramipexole dopamine agonist involuntary movement moving toes painful legs This work was supported in part by a Grant-in-Aid for Scientific Research (C) (grant number 20K07896 for Takafumi Hasegawa) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Painful legs and moving toes syndrome (PLMTS), first described by Spillane et al. in 1971, is a rare clinical condition characterized by involuntary toe movements accompanied by discomfort and pain sensation in the legs . The nature of the abnormal toe movements varies, and patients describe them as flexion-extension, fanning, or circular movements. Many patients are affected more by persistent, severe pain than involuntary movements . Peripheral neuropathy, history of trauma, and radiculopathy have been reported as the causative conditions of PLMTS, but the etiology cannot be identified in 40% of cases [2-4]. Here, we report a case of idiopathic PLMTS in which low-dose dopamine agonist, pramipexole, showed a significant effect on both leg pain and abnormal toe movements. Case presentation A woman in her seventies developed persistent burning pain in her right toes and ankle five years ago, accompanied by constant, involuntary twitching movements in the same areas. Her past medical history included hypertension, dyslipidemia, and depression. No history of taking antidepressants or antipsychotics in the past few years. There was no family history of consanguineous marriage or neuromuscular disease. The patient was referred to our hospital as a local hospital failed to reach a diagnosis. Neurological examination on admission revealed persistent involuntary movement comprising abduction-adduction and twisting movements of the right toes, as well as the flexion-extension movement of the right ankle, accompanied by pain. No parkinsonism was observed. These abnormal movements were less noticeable during walking (Video 1). In addition to being accompanied by sustained severe leg pain, the abnormal movements, in this case, were distinct from the symptom of restless legs syndrome (RLS), i.e., they appeared involuntary, were not accompanied by an irresistible urge to move, and did not fluctuate within the day, such as being more likely to occur in the evening or at night . An extensive survey, including routine blood and urine tests, biochemical analysis of cerebrospinal fluid, magnetic resonance imaging of the brain and spine, and nerve conduction studies, was unremarkable. Based on the characteristic nature of the involuntary movements with excruciating pain and the lack of background etiology, a diagnosis of idiopathic PLMTS was made. The first therapeutic intervention of clonazepam (0.5 mg/day) failed; however, after taking a low-dose non-ergot dopamine agonist, pramipexole (0.25 mg before bedtime), her involuntary movement disappeared quickly and completely and the pain greatly relieved (Video 2). At six months after discharge, the treatment was still effective with no adverse effects. Video 1 Involuntary movements of the right toes and ankle joint before treatment. The patient shows involuntary movement consisting of abduction-adduction and twisting movements of the right toes, as well as the flexion-extension movement of the right ankle, accompanied by pain. These abnormal movements are not noticeable during walking. Video 2 Changes in motor symptoms of the toes and ankle joints after two days of oral pramipexole. Oral administration of pramipexole (0.25 mg before bedtime) markedly alleviates involuntary movements, and the pain is greatly relieved. Discussion Although the pathophysiology of PLMT remains unclear, there are a certain number of cases in which peripheral neuropathy or nerve root involvement is thought to be a background etiology . Nathan hypothesized that impulses generated by lesions in the peripheral nerves, dorsal root ganglia, and cauda equina may be responsible for transmitting pain to the central nervous system (CNS), while spinal interneurons may excite anterior horn cells, resulting in involuntary movements . In addition, several reports claimed that sympathetic blockade was effective in improving symptoms , suggesting the involvement of the sympathetic nervous system in the pathogenesis of PLMTS. Although very rare, there have been reports of painless legs and moving toes associated with Wilson's disease and parasagittal meningioma , suggesting that functional abnormalities in the CNS may also be involved in the pathogenesis of PLMTS. Treatment of PLMTS is often challenging. Oral medications such as GABAergic agents, benzodiazepines, dopaminergic agents, antiepileptic agents, and other therapeutic interventions (e.g., botulinum toxin injection, epidural block, and local anesthetic nerve block) have been tried, with limited success . The lack of reliable treatment, combined with a lack of understanding by those around them, leads many patients to become depressed. Because the underlying etiology of PLMTS varies from case to case, it is easy to imagine that treatment efficacy is inconsistent. In general, the degree of involuntary movements and pain often correlate with each other in PLMTS, but in some cases, there is a discrepancy in treatment efficacy . These variations in treatment responsiveness also raise the various pathological mechanisms. From a clinical perspective, PLMTS shares some characteristics with RLS in that both cause abnormal motion and pain in the lower extremities. Our patient did not respond to clonazepam but showed marked improvement with pramipexole, suggesting the involvement of the dopaminergic system in the pathogenesis. In RLS, many patients show favorable responses to dopamine agonists , and intriguingly, there are a small number of cases of PLMTS, in which non-ergot dopamine agonists such as pramipexole, rotigotine, and ropinirole were effective . Pramipexole is a dopamine D2 and D3 receptor agonist, which is widely used for the treatment of motor symptoms in Parkinson's disease and RLS . The pharmacological mechanism by which pramipexole alleviates the symptoms of PLMTS remains unknown; however, in a rodent model of RLS caused by the lesioning of diencephalic-spinal A11 dopamine neuron, pramipexole administration does not alter dopamine content in the spinal cord but reduces dopamine D3 receptor density and enhances D1 receptor affinity . These results raise a possibility that pramipexole might reduce PLMTS symptoms by modulating dopamine receptor function in the spinal cord. Despite various hypotheses described earlier, many of the pathomechanisms of PLMTS remain to be elucidated and require further study. Conclusions We describe an adult case of PMLTS in which low doses of pramipexole markedly resolved both abnormal toe movement and leg pain. PLMTS has a significant impact on the patient's quality of life, but its presence is not well known to healthcare professionals, often leading to delays in diagnosis and treatment. The phenomenology of involuntary movement is often unfamiliar to all but experienced neurologists. We believe that this case report will be helpful in the early diagnosis and treatment selection of PLMTS. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. Tohoku University Hospital ethics review committee issued approval NA. All procedures performed in studies involving human participants were per the ethical standards of the 1975 Helsinki declaration. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. References 1 Painful legs and moving toes Brain Spillane JD Nathan PW Kelly RE Marsden CD 541 556 94 1971 4255783 2 Painful legs and moving toes syndrome: a 76-patient case series Arch Neurol Hassan A Mateen FJ Coon EA Ahlskog JE 1032 1038 69 2012 22490324 3 Case series of painful legs and moving toes: clinical and electrophysiologic observations Mov Disord Alvarez MV Driver-Dunckley EE Caviness JN Adler CH Evidente VG 2062 2066 23 2008 18759340 4 The syndrome of painful legs and moving toes Mov Disord Dressler D Thompson PD Gledhill RF Marsden CD 13 21 9 1994 7511213 5 Painful legs and moving toes syndrome responsive to pregabalin J Postgrad Med Rossi FH Liu W Geigel E Castaneda S Rossi EM Schnacky K 116 119 61 2015 25766346 6 Painful legs and moving toes: evidence on the site of the lesion J Neurol Neurosurg Psychiatry Nathan PW 934 939 41 1978 215727 7 Painless legs moving toes in a patient with Wilson's disease Mov Disord Papapetropoulos S Singer C 579 580 21 2006 16416415 8 Painless legs and moving toes from parasagittal meningioma Mov Disord Yabe I Kano T Sakushima K Terasaka S Sasaki H 586 587 27 2012 22237818 9 Case reports: Painful limbs/moving extremities: report of two cases Clin Orthop Relat Res Miyakawa T Yoshimoto M Takebayashi T Yamashita T 3419 3425 468 2010 20585912 10 Treatment of restless legs syndrome: evidence-based review and implications for clinical practice (Revised 2017)(SS) Mov Disord Winkelmann J Allen RP Hogl B 1077 1091 33 2018 29756335 11 Painful legs and moving toes syndrome associated with dementia with Lewy bodies responsive to rotigotine-induced analgesia Neurol Sci Madokoro Y Mizuno M Kawashima S Okita K Matsukawa N 6569 6570 43 2022 35857160 12 Painful legs and moving toes syndrome: responsive to dopaminergic treatment Acta Neurol Belg Beckmann Y Gurgor N Bulbul NG Secil Y Turkmen N 87 88 115 2015 24817382 13 Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome Mov Disord Ondo WG He Y Rajasekaran S Le WD 1 154 15 2000 14 The long-term effects of the dopamine agonist pramipexole in a proposed restless legs syndrome animal model Sleep Med Luo F Li C Ondo WG Xu P Xie W Le W 41 46 12 2011 21044864 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34776 Family/General Practice Obstetrics/Gynecology Urology Retention of a Foreign Body in the Vagina of an Adult for 13 Years: A Case Report Muacevic Alexander Adler John R Sharaf Omar M 1 Wilkinson Elizabeth A 2 Elbadri Elizabeth 2 Weber LeBrun Emily E 2 1 College of Medicine, University of Florida, Gainesville, USA 2 Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Florida Health, Gainesville, USA Emily E. Weber LeBrun [email protected] 8 2 2023 2 2023 15 2 e347763 2 2023 Copyright (c) 2023, Sharaf et al. 2023 Sharaf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Cases in which foreign bodies have been inserted into the vagina predominately occur in the pediatric population. This report presents the case of an adult woman with a retained foreign body for 13 years. A duplicated ureter suggestive of a Mullerian anomaly was incidentally identified on intraoperative cystoscopy. Mullerian anomalies may be associated with complex patient presentations and are associated with reproductive implications that should be discussed based on patient-specific characteristics. duplicated ureter vaginal foreign body mullerian anomaly transverse vaginal septum chronic pelvic pain The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Vaginal foreign bodies include a wide variety of objects depending on age group and may lead to complications such as pelvic inflammation, necrosis with fistula formation, vaginal stenosis, or toxic shock syndrome . Most cases of vaginal foreign bodies are reported in pediatrics although some cases have been reported in adults. Symptoms primarily include malodorous, purulent blood-stained vaginal discharge, and lower abdominal pain with menses . Patients may not remember foreign body insertion ; thus, vaginal foreign bodies often go undetected for long periods of time, up to 20 years in one case . In cases where routine pelvic examination does not identify a vaginal foreign body, imaging with X-ray and/or pelvic ultrasound may be performed, but these objects are best detected with magnetic resonance imaging (MRI) . Surgical removal is typically successful with fibrosis and vaginal stenosis commonly present at the time of diagnosis . We present a case of an adult female with chronic pelvic pain who had a vaginal foreign body undetected for 13 years. This paper was previously presented at the American Urogynecologic Society 41st Annual Meeting in Vancouver, Canada, in 2020. Case presentation The University of Florida does not require Institutional Review Board approval for case reports. Patient informed consent was obtained. A 31-year-old, gravida zero female presented to the clinic with chronic pelvic pain for several years. She had a menstrual history of regular cycles every month, and she had never been sexually active. The patient reported a history of using tampons while she was in high school for menstrual control; however, she had used pads ever since due to malodorous discharge of unknown etiology. She reported that she had been getting yearly gynecologic exams and had reportedly normal pap smears at another institution although there was no record of this. The patient's pelvic pain was thought to be related to endometriosis, and she had previously been started on oral contraceptive medication. On speculum examination at our institution, an obstruction was noted in the upper one-third of the vagina, obscuring the cervix. A bimanual examination revealed anterior/posterior fibrotic-like adhesions. Transvaginal ultrasound was ordered for imaging and showed distorted anatomy with no identifiable cervix. An MRI was obtained to further define the anatomy and demonstrated a 5 cm x 2 cm tubular foreign body positioned obliquely within the endocervical canal and upper vagina with surrounding fluid . Based on the size and shape of the foreign object, it was suspected to be a plastic tampon applicator that had been in place for 13 years as the patient had not used tampons since high school. Figure 1 MRI displaying the anatomy of the cervix and upper vagina: a tubular foreign body is visualized within the endocervical canal and upper vagina. MRI, magnetic resonance imaging The patient went to the operating room for removal. Cystoscopy was performed first and was significant for an incidental finding of a duplicated ureter on the left side . On examination under anesthesia, the patient had near-complete obliteration of the vaginal canal with circumferential vaginal stenosis with a vertical midline scar at the apex. There was a small dimple at the base of the scar that was probed cephalad demonstrating a patent canal . A vertical incision was made, and further probing expressed purulent fluid . A 30 cc Foley was placed through the narrowed opening and into the cavity. The Foley assisted with the direction of the additional dissection. The foreign body was visualized and grasped with a Babcock clamp and gently removed . Care was taken to prevent fragmentation of the specimen. A repeat cystoscopy was performed and noted no injury to the bladder. Vaginoscopy was performed, and additional pieces of foreign material were removed with cystoscopic graspers. The cervix itself could not be discerned from the surrounding inflamed and excoriated tissue. No fistula tract was noted. Once open, the vaginal canal measured 15 cm from the hymen to the cervix. The final specimen was a cylindrical plastic tube measuring 1 cm x 5 cm and broken into eight pieces, consistent with a plastic tampon applicator . Figure 2 Intraoperative cystoscopy; a duplicated left ureter identified intraoperatively. Figure 3 Circumferentially stenosed vaginal canal: a small dimple could be probed with a right-angle clamp. Figure 4 Incising the stenosed vaginal canal: a scar was incised with a 15-blade scalpel, while spreading tissue with a right-angle clamp; expression of purulent fluid. Figure 5 Tampon applicator removal: the opening was further stretched and incised, eventually allowing the removal of the plastic tampon applicator. Figure 6 A plastic tampon applicator broken into eight segments. Discussion Most cases of vaginal foreign bodies are reported in the pediatric population. In a retrospective review of 35 girls aged 2.6 to 9.2 years with vaginal foreign bodies, predominant symptoms included vaginal bleeding and blood-stained, foul-smelling vaginal discharge . Additionally, 46% of the patients did not recall the insertion of the foreign object . The duration between the onset of symptoms to diagnosis varied from one day to two years in this pediatric population . In adult women, there are a few case reports of vaginal foreign bodies. In a case series, two adult patients aged 34 and 44 years with a known history of vaginal foreign body insertion developed symptoms of vaginal discharge and lower abdominal discomfort with identification of the item seven days and two weeks after entry, respectively, via pelvic examination, X-ray, and abdominal ultrasound . Chopra et al. reported on another case of a vaginal foreign body in a 50-year-old postmenopausal woman, with no recollection of foreign body insertion. She presented with foul-smelling, blood-stained vaginal discharge for three months . The pelvic examination, X-ray, and pelvic ultrasound identified the foreign body, and surgical removal was successful without complications . These reports suggest that recollection of vaginal foreign body insertion may be associated with more prompt identification and removal, as would be expected. However, given the frequency of cases in which a patient does not recollect foreign body insertion, it is necessary to consider the vaginal foreign body in patients with vaginal symptoms or abdominal discomfort with no known history of foreign body insertion. Timely recognition and removal of vaginal foreign bodies are necessary because undetected vaginal foreign bodies are associated with morbidity, which may include infertility, toxic shock syndrome, or fistula formation . In the present case, a 31-year-old female presented with chronic pelvic pain and normal menstrual cycles. She was misdiagnosed with endometriosis based on clinical symptoms while a thorough cervical/pelvic evaluation was incomplete. After unsuccessful treatment with oral contraceptives, the pelvic examination and transvaginal ultrasound revealed distorted pelvic anatomy. MRI revealed a vaginal foreign body, although the patient had no recollection of foreign body insertion. The foreign body was surgically removed, during which intraoperative cystoscopy revealed a duplicated ureter. There is a well-recognized association between renal malformations and Mullerian anomalies . The duplicated ureter suggested a potentially coexistent Mullerian anomaly. Given the patient's pelvic exam and intraoperative findings, this patient likely has a Mullerian anomaly consistent with an incomplete transverse vaginal septum. An undiagnosed Mullerian anomaly may have predisposed this patient to long-term foreign body retention and complex surgical removal. To our knowledge, this is the first reported case in the literature of a patient with a transverse vaginal septum and retained vaginal foreign body. The finding of a duplicated ureter suggesting a coexistent Mullerian anomaly additionally makes this case unique. This case highlights the need to evaluate for vaginal foreign bodies in adult women who present with malodorous vaginal discharge or chronic pelvic pain, even when they have no recollection of foreign body insertion. Although X-ray and pelvic ultrasound may detect vaginal foreign bodies, MRI provides the best visualization and may facilitate complete removal. A vaginal surgical approach was appropriate for this patient to access and remove the retained foreign body. In cases where the transverse septum is too thick to dilate, a laparoscopic approach with posterior colpotomy and removal of the foreign body using an Endo-Catch bag may be a reasonable approach. When present concomitantly with a vaginal foreign body, the transverse vaginal septum should be addressed during foreign body removal as vaginal foreign bodies are associated with significant morbidity . However, when present in isolation, there are important reproductive implications to consider when deciding whether to resect a transverse vaginal septum. In a reproductive-aged individual in whom a Mullerian anomaly is suspected, it is important to counsel the patient regarding the impact of this diagnosis on reproduction. A transverse vaginal septum is associated with infertility and the arrest of labor . Although surgical management has improved with modern techniques, resection of the transverse vaginal septum is still associated with restenosis and hematocolpos . Thus, surgical resection is best performed in patients who are committed to postoperative therapies such as vaginal dilation. Patients' reproductive plans should be discussed to guide this decision. If a patient desires future childbearing, it would be important to determine her ideal family number. If she desires a small family, she may benefit from primary cesarean section rather than surgical septum resection and subsequent dilation therapy. However, in a patient who has a desire for a large family, there could be significant benefit from surgical septum resection compared to repeat cesarean section, given the subsequent risk of invasive placenta with each cesarean section. Although the presence of a vaginal foreign body in the current patient was an indication for operative removal with concomitant transverse vaginal septum resection, this highlights an additional consideration in patients with isolated Mullerian anomalies, and management recommendations may differ based on individual patient circumstances. Conclusions Retained vaginal foreign bodies in adult patients are rare and often overlooked. Patients frequently do not recall foreign body insertion but may present with malodorous vaginal discharge and/or abdominal pain. Vaginal foreign bodies are best visualized with MRI and should be removed promptly to avoid morbidity. Vaginal foreign body removal may be achieved with vaginal or laparoscopic surgical approaches depending on intraoperative findings. Mullerian anomalies may be associated with complex patient presentations and are associated with reproductive implications that should be discussed based on patient-specific characteristics. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. University of Florida Institutional Review Board issued approval N/A. The University of Florida does not require Institutional Review Board approval for case reports. Patient informed consent was obtained. References 1 Vaginal Foreign Body Evaluation and Treatment Anderson J Paterek E Treasure Island, FL StatPearls 2022 2 Vaginal foreign bodies J Paediatr Child Health Stricker T Navratil F Sennhauser FH 205 207 40 2004 15009550 3 Vaginal foreign body causing recurrent discharge and vaginal stenosis a case report Nepal Med Coll J Gurung G Rana A Amatya A 136 137 9 2007 17899968 4 Foreign body in the vagina for twenty years; report of a case Am J Obstet Gynecol Caldwell J 899 901 66 1953 13092175 5 Magnetic resonance imaging in the evaluation of vaginal foreign bodies in a young girl Arch Gynecol Obstet Kihara M Sato N Kimura H Kamiyama M Sekiya S Takano H 221 222 265 2001 11789752 6 Foreign objects of long duration in the adult vagina J Obstet Gynaecol Nwosu EC Rao S Igweike C Hamed H 737 739 25 2005 16263567 7 A case of intravaginal foreign body Med J Armed Forces India Chopra S Singh Y Magon N 266 268 66 2010 27408315 8 Renal and urological abnormalities occurring with Mullerian anomalies J Pediatr Urol Hall-Craggs MA Kirkham A Creighton SM 27 32 9 2013 22129802 9 Mullerian duct anomalies: from diagnosis to intervention Br J Radiol Chandler TM Machan LS Cooperberg PL Harris AC Chang SD 1034 1042 82 2009 19433480 10 Double cross plasty for management of transverse vaginal septum: A 20-year retrospective review of our experience J Obstet Gynaecol India Sardesai SP Dabade R Chitale V 181 185 65 2015 26085740 |
Pulmonary Peripheral Lesions (PPLs) diagnosis is usually performed using a guidance system in combination with bronchoscopes and diagnostic tools. We report two cases of PPLs sampling procedures combining the use of the single-use bronchoscope Ambu aScope 5 Broncho and CIOS 3D Spin Mobile (Siemens Healthineers) fluoroscopy system. A 69-year-old-female was found to have a lesion located in right B6 segment and a 73-year-old-male with a mass in the upper right lobe. We used for both cases a single-use bronchoscope to reach the correct area and the fluoroscopy system to guide peripheral transbronchial aspiration needle (TBNA) sampling. After the confirmation of the correct location of the TBNA tool, the sampling was performed. Rapid onsite evaluation (ROSE) confirmed the adequacy of the sample for molecular analysis and the final diagnosis. Thus, the use of ever-new disposable bronchoscopes for sampling peripheral lesions is a viable alternative to reusable bronchoscopes for advanced bronchoscopy procedures. Pulmonary peripheral lesions (PPLs) diagnosis is usually performed using a guidance system that combines bronchoscopes and diagnostic tools. We report two cases of PPLs sampling procedures combining the use of aScope 5 single-use bronchoscope and CIOS 3D Spin Mobile fluoroscopy system. The use of ever-new disposable bronchoscopes for sampling peripheral lesions is a viable alternative to reusable bronchoscopes for advanced bronchoscopy procedures. 3D fluoroscopy lung cancer peripheral lesions single-use bronchoscopes solitary pulmonary nodule source-schema-version-number2.0 cover-dateApril 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:10.03.2023 Patrucco F , D'Alessio A , Brambilla M , Balbo PE . Combining three-dimensional fluoroscopy guide system with single-use bronchoscopes for diagnosis of peripheral lesions: First two cases. Respirology Case Reports. 2023;11 :e01113. 10.1002/rcr2.1113 Associate Editor: Tracy Leong pmcINTRODUCTION Pulmonary peripheral lesions (PPLs) diagnosis represents one of the most intriguing challenges for interventional pulmonologists. Although several devices, diagnostic tools and guidance systems have been developed to reach PPLs, diagnostic performances outside research studies remain non satisfactory. 1 Fluoroscopy represents the most commonly used system worldwide, using a C-arm or a biplane fluoroscope which allows the real-time visualization of the sampling instrument and PPL, both in antero-posterior and lateral views. 1 The diagnostic yields are variable among studies (19%-83%) and are influenced by PPLs characteristics (size, location, presence of bronchus sign) as well as sampling tool used (forceps, TBNA needles). 1 The CIOS 3D Spin Mobile system is a portable C-arm, with a three-dimensional (3D) fluoroscopy system that, rotates around the patient's chest by a +- 100deg, generates a CT image allowing the operator to confirm the correct position of the tool before the sampling. 2 This system partially overcomes the limitations of conventional fluoroscopy systems, permitting the correct visualization of the interrelationship between the bronchial path, in which the sampling tool is inserted, and lesion's shape, ensuring promising results in terms of diagnostic performances and complications. 2 Single-use bronchoscopes (SUBs) are typically used for diagnostic and therapeutic purposes (mainly bronchoalveolar lavage, removal of clots and mucous plugs) although more complex diagnostic procedures have been recently described: sampling of endobronchial lesions using forceps, endobronchial valve placement, thermal ablative therapy, cryotherapy, tumour debulking, foreign body retrieval, airway stent deployment, guidance for percutaneous tracheostomy procedure. 3 Up until now, several technical characteristics of SUBs limited their role in PPLs diagnostics: the small diameter of working channel was not compatible with TBNA needles; the flexibility of the distal extremity with tools inserted would limit the manoeuvrability, especially in case of PPLs located in upper lobes; the concern that SUBs might not be robusts enough to allow them to withstand the stress of repeated sampling passes. Ambu(r) aScopeTM 5 Broncho is the 5th generation of the Ambu single-use bronchoscopes: it is designed for use with the diagnostic and therapeutic endotherapy instruments commonly used in the bronchoscopy suite such as biopsy forceps and needles, cytology brush, cryoprobes and high-frequency tools. The combination of the bending angles, distal tip angulation range (195deg/195deg) and the flexibility of the insertion tube is designed to help access difficult-to-reach areas. According to a recent publication, the aScope 5 has more degrees of flexion/extension with tools compared to reusable flexible bronchoscopes (RBs). The manoeuvrability is further enhanced by 120deg left/right rotation designed to make it easy to adjust the position of the tip to ease navigation and insertion of endotherapy instruments. 4 We report two cases of PPLs sampling procedures combining the use of aScope 5 single-use bronchoscope and CIOS 3D Spin Mobile fluoroscopy system. CASE REPORT Case 1 A 69-year-old female, active smoker, come to our attention after the onset of 8 kilograms of weight loss associated with dry cough. She performed a chest X-ray and then a thorax CT scan revealing a pulmonary mass (54 x 44 x 55 mm) located in right B6 segment: the lesion presented a bronchus sign type A (bronchus reaches the inside of the target lesion) and infiltrates the fissure repassing it. The next positron emission tomography (PET) CT scan confirmed the high concentration of 18F-FDG in correspondence with the lesion without suspected lymph nodes involvement . FIGURE 1 (A) 18F-fluorodeoxyglucose (FDG) PET/CT uptake in correspondence to the right B6 segment; (B) aScope 5 Broncho HD 5.6/2.8 single-use bronchoscope reaches the lesion guided by 3D fluoroscopy CIOS guidance system; C. fluoroscopic image of TBNA sampling of the lesion. We performed the bronchoscopy in spontaneous breathing, in conscious sedation. We used aScope 5 Broncho HD 5.6/2.8 single-use bronchoscope: endoscopically no lesions were detectable, so we used the CIOS system to guide peripheral TBNA sampling (21-Gauge needle). After the confirmation of the correct location of the TBNA tool , we proceeded with the sampling. ROSE confirmed that we reached the lesion (adequate material suspected for presence of neoplastic cells) so we completed the sampling with another three passes. No procedure-related complications were recorded; the TBNA tool was easily introduced in the bronchoscope working channel without problems of manoeuvrability, with or without the needle inserted in; the bronchoscope was correctly operating after the procedure. Acquisition time and dosimetric index (air kerma-area product, KAP) were respectively 79 s and 10.2 Gycm2. Final diagnosis was adenocarcinoma and the material obtained was adequate for molecular analysis. Case 2 A 73-year-old male, past smoker, came to our attention after the accidental finding of a pulmonary nodule located at the right upper lobe. The nodule characteristics were: dimensions 18 x 14 mm, not in contact with pleural surface, a bronchus sign type B, adjacent to the lesion. A 18F-FDG PET was performed confirming the suspected malignancy nature of the lesion (Standardized Uptake Value max 5.34) without contrast uptake in correspondence with hilar lymph nodes . FIGURE 2 (A and B) 18F-fluorodeoxyglucose (FDG) PET/CT uptake in correspondence of the right upper lobe; (B and C) aScope 5 Broncho HD 5.6/2.8 single-use bronchoscope reach the lesion guided by 3D fluoroscopy CIOS guidance system: TBNA (C) and forceps (D) sampling (B). We performed bronchoscopy under general anaesthesia in laryngeal mask. We used aScope 5 Broncho HD 5.6/2.8 single-use bronchoscope: after the confirmation of absence of endoscopically visible lesions, we proceeded with peripheral sampling with CIOS system. We introduced the 21-Gauge TBNA tool through right B1 bronchus and, after the confirmation of the correct position of the needle into the lesion, we proceeded with the sampling. ROSE confirmed the adequacy of the sample and so we completed the sampling with another 2 passes with TBNA and 4 with biopsy forceps . No procedure-related complications were recorded. Both TBNA and biopsy forceps were easily introduced through the bronchoscope working channel without problems of manoeuvrability and the instrument was correctly operating after the procedure. Total acquisition time and KAP were 530 s and 72.1 Gycm2. Final diagnosis was adenocarcinoma and the material was adequate for molecular analysis. DISCUSSION These cases focus our attention on the use of SUBs in sampling PPLs under fluoroscopic guidance; each instrument used gave us some advantages. CIOS Mobile 3D spin system generates a CT image that allows the operator to confirm the tool-in-lesion during the sampling procedure, with higher rates if it is combined with other guidance instruments. Some recent studies demonstrate that the radiation dosage emitted by CIOS is similar to Cone Beam CT (CBCT) but, after the acquisition of expertise, this would decrease. In both our cases, the CIOS system allowed us to visualize the sampling tool in direct proximity to the lesion, and ROSE confirmed the adequacy of specimens. Although there is a brief latency between the acquisition (30 s) and elaboration (about 10 s) of images, the CIOS system gives us a 3D image of the bronchial tree and defines the relationship between lesion and sampling tool instrument. This is the main advantage with respect to conventional fluoroscopic guidance systems that, even if C-arm would be rotated around the patient, giving us multiplanar prospective, the quality of images is lower. As interventional pulmonologist we were familiar with RBs especially for their robustness that permits to stress the bronchoscopes during the sampling with tools inside, by rotating and bending them, passing through endotracheal tubes. Thin and ultrathin bronchoscopes overcome the limitation to achieve very distal lesions and bringing to the periphery of the lung thinner and more flexible 21-Ga needles and cryoprobes. 1 Nevertheless, the availability of ultrathin bronchoscopes is limited. Moreover, repair costs of RBs are not negligible: Rozman et al. calculated a repair cost of 5.25EUR per procedure. The majority of the damages reported were located to the rubber coat on the distal bending section (59%), mainly caused by the repeated stress on the instruments' materials during procedures. 5 The extreme bending generates a great mechanical stress of the angulation control lever and working channel. Furthermore, the introduction of needles and forceps increases the rigidity of the distal bending section, especially when the instrument is bended to reach lesions located in upper lobes. New generation Ambu(r) aScopeTM 5 offers two distal diameters (5.6 and 5.0 mm) with different working channels (2.8 and 2.2 mm), improving the distal tip angulation range and flexibility. This increased manoeuvrability, in addition to a greater robustness of the entire bronchoscope, makes it more suitable for stressing procedures such as the sampling of peripheral nodules. Moreover, the diameter of the working channel is fit for an easy insertion of all sampling instruments (forceps and TBNA needles). Other factors supported the introduction of SUBs in the sampling of PPLs. The portability of the system, consisting of the instrument and full-HD monitor, allows examinations to be performed in hybrid operating rooms or other suites where guidance systems are present, since most bronchoscopy suites are not equipped with advanced medical imaging devices. This also allows examinations to be performed during surgery. Any possible damage caused by the sampling procedure would not let us without instrument for the subsequent procedure. From an organizational and economic perspective, SUBs are a better solution than a RBs in 75% of cases. 6 From a clinical point of view, SUBs have many advantages, mainly the reduction of patient-to-patient infection transmission and personnel exposure to fomites or aerosol. However, considering the costs of a procedure performed with a reusable instrument varies from 355EUR to 71EUR, and those using a SUBs is fixed at 232EUR, in a hospital performing less than 328 procedures per year, the use of SUBs becomes economically viable. 5 Nevertheless, in a hospital with a large volume of procedures, the two solutions could be both valid and accessible, choosing the instrument on the basis of the indication. In endobronchially invisible PPLs, the 3D fluoroscopy systems allow the operator to confirm the correct position of the sampling tools. Although SUBs are not routinely being used for advanced diagnostic bronchoscopy, the aScope 5 Broncho performed comparably to a reusable bronchoscope in terms of manoeuvrability with and without instruments in the working channel. aScope 5 Broncho may be a viable alternative to RBs for advanced diagnostic bronchoscopy. AUTHOR CONTRIBUTIONS The authors equally contributed to the present work. CONFLICT OF INTEREST STATEMENT None declared. ETHICS STATEMENT The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34783 Internal Medicine Gastroenterology Anatomy Mirizzi Syndrome: A Case Report Muacevic Alexander Adler John R Grohol Bryce 1 Fortin Grayson T 1 Ingold Tyler 1 Bennett Paul 2 1 Medicine, Liberty University College of Osteopathic Medicine, Lynchburg, USA 2 Internal Medicine, Centra Lynchburg General Hospital, Lynchburg, USA Bryce Grohol [email protected] 8 2 2023 2 2023 15 2 e3478318 1 2023 8 2 2023 Copyright (c) 2023, Grohol et al. 2023 Grohol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Mirizzi syndrome (MS) describes a rare complication of cholelithiasis resulting from extrinsic compression of the common hepatic duct by impacted gallstones in the cystic duct or Hartmann's pouch. MS is most commonly seen in adults and is more prevalent in the female population. Due to the pathophysiology of MS being similar to other causes of cholecystitis and biliary obstruction, the symptomatology is rather nonspecific. While ultrasound and magnetic resonance cholangiopancreatography are commonly used for diagnosis, treatment of this condition typically involves cholecystectomy. Identifying MS versus other more common causes of obstructive jaundice is paramount in limiting complications. In this report, we describe a case of MS diagnosed in a 32-year-old male who presented with nonspecific abdominal pain and other signs of obstructive jaundice. The goal of this study is to show how identifying a rare underlying cause of a common presentation can lead to improved patient outcomes. gallbladder removal common bile duct dilatation cystic duct injury gallstone disease (gsd) mirizzi syndrome The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Mirizzi syndrome (MS) describes a rare complication of cholelithiasis leading to obstructive jaundice. The pathophysiology of the condition involves gallstones becoming impacted in either the cystic duct or in Hartmann's pouch. These stones then produce a mass effect that extrinsically compresses the common hepatic duct resulting in the symptoms of obstructive jaundice [1-3]. First characterized in 1905 by German physician Kehr, and later named syndrome del conducto hepatico by Argentinian surgeon Pablo Mirizzi, MS often presents with nonspecific symptoms that can make the diagnosis challenging . Given its unique presentation, early intervention is important to reduce further complications. MS typically peaks in late adulthood and appears to have a greater incidence in women compared to men . The cited prevalence of MS is rare at approximately 1%, but in some underdeveloped countries in Latin America, the prevalence was documented as high as 5.7% . While ultrasound is typically the first-line imaging study of choice, magnetic resonance cholangiopancreatography is also a highly effective and safe tool for working up patients suspected of MS. The mainstay treatment of MS most often involves cholecystectomy or subtotal cholecystectomy. While laparoscopy has its advantages, there is a high rate of conversion to open laparotomy which can result in high rates of complications . Here we describe a case of MS diagnosed in a 32-year-old male who presented with nonspecific abdominal pain and other signs of obstructive jaundice. Case presentation A 32-year-old male with a past medical history of irritable bowel syndrome and obesity presented to urgent care with chronic episodic epigastric pain radiating to his back and his right side. He described the pain as dull, however, periods of exacerbation were deep and gnawing. The patient described the pain as six out of 10 at baseline, however, exacerbations of the pain were up to a nine out of 10 at their worst. The patient did not believe the pain changed with his consumption of different foods. It typically lasted for approximately 48 hours and then temporarily alleviated until the next flare. He describes the pain as "a ball of discomfort at the base of my esophagus." He denied any fever, change in bowel habits, nausea, or vomiting. Physical examination at urgent care showed a large abdomen with normoactive bowel sounds in all four quadrants. Mild epigastric pain was present, but the abdomen was otherwise nontender. There were no peritoneal signs, organomegaly, or costovertebral angle tenderness. Murphy's sign was negative. Radial and dorsalis pedis pulses were 2+ bilaterally. The skin was warm and dry without rash or lesions. There was no scleral icterus or change in weight. Vital signs were within normal limits and an electrocardiogram showed no acute cardiovascular changes. Due to a concern for gastritis, the patient's esomeprazole was increased from 40 mg once daily to twice daily and Carafate was prescribed. The patient was instructed to go to the emergency department if he experienced any new or worsening symptoms. The following day, the patient presented to the emergency department with worsening of his epigastric pain as well as new-onset nausea and vomiting. His labs returned with normal white blood cell count, hemoglobin, hematocrit, electrolytes, and nonelevated troponins. Initial liver function tests (LFTs) revealed total bilirubin of 4.7 mg/dL (normal range: 0.3-1.0 mg/dL), alkaline phosphatase (ALP) 156 U/L (normal range: 34-104 U/L), alanine aminotransferase (ALT) 1066 U/L (normal range: 7-52 U/L), and aspartate aminotransferase (AST) 1041 U/L (normal range: 13-39 U/L). The emergency physician at the time suspected transient common bile duct (CBD) obstruction and referred the patient to the hospitalist service for admission. Gastroenterology was also consulted. Right upper quadrant (RUQ) gallbladder ultrasound later that day was limited due to body habitus and bowel gas. Fatty infiltration of the liver was noted, however, no other abnormalities were present including an absence of gallstones. Magnetic resonance cholangiopancreatography (MRCP) was completed the same day and showed a gallbladder with cholelithiasis present in the gallbladder neck, but showed no evidence of cholecystitis. There was no CBD dilatation, biliary strictures, or filling defects. The pancreas, spleen, kidney, and adrenals all were of normal size and signal intensity. The patient's first MRCP is shown below in Figure 1. Figure 1 Patient's first MRCP on admission day one. MRCP: magnetic resonance cholangiopancreatography On the second day of admission, gastroenterology discussed MS as a possibility for the first time. Due to endoscopic retrograde cholangiopancreatography (ERCP) not being able to be completed by the weekend physician, an endoscopic ultrasound (EUS) was performed to better visualize the biliary tree. LFTs were redrawn and showed a total bilirubin of 6.4 mg/dL, direct bilirubin of 4.6 mg/dL, ALP of 179 U/L, AST of 787 U/L, and ALT of 1182 U/L. Hepatitis serologies were negative. EUS showed no signs of ampulla abnormality and no masses, cysts, calcifications, or biliary sludging. Both the CBD and the common hepatic duct (CHD) showed dilatation. There were multiple small stones in the gallbladder with one larger stone in the gallbladder neck, however, there was no evidence of choledocholithiasis in the CBD. The gastroenterologist felt that this imaging study confirmed the diagnosis of MS. General surgery was consulted and they scheduled a laparoscopic cholecystectomy for the following day. The patient's EUS can be seen below in Figure 2. Figure 2 Endoscopic ultrasound completed on admission day two. The patient underwent a successful cholecystectomy on hospital day three. Surgical findings included a very short, wide, and firm cystic duct as well as the hepatic artery in very close proximity to the top of the CBD. The hepatic artery was adherent to the infundibulum of the gallbladder. This was speculated by the gastroenterologist to be due to inflammation from the gallstone's compression. The gallbladder itself showed severely progressive diffuse inflammation as well. Two days later, on hospital day five, a second MRCP was performed due to the patient's persistently increased LFTs and a worsening jaundiced state post-cholecystectomy. Although the gallbladder was removed, there was new onset hepatic biliary dilatation with a 3 mm CBD stone. The patient's second MRCP is pictured below in Figure 3. Figure 3 Patient's second MRCP completed on admission day five post-cholecystectomy. MRCP: magnetic resonance cholangiopancreatography On admission day seven the patient underwent ERCP with biliary sphincterotomy and all visible stones were removed. Over the course of the next two admission days, his LFTs gradually improved. The patient continued to remain stable and was discharged home with gastroenterology to follow up in two weeks. Discussion Mirizzi syndrome is a rare complication of cholelithiasis involving external compression of the common hepatic duct from stones lodged in either the cystic duct or Hartmann's pouch [1-3]. While this impingement typically remains external, if left untreated the chronic inflammation can lead to hepatic duct wall necrosis and subsequent cholecystobiliary fistula formation between the cystic duct and the CHD . Epidemiology of MS varies dramatically between different studies, however, most research documents an overall incidence of around 1% in patients undergoing ERCP for cholecystitis . Although extremely rare and thus difficult to diagnose, recognizing MS early through a combination of physical examination, labs, and imaging is important for successful treatment. McSherry was the first physician to differentiate upon the classifications of patients with MS . This system separated the condition into two different subtypes as follows: type I involves external obstruction of the common hepatic duct by a stone impacted in either the cystic duct or the Hartmann pouch, resulting in inflammation of the Calot triangle. Type II involves similar obstruction, however, it also includes erosion of the stone into the CHD from the cystic duct, forming a cholecystobiliary fistula . While these definitions still hold true, the Csendes classification, which later expanded type II into three different subtypes based on the percentage of the CHD diameter which was obstructed, is the most widely accepted classification . Csendes type II includes the presence of a cholecystobiliary fistula with <33% of the CHD, whereas type III and type IV obstruct 33-66% and >66%, respectively [10-12]. Table 1 describes the four classifications of MS. In the case previously described, our patient likely had type III or type IV MS due to obvious inflammation as well as severely elevated LFTs [10-12]. Table 1 Csendes classification of Mirizzi syndrome subtypes one through four. CHD: common hepatic duct Mirizzi syndrome classification Type I Type II Type III Type IV Pathophysiologic description External compression of CHD without cholecystobiliary fistula formation Cholecystobiliary fistula with <33% of the width of the CHD obstructed Cholecystobiliary fistula with 33-66% of the width of the CHD obstructed Cholecystobiliary fistula with >66% of the width of the CHD obstructed Due to the pathophysiology of MS being similar to other causes of cholecystitis and biliary obstruction, the symptomatology is also rather nonspecific. Patient complaints classically resemble obstructive jaundice with symptoms such as nausea, vomiting, bloating, flatulence, and dull RUQ pain which radiates to the upper back. These symptoms often present in the evening after ingestion of a fatty meal . Physical examination findings include scleral icterus, abdominal pain, and possible hepatomegaly. A positive Murphy's sign is found in roughly 50% of patients . Similar to physical presentation, labs are nonspecific and of little use in differentiating MS from other more common causes of obstructive jaundice such as choledocholithiasis and malignancy . In one study, AST and ALT were found to be elevated in up to 98% of MS patients. ALP was elevated in 94% of patients, total bilirubin was elevated in 92%, and mild leukocytosis was seen in 73% due to the inflammatory processes of the obstruction . Due to the low specificity, these symptoms, physical examination findings, and lab results are most useful in ruling out MS rather than aiding in its diagnosis. Preoperative diagnosis of MS is of the utmost importance, as it is associated with decreased intraoperative complication rate, better outcomes, and avoidance of bile duct injury . The initial imaging modality of choice for patients with symptoms of MS is a RUQ ultrasound. While ultrasound is very commonly used, diagnostic accuracy can be limited . MRCP is generally the next step when right upper quadrant ultrasound reveals findings specific to obstructive jaundice such as atrophic gallbladder and dilated bile ducts. Due to its non-invasive imaging technique and diagnostic accuracy of up to 50%, MRCP is a highly effective and safe tool for working up patients suspected of MS . Although the previously mentioned imaging modalities are first-line for evaluating patients with obstructive jaundice, the gold standard for diagnosing MS is the ERCP. With an average sensitivity of 76%, this technique yields superior visualization of the biliary tract and can clearly show external compression of the CHD by impacted gallstones. ERCP can also accurately diagnose cholecystobiliary fistulas in more advanced cases of this condition. Although there are clear advantages of ERCP, there is also an increased risk of complications, so caution should be taken when used in suspected MS . As is referenced in the description of the aforementioned case, many of these imaging modalities were completed prior to coming to a consensus diagnosis. The mainstay treatment of MS most often involves cholecystectomy or subtotal cholecystectomy . Traditionally, open laparotomy is the technique of choice, largely due to relative safety compared to laparoscopy. Minimally invasive laparoscopy has many advantages such as shorter length of stay as well as reduced waste of resources, however, the conversion rate to open procedure is extremely high in MS, with some studies reporting it to be close to 80% . This increased conversion rate has classically been attributed to the lack of preoperative diagnoses discussed previously . Some experts recommend limiting laparoscopic approaches to patients with type I MS only, as further inflammation from the procedure could potentially exacerbate bile duct injury in patients with cholecystobiliary fistulas . Complications from surgery are also quite common in patients undergoing treatment for MS, with one study stating the rate of complications being roughly 16%. The most common complications include bile duct injury, residual gallstones, and bile leakage . Residual gallstones were found in the case described in this manuscript. The patient described in this report underwent a relatively uncharacteristic diagnostic path with a EUS prior to ERCP secondary to temporary unavailability of the latter procedure. As is typical of MS, multiple different imaging modalities were utilized not only to diagnose that specific condition, but also to rule out all other more common causes of obstructive jaundice. Although less common than open laparotomy, his subsequent treatment with laparoscopic cholecystectomy yielded only partial relief of symptoms due to remnant stones migrating down to the CBD causing a subsequent choledocholithiasis. Once ERCP was able to be completed, complete resolution was possible when the final stones were removed from the CBD. Conclusions Due to its relative infrequency and nonspecific symptomatology, MS can be difficult to diagnose leading to intraoperative complications or biliary duct injury. Here we presented a unique case of acute biliary colic and obstructive jaundice in a 32-year-old male. In a presentation such as this, MS should be considered in the differential. MRCP and ERCP are key in establishing a diagnosis, as seen in this case, with cholecystectomy being the treatment of choice. A careful classification of MS can determine the proper modality of cholecystectomy to ensure safe and effective treatment. This case provides an example of how MS can present without definitive radiological evidence and how proper treatment will lead to an uncomplicated clinical course. Further reporting of MS presentation and workup is needed to aid in prompt diagnosis and reduce possible intraoperative complications. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Safety and feasibility of laparoscopic approaches for the management of Mirizzi syndrome: a systematic review Surg Endosc Zhao J Fan Y Wu S 4717 4726 34 2020 32661708 2 Die in Meiner Klinik Geubte Technik Der Gallensteinoperationen MIT Einem Hinweis Auf Die Indikationen Und Die Dauererfolge Munchen: J.F. Lehmann Kehr H Munich, Germany J.F. Lehmann 1905 3 Sindrome del conduct hepatico J Int Chir Mirizzi PL 731 777 8 1948 4 Post-cholecystectomy Mirizzi syndrome: a case report and review of the literature Am J Case Rep Borz-Baba C Levy DA Cohen ME 1290 1298 20 2019 31473761 5 Mirizzi syndrome: history, current knowledge and proposal of a simplified classification World J Gastroenterol Beltran MA 4639 4650 18 2012 23002333 6 The relationship of Mirizzi syndrome and cholecystoenteric fistula: validation of a modified classification World J Surg Beltran MA Csendes A Cruces KS 2237 2243 32 2008 18587614 7 Laparoscopic treatment of Mirizzi syndrome: a systematic review Surg Endosc Antoniou SA Antoniou GA Makridis C 33 39 24 2010 19466486 8 The current approach to the diagnosis and classification of Mirizzi syndrome Diagnostics (Basel) Klekowski J Piekarska A Goral M Kozula M Chabowski M 11 2021 9 The Mirizzi syndrome: suggested classification and surgical therapy Surg Gastroenterol McSherry CK Fernstenberg H Virshup M 219 225 1 1982 10 Mirizzi syndrome and cholecystobiliary fistula: a unifying classification Br J Surg Csendes A Diaz JC Burdiles P Maluenda F Nava O 1139 1143 76 1989 2597969 11 Complications of gallstones: the Mirizzi syndrome, gallstone ileus, gallstone pancreatitis, complications of "lost" gallstones Surg Clin North Am Zaliekas J Munson JL 1345 1368 88 2008 18992599 12 Mirizzi syndrome StatPearls [Internet] Jones MW Ferguson T Treasure Island, FL StatPearls Publishing 2022 13 Obstructive jaundice and perioperative management Acta Anaesthesiol Taiwan Wang L Yu WF 22 29 52 2014 24999215 14 Current trends in the management of Mirizzi syndrome: a review of literature Medicine (Baltimore) Chen H Siwo EA Khu M Tian Y 97 2018 15 Delayed diagnosis of Mirizzi syndrome Semin Intervent Radiol Oladini O Zangan SM Navuluri R 332 336 33 2016 27904253 |
Mol Psychiatry Mol Psychiatry Molecular Psychiatry 1359-4184 1476-5578 Nature Publishing Group UK London 36564488 1920 10.1038/s41380-022-01920-0 Correspondence Relapse and its modifiers in major depressive disorder after antidepressant discontinuation: meta-analysis and meta-regression Kishi Taro [email protected] 1 Sakuma Kenji 1 Hatano Masakazu 12 Okuya Makoto 1 Matsuda Yuki 3 Kato Masaki 4 Iwata Nakao 1 1 grid.256115.4 0000 0004 1761 798X Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192 Japan 2 grid.256115.4 0000 0004 1761 798X Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192 Japan 3 grid.411898.d 0000 0001 0661 2073 Department of Psychiatry, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461 Japan 4 grid.410783.9 0000 0001 2172 5041 Department of Neuropsychiatry, Kansai Medical University, Hirakata, Osaka 573-1191 Japan 23 12 2022 23 12 2022 2023 28 3 974976 13 9 2022 12 11 2022 12 12 2022 (c) The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Subject terms Depression Drug discovery Grant-in-Aid for Young Scientists (21K15738)issue-copyright-statement(c) The Author(s), under exclusive licence to Springer Nature Limited 2023 pmcRecent pairwise meta-analysis including only double-blind, randomized placebo-controlled trials (DBRPCTs) with an enrichment design in which individuals with MDD were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or a placebo was conducted . The meta-analysis reported that the antidepressant maintenance group had a significantly lower relapse rate than the antidepressant discontinuation group (K = 40, n = 8890) . A subgroup meta-analysis revealed similar relapse rates for maintenance periods of 6 months and 1 year . Therefore, the authors recommended antidepressant maintenance treatment for at least 6 months after remission to prevent relapse . A subsequent DBRPCT found relapse rates for an antidepressant maintenance group and a discontinuation group at 26 weeks of 32 and 56% (24% difference), respectively; and relapse rates at 39 weeks of 40 and 69% (29% difference), respectively . This means there was a 5% difference in relapse rates between the two groups from 26 to 39 weeks. Thus, the differences in relapse rates between individuals with MDD who continued antidepressants that were effective during acute treatment and those who discontinued the antidepressants are still unclear. Trends in the magnitude of the benefit of medication maintenance over time are important in determining how long individuals with MDD should continue taking antidepressants. While the meta-analysis described above was conducted using the relapse rate at the endpoint of each DBRPCT for individuals with MDD including general adults, children and adolescents or older individuals (range of study duration: 14-100 weeks) , the current systematic review and pairwise meta-analysis included DBRPCTs with adult participants only and compared relapse rates at matched observation time points (i.e., 3, 6 [primary outcome], 9, 12, 15, and 18 months) between discontinuation and maintenance groups to more accurately determine the temporal relapse trend. Other recent meta-analyses for acute depression reported a correlation between antidepressant dosage or the type of antidepressant and efficacy . However, it remains unknown which clinical factors are associated with antidepressant efficacy in adults with MDD during the maintenance phase. In the current meta-regression analyses, we attempted to identify the variables in participants, treatment, and/or study design that influence the effect size for the primary outcome. Our meta-regression also aimed to identify modifiers of the antidepressant response and the interplay between these modifiers and the placebo response in the formation of effect sizes. This systematic review and pairwise meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Table S1) , and was registered with the Open Science Framework ). Table S2 presents the definitions of relapse/recurrence used by each included study. Table S3 shows the results of the data synthesis. This pairwise meta-analysis used a random-effects model . We calculated risk ratios (RRs) with 95% confidence intervals (95% CIs). We assessed the heterogeneity of the included studies using the I2 statistic, with an I2 of >=50% indicating heterogeneity . We also conducted a single-group summary meta-analysis to determine the exact relapse rates with 95% CIs in both the maintenance and discontinuation groups. When the pairwise meta-analysis showed significant differences in the relapse rates between the treatment groups, the number needed to treat to benefit (NNTB) was estimated. We performed all statistical analyses using Comprehensive Meta-Analysis software version 3 (Biostat Inc., Englewood, NJ, USA). Fig. S1 shows the literature search and selection strategy. We identified 35 DBRPCTs with a total of 9442 adults with MDD (68% female with a mean age of 43.5 years; range of mean age among all 35 studies = 37.0-51.0 years). Table S4 summarizes the characteristics of the included DBRPCTs. The mean study duration was 41.9 +- 17.2 weeks. No studies were found to have a high risk of bias in at least one domain of the Risk of Bias 2 tool (Fig. S2). The RRs for the relapse rates at 3, 6, 9, and 12 months were similar; however, the NNTB slightly decreased over time (Figs. 1 and S3-8). Although the average relapse rates in both the maintenance group and discontinuation group increased over time, the rate of relapse increased faster in the discontinuation group than in the maintenance group (Fig. 1). The effect of antidepressants on the prevention of relapse in the maintenance group was greater at 15 and 18 months than at 12 months or less; however, the number of studies showing relapse rates for 15 months and 18 months was small, so these results might not be robust. Nevertheless, this suggests that in individuals with MDD whose acute symptoms are improved by antidepressant treatment, maintenance treatment with antidepressants should be continued for 18 months (or at least 12 months) to prevent relapse. As in the previous meta-analysis , we found a significantly lower all-cause discontinuation rate (Fig. S9) in the maintenance group than in the discontinuation group, but no significant difference was observed between the groups in discontinuation due to adverse events (Fig. S10).Fig. 1 Major depression relapse rates with discontinuation or maintenance of antidepressant treatment. The error bar represents the standard error. 95% CI, 95% confidence interval; K, number of studies; n, number of patients; NNTB number needed to treat to benefit, RR risk ratio. We found effect size to be correlated with average age (Fig. S11), total number of participants (Fig. S12), dosing schedule (Fig. S13), drug class (Fig. S14), and publication year (Fig. S15 and Table S5). Among these moderators, only average age was associated with the relapse rate in both the maintenance and discontinuation groups, i.e., there were lower relapse rates in both groups for older than younger adults. However, studies including older adults had greater effect sizes than studies including younger adults. Thus, despite their lower relapse rate, older adults might benefit more from continued antidepressant medication than younger adults. These results were confirmed by the multivariate analysis (Table S6). However, it was difficult to identify the reasons for the associations between effect size and the other moderators, since the moderators were not associated with relapse rates in both treatment groups. Our study had several limitations. These are presented in the Supplementary text; e.g., we detected a significant publication bias for the primary outcome (Fig. S16). We also were unable to perform a meta-analysis on those outcomes since data on the relapse rates at time points longer than 18 months of observation was insufficient. Therefore, it remains unclear at this time whether a longer period of antidepressant treatment for those individuals is necessary. Supplementary information Supplementary materials Supplementary information The online version contains supplementary material available at 10.1038/s41380-022-01920-0. Acknowledgements We would like to thank all participants of the studies included in this systematic review and meta-analysis. We would also like to thank Maruzen-Yushodo Co., Ltd. for the English language editing. Author contributions TK had full access to all data and takes full responsibility for the integrity of the data and the accuracy of the data analysis. TK developed the study concept and design and performed the statistical analyses. All authors acquired and interpreted the data, and wrote the manuscript. NI supervised the review. Funding The present study was supported by Grant-in-Aid for Young Scientists (21K15738) and Fujita Health University School of Medicine Research Grant for Early-Career Scientists. Data availability The data used for the current study were reported in the articles of the studies included in our meta-analysis. Competing interests The authors have no conflicts of interest to declare regarding the subject of this study. Interests from the past 3 years are as follows. TK received speaker's honoraria from Sumitomo, Eisai, Takeda, Janssen, Otsuka, Meiji, Viatris, MSD, and Mitsubishi Tanabe; a Grant-in-Aid for Scientific Research; and a research grant from the Japanese Ministry of Health, Labour and Welfare, the Japan Agency for Medical Research and Development, and Fujita Health University School of Medicine. KS received speaker's honoraria from Sumitomo, Eisai, Kissei, Meiji, and Otsuka; a Grant-in-Aid for Young Scientists and a Research Grant for Early-Career Scientists from Fujita Health University School of Medicine; and a research grant from the Japan Agency for Medical Research and Development. MH received speaker's honoraria from Sumitomo, Janssen, Kyowa, Otsuka, Tanabe-Mitsubishi, and Yoshitomi. MO received speaker's honoraria from Sumitomo, Eisai, Kissei, Meiji, and Otsuka; a Grant-in-Aid for Young Scientists (21K15738), and a Research Grant for Early-Career Scientists from Fujita Health University School of Medicine. YM received speaker's honoraria from Sumitomo, Janssen, Kyowa, Otsuka, and Mitsubishi Tanabe, and a research grant from the Japan Agency for Medical Research and Development. MK received speaker's honoraria from Sumitomo, Otsuka, Meiji, Eli Lilly, MSD, Pfizer, Janssen, Mitsubishi Tanabe, Takeda, Lundbeck, Viatris, Eisai, Kyowa, and Ono; and a research grant from the Ministry of Health, Labor, and Welfare of Japan, the Japan Society for the Promotion of Science, SENSHIN Medical Research Foundation, the Japan Agency for Medical Research and Development, and the Japan Research Foundation for Clinical Pharmacology. He is also a consultant and/or advisory board member for Sumitomo, Otsuka, Lundbeck, Takeda, and Shionogi. NI received speaker's honoraria from Sumitomo, Eisai, Takeda, Eli Lilly, Viatris, Janssen, Otsuka, Meiji, Shionogi, and Mitsubishi Tanabe and research grants from Eisai, Takeda, Sumitomo, and Otsuka. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Kato M Hori H Inoue T Iga J Iwata M Inagaki T Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis Mol Psychiatry 2021 26 118 33 10.1038/s41380-020-0843-0 32704061 2. Lewis G Marston L Duffy L Freemantle N Gilbody S Hunter R Maintenance or discontinuation of antidepressants in primary care N. Engl J Med 2021 385 1257 67 10.1056/NEJMoa2106356 34587384 3. Furukawa TA Cipriani A Cowen PJ Leucht S Egger M Salanti G Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis Lancet Psychiatry 2019 6 601 9 10.1016/S2215-0366(19)30217-2 31178367 4. Cipriani A Furukawa TA Salanti G Chaimani A Atkinson LZ Ogawa Y Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis Lancet 2018 391 1357 66 10.1016/S0140-6736(17)32802-7 29477251 5. Page MJ McKenzie JE Bossuyt PM Boutron I Hoffmann TC Mulrow CD The PRISMA 2020 statement: an updated guideline for reporting systematic reviews BMJ 2021 372 n71 10.1136/bmj.n71 33782057 6. DerSimonian R Laird N Meta-analysis in clinical trials Controlled Clin Trials 1986 7 177 88 10.1016/0197-2456(86)90046-2 3802833 7. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.2. wwwtrainingcochraneorg/handbook (2021). |
J Expo Sci Environ Epidemiol J Expo Sci Environ Epidemiol Journal of Exposure Science & Environmental Epidemiology 1559-0631 1559-064X Nature Publishing Group US New York 36750746 525 10.1038/s41370-023-00525-1 Comment Why we need a national repository of consumer product lead surveillance data Alex-Oni Kolapo [email protected] Sedlar Slavenka Hore Paromita [email protected] grid.238477.d 0000 0001 0320 6731 Bureau of Environmental Disease and Injury Prevention, New York City Department of Health and Mental Hygiene, 125 Worth Street, CN34C New York, NY USA 7 2 2023 7 2 2023 2023 33 2 157159 21 12 2022 12 1 2023 13 1 2023 (c) The Author(s) 2023 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit issue-copyright-statement(c) The Author(s), under exclusive licence to Springer Nature America, Inc. 2023 pmc"Is this a problem in the rest of the United States?" was a question posed by delegates from an international governmental agency during a meeting convened by the New York City (NYC) Department of Health and Mental Hygiene (DOHMH). The meeting was called to discuss the issue of elevated levels of lead in spices that were purchased in the representatives' country and associated with lead poisonings in NYC residents. "Is the issue of lead in spices seen in other jurisdictions across the United States?" asked the delegates. "If so, where are the supporting data?" While some research studies and case reports affirm that NYC is not the only jurisdiction contending with exposures to lead-containing consumer products [1-7], these types of findings may not always be reported or are released ad hoc and thus, cannot be sufficiently harnessed to show the potential depth of the issue. A comprehensive and systematically tracked national dataset could be an effective solution to address this need. Such a centralized repository of consumer product lead surveillance data could reveal the extent of product-related lead exposures around the United States and help to monitor associated trends. This data can also illuminate product use patterns among various demographics and inform intervention strategies to reduce potential lead exposures. Despite declines in blood lead levels of children and adults in the United States, lead exposures, including from lead-containing products , still occur, and because of the many harmful health effects of lead exposure often in the absence of symptoms prevention is key. Many factors are increasing the need for systematic monitoring of product-related lead exposures: (1) the growth of immigrant and refugee populations, who are disproportionately impacted by lead poisoning partly due to their use of lead-containing cultural products , (2) the proliferation of cross-cultural consumption of traditional foods, health remedies and similar products and (3) the interconnectedness of the global supply chain. Such a surveillance system has been in-place in NYC for over a decade. DOHMH receives blood lead test results for NYC residents and routinely investigates child and adult lead poisoning cases . During case investigations, DOHMH uses a detailed risk assessment questionnaire and conducts environmental sampling, when pertinent, to identify potential lead sources. Samples of products suspected to contain lead and that may be mouthed or ingested are collected by DOHMH and tested for lead by an accredited laboratory. Laboratory results for each sample collected, along with a description of the sample, including product name, usage and purchase source information are documented electronically in a proprietary Structured Query Language Server database. Through these investigations, DOHMH has identified a variety of lead-containing consumer products from around the world, such as certain foods, spices, health remedies, traditional cook or dish ware and cultural powders, used by diverse groups, including NYC's South Asian, Georgian and Mexican communities (Fig. 1) [12-16]. Lead-containing consumer products are the second most common potential source of lead exposure for NYC children; additionally, in approximately, 80% of NYC pregnant cases, imported products are a potential lead source .Fig. 1 Countries of purchase for products with detectable lead identified during NYC investigations, 2010-2022. Blue shading indicates countries where products with detectable lead levels were purchased, illustrating the global availability of lead-containing products. DOHMH's systematic monitoring of consumer product lead data has not only helped to identify new lead sources impacting New Yorkers but has also informed risk communication strategies for communities at an increased risk for lead poisoning due to use of such products . In addition, the identification of these types of products has driven enforcement activities to eliminate their availability in the local marketplace, resulting in the removal of tens of thousands of hazardous consumer products from NYC store shelves. Broader impact of the NYC data is evidenced by surveillance and enforcement by external agencies, product recalls, import alerts, national and international health alerts and investigative activities in the products' countries of origin (Fig. 2). Although the NYC consumer product lead surveillance dataset is robust, this data only provides a local perspective.Fig. 2 Selected actions triggered by NYC DOHMH consumer product surveillance, 2010-2022. NYC DOHMH uses a multi-pronged approach that incorporates enforcement and education activities to address lead-containing consumer products. NYC product surveillance has resulted in the removal of tens of thousands of hazardous consumer products from NYC stores and the issuance of press releases, consumer advisories, health alerts, import alerts and recalls. Some of these actions are illustrated in this figure. A national data repository can facilitate a solution An effort to track national lead data for the purpose of identifying populations at risk is not entirely new. The Centers for Disease Control and Prevention's Adult Blood Lead Epidemiology and Surveillance (ABLES) program has a similar purpose. ABLES collects blood lead level data from state programs to examine trends and guide interventions to prevent work-related lead exposures. As a result of this initiative, ABLES data has been used to monitor workplace lead exposure trends, initiate investigations and promote prevention interventions . A similar national surveillance system could be implemented for consumer product data collected during local and state lead poisoning investigations, whereby product-related information, such as product name, purchase source, usage patterns, supply chain details and lead concentration, along with associated blood lead levels, could be systematically reported. Since lead poisoning prevention programs across the country currently investigate cases of elevated blood lead levels to identify potential lead exposures, an opportunity to track non-paint lead sources already exists. Such a national repository of consumer product lead data could elucidate and quantify the extent of product-related lead exposures around the country, identify patterns of exposure and motivate data-driven solutions to address these types of exposures. Such evidentiary data can also inform policies aimed at removing lead sources at the countries of origin protecting consumers nationally and internationally by engaging global stakeholders, including international health authorities, non-governmental organizations and academics. The overall benefits of a national repository of consumer product lead surveillance data are evident and wide-ranging, with implications for case management, education, outreach and policy development. However, the groundwork must be laid federally to make this process standardized and effective, and ultimately, to be able to assess the issue on a national scale. Without a national dataset of lead-containing consumer products associated with elevated blood lead levels, an understanding of the magnitude of this issue will remain fragmented, leaving us to wonder, "Is this a problem in the rest of the United States?". Acknowledgements The authors acknowledge the contributions of the Bureau of Environmental Disease and Injury Prevention's staff including inspectors, nurses and other valued members of the bureau for their tireless work around identifying lead sources and reducing lead exposures for New York City's lead-poisoned children and adults. This work is partially supported by the Lead Poisoning Prevention and Surveillance grant from the Centers for Disease Control and Prevention (6NUE1EH001275-03-01) and a contract with New York State Department of Health, Lead Poisoning Prevention Program (DOH01-C30933GG-3450000). Author contributions All authors [KA, SS and PH] contributed to the conception, drafting and revision of content. Data availability Data generated and analyzed in support of this comment article is available on request from the corresponding authors. Competing interests The authors declare no competing interests. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Hore P Ahmed M Nagin D Clark N Intervention model for contaminated consumer products: a multifaceted tool for protecting public health Am J Public Health 2014 104 1377 83 10.2105/AJPH.2014.301912 24922141 2. Angelon-Gaetz KA Klaus C Chaudhry EA Bean DK Lead in spices, herbal remedies, and ceremonial powders sampled from home investigations for children with elevated blood lead levels - North Carolina, 2011-2018 Morb Mortal Wkly Rep 2018 67 1290 4 10.15585/mmwr.mm6746a2 3. Fellows KM Samy S Rodriguez Y Whittaker SG Investigating aluminum cookpots as a source of lead exposure in Afghan refugee children resettled in the United States J Expo Sci Environ Epidemiol 2022 32 451 60 10.1038/s41370-022-00431-y 35501355 4. U.S. Food and Drug Administration FDA warns consumers not to use Balguti Kesaria Ayurvedic Medicine due to high levels of lead. 2018. Accessed 22 Sep 2022. 5. Garcia P Haile J Notes from the field: lead poisoning in an infant associated with a metal Bracelet - Connecticut, 2016 Morb Mortal Wkly Rep 2017 66 916 10.15585/mmwr.mm6634a6 6. Woolf AD Woolf NT Childhood lead poisoning in 2 families associated with spices used in food preparation Pediatrics. 2005 116 e314 e318 10.1542/peds.2004-2884 16061585 7. Kappel M Kraushaar V Mehretu A Slater W Marquez E Notes from the field: childhood lead poisoning associated with turmeric spices - Las Vegas, 2019 Morb Mortal Wkly Rep 2021 70 1584 5 10.15585/mmwr.mm7045a4 8. Dignam T Kaufmann RB LeStourgeon L Brown MJ Control of lead sources in the United States, 1970-2017: Public health progress and current challenges to eliminating lead exposure J Public Health Manag Pract 2019 25 Suppl 1 S13 S22 10.1097/PHH.0000000000000889 30507765 9. The National Institute for Occupational Safety and Health (NIOSH). Lead. 2021. Accessed September 2022. 10. U.S. Centers for Disease Control and Prevention. Refugees and other newcomer persons resettled to the United States. 2022. Accessed September 2022. 11. Byrnes K 2007. The sharing of culture: Global consumerism. 2007. Accessed September, 2022. 12. Hore P Alex-Oni K Sedlar S Nagin D A spoonful of lead: A 10-year look at spices as a potential source of lead exposure J Public Health Manag Pract 2019 25 Suppl 1 S63 S70 10.1097/PHH.0000000000000876 30507772 13. Hore P Ahmed MS Sedlar S Saper RB Nagin D Clark N Blood lead levels and potential risk factors for lead exposures among South Asians in New York City J Immigr Minor Health 2017 19 1322 9 10.1007/s10903-016-0403-5 27015835 14. 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Childs Nerv Syst Childs Nerv Syst Child's Nervous System 0256-7040 1433-0350 Springer Berlin Heidelberg Berlin/Heidelberg 36220936 5698 10.1007/s00381-022-05698-y Case Report Hemidystonia secondary to pediatric thalamic glioblastoma: a case report Wolff Fernandes Filipe [email protected] Saryyeva Assel Ertl Philipp Krauss Joachim Kurt grid.10423.34 0000 0000 9529 9877 Department of Neurosurgery, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany 12 10 2022 12 10 2022 2023 39 2 557559 21 8 2022 28 9 2022 (c) The Author(s) 2022 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Introduction Thalamic tumors are rare and uncommonly manifest as movement disorders, including hemidystonia. Despite this association, little is known about the evolution of hemidystonia. Case description We report on a 11-year-old boy who complained of hypaesthesia and fine motor problems in the left hand. A magnetic resonance imaging showed a large mass in the right thalamus. Stereotactic biopsy revealed a WHO grade 4 astrocytoma, and the patient underwent normofractioned radiochemotherapy with proton-beam radiation and temozolomide. Three months later, a spastic hemiparesis developed on the left side, which progressed over months. Over the following months, the hemiparesis slowly improved, but hemidystonia in the same side developed. This was accompanied with radiological evidence of tumor regression, showing a persistent lesion in the ventral posterolateral and the intralaminar thalamus. Conclusion This case illustrates the unusual and complex temporal course of appearance and disappearance of hemidystonia along with the regression and growth in glioblastoma involving the thalamus. Supplementary Information The online version contains supplementary material available at 10.1007/s00381-022-05698-y. Keywords Glioblastoma Hemidystonia Hemiparesis Stereotactic biopsy Thalamus Medizinische Hochschule Hannover (MHH) (3118)Open Access funding enabled and organized by Projekt DEAL. issue-copyright-statement(c) Springer-Verlag GmbH Germany, part of Springer Nature 2023 pmcIntroduction Thalamic tumors account for about 1% of all intracranial tumors, appearing only rarely as glioblastoma . Movement disorders are quite uncommon in such tumors, occurring in only 1-9% of patients [2-4]. Hemidystonia typically is the manifestation of a structural lesion in the basal ganglia or in the thalamus developing only months or years after the lesion [3, 5-8]. Although cerebral tumors have been identified as a possible cause for hemidystonia, little is known about the evolution of this rare manifestation of dystonia . Here, we report on the transient appearance of hemidystonia in a child with a thalamic glioblastoma and its complex relationship both with tumor growth and hemiparesis. Case report A 11-year-old right-handed boy complained of headaches and nausea, followed by hypaesthesia in the left hand and fine motor problems. Magnetic resonance imaging (MRI) showed a large mass (28 x 30 x 35 mm) in the right thalamus (Fig. 1A). The tumor was enhancing inhomogeneously after application of gadolinium. Stereotactic biopsy revealed a WHO grade 4 astrocytoma, IDH1/2 wild-type, MGMT unmethylated. Concomitant radiochemotherapy with proton beam radiation (54.9 Gy) and temozolomide was administered.Fig. 1 Development of a thalamic glioblastoma in an 11-year-old boy. T2-weight axial MRI scans show the tumor at different stages. A The tumor appears as a hyperintense lesion in the right thalamus with a local mass effect. B At 6 months post-stereotactic biopsy, there is a marked enlargement of the tumor with involvement of the posterior limb of the internal capsule, and accompanying edema paralleled by a progressive left-sided spastic hemiparesis. C At 16 months post-biopsy, there is a marked regression of the tumor with a lesion affecting the ventral posterolateral and intralaminar thalamus paralleled by improvement of the hemiparesis and development of left-sided hemidystonia Three months later, a spastic hemiparesis developed on the left side, which was progressive over months, and the patient subsequently needed assistance with a wheel chair. He continued to take temozolomide according to monthly cycles. A MRI 6 months post-biopsy revealed tumor enlargement (39 x 30 x 43 mm) with tumor extension to the subthalamic region and compression of the internal capsule with massive edema (Fig. 1B). Over the following months, the hemiparesis slowly improved, but hemidystonia developed. A MRI 16 months post-biopsy showed tumor regression (18 x 19 x 14 mm) with a focal lesion in the ventral posterolateral and the intralaminar thalamus (Fig. 1C). The patient continued treatment with temozolomide. The hemidystonia was more evident when walking or performing daily activities as shown in the video (Online Resource 1). At 26 months post-biopsy, the Burke-Fahn-Marsden dystonia rating scale motor score was 28, and the disability score was 9. Family history for dystonia was negative. Over the next 2 months, the tumor recurred along with an increase of the left-sided hemiparesis and concurrent subsidence of hemidystonia. Discussion It has always been puzzling why tumors of the basal ganglia and thalamus present rarely with dystonia, tremor, or chorea, while discrete lesions in particular certain areas of the structures pertaining to the cortico-basal ganglia-thalamic-cortical circuitry are well known to underlie the development of movement disorders . In our case, the unusual temporal course of appearance and disappearance of hemidystonia along with the changes in imaging nevertheless allows to draw several conclusions. While movement disorders may rarely be caused primarily by the tumor affecting the subcortical sensorimotor loop [2-4], they may also appear subsequently to specific treatment measures including surgery, chemotherapy, or targeted radiotherapy . This has been exemplified by a recent study of Sadighi et al. reporting two patients in whom dystonia became manifest only after removal of thalamic tumors in a cohort of 83 patients . Of note, in our case dystonia became manifest only after radiotherapy lead to a marked reduction of the tumor volume but resulting in a thalamic lesion. Previous studies have shown that hemidystonia most often is associated with lesions of the anterior putamen often combined with lesions of the caudate, while thalamic lesions have been observed more rarely . The most common manifestation of dystonia secondary to thalamic lesions is focal hand dystonia is occasionally associated with sensory deficits, but few cases of hemidystonia have been described as well . While various sites in the thalamus have been described to be involved, our case clearly demonstrates a discrete lesion affecting both the ventral posterolateral and the intralaminar thalamus. In several instances, as of hemidystonia described earlier, a pre-existent or concomitant hemiparesis was an accompanying feature indicating involvement of the posterior limb of the internal capsule . While it is possible that the phenomenological appearance of dystonia is simply overshadowed by the presence of motor weakness, it has also been postulated that dystonia may be the result of faulty reorganization of subcortical circuitries in the presence of lesions in the sensorimotor loop. The dynamics in our case suggests that both are relevant. The prognosis of movement disorders associated with pediatric thalamic tumors is quite variable . The effect of medication is limited . The primary concern is to obtain control of tumor growth. As shown here, the later may be the primary determinant for the dynamics of the movement disorders in such cases. Supplementary Information Below is the link to the electronic supplementary material.Supplementary file1 Online Resource 1 Hemidystonia after the improvement of hemiparesis of the left side. First segment of the video corresponds to presentation 20 months post-biopsy, and the second segment at 26 months post-biopsy. (MP4 2822 KB) Author contribution Filipe Wolff Fernandes and Joachin Kurt Krauss prepared the first version of the manuscript. All authors were involved in taking care and the treatment. All authors critically reviewed, worked on the manuscript, and approved its final version. Funding Open Access funding enabled and organized by Projekt DEAL. Data Availability Upon reasonable request. Declarations Ethics approval and consent to participate This case report complies with the established ethics rules at Hannover Medical School. Consent for publication Verbal and written consent as obtained from the patients and his parents for the publication of this case report. Conflict of interest Joachim Kurt Krauss is a consultant for Boston Scientific and Medtronic. The authors Filipe Wolff Fernandes, Assel Saryyeva, and Philipp Ertl declare that there are no additional disclosures to report. No funds, grants, or other support was received. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Gupta A Shaller N McFadden KA Pediatric thalamic gliomas: an updated review Arch Pathol Lab Med 2017 141 10 1316 1323 10.5858/arpa.2017-0249-RA 28968159 2. Krauss JK Nobbe F Wakhloo AK Mohadjer M Vach W Mundinger F Movement disorders in astrocytomas of the basal ganglia and the thalamus J Neurol Neurosurg Psychiatry 1992 55 12 1162 1167 10.1136/jnnp.55.12.1162 1479396 3. Krauss JK Braus DF Mohadjer M Nobbe F Mundinger F Evaluation of the effect of treatment on movement disorders in astrocytomas of the basal ganglia and the thalamus J Neurol Neurosurg Psychiatry 1993 56 10 1113 1118 10.1136/jnnp.56.10.1113 8410011 4. Sadighi ZS Zabrowski J Boop FA Broniscer A Gajjar A Khan RB Clinical characteristics and long-term outcomes of movement disorders in childhood thalamic tumors Pediatr Neurol 2016 65 71 77 10.1016/j.pediatrneurol.2016.08.012 27773422 5. Marsden CD Obeso JA Zarranz JJ Lang AE The anatomical basis of symptomatic hemidystonia Brain 1985 108 2 463 483 10.1093/brain/108.2.463 4005532 6. Lee MS Marsden CD Movement disorders following lesions of the thalamus or subthalamic region Mov Disord 1994 9 5 493 507 10.1002/mds.870090502 7990845 7. Pettigrew LC Jankovic J Hemidystonia: a report of 22 patients and a review of the literature J Neurol Neurosug Psychiatry 1985 48 650 657 10.1136/jnnp.48.7.650 8. Krauss JK Mohadjer M Braus DF Wakhloo AK Nobbe F Mundinger F Dystonia following head trauma: a report of nine patients and review of the literature Mov Disord 1992 7 3 263 272 10.1002/mds.870070313 1620145 9. Narbona J Obeso JA Tunon T Martinez-Lage JM Marsden CD Hemi-dystonia secondary to localized basal ganglia tumour J Neurol Neurosurg Psychiatry 1984 47 704 709 10.1136/jnnp.47.7.704 6747646 10. Van Egmond ME Kuiper A Eggink H Sinke RJ Brouwer OF Verschuuren-Bemelmans CC Sival DA Tijssen MAJ Koning TJD Dystonia in children and adolescents: a systematic review and a new diagnostic algorithm J Neurol Neurosurg Psychiatry 2015 86 7 774 781 10.1136/jnnp-2014-309106 25395479 |
Parasitol Res Parasitol Res Parasitology Research 0932-0113 1432-1955 Springer Berlin Heidelberg Berlin/Heidelberg 36781471 7791 10.1007/s00436-023-07791-w Brief Report In memoriam: Theodor Hiepe (1929-2022) great German scholar of parasitology Matuschewski Kai [email protected] 1 Lucius Richard 1 von Samson-Himmelstjerna Georg 2 1 grid.7468.d 0000 0001 2248 7639 Dept. of Molecular Parasitology, Institute of Biology, Humboldt Universitat zu Berlin, 10115 Berlin, Germany 2 grid.14095.39 0000 0000 9116 4836 Institute for Parasitology and Tropical Veterinary Medicine, Freie Universitat Berlin, 14163 Berlin, Germany Handling Editor: Julia Walochnik 13 2 2023 13 2 2023 2023 122 4 10331035 27 1 2023 3 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Theodor Hiepe (1929-2022) was an outstanding researcher, a world-renowned scientist, a dedicated teacher and a great mentor. During his scientific career, which spanned over 60 years, he made major contributions to many different fields of parasitology. With the passing of Dr. h.c. mult. Theodor Hiepe in September 2022 the scientific community suffered a great loss. Keywords Zoonotic parasitic diseases Parasite control Small ruminants Applied parasitology Humboldt-Universitat zu Berlin (1034)Open Access funding enabled and organized by Projekt DEAL. issue-copyright-statement(c) Springer-Verlag GmbH Germany, part of Springer Nature 2023 pmcOn September, 2, 2022, the scientific community lost a great scholar, a highly regarded scientist, and a passionate mentor, Prof. Dr. Dr. h.c. mult. Theodor Hiepe. Theo, as his friends and close coworkers called him, devoted his entire life to understand and teach, the essence (das Wesen) of parasitism (Hiepe 1971). Everyone, who had the pleasure of meeting him, perceived him as a great thinker who has helped us understand more about the parasitic life style, the phenomenal complexity and inventory to adapt to animal hosts, the vast diversity of parasite species and life history traits, and the translational implications for parasite control. Theodor Hiepe was born in Weimar, Germany in 1929. After forced military service as a teenager towards the end of World War II and imprisonment following the liberation, he moved to Leipzig, former German Democratic Republic, to study veterinary medicine, where he later worked as an assistant at the animal hospital. In 1956, he was hired as chief veterinarian at the Leipzig Zoological Garden, and at that time initiated his scientific work on the control of ectoparasites, helminths, and coccidia of farm and zoo animals, with an emphasis on small ruminants (Hiepe 1956; Hiepe et al. 1959). Four years later, at the young age of 31, Theodor Hiepe was appointed to the Chair of Parasitology and Veterinary Zoology of the Faculty of Veterinary Medicine at the capital university, Humboldt Universitat zu Berlin. He succeeded Alfred Borchert, who was renown for his surveys on diseases of bees. Theodor Hiepe initiated a broad research agenda and established four working groups, namely protozoology, helminthology, arachno-entomology, and diagnostics. Throughout his 35 years as head of the parasitology institute, Theodor Hiepe maintained a particular scientific interest in translating laboratory findings to parasite control and understanding immune processes in parasite infections. Theodor Hiepe's main research areas were zoonotic parasitic diseases, parasite control strategies, and parasitic diseases of small ruminants, e.g., sheep and goats. His research was marked by his persistence, attention to detail and rigorous standards. Early on, parasite diagnostics were a major mandate of the institute, and on average 1000 samples/month were processed and examined. In the 1960s, infections with Dictyocaulus viviparus (bovine lungworm) amounted to annual losses of thousands of young cattle, since well-tolerated anthelmintics or the highly effective, radiation-attenuated larval bovine lungworm vaccine (Jarret et al. 1958) were not yet readily available (Hiepe 1964). Similarly, appr. 75% of the livers of grazing cattle and sheep were infested with Fasciola hepatica (liver fluke) (Hiepe und Grunwoldt 1965). Theodor Hiepe's institute developed integrated parasite control approaches combining hygiene measures, presumptive treatment with antiparasitic drugs and on-farm training (Hiepe 1961; Hiepe et al. 1963). Likewise, long-lasting control of large flies of the genus Hypoderma (warble flies) became increasingly important largely due to their economic impact on cattle and small ruminants. After an impressive survey of over 150,000 heifers and cows to establish the seasonal dynamics of Hypoderma bovis infestation in cattle and treatment efficacy (Mieth et al. 1969), a control program based on a mathematical model was developed in cooperation with practicing veterinarians. In iterative steps, first in individual cattle herds, followed by municipalities, counties, districts, and eventually the entire country, eradication of the H. bovis was successful in as few as 4 years (Hiepe et al. 1974). This accomplishment prompted a large-scale bilateral project between the former German Democratic Republic and Mongolia, which was financed for 20 years with the aim to eradicate hypodermosis and market Mongolian rawhide globally (Hiepe et al. 1973; Hiepe and Splisteser 1976). Although the ambitious goal of country-wide eradication of major ectoparasites on-farm animals was not met, control of H. bovis and Hypoderma lineatum was very successful and established the foundation for national control programs (Ribbeck et al. 1979). Theodor Hiepe took great pride in that neither he nor any of his coworkers participated in opportunistic political activities and stayed clear of any party memberships. He intuitively and positively followed Hermann Hesse's belief that the antagonist of the intellectual is the party member, who can be put into service again and again. Strikingly, thanks to his international recognition and merits, he was permitted to travel regularly to congresses and meetings in Western Europe. His numerous academic and scientific merits include honorary doctorates from the University of Veterinary Medicine in Vienna, Austria and the University of Leipzig, Germany. He was a leading member of the German Academy of Natural Scientists Leopoldina, the actual National Academy of Sciences, and a founding member of the Berlin-Brandenburg Academy of Sciences after the fall of the Berlin Wall. Two parasite species were named after him: Eimeria hiepei, a hepatic coccidian parasite in the American mink (Neovison vison) (Grafner et al. 1967), and Madathamugadia hiepei, a filarial worm in Turner's thick-toed gecko (Chondrodactylus turneri) in Southern Africa and likely transmitted by sand flies (Phlebotominae) (Hering-Hagenbeck et al. 2000). Theodor Hiepe is widely recognized in the German-speaking community for his instructive academic textbooks. His first book on diseases of sheep (Hiepe 1970), which has continuously evolved over half a century (Bostedt et al. 2021), remains the authoritative textbook on diseases of small ruminants. Together with Regine Ribbeck, Renate Buchwalder, and Ruth Jungmann, he published a multi-volume textbook of parasitology (Hiepe et al. 1981; Hiepe et al. 1985; Hiepe and Ribbeck 1982; Hiepe and Jungmann 1983). Similarly, remembered is the more recent course book on general parasitology (Hiepe et al. 2006). His scholarial and scientific achievements were furthermore acknowledged by the German Society for Parasitology who's honorary member he became in 2012 and which awarded him with the prestigious Rudolphi and Leuckart medals in 1997 and 2000, respectively. In 1997, he also became an honorary member of the World Association for the Advancement of Veterinary Parasitology (WAAVP). Already in 1989 and in the still divided Berlin (and until to date the only time in Germany), he had organized with great success the biannual meeting of this global association of veterinary parasitologists (Eckert 2013). He was an immensely intelligent man and an outstanding scholar. His passion for parasitology and his insights into parasite/host dynamics inspired generations of early career scientists. He will be sadly missed (Fig. 1). Fig. 1 Theodor Hiepe (1929-2022) Author contribution Kai Matuschewski, Richard Lucius, and Georg von Samson-Himmelstjerna wrote the article and reviewed and edited the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Data availability Access to the photograph of Prof. Dr. Dr. h.c. mult. Theodor Hiepe is available upon request. Declarations Ethics approval Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Conflict of interest The authors declare no competing interests. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References Bostedt H Ganter M Hiepe T Klinik der Ziegenkrankheiten [Sheep and goat disease clinic] 2021 2 Stuttgart, Germany Thieme Verlag Eckert J World Association for the Advancement of Veterinary Parasitology (WAAVP): the 50th anniversary in 2013 - History, achievements, and future perspectives Vet Parasitol 2013 195 206 217 10.1016/j.vetpar.2013.04.002 23683652 Grafner G Graubmann HD Dobbriner W Hepatic coccidiosis in minks (Lutreola visono Schreb.) caused by a newly identified species of coccidiae (Eimeria hiepei n. sp.) Monatsh Veterinarmed 1967 22 696 700 5627647 Hering-Hagenbeck S Booker J Petit G Killick-Kendrick M Bain O Description of Madathamugadia hiepei n. sp. (Nematoda: Splendidofilariinae), a parasite of a South African gecko, and its development in laboratory bred Phlebotomus dubosqi (Diptera: Psychodidae) System Parasitol 2000 47 207 213 10.1023/A:1006452620865 Hiepe T Beitrag zur Technik der Ektoparasitenbekampfung bei Schafherden [Control of ectoparasites on sheep by pressure-spraying with powdered parasiticides] Monatsh Veterinarmed 1956 11 490 492 Hiepe T Erfahrungsbericht uber die Durchfuhrung des Schafherdengesundheitsdienstes und die dabei beobachteten Herdenkrankheiten [Experiences of the sheep health service in East Germany] Monatsh Veterinarmed 1961 16 283 288 Hiepe T Zur Bekampfung der Dictyocaulose in Rinderbestanden unter den Bedingungen einer intensiven Grossraumwirtschaft [Control of dictyocaulosis in cattle under conditions of intensive large-scale farming] Wiss Z Humboldt-Univ Berl 1964 13 605 610 Hiepe T Schafkrankheiten [Sheep diseases] 1970 Jena, Germany Gustav Fischer Verlag Hiepe T Thesen zum Vortrag uber das Wesen des Parasitismus [Propositions on the lecture on the nature of parasitism] Angew Parasitol 1971 11 129 130 Hiepe T Grunwoldt J Untersuchungen uber den Leberegelbefall bei Rindern unter besonderer Berucksichtigung des Fleischbeschaubefundes [Investigations on liver fluke infection in cattle with particular reference to meat inspection reports] Berlin Munch Tierarztl Wochenschr 1965 78 114 115 Hiepe T Jungmann R Veterinarmedizinische Protozoologie [Veterinary protozoology] Lehrbuch der Parasitologie Vol. 2 1983 Jena, Germany Gustav Fischer Verlag Hiepe T Ribbeck R Veterinarmedizinische Arachno-Entomologie [Veterinary arachno-entomology] Lehrbuch der Parasitologie Vol. 4 1982 Jena, Germany Gustav Fischer Verlag Hiepe T Splisteser H Durchfuhrung und gegenwartiger Stand der planmassigen Hypodermosebekampfung in der Mongolischen Volksrepublik [Latest developments in planned control of hypodermatosis in the Mongolian People's Republic] Monatsh Veterinarmed 1976 31 390 393 Hiepe T Heide D Lippmann R Erfahrungen mit Cyanessigsaurehydrazid (CESH) in der Bekampfung des Lungenwurmbefalles beim Schaf [Experience with cyacetacide in the control of lungworm infestation in sheep] Berl Munch Tierarztl Wochenschr 1959 72 315 319 Hiepe T Jungmann R Manzer A Untersuchungen uber die Anwendung von Zyanazethydraziden bei der Lungenwurmbekampfung in Rinderbestanden [Cyacetacide in the control of lung worms in cattle] Monatsh Veterinarmed 1963 18 697 702 Hiepe T Splisteser H Rauch H Ein Beitrag zur Zusammenarbeit des Veterinarwesens der Deutschen Demokratischen Republik und der Mongolischen Volksrepublik [Cooperation between the veterinary services of East Germany and Mongolia] Monatsh Veterinarmed 1973 28 561 562 Hiepe T Ribbeck R Mieth K Garz I Ergebnisse der staatlich geleiteten, planmassigen Hypodermosebekampfung in der Deutschen Demokratischen Republik [Results of the state-directed systematic campaign for the control of Hypoderma in the German Democratic Republic] Angew Parasitol 1974 15 57 67 4849632 Hiepe T Buchwalder R Ribbeck R Allgemeine Parasitologie [General parasitology] Lehrbuch der Parasitologie Vol. 1 1981 Jena, Germany Gustav Fischer Verlag Hiepe T Buchwalder R Nickel S Veterinarmedizinische Helminthologie [Veterinary helminthology] Lehrbuch der Parasitologie Vol. 3 1985 Jena, Germany Gustav Fischer Verlag Hiepe T Lucius R Gottstein B Allgemeine Parasitologie - Mit den Grundzugen der Immunologie, Diagnostik und Bekampfung [General parasitology - principles of immunology, diagnostics and control] 2006 Stuttgart MVS Medizinverlage Jarret WFH Jennings FW Martin B Mcintyre WIM Mulligan W Sharp NCC Urquhart GM A field trial of a parasitic bronchitis vaccine Vet Rec 1958 70 451 454 Mieth K Hiepe T Ribbeck R Eschholz H Gahtow I Kratschmer H Theus J Dynamics of Hypoderma bovis infestation in cattle I. Appearance of 3rd-stage larvae under the skin of the back, with particular reference to late-appearing larvae Monatsh Veterinarmed 1969 24 8 14 5407783 Ribbeck R Splisteser H Rauch H Hiepe T Probleme der Ektoparasitenbekampfung in der Mongolischen Volksrepublik [Problems in the control of ectoparasites in the Mongolian People's Republic] Angew Parasitol 1979 20 221 229 547747 |
Arch Virol Arch Virol Archives of Virology 0304-8608 1432-8798 Springer Vienna Vienna 36899117 5733 10.1007/s00705-023-05733-6 Brief Report A novel vesivirus (family Caliciviridae) in European badgers (Meles meles) in Hungary, 2020/2021 Reuter Gabor [email protected] 1 Pankovics Peter 1 Nagy Gabor 2 Szekeres Sandor 3 Boros Akos 1 1 grid.9679.1 0000 0001 0663 9479 Department of Medical Microbiology and Immunology Medical School, University of Pecs, Szigeti ut 12, H-7624 Pecs, Hungary 2 Department of Animal Physiology and Health, Hungarian University of Agriculture and Life Science, Kaposvar Campus, Kaposvar, Hungary 3 grid.483037.b 0000 0001 2226 5083 Department of Parasitology and Zoology, University of Veterinary Medicine, Budapest, Hungary Communicated by Pablo Pineyro 11 3 2023 11 3 2023 2023 168 4 10811 1 2023 18 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit In this study, a novel vesivirus (family Caliciviridae) was detected and characterized in faecal and tissue (blood and spleen) specimens collected from three (23.1%) out of 13 European badgers (Meles meles) in Hungary that were tested using RT-PCR and sequencing methods. The complete genome of the vesivirus strain European badger/B40/2021/HUN (OQ161773) is 8,375 nucleotides in length. The ORF1, ORF2, and ORF3 proteins have 81.1%, 70.5%, and 64.2% amino acid sequence identity, respectively, to the corresponding proteins of Asian badger vesivirus, which was first reported in badgers in China in 2022. These results indicate that more than one lineage/species of vesiviruses circulates in mustelid badgers in geographically different regions. Supplementary Information The online version contains supplementary material available at 10.1007/s00705-023-05733-6. National Research, Development and Innovation Office FK134311 University of PecsOpen access funding provided by University of Pecs. issue-copyright-statement(c) Springer-Verlag GmbH Austria, part of Springer Nature 2023 pmcThe family Caliciviridae includes viruses with a linear, positive-sense single-stranded RNA genome of 6.4-8.5 kb with two to three open reading frames (ORFs). The family consists of 11 genera that include caliciviruses of mammals (Lagovirus, Norovirus, Nebovirus, Recovirus, Sapovirus, Valovirus, and Vesivirus), birds (Bavovirus and Nacovirus), and fish (Minovirus and Salovirus) . Members of the genus Vesivirus have three ORFs. ORF1 encodes the nonstructural polyprotein (NS), which is post-translationally cleaved into six proteins. ORF2 and ORF3 encode the viral capsid proteins: the major capsid protein, VP1, and the minor basic protein, VP2, respectively. ORF1 and ORF2 are separated by either 2 nt (GC for feline calicivirus) or 5 nt (CCACT/C for marine vesiviruses) . Vesiviruses have been identified in a wide range of terrestrial (e.g., cat, dog, swine, mink, rabbit, and cattle) and marine (e.g., San Miguel sea lion) mammals. However, there are only limited data available about vesivirus infections and diseases in humans [2-5]. Vesicular exanthema of swine virus (VESV) is the prototype vesivirus causing clinical signs of vesicles and fetal damage in swine. At present, there are two official vesivirus species, Vesicular exanthema of swine virus and Feline calicivirus, but several others are awaiting recognition . Vesivirus has been reported recently in Asian badgers (Meles leucurus), which are frequently traded and consumed game animals in China . Fifteen species of mustelid badgers are known. The European badger (Meles meles) is native to almost all of Europe, extending to the Volga River in the East. It is a carnivorous and highly adaptable and opportunistic omnivore whose diet encompasses a wide range of animals and plants. The European badger is found in deciduous and mixed woodlands, clearings, spinneys, pastureland, and scrub. It has also adapted to life in suburban areas and urban parks [7; In this study, a novel vesivirus was identified in faecal and tissue specimens collected from European badgers, and its complete genome sequence was determined. A total of 13 faecal specimens were collected from European badgers (eight females and five males) between May 2020 and April 2021 in South Transdanubia (Baranya and Somogy Counties) in Hungary (Supplementary Table S1). Available tissue specimens (blood, thigh muscle, diaphragm, and spleen) from selected animals were also tested. Badgers were either legally hunted by a professional hunter with the approval of the national control program for wildlife or were found dead due collisions with vehicles. Viral RNA was isolated using TRIzol Reagent (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer's instructions. A conventional RT-PCR method was applied using a newly designed common vesivirus screening primer pair (vesivirus-screen-F, 5'-GCTGAAGCCGAGGGAAAGGTT-3', corresponding to nt 3674-3694 of the study strain European badger/B40/2021/HUN, OQ161773, and vesivirus-screen-R, 5'-GCCTTYTGTCCCAACACATAG-3,' corresponding to nt 3831 - 3811 of the study strain) based on the border of VPg/Pro of the genome sequences of mink calicivirus (MF677852), San Miguel sea lion calicivirus (KM244552), Asian badger vesivirus (OM480529), and ferret-badger vesivirus (KJ701554). The complete vesivirus genome was amplified and sequenced by various RT-PCR techniques (3'/5' RACE PCR and long-range PCR) using primers designed based on the sequences of the closest vesivirus relatives and by the "primer-walking" method. PCR products were sequenced directly by the Sanger method using a BigDye Terminator v1.1 Cycle Sequencing Kit (Thermo Fisher Scientific), using an automated sequencer (AB3500 Genetic Analyzer, Applied Biosystems, Hitachi, Tokyo, Japan). Three (specimens B10, B40, and B41) of the 13 faecal samples from European badger were RT-PCR-positive for vesivirus (Supplementary Table S1). The complete genome sequence of European badger vesivirus strain European badger/B40/2021/HUN (OQ161773) was determined from one selected sample (B40). The European badger/B40/2021/HUN genome is 8,375 nt long, excluding the poly(A) tail (Fig. 1). The genome has three ORFs. ORF1 is 5,742 nt long and encodes a 1,913-aa-long nonstructural NS polyprotein with 81.1% aa sequence identity (query coverage, 99%) to the corresponding nonstructural polyprotein of Asian badger vesivirus (OM480529), its closest match in the GenBank database. ORF2 is 2,106 nt long and it encodes a 701-aa-long VP1 capsid protein with 70.5% aa sequence identity (query coverage, 100%) to the corresponding VP1 protein of Asian badger vesivirus (OM451121), its closest match in the GenBank database. Alignment of the aa sequence revealed the presence of a potential leader capsid (LC) of VP1 with the capsid cleavage site FRAE170/S (Fig. 1). ORF3 is 411 nt long and encodes a 136-aa-long VP2 minor basic capsid protein with 64.2% aa sequence identity (query coverage, 90%) to the corresponding VP2 protein of Asian badger vesivirus (OM480529), its closest match in the GenBank database. ORF1 and ORF2 of European badger vesivirus are separated by 3 nt (GCG instead of GC for Asian badger vesivirus), such that ORF1 and ORF2 are in the same reading frame (Fig. 1). The 5' and 3' untranslated regions (UTR) are 13 and 104 nt long, respectively. Fig. 1 Schematic genome organization (line) and protein products (box) of European badger vesivirus strain European badger/B40/2021/HUN (OQ161773). The complete genome and protein map are drawn to scale. Nucleotide (nt) sequences of the extreme 5' untranslated region (UTR) and the border of the open reading frames ORF1/ORF2 and ORF2/ORF3 are shown with stop and start codons. Also shown are the conserved caliciviral amino acid (aa) motifs, first and last amino acids of the ORFs, and the predicted P4/P4' protein cleavage sites The three European badger vesivirus isolates from this study (B10, B40, and B41) differed in their nucleotide sequences. In the 116-nucleotide-long amplified common region (ORF1), there was 89-93% nucleotide sequence identity between the strains. The 4,703-long 3' part (partial ORF1, complete ORF2/ORF3 and 3'UTR) of the European badger/B10/2020/HUN (OQ161774) and European badger/B41/2021/HUN (OQ161775) genomes were also sequenced. The ORF2 of European badger/B10/2020/HUN and European badger/B41/2021/HUN (OQ161775) showed 84/85% nt and 94/95% aa sequence identity, respectively to the corresponding nt and aa sequences of the strain European badger/B40/2021/HUN. Phylogenetic analysis based on amino acid sequences of the NS (ORF1) and VP1 (ORF2) proteins showed that the European badger vesiviruses were clustered together with vesiviruses from Asian badgers and ferret badgers (Melogale moschata) from China, with the three European badger vesivirus variants forming a distinct lineage (Fig. 2). Fig. 2 Phylogenetic analysis based on amino acid sequences of (A) NS (ORF1) and (B) VP1 (ORF2) proteins of the study strains European badger/B40/2021/HUN (OQ161773), European badger/B10/2020/HUN (OQ161774), and European badger/B41/2021/HUN (OQ161775) (in bold) and representative members of the genus Vesivirus. Norwalk virus (genus Norovirus) was used as an outgroup. Neighbor-joining trees were generated from MUSCLE-based amino acid (aa) alignments using the Jukes-Cantor model and 1000 bootstrap replicates in MEGA 11 software . The scale bars indicate the number of aa substitutions per site. The designation of the sequences is as follows: virus name, isolate or strain name, accession number in brackets.The two officially classified vesivirus species are indicated by dotted lines Available tissue samples (blood, thigh muscle, diaphragm, and spleen) from animals (B10, B40, and B41) that had vesivirus-positive faecal specimens were also investigated by RT-PCR using the screening primers. Vesivirus RNA was found in all of the blood (N = 3) and spleen (N = 3) samples by RT-PCR and sequencing; however, viral RNA was not detected in muscle (thigh muscle and diaphragm) specimens (Supplementary Table S1). Vesiviruses have been shown to be capable of infecting a variety of terrestrial and marine mammal host species, raising concern about their zoonotic potential [2-5]. In this study, a novel vesivirus from European badgers in Europe was identified and characterized. The European badger vesivirus forms a common (phylo)genetic cluster with vesiviruses from Asian badger , Chinese ferret-badger , mink , and San Miguel sea lion (SMSV8, ; Knowles et al., unpublished). While the European badger vesivirus genome sequence had the highest sequence similarity to a vesivirus identified recently in Asian badgers in China, these two groups of badger vesiviruses are significantly different genetically (and likely antigenically), with 29.5% aa sequence difference in VP1. This indicates that more than one lineage or species of vesiviruses circulates in mustelid badgers in geographically different regions. There are only two officially recognized vesivirus species in the genus Vesivirus (family Caliciviridae): the species Vesicular exanthema of swine virus and the species Feline calicivirus ). However, several further unclassified vesiviruses from different host species are awaiting species classification, including a cluster of vesiviruses from dogs, minks, San Miguel sea lions (SMSV types 8 and 12), badgers, and ferrets. Some types of vesiviruses have been associated with skin lesions, hepatitis, abortions, pneumonia, diarrhoea, and encephalitis in animals [11-13] and humans . Skin and mucosal diseases are associated with itching vesicles, blisters, or skin ulcers . In our study, vesivirus RNA was detected not only in faecal specimens but also in available tissue samples (blood and spleen) in all three vesivirus-infected badgers. This suggests that the badger is a host species of this vesivirus and that viral RNA (or infectious virions) enters into the bloodstream and may cause viremia and generalized infections. In our study, two of the three animals infected with vesivirus were clinically healthy without visible skin lesions (blisters or ulcers); however, animal B40 had a minor skin abrasion of unknown origin/aetiology (potentially from physical injuries) in the neck area. In contrast to other caliciviruses (e.g., noroviruses), some types of vesiviruses receive relatively little clinical and scientific attention. A common screening RT-PCR primer pair (Vesivirus-screen-F/R) was designed in this study based on the cluster of known vesivirus genome sequences from badgers, ferret-badgers, and minks and the SMSV8 sequence from San Miguel sea lions, which are suitable for molecular epidemiological studies and further discovery of novel vesiviruses. Electronic supplementary material Supplementary Table S1 Acknowledgements This work was financially supported by a grant from the National Research, Development and Innovation Office, Hungary (FK134311). Funding National Research, Development and Innovation Office, Hungary (NKFIH FK134311). Open access funding provided by University of Pecs. Declarations Conflict of Interest The authors declare that they have no conflict of interest. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Vinje J Estes MK Esteves P Green KY Katayama K Knowles NJ L'Homme Y Martella V Vennema H White PA ICTV virus taxonomy profile: Caliciviridae J Gen Virol 2019 100 1469 1470 10.1099/jgv.0.001332 31573467 2. Smith AW Iversen PL Skilling DE Stein DA Bok K Matson DO Vesivirus viremia and seroprevalence in humans J Med Virol 2006 78 693 701 10.1002/jmv.20594 16555277 3. Lee H Cho YH Park JS Kim EC Smith AW Ko G Elevated post-transfusion serum transaminase values associated with a highly significant trend for increasing prevalence of anti-Vesivirus antibody in Korean patients J Med Virol 2012 84 1943 1952 10.1002/jmv.23422 23080501 4. Di Martino B Di Profio F Lanave G De Grazia S Giammanco GM Lavazza A Buonavoglia C Marsilio F Antibodies for strain 2117-like vesiviruses (caliciviruses) in humans Virus Res 2015 210 279 282 10.1016/j.virusres.2015.08.016 26319448 5. Desselberger U Caliciviridae other than noroviruses Viruses 2019 11 3 286 10.3390/v11030286 30901945 6. He WT Hou X Zhao J Sun J He H Si W Wang J Jiang Z Yan Z Xing G Lu M Suchard MA Ji X Gong W He B Li J Lemey P Guo D Tu C Holmes EC Shi M Su S Virome characterization of game animals in China reveals a spectrum of emerging pathogens Cell 2022 185 7 1117 1129 10.1016/j.cell.2022.02.014 35298912 7. Wozencraft WC (2005) Order carnovora. In: Wilson DE, Reeder DAM eds., Mammal species of the world: A taxonomic and geographic reference. 3rd edition, The Johns Hopkins University Press, Baltimore, Maryland, USA, pp. 532-628 8. Miao FM, Li YH, Liu Y, Zhang SF, Miao FC, Zhao JH, Hu RL (2015) Novel calicivirus from a ferret badger (Melogale moschata) in China.Arch Virol, ;1601797-1800 9. Yang B Wang F Zhang S Xu G Wen Y Li J Yang Z Wu H Complete genome of a mink calicivirus in China J Virol 2012 86 13835 10.1128/JVI.02582-12 23166245 10. Neill JD The complete genome sequence of the San Miguel sea lion virus-8 reveals that is not a member of the Vesicular exanthema of swine virus/San Miguel sea lion virus species of the Caliciviridae Genome Announc 2014 2 e01286 e01214 10.1128/genomeA.01286-14 25502676 11. Kurth A Skilling DE Smith AW Serologic evidence of vesivirus-specific antibodies associated with abortion in horses Am J Vet Res 2006 67 6 1033 1039 10.2460/ajvr.67.6.1033 16740098 12. Renshaw RW Griffing J Weisman J Crofton LM Laverack MA Poston RP Duhamel GE Dubovi EJ Characterization of a vesivirus associated with an outbreak of acute hemorrhagic gastroenteritis in domestic dogs J Clin Microbiol 2018 56 5 e01951 e01917 10.1128/JCM.01951-17 29444830 13. Hoffmann-Lehmann R Hosie MJ Hartmann K Egberink H Truven U Tasker S Belak S Boucraut-Baralon C Frymus T Lloret A Marsilio F Pennisi MG Addie DD Lutz H Thiry E Radford AD Mostl K Calicivirus infection in cats Viruses 2022 14 5 937 10.3390/v14050937 35632680 14. Tamura K Stecher G Kumar S MEGA11: Molecular Evolutionary Genetics Analysis version 11 Mol Biol Evol 2021 38 3022 3027 10.1093/molbev/msab120 33892491 |
Childs Nerv Syst Childs Nerv Syst Child's Nervous System 0256-7040 1433-0350 Springer Berlin Heidelberg Berlin/Heidelberg 36355194 5620 10.1007/s00381-022-05620-6 Case Report Managing an open nasofrontal encephalocele after birth Apostolou Nicolas [email protected] 1 Grafe Daniel 2 Knupfer Matthias 3 Krause Matthias 1 1 grid.411339.d 0000 0000 8517 9062 Department of Pediatric Neurosurgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany 2 grid.411339.d 0000 0000 8517 9062 Division of Neuroradiology, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany 3 grid.411339.d 0000 0000 8517 9062 Department of Neonatology, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany 10 11 2022 10 11 2022 2023 39 2 535540 25 5 2022 23 7 2022 (c) The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Encephaloceles are relatively uncommon in western countries. Most of the reported cases involve occipital encephaloceles. Open frontal encephaloceles comprise a rare entity. Most of them will be detected during early prenatal diagnostic, whereas the majority of the pregnancies will be terminated after the consent of the parents. Open frontal encephaloceles pose a great challenge to neurosurgeons as well as anesthesiologists, as these infants present with a microcephaly, non-physiological intracranial anatomy, and low birth weight, thus making the infant prone to excessive blood loss, hypothermia, and death. Neonates born with an incomplete cutaneous coverage are exposed to an imminent threat to life due to the risk of meningitis, necessitating surgical repair in the first days of life. We represent a rare case of an open nasofrontal encephalocele managed surgically in the first day of life. Surgery did not influence the neurological outcome of the patient. Keywords Case report Encephalocele Nasofrontal Universitatsklinikum Leipzig (8929)Open Access funding enabled and organized by Projekt DEAL. issue-copyright-statement(c) Springer-Verlag GmbH Germany, part of Springer Nature 2023 pmcIntroduction Encephalocele is usually a congenital type of neural tube defect (NTD), where a sac containing brain/meninges/cerebrospinal fluid (CSF) forms outside the skull through a bone defect. On occasions, acquired, encephaloceles may result from trauma, tumors, or iatrogenic injury. If the sac is formed by protrusion of meninges and CSF, it is appropriately called a meningocele, but it is called an encephalocele when it contains brain tissue . Encephaloceles are classified according to the anatomical defect location and the herniated contents . Surgical repair of the encephalocele does not require always an immediate surgical intervention. In the case of an incomplete cutaneous coverage, a rapid surgery is required due to the high risk of meningitis [1, 4-8]. Approximately 70 to 90% of encephaloceles involve the occipital area [9-11]. Frontoethmoidal encephaloceles are extremely rare, with an incidence of 1 in 35,000 live births . They result from CNS herniation through the anterior skull at the junction of the frontal and ethmoidal bones . The subgroup of nasofrontal encephaloceles herniates at the junction of the frontal and nasal bones resulting in deformation of the nasal bones and supraorbital ridge . Here, we present a case of an open nasofrontal encephalocele requiring an immediate surgical reconstruction within the first 24 h of life. Case presentation Our male patient was born at 35 weeks + 6 days. During the fetal malformation scan, the family was informed about the encephalocele and decided to continue with the pregnancy. The delivery was performed by a caesarean section. The baby was immediately transferred to our University Hospital and the defect was secured in sterile covers. The patient was admitted in a stable, awake condition. The pupils were fully dilated and irresponsive to light. There was no apparent neurological deficit. We performed preoperatively an MRI and MR-angiography (Figs. 1 and 2), revealing an anatomical malposition of the hemispheres as well as an altered arterial supply. We decided for a mid-facial incision, reducing the bleeding and avoiding unnecessary injury in comparison to a bicoronal approach. The incision was made from the level of coronal suture and ending on nasion (Fig. 3). The entire operation was performed microsurgically. The herniated brain needed to be resected en bloc. The periorbital bone was exposed and explored. No bone defect was found (Fig. 4). Gradually, we gained access to the frontal basis where complete bony closure was confirmed. As expected, there was a broad dural defect. The closure was achieved using Galea periosteum. In order to reconstruct the bony defect, we harvested a 2-cm-wide autologous split calvarial bone graft, from the parietal bone on the left site. The bone graft was fixated over the frontal defect using fibrin glue. Strategically, we created a fontanel that was primarily non existing. Due to the uncertain status of CSF circulation and enlarged ventricles, there was a high risk for development of hydrocephalus. The fontanel gave access to the ventricular system. Furthermore, we inserted an external ventricular drainage (EVD) under ultrasound Guidance. The skin was closed using 5-0 Monocryl sutures.The patient was discharged 12 days after the operation in a stable clinical status. The postoperative course was uneventful. The EVD could be removed after 3 days in the absence of signs of hydrocephalus. The follow-up clinical examinations would be performed through pediatric neurosurgeons and pediatric neurologists. The patient developed therapy-resistent epileptic seizures that required treatment with a combination of five different anti epileptic drugs. An MRI-scan 6 months after surgery prevailed a growing hydrocephalus. Upon these clinical and radiological findings, the implantation of a ventriculoperitoneal shunt was performed (Fig. 5).Fig. 1 Preoperatively MRI Scans. (Sagittal, Axial and Coronal). In the T2-weighted image scans the encephalocele is identified together with the monoventricle. On the coronal slide the 90-degree hemispheric rotation is to be noted Fig. 2 Preoperatively MR-Angiography Fig. 3 Intraoperative photographs showing the defect before the operation presenting the (a) nasofrontal encephalocele. Furthermore (b, c) presenting the midfacial incision and use of Raney Clips to avoid blood loss. The skin closure with 5-0 Monocryl sutures Fig. 4 A series of images showing the intraoperative Steps. At first mobilising the Encephalocele, followed by resecting it en toto. The closure of the bony defect using a bone flap from the parietal bone. Lumbar Drainage used as an external ventricle drainage Fig. 5 MRI Scan ( axial and coronal ) 6 months after Operation demonstrating the Hydrocephalus Discussion We present the second case of an open frontonasal encephalocele with pre and post MRI imaging. According to the pathogenesis, encephaloceles could be divided to primary and secondary (i.e., posttraumatic or iatrogenic origin). Although cases have been recorded since the sixteenth century, there is still a scarcity of knowledge on the exact causes and factors associated with the development of the disease. Many studies have determined these to be caused by a combination of genetic and environmental factors . As mentioned, a primary open encephalocele presents a very rare entity, taking into consideration the availability of the extensive intrauterine examination of the fetus throughout pregnancy. The defect is usually located at the Foramen cecum, anterior to the cribriform plate of the ethmoid bone, and posterior to the frontal bone, within the frontoethmoidal suture. A primary understanding of the anatomy before surgery is essential. We achieved it with a series of MRI scans including MR angiography. As shown on the MRI scans, we identified a 90deg anticlockwise rotation of the telencephalon. The unique anatomical variation was revealed including a singular ventricle, as well as the absence of transverse and sigmoid sinus. We were not able to identify the arteries of circle of Willis. The great responsibility of accompanying a neonate with an open encephalocele should be performed in clinical centers, where an experienced team of obstetricians, anaesthesiologists, neurosurgeons, and neonatologists work under the same roof. Surgery is prompted due to CSF leakage and exposed cerebral structures. The technical aspects of the operation, both from the anaesthesiological point of view and from our neurosurgical point of view, presented a high degree of challenge. The use of an EVD, and the creation of a fontanel (from removing a small bone from the parietal bone) gave us the great benefit of postoperatively controlling and excluding hydrocephalus. The ethical issue remains open to debate whether the operation was beneficial to our patient. From our point of view, the parents were aware of the situation of their unborn baby months since prenatal counselling and decided to carry on the pregnancy. During the informed consent, the parents were clear that a full treatment was desired, acknowledging the possible detrimental neurological development. Therefore, a conservative approach was not a treatment option. Conclusion We present the second case of an open nasofrontal encephalocele, urging to a surgical intervention within 24 h after birth. Despite the early surgical intervention as well the uneventful postoperatively course, the detrimental neurological developmental delay could not be influenced. Author contribution NA drafted the manuscript and collected all the clinical data. DG compiled the radiological data and imaging. MKnupfer revised the manuscript and additional clinical data. MKrause revised and finalized the manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Data availability Data and material are available. Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of the medical faculty (Ethikkommission Universitat Leipzig Az 330-13-18112013). Consent for publication Caregivers gave consent. Conflict of interest The authors declare no competing interests. Abbreviations NTD Neural tube defect CSF Cerebrospinal fluid CNS Central nervous system. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Gump WC Endoscopic endonasal repair of congenital defects of the anterior skull base: developmental considerations and surgical outcomes J Neurol Surg B Skull Base 2015 76 4 291 295 10.1055/s-0034-1544120 26225319 2. Suwanwela C,Sukabote C, Suwanwela N (1971) Frontoethmoidal encepahlomeningocele. Surgery 69:617-625 3. Andrewas BT, Meara JG (2010) Reconstruction of frontoethmoidal encephalocele defects. Atlas Oral Maxillofacial Surg Clin NAm 18:129-138 4. Singh AK, Upadyaya DN (2009) Sinsipital encephaloceles. J Craniofacial Surgery 20:1851-1855 5. Holmes AD, Meara JG, Kolker AR et al (2001) Frontoethmoidal encephaloceles: reconstruction and refinements. J Craniofac Surg 12(1):1-18 6. David DJ Sheffield L Simpson D Fronto-ethmoidal meningo-encepaloceles:morphology and treatment Br J Plast Surg 1984 37 271 284 10.1016/0007-1226(84)90067-5 6743894 7. Mahapapatra AK, Tandon PN, Dhawan IK, Khazanchi RK (1994) Anterior encepaloceles: a report of 30 cases. Childs Nerv System 10:510-504 8. French BN (1982) Midline fusion defect and defects of formation; in Youman JR(ed): Neurological Surgery ,ed 2. Philadelphia, Saunders, 3:1236-1287 9. Siffel C Wong LY Olney RS Correa A Survival of infants diagnosed with encephalocele in Atlanta, 1979-98 Paediatr Perinat Epidemiol 2003 17 1 40 48 10.1046/j.1365-3016.2003.00471.x 12562471 10. Arora P Mody S Kalra VK Altaany D Bajaj M Occipital meningoencephalocele in a preterm neonate BMJ Case Rep 2012 25 2012 11. Macfarlane R Rutka JT Armstrong D Phillips J Posnick J Forte V Humphreys RP Drake J Hoffman HJ Encephaloceles of the anterior cranial fossa Pediatr Neurosurg 1995 23 3 148 158 10.1159/000120952 8751296 12. David DJ (1984) New perspectives in the management of severe cranio-facial deformity. Ann R Coll Surg Engl 66:270-279 13. Tirumandas M, Sharma A, Gbenimacho I, Shoja MM, Tubbs RS, Oakes WJ, Loukas M Nasal encephaloceles: a review of etiology, pathophysiology, clinical presentations, diagnosis, treatment, and complications |
J Comp Physiol A Neuroethol Sens Neural Behav Physiol J Comp Physiol A Neuroethol Sens Neural Behav Physiol Journal of Comparative Physiology. A, Neuroethology, Sensory, Neural, and Behavioral Physiology 0340-7594 1432-1351 Springer Berlin Heidelberg Berlin/Heidelberg 36813948 1621 10.1007/s00359-023-01621-1 Editorial Functional morphology and biomechanics of arthropods Wan Chao [email protected] 13 Gorb Stanislav [email protected] 2 1 grid.43555.32 0000 0000 8841 6246 Department of Mechanics, School of Aerospace Engineering, Beijing Institute of Technology, Beijing, China 2 grid.9764.c 0000 0001 2153 9986 Functional Morphology and Biomechanics, Zoological Institute, Kiel University, Kiel, Germany 3 grid.43555.32 0000 0000 8841 6246 Tangshan Research Institute, Beijing Institute of Technology, Tangshan, China 22 2 2023 22 2 2023 2023 209 2 215218 4 9 2022 8 2 2023 10 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Representatives of arthropods, the largest animal phylum, occupy terrestrial, aquatic, arboreal, and subterranean niches. Their evolutionary success depends on specific morphological and biomechanical adaptations related to their materials and structures. Biologists and engineers have become increasingly interested in exploring these natural solutions to understand relationships between structures, materials, and their functions in living organisms. The aim of this special issue is to present the state-of-the-art research in this interdisciplinary field using modern methodology, such as imaging techniques, mechanical testing, movement capture, and numerical modeling. It contains nine original research reports covering diverse topics, including flight, locomotion, and attachment of the arthropods. The research achievements are essential not only to understand ecological adaptations, and evolutionary and behavioral traits, but also to drive prominent advances for engineering from exploitation of numerous biomimetic ideas. Keywords Functional morphology Biomechanics Movement Arthropods Christian-Albrechts-Universitat zu Kiel (3094)Open Access funding enabled and organized by Projekt DEAL. issue-copyright-statement(c) Springer-Verlag GmbH Germany, part of Springer Nature 2023 pmcIntroduction As the largest phylum of animals, arthropods live all over the world occupying terrestrial, aquatic, arboreal, and subterranean niches. The distinct living environments resulted in evolving numerous complex adaptations associated with movement and other mechanical functions. Schroeder et al. (2018) proposed that such functions as locomotion, mechanical detection, adhesion, sound production, communication, etc., result from specific combinations of cuticle-derived exoskeleton. Although the exoskeleton in arthropods is mainly formed by three main constituents (chitin, proteins, and lipids), hierarchically structured materials with tremendous diversity of properties have evolved resulting in different morphological features and specific biomechanical characteristics. It has been previously reported by Vincent and Wegst (2004) that insect cuticles have seven-order range of Young's modulus, ranging from 1 kPa for soft cuticles, like in the case of intersegmental membranes, to 20 GPa for sclerotized cuticle, such as in the beetle elytra. The distinct elastic properties greatly satisfy the mechanical requirements of the cuticles for realizing a wide range of biomechanical and other physiological functions. To better understand the extraordinary mechanical behaviors of biological materials, numerous studies have been performed using imaging techniques, experimental measurements, and numerical simulations. Interesting recent findings include the presence of gradient elasticity in adhesive tarsal setae of beetles caused by inhomogeneous resilin distribution (Peisker et al. 2013), anti-friction properties of porous fluid-filled sand hopper cuticle surface (Wan and Gorb 2020), and fracture resistance of multi-layered locust semi-lunar process cuticle (Wan and Hao 2020), to name a few. In addition to the reinforcement mechanism of the functional biological materials, scientists and engineers are also interested in revealing how specific materials and structures of arthropods are related to their properties and functions. However, investigations should not just report some statistical relations between anatomical features and performance characteristics, to speculate about potential reasons. Instead, multidisciplinary methodology should be implemented to explore the key mechanisms and principles behind their outstanding performance. This is quite a difficult task, because many different features in organisms are simultaneously adapted, to achieve multi-optimized properties, rather than a single one. The reason for multi-optimized properties is that organisms are usually adapted to different environmental stresses and sometimes face unexpected risks. The protective shell of the mussel Mytilus edulis (though it is not representative of Arthropoda) is a good long-term studied example to explain this viewpoint. Its shell is a multi-layered biomineralized system consisting of several different materials for protecting its soft body inside. Compared to the outer prismatic calcite in the shell, the inner nacre layer is stronger, although from the engineering point of view should be actually deposited outside the shell for providing more effective protection against external impacts. However, this disagrees with the natural situation that nacre is situated on the inner side of the shell rather than on the outer side. Both acid etching test and mechanical loading tests (including static loading and dynamic impact) were performed in our previous research (Wan et al. 2019), revealing an interesting compromise of the mussel shell in that the current pattern of outside prismatic calcite and inside nacre can provide optimal multi-protection against both mechanical and chemical stresses. Perhaps, in view of just mechanical protection, the current pattern of layers is not the best solution, but the present evolutionary optimized distribution of layers offers the mussel sufficient multi-protective abilities against complex environmental stresses (like acid attack of dog whelk gastropods and mechanical attack of decapod crabs). Due to the complexity of the research object of biological materials, modern imaging and characterization techniques must be simultaneously used to decode the mysteries of the arthropods. General technologies include imaging techniques (micro-CT, transmission electron microscope, scanning electron microscope), compositional identification (X-ray energy spectrometry, Fourier transform infrared spectroscopy, Raman spectrometry, immunohistological staining, confocal laser scanning microscopy), mechanical testing (nanoindentation, atomic force microscopy, universal material testing technology, adhesion force testers, and various tribometers), movement capture (high-speed videography, videography under synchrotron radiation light source), and numerical simulations (finite element modeling, computational fluid dynamics simulation, fluid-solid coupling modeling, multibody dynamics simulation). In this special issue of the Journal of Comparative Physiology A, some recent research on functional morphology and biomechanics of arthropods will be presented to link morphology and biomechanics of materials and structures to their mechanical functions, such as flapping flight, legged locomotion, and gripping. Wings and flight The first topic of this special issue is insect flight and associated structures. O'Callaghan and Lehmann (2023) studied the flight movement of the tiny thrips Gynaikothrips ficorum, which has a bristled wing rather than a membranous wing. They quantified the aerodynamic performance of upscaled artificial bristled wings during wing flapping, scored its circulation during wing translation, and investigated its fate at the stroke reversals. Their results indicated that the aerodynamic force of the bristled wing is approximately 9% less than the common insect wing of solid membranes. This work clarifies the flow conditions of the bristled insect wing and deepens our understanding of flying in tiny insects. The cross-veins in the hind wing of locust Locusta migratoria were quantitatively investigated by Zhao et al. (2022). They evaluated the cross-veins at different regions of the locust hind wing using uniaxial tensile tester, scanning electron microscope, and finite element modeling method. Four cross-vein types were found at different sites of the hind wing, which exhibit similar tensile stiffness and various bending compliances. The naturally distributed cross-veins with different mechanical properties can be attributed to their biomechanical functions, like lift force production, damage reduction, and resistance against other environmental impacts. Finally, Shen et al. (2022) examined the morphological and mechanical characteristics of the wings of butterfly Tirumala limniace using scanning electron microscopy, tensile experiments, finite element, and computational fluid dynamics simulation. Specific orientation of fiber alignment was found in the multi-layered structures of the wings and the small deformation of the wings under various loads verified the stability of the butterfly wing structure. All the results confirmed the effect of wing veins in maintaining the flight performance of the butterfly. Legs and locomotion on solid ground The second topic of this special issue is ground mobility or terrestrial locomotion of insects. Zong et al. (2022) filmed the take-off, flight, and landing of flea beetles Altica cirsicola on a configurable angled platform to investigate their landing behavior. They found three in-flight modes for the flea beetle, which significantly affected take-off speed, acceleration, and the deploying time of wings. Durr and Mesanovic (2023) compared three species of stick insects (Phasmatodea) with strong different antennae-leg length ratios and further explored how relative limb length varied between sexes and throughout postembryonic development. They found that relative limb length directly related with the near-range exploration effort, and the antennae and front legs serve as complementary effect. The limb-to-body proportion is species characteristic while both antennae and front leg had different growth rate. Bruns et al. (2022) built up a novel experimental methodology for analyzing 3D-escape behaviors of insects and quantified the spatial orientation performance of house crickets Acheta domesticus. The comparison between their measurements and literature results validates the usefulness of this new experimental setup in studying various strategies of animal spatial orientation. Gripping The third topic of this special issue focuses on the gripping ability of arthropods. Salerno et al. (2022) compared the attachment ability to plants in three Coleoptera species with different claw shapes. The attachment forces on various substrates were measured using traction force experiments or centrifugal force test. It was indicated that the attachment performance on the plant surface with trichomes is stronger and directly related to the trichome stiffness. Special claws-associated structures are revealed in the coccinellid beetles that are able to grasp plants surfaces covered with soft unbranched trichomes. Furthermore, Winand et al. (2022) investigated the gripping forces of stick insect Sungaya inexpectata on multiple substrates with various roughnesses and directions to address the question why the majority of adult insects developed paired claws. They found that the gripping forces decreased even on smooth substrates, when the claws were removed. It revealed the collective effects of different attachment devices during locomotion. It is well known that the morphology of the benthic stream insects is well adapted for locomotion function under these specific environmental conditions. In the paper by Ditsche et al. (2023), the role of femora in attachment of the mayfly larvae Ecdyonurus sp. under stream conditions was investigated using microscopic techniques, 3D printing, and drag-lift measurements of artificial femoral profiles in a wind tunnel. The authors found that the widened femora of Ecdyonurus sp. aid in the negative lift force generation. Additionally, lift can be regulated by the animals through adjusting tilt of their femora or changing distance to the ground. Outlook Taken together, the above contributions collected in this special issue aim to reveal the novel morphological and biomechanical characteristics for some biomechanical functions of arthropods. We hope this special issue will not only deepen our understanding of the key principles behind biological functions, but also provide some innovative idea for future bioinspired technologies in engineering and industry. Author contributions CW and SG wrote the main manuscript text and reviewed the manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Declarations Conflict of interest The authors declare no conflict of interest. Handling Editor: Gunther K.H. Zupanc. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References Bruns C Labisch S Dirks J-H 3D-Escape: an alternative paradigm for spatial orientation studies in insects J Comp Physiol A 2022 10.1007/s00359-022-01574-x Ditsche P Hoffmann F Kaehlert S Kesel A Gorb SN Hydrofoil-like legs help stream mayfly larvae to stay on the ground J Comp Physiol A 2023 10.1007/s00359-023-01620-2 Durr V Mesanovic A Behavioural function and development of body-to-limb proportions and active movement ranges in three stick insect species J Comp Physiol A 2023 10.1007/s00359-022-01564-z O'Callaghan F Lehmann F-O Flow development and leading edge vorticity in bristled insect wings J Comp Physiol A 2023 10.1007/s00359-023-01617-x Peisker H Michels J Gorb SN Evidence for a material gradient in the adhesive tarsal setae of the ladybird beetle Coccinella septempunctata Nat Commun 2013 4 1661 10.1038/ncomms2576 23552076 Salerno G Rebora M Piersanti S Saitta V Gorb E Gorb SN Coleoptera claws and trichome interlocking J Comp Physiol A 2022 10.1007/s00359-022-01554-1 Schroeder TBH Houghtaling J Wilts BD Mayer M It's not a bug, it's a feature: functional materials in insects Adv Mater 2018 30 19 e1705322 10.1002/adma.201705322 29517829 Shen H Ji A Li Q Li X Ma Y Tensile mechanical properties and finite element simulation of the wings of the butterfly Tirumala limniace J Comp Physiol A 2022 10.1007/s00359-022-01556-z Vincent JF Wegst UG Design and mechanical properties of insect cuticle Arthropod Struct Dev 2004 33 3 187 199 10.1016/j.asd.2004.05.006 18089034 Wan C Gorb S Friction reduction mechanism of the cuticle surface in the sandhopper Talitrus saltator (Amphipoda, Talitridae) Acta Biomater 2020 101 414 421 10.1016/j.actbio.2019.10.031 31669541 Wan C Hao ZX Natural arrangement of micro-strips reduces shear strain in the locust cuticle during power amplification J Biomech 2020 107 109842 10.1016/j.jbiomech.2020.109842 32517861 Wan C Ma Y Gorb SN Compromise between mechanical and chemical protection mechanisms in the Mytilus edulis shell J Exp Biol 2019 222 jeb201103 10.1242/jeb.201103 31315934 Winand J Gorb SN Buscher TH Gripping performance in the stick insect Sungaya inexpectata in dependence on the pretarsal architecture J Comp Physiol A 2022 10.1007/s00359-022-01570-1 Zhao W Ma Q Li Z Wan C Functional compliance and protective stiffness: cross-veins in the hind wind of locust Locusta migratoria J Comp Physiol A 2022 10.1007/s00359-022-01587-6 Zong L Wu J Yang P Ren J Shi G Ge S Hu DL Jumping of flea beetles onto inclined platforms J Comp Physiol A 2022 10.1007/s00359-022-01567-w |
Childs Nerv Syst Childs Nerv Syst Child's Nervous System 0256-7040 1433-0350 Springer Berlin Heidelberg Berlin/Heidelberg 35962221 5643 10.1007/s00381-022-05643-z Case Report Combined sclerotherapy followed by surgical resection of a large extracranial venous malformation in a 14-month-old child: preoperative workup and technical note Lave Alexandre [email protected] 1 Yilmaz Hasan 2 Rosi Andrea 2 Paun Luca 1 Patet Gildas 1 Bartoli Andrea 1 1 grid.150338.c 0000 0001 0721 9812 Division of Neurosurgery, Faculty of Medicine, Geneva University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland 2 grid.150338.c 0000 0001 0721 9812 Division of Diagnostic and Interventional Neuroradiology, Faculty of Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland 13 8 2022 13 8 2022 2023 39 2 527533 26 5 2022 3 8 2022 (c) The Author(s) 2022 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Introduction Venous malformations affect around 2 per 10,000 newborn and are the most common type of congenital vascular malformation. They are always present at birth and are often misdiagnosed with hemangiomas. Accurate diagnosis and adequate targeted therapy through a multidisciplinary approach is advocated for a successful treatment, considering a combination of modalities in complex cases. We present here the workup and treatment of a venous malformation in a 14 month old child by combining a preoperative sclerotherapy with sodium tetradecyl sulfate (STS) followed by complete surgical excision respecting the calvarium. Case presentation. A large right extracranial fronto-parietal venous malformation and scalloping of the underlying calvarium, attached to the pericranium, surgically excised after preoperative sclerotherapy with STS in a 14-month-old child. Results The patient had an uneventful postoperative course with complete resection of the lesion, satisfying cosmetic appearance and no complications. Histopathological examination confirmed a venous malformation. Conclusion We demonstrated the workup and the rationale of the combined sclerotherapy followed by surgical resection of a large growing extracranial venous malformation. Preoperative direct contrast injection and sclerotherapy allowed to rule out significative extracranial to intracranial venous inflow and reduce blood loss for the surgical procedure, respectively. Complete removal of the malformation minimized the impact on future growth of the calvarium. Keywords Venous malformation Vascular anomalies Pediatric cranial surgery Sclerotherapy University of GenevaOpen access funding provided by University of Geneva. issue-copyright-statement(c) Springer-Verlag GmbH Germany, part of Springer Nature 2023 pmcIntroduction Venous malformations (VMs) have been described by the Mulliken and Glowacki classification of vascular anomalies in 1982 . They are classified as low-flow vascular malformations in opposition to high flow lesions such as arteriovenous malformation and arteriovenous fistula. These malformations are well distinguished from vascular tumors (most often hemangiomas) based on endothelial characteristics, as VMs are composed of normal endothelial-lined vascular spaces without hypercellularity, whereas hemangiomas are characterized by several histological abnormalities, including hyperplasia. The Mulliken and Glowacki classification has been revised since its creation, and the ISSVA (International Society for the Study of Vascular Anomalies) classification of vascular anomalies is now used to define vascular anomalies (as shown in Table 1).Table 1 ISSVA classification for vascular anomalies 2014, revised in 2018. Adapted from Vascular tumors Vascular malformations Benign Simple Combined Of major named vessels Associated with other anomalies Capillary malformations CVM (capillary-venous malformation) Affect: - lymphatics - veins - arteries Anomalies of: -origin -course -number -length -diameter (aplasia, hypoplasia, stenosis, ectasia/aneurysm) -valves -communication (AVF) -persistence (of embryonal vessel) Klippel-Trenaunay syndrome Parkes-Weber syndrome Servelle-Martorell syndrome Sturge-Weber syndrome Limb CM + congenital non-progressive limb overgrowth Maffucci syndrome Macrocephaly CM (M-CM/MCAP) Microcephaly-CM (MICCAP) CLOVES syndrome Proteus syndrome Bannayan-Riley-Ruvalcaba syndrome CLAPO syndrome CLM (capillary-lymphatic malformation) Locally aggressive or borderline Lymphatic malformations LVM (lymphatic-venous malformation) CLVM (capillary-lymphatic-venous malformation) Malignant Venous malformations CAVM (capillary-arteriovenous malformation) Arteriovenous malformations CLAVM (capillary-lymphatic-arteriovenous malformation) Arteriovenous fistulas Others The revised version of 2018 continues to divide vascular anomalies into vascular tumors and vascular malformations and classifies vascular malformations in simple or combined (if two or more vascular malformations are found in one lesion) rather than high or low flow. Associated syndromes (Klippel-Trenaunay, blue-rubber bleb nevus, familial cutaneomucosal venous malformation, Maffucci's) and specific mutations (TIE2 mutation) have been also included in the classification. VMs are always present at birth by definition, thus have to be considered congenital lesions, and grow in parallel with the child's development , with a peak from infancy to puberty. VMs may be very small initially and thus be identified only later in childhood or teenagehood . Both sexes are equally affected with a reported incidence of 1-2 per 10,000 births and a prevalence of 1% . Clinically, these lesions are superficial, soft, without pulsations, thrill, or increase of temperature relative to adjacent skin, in contrast to arteriovenous malformations. The size of the VM can increase with activity, Valsalva, or supine position . Classical appearance changes from light to dark-blue lesions. VMs can sometimes be painful, especially in cases of facial VMs, if the temporal muscle is affected (patients can complain of migraine). Patients could also present with swelling and pain due to thrombosis of a portion of the lesion . Diagnostic workup should start first with ultrasonography (US) to identify the classic hypoechoic, heterogeneous, and compressible appearance of VMs. Duplex is then used to show the low flow and identify the feeding vessels and intralesional thrombosis. Duplex ultrasound is also the best modality to differentiate hemangioma (high flow on duplex) from VMs (low flow). This discrimination is important because in case of misdiagnosis, inappropriate beta-blocker therapy may be proposed (9). MRI T2-weighted sequences are considered the gold standard to assess VMs . On fat-saturated T2-weighted MR, VMs appear hyperintense, heterogeneous with lobulated margins. Phleboliths are sometimes visible inside the lesion. In selected cases, contrast venogram, CT scan, or even scintigraphy could be useful . Treatment options include medications, surgery, sclerotherapy, cryoablation, and laser photocoagulation; the decision for treatment should be ideally done after interdisciplinary discussion. Small well-localized VMs are often treated successfully with a single modality (surgery, sclerotherapy), whereas larger venous malformations may require a combination of technique [3-5, 9]. Compressive therapy is a simple and efficient option mostly for VMs of the extremities to reduce pain and thrombosis; targeted medical treatment consists of low-dose aspirin, anti-inflammatory drugs, or low-molecular-weight heparin in cases of pain associated with thrombophlebitis . The modality of choice for the treatment of VMs is considered to be sclerotherapy, which can be curative, or used prior to surgery as a neo adjuvant solution, mostly to induce thrombosis inside the lesion to facilitate excision . Many different sclerosants are available, including alcohols, detergents, antitumor agents, and doxycycline. Alcoholic agents are considered to be the most effective, with a very low recurrence rate , but also associated with an increased risk of lesions for adjacent skin, nerves, and soft tissues. Surgery alone is sometimes preferred to sclerotherapy, especially when the venous malformation is small and does not involve vital structures; the use of sclerotherapy as an neoadjuvant therapy is often advocated mostly to reduce intraoperative blood loss, to decrease the volume of the malformation to be resected, and to improve visualization of vital structures. Case presentation We present here the case of a 14-month-old child, without any relevant past medical history, with a large right fronto-parietal soft tissue mass, more prominent in the supine position, and which gradually increased in size with the child growth. Final size was estimated around 7 cm in maximal diameter. The perinatal history was unremarkable, the delivery uneventful, and no previous trauma was recorded. The child's weight at the time of presentation at our clinic was around 11 kg. The child did not show any particular complaint in relation to this lesion. Clinical examination showed a soft lesion, not mobile to deep structures of the scalp. Recumbent position showed an enlargement of the lesion. The skin was intact, and the rest of the inspection and palpation of the cranial vault were normal (as shown in Fig. 1). No neurological deficits were observed.Fig. 1 Inspection of the 7 x 3 cm subgaleal venous malformation prior to the surgery. Note that the skin mark in the frontal part was due to Trombovar injection; the overlying skin is intact The presurgical work up began with a Doppler ultrasonography which showed a deep lenticular soft tissue formation, purely extracranial, with heterogeneous content. There was no sign of arterial feeding by large-caliber intracranial or extracranial arteries. The Doppler analysis showed a low flow, without any visible venous drainage at the cortical level through the bony lacunae (as shown in Fig. 2).Fig. 2 Pre-operative imaging workup. A Doppler ultrasonography showing the low-flow heterogeneous content, without intradural venous drainage through the bone lacunae. B Brain 3D T2 MRI sequences in the axial and coronal planes with heterogeneous signal, sharp boundaries, and with internal septations inside the mass. C, D The MRI TOF sequences did not show any communication with the intracranial vessels. The yellow arrow shows the frontal branch of the superficial temporal artery (STA). E, F Scalloping of the calvaria bones is evident under the mass on the CT scan Scalloping and lacunae of the calvarium underlying the lesion were visible on the CT scan of the head (as shown in Fig. 2). Cerebral magnetic resonance imaging (MRI) revealed large vascular spaces, with minimal intracranial extension abutting the dural surface through bony lacunae. No extra to intracranial shunts were demonstrated on TOF sequences. Heterogeneous signal, sharp boundaries, and serpiginous content with a low flow were highly suggestive of a vascular lesion with venous characteristics. After a multidisciplinary meeting, including neurosurgeons, interventional neuroradiologists, dermatologists, angiologists, and pediatric surgeons, surgery was offered to parents because of the significant cosmetic discomfort, the tendency of the mass to grow, and the scalloping of the calvarium. We decided to perform the procedure in a hybrid operating room, with preoperative direct contrast injection and sodium tetradecyl sulfate (STS) sclerotherapy. The aim of the direct contrast injection followed by sclerotherapy was to rule out any extra to intracranial venous shunt and to reduce blood loss respectively, prior to surgery. Angiographic procedure The patient is in supine position; antibiotic prophylaxis with intravenous cefazolin 25 mg/kg is given prior to the endovascular procedure. The angiographic procedure began with a direct injection of contrast (30 mL of Iopamiro 300 mg/mL) into the lesion (as shown in Fig. 3). It confirmed the presence of a right fronto-parietal vascular multiloculated malformation of about 7 x 3 cm.Fig. 3 Pre-surgical percutaneous sclerotherapy procedure in the hybrid operating room/angio-suite. Multiple 21-gauge butterfly needles were placed in the different compartments of the venous malformation The anterior compartment of the malformation was connected to 2 small dural veins (one running cranially into to the superior sagittal sinus and the other to the basal dura) and one small frontal cortical vein. After ruling out any extra to intracranial venous shunt, sclerotherapy was slowly performed via direct puncture of the lesion using 4 21-gauge butterfly needles in the different compartments. We injected 4 mL of sodium tetradecyl sulfate foam (Trombovar(r) 1%) mixed with contrast and air (in proportion of 1:1:1). No diffusion to the previously described veins was seen under fluoroscopy during the procedure (as shown in Fig. 4).Fig. 4 Sequential injection of trombovar 1% during the sclerotherapy (from left to right) showing the complete opacification of the mass without any signs of diffusion into the dural veins Surgical procedure We marked a linear incision line, limited by the hair line. A right fronto-parietal arciform incision with a cold scalpel was done followed by a monopolar dissection to expose the galea. The lesion was lying within the subaponeurotic plane between the galea and the pericranium. Subsequently, dissection with Metzenbaum scissors was performed following a plane between the subcutaneous layer and the galea (as shown in Fig. 5). Keeping an extracapsular dissection, we detached the vascular malformation with the pericranium from the underlying bone.Fig. 5 Complete exposure of the margins of the venous malformation between the galea and the subcutaneous plane We observed an emptying of the vascular malformation during its dissection and we finally achieved an en-bloc resection (as shown in Fig. 6).Fig. 6 En-Bloc resection of the venous malformation Bone wax, Spongostan(r) (EthiconTM), and Evicel(r) (EthiconTM) were used for hemostasis. The deep plane and subcutaneous plane were closed with Vicryl(r) 3.0. An intradermal suture of Monocryl(r) 3.0 was used to close the skin and a pressure dressing was applied for 3 days (as shown in Fig. 7). Total hematic loss of the entire procedure was estimated between 50 and 100 cc.Fig. 7 Intradermal suture allowed an excellent esthetic result, without excess of cutaneous tissue Postoperative follow-up Surgery was performed without perioperative complications. Pain was controlled by a combination of NSAIDs and paracetamol from post-operative day (POD) 1. Immediate postoperative follow-up was unremarkable and patient was discharged at POD 4. Conclusion To our knowledge, this is the first description of the successful treatment of a cranial venous malformation threatening calvarium development in a pediatric case by combining sclerotherapy to surgical excision. Pre-operative sclerotherapy allowed easier manipulation, decreased the per operative blood loss, and shortened surgical procedure and therefore the length of general anesthesia. Finally, by a direct injection of contrast into the malformation at the beginning of the procedure, we were able to rule out any significative extra to intracranial venous shunt. Management of venous malformations requires a multidisciplinary approach from the diagnostic workup to the treatment. It should involve interventional radiologists or neuroradiologists, surgeons, dermatologists, and angiologist in order to maximize the success rate while avoiding iatrogenic complications. Abbreviations VMs Venous malformations STS Sodium tetradecyl sulfate MRI Magnetic resonance imaging POD Post-operative day Author contribution Conceptualization, A.L. and A.B.; data curation, A.L. and A.B.; formal analysis, A.L.,H.Y., A.R., L.P., and G.P.; writing A.L., H.Y., A.R., L.P., G.P., and A.B.; critical manuscript revision, A.L. and A.B. All authors have read and agreed to the published version of the manuscript. Funding Open access funding provided by University of Geneva. Data availability Publicly available datasets were used in this study. Authors confirmed that the data supporting the study are available within the article in the References section. Declarations Ethics approval and consent to participate The paper was written ethically in accordance with the World Medical Association Declaration of Helsinki. Consent was obtained from parents for publication of the details of their child medical case and accompanying images. Conflict of interest The authors have no conflicts of interest to declare. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Mulliken JB Glowacki J Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics Plast Reconstr Surg 1982 69 3 412 422 10.1097/00006534-198203000-00002 7063565 2. Wassef M Blei F Adams D Alomari A Baselga E Berenstein A Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies Pediatrics 2015 136 1 e203 e214 10.1542/peds.2014-3673 26055853 3. Cahill AM Nijs EL Pediatric vascular malformations: pathophysiology, diagnosis, and the role of interventional radiology Cardiovasc Intervent Radiol 2011 34 4 691 704 10.1007/s00270-011-0123-0 21409475 4. Legiehn GM, Heran MK (2008) Venous malformations: classification, development, diagnosis, and interventional radiologic management. Radiol Clin North Am 46(3):545-97, vi 5. Dompmartin A Vikkula M Boon LM Venous malformation: update on aetiopathogenesis, diagnosis and management Phlebology 2010 25 5 224 235 10.1258/phleb.2009.009041 20870869 6. Mahady K Thust S Berkeley R Stuart S Barnacle A Robertson F Vascular anomalies of the head and neck in children Quant Imaging Med Surg 2015 5 6 886 897 26807370 7. Lee BB Venous malformation and haemangioma: differential diagnosis, diagnosis, natural history and consequences Phlebology 2013 28 Suppl 1 176 187 10.1177/0268355513475960 23482556 8. Dasgupta R Patel M Venous malformations Semin Pediatr Surg 2014 23 4 198 202 10.1053/j.sempedsurg.2014.06.019 25241098 9. Buckmiller LM Richter GT Suen JY Diagnosis and management of hemangiomas and vascular malformations of the head and neck Oral Dis 2010 16 5 405 418 10.1111/j.1601-0825.2010.01661.x 20233314 10. Dubois J Soulez G Oliva VL Berthiaume MJ Lapierre C Therasse E Soft-tissue venous malformations in adult patients: imaging and therapeutic issues Radiographics 2001 21 6 1519 1531 10.1148/radiographics.21.6.g01nv031519 11706222 11. Konez O, Burrows PE (2002) Magnetic resonance of vascular anomalies. Magn Reson Imaging Clin N Am 10(2):363-88, vii 12. Hage AN Chick JFB Srinivasa RN Bundy JJ Chauhan NR Acord M Treatment of venous malformations: the data, where we are, and how it is done Tech Vasc Interv Radiol 2018 21 2 45 54 10.1053/j.tvir.2018.03.001 29784122 13. 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Cell Mol Neurobiol Cell Mol Neurobiol Cellular and Molecular Neurobiology 0272-4340 1573-6830 Springer US New York 35759137 1239 10.1007/s10571-022-01239-y Correction Correction to: cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection Calandria Jorgelina M. 1 Do Khanh V. 13 Kala-Bhattacharjee Sayantani 1 Obenaus Andre 2 Belayev Ludmila 1 Bazan Nicolas G. [email protected] 1 1 grid.279863.1 0000 0000 8954 1233 Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112 USA 2 grid.266093.8 0000 0001 0668 7243 Department of Pediatrics, University of California, Irvine, CA 92618 USA 3 grid.511102.6 0000 0004 8341 6684 Present Address: Faculty of Medicine, PHENIKAA University and PHENIKAA Research and Technology Institute (PRATI), A&A Green Phoenix Group JSC, Hanoi, Vietnam 27 6 2022 27 6 2022 2023 43 3 10971103 (c) The Author(s) 2022 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit issue-copyright-statement(c) Springer Science+Business Media, LLC, part of Springer Nature 2023 pmcCorrection to: Cellular and Molecular Neurobiology 10.1007/s10571-022-01231-6 The original version of this article, unfortunately, contained errors in the figures (Figs. 1-6) and to the caption of Fig. 5i. The correct Figs. 1, 2, 3, 4, 5 and 6 are presented with this erratum, and the corrected Fig. 5i caption is given below: Fig. 1 Docosanoids counteract UOS-dependent increase in Wnt5a, FZD5 expression, and apoptosis. (a) Design to determine apoptotic cells. (b) DHA (1) and its derivatives: NPD1 (2), 10R, 17R diHDHA (3), Maresin-1 (4), RvD1 (5), and RvD2 (6) counteracted these effects. (c, e, and f) Docosanoids prevented transcription increase in cells undergoing UOS. SYBR green real-time PCR was used to determine semi-quantitatively Wnt5a (c) and FZD5 (e) in hRPE cells and receptors linked to Wnt signaling (f) in ARPE-19 induce a decrease of UOS-triggered Wnt5a transcription. Standardization was performed using b-actin and GAPDH. (d) Wnt5a enhanced cell death triggered by H2O2. Apoptosis was measured using Hoechst staining and ImageJ using parameters shown in (a). (g) FZD5 was measured in hpRPE cells undergoing UOS treated with 100 nM NPD1 or 100 ng/ml Box5 in the presence or absence of 50 ng/ml Wnt5a. The bands were standardized by total protein stain (see Materials and Methods for description). The bars represent the average of triplicates (Supplementary Fig. S2). (h) Deglycosylation of Wnt5a secreted by hpRPE cells. The secreted Wnt5a protein was concentrated from the medium by Chloroform/Methanol precipitation. The pellet was resuspended and digested with N and O-glycosylases (Degly). In parallel, non-digested samples (Gly) were run. Western blots were replicated using two different antibodies and a positive control (Supplementary Fig. S3). (i-j) Content of Wnt5a in a medium of human RPE cells in the presence of 1600 mM H2O2 and 10 ng/ml TNFa. (i) Exosome enrichment protocol using ultracentrifugation. (j) Content of Wnt5a in the different fractions of the medium. The bars represent the mean of three measurements and the standard error of the mean. *p < 0.05 Fig. 2 Wnt5a and FZD5 are internalized via CME. (a) Blow-up of a single cell showing vesicles positives to Wnt5a (green), FZD5 (red), or both (yellow). The fourth panel shows a nucleus drawing (blue) and the position of vesicles in which FZD5 colocalizes with Wnt5a. (b) Quantification of colocalized spots in RPE cells undergoing UOS +- lipids in Fig. 1b. Pearson colocalization coefficient was plotted in fig. S8D. Bars: mean of 3 measurements and standard error of the mean. * p < 0.05. (c) Blow-up of a cell showing large cluster of Wnt5a signal (red) present most frequently in certain treatments (Supplementary Fig. S8c). (d) Timeline of experiment depicted in e and f. (e) Western blot analysis of ROR2, FZD5, and Wnt5a in hpRPE cells overexpressing ROR2-His tag ORF, FZD5 ORF, ROR2-His tag and FZD5 ORFs together and Wnt5a. Duplicates of whole membranes are shown in Supplementary Fig. S4. (f) IMARIS analysis of the vesicles observed by immunocytochemistry targeting Wnt5a, FZD5, and Clathrin. The sum of the intensity for the colocalization of the signal observed for Wnt5a/Clathrin, FZD5/Clathrin, and FZD5/Wnt5a was measured with the Spots module using batch processing. Each spot corresponds to one individual or clusters of vesicles observed in hpRPE cells under UOS in the presence or absence of NPD1or Box5 and Wnt5a in the cells expressing the ORFs (open reading frame) tested by WB in (d). Five fields per well were averaged and computed to obtain the bars plotted. Two ways ANOVA and Tukey's HSD was applied to determine the pairwise comparison significance. The number of Spots plots for each histogram is depicted in Supplementary Fig. S5. (g) Vesicle-like signal in the Z axes of the Z-stack. Whole arrow shows a fusion between an FZD5 and Wnt5a positive to a large Wnt5a-positive cluster. Arrowhead shows an already fused colocalized cluster. (h) Model of internalization and recycling of Wnt5a and FZD5 to activate NFkB/p65. The bars represent the mean of three measurements and the standard error of the mean. *p < 0.05 Fig. 3 Wnt5a triggers the activation of p65 in human RPE cells undergoing UOS. (a, b) Luciferase assay using NFkB/p65 binding site construct (Supplementary Fig. S6) to determine its activation in the presence or absence of Wnt5a in hpRPE cells undergoing UOS plus/minus NPD1. The standardization was made co-expressing constitutively GFP. (b) hRPE cells were co-transfected with the NFkB/luciferase plasmid and siRNA targeting FZD5 and ROR2 separately and together or control non-specific siRNA. UOS was induced +- 100 nM NPD1 and Wnt5a. The yield of expression for FZD5 and ROR2 are presented in Supplementary Fig. S9. Bars show the mean of three measurements and the standard error of the mean. *p < 0.05. (c, d) Specificity of Wnt5a/FZD receptor activity on the activation of p65. (c) Timeline showing experimental design. (d) Silencing of FZD1, FZD2, FZD5, and FZD7 alone or together with ROR2 (Supplementary Fig. S10) in hpRPE cells expressing p65-GFP were treated with 50 ng/ml Wnt5a, in the presence or absence of H2O2 to induce uncompensated oxidative stress and NPD1 for two hours. Nuclear p65 was assessed by analyzing confocal Z-stack images with Imaris 9.8 to determine nuclear translocation (colocalization of GFP and Hoechst staining), Intensity (upper histogram), and number of cells (lower histogram). (e-g) In vivo monitoring of p65 nuclear translocation in resting hRPE cells or undergoing UOS cells and exposed to Wnt5a. hRPE cells expressing human p65fused to GFP incubated for 120 min in an Incucyte SX5 Life-cells Analysis instrument and registered every 10 min. TNFa was used as a positive control. (e) Cell death using Propidium Iodide (PI) (orange), total cell staining DRAQ5 (blue), and p65-GFP (green). Solid white arrows = Nuclear GFP (computed as DRAQ5/p65-GFP overlapped signal); solid white arrowheads = PI dying cells, open white arrows = normal cells. (f) Upper panel shows the percentage of cells depicting nuclear p65, (g) lower panel shows the percentage of dead cells that became permeable to PI staining. Nine fields per well for a total of 4 wells per condition were computed (f, g). (d, f, and g) 2-way ANOVA and Tukey HSD multiple comparisons were applied to obtained pairwise significance. *p < 0.05. (h, i) Pitstop2 halts activation of NFkB. (h) Experimental design. (i) Luciferase Reporter assay of three NFkB/p65 binding sites in tandem driving the expression of luciferase ORF; the construct was depicted in Supplementary Fig. S6. NPD1 = 100 nM and 1600 mM H2O2. (j) Model of alternative pathways of activation of p65 and the action of NPD1 Fig. 4 NPD1-dependent cRel binding to promoter A decreases Wnt5a expression. (a) Hypothesis of the role of cREL in the modulation of the expression of Wnt5a. (b, c) Quantification of cRel (b) and Wnt5a (C) mRNA by the means of SYBR green-based real-time PCR in hpRPE cells undergoing UOS, +- NPD1. (B) Cells transfected with cREL ORF were exposed to UOS in the presence or absence of NPD1 for 4 h. cREL (left) and Wnt5a (right) mRNA was quantified by real-time PCR. (c) Wnt5a mRNA quantification of non-transfected cells (Control for b). (d, f) Possible regulation of NFkB sites by cRel: in silica analysis of Wnt5a promoter (Katula et al. 2012) showing that the two binding sites for NFkB have high affinity for p65, p50, and cRel. The cartoon shows the possible direction in which transcription factors act. NFkB site prediction is in Supplementary Table S1. Other possible NFkB binding sites were detected by TRED. Region 2 corresponds to upstream NFkB binding site, and Region 6 to the downstream binding site depicted in d and f. Regions 1, 3, 4, 5, and 7 showed up in the general TRED search with high score (Supplementary Table S1) for the three NFkB. Four amplicons were designed close to or sitting on these regions to assess each site. CpG islands that encompass the putative binding sites are depicted in purple (Supplementary Table S2). (e) SYBR green-based real-time PCR using as template the proteinase digested genomic DNA fragments resulting from micrococcal DNAs digestion and cRel pull-down. 1600 mM H2O2 plus 10 ng/ml TNFa. NPD1 = 100 nM and Wnt5a 50 ng/ml unless stated otherwise. The bars represent mean of three measurements and standard error of the mean. *p < 0.05 Fig. 5 Neuroprotection by DHA prevents Wnt5a overexpression and secretion in response to brain ischemia-reperfusion and by Box5 that blocks its action. (a) DHA, Box5, or saline were administered at 1 h after 2 h of MCAo, and rats were sacrificed on days 1, 2, 3, or 7. (b) Neurological recovery. Total score (normal score = 0, maximal deficit = 12), tactile placing (dorsal, lateral, proprioceptive reactions; normal score = 0, maximal deficit = 2). DHA or saline was administered at 1 h after 2 h of MCAo, and rats were sampled on days 1, 2, 3, or 7. Values are mean +- SD; n = 4 rats/ group. *Significantly different from saline group (p < 0.05, repeated measures ANOVA followed by Bonferroni tests). (c-e) 400 mg Box5 IV administration, 1 h after MCAo (c) Total neurological score at days 1, 3, and 7; (d) MRI quantification at day 7 of lesion volume depicting total, core and penumbra and (e) representative coronal sections showing T2-weighted image (T2WI), the defined core and penumbra region (red and blue, respectively) in the second column; and a 3D reconstruction of the lesion. (f) Wnt5a mRNA assessment by SYBR-green real-time PCR in rat cortex Ipsilateral (Ipsi) or contralateral (Contra) of MCAo, treated with saline (vehicle) or DHA. (g, h) Wnt5a protein in plasma 2 h after MCAo with DHA (N = 4); (g) or Box5 (N = 4); (h) at 1, 3 and 7 days post-surgery. (i) Representative bands are depicted above the plot. (j) Wnt5a and NFkB linked gene expression in MCAo. MCAo and saline (vehicle) and DHA for 3 days (N = 3); each reaction was run in triplicate. mRNA measured using SYBR green RT-PCR. Color-coded region to test gene expression is depicted. Bars represent t mean of 3 measurements and standard error of the mean. *p < 0.05. (k) Wnt5a inflammatory signaling after increased abundance due to ischemia/reperfusion Fig. 6 NPD1 Neuroprotection sites model. In retina pigment epithelial cells (left panel), the evidence gathered in the present manuscript points to a Wnt5a-positive feedback loop consisting of the initiation of the signaling; when Wnt5a interacts with FZD5 and ROR2, it is internalized via clathrin-mediated endocytosis, and the process elicits the activation of NFkB/p65 in cells undergoing oxidative stress conditions. NPD1 interferes with this amplification of the inflammatory signaling at two sites: 1) by reducing the availability of FZD5 (Fig. 1e, g) and thus the internalization of Wnt5a and downstream events, and 2) by increasing the availability of cREL that competes with p65 in the dimeric NFkB and decrease the transcription of Wnt5a (Fig. 4). In ischemic stroke (right panel), the reperfusion after the ischemic episode induces an oxygen-rich environment, similar to uncompensated oxidative stress status. Here, the addition of box5, a hexapeptide that competes for the binding of Wnt5a to the receptor, demonstrated that wnt5a inflammatory loop occurs under these conditions, and it is responsible for at least part of the damage observed in ischemic stroke. DHA, known to be converted into NPD1 and for activating cREL in rat brain (Calandria et al. 2015), reduced the initial increase of Wnt5a messenger in brain tissue (Fig. 5f, i) and circulated Wnt5a protein (Fig. 5g). Treatment with DHA also induced a steep decrease in proinflammatory cytokines, and SASP-related expression downstream of the Wnt5a signaling loop was in agreement with the model established in RPE cells In Fig. 5, the caption of part i should read as "Representative bands are depicted above the plot." In addition, author Khanh V. Do's present address Faculty of Medicine, PHENIKAA University, and PHENIKAA Research and Technology Institute (PRATI), A&A Green Phoenix Group JSC, Hanoi, Vietnam is included. The original article has been corrected. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
Egypt Heart J Egypt Heart J The Egyptian Heart Journal 1110-2608 2090-911X Springer Berlin Heidelberg Berlin/Heidelberg 36897475 343 10.1186/s43044-023-00343-8 Case Report Management of PDA device closure complicated by severe hemolysis by transcatheter retrieval and deployment of new device Rashid Aamir [email protected] Lone Ajaz [email protected] Rather Hilal [email protected] Hafeez Imran [email protected] grid.414739.c 0000 0001 0174 2901 Department of Cardiology, SKIMS, Soura, Srinagar, J& K India 10 3 2023 10 3 2023 12 2023 75 1721 2 2022 25 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Background Hemolysis after Patent ductus arteriosus (PDA) device closure is rare. Although in most cases, hemolysis settles on its own; however, in some cases it may not settle spontaneously and may require additional procedures like putting additional coils, gel foam or thrombin instillation, balloon occlusion, or removing it surgically. We report a case of adult PDA device closure who persisted with hemolysis and was managed by transcatheter retrieval. Case presentation A 52-year-old gentleman presented to us with a diagnosis of large PDA with operable hemodynamics. Descending thoracic aortic Angio showed a large 11 mm PDA. Transcatheter device closure was done in the same sitting with a 16 x 14 Amplatzer Ductal Occluder I(ADO) device,;however, after device release, the aortic end of the device was not fully formed and there was residual flow. The next morning patient started with gross hematuria with persistent residual flow. We tried to manage with conservative means including hydration, and blood transfusion; however, residual flow persisted for 10 days and his hemoglobin dropped from 13 gm/dl preprocedural to 7 gm/dl, creatinine increased from 0.5 mg/dl to 1.9 mg/dl, bilirubin increased to 3.5 mg/dl & urine showed hemoglobinuria. As the patient continued to deteriorate it was planned to retrieve the device by transcatheter approach. 10 French amplatzer sheath was parked in the pulmonary artery near the ductus. We tried with a combination of multiple catheters and Gooseneck snare (10 mm) and finally, we successfully retrieved with a combination of Multipurpose (MP) catheter and 10 mm Gooseneck snare. After that, we closed the defect successfully with a double disk device (muscular Ventricular septal defect 14 mm Amplatzer). The patient's hematuria settled and was discharged after 2 days with normal hemoglobin and creatinine. Conclusions Patent ductus arteriosus ADO 1 device should not be released if the aortic end of the disk is not fully formed Patient should be carefully monitored for hemolysis if evidence of residual shunt and given supportive treatment. If conservative treatment fails, residual flow needs to be eliminated. Transcatheter retrieval although technically challenging is a feasible treatment. A muscular VSD device is a good alternative to the usual PDA device to close PDA, especially in adults. Keywords Hemolysis Catheter intervention Amplatzer duct occluder issue-copyright-statement(c) The Author(s) 2023 pmcBackground Although transcatheter defect closure is the mainstay for treating shunt lesions like PDA, and Atrial septal defect (ASD) this method might cause hemolysis due to residual shunt or mechanical exposure of the device to blood flow . Hemolysis after PDA device closure is usually associated with the presence of residual duct flow . Although in most cases, hemolysis settles on its own and requires supportive care only ; however, in some cases it may not settle spontaneously and may require additional procedures like putting additional coils, gel foam or thrombin instillation, balloon occlusion, or removing it surgically. We report a case of adult PDA device closure who persisted with hemolysis and was managed by transcatheter retrieval. Case presentation A 52-year-old gentleman presented to us with New York heart association (NYHA) functional class II dyspnea on exertion (DOE). On physical examination, he was found to have wide pulse pressure, cardiomegaly, left Ventricular third heart sound (LVS3), loud pulmonary heart sound (P2), and continuous murmur in the pulmonary area. Electrocardiography (ECG) and chest X-ray (CXR) showed cardiomegaly and features of increased pulmonary blood flow. Echocardiography (Echo) showed 11 mm large PDA with dilated Left atrium & left ventricle. The right ventricular systolic pressure (RVSP) was 60 plus the right atrial mean. Cardiac cath showed operable hemodynamics with moderate pulmonary arterial hypertension{(Saturation (Superior vena cava 70%, Inferior vena cava 72%, Pulmonary artery (PA) 94%, Ascending aorta and femoral artery (FA) 100%) &Pressure (PA = 55/30 m42, FA = 210/60)}. The calculated Pulmonary vascular resistance (PVR) was 3.5 woods units and Systemic Vascular Resistance (SVR) was 14.85 woods units. Calculated Pulmonary blood flow /systemic blood flow ratio (Qp/Qs) was > 2.1. Descending thoracic aorta (DTA) Angio showed a large 11 mm PDA. Transcatheter device closure was done in the same sitting with a 16 x 14 Amplatzer Ductal Occluder I (ADO)device. After device deployment, though the device was stable the aortic end of the device was not fully formed (Fig. 1) and there was residual ductal flow. Multiple attempts were done to retrieve the device back into the sheath but each time we redeployed it, it took the same shape. Since the device looked stable it was decided to release the device, assuming that once released, the tug of the cable would go and the device will assume the proper shape and residual flow would come down. We also did not consider using another device before releasing as we thought 14 x 16 size to be appropriate since the PDA measured 11 mm at the Pulmonary end. Downsizing would have carried the risk of embolization while increasing the size may not have helped as the device was stable despite giving a good tug to the device. Although the device did not form, we assumed that it will get formed properly once we release it; however, it did not happen and after release, the aortic end of the device was still not fully formed. The residual flow also persisted. The next morning patient started with gross hematuria. Examination showed continuous murmur. Echo (Fig. 2) revealed significant residual ductal flow. Initially, we tried to manage with conservative means including hydration, and blood transfusion; however, the residual flow persisted for 10 days and his hemoglobin dropped from 13 gm/dl preprocedural to 7 gm/dl after 10 days, and creatinine increased from 0.5 mg/dl to 1.9 mg/dl, bilirubin increased to 3.5 mg/dl & urine showed hemoglobinuria. We discussed the case with our surgical team. As the patient had severe anemia with renal failure and the surgeons had to go on cardiopulmonary bypass, it was considered high risk, so it was planned to attempt transcatheter retrieval of the device failing which, the patient would be taken for surgery. After informed consent, the patient was again taken for procedure and 10 French amplatzer sheath was parked in the pulmonary artery near the ductus. Initially, we tried to screw with the device cable, however, it failed. Then combination of multiple catheters and a Gooseneck snare (10 mm) was used and finally, we successfully retrieved with a combination of a Multipurpose (MP) catheter and 10 mm Gooseneck snare (Fig. 3). After that, we closed the defect successfully with a double disk device (muscular Ventricular septal device (VSD) 14 mm Amplatzer) (Fig. 4). The patient's hematuria settled and was discharged after 2 days with normal hemoglobin and creatinine.Fig. 1 Lateral View on fluoroscopy showing aortic disk of 16 x 14 Amplatzer Duct occluder I not properly formed Fig. 2 Parasternal short axis view on transthoracic echo showing significant Peri device leak Fig. 3 Left anterior oblique (LAO) view on fluoroscopy showing 10 mm Gooseneck snare catching screw of PDA device Fig. 4 Lateral view on fluoroscopy showing 14 mm Double disk muscular VSD device deployed Discussion We reported an unusual case of severe hemolysis following a PDA device closure with Amplatzer ADO I device which was managed successfully by transcatheter retrieval. The reported incidence of hemolysis is 0.5 to 3% following coil occlusion of PDA . However, significant hemolysis after occlusion with Amplatzer-type duct occluders is extremely rare . A possible cause of hemolysis in our case was that the aortic disk was not fully formed which could have led to the failure of polyester fabrics in nitinol mesh to thrombose. There are limited case reports on the management of hemolysis post ADO I device. Godart et al. reported the first case of hemolysis after implantation of 8 x 6 ADO I in an 11-month-old infant. They managed to abolish hemolysis by temporary occlusion of the aortic ampulla with a 5 Fr Berman balloon catheter. However, in our case, we did not consider it as our patient was an adult patient with large size of DTA, and balloon occlusion would not have helped. Joseph et al. deployed 0.018 coils into the nitinol wire cage within the device to abolish hemolysis. We assumed the leak in our case to be both peri device and through the device. The device had not formed properly which could have led to the failure of polyester fabrics in nitinol mesh to thrombose. So, implanting an additional device/coil might have stopped the peri device but not the intradevice leak. Also implanting another device/coils involved manipulation and could have led to the embolization of the first device. Besides putting additional micro coils require additional hardware and had financial implications. We work in resource-limited settings where patients usually have limited finances. Anil et al. reported the use of thrombin instillation into the ductal ampulla after balloon occlusion of the ampulla which resulted in successful flow elimination. However, in our case because of the large size of PDA and aorta, it was difficult to occlude the ampulla and there was a risk of spillover of thrombin into the systemic circulation. We instead planned to retrieve the device. Although it was technically challenging and took us fluoroscopic time of 1 h, finally we were able to retrieve it with a 10 mm snare. After that, we used a double device (Muscular VSD) to occlude the ductus. The rationale was that the double disk device has additional layers which would result in less residual flow. The device was well formed and abolished the residual flow without causing any obstruction to LPA or DTA. To the author's best knowledge this is the first reported case of management of hemolysis by transcatheter retrieval and deployment of a new device. Conclusions PDA ADO 1 device should not be released if the aortic end of the disk is not fully formed Patient should be carefully monitored for hemolysis if evidence of residual shunt and given supportive treatment with IV fluids and blood transfusion. If conservative treatment fails, residual flow needs to be eliminated. Transcatheter retrieval although technically challenging is a feasible treatment and can avoid surgical procedure. A muscular VSD device is a good alternative to the usual PDA device to close PDA, especially in adults. Abbreviations PDA Patent ductus arteriosus ASD Atrial septal defect VSD Ventricular septal defect ADO Amplatzer duct occluder DTA Descending thoracic aorta DOE Dyspnea on exertion NYHA New York heart association MPA Main pulmonary artery LPA Left pulmonary artery Acknowledgements We acknowledge and thank Mr. Syed Bilal (chief Cath lab technologist) for his tremendous technical support during the case. Author contributions All authors have read and approved the manuscript. AR compiled all data. AL collected review of literature.HR wrote the manuscript. IH reviewed the manuscript. All authors read and approved the final manuscript. Funding No funding received. Availability of data and materials All data generated or analyzed during this study are included in this published article. Declarations Ethics approval and consent to participate Ethical approval was taken from the Sherikashmir Institute of Medical sciences, Institute ethical committee.(IEC/SKIMS).No concerns were raised as it is only a case report and patients consent has been taken. Consent for publication Informed written consent was obtained from the patient for publication of this case report. The copy is available with the corresponding author. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Jang GY Son CS Lee JW Lee JY Kim SJ Complications after transcatheter closure of patent ductus arteriosus J Korean Med Sci 2007 22 3 484 490 10.3346/jkms.2007.22.3.484 17596658 2. Jung JW Recent strategies and outcomes of transcatheter closure for patent ductus arteriosus Kor Circ J 2010 40 5 216 8 10.4070/kcj.2010.40.5.216 3. Amoozgar H Soltani R Edraki M Hemolysis and its outcome following percutaneous closure of cardiac defects among children and adolescents: a prospective study Ital J Pediatr 2019 45 128 10.1186/s13052-019-0728-5 31627743 4. Khan A Ullah Z Ilyas S The outcome of trans-catheter closure of patent ductus arteriosus: a single-center experience Cureus 2022 14 1 21577 10.7759/cureus.21577 5. Henry G Danilowicz D Verma R Severe hemolysis following partial coil-occlusion of patent ductus arteriosus Cathet Cardiovasc Diagn 1996 39 410 412 10.1002/(SICI)1097-0304(199612)39:4<410::AID-CCD19>3.0.CO;2-G 8958434 6. Godart F Rodes J Rey C Severe hemolysis after transcatheter closure of a patent arterial duct with the new Amplatzer duct occluder Cardiol Young 2000 10 265 267 10.1017/S1047951100009215 10824909 7. George J Asishkumar M Zacharias TU Severe intravascular hemolysis after transcatheter closure of a large patent ductus arteriosus using the amplatzer duct occluder successful resolution by intradevice coil deployment Catheterizat Cardiovasc Interv 2002 55 245 249 10.1002/ccd.10046 8. Anil SR Sivakumar K Philip AK Clinical course and management strategies for hemolysis after transcatheter closure of patent arterial ducts Catheterizat Cardiov Interv 2003 59 538 543 10.1002/ccd.10593 |
Data Brief Data Brief Data in Brief 2352-3409 Elsevier S2352-3409(23)00123-3 10.1016/j.dib.2023.109005 109005 Data Article Whole-genome sequence data of a Salmonella enterica serovar Rissen sequence type 8877 isolated from cracked table egg in Sudan Elhassan Mortada M.O. [email protected] a* Adam Habiba B.A. a Fagir Shaimaa S.A.O. a Mohamed Sofia B. b Khaier Mona A.M. a Abdulaziz Romisa c Ismail Arshad d Allam Mushal c a College of Veterinary Medicine, University of Bahri, Khartoum, Sudan b National University Biomedical Research Institute National University, Khartoum, Sudan c College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates d National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa * Corresponding author. [email protected] 23 2 2023 4 2023 23 2 2023 47 10900529 12 2022 13 2 2023 16 2 2023 (c) 2023 The Author(s) 2023 This is an open access article under the CC BY license ). Salmonella enterica serovar Rissen is an emerging and important Salmonella serovar prevalent in live animals and foods from retail markets worldwide. Here, we describe the whole-genome sequence of Salmonella enterica Serovar Rissen Sequence Type 8877 isolated from a cracked table egg in Sudan. The whole-genome sequencing was obtained using Illumina Miseq platform. The quality of the sequenced read, the De novo assembly, and the sequencing typing was conducted by JEKESA pipeline ). The assembled genome was also uploaded to the Center for Genomic Epidemiology web server to determine acquired antibiotic resistance genes, predict the serovar, and the antigenic profile. The genome of Salmonella enterica serovar Rissen 1-M1 was found to harbor 4,689 protein-coding genes, 96 RNA genes, and 115 pseudogenes, as predicted by NCBI Prokaryotic Genome Annotation Pipeline. This whole genome shotgun project has been deposited at DDBJ/ENA/GenBank under accession JAPSFB000000000. Keywords Rissen ST8877 Salmonella Sudan pmc Specifications Table Subject Microbiology Specific subject area Pathogen genomics Type of data Genome sequence data How the data were acquired Illumina MiSeq Data format Raw, filtered, and assembled genome Description of data collection Salmonella enterica Serovar Rissen was isolated from a cracked table egg using Xylose Lysine Deoxycholate medium. Bacterial DNA was extracted from a pure colony of Salmonella using DNA QIAamp DNA Mini Kit (Qiagen). The genome sequence was obtained by Illumina Miseq platform. Data source location * Institution: College of Veterinary Medicine, University of Bahri * City/Town/Region: Khartoum * Country: Sudan Data accessibility Repository name: GenBank (at National Center for Biotechnology Information, NCBI) Data identification number: JAPSFB000000000.1 Direct URL to data: Value of the Data * The whole genome sequence data can be used successfully to evaluate the genetic diversity of Salmonella enterica serovar Rissen. * Bioinformaticians can use the genome data in comparative genome analysis as well as evolution of Salmonella enterica serovar Rissen. * The data may also help to investigate the genomic epidemiology of this pathogen. Objective Chicken-derived products, particularly table eggs, are the most common source of salmonellosis, one of the most difficult diseases to control in the poultry production industry. Several outbreaks of salmonellosis have been reported, in which the eggs are the source of human infection; especially in the case of undercooked or raw eggs . Table eggs can be contaminated on the outer shell surface and internally by any species or serovars of Salmonella . Here, we present a whole-genome sequence analysis of a newly described sequence type of Salmonella enterica serovar Rissen ST8877 isolated from a cracked table egg obtained from a local market in Khartoum, Sudan. To our knowledge, this is the third detection of Rissen ST8877 , , , however, this is the first description of its whole genome. 1 Data Description Table 1 shows the genome features of Salmonella enterica serovar Rissen sequence type 8877. The sequencing of isolate 1-M1 yielded 2089,086 raw reads. The high-quality reads (2038,422 reads) were assembled to 55 contigs (the longest contig was 521,231 bp) covering 4875,799 bp, with a GC content of 52.1% and N50 value of 237,445 bp. The genome of 1-M1 was found to harbor 4689 protein-coding genes, 96 RNA genes, and 115 pseudogenes, as predicted by the NCBI PGAP. MLST based on the Salmonella enterica seven-allele scheme indicated ST8877. ResFinder detected aminoglycoside resistance gene aac(6')-Iaa (98.1%, NC_003197) which increases resistance to tobramycin and/or amikacin . Serotyping of 1-M1 resulted in the serovar Rissen and the antigenic profile was identified as O7:H1f.g:H2- (H2 antigen was not identified). PlasmidFinder identified only Col (pHAD28) plasmid replicon sequence (91.6 %, KU674895). Up to 23 SPIs were detected in these genomes, including SPI-1 (7 islands), SPI-2 (8 islands), SPI-3 (2 islands), SPI-4 (1 island), SPI-5 (1 island), SPI-8 (1 island), SPI-9 (1 island), C63PI (1 islands), and CS54 (1 island). The Whole Genome Shotgun project has been deposited at DDBJ/ENA/GenBank under the accession JAPSFB000000000. The version described in this report is version JAPSFB010000000.Table 1 The genome characteristics of Salmonella enterica serovar Rissen sequence type 8877 isolated from a cracked table egg. Table 1Item Value GenBank accession number JAPSFB000000000.1 NCBI BioSample No. SAMN32036406 Number of reads 2,086,086 Number of contigs 55 GC content (%) 52.1 N50 (bp) 237,445 Coverage (x) 100X Total length (bp) 4,875,799 Total No. of CDS 4689 Serovar Rissen Sequence type ST8877 AMR genes aac(6')-Iaa (Aminoglycoside) SPI SPI-1 (7), SPI-2 (8), SPI-3 (2), SPI-4 (1), SPI-5 (1), SPI-8 (1), SPI-9 (1), C63PI (1), and CS54 (1) CRISPR Arrays 2 2 Experimental Design, Materials and Methods In 2019, a cracked egg (produced by a white Leghorn commercial laying chicken) was collected from a retail shop in a local market in Khartoum city in Sudan. The egg was collected under aseptic conditions and analyzed immediately within 2 hours using previously described methods for isolation and identification . The egg content was mixed thoroughly before taking a sample for bacteriology. A sterile swab was soaked in normal saline and then applied to the surface of the egg. The swab was then dipped into a test tube containing 10 ml normal saline and the contents were mixed thoroughly using a vortex mixer. Serial dilutions up to 105 were then prepared. One ml was taken from appropriate dilution and inoculated into Xylose-Lysine Deoxycholate agar (M031, HiMedia, India), a proper selective medium for the isolation of Salmonella . The culture was incubated at 37 degC for 2-48 h and examined for the presence of typical colonies of Salmonella (red with a black centre). The colonies were further subjected to biochemical testing. The DNA was extracted using the QIAamp DNA minikit (Qiagen, Germany), and paired-end libraries were prepared using the Nextera DNA Flex library kit, followed by 2 x 300 bp sequencing on a MiSeq machine (Illumina, Inc., USA). For whole-genome sequence analysis and typing, the JEKESA pipeline ) was used. Briefly, Trim Galore v0.6.2 ) was used to filter the sequence reads (Q, >= 20; length, >= 50), de novo assembly was performed using SPAdes v3.13.2 ),the assemblies were polished and optimized using Shovill v1.1.0 ), and sequence typing was done using the multilocus sequence typing (MLST) tool v2.16.4 ). Assembly metrics, including the GC content and number of contigs, were calculated using QUAST v5.0.2 ). All resultant contiguous sequences were annotated using the NCBI Prokaryotic Genome Annotation Pipeline v4.13 . Furthermore, the assembled genome was uploaded to the Center for Genomic Epidemiology web server; to determine acquired antibiotic resistance genes using ResFinder v4.1 , , ; to predict the serovar and the antigenic profile (O, H1 and H2 antigens) using SeqSero v1.2 , to identify plasmids using PlasmidFinder v2.1 , and to determine salmonella pathogenicity islands using SPIFinder v2.0 . Ethics Statements This work did not involve studies with animals or humans. Credit Author Statement Mortada M. O. Elhassan: Conceptualization, design of the research, and the analysis of the results; Habiba B. A. Adam: Collection of samples and bacteriology work; Shaimaa S. A. O. Fagir: Bacteriology work; Sofia B. Mohamed and Mona A. M. Khaier: DNA extraction; Romisa Abdulaziz: Analysis of the results; Arshad Ismail: Whole genome sequencing; Mushal Allam: Analysis of the results, writing and editing. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data Availability Salmonella enterica subsp. enterica serovar Rissen strain 1-M1, whole genome shotgun sequencing project (Original data) (GenBank). 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BMC Med Educ BMC Med Educ BMC Medical Education 1472-6920 BioMed Central London 3872 10.1186/s12909-022-03872-z Research Article A novel use of an artificially intelligent Chatbot and a live, synchronous virtual question-and answer session for fellowship recruitment Yi Peter K. [email protected] Ray Neil D. Segall Noa grid.26009.3d 0000 0004 1936 7961 Department of Anesthesiology and Critical Care, Duke University School of Medicine, Durham, North Carolina USA 11 3 2023 11 3 2023 2023 23 1527 1 2022 7 11 2022 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Introduction Academic departments universally communicate information about their programs using static websites. In addition to websites, some programs have even ventured out into social media (SM). These bidirectional forms of SM interaction show great promise; even hosting a live Question and Answer (Q&A) session has the potential for program branding. Artificial Intelligence (AI) usage in the form of a chatbot has expanded on websites and in SM. The potential use of chatbots, for the purposes of trainee recruitment, is novel and underutilized. With this pilot study, we aimed to answer the question; can the use of an Artificially Intelligent Chatbot and a Virtual Question-and-Answer Session aid in recruitment in a Post-COVID-19 era? Methods We held three structured Question-and-Answer Sessions over a period of 2 weeks. This preliminary study was performed after completion of the three Q&A sessions, in March-May, 2021. All 258 applicants to the pain fellowship program were invited via email to participate in the survey after attending one of the Q&A sessions. A 16-item survey assessing participants' perception of the chatbot was administered. Results Forty-eight pain fellowship applicants completed the survey, for an average response rate of 18.6%. In all, 35 (73%) of survey respondents had used the website chatbot, and 84% indicated that it had found them the information they were seeking. Conclusion We employed an artificially intelligent chatbot on the department website to engage in a bidirectional exchange with users to adapt to changes brought on by the pandemic. SM engagement via chatbot and Q&A sessions can leave a favorable impression and improve the perception of a program. Supplementary Information The online version contains supplementary material available at 10.1186/s12909-022-03872-z. Keywords Innovation and technology Graduate medical education Recruitment Social media Artificial intelligence issue-copyright-statement(c) The Author(s) 2023 pmcBackground The COVID-19 pandemic has brought sweeping changes to how we recruit residents and fellows. Due to travel restrictions, social distancing and limits on gatherings, the norm of in-person interviews has been replaced by virtual interview platforms. Multiple regulatory bodies, including the Accreditation Council for Graduate Medical Education (ACGME), have called accredited programs to "commit to online interviews and virtual visits" ). Although web based interviews (WBIs) have substantial cost and time benefits, they do pose their own new challenges; mainly due to the lack of in-person, face-to-face interactions and the difficulty in picking up non-verbal cues on a screen . However, despite these short-comings, WBIs may signal the start of changes and innovation to the traditional interview format and may even become a commonly used modality post-pandemic. As Graduate Medical Education programs pivot towards WBIs, a focus on other virtual recruitment tools has also gained traction. In addition to WBIs, recruitment tactics have also shifted to more digital media-centric content . Academic departments universally communicate information about their programs and about the department in general, using static websites. Residency websites have been shown to influence applicants' first impression of a program and are a critically important factor in decision making . In addition to websites, some programs have even ventured out into social media (SM) such as Twitter and Instagram to offer more engaging and detailed content . Most applications of this type of SM are unidirectional, meaning that the host specifically curates information to present. However, opportunities for bidirectional communication can potentially pave the way for additional innovative uses. Very few programs use this type of SM interaction either in an asynchronous or synchronous manner. An example of synchronous, bidirectional use of SM is Google Hangouts . These bidirectional forms of SM interaction show great promise; even hosting a live Question and Answer (Q&A) session has the potential to improve the overall perception of a program. Hass, et al. recently mentioned that traditional strategies of recruitment including branding, fostering a national reputation, developing a website, and utilizing a SM presence have been emphasized in the past . The COVID-19 pandemic brought upheaval to these traditional methods of recruitment and has forced us to reimagine innovative ways to recruit residents and fellows. Virtual program branding has become essential and SM use, along with Q&A sessions, could be a key component to the type of branding that is necessary for virtual residency recruitment . SM appears to have an increasing influence on residency decisions . With the concurrent expansion of SM, technological development in the realm of Artificial Intelligence (AI) has grown exponentially as well. AI is a field which combines computer science and robust datasets, to enable problem-solving ). With the growth of AI, its effects have permeated into various aspects of our lives, including the medical field. AI is changing traditional methods of medical imaging analysis, health data acquisition, and even medical education. AI has practical uses for distance learning and various inquiry systems, however AI for the application of trainee recruitment has not been reported . AI usage in the form of a chatbot or virtual concierge agent has expanded on websites and in SM. A chatbot is defined as "a computer program designed to simulate conversation with human users, especially over the Internet" and is also known as a smart bot or digital assistant . Chatbots can mimic human conversation and are useful in applications such as information retrieval and education . While there are uses of chatbot as recruiters in the business world, there are no reports of chatbot use in Graduate Medical Education . While much of the technology behind these uses are continuously being developed and applied, the potential use of AI and chatbots, for the purposes of trainee recruitment, is novel and underutilized. The proposed benefits of AI include relieving and splitting work performed by humans as well as replacing and augmenting human work . AI and chatbots are continuously pushing the limits of the tasks machines can take over from humans and can potential save time and human resources. In order to adapt to changes brought on by the pandemic, we recently employed an artificially intelligent chatbot on the department website to engage users in a bidirectional exchange. The chatbot is a conversational AI agent which uses natural language to understand phrases. It was tested by a third party to create the appropriate flow of information and allow users to ask questions and search for information. For example, applicants could ask the chatbot "Show me faculty that trained at <applicants home residency> or where do fellows live?" The chatbot would then return profiles of faculty that met criteria and an interactive google map of where fellows live, respectively. In addition, we used the chatbot to schedule and coordinate live, synchronous Question and Answer sessions about our program. Instead of using separately purchased scheduling software which would still rely on human monitoring, we employed the use of a chatbot to aid in some of the work usually performed by a human coordinator. We used these new technologies to complement the traditional strategies that are used to engage potential applicants. With this preliminary study, we aimed to answer the questions; can the use of an Artificially Intelligent Chatbot and a Virtual Question-and-Answer Session aid in recruitment in a Post-COVID-19 era and how will AI change what tasks machines can perform? Methods We held three structured Question-and-Answer Sessions over a period of 2 weeks. These sessions were coordinated to be live and synchronous. Invites to these sessions were sent out to all applicants to our program through the Electronic Residency Application Service (ERAS) email contact information provided. Applicants were instructed to sign up through the chatbot for one of three Q&A sessions. The chatbot registered each invitee and sent out a calendar invite with a direct web link to the Q&A session. This way each applicant that signed up would have a reminder for our Q&A session with a link on their calendars. These sessions were held 2 months prior to sending out interview invitations and participation had no bearing on the decision to offer an interview. Each 30 minute session briefly covered the mission and vision of the division (led by Division Chief), highlighted the local area and attractions (led by Program Coordinator who is local to the area), then described clinical sites and the details of the fellowship throughout the year (led by Program Director). The moderators discussed research opportunities and emphasized the multidisciplinary aspect of training. Finally, participants were given a chance to ask any program specific questions. This pilot study was performed after completion of the three Q&A sessions, in March-May, 2021. All 258 applicants to the pain fellowship program were invited via email (by a third party) to participate in the survey. A 16-item survey assessing participants' perception of the chatbot was administered online via Qualtrics. The items were adapted from the System Usability Scale and from a survey for gauging consumers' perceptions of chatbots ). If participants indicated that they participated in a Q&A session, they were presented with 7 additional items (see Additional file 1) that evaluated the usefulness of the sessions and their effect on participants' attitudes toward the pain fellowship program. Questions were designed to gauge ease of use with the chatbot and evaluate a participant's overall perception of the program. We used descriptive statistics to gauge these constructs. The study protocol was approved by the Institutional Review Board. Results Forty-eight pain fellowship applicants completed the survey, for an average response rate of 18.6%. In all, 35 (73%) of survey respondents had used the Department of Anesthesiology website chatbot, and 84% indicated that it had found them the information they were seeking. Respondents often asked the chatbot multiple questions, with 31% asking at least 5 questions. Not surprisingly, most survey respondents used the chatbot to find information about the fellowship program (69%), and many also sought to learn about the University (41%), the Anesthesiology Department (37.5%), and its residency program (28%). 37.5% of respondents used the chatbot to sign up for a Q&A session. Less often, they used the chatbot to find people in the department, to learn about the city, and where the program is located. Of the chatbot's features, 31% of respondents found scheduling a Q&A session most appealing and an additional 31% found asking it questions to be the most appealing feature. Another 22% found all features appealing and 6% found none to be appealing. Survey questions also targeted the chatbot's advantages and disadvantages. Most respondents perceived the chatbot to provide a quick (84%) or helpful (56%) response, to be a cool new technology (66%), and to be friendly (50%). In terms of disadvantages, 22% indicated the chatbot was unable to help them, 11% said that finding the information they needed required a prolonged effort, and the chatbot couldn't understand an additional 11% of survey respondents. However, 59% of respondents found no disadvantages to the chatbot. Overall, respondents seemed to find conversations with the chatbot a positive experience and the chatbot to be useful and usable (Figs. 1, 2, 3 and 4).Fig. 1 Chatbot usefulness question Fig. 2 Chatbot usability questions Fig. 3 Question about recommending the chatbot to others Fig. 4 Appealing and unappealing features of the pain fellowship program Seventeen (39%) survey respondents participated in a Q&A session out of a total of 58 participants who logged on for a Q&A session. Of these, 93% participated to learn more about the pain fellowship program and 87% to show interest in the program. Q&A session participants indicated they learned more about the program from the Q&A session than from the Department Anesthesiology website (73%) or that both sources of information were equally useful (27%); none found the website more useful for learning about the program than the Q&A session. The perception of the pain fellowship program improved for 87% of participants after the Q&A session and made them more likely to interview for the program. Many found the research, education, and clinical experience provided to be appealing; a minority found the education and location of the program to be unappealing (Fig. 4). Discussion Using AI technology, in the form of a chatbot, to provide auxiliary information appears to have advantages. Once participants landed on the website, they did use the chatbot frequently to ask specific questions. They found the chatbot to be more useful than the information found on the website and interacted with the chatbot for multiple questions. Using the chatbot to coordinate Q&A sessions was well accepted by applicants. Finally, hosting a live, synchronous Q&A session scheduled through the chatbot, had an overwhelmingly positive effect on the perception of the program. Participants found many aspects of the program appealing after the Q&A session and were more likely to interview if given the opportunity. We know that interview days heavily influence match list rankings giving applicants an overall impression of the atmosphere of the program . The loss of this opportunity prompts a need to look at alternatives to the in-person interview to allow applicants to gauge the suitability of the program. Using technology and taking advantage of SM may be a way to fill this void. We know that use of SM is one method for a program to increase applications and interviews as well as increase a program's position on a rank list . However, few programs take full advantage of SM for these purposes or even for the intent to give more insight about a program after pivoting to virtual interviews . Taking additional steps to incorporate AI and a chatbot may be another way for programs to maximally utilize SM and offer a way to engage. While Machine Learning and AI have been incorporated into certain aspects of medical education such as procedural assessment tools for cases involving image analysis , to our knowledge, there have been no other studies examining the use of AI integrated into SM for the use of applicant recruitment. While this pilot study is interesting and useful, more studies should look at this emerging technology for the purposes of potential recruitment. Future study efforts could focus on more specific outcomes related to matriculation and also explore how much time and resources an AI Chatbot could ultimately save. Limitations of this study include a low response rate, making it difficult to generalize participant responses to all fellowship applicants. Demographic and social media use information on survey participants could have been analyzed to further tease out trends. Although we explicitly stated the survey had no bearing on the application process, participants may have believed that completing the survey would increase their chance of acceptance. Conclusions With an increase in SM use, especially due to the pandemic, a program's website and SM platforms can have a significant impact on recruitment and application decisions . Incorporating AI chatbots may provide additional information to applicants and reduce the need for human intervention for certain tasks. The development and implementation of chatbots are relatively easy with many industry sponsored platforms available to seamlessly incorporate into SM. Chatbots may therefore be a way to engage potential applicants . Q&A sessions are also a relatively simple way to offer bidirectional interaction with applicants. SM engagement can leave a favorable impression and improve the perception of a program; both chatbots and virtual live Q&A sessions may be creative ways to optimally use this existing technology. Supplementary Information Additional file 1: Survey Questions. Abbreviations ACGME Accreditation Council for Graduate Medical Education AI Artificial Intelligence ERAS Electronic Residency Application Service Q&A Question and Answer SM Social media WBIs Web based interviews Acknowledgements None. Authors' contributions All authors have read and approved the manuscript. PY-Study design and manuscript. NR-Study design. design and manuscript. Funding N/A. Availability of data and materials Please contact Peter Yi at [email protected] for data. Declarations Ethics approval and consent to participate This was a pilot study completed as a quality improvement project asking participants to voluntary take a 16-item survey. Consent is assumed on completion of the questionnaire and participants were aware that this was for quality improvement reasons and related study purposes. Duke Health Institutional Review exemption obtained. Consent for publication Not applicable. Competing interests None. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Wolff M Burrows H Planning for virtual interviews: residency recruitment during a pandemic Acad Pediatr 2021 21 1 24 31 10.1016/j.acap.2020.10.006 33068812 2. Haas MRC He S Sternberg K Jordan J Deiorio NM Chan TM Yarris LM Reimagining residency selection: part 1-a practical guide to recruitment in the post-COVID-19 era J Grad Med Educ 2020 12 5 539 544 10.4300/JGME-D-20-00907.1 33149819 3. 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34791 Internal Medicine Obstetrics/Gynecology Gitelman's Syndrome in Pregnancy With Adverse Foetal Outcome: A Case Report Muacevic Alexander Adler John R Najam Rehana 1 Tomar Yugantika 1 Singh Mrinalini 1 1 Obstetrics and Gynaecology, Teerthanker Mahaveer Medical College and Research Center, Moradabad, IND Yugantika Tomar [email protected] 9 2 2023 2 2023 15 2 e347919 2 2023 Copyright (c) 2023, Najam et al. 2023 Najam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Gitelman's syndrome (GS) is a disorder characterized by hypokalaemia, hypomagnesemia, hypocalciuric and metabolic alkalosis. Despite the fact that it affects women of child-bearing age, only limited information is available regarding its impact on maternal and foetal outcome. We present the case of an un-booked and un-investigated 23-year-old primigravida who presented with chief complaints of vomiting and loose stools. The patient also complained of absent foetal movements in the last 12 hours. Investigations revealed hypokalaemia and hypomagnesemia and ultrasound revealed intra-uterine foetal demise. The patient was symptomatically relieved after electrolyte correction. Scarce reports on Gitelman's syndrome in pregnancy have been documented with the majority of cases showing positive outcomes for the foetus. We hereby present a report of a primigravida with Gitelman's syndrome and foetal loss which is considered uncommon. foetal outcome metabolic alkalosis hypocalciuria hypomagnesemia hypokalemia gitleman's syndrome The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Maintaining an electrolyte as well as fluid balance is a necessity for a successful pregnancy. Disturbance in fluid and electrolyte balance has been related to an upsurge in the chances of morbidity and mortality, particularly among the elderly . Dehydration can be caused by a variety of factors, including Gitelman's syndrome, which is discussed in detail here. Gitelman's syndrome (familial hypokalaemia-hypomagnesemia) is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia, and inadequate urinary calcium excretion. It is a relatively prevalent but overlooked cause of hypokalaemia. It is a hereditary renal tubular illness with an incidence of 1-10/40,000 , that was initially discovered in 1966 . It might be because of the inactivation of mutations in the SLC12A3 gene, which codes for the apical sodium chloride cotransporter and is found on chromosome 16 (16q13), leading to salt wasting, hypokalaemia, alkalosis, and hypocalciuria . As a result of increased sodium delivery to the cortical collecting duct, sodium reabsorption by the epithelial sodium channel increases, which is counterbalanced by potassium loss, resulting in hypokalaemia. The increased distal exchange of magnesium ions for sodium ions causes hypomagnesaemia. Salt cravings, exhaustion, and postural hypotension are all common symptoms of this condition. Gitelman's syndrome has been related to a higher chance of miscarriage as well as Intra Uterine Growth Restriction (IUGR) during pregnancy along with significant maternal morbidity due to electrolyte imbalance concerns [6-9]. Case presentation A 23-year-old primigravida at 37 weeks period of gestation, un-booked and un-investigated, presented to the emergency with chief complaints of absent fetal movements in the last 12 hours, vomiting for five days (5-6 episodes per day), loose stools for three days, itching over palms and soles for two weeks. Her vitals were normal with a mild degree of fever. There was no jaundice. Abdominal findings revealed no focal tenderness or guarding, the uterus was relaxed and corresponding to 36 weeks period of gestation, cephalic presentation, and on auscultation, the foetal heart sound could not be localized clinically. Per vaginal examination was done and the patient was found to be in the latent phase of labour. Laboratory examination including a complete haemogram, kidney and liver function test, and urine analysis was performed. Arterial blood gas revealed pH 7.5, pCO2 43 mm of Hg, Na+ 135 mEq/L, K 1.92 mEq/L, chloride 99 mEq/L, bicarbonate 31.7 mmol/L. The electrocardiogram revealed PR interval prolongation of 0.24 seconds, flat t waves, and prominent U waves. Her serum potassium level was 2.5 mEq/L, and her serum Mg level was 1.2 mEq/L, according to her first chemistry panel (Table 1). Table 1 Laboratory findings on admission SGOT: Serum glutamic-oxaloacetic transaminase; SGPT: Serum glutamic-pyruvic transaminase PARAMETERS RESULTS NORMAL RANGE Sodium (mEq/L) 134 135-155 Potassium (mEq/L) 2.5 3.5-5.5 Chloride (mEq/L) 99 90-120 Calcium (mg/dl) 9.3 8.2-10.5 Magnesium (mEq/L) 1.2 1.4-4 Phosphorus (mg/dl) 4.7 2.5-6.2 Urea (mg/dl) 52 13-45 Creatinine (mg/dl) 3.13 0.5-1.2 Uric Acid (mg/dl) 8.6 3.5-7.2 Albumin (g/dl) 4.3 3. HbA1c (%) 4.8 < 5.7% SGOT (U/L) 20 5-40 SGPT (U/L) 10 5-40 ARTERIAL BLOOD GAS ANALYSIS pH 7.5 pCO2 43 mm of Hg Na+ 135 mEq/L K+ 1.92 mEq/L Bicarbonate 31.7 mmol/L mEq/L Her ultrasound revealed a single intrauterine foetus of 34 weeks 6 days with absent cardiac activity suggestive of intra-uterine foetal demise. Injectable ondansetron was used to reduce nausea and vomiting, and racecadotril was used to manage loose stools, but electrolyte imbalances were critically low despite the recovery of hyperemesis. The first line of treatment was intravenous (IV) isotonic saline and parenteral potassium. Labour induction of intra-uterine fetal demise was done using two doses of cerviprime gel six hours apart, followed by two doses of tablet misoprostol 50 mcg four hours apart. The patient was then taken up for emergency lower segment cesarean section (LSCS) in view of obstructed labour. Serum potassium level was checked continuously during her hospitalisation (Table 2). Table 2 Serial potassium values DAY OF HOSPITALISATION SERUM POTASSIUM (mEq/L) DAY 0 2.5 DAY 1 2.7 DAY 2 2.7 DAY 3 2.9 DAY 4 2.6 DAY 5 3.2 DAY 6 3.6 This patient was readmitted many times during her first trimester of pregnancy for recurrent nausea and vomiting, each time with severe hypokalemia and hypomagnesemia, and her care was continued according to the previous plan. She was relatively asymptomatic except for nausea and emesis, and she denied muscle cramps, weakness, palpitations, or syncopal attacks. Discussion Renal potassium wasting is promoted by physiological changes during pregnancy, while blood potassium level is controlled in the physiologic array due to an increase in progesterone level that opposes kaliuresis. This compensatory mechanism is rapidly overcome in the presence of Gitleman syndrome, resulting in severe hypokalemia. Maintenance of fluid balance in pregnant women with Gitleman syndrome might be a challenging task. Despite various physiological changes, such as volume expansion, increased renal blood flow, increased glomerular filtration rate (GFR), and activation of the renin-angiotensin-aldosterone axis, that contribute to renal potassium squandering during pregnancy, potassium homeostasis typically remains normal. Increased progesterone levels, which fight kaliuresis, maintain normal serum potassium levels . As was the case in our instance, moderate diarrhoea, vomiting, and pregnancy are common precipitating events. An ideal environment for the development of severe symptomatic hypokalaemia is created in pregnancy by the surge in demand for magnesium and potassium accompanied by increased urine loss. The typical finding of hypomagnesaemia along with metabolic alkalosis, hypokalaemia, hypocalciuria, and hypermagnesuria in 24-hour urine samples serves as the basis for the diagnosis. Genetic testing and the identification of the SCL12A3 gene mutation are the sole methods for diagnosing this condition . Table 3 Summary of cases of Gitelman syndrome during pregnancy Author Symptoms Serum Potassium values Mode of Delivery Pregnancy Outcome Treatment Gestational Complication Basu et al. Easy fatigability in 3rd trimester 2.5 mmol/L Induced vaginal delivery Healthy female child of 2.4 kg Potassium and Magnesium supplementation Oligohydramnios Jones et al. New onset seizures ~3.2 mEq/L Induced vaginal delivery Healthy male child of 2.5 kg Potassium and Magnesium supplementation Oligohydramnios Talaulikar et al. Fatigue, Muscle cramps 2.7 mmol/L Spontaneously delivered vaginally Healthy male child of 2.6 kg Potassium and Magnesium supplementation None De Haan et al. Fatigue, Muscle weakness Not available Delivery by caesarean section Healthy female child of 2.9 kg Intravenous Potassium and Magnesium supplementation Oligohydramnios, Intra uterine growth restriction De Arriba et al. Limb paraesthesia, myalgia 2.4-2.8 mEq/L Elective caesarean section. Healthy female child of 3 kg Spironolactone, Potassium and Magnesium supplementation Oligohydramnios Daskalakis et al. Fatigability, muscle weakness and tenderness in bilateral lower limbs Not available Elective caesarean section (breech presentation) Healthy female child of 3.3 kg Potassium and Magnesium supplementation Oligohydramnios McCarthy et al. Postural hypotension, severe fatigue 2.6 mmol/L Cesarean section (failure to progress in 1ststage of labour) Healthy female child of 2.9 kg Amiloride, Intravenous Potassium and Magnesium supplementation. Required 39 hospitalizations Oligohydramnios Raffi et al. Severe fatigue 3 mmol/L Cesarean section Healthy male child of 3 kg Potassium and Magnesium supplementation Fetal macrosomia (patient had gestational diabetes mellitus) Morton et al. Lethargy, Muscle cramps, nausea, thirst, nocturia 2.6 mmol/L Vaginal Delivery Healthy female child of 3.6 kg Potassium and Magnesium supplementation None Present Study Absent fetal movements, loose stools, vomiting 1.90 mEq/L Emergency caesarean section Intra-uterine fetal demise Oral Potassium and Magnesium supplementation Intrauterine fetal demise Conclusions Gitelman syndrome in pregnancy is a common but overlooked cause of hypokalemia in pregnancy which can have a grave effect on the fetomaternal outcome. Due to its varied presentations, it is often misdiagnosed and hence not appropriately managed. Gitelman's syndrome diagnosis must be made with a valid index that is very accurate, followed by meticulous monitoring and aggressive care, for a better prognosis of the mother and the foetus. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Prenatal programming of hypernatremia and hypertension in neonatal lambs Am J Physiol Regul Integr Comp Physiol Ross MG Desai M Guerra C Wang S 0 103 288 2005 2 Gitelman syndrome Orphanet J Rare Dis Knoers NV Levtchenko EN 22 3 2008 18667063 3 A familial disorder characterized by hypokalemia and hypomagnesemia Ann N Y Acad Sci Gitelman HJ Graham JB Welt LG 856 864 162 1969 5259575 4 An improved terminology and classification of Bartter-like syndromes Nat Clin Pract Nephrol Seyberth HW 560 567 4 2008 18695706 5 Hyperemesis gravidarum in undiagnosed Gitelman's syndrome Case Rep Med Acelajado MC Culpepper RM Bolton Iii WD 2407607 2016 2016 27579038 6 Is normalisation of serum potassium and magnesium always necessary in Gitelman syndrome for a successful obstetric outcome? BJOG Basu A Dillon RD Taylor R Davison JM Marshall SM 630 634 111 2004 15198796 7 Outcome of two pregnancies in a patient with Gitelman's syndrome-a case report J Matern Fetal Investig Jones JM Dorrell S 147 148 8 1998 8 Outcome of pregnancy in a patient with Gitelman syndrome: a case report Nephron Physiol Talaulikar GS Falk MC 0 8 101 2005 9 The transtubular potassium concentration in patients with hypokalemia and hyperkalemia Am J Kidney Dis Ethier JH Kamel KS Magner PO Lemann J Jr Halperin ML 309 315 15 1990 2321642 10 Gitelman syndrome: presenting during pregnancy with adverse foetal outcome J Assoc Physicians India Nand N Deshmukh AR Mathur R Chauhan V Brijlal Brijlal 104 105 64 2016 11 Gitelman syndrome in pregnancy Int J Gynaecol Obstet de Haan J Geers T Berghout A 69 71 103 2008 18639243 12 Gitelman syndrome during pregnancy: a therapeutic challenge Arch Gynecol Obstet de Arriba G Sanchez-Heras M Basterrechea MA 807 809 280 2009 19241082 13 Gitelman syndrome-associated severe hypokalemia and hypomagnesemia: case report and review of the literature J Matern Fetal Neonatal Med Daskalakis G Marinopoulos S Mousiolis A Mesogitis S Papantoniou N Antsaklis A 1301 1304 23 2010 20350237 14 Gitelman's syndrome in pregnancy: case report and review of the literature Nephrol Dial Transplant McCarthy FP Magee CN Plant WD Kenny LC 1338 1340 25 2010 20100726 15 Pregnancy with Gitelman's syndrome Obstet Med Raffi F Fairlie FM Madhuvrata P Bennet WM 39 41 4 2011 27579097 16 Eplerenone for Gitelman syndrome in pregnancy Nephrology (Carlton) Morton A Panitz B Bush A 349 16 2011 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34790 Urology Oncology Metastatic Renal Cell Carcinoma to the Scalp: A Case Report With Review of Literature Muacevic Alexander Adler John R Meshikhes Huda A 1 Al Khatem Raihanah S 1 Albusaleh Hassan M 2 Alzahir Ali A 2 1 Medicine and Surgery, Imam Abdulrahman Bin Faisal University, Dammam, SAU 2 Surgery, King Fahad Specialist Hospital, Dammam, SAU Huda A. Meshikhes [email protected] 9 2 2023 2 2023 15 2 e347908 2 2023 Copyright (c) 2023, Meshikhes et al. 2023 Meshikhes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Renal cell carcinoma (RCC) is the most common type of renal neoplasm. It accounts for 3% of solid tumors in adults and mostly affects men with the peak incidence between the fifth and seventh decades. It metastasizes mainly through the hematogenous spread, and the lung is the most common site of metastasis followed by bone, lymph node, liver, brain, and adrenal glands. Skin metastasis is extremely rare and accounts for <7% of RCC metastases, with the scalp and face being the most reported sites. Skin metastases are usually diagnosed at a later stage of the disease, commonly post-nephrectomy, and are regarded as a poor prognostic factor. Here we report a case of a 54-year-old male who presented with a red, pedunculated, bleeding, and nontender scalp lesion (2x2cm in size) found on the right parietal area. with a history of left radical nephrectomy and adjuvant chemotherapy for clear cell RCC 17 years ago, as well as laminectomy and radiotherapy for bone metastases in C5 and C6 in 2015. After surgical excision of the scalp lesion, histology revealed metastatic clear cell RCC. The patient was doing well post-surgical excision and was referred back to oncology where palliative care and supportive treatment were initiated. In the span of five months post-resection, he developed several conditions where his health further deteriorated. He was announced dead in September 2022 due to cardiac arrest. This case highlights the occurrence of scalp metastases long after the surgical resection of RCC. surgical excision scalp lesion nephrectomy skin metastases renal cell carcinoma The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Renal cell carcinoma (RCC) is the most common type of renal malignancy. It accounts for over 3% of all adult solid malignancies . It has several histological subtypes, the clear cell being the most common and is more prevalent among males with increasing incidence in the elderly population above the fifth to seventh decades . RCC is often diagnosed incidentally during radiologic imaging and only about 10% of patients present with the classical triad of hematuria, flank pain, and a palpable mass . RCC metastasizes primarily through hematogenous spread . It is estimated that 33% of patients with RCC develop metastasis , and the lung is the most common site of metastasis followed by bone, lymph nodes, liver, brain, and adrenal glands . Skin metastasis is extremely rare, and its presence is considered a poor prognostic factor . We report here a case of RCC metastasizing to the scalp, 17 years after nephrectomy and adjuvant chemotherapy. Furthermore, we reviewed the literature on the clinical evaluation and management of similar cases. Case presentation A 54-year-old male known case of type II diabetes mellitus, hypertension, dyslipidemia, and stage V chronic kidney disease on hemodialysis. In 2005, he underwent a left radical nephrectomy for incidentally found RCC, clear cell type, grade 2 out of 4, TNM stage pT3apN not assigned (no nodes submitted or found). Ten years later, he developed lytic bone metastases in C5 and C6 vertebrae. Laminectomy was performed and he was started on radiotherapy was completed in March 2015. Palliative Suntinib was started in July 2015 but then switched to Pazopanib in January 2017 at 400 mg once daily and escalated gradually to 800 mg once daily. Pazopanib was continued at a dose of 600 mg once daily but then stopped in March 2020 due to ischemic heart disease. He was referred by his oncologist to our clinic with a history of scalp swelling which was noticed two years earlier and was increasing in size over the past three months. On examination, a red pedunculated and pulsatile mass on the right parietal area of the scalp was noted. The mass was about 2x2cm in size, mobile, non-tender, and bled easily on scratching or touching . Complete surgical excision was performed under local anesthesia and the histology revealed metastatic clear cell RCC grade 2 with negative margins . He was doing well after the removal of the scalp lesion and was referred back to the oncology team and decided to go for palliative care and supportive treatment. Figure 1 The scalp lesion before the surgical excision. Figure 2 Histological micrograph showing skin with underlying renal cell carcinoma comprising cords for clear cells with a rich vascular background, magnification 4X (2A) and 20X (2B). The patient's health deteriorated five months after the excision, and he was admitted multiple times. He further developed bilateral peripheral neuropathy due to uncontrolled diabetes, right internal jugular vein thrombosis, and encephalopathy secondary to infection. CT brain was done and showed brainstem infarctions with no metastasis noted. Whole body PET/CT scan showed no local recurrence or distant metastases. During his last admission, he was transferred to the intensive care unit and was intubated as his Glasgow coma scale dropped to 6/15. Unfortunately, he passed away from cardiac arrest in September 2022. Discussion Metastatic RCC to the skin is very rare and accounts for 1%-6.5% of all RCC metastases with the scalp and face being the most prominent sites . Our review of the literature revealed a total of 25 reported cases of RCC metastases to the scalp. The mean age of the patients was 57.4 (range: 30-83) years, and most of them were males (80%). Thirteen cases were post-nephrectomy for RCC before the presentation of their scalp lesions [1,4-14]. However, three patients have confirmed the diagnosis of RCC without nephrectomy [15-17]. The mean time interval between the treatment of the primary RCC and the diagnosis of the scalp lesion was 33 (range: 0-180) months. In nine patients, the first presentation was scalp metastasis [2,3,12,18-21], and five of the nine cases were subsequently diagnosed and confirmed with RCC after nephrectomy [2,18-21]. Table 1 summarizes the data of all reported cases of metastatic RCC to the scalp (from 1977 to 2022). Table 1 Summary of reported cases of renal cell carcinoma metastatic to the scalp. Pt No. Author Age (Years) Sex First presentation Treatment to primary tumor Location of skin metastasis Location of other metastases Treatment of skin metastasis Time interval to skin metastasis (Months) Survival after detection of skin metastasis (Months) 1 Abbasi, et al 42 M Flank pain, intermittent gross hematuria Nephrectomy and chemotherapy Scalp None Surgical excision 1 - 2 Yang, et al 83 F Incidental renal mass Nephrectomy Scalp Lung, left iliac bone, spine Surgical excision 180 - 3 Altinkaya, et al 77 M Flank pain and fatigue Chemotherapy Scalp Lung, diaphragmatic pleura, neck lymph nodes, mediastinum, abdomen Surgical excision 144 5 4 Krogerus, et al 65 M Scalp lesion Nephrectomy Scalp Lung Surgical excision 0 - 5 Anzalone, et al 52 M - Chemotherapy Scalp - Surgical excision 30 24 6 Leve, et al 75 M Incidental renal mass Nephrectomy Scalp None Surgical excision 84 - 7 Errami, et al 64 M Incidental renal mass Nephrectomy Scalp Tonsils, cervical lymphadenopathy, bone Chemotherapy 36 - 8 Snow, et al 69 F Acute onset hematuria Nephrectomy Scalp Bicep, mediastinum, spine Surgical excision 72 - 9 Smyth, et al 67 M - Nephrectomy Scalp Left ureter, rectus abdominus muscle, pancreas, brain Surgical excision 120 9 10 Ferhatoglu, et al 40 F - Nephrectomy Scalp None Surgical excision 14 - 11 Selvi, et al 51 M - Nephrectomy Scalp, distal phalanx Oral cavity, brain, lung Surgical excision 36 6 12 Kishore, et al 54 M - Palliative therapy Scalp, upper lip Bone, retromolar, mediastinum, bilateral hilar lymphadenopathy, lung, left adrenal Chemotherapy, radiotherapy 2 - 13 Dorairajan, et al 55 M - Nephrectomy Scalp, cheek Abdomen, brain Interferon 10 4 14 55 M Scalp lesion None Scalp Liver, bone None 0 3 15 30 M Scalp lesion None Scalp Liver, bones, brain Surgical excision 0 3 16 40 M Scalp lesion None Scalp Lung Interferon 0 8 17 56 M - Nephrectomy Scalp Bones None 19 7 18 Estrada-Chavez, et al 80 M - Nephrectomy Scalp None None 48 - 19 de Paula, et al 61 M Incidental renal mass Nephrectomy was not done due to heart failure decompensation Scalp, dorsum, face Lung Surgical excision 0 Dead from acute respiratory failure 20 Pan, et al 63 M Scalp lesion Nephrectomy Scalp None Surgical excision 0 - 21 Eke, et al 42 F Scalp lesion, hematuria Nephrectomy Scalp None None 0 Lost to follow-up 22 Singla, et al 53 M Weight loss, flank mass Nephrectomy, chemotherapy Scalp Upper jaw Surgical excision, chemotherapy 17 - 23 Gandla, et al 45 M - Nephrectomy Scalp Adrenal Radiotherapy 12 - 24 Wahner-Roedler, et al 72 F Scalp lesion Nephrectomy Scalp None Radiotherapy 0 15 25 Livingston, et al 45 M Scalp lesion Nephrectomy Scalp None Surgical excision 0 - 26 Our case 54 M Incidental renal mass Nephrectomy Scalp Spine Surgical excision 204 Cardiac arrest The clinical presentation of the scalp metastasis was either only a red to purple, firm, and well-defined mass or accompanied by other characteristics, such as itching, bleeding, painless, erythematous, vegetated, ulcerated, or expanding pulsatile lesion. Because cutaneous metastasis of RCC mimics other common dermatological conditions such as hemangioma, cutaneous angiosarcoma, basal cell carcinoma, melanoma, or pyogenic granuloma, it is challenging to diagnose it at an early stage . This requires physicians to have a high index of suspicion for such cases. Despite substantial research into the methods of dissemination of RCC, the precise process is still unknown. Hematogenous metastasis, lymphogenous dissemination through the thoracic duct, direct invasion, or implantation from procedures are a few suggested pathways. The major mechanism of metastasis is thought to be through the hematogenous spread. The highly vascular nature of these tumors allows the cells to spread to several organs via the renal vein. For instance, the pathway for metastasis to the lung is from the renal vein to the vena cava reaching the right atrium to the lungs. It has been postulated that the valveless vertebral veins (plexus of Batson) act as a conduit for RCC to travel from the renal vein to the emissary scalp veins ultimately reaching the scalp and skin . Partial or radical nephrectomy is the mainstay management of RCC, and it is considered a cytoreductive strategy in patients with metastatic RCC . For most cases in the literature, surgical excision was done for the scalp mass [1-4,6,8-13,15,16,18,20]. Our patient was similarly managed by excising the scalp lesion. However, in some instances where surgical excision is not an option, chemotherapy, radiotherapy, or interferon are considerable alternatives . Since metastatic RCC is becoming refractory to conventional chemotherapy, more advanced targeted therapy has emerged including sorafenib, sunitinib, bevacizumab, pazopanib, and lenvatinib. These agents are regarded as tyrosine kinase inhibitors that function by inhibiting the vascular endothelial growth factor (VEGF) signaling axis. Sunitinib and pazopanib are approved as first-line management, while the mTOR inhibitors, everolimus, and temsirolimus, are accepted as second-line treatment . Another option is the use of interleukin-2 and interferon alfa, however, these cytokines showed lower response rates and shorter progression-free survival compared to sunitinib (5%-20% vs. 30%-40%) . Our patient was started on sunitinib after undergoing laminectomy of C5 and C6 but switched to pazopanib due to poor compliance. It was found in a study by Motzer et al that pazopanib, despite having similar efficacy to sunitinib, performed better in terms of safety and quality of life . The presence of skin metastasis from RCC is considered a poor prognostic factor where up to 90% are associated with synchronous visceral metastases . The median survival of metastatic clear cell RCC is about 13 months with five-year survival under 10% . When the literature was reviewed, 10 patients died within a mean of 8.4 months after the detection of skin metastasis . Conclusions In conclusion, metastatic RCC to the scalp needs a high index of suspicion to detect. Patients are mostly diagnosed with scalp metastasis in a later stage of their disease even after nephrectomy. The management plan for these cases is usually surgical excision, but when it is not feasible, chemotherapy, radiotherapy, or interferon are alternative options. Although skin metastasis of RCC is a rare occurrence, it may warrant the incorporation of a follow-up strategy as it carries a poor prognosis. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Cutaneous metastasis of bilateral renal cell carcinoma J Pak Med Assoc Abbasi F Alizadeh M Noroozinia F Moradi A 111 113 63 2013 23865145 2 Isolated scalp nodule in patient with undiagnosed RCC ScientificWorldJournal Pan D Niall O Sharma H Gya D 2430 2432 6 2006 17619712 3 Renal cell carcinoma with cutaneous metastasis: case report J Bras Nefrol de Paula TA da Silva PS Berriel LG 213 215 32 2010 21103681 4 Cutaneous metastatic renal cell carcinoma to the scalp Arch Craniofac Surg Yang HJ Kang SY 392 396 20 2019 31914495 5 Scalp metastases of a renal cell carcinoma Skinmed Estrada-Chavez G Vega-Memije ME Lacy-Niebla RM Toussaint-Caire S 148 150 5 2006 16687987 6 Recurrent renal cell carcinoma presenting as a cutaneous metastasis: a case report and review of the literature Urol Ann Leve PP Felicio J Carneiro R Zagalo C 174 176 13 2021 34194146 7 Renal cell carcinoma metastatic to the scalp Rare Tumors Errami M Margulis V Huerta S 6400 8 2016 28191289 8 Renal cell carcinoma metastatic to the scalp: case report and review of the literature Dermatol Surg Snow S Madjar D Reizner G MacK E Bentz M 192 194 27 2001 11207697 9 Renal cell carcinoma presenting as an ominous metachronous scalp metastasis Can Urol Assoc J Smyth LG Casey RG Quinlan DM 0 6 4 2010 10 Skin metastasis of renal cell carcinoma: a case report Cureus Ferhatoglu MF Senol K Filiz AI 0 10 2018 11 Three synchronous atypical metastases of clear cell renal carcinoma to the maxillary gingiva, scalp and the distal phalanx of the fifth digit: a case report J Oral Maxillofac Surg Selvi F Faquin WC Michaelson MD August M 1286 1289 74 2016 12 Cutaneous metastases in renal cell carcinoma Urol Int Dorairajan LN Hemal AK Aron M 164 167 63 1999 10738187 13 Rare metastatic sites of renal cell carcinoma: a case series Pan Afr Med J Singla A Sharma U Makkar A 26 42 2022 35910051 14 Metastatic renal cell carcinoma in the head and neck region Int J Otorhinolaryngol - Head Neck Surg Gandla S Ramaswamy V Rao V 1092 4 2018 15 Large solitary scalp metastasis of renal cell carcinoma: a case report Niger J Clin Pract Altinkaya A Yazar S Karadag EC Er O 629 631 24 2021 33851688 16 Mohs surgery in metastatic cancer: renal cell carcinoma solitary cutaneous metastasis and visceral tumor metastases to skin treated with microscopically controlled surgical excision Int J Dermatol Anzalone CL Cohen PR Migden MR Tannir NM 856 861 52 2013 23675612 17 Unusual presentation of renal cell carcinoma: a rare case report J Lab Physicians Kishore M Chauhan DS Dogra S 241 244 10 2018 29692595 18 Renal cell carcinoma presenting as a tumor on the scalp: a case report Int J Surg Case Rep Krogerus C Svenning M Pilt AP Trostrup H 56 59 76 2020 33011655 19 Renal cell carcinoma presenting as a scalp swelling Niger J Med Eke N Eghwrudjakpor P Echem RC 154 156 12 2003 14737987 20 Solitary scalp metastasis as the presenting feature of a renal carcinoma Br J Plast Surg Livingston WD Jr. Becker DW Jr. Lentz CW 3rd 319 320 30 1977 588798 21 Renal cell carcinoma: diagnosis based on metastatic manifestations Mayo Clin Proc Wahner-Roedler DL Sebo TJ 935 941 72 1997 9379697 22 Latent distant metastasis of renal cell carcinoma to skin: a case report Clin Case Rep Singh P Somani K 1138 1141 8 2020 32695344 23 Lymphatic drainage in renal cell carcinoma: back to the basics BJU Int Karmali RJ Suami H Wood CG Karam JA 806 817 114 2014 24841690 24 Renal cell carcinoma presenting with cutaneous metastasis: a case report Case Rep Med Onak Kandemir N Barut F Yilmaz K Tokgoz H Hosnuter M Ozdamar SO 2010 2010 25 Renal cell carcinoma Nat Rev Dis Primers Hsieh JJ Purdue MP Signoretti S 17009 3 2017 28276433 26 Sunitinib versus interferon alfa in metastatic renal-cell carcinoma N Engl J Med Motzer RJ Hutson TE Tomczak P 115 124 356 2007 17215529 27 Pazopanib versus sunitinib in metastatic renal-cell carcinoma N Engl J Med Motzer RJ Hutson TE Cella D 722 731 369 2013 23964934 28 Calvarial and cutaneous metastasis as the primary presentation of a renal cell carcinoma BMJ Case Rep Jindal T Sinha RK Mukherjee S Karmakar D 2014 2014 29 Clear Cell Renal Carcinoma StatPearls. 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Int J Surg Case Rep Int J Surg Case Rep International Journal of Surgery Case Reports 2210-2612 Elsevier S2210-2612(23)00081-0 10.1016/j.ijscr.2023.107953 107953 Case Report Purple urine bag syndrome in neurological deficit patient: A case report Tirtayasa Pande Made Wisnu [email protected] a Sugianto Ronald [email protected] b* Valentina Isabella [email protected] c Samuel Alwyn Geraldine [email protected] d a Department of Urology, Faculty of Medicine, Universitas Udayana, Universitas Udayana Teaching Hospital, Bali, Indonesia b Medical Doctor Study Program, Faculty of Medicine, Universitas Udayana, Bali, Indonesia c Department of Clinical Pathology, Tarakan Regional Hospital, Jakarta, Indonesia d Department of Surgery, Tarakan Regional Hospital, Jakarta, Indonesia * Corresponding author at: Medical Doctor Study Program, Faculty of Medicine, Universitas Udayana Jl. PB Sudirman, Denpasar 80232, Bali, Indonesia. [email protected] 24 2 2023 3 2023 24 2 2023 104 1079538 11 2022 18 1 2023 22 2 2023 (c) 2023 The Authors 2023 This is an open access article under the CC BY license ). Introduction and importance Purple urine bag syndrome (PUBS), described first in 1978, is a rare phenomenon with purplish discolorations in the urine collecting bag. This report aims to provide a general overview of PUBS, its pathogenesis, and the recommended treatments. Case presentation A woman patient, 27 years old, with prior history of congenital rubella infection complained of urinary retention. The patient routinely had foley catheterization due to neurogenic bladder accompanied by paraparesis inferior for 1.5 years. She also suffered bilateral lower extremities edema with infected wounds for two weeks, which showed a purple urine color in the urine bag. The laboratory examination demonstrated iron deficiency anemia, hypokalemia, and blood alkalosis. Clinical discussion The cause of purplish discolorations of PUBS is the mixing of indigo, blue pigment, and indirubin, red pigment, which are results of dietary digestion, hepatic enzymes, and bacterial urine oxidation. The main risk factors are female patients, constipation, older age, recurrent UTI, renal failure, and urinary catheterization, dominantly on chronic treatment with polyvinyl chloride (PVC) urinary catheter or bag. Conclusion The management should be promptly, rigorously, and appropriately because the complicated UTI has a high-risk progression of urosepsis. Highlights * Purple urine bag syndrome is a rare medical phenomenon. * Purplish discolorations are shown by mixing indigo and indirubin. * The main risk factors are female, constipation, and urinary catheterization. * The main etiology of urosepsis was gram-negative bacteria, similar to PUBS. * PUBS management has to be appropriate due to high morbidity and mortality. Keywords Purple urine bag syndrome Neurogenic bladder Paraparesis Congenital rubella infection pmc1 Introduction and importance Purple urine bag syndrome (PUBS) is a phenomenon of purplish discolorations in the urine collecting bag, which remains underdiagnosed. PUBS described first in 1978 by Barlow and Dickson , has been associated with constipation, urinary tract infections (UTI), renal failure, and urinary catheterization, dominantly on chronic treatment , . Even though the urine is relatively clear, the cause of purplish discolorations of the tube or collecting bag is the mixing of indigo, blue pigment, and indirubin, red pigment, which are results of dietary digestion, hepatic enzymes, and bacterial urine oxidation , . This report aims to provide a general overview of PUBS, its pathogenesis, and the recommended treatments. 2 Case presentation A woman patient, 27 years old, with prior history of congenital rubella infection complained of urinary retention. The patient routinely had foley catheterization due to neurogenic bladder accompanied by paraparesis inferior for 1.5 years. She also suffered bilateral lower extremities edema with infected wounds for two weeks. The patient's vital signs and physical examinations were hypotension, tachypnea, and hypoxia, and the bladder was full. The following laboratory examination demonstrated hemoglobin 9.2 g/dL with microcytic and hypochromic erythrocytes, serum iron 14 mg/dL, ferritin, 4.45 ng/mL, potassium 2.9 mEq/L, blood urea nitrogen 14 mg/dL, serum creatinine 0.4 mg/dL, blood pH 7.65, PaCO2 20.2 mmHg, PaO2 212.3 mmHg, leucocytes urine sedimentation 5-8 LPF. Therefore, the patient was diagnosed with iron deficiency anemia, hypokalemia, and blood alkalosis. Based on those data, the patient underwent emergency treatment with 15 L of oxygen per minute by non-rebreathing mask, rehydration, empirical antibiotics, and foley catheterization replacement. After that, a purple urine color was found in the urine bag (Fig. 1). Then, urine culture yielded Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumonia, gram-negative bacteria sensitive to meropenem, so the antibiotic was changed. The disappearance of purple discoloration in the urine bag and the patient becoming asymptomatic after one week of treatment. This case presentation followed SCARE Guideline Checklist 2020 .Fig. 1 Purple urine in collecting bag. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Fig. 1 3 Clinical discussion The pathogenesis of PUBS (Fig. 1) initiates by the tryptophan in the bowel from the gastrointestinal process, digestion, and absorption. The bacteria in the intestine generated indoxyl sulfate from tryptophan metabolism . Then, hepatic enzymes turned into the conjugate indoxyl sulfate form and secreted into the kidney. In the urinary tract, the conjugate indoxyl sulfate was metabolized to indoxyl through the complete oxidation of gram-negative bacteria phosphatases and sulfatases, which convert into indigo and indirubin. Then, purplish discolorations were shown by mixing indigo, blue pigment, and indirubin, a red pigment , , . The most common bacteria related to PUBS were: E. coli 20.8 %, Proteus mirabilis 16.2 %, and Klebsiella pneumonia 13,6 % . The purple discoloration of urine is known to be associated with multiple risk factors. The main risk factors are female patients, constipation, older age, recurrent UTI, renal failure, and urinary catheterization, dominantly on chronic treatment with polyvinyl chloride (PVC) urinary catheter or bag , followed by dementia, prolonged bed rest, institutionalization, dehydration, high urinary bacterial counts and alkaline urine , . In this report, the patient had four main risk factors followed by three additional risks. The main etiology of urosepsis is gram-negative bacteria, similar to bacteria related to PUBS, as follows: E. coli 50 %, Proteus spp. 15 %, Enterobacter and Klebsiella 15 %, P. aeruginosa 5 %, and the others are gram-positive bacteria . For a quick and accurate diagnosis, the quick Sequential Organ Failure Assessment (qSOFA) scoring system is mandatory, including altered mental status (GCS < 15), compromising respiratory rate (>22/min), and systolic blood pressure of 100 mmHg or less . Our patient's urine cultures yielded the same bacteria with two qSOFA scores. Since there is no guideline for PUBS management, the treatment of PUBS has varied according to the pathogenesis and the patient's condition. Moreover, the treatment should be appropriate due to high morbidity and mortality . Based on our case, we recommend stabilizing the vital sign and treating the systemic disease first, such as oxygenation and intravenous rehydration. Afterward, the empirical antibiotics and the catheter replacement should be done, and non-plastic catheter bags could be an alternative . The broad spectrum of antibiotics therapy that covers extended-spectrum was recommended . The antibiotic switching can be performed once the urine culture and antibiotic sensitivity results showed up. 4 Conclusion The complicated UTI has a high-risk progression of urosepsis. The management should promptly, rigorously, and appropriately, including the specified antibiotics for UTI infections, replacing the catheter, and the prevention of recurrence or persistence of the PUBS phenomenon. Consent The informed consent was written by the patient in the Indonesian language for further publication of this case report anonymously. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Source of funding None. Ethics committee approval Not applicable. Author contribution Pande Made Wisnu Tirtayasa: Conceptualization; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Visualization. Ronald Sugianto: Roles/Writing - original draft; Writing - review & editing, Conceptualization; Formal analysis; Investigation; Methodology; Project administration; Visualization. Isabella Valentina: Data curation; Funding acquisition; Investigation; Resources; Software; Supervision; Validation; Visualization. Alwyn Geraldine Samuel: Performed the procedure, Data curation; Funding acquisition; Investigation; Resources; Supervision; Validation; Visualization. Research registration None. Declaration of competing interest None. References 1 Chung S.D. Liao C.H. Sun H.D. Purple urine bag syndrome with acidic urine Int. J. Infect. Dis. 12 5 2008 526 527 18514009 2 Shaeriya F. Remawy R.A. Makhdoom A. Alghamdi A. Shaheen F.A.M. Purple urine bag syndrome Saudi J. Kidney Dis. 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Sensors (Basel) Sensors (Basel) sensors Sensors (Basel, Switzerland) 1424-8220 MDPI 10.3390/s23052847 sensors-23-02847 Editorial Editorial-Special Issue on "Sensor Technology for Enhancing Training and Performance in Sport" Kong Pui Wah Physical Education and Sports Science Academic Group, National Institute of Education, Nanyang Technological University, Singapore 637616, Singapore; [email protected] 06 3 2023 3 2023 23 5 284707 2 2023 27 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmc1. Introduction Sensor technology opens up exciting opportunities for sports. For example, advancements in motion tracking devices allow monitoring athletes' movement patterns indoors and outdoors . Wearable sensors offer insightful information on the demands of the sport during both training and competition . Such data are important for coaches and athletes to optimize their training plan, minimize the risk of injuries, and improve sport performance. This Special Issue focuses on the innovative development and application of sensors for enhancing training and performance in sport. We received a total of 9 original and 1 review articles covering a variety of sports, including those on land and in water . 2. Swimming Providing performance feedback to swimmers is important for enhancing their training and competition but placing sensors in water can be technically challenging. A systematic review paper by Morais and colleagues comprehensively summarized the currently available wearables that can provide real-time feedback in swimming. They reported that most systems are in-house built wearables with very few commercially available systems. The wearables were mostly placed on the lower back (44.4%) or the head (38.9%). Many studies assessed the accuracy, measurement errors, and/or consistency of the wearables and the majority reported the current swimming wearables as accurate. As the authors have pointed out that most researcher focused only on the front-crawl stroke, future work can expand the scope into other swimming strokes such as the breaststroke, backstroke, and butterfly stroke. We can also look forward to more commercially available wearables for swimming and other types of aquatic activities. 3. Global and Local Positioning Systems Global Navigation Satellite System (GNSS) are wearables that allow continuous tracking of movement patterns of one or multiple players. Such technologies have been widely applied in sports such soccer, rugby, and field hockey. In this special issue, we published two articles concerning the applications of GNSS in sports. Chahal et al. evaluated the inter-unit consistency and validity of multiple 10-Hz GNSS units in measuring straight-line sprint performance. Their participants worn 8 Catapult GNSS units at once and performed a maximum effort sprint. Poor inter-unit consistency for distance and speed measurements were found. For validity, most units recorded greater total distances and lower peak speeds than the reference values. Since variations exist among different units of the same GNSS system, the authors advised that if logistically possible, players should wear the same unit every time rather than swapping the units among teammates. This practice would allow a more meaningful comparison of the GNSS data of the player over a season. Another article by Bursais and colleagues assessed and compared the ability of four accelerometry-based metrics and GNSS to predict the known distance completed using different movement constraints. In their study, participants were asked to walk around small and big circles of known distances. Acceleration data were collected via a tri-axial accelerometer at 100 Hz while positional data were sampled at 10 Hz using a triple GNSS unit. They reported promising regression model results, suggesting that both GNSS and accelerometry may be used to indicate the total distance completed while walking. While GNSS are commonly used for outdoor sports, such systems do not work for indoor activities. As such, local positioning systems are developed to study match demands for indoor sports. In this special issue, one article by Guignard et al. attempted to automatically define defensive organizations in professional handball with the use of local positioning systems. The research team first developed an automatic tool to detect and classify the defensive organization of the team. They then quantified the match demands per defensive organization. Using player data from a team in the Spanish League, the algorithm developed successfully quantified the physical demands of the game (distance stand, walk, jog, run, and sprint). Their results are promising, opening new opportunities for optimizing specific players' roles as well as game strategies (e.g., defensive organization) at the team level. 4. Validity and Reliability Different types of wearables sensors have been developed to support training for individuals participating in different types of sports. The validity and reliability of the wearables or smart devices may vary depending on the exercise intensity and the types of activities. With wrist-worn wearables becoming increasingly available, Cai and colleagues investigated the reliability and validity of the Lexin Mio smart bracelet in physiological responses in 65 individuals with different physical activity levels exercising at different intensities. They found that the Lexin Mio smart bracelet showed good reliability and validity for heart rate measurement but low validity for the estimation of energy expenditure. In the sport of indoor cycling, Fiolo et al. evaluated the validity and reliability of a tire pressure sensor cycling power meter against a gold standard. Twelve recreationally active participants completed 8 trials of 90-s cycling at different pedaling and gearing combinations while power outputs were measured. It is concluded that the tire pressure sensor can provide an accurate and reliable assessment of average power over a timeframe of 1-min duration or longer on an indoor roller trainer. The authors recommended this tool for practical use during general exercise or power with power outputs below 300 W and with less stringent error tolerance (+-5%). Future research for outdoor use and under additional testing parameters, such as long-duration cycling, standing, sprinting, and inconsistent pedaling are recommended. Our last example is on running which is a very popular physical activity across many countries. Chow and colleague compared the use of accelerometer and gyroscope in predicting running kinematics. Their team explored the use of convolutional neural network (CNN) to predict selected running kinematics (e.g., knee and hip angles) during level-ground running on a treadmill. The results reported that kinematics predictions in the sagittal plane were better for the knee joint than for the hip joint, and that predictions using the gyroscope as the regressor were better than those using the accelerometer. 5. Application of Wearables in Sports After wearable sensors are developed and validated, it is of interest to see how they can be applied in real-life sport settings. This Special Issues included 3 articles demonstrating how different types of sensors are applied in field hockey , tennis , and running . Cuadrado-Penafiel et al. compared the efficiency and effectiveness of two different configurations of within-season training load distribution in professional field hockey players over 6 weeks. They applied many types of equipment and sensors to monitor the players' performance, for example, Global Positioning System (GPS), inertial measurement units (IMU), and Dynaspeed linear motorized system. The authors concluded that implementing strategies such as microdosed training load distribution can be an effective and efficient alternative for sprint training in team sports such as hockey. In tennis, Kramberger et al. performed a case study to demonstrate how a wearable device can potentially contribute towards injury prevention in tennis. This study used the Armbeep wearable device to monitor the workload and recovery of a tennis player over 6 months. Using the data collected, the researchers instructed the coach and the player to adjust the daily workload with a goal to optimize the level of an athlete's training load, increase the effectiveness of training, enable an individual approach, and reduce the possibility of overuse or injuries. This study is a real-life practical example of the use of modern technology in the supporting athletes' training and competition over a sustained period of time. Finally, one randomized controlled trial was conducted to examine the effectiveness of sensor-based gait retraining in lowering risk factors and symptoms of knee osteoarthritis (OA) . This study randomized 71 participants with early medial knee OA in to either walking exercise or gait retraining groups. During the gait retraining intervention, real-time visual feedback was provided based on IMU measurements while participants were walking on a treadmill. The authors concluded that a six-week sensor-based gait retraining, compared with walking exercise, was an effective intervention to lower medial knee loading, relieve knee pain, and improve symptoms for patients with early medial knee OA. 6. Summary I am delighted to see that the research articles in this Special Issue have generated new knowledge to the field of sensor technology for sports, identified research gaps for future advancement, and opened new opportunities for innovation and collaboration. As a final remark, I would like to thank all the authors for their contributions to this Special Issue. My thanks also go to the reviewers for their insightful comments and helpful feedback for the authors. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Prigent G. Aminian K. Rodrigues T. Vesin J.-M. Millet G.P. Falbriard M. Meyer F. Paraschiv-Ionescu A. Indirect Estimation of Breathing Rate from Heart Rate Monitoring System during Running Sensors 2021 21 5651 10.3390/s21165651 34451093 2. Fischer G. Wirth M.A. Balocco S. Calcagni M. In Vivo Measurement of Wrist Movements during the Dart-Throwing Motion Using Inertial Measurement Units Sensors 2021 21 5623 10.3390/s21165623 34451068 3. Elfmark O. Ettema G. Groos D. Ihlen E.A.F. Velta R. Haugen P. Braaten S. Gilgien M. Performance Analysis in Ski Jumping with a Differential Global Navigation Satellite System and Video-Based Pose Estimation Sensors 2021 21 5318 10.3390/s21165318 34450758 4. Lim J.Z. Sim A. Kong P.W. Wearable Technologies in Field Hockey Competitions: A Scoping Review Sensors 2021 21 5242 10.3390/s21155242 34372481 5. Cuadrado-Penafiel V. Castano-Zambudio A. Martinez-Aranda L.M. Gonzalez-Hernandez J.M. Martin-Acero R. Jimenez-Reyes P. Microdosing Sprint Distribution as an Alternative to Achieve Better Sprint Performance in Field Hockey Players Sensors 2023 23 650 10.3390/s23020650 36679451 6. Guignard B. Karcher C. Reche X. Font R. Komar J. Contextualizing Physical Data in Professional Handball: Using Local Positioning Systems to Automatically Define Defensive Organizations Sensors 2022 22 5692 10.3390/s22155692 35957247 7. Cai Y. Wang Z. Zhang W. Kong W. Jiang J. Zhao R. Wang D. Feng L. Ni G. Estimation of Heart Rate and Energy Expenditure Using a Smart Bracelet during Different Exercise Intensities: A Reliability and Validity Study Sensors 2022 22 4661 10.3390/s22134661 35808157 8. Kramberger I. Filipcic A. Germic A. Kos M. Real-Life Application of a Wearable Device towards Injury Prevention in Tennis: A Single-Case Study Sensors 2022 22 4436 10.3390/s22124436 35746218 9. Bursais A.K. Bazyler C.D. Dotterweich A.R. Sayers A.L. Alibrahim M.S. Alnuaim A.A. Alhumaid M.M. Alaqil A.I. Alshuwaier G.O. Gentles J.A. The Relationship between Accelerometry, Global Navigation Satellite System, and Known Distance: A Correlational Design Study Sensors 2022 22 3360 10.3390/s22093360 35591051 10. Chahal A.K. Lim J.Z. Pan J.W. Kong P.W. Inter-Unit Consistency and Validity of 10-Hz GNSS Units in Straight-Line Sprint Running Sensors 2022 22 1888 10.3390/s22051888 35271035 11. Fiolo N.J. Lu H.-Y. Chen C.-H. Fuchs P.X. Chen W.-H. Shiang T.-Y. The Validity and Reliability of a Tire Pressure-Based Power Meter for Indoor Cycling Sensors 2021 21 6117 10.3390/s21186117 34577323 12. Wang S. Chan P.P.K. Lam B.M.F. Chan Z.Y.S. Zhang J.H.W. Wang C. Lam W.K. Ho K.K.W. Chan R.H.M. Cheung R.T.H. Sensor-Based Gait Retraining Lowers Knee Adduction Moment and Improves Symptoms in Patients with Knee Osteoarthritis: A Randomized Controlled Trial Sensors 2021 21 5596 10.3390/s21165596 34451039 13. Chow D.H.K. Tremblay L. Lam C.Y. Yeung A.W.Y. Cheng W.H.W. Tse P.T.W. Comparison between Accelerometer and Gyroscope in Predicting Level-Ground Running Kinematics by Treadmill Running Kinematics Using a Single Wearable Sensor Sensors 2021 21 4633 10.3390/s21144633 34300372 14. Morais J.E. Oliveira J.P. Sampaio T. Barbosa T.M. Wearables in Swimming for Real-Time Feedback: A Systematic Review Sensors 2022 22 3677 10.3390/s22103677 35632086 |
Polymers (Basel) Polymers (Basel) polymers Polymers 2073-4360 MDPI 10.3390/polym15051264 polymers-15-01264 Editorial Special Issue "State-of-the-Art Polymer Science and Technology in Greece" Pispas Stergios 1* Anastasiadis Spiros H. 23 Iatrou Hermis 4 1 Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 11635 Athens, Greece 2 Institute of Electronic Structure and Laser, Foundation for Research and Technology-Hellas, N. Plastira 100, 70013 Heraklion Crete, Greece 3 Department of Chemistry, University of Crete, Vasilika Vouton, 71003 Heraklion Crete, Greece 4 Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771 Athens, Greece * Correspondence: [email protected]; Tel.: +30-210-727-3824 02 3 2023 3 2023 15 5 126414 2 2023 24 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcPolymer science and technology is an active and continuously developing field of research and innovation in Greece. Many research groups in the country are active in different subfields of polymer science and technology including polymer synthesis, polymer characterization and properties elucidation, polymer physics, polymer physical chemistry, and the theoretical description and understanding of polymer systems. The aim of this Special Issue has been to collect original contributions, both research papers and reviews, demonstrating recent results and advances from the polymer-related research performed in Greece at the beginning of the 21st century. A brief account of the works presented in the issue is given below. Iatrou and coworkers report on the synthesis of a novel monomer, namely Ne-9-fluorenylmethoxycarbonyl-l-lysine N-carboxy anhydride (Ne-Fmoc-l-Lysine NCA). The monomer was used for the synthesis of linear peptide homopolymers and well-defined block-graft lysine and histidine-based copolypeptides . The new copolypeptides were characterized in aqueous media in terms of their conformational and aggregation properties under different conditions. The future perspectives of using this monomer for the synthesis of copolypeptides of complex macromolecular architecture, able to be utilized as drug nanocarriers, have been discussed. Kafetzi and Pispas report on the synthesis of hydrophobically modified poly(2-(dimethylamino) ethyl methacrylate)-b-poly(oligo(ethylene glycol) methyl ether methacrylate) diblock copolymers using RAFT polymerization and post-polymerization quaternization of the PDMAEMA block with long alkyl chains in a random fashion . Due to their amphiphilic character the copolymers self-assemble into nanoaggregates in aqueous media in response to pH and temperature and can be used as nanocarriers for indomethacine. Bogiatzidis and Zoumpoulakis present the preparation of thermoset composites based on commercially available epoxy and unsaturated polyester resins, as well as laboratory synthesized phenolic resin (novolac) filled with construction and demolition (C&D) waste powder of different grain size in the micro-scale, and in the 30-50% w/w C&D wastes composition range . The mechanical properties of the composites were investigated. Pitsikalis and his group present the synthesis of statistical copolymers of N-vinylpyrrolidone and isobornyl methacrylate utilizing traditional free radicals and RAFT polymerization . The reactivities of the monomers were determined in each polymerization scheme. The thermal properties and thermal decomposition of the new copolymers are studied as well. Sakellariou and coworkers propose the direct functionalization of single-walled carbon nanotubes with diphenylethylene cyclobutene (DPE-CB) end-capped polystyrene chains using a facile, single-step, [4+2] Diels-Alder cycloaddition reaction . Direct evidence for the efficient surface functionalization and the presence of a thin polystyrene film was provided by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Tsitsilianis, et al. discuss the preparation of mesoporous silica nanoparticles covered by alternative layers (via a layer-by-layer deposition process, LbL) of oppositely charged weak polyelectrolytes . Poly(allylamine hydrochloride) (PAH) and sodium alginate, highly grafted by N-isopropylacrylamide/N-tert-butylacrylamide random copolymers (NaALG-g) were utilized for the LbL assembly. Due to the pH-responsive properties and LCST-type thermoresponse of the NaALG-g polymer, the hybrid nanoparticles exhibit pH and thermo-responsive drug delivery properties. Charitidis and coworkers examine the utilization of core-shell super absorbent polymers (SAPs) as triggerable materials in coating binders . SAPs acrylic binders were applied onto acrylonitrile-butadiene-styrene/polycarbonate plastic substrates (at 1 and 5 wt.% SAPs) and facilitated the debonding of the coatings from the plastic substrates by a steam treatment. The study is strongly related to the recycling of plastics. The contribution by the groups of Vamvakaki and Chatzinikolaidou focuses on the synthesis of novel polyesters with pH-responsive carboxylic groups and alkene functionalities utilizing condensation polymerization and photo-induced thiol-ene click reactions . The novel polyesters show water solubility and biocompatibility, while their crosslinked analogues showed promise as cell culturing substrates and in tissue engineering applications. Vamvakaki and coworkers also report on the synthesis and properties of novel, linear, main-chain acid-degradable copolymers based on acylhydrazone bonds by applying step growth copolymerization based synthetic schemes . acid-induced degradation of the copolymer in dimethylsulfoxide and water was demonstrated by UV-vis spectroscopy. The authors succeeded in attaching the anticancer drug doxorubicin onto the copolymers forming amphiphilic drug-polymer conjugates which form nanoscale aggregates in aqueous media. UV light and acid degradation of these particles result in the efficient release of the drug cargo. Paipetis, et al. study the healing properties of urea-formaldehyde (UF) shell-wall microcapsules after the addition of multi-walled carbon nanotubes (MWCNTs), under different concentrations of the filler particles . The addition of MWCNTs resulted in a decrease in the size of microcapsules and an improvement in the electromagnetic interference shielding effectiveness and the mechanical properties of the composites, even at low MWCNT content, without affecting the healing properties of the materials. Manouras, et al. investigate the antibacterial properties of lightly quaternized poly(2-(dimethylamino)ethyl methacrylate)s which were prepared using alkyl halides of different alkyl chain structures . Quaternization affected the LCST behavior of the copolymers in aqueous media compared to the PDMAEMA precursor in different ways depending on the nature of the quaternizing agent. The copolymers show inhibitory action against Escherichia coli and Staphylococcus aureus strains. Tsioptsias, et al. study the tensile strength and thermal stability of isotactic polypropylene (PP) composite drawn fibers reinforced with five different fillers (microtalc, ultrafine talc, wollastonite, attapulgite, and single-wall carbon nanotubes) . The use of ultrafine talc particles results in better mechanical and thermal performance. Raptis and Karatasos present a theoretical investigation of the interactions of essential oil ingredients, having therapeutic potential, with hyperbranched PEI and PG homopolymers in aqueous media using molecular dynamics simulations . Despite the fact that clustering phenomena are observed for the terpenoids under study, sufficient polymer-drug interaction and association are observed over the whole composition range. Finally, in their review article, Papagiannopoulos and Sotiropoulos discuss the methods for the preparation of polysaccharide nanogels and microgels as well as their potential utilization in biomedical and food research, mainly as nanocarriers for bioactive substances and emulsion stabilizers . Acknowledgments S. Pispas, S. H. Anastasiadis and H. Iatrou wish to sincerely thank all participants to this Special Issue, authors, reviewers, and members of the Editorial Office. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Athanasiou V. Thimi P. Liakopoulou M. Arfara F. Stavroulaki D. Kyroglou I. Skourtis D. Stavropoulou I. Christakopoulos P. Kasimatis M. Synthesis and characterization of the novel Ne-9-fluorenylmethoxycarbonyl-l-lysine N-carboxyanhydride. Synthesis of well-defined linear and branched polypeptides Polymers 2020 12 2819 10.3390/polym12122819 33261159 2. Kafetzi M. Pispas S. Effects of hydrophobic modifications on the solution self-assembly of P(DMAEMA-co-QDMAEMA)-b-POEGMA random diblock copolymers Polymers 2021 13 338 10.3390/polym13030338 33494531 3. Bogiatzidis C. Zoumpoulakis L. Thermoset polymer matrix composites of epoxy, unsaturated polyester, and novolac resin embedding construction and demolition wastes powder: A comparative study Polymers 2021 13 737 10.3390/polym13050737 33673641 4. Kokkorogianni O. Kontoes-Georgoudakis P. Athanasopoulou M. Polizos N. Pitsikalis M. Statistical copolymers of N-vinylpyrrolidone and isobornyl methacrylate via free radical and RAFT polymerization: Monomer reactivity ratios, thermal properties, and kinetics of thermal decomposition Polymers 2021 13 778 10.3390/polym13050778 33802615 5. Stathouraki M.M. Pantazidis C. Mygiakis E. Avgeropoulos A. Sakellariou G. Functionalization of single-walled carbon nanotubes with end-capped polystyrene via a single-step Diels-Alder cycloaddition Polymers 2021 13 1169 10.3390/polym13071169 33917281 6. Theodorakis N. Saravanou S.F. Kouli N.P. Iatridi Z. Tsitsilianis C. pH/Thermo-responsive grafted alginate-based SiO2 hybrid nanocarrier/hydrogel drug delivery systems Polymers 2021 13 1228 10.3390/polym13081228 33920243 7. Kartsonakis I.A. Goulis P. Charitidis C.A. Triggerable super absorbent polymers for coating debonding applications Polymers 2021 13 1432 10.3390/polym13091432 33946709 8. Mountaki S.A. Kaliva M. Loukelis K. Chatzinikolaidou M. Vamvakaki M. Responsive polyesters with alkene and carboxylic acid side-groups for tissue engineering applications Polymers 2021 13 1636 10.3390/polym13101636 34070123 9. Psarrou M. Kothri M.G. Vamvakaki M. acid-degradable polyacylhydrazone-doxorubicin conjugates Polymers 2021 13 2461 10.3390/polym13152461 34372064 10. Kosarli M. Polymerou A. Foteinidis G. Vazouras C. Paipetis A.S. Healing efficiency of CNTs-modified-UF microcapsules that provide higher electrical conductivity and EMI shielding properties Polymers 2021 13 2753 10.3390/polym13162753 34451294 11. Manouras T. Platania V. Georgopoulou A. Chatzinikolaidou M. Vamvakaki M. Responsive quaternized PDMAEMA copolymers with antimicrobial action Polymers 2021 13 3051 10.3390/polym13183051 34577950 12. Tsioptsias C. Leontiadis K. Messaritakis S. Terzaki A. Xidas P. Mystikos K. Tzimpilis E. Tsivintzelis I. Experimental investigation of polypropylene composite drawn fibers with talc, wollastonite, attapulgite and single-wall carbon nanotubes Polymers 2022 14 260 10.3390/polym14020260 35054667 13. Raptis V. Karatasos K. Molecular dynamics simulations of essential oil ingredients associated with hyperbranched polymer drug carriers Polymers 2022 14 1762 10.3390/polym14091762 35566930 14. Papagiannopoulos A. Sotiropoulos C. Current advances of polysaccharide-based nanogels and microgels in food and biomedical sciences Polymers 2022 14 813 10.3390/polym14040813 35215726 |
Sensors (Basel) Sensors (Basel) sensors Sensors (Basel, Switzerland) 1424-8220 MDPI 10.3390/s23052717 sensors-23-02717 Editorial Biosensor Development and Innovation in Healthcare and Medical Applications Mills David K. 12* Nestorova Gergana G. 12* 1 The School of Biological Sciences, Louisiana Tech University, Ruston, LA 71272, USA 2 Molecular Science and Nanotechnology, Louisiana Tech University, Ruston, LA 71272, USA * Correspondence: [email protected] (D.K.M.); [email protected] (G.G.N.) 02 3 2023 3 2023 23 5 271724 1 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). NSF2228581 This research was funded by NSF grant number 2228581. pmc1. Introduction The pandemic necessitated a change to the historical diagnostics model. It accelerated a shift to a hybrid approach that includes an analysis of patient samples collected in distributed settings, such as at the point of care and in workplaces, schools, and community centers. Perhaps the most radical change in response to the pandemic was the large-scale production and distribution of over-the-counter SARS-CoV-2 testing technologies that could be purchased. It produced a foundational shift in the approaches of nations and their health systems for detecting and diagnosing diseases and conditions, especially infectious diseases. The demand for diagnostic, monitoring, and measuring sensors with clinical applications is growing . The development of affordable, easy-to-use, and accurate medical devices to provide timely and actionable health status information remains critical. New healthcare delivery models foresee an empowered patient engaged in informed decision-making and care management in partnership with physicians, nurses, and healthcare practitioners. This model requires an innovation in medical device technologies that overcome the delay issues using centralized, lab-based approaches, with the patient-to-provider interaction occurring at the point of care. The near future will see the development of diagnostic systems that can help predict and stop the spread of disease. Molecular-level sensor detection networks that provide real-time pathogens or pollution monitoring of the agricultural, animal, environmental, and health fields will radically improve global healthcare. New biosensors are needed for diagnostic tools for evaluating patient samples, such as blood, saliva, and urine in non-laboratory settings, and real-time patient data . In addition, monitoring devices for the home-based management of chronic conditions and communication technologies enable data sharing and team-based care approaches across settings. Microphysiological analysis platforms predict the most effective treatment of diseases and provide an ideal model to address fundamental questions of development and disease pathogenesis . They will provide a significant stimulus for new proactive, predictive, and preventive medical devices. We predict that diagnostics will become tightly integrated into treatment strategies . These devices can expand the capabilities of primary care physicians, nurses, pharmacists, and other health care practitioners, as well as patients, to rapidly determine and deliver the appropriate treatments and prevention strategies. These smart devices will save patients' lives, assist in controlling bacterial and viral outbreaks, and reduce healthcare costs. Point-of-care (POC) technologies involve the use of portable devices to medically examine a patient during a consultation. POC devices can provide instantaneous results, enabling patients to receive better-informed healthcare information. POCs also provide an opportunity to deliver healthcare in low-resource settings, such as in middle-income countries or disaster environments, where there is often a lack of diagnostic and monitoring tools. The combination of highly sensitive biosensor designs with microfluidics has increased in various lab-on-a-chip devices. These devices can reduce sample volume and detection time and improve sensitivity with high throughput operation . With this in mind, the goal of this Special Issue of the Journal Sensors, belonging to the section "Biosensor Development and Innovation in Healthcare and Medical Applications", was to collect original research manuscripts which describe cutting-edge developments in biosensor technology for medicine and clinical translational applications, as well as reviews that provide an update on the latest progress in this field. A total of seven manuscripts have been accepted for publication. The final collection includes five original research manuscripts and two reviews by authors from several different countries. A quick overview and general classification of the manuscripts are provided below. 2. Contributions (1). "DE-PNN: Differential Evolution-Based Feature Optimization with Probabilistic Neural Network for Imbalanced Arrhythmia Classification" was authored by Amanah Nasim and Yoon Sang Kim. A heartbeat classification method was developed based on evolutionary feature optimization using differential evolution (DE) and classification using a probabilistic neural network (PNN) to discriminate between normal and arrhythmic heartbeats. The proposed method follows four steps: (1) preprocessing; (2) heartbeat segmentation; (3) DE feature optimization; and (4) PNN classification and employed direct signal amplitude points constituting the heartbeat acquired from the ECG holter device with no secondary feature extraction steps. The proposed DE-PNN scheme can provide better classification accuracy considering 8 classes with only 36 features optimized from a 253-element feature set, thus implying an 85.77% reduction in direct amplitude features. Our proposed method achieved overall 99.33% accuracy, 94.56% F1, 93.84% sensitivity, and 99.21% specificity. (2). The article, "Wearable E-Textile and CNT Sensor Wireless Measurement System for Real-Time Penile Erection Monitoring", was authored by Yongki Heo, Jinhyung Kim, Cheolung Cha, Kyusik Shin, Jihyoung Roh, and Jungki Jo. Erectile measurements are an important indicator of male urological disease diagnosis, treatment, and results. Rigiscan has been widely used in studies and diagnoses for evaluating nocturnal erectile dysfunction during sleep. There are some limitations to this technique. In this study, we used a real-time wearable monitoring system that can quantitatively measure the length and circumference of the penis using electronic textiles (E-textile) and carbon nanotube (CNT) sensors. The E-textile sensor was used to measure the length, circumference, and gradient with portability, convenience, and comfort. The results of this study call for supplementary sensor development coupled with new technologies or existing methods for measuring erection function. (3). "Open Software/Hardware Platform for Human-Computer Interface Based on Electrooculography (EOG) Signal Classification" was authored by Jayro Martinez-Cervero, Majid Khalili Ardali, Andres Jaramillo-Gonzalez, Shizhe Wu et al. They discuss electrooculography (EOG) signals and Human-Computer Interfaces (HCI) for classifying four directions of eye movements employing EOG signals. The system is based on open-source ecosystems, the Raspberry Pi single-board computer, the OpenBCI biosignal acquisition device, and an open-source python library. The design is inexpensive, compact, and transportable. Their classification system can be used for input into an HCI and new assistive technology for assisted communication in paralyzed people. (4). "Hydration Assessment Using the Bio-Impedance Analysis Method", authored by Reem AlDisi, Qamar Bader, and Amine Bermak, discusses the bio-impedance analysis technique for the measurement of skin hydration. The study simulated a human skin model and considered the change in dielectric properties for hydration and dehydration and the frequency of the applied signal. Impedance measurements were performed using silver ink jet-printed electrodes. Simulations were performed to investigate the relationship between skin mode, the electrode design, and the measured parameters. The skin model considered the change in the dielectric properties of the skin based on the hydration status and the frequency of the applied signal. The experimental study measured and analyzed the resistance, capacitance, and phase change. The measurements for hydrated and dehydrated skin display the distinguishable difference that can be used for a non-invasive assessment of hydration levels. (5). "Parametric Study of Bolt Clamping Effect on Resonance Characteristics of Langevin Transducers with Lumped Circuit Models" was authored by Jinhyuk Kim and Jungwoo Lee. They developed a numerical model to analyze the resonance characteristics of Langevin transducers and experimentally compare them with corresponding experimental data, regarding the input electrical impedance and effective electromechanical coupling coefficient for the transducer at resonance modes. The experimental and theoretical values of the resonance and anti-resonance frequencies and impedance differences were closely matched. The work presented in this study provides guidelines for the pre-loading conditions of intended resonance characteristics of Langevin transducers. (6). "Situation Awareness-Oriented Patient Monitoring with Visual Patient Technology: A Qualitative Review of the Primary Research", authored by David Werner Tscholl, Julian Rossler, Sadiq Said, Alexander Kaserer, Donat Rudolf Spahn, and Christoph Beat Nothiger, discusses the current state of research on the Visual Patient technology, of which is a situation-awareness-oriented patient monitoring approach. This review provides a historical context of the patient monitoring approach and discusses its limitations. Clinical studies were discussed to assess the effects of Visual Patient technology on outcomes closely related to the concept of situation awareness. In multiple computer-based laboratory studies, Visual Patients transferred more information per unit of time with a reduced subjectively perceived workload and increased diagnostic certainty. (7). "Advances in Biosensors Technology for Detection and Characterization of Extracellular Vesicles", authored by Saif Mohammad Ishraq Bari, Faria Binte Hossain, and Gergana G. Nestorova, discusses the most recent advancement in lab-on-a-chip biosensing for the isolation, detection, and characterization of extracellular vesicles. The review summarizes the principle of operation, sensitivity, and specificity of fluorescence-based, colorimetric, magnetic, surface plasmon resonance, electrochemical, and immunoaffinity sensors for the detection and molecular characterization of extracellular vesicles. 3. Conclusions In conclusion, we are pleased to serve as editors on this Special Issue of which is focused on biosensors for analytical, diagnostic, and predictive functions. We hope our efforts and the authors' insightful manuscripts may assist the readers in conceiving new directions in biosensor development. Biosensors have been widely employed as they are cost-effective, provide data quickly, enable in situ placement, and provide real-time analytical data. There is an urgent need for their use in the detection of monitoring for air, water, soil pollutants, toxins, endocrine-disrupting chemicals, precision agriculture, and for monitoring climate change and its impacts. Acknowledgments The Guest Editors would like to express their sincere thanks to all authors for their valuable contributions and all peer-reviewers for their constructive comments and suggestions. Author Contributions All authors have contributed to the conceptualization, writing, review, and editing of this manuscript. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Nasim A. Kim Y.S. DE-PNN: Differential Evolution-Based Feature Optimization with Probabilistic Neural Network for Imbalanced Arrhythmia Classification Sensors 2022 22 4450 10.3390/s22124450 35746232 2. Heo Y. Kim J. Cha C. Shin K. Roh J. Jo J. Wearable E-Textile and CNT Sensor Wireless Measurement System for Real-Time Penile Erection Monitoring Sensors 2022 22 231 10.3390/s22010231 3. Martinez-Cervero J. Ardali M.K. Jaramillo-Gonzalez A. Wu S. Tonin A. Birbaumer N. Chaudhary U. Open Software/Hardware Platform for Human-Computer Interface Based on Electrooculography (EOG) Signal Classification Sensors 2020 20 2443 10.3390/s20092443 32344820 4. 4AlDisi R. Bader Q. Bermak A. Hydration Assessment Using the Bio-Impedance Analysis Method Sensors 2022 22 6350 10.3390/s22176350 36080808 5. Kim J. Lee J. Parametric Study of Bolt Clamping Effect on Resonance Characteristics of Langevin Transducers with Lumped Circuit Models Sensors 2020 20 1952 10.3390/s20071952 32244353 6. Tscholl D.W. Rossler J. Said S. Kaserer A. Spahn D.R. Nothiger C.B. Situation Awareness-Oriented Patient Monitoring with Visual Patient Technology: A Qualitative Review of the Primary Research Sensors 2020 20 2112 10.3390/s20072112 32283625 7. Bari S.M.I. Hossain F.B. Nestorova G.G. Advances in Biosensors Technology for Detection and Characterization of Extracellular Vesicles Sensors 2021 21 7645 10.3390/s21227645 34833721 |
Sensors (Basel) Sensors (Basel) sensors Sensors (Basel, Switzerland) 1424-8220 MDPI 10.3390/s23052850 sensors-23-02850 Communication Epoxy-Coated Side-Polished Fiber-Optic Temperature Sensor for Cryogenic Conditions Sampath Umesh Conceptualization Methodology Software Validation Formal analysis Investigation Resources Data curation Writing - original draft Writing - review & editing Visualization 12 Song Minho Conceptualization Writing - review & editing Supervision Project administration Funding acquisition 1* Zhou Ciming Academic Editor 1 Department of Electronics and Information Engineering, Jeonbuk National University, Jeonju 54896, Republic of Korea 2 Electronic & Control Group, INZI Controls Co., Ltd., Siheung 15090, Republic of Korea * Correspondence: [email protected] 06 3 2023 3 2023 23 5 285025 1 2023 16 2 2023 28 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). We propose coating side-polished optical fiber (SPF) with epoxy polymer to form a fiber-optic sensor for cryogenic temperature measuring applications. The thermo-optic effect of the epoxy polymer coating layer enhances the interaction between the SPF evanescent field and surrounding medium, considerably improving the temperature sensitivity and robustness of the sensor head in a very low-temperature environment. In tests, due to the evanescent field-polymer coating interlinkage, transmitted optical intensity variation of 5 dB and an average sensitivity of -0.024 dB/K were obtained in the 90-298 K range. side-polished optical fiber optical sensor epoxy cryogenic temperature refractive index National Research Foundation of Korea (NRF)Korea government (MSIT)2022R1F1A1068258 Jeonbuk National UniversityThis work was jointly supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2022R1F1A1068258); Research Base Construction Fund Support Program funded by Jeonbuk National University in 2020. pmc1. Introduction For decades, efforts have been made to develop optical fiber sensors for a broad range of chemosensing, biosensing, structural health monitoring applications, as well as physical properties detection. Optical fiber sensors have certain advantages over conventional electrical sensors, such as electromagnetic interference immunity, corrosion resistance, and fast response, which make them excellent candidates for various types of measurement applications, including temperature sensing . Among optical fibers, side-polished optical fibers (SPFs) are utilized extensively in the field of optimal design methods and sensing applications based on the tunability of the effective index parameter and the energy distribution in the optical fiber transmission. The SPF sensors function by monitoring the interactions between the evanescent waves and surrounding medium. When the SPF is utilized for an optical sensor, this is considered to be the Kretchmann's configuration . The SPF sensor is realized by depositing the analyte on the SPF area, and it can be a functional material that is sensitive to a change in external conditions such as temperature, pH, magnetic field, and humidity . Many SPF sensor schemes have been employed to measure ambient temperatures. He et al. have tested an all-fiber temperature sensor on coreless SPF wrapped with polydimethylsiloxane and reported high sensitivity of -0.4409 nm/degC in the temperature range of 30-85 degC. Lu et al. have lowered the temperature range down to -7 degC by depositing TiO2 nanoparticles on SPFs. Although all the techniques mentioned above can be successfully used in the environments around room temperature, certain complex applications such as superconducting magnets and wires, aerospace, and biological experiments may demand fiber-optic sensors with cryogenic temperature monitoring capability . To the best of our knowledge, the SPF sensor working under the cryogenic condition has not been reported. Usually, the fiber Bragg grating (FBG) has been employed to achieve cryogenic temperature measurement . Chiuchiolo et al. have measured the cryogenic temperature with enough sensitivity by using an FBG sensor coated with epoxy and PMMA. Additionally, Lupi et al. and Rajini et al. have improved the sensitivity of the FBG sensor at cryogenic temperatures by depositing various metals on aluminum pre-coated bare FBG. However, due to the increases in cost and the complexity of the design, alternative research efforts have focused on developing simple sensor structure and cost-effective demodulation techniques . In this study, we demonstrate a simple and cost-effective evanescent field-based optical platform for cryogenic temperature sensing. An SPF is coated with epoxy that has a large thermo-optic coefficient and the coated layer is used as a sensor head for very low temperature monitoring. The strong evanescent light of the SPF can couple with the interface between the epoxy and the polished fiber surface, which enhances the interaction between light and the surrounding medium, resulting in stronger sensitivity to the external temperature change. The proposed epoxy-coated SPF sensor is a transmission-type sensor: the temperature changes in surrounding medium can be traced by measuring the optical power passing though the sensor head. We conducted a series of experiments testing the feasibility, the repeatability, and the robustness of the proposed epoxy-coated SPF sensor in temperature range of 90 to 298 K. 2. Principle and Device Fabrication Light propagations in the optical fiber depend on the principle of attenuated total reflection (ATR) . The light propagating along the fiber core strikes the core-cladding interface at an angle th greater than the critical angle, which results in a total internal reflection. However, only small amounts of light energy escape into the cladding medium and it generates its own electromagnetic field in the cladding or surrounding medium, which is known as an evanescent wave (EW) . Absorption of EW into the surrounding medium of the fiber leads to rapid attenuation of the light, which was explained by the theory of ATR. The lights in a de-cladded fiber section interact with the surrounding medium, which is the material under investigation. This interaction modulates or attenuates the light signal due to a change in the refractive index of the material under investigation . We used a single-mode fiber (SMF28) with effective core and cladding dimensions of ~10 and 125 mm, respectively, to fabricate SPFs. The epoxy substrate was used as mechanical support and the material was the same as the epoxy coating material. The optical fiber was embedded in the substrate and polished until the cladding remained only few microns from the core. A matured wheel side-polishing technique was used for polishing, and the total length of the polished region was 17 mm. The insertion loss with ambient air condition was measured to be less than 0.1 dB. Figure 1a is the SEM (scanning electron microscope) image of the SPF's cross-section, which we constructed later using a modified cladding with epoxy resin. The polymer base used for the cladding was bisphenol-A diglycidyl ether, and the curing agent was 4, 4' diamino-diphenylmethane. Figure 1b-d shows the basic structure of the SPF sensor head with modified cladding, the SPF sensor's cross-sectional schematic diagram, and the refractive index distribution of the core, cladding, and epoxy resin, noted as n1, n2, and n3, respectively. The primary criteria of SPF-based temperature sensors are the changes in the refractive index of the material against the applied temperature changes. Additionally, the model for effective evanescent wave sensor reveals that the variation in the refractive index of coating material should be greater than the changes in the refractive indices of cladding and core, which are mostly silica glass (SiO2). Considering our previously reported results from the Fresnel reflection-based cryogenic temperature sensor, we prepared the SPF sensors with an epoxy polymer coating. The thermo-optic coefficient of epoxy is dn/dT=-1.3x10-4/degC at room temperature . Because silica glass has dn/dT=9.2x10-6/degC that is approximately one order of magnitude less than the polymer's, most of the change in transmission intensity is due to the variation in the refractive index of the epoxy polymer. The thermo-optic coefficient of polymer is theoretically modeled as follows:(1) dndT=n2-1n2+26nPh-b where Ph is the temperature coefficient of the electronic polarizability and b is the thermal expansion coefficient . The value is not constant over a wide temperature range because density and electronic polarizability change with temperature, resulting in a relationship between transmission light intensity and temperature change. In epoxy, dn/dT is negative and decreases with increasing temperature because their b are always much higher than their polarizability Ph . 3. Experiments and Results To test the epoxy-coated-SPF sensor in cryogenic temperature detection, we constructed a fiber-optic sensor system . As a light source, we used a C-band ASE (amplified spontaneous emission) BBS (broadband light source), which had a center wavelength and output power of 1550 nm and 12 dBm, respectively. The light passed though the sensor and the transmitted light was collected by photodetector PD2. The transmittance was determined based on the temperature-dependent refractive index difference at the sensing layer of the coated SPF sensor. To minimize errors resulting from possible fluctuations in the light-source power and transmission losses in the fiber-optic links, a fiber-optic directional coupler was used to tap a certain portion of light and its power was measured with PD21 and used for referencing. The fabricated epoxy-coated SPF was placed in a temperature chamber, and the temperature variation was monitored by a reference thermocouple as well as the proposed fiber-optic sensor. By pouring liquid nitrogen (LN2) and waiting for the natural evaporation process, the temperature measurements were conducted in the range of 90-298 K. Figure 3 shows the results of the tests. As the temperature increased from 90 K, the cryogenic temperature of liquid nitrogen, the transmitted light intensity decreased in linear fashion by as much as 5 dB for the whole measurement range. Almost the same results were obtained in the subsequent measurement cycles. From the measured data and their linear regression, the average temperature sensitivity and R2 value were -0.024 dB/K and 0.999, respectively. For additional feasibility test, we compared the sensor result with those of commercially available high-resolution T-type reference thermocouple (73-623 K) and a customized FBG sensor that was proposed in the earlier report . The low thermal response of FBG in cryogenic temperature conditions was overcome by the polymer coated-FBG (PCFBG). The average temperature sensitivity of the PCFBG sensor was 48 pm/K in the range of 92-298 K, and the reflected Bragg wavelength was demodulated by a spectrometer (FBGA, Bayspec), which had a wavelength readout resolution of 1 pm. The sensors were placed in the temperature chamber at room temperature and then liquid nitrogen was poured. As the LN2 evaporated, the temperature slowly increased and reached initial room temperature in 40 min. In Figure 4a, the measured outputs of the reference sensors (PCFBG and thermocouple) mostly agreed well in the whole range. Additionally, the output of the proposed epoxy-coated SPF matched with the reference sensors' outputs, although it was not calibrated in the temperature unit and changed in the negative direction due to the epoxy's negative thermo-optic coefficient. In general, an intrinsic, bare SPF is very sensitive to changes in the external environment. A sensitive reaction, however, does not necessarily indicate that the sensor is good. To demonstrate the advantage of epoxy coating, a bare SPF was employed with the same measurements as the epoxy-coated one. Figure 4b shows the measurement results of the different SPFs. The epoxy-coated SPF sensor with the substrate presented full function of temperature sensing from the sharp output increase at LN2 injection until it finally reached the original output at room temperature. The bare SPF, however, was disrupted and the output fluctuated in the middle of warming cycle and never regained its original position at room temperature. This could be attributed to the fragile and weak structure with only 2 mm of cladding thickness. Repeatability is one of the most desirable traits of sensors, especially in harsh environments. By applying repeated cycles of LN2 injection and evaporation, we tested the repeatability of the epoxy-coated SPF sensor. Based on the measurement results of three cycles , no significant deviations from the other cycles could be found, and a thermocouple output was successfully used as a reference. No noticeable damage to the epoxy-coated SPF sensor was found, even after multiple cycles of cryogenic temperature measurements. 4. Conclusions In conclusion, we have successfully demonstrated that an epoxy-coated side-polished fiber could be used in cryogenic temperature monitoring. Due to the surface evanescent field enhancement along the side-polished waveguide resulting from the epoxy polymer coating, sensitivity of -0.024 dB/K, good repeatability, and a robust and stable sensing capability in a very low temperature range, 90-298 K, could be obtained. Considering the simple structure, the low cost, the easy demodulation processing, and the fast response, the proposed epoxy-coated SPF sensor is an excellent candidate sensor, with inherent dielectric nature, for cryogenic temperature sensing applications. By further optimizing the structure of the SPF sensor, for example, by decreasing the coating thickness and/or varying the coating material, a higher sensitivity might be achieved, and the temperature range could be extended. Author Contributions Conceptualization, U.S. and M.S.; methodology, U.S. and M.S.; software, U.S.; validation, U.S.; formal analysis, U.S.; investigation, U.S.; resources, U.S.; data curation, U.S.; writing original draft preparation, U.S.; writing review and editing, U.S. and M.S.; visualization, U.S.; supervision, M.S.; project administration, M.S.; funding acquisition, M.S. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Data sharing is not applicable to this article. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Side-polished optical fiber (SPF) (a) SEM cross-section image of SPF, (b) schematic diagram of SPF with epoxy coating, (c) schematic cross-sectional view of coated SPF, (d) refractive index: core, cladding, and epoxy. Figure 2 Experimental setup of the proposed fiber-optic sensor system. SM single mode; SPF side-polished fiber; PD photo detector; DAQ data acquisition; ASE BBS amplified spontaneous emission broadband source. Figure 3 Cryogenic temperature measurements with epoxy-coated SPF sensor. The output is optical intensity variation according to temperature change in 90-298 K. Figure 4 Performance comparison of the proposed sensor: (a) Bare SPF sensor vs. epoxy-coated SPF sensor; (b) reference sensors (PCFBG and T-type thermocouple) vs. epoxy-coated SPF sensor. Figure 5 Repeatability test in multiple measurement cycles. Upper trace: thermocouple output; lower trace: output from the epoxy-coated SPF sensor. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). 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Sensors (Basel) Sensors (Basel) sensors Sensors (Basel, Switzerland) 1424-8220 MDPI 10.3390/s23052448 sensors-23-02448 Editorial Sensors and Communications for the Social Good Palazzi Claudio 1 Gaggi Ombretta 1 Manzoni Pietro 2* 1 Department of Mathematics, University of Padua, Via Trieste, 35131 Padova, Italy 2 Department of Computer Engineering (DISCA), Universitat Politecnica de Valencia, 46022 Valencia, Spain * Correspondence: [email protected] 22 2 2023 3 2023 23 5 244807 2 2023 07 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcThis topical collection focuses on applying sensors and communications technologies for social good. Social good is typically defined as an action that provides some sort of benefit to the general public. In this case, the Internet connection, education, and health care are all excellent examples of social good. However, the development of new media and the explosion of online communities have added a new meaning to the term. Social good is now about global citizens uniting to unlock the potential of individuals, technology, and collaboration to create a positive societal impact. This reprint includes the recent advances and novel contributions from academic researchers and industry practitioners in this growing area. Each article was assigned and reviewed by at least three experts in the field during the review process, with a rigorous multi-round review process. Consequent to the great support and dedicated work of numerous reviewers, we accepted 10 excellent articles covering various topics under the umbrella of "Sensors and Communications for the Social Good". We will introduce these articles and highlight their main contributions in what follows. The first paper focuses on how the need to provide safe environments and reduce the risks of virus exposure plays a crucial role in our daily lives. Contact tracing is a well-established and widely used approach to tracking and suppressing the spread of viruses. Most digital contact tracing systems can detect direct face-to-face contact based on estimated proximity without quantifying the exposed virus concentration. In particular, they rarely allow for the quantitative analysis of indirect environmental exposure due to virus survival time in the air and constant airborne transmission. The authors of proposed an indoor spatiotemporal contact awareness framework (iSTCA), which explicitly considers the self-containing quantitative contact analytics approach with spatiotemporal information to provide accurate awareness of the quanta concentration of virus in different origins at various times. Smartphone-based pedestrian dead reckoning (PDR) was employed to precisely detect the locations and trajectories for distance estimation and time assessment without additional infrastructure. The PDR technique calibrates the accumulative error by automatically identifying spatial landmarks. They utilized a custom deep-learning model composed of bidirectional long short-term memory (Bi-LSTM) and multi-head convolutional neural networks (CNNs) to extract the local correlation and long-term dependency to recognize landmarks. By considering the spatial distance and time difference in an integrated manner, they quantified the virus quanta concentration in the indoor environment at any time with all contributed virus particles. They conducted an extensive experiment based on practical scenarios to evaluate the performance of the proposed system. They showed that the average positioning error is reduced to less than 0.7 m. Big Tech companies operating in a data-driven economy offer services that rely on their users' data and usually store this personal information in "data silos", which prevent transparency about their use and opportunities for data sharing for the public interest. In , the authors presented a solution that promotes the development of decentralized personal data marketplaces, exploiting the use of distributed ledger technologies (DLTs), decentralized file storages (DFSs), and smart contracts to store personal data and manage access control in a decentralized way. Moreover, they focused on the lack of efficient decentralized mechanisms in DLTs and DFSs for querying a specific data type. For this reason, the authors proposed using a hypercube-structured distributed hash table (DHT) on top of DLTs, organized for the efficient processing of multiple keyword-based queries on the ledger data. They tested their approach by implementing a use case for creating citizen-generated data based on direct participation and decentralized autonomous organization (DAO) participation. Performance evaluation demonstrated the viability of their approach for decentralized data searches, distributed authorization mechanisms, and smart contract exploitation. In , the authors focused on how population aging requires innovative solutions to increase the quality of life and preserve autonomous and independent living at home. A need of particular significance is the identification of behavioral drifts. A relevant behavioral drift concerns sociality: Older people tend to isolate themselves. There is a need to find methodologies to identify if, when, and for how long the person is in the company of other people (possibly also considering the number). The challenge is to address this task in poorly sensorized apartments, with non-intrusive sensors that are typically wireless and can only provide local and simple information. The proposed method addresses technological issues, such as PIR (passive infrared) blind times, topological issues, such as sensor interference due to the inability to separate detection areas, and algorithmic issues. A house was modeled as a graph to constrain the transitions between adjacent rooms. Each room was associated with a set of values for each identified person. These values would decay over time and represent the probability that each person is still in the room. Because the used sensors cannot determine the number of people, this approach is based on a multi-branch inference that, over time, differentiates the movements in the apartment and estimates the number of people. Sensor technology that captures information from the user's neck region can enable a variety of new possibilities, including less intrusive mobile software interfaces. In , the authors investigated the feasibility of using a single inexpensive flex sensor mounted at the neck to capture information about head gestures, mouth movements, and the presence of audible speech. Different sensor sizes and various sensor positions on the neck were experimentally evaluated. With data collected from experiments carried out on the finalized prototype, a classification accuracy of 91% was achieved to differentiate common head gestures, a classification accuracy of 63% was achieved to differentiate mouth movements, and a classification accuracy of 83% was achieved in speech detection. The work in highlighted the fact that the linguistic and social impact of multi-culturalism cannot be ignored in any sector, creating the urgent need to create systems and procedures for managing and sharing cultural heritage in both supranational and multi-literate contexts. Text sensing is one of the most crucial research areas to achieve this goal. The long-term objective of the DigitalMaktaba project, born from an interdisciplinary collaboration between computer scientists, historians, librarians, engineers, and linguists, is to establish procedures for creating, managing, and cataloging archival heritage in non-Latin alphabets. In this paper, the authors discussed the currently ongoing design of an innovative workflow and tool in the area of text sensing, for the automatic extraction of knowledge and cataloging of documents written in non-Latin languages (Arabic, Persian, and Azerbaijani). The current prototype leverages different OCR, text processing, and information extraction techniques to provide highly accurate extracted text and rich metadata content (including automatically identified cataloging metadata), overcoming the typical limitations of current state-of-the-art approaches. The initial tests revealed promising results. The paper included a discussion of future steps (e.g., AI-based techniques further leveraging the extracted data/metadata and making the system learn from user feedback) and of the many foreseen advantages of this research, both from a technical and a broader cultural preservation and sharing points of view. In , the authors focused on several smart home architecture implementations proposed in the last decade. These architectures are mostly deployed in laboratories or inside real habitations built for research purposes to enable ambient intelligence using various sensors, actuators, and machine learning algorithms. However, the major issues for most related smart home architectures are their price, proprietary hardware requirements, and the need for highly specialized personnel to deploy such systems. To address these challenges, lighter forms of smart home architectures known as smart homes in a box (SHiB) have been proposed. While SHiB remains an encouraging first step towards lightweight yet affordable solutions, they still suffer a few drawbacks. Indeed, some of these kits lack hardware support for some technologies, and others do not include enough sensors and actuators to cover the requirements of most smart homes. Thus, this paper introduced the LIARA Portable Smart Home Kit (LIPSHOK), designed to provide an affordable SHiB solution that anyone can install in an existing home. Moreover, LIPSHOK is a generic kit that includes four specialized sensor modules that have been independently introduced since the authors' laboratory has been working on their development over the last few years. This paper first summarized these modules and their respective benefits within a smart home context. Then, it mainly focused on introducing the LIPSHOK architecture, which provides a framework to unify the use of the proposed sensors owing to a common modular infrastructure capable of managing heterogeneous technologies. Finally, the authors compared their work to existing SHiB kit solutions and revealed that it offers a more affordable, extensible, and scalable solution with resources distributed under an open-source license. The ever-increasing pace of IoT deployment is opening the door to the concrete implementations of smart city applications, enabling the large-scale sensing and modeling of (near) real-time digital replicas of physical processes and environments. This digital replica could serve as the basis of a decision support system, providing insight into the possible optimizations of resources in a smart city scenario. In , the authors discussed an extension of prior work, presenting a detailed proof-of-concept implementation of a digital twin solution for the urban facility management (UFM) process. The Interactive Planning Platform for Adaptive Maintenance Operations for the City District (IPPODAMO) is a distributed geographical system fed and ingested heterogeneous data sources from different urban data providers. The data are subject to continuous refinements and algorithmic processes used to quantify and build synthetic indexes measuring the activity level inside an area of interest. IPPODAMO considers the potential interference from other stakeholders in the urban environment, enabling informed operations scheduling to minimize interference and operating costs. The authors of revealed that future university campuses will be characterized by a series of novel services enabled by the vision of the Internet of Things, such as smart parking and smart libraries. In this paper, the authors proposed a complete solution for a smart waste management system to increase the recycling rate on campus and better manage the entire waste cycle. The system is based on a prototype of a smart waste bin, which can accurately classify pieces of trash typically produced on campus premises with a hybrid sensor/image classification algorithm and automatically separate the different waste materials. The authors discussed the system prototype's entire design, from the analysis of the requirements to the implementation details, and evaluated its performance in different scenarios. Finally, they discussed advanced application functionalities built around the smart waste bin, such as optimized maintenance scheduling. Automation plays an important role in modern transportation and handling systems, e.g., controlling aircraft and ground service equipment routes in airport aprons, automated guided vehicles in port terminals or public transportation, handling robots in automated factories, drones in warehouse picking operations, etc. Information technology provides hardware and software (e.g., collision detection sensors, routing, and collision avoidance logic) that contribute to safe and efficient operations, with relevant social benefits in terms of improved system performance and reduced accident rates. In this context, the authors of addressed the design of efficient collision-free routes in a minimum-sized routing network. They considered a grid and a set of vehicles, each moving from the bottom of the origin column to the top of the destination column. Smooth nonstop paths are required, without collisions or deviations from shortest paths, and they investigated the minimum number of horizontal lanes allowing for such routing. The problem is known as the fleet's quickest routing problem on grids. They proposed a mathematical formulation solved for small instances using standard solvers. For larger instances, they devised heuristics that define priorities based on known combinatorial properties and design collision-free routes. Their experiments on random instances showed that their algorithms could quickly provide good-quality solutions. Finally, in , the authors considered how the pandemic crisis has forced the development of teaching and evaluation activities exclusively online. In this context, the emergency remote teaching (ERT) process, which raised many problems for institutions, teachers, and students, led the authors to consider it important to design a model to evaluate teaching and evaluation processes. The study objective presented in this paper was to develop a model for the evaluation system called the learning analytics and evaluation model (LAEM). The authors also validated a software instrument they designed called the EvalMathI system, which is to be used in the evaluation system and was developed and tested during the pandemic. The evaluation process was optimized by including and integrating the dashboard model in a responsive panel. The EvalMathI dashboard monitored six online courses in the 2019/2020 and 2020/2021 academic years. For each of the six monitored courses, the curricula were evaluated through the analyzed parameters by highlighting the percentage achieved by each course on various components, such as content, adaptability, skills, and involvement. In addition, after collecting the data through interview guides, the authors determined the extent to which online education during the COVID-19 pandemic has influenced the educational process. Through the developed model, the authors also found software tools to solve problems raised by teaching and evaluation in the ERT environment. The editors and authors express their thanks to the publisher and staff members for their ongoing dedication and valuable advice and encouragement, which helped to improve the quality of this reprint. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Gao L. Konomi S. Indoor Spatiotemporal Contact Analytics Using Landmark-Aided Pedestrian Dead Reckoning on Smartphones Sensors 2023 23 113 10.3390/s23010113 36616711 2. Zichichi M. Ferretti S. Rodriguez-Doncel V. Decentralized Personal Data Marketplaces: How Participation in a DAO Can Support the Production of Citizen-Generated Data Sensors 2022 22 6260 10.3390/s22166260 36016019 3. Masciadri A. Lin C. Comai S. Salice F. A Multi-Resident Number Estimation Method for Smart Homes Sensors 2022 22 4823 10.3390/s22134823 35808320 4. Lacanlale J. Isayan P. Mkrtchyan K. Nahapetian A. Sensoring the Neck: Classifying Movements and Actions with a Neck-Mounted Wearable Device Sensors 2022 22 4313 10.3390/s22124313 35746095 5. Bergamaschi S. De Nardis S. Martoglia R. Ruozzi F. Sala L. Vanzini M. Vigliermo R.A. Novel Perspectives for the Management of Multilingual and Multialphabetic Heritages through Automatic Knowledge Extraction: The DigitalMaktaba Approach Sensors 2022 22 3995 10.3390/s22113995 35684615 6. Chapron K. Thullier F. Lapointe P. Maitre J. Bouchard K. Gaboury S. LIPSHOK: LIARA Portable Smart Home Kit Sensors 2022 22 2829 10.3390/s22082829 35458814 7. Bujari A. Calvio A. Foschini L. Sabbioni A. Corradi A. A Digital Twin Decision Support System for the Urban Facility Management Process Sensors 2021 21 8460 10.3390/s21248460 34960550 8. Longo E. Sahin F.A. Redondi A.E.C. Bolzan P. Bianchini M. Maffei S. A 5G-Enabled Smart Waste Management System for University Campus Sensors 2021 21 8278 10.3390/s21248278 34960367 9. Andreatta G. De Francesco C. De Giovanni L. Algorithms for Smooth, Safe and Quick Routing on Sensor-Equipped Grid Networks Sensors 2021 21 8188 10.3390/s21248188 34960283 10. Corbu E.C. Edelhauser E. Responsive Dashboard as a Component of Learning Analytics System for Evaluation in Emergency Remote Teaching Situations Sensors 2021 21 7998 10.3390/s21237998 34884005 |
Polymers (Basel) Polymers (Basel) polymers Polymers 2073-4360 MDPI 10.3390/polym15051185 polymers-15-01185 Editorial Natural Fibre Composites and Their Mechanical Behaviour Banea Mariana Doina 12 1 Federal Center of Technological Education in Rio de Janeiro, Rio de Janeiro 20271-110, Brazil; [email protected] or [email protected] 2 CICECO Aveiro Institute of Materials, Department of Materials and Ceramic Engineering, University of Aveiro, 3810-193 Aveiro, Portugal 26 2 2023 3 2023 15 5 118508 2 2023 23 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Project CICECO-Aveiro Institute of MaterialsUIDB/50011/2020 UIDP/50011/2020 LA/P/0006/2020 FCT/MEC (PIDDAC)This work was developed within the scope of the Project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MEC (PIDDAC). pmcAt present, natural-fibre-reinforced-composites (NFRCs) are seen as realistic alternatives to synthetic- (e.g., glass) fibre-reinforced composites in many applications. Natural fibres (e.g., sisal , ramie , hemp , curaua , bamboo , kenaf , flax , jute , etc.) have attracted the attention of researchers for their application in several industries, such as automotives, construction and furniture, sports, and music instruments, among others. The lower weight and relatively lower cost of natural fibres are the main reasons for their use in composites in these applications. Another relevant factor in using natural fibres as reinforcement materials in composites is their eco-friendliness associated with the lower energy consumption in their manufacturing process. However, their recyclable properties also depend on the type of matrices used in composite production. The main objective of this Special Issue was to provide a platform for the dissemination of the latest scientific and technical advancements in the optimization of the mechanical properties, durability, processing, and applications of natural-fibre-reinforced composites. Natural-fibre-reinforced composites vary greatly in their mechanical properties. Mechanical properties (e.g., tensile, flexural, and impact) are highly dependent on different factors such as fibre and matrix type, interfacial bonding between fibre and matrix, fibre dispersion and orientation, and processing, among others. By increasing their mechanical performance, the capabilities and applications of natural-fibre-reinforced composites will be expanded. One method to increase the mechanical performance of NFRCs to broaden their applications is hybridization . Generally, natural-fibre-reinforced hybrid composites are produced by hybridizing natural fibres with another either natural or synthetic fibres with superior properties (e.g., higher mechanical strength, chemical stability, nontoxicity, resistance to high temperatures, and thermal or acoustic insulation). Pereira et al. investigated the influence of hybridisation on the mechanical and thermal properties of intralaminar natural-fibre-reinforced hybrid composites. They concluded that the mechanical properties are improved via the hybridization of sisal-based composites with ramie, sisal, and curaua fibres. On the other hand, they stated that hybridization did not significantly affect the thermal stability of the composites studied. Alonso-Montemayor et al. studied natural-fibre-reinforced composites using 10, 20, and 30% bleached hemp fibres (by weight) into the polyamide 6 polymer matrix structure. They stated that it is possible to obtain tensile strengths higher than glass-fibre-reinforced polyolefin and explained that this effect was due to the strong adhesion between the fibres and the polymer matrix and the good distribution of the fibres into the composite. It is known that the thermal stability of natural-fibre-reinforced composites is a relevant aspect to be considered as the processing temperature plays a crucial role in the fabrication process. At higher temperatures, the natural fibre components (e.g., cellulose, hemicellulose, and lignin), start to degrade, and the major properties (mechanical and thermal) of the composite change. Neto et al. presented an overview of the recent advancements made regarding the thermal properties of hybrid-fibre-reinforced composites in thermoset and thermoplastic polymeric matrices. The methods used to determine the thermal properties of natural and hybrid composites along with the main factors that affect the thermal properties of natural and hybrid fibre composites (fibre and matrix type, the presence of fillers, fibre content and orientation, the treatment of the fibres, and manufacturing process) were discussed. They stated that it is crucial to ensure that the natural fibres used in composites can withstand the heat required during the fabrication process and retain their characteristics in service. da Silva et al. studied the thermal properties and ballistic performance of kenaf-fibre-reinforced epoxy composites and concluded that the composites reinforced with 30 vol.% kenaf fibre presented the best results. Neves et al. investigated the ballistic behaviour of bidirectional pineapple leaf fibre (PALF)-reinforced epoxy composites functionalized with graphene oxide (GO). They found that bidirectional GO non-functionalized PALF fibres in a GO-reinforced matrix showed the best results, indicating its possible application as a second layer in multilayered armour systems. Ahmad-Saffian et al. studied the possibility of improving the mechanical, thermal, and electrical properties of kenaf-fibre-reinforced composites via the incorporation of 30% lignin in polypropylene (PP) matrix composites. They found improved thermal stability and higher thermal diffusivity compared to pure PP, but the tensile strength decreased. It was concluded that further studies are necessary in order to improve the adhesion between the PP polymer matrix and kenaf core fibres and lignin. The main natural fibres studied and used in the industry (e.g., jute, sisal, kenaf, and flax) are well-established on the global market with a well-defined production line. However, new promising types of natural fibres are being discovered and studied. For instance, Neuba et al. investigated sedge fibres from the seven-islands-sedge plant (Cyperus malaccensis), while Souza et al. studied the properties of Caranan fibre (Mauritiella armata) for possible application as a natural fibre reinforcement in composite materials. Nevertheless, some improvements are needed in their production line to be more commercially affordable and to enable their widespread use. Both thermoplastic and thermoset polymers are used as matrices in natural-fibre-reinforced polymer composites. There is an increased interest in the scientific community regarding the use of bio-based polymers in composites, as combining these matrices with natural fibres produces "green composites" or "bio-composites". Bolcu and Stanescu used three types of hybrid matricies based on the Dammar natural hybrid resin and studied the mechanical and chemical properties of flax-fibre-reinforced composite materials, while Dolza et al. used bio-based high-density polyethylene (BioHDPE) to fabricate green composites reinforced with short flax, hemp, and jute fibres. However, the price of these bio-based matrices is still higher than their corresponding petroleum-based counterparts. Finally, another area currently undergoing rapid development is the application of natural fibres as reinforcements in composites produced via additive manufacturing (AM or 3D printing). This technology allows for the fabrication of complex geometries without the need for expensive tooling and moulds. The use of natural fibres as filament reinforcements was investigated by Cavalcanti et al. . Short curaua fibres with different lengths (3, 6, and 8 mm) and concentrations in terms of weight percentage (2, 3.5, and 5 wt. %) were used to fabricate polylactic acid (PLA) filaments which were subsequently used to fabricate composites via fused deposition modelling. They concluded that curaua-fibre-reinforced PLA composites may be a promising innovation to improve the performance of these materials, which might enable them to be used in new applications. However, some challenges remain to be solved in the fabrication of the reinforced filaments, such as difficulty in quality control due to voids and porosities, among others. To summarize, this subject is vast and cannot be collected in a single volume. However, this Special Issue provides readers with a broad and updated overview of this topic. Acknowledgments I would like to acknowledge all the authors and reviewers who have contributed to this Special Issue. Institutional Review Board Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Pereira A.L. Banea M.D. Neto J.S.S. Cavalcanti D.K.K. Mechanical and thermal characterization of natural intralaminar hybrid composites based on sisal Polymers 2020 12 866 10.3390/polym12040866 32283753 2. Alonso-Montemayor F.J. Tarres Q. Oliver-Ortega H. Espinach F.X. Narro-Cespedes R.I. Castaneda-Facio A.O. Delgado-Aguilar M. Enhancing the Mechanical Performance of Bleached Hemp Fibers Reinforced Polyamide 6 Composites: A Competitive Alternative to Commodity Composites Polymers 2020 12 1041 10.3390/polym12051041 32370263 3. Ban Y. Zhi W. Fei M. Liu W. Yu D. Fu T. Qiu R. Preparation and Performance of Cement Mortar Reinforced by Modified Bamboo Fibers Polymers 2020 12 2650 10.3390/polym12112650 33187069 4. Ahmad Saffian H. Talib M.A. Lee S.H. Md Tahir P. Lee C.H. Ariffin H. Asa'ari A.Z.M. Mechanical Strength, Thermal Conductivity and Electrical Breakdown of Kenaf Core Fiber/Lignin/Polypropylene Biocomposite Polymers 2020 12 1833 10.3390/polym12081833 32824275 5. da Silva T.T. Silveira P.H.P.M.d. Figueiredo A.B.-H.d.S. Monteiro S.N. Ribeiro M.P. Neuba L.d.M. Simonassi N.T. Garcia Filho F.d.C. Nascimento L.F.C. Dynamic Mechanical Analysis and Ballistic Performance of Kenaf Fiber-Reinforced Epoxy Composites Polymers 2022 14 3629 10.3390/polym14173629 36080703 6. Bolcu D. Stanescu M.M. A Study of the Mechanical Properties of Composite Materials with a Dammar-Based Hybrid Matrix and Two Types of Flax Fabric Reinforcement Polymers 2020 12 1649 10.3390/polym12081649 32722153 7. Dolza C. Fages E. Gonga E. Gomez-Caturla J. Balart R. Quiles-Carrillo L. Development and Characterization of Environmentally Friendly Wood Plastic Composites from Biobased Polyethylene and Short Natural Fibers Processed by Injection Moulding Polymers 2021 13 1692 10.3390/polym13111692 34067283 8. Neto J.S.S. de Queiroz H.F.M. Aguiar R.A.A. Banea M.D. A Review on the Thermal Characterisation of Natural and Hybrid Fiber Composites Polymers 2021 13 4425 10.3390/polym13244425 34960977 9. Neves P.P. Costa U.O. Bezerra W.B.A. Figueiredo A.B.-H.d.S. Monteiro S.N. Nascimento L.F.C. Dynamic and Ballistic Performance of Bidirectional Pineapple Leaf Fibers (PALF)-Reinforced Epoxy Composites Functionalized with Graphene Oxide Polymers 2022 14 3249 10.3390/polym14163249 36015506 10. Neuba L.d.M. Junio R.F.P. Souza A.T. Ribeiro M.P. da Silveira P.H.P.M. da Silva T.T. Pereira A.C. Monteiro S.N. Evaluation of the Change in Density with the Diameter and Thermal Analysis of the Seven-Islands-Sedge Fiber Polymers 2022 14 3687 10.3390/polym14173687 36080761 11. Souza A.T. Neuba L.d.M. Junio R.F.P. Carvalho M.T. Candido V.S. Figueiredo A.B.-H.d.S. Monteiro S.N. Nascimento L.F.C. da Silva A.C.R. Ballistic Properties and Izod Impact Resistance of Novel Epoxy Composites Reinforced with Caranan Fiber (Mauritiella armata) Polymers 2022 14 3348 10.3390/polym14163348 36015605 12. Cavalcanti D.K.K. Neto J.S.S. Queiroz H.F.M.D. Wu Y. Neto V.F.S. Banea M.D. Development and Mechanical Characterization of Short Curaua Fiber-Reinforced PLA Composites Made via Fused Deposition Modeling Polymers 2022 14 5047 10.3390/polym14225047 36433175 |
Sensors (Basel) Sensors (Basel) sensors Sensors (Basel, Switzerland) 1424-8220 MDPI 36904978 10.3390/s23052774 sensors-23-02774 Communication Near-Ultrasonic Transfer Function and SNR of Differential MEMS Microphones Suitable for Photoacoustics Falkhofen Judith Writing - original draft 12* Wolff Marcus Supervision 1 Lazaro Antonio Academic Editor 1 Heinrich Blasius Institute of Physical Technologies, Hamburg University of Applied Sciences, 20099 Hamburg, Germany 2 School of Computing, Engineering and Physical Sciences, University of the West of Scotland, Scotland High Street, Paisley PA1 2BE, UK * Correspondence: [email protected] 03 3 2023 3 2023 23 5 277402 2 2023 19 2 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Can ordinary Micro-Electro-Mechanical-Systems (MEMS) microphones be used for near-ultrasonic applications? Manufacturers often provide little information about the signal-to-noise ratio (SNR) in the ultrasound (US) range and, if they do, the data are often determined in a manufacturer-specific manner and are generally not comparable. Here, four different air-based microphones from three different manufacturers are compared with respect to their transfer functions and noise floor. The deconvolution of an exponential sweep and a traditional calculation of the SNR are used. The equipment and methods used are specified, which makes it easy to repeat or expand the investigation. The SNR of MEMS microphones in the near US range is mainly affected by resonance effects. These can be matched for applications with low-level signals and background noise such that the highest possible SNR can be achieved. Two MEMS microphones from Knowles performed best for the frequency range from 20 to 70 kHz; above 70 kHz, an Infineon model delivered the best performance. photoacoustic spectroscopy MEMS microphones ultrasound deconvolution SNR sensitivity Open Access Publication Fund of Hamburg University of Applied SciencesWe acknowledge support for the article processing charge by the Open Access Publication Fund of Hamburg University of Applied Sciences. pmc1. Introduction In photoacoustic spectroscopy, energy is applied to a sample by means of modulated laser excitation. The absorbed energy is converted into a local temperature increase, which results in expansion of the gas, followed by relaxation . This pressure or sound wave is usually inaudible due to small amplitude and, often, high frequency. Therefore, photoacoustic methods require very sensitive sound sensors. Micro-Electro-Mechanical-Systems (MEMS) microphones have many advantages in the application, as they are produced cheaply and, due to their compact form, can be integrated in small sensors. Many MEMS microphones can be applied in the ultrasonic range, even if they have not been explicitly designed for this purpose. However, above the first mechanical resonance, the sensitivity of the microphone is strongly frequency dependent . Therefore, the analysis of the transfer function is particularly relevant. In addition, the signal-to-noise ratio (SNR) is often quantified by the manufacturers only up to 20 kHz. Therefore, a thorough characterization is advisable before selecting a microphone. MEMS microphones have been the subject of reviews and are considered as ultrasonic transducers, especially for photoacoustic imaging . Photoacoustic sensors often take advantage of resonators to amplify the acoustic signal. Since the PA signal is inversely proportional to the volume of the cell (or the resonator), often high frequencies in the ultrasound range occur. For instance, the resonant frequency of the optimized resonator for non-invasive glucose measurement falls within the near-ultrasound (US) range . Frequencies between 20 kHz and 1 MHz are also of interest for PA imaging, as these relatively low frequencies come along with less acoustic attenuation. Therefore, deeper tissue layers can be investigated . Here we compare transfer functions and SNRs of four differential MEMS microphones in the frequency range between 20 and 80 kHz. Section 2 presents the experimental setup and the applied methods. Section 3 provides the results followed by a conclusion. 2. Materials and Methods 2.1. Materials After a systematic market study, the four MEMS microphones listed in Table 1 were selected for the comparative investigation. The sensitivity and the SNR, both measured by the manufacturer with a sinewave of 1 kHz and 94 dB SPL and noise from 20 Hz to 20 kHz, were extracted from the datasheet. The transfer function and the SNR were measured with the experimental setup shown in Figure 1. Since ultrasonic loudspeakers are not standardized, a well characterized piezo loudspeaker was used (Kemo Electronic, L10, Geestland, Germany). ut represents its voltage and pt is the resulting pressure wave. st is the output signal of the MEMS microphone after differential amplification. The two channels ut and st are recorded simultaneously by an oscilloscope (Pico Technology, Picoscope 544D, St. Neots, Cambridgeshire, UK). A function generator (Agilent, 32220a LXI, Santa Clara, CA, USA) was operated via SCPI by a PC to control the ultrasound speaker. The microphone was centrally positioned 19 cm in front of the speaker. The distance represents a compromise between high signal level and the fulfillment of the requirement for the far-field condition, where interference effects have a minor influence. In the sound field between the loudspeaker and the microphone, reflections were reduced with the aid of absorber material placed all around. The entire setup is controlled by a MatLab program running on the PC. To put the differential microphones into operation, the electronic circuit shown in Figure 2a was designed. It is based on a commercial differential amplifier (Burr-Brown, INA105, Tucson, AZ, USA). The differential amplifier has a gain of 1, therefore it has no effect on the sensitivity. In addition, it exhibits a low noise amplitude spectral density of 60 nVHz, with 0.001% maximum nonlinearities and 0.01% maximum gain error . The IN+/- inputs are suitable for the differential outputs of the different microphone boards. An exemplarily technical drawing is shown in Figure 2b. C1 represents a blocking capacitor. Through the openings at the bottom, the boards can be mounted in a soundproof way. The SMD components were soldered using a reflow oven (Lektor electronics: SMTprecision Lead-free Reflow Oven, SMTmax, Chino, CA, USA). 2.2. Methods The SNR is determined using a traditional calculation according to Equation (1) . This includes the power of the signal PSignal and the power of the noise floor PNoise. Equivalently, the ratio of the effective values of the voltages, Ueff,Signal and Ueff,Noise, can be used (1) SNR=10logPSignalPNoise=20logUeff,SignalUeff,Noise . Another definition is often used for the case of an ultrasound field . The power of a given band is calculated as the integral of the power spectral density (PSD) (2) SNRUS=10 log f-12 BWf+12BWPSDSignalff-12 BWf+12BWPSDNoisef . The determination of the transfer function was performed following the model of Novak , i.e., the deconvolution with an analytical exponential sweep xt with the parameter L (refer to ) which depends on the time length of the sweep signal and the frequency range from f1 to f2 to be swept (3) xt=f1Lexp-tL u-t In doing so, the sinusoidal frequencies contained at each point in time are convolved with the respective inverse group delay, which is why these components are transformed from the so-called deconvolution to a Dirac pulse. This is possible because the analytical signal xt was calculated exactly for this purpose. However, if higher harmonics are contained in the signal, they occur with a lower group delay and thus in the deconvolved signal before the Dirac pulse . In the time domain, the signal components are obtained as impulse responses hm. In this way, the associated transfer function of the measured signal st is separated from its harmonics of orders m>=2 in time with Dtn (4) st*xt=m=1hmt+Dtn=F-1Fst*Fxt . This calculation was performed analogously for the loopback channel ut to confirm that a constant transfer function is obtained after deconvolution, as it should be according to theory, if the analytical signal was correctly inverted. Using a Gaussian function, the impulse responses are then cut out and the transfer functions are obtained by Fourier transform. Thereupon, the transfer function of the recorded signal Fh1, stDt1 is divided by one of the ultrasonic loudspeaker HSpeaker which has been measured by Albuquerque et al. (5) Hmf=20logFhm, stDtmHSpeakerf . 3. Results 3.1. Transfer Function Figure 3 shows the transfer functions of the four MEMS microphones between 20 and 80 kHz. The results were normalized according to the maximum. They are proportional to their respective detection sensitivities. It reveals that the sensitivity of a microphone is strongly frequency dependent. Above all, the frequency of the first mechanical resonance, which is formed primarily by the diaphragm mass, its stiffness, and the pre-volume as well as the sound channel , has an influence on the sensitivity. However, MEMS microphones often exhibit a second resonance significantly above 30 kHz, which is based on effects of the counter electrode and the back volume . A sensitive microphone is particularly well suited for applications with low-level signals. Table 2 summarizes the frequencies with highest sensitivity measured in this work. The two peaks of the ICS40740 microphone originate from the same underlying resonance. Because of that, the average frequency of 55 kHz has been chosen. For some models (IM73A135V01, Ellen and Lazarus), ultrasound sensitivities are specified by the manufacturer. The first resonance frequencies roughly agree with the values measured here. However, the manufacturer's specifications are smoothed and provide considerably less information than the measurements shown here. Environmental conditions, such as temperature and relative humidity (values here: 19 degC, 50%, respectively), can lead to minor frequency shifts. Above 70 kHz, the IM73A135V01 has the highest sensitivity, while between 30 and 40 kHz, the Lazarus and Ellen microphones stand out. The ICS40740 has a strongly fluctuating sensitivity in the range above 40 kHz and is therefore less suitable for ultrasonic applications. In order to estimate the proportion of harmonics, the transmission behavior of the first, see Figure 4, and second harmonic transfer function, see Figure 5, were measured. All harmonics were also normalized according to the maximum of the fundamental . It was found that the contribution of the higher harmonics is also strongly frequency dependend. Above 70 kHz, the harmonics are continously increasing for all microphones. The frequency dependency of the harmonics roughly follows the course of the fundamentals. However, the magnitude of the first harmonic is approximately 25 dB smaller than that of the fundamental transfer function, while from 20 to 40 kHz the second harmonic is smaller by another 10 dB on average. A large difference between the fundamental and the harmonics indicates a lower distortion factor and also reduces the SNR to a certain degree. Thus, the applicability of the microphones for low-level signals, as in photoacoustic measurements, improves. In comparison, the IM73 exhibits a relatively low contribution of first and second harmonics. Above 70 kHz, the first harmonic of the Ellen microphone increases significantly; between 50 and 60 kHz, the contribution of the second harmonic is especially large for the ICS microphone and, at 55 and 57 kHz, has even a larger magnitude than the fundamental itself. This has also an influence on the SNR. 3.2. Signal-to-Noise Ratio High microphone sensitivity is of little use if the SNR is low. For instance, in medical applications, moving the sensor or the patient as well as interferences can increase the noise significantly. In any case, it must be possible to clearly distinguish a low-level signal from the noise floor of the microphone. Therefore, in addition to a high sensitivity, a high SNR is desirable. Due to its simplicity, the SNR was calculated according to the classical definition (Equation (1)). The SNR definition for the US range (Equation (2)) was also tested. It results in a value that is a few dB higher owing to a narrower bandwidth in the low-frequency range which is not relevant for a comparison of microphones. However, the calculation of the power density spectrum requires significantly more computing time. Figure 6 displays the SNR of the four MEMS microphones from 20 to 80 kHz which was normalized according to its maximum. It confirms a strong frequency dependency. The Lazarus and the Ellen microphone exhibit the highest SNR in the frequency range between 30 and 55 kHz. Above 65 kHz, the IM73 has an even better value; above 75 kHz it is more than 5 dB better than the next best. From 25 kHz on, the ICS40740 has the lowest SNR of all. Good performances are possibly related to an optimization of stiffness, shape, and suspension of the membrane, as well as optimization of the front and back volumes and the adapted circuit elements of the ASIC in the microphone. 4. Conclusions The performance of MEMS microphones in the near-ultrasonic range is strongly dependent on the microphone design and, as a result of that, on the frequency. This behavior is more pronounced in the ultrasonic than in the audible range. Therefore, an accurate characterization in the target frequency range is desirable before purchase. The results shown here provide an overview of the performance of various analog MEMS microphones in the near-ultrasonic range and are intended to help users select the most suitable microphone for their application. Table 3 summarizes the SNR and the transfer function at different frequencies. The magnitude of the transfer function is proportional to the combined sensitivity of microphone and differential amplifier. A high SNR is desirable for noisy applications. Table 3 clearly proves that a high sensitivity is not necessarily associated with a high SNR, which is essential for medical applications. A high SNR also allows the signal to be processed without many computationally expensive noise removal algorithms. If the sensor is to be miniaturized, it is helpful to dispense with other components, such as additional amplifiers. This is realistic if the selected microphone has a high sensitivity. The authors divide the near-ultrasonic range into three sub-ranges and recommend the following microphones: 20-50 kHz: Lazarus (Knowles) 50-70 kHz: Ellen (Knowles) >70 kHz: IM73A135V01 (Infineon) To get precise values of the SNR for a certain sound field in the desired range, individual measurements with the respective setup are useful. Among others, the presented method of deconvolution for the relative course of the sensitivity can be used for this purpose, without expensive equipment such as sound calibrators. Author Contributions Conceptualization, J.F. and M.W.; methodology, J.F. and M.W.; software, J.F.; validation, J.F. and M.W.; formal analysis, J.F. and M.W.; investigation, J.F.; resources, J.F. and M.W.; data curation, J.F.; writing original draft preparation, J.F.; writing review and editing, J.F and M.W..; visualization, J.F.; supervision, M.W.; project administration, J.F.; funding acquisition, J.F. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement The measurement data will be provided by the authors upon request. Contact the correspondence address. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Block diagram of the experimental setup. Figure 2 (a) Exemplary technical drawing of a microphone board; (b) electronic circuit for the differential amplifier. Figure 3 Fundamental transfer functions of the four MEMS microphones from 20 to 80 kHz. Figure 4 First harmonic transfer functions of the four MEMS microphones from 20 to 80 kHz. Figure 5 Second harmonic transfer functions of the four MEMS microphones from 20 to 80 kHz. Figure 6 SNR of the four MEMS microphones from 20 to 80 kHz. sensors-23-02774-t001_Table 1 Table 1 Compared MEMS microphones and manufacturer characteristics for 1 kHz. Manufacturer Model Sensitivity in dBV SNR in dBV/Pa Infineon IM73A135V01 -38.0 73.0 TDK Invensense ICS40740 -37.5 70.0 Knowles Lazarus PH18C3LM4H-1 -38.0 68.5 Knowles Ellen SPW0878LR5H-1 -38.0 65.0 sensors-23-02774-t002_Table 2 Table 2 Resonance frequencies of the four MEMS microphones. Microphone Frequency in kHz First Resonance Higher Resonances IM73A135V01 28 40/57 ICS40740 20 40/55 Lazarus 33 48/55 Ellen 37 48/55 sensors-23-02774-t003_Table 3 Table 3 Transfer function (H) and SNR of the four microphones at different frequencies. Microphone 20 kHz 40 kHz 75 kHz SNR H SNR H SNR H IM73A135V01 -16.34 -25.35 -17.94 -23.31 -10.16 -19.97 ICS40740 -19.88 -17.12 -16.14 -24.28 -24.64 -32.72 Ellen -25.72 -30.94 -15.14 -19.33 -15.03 -26.67 Lazarus -16.90 -26.50 -12.03 -18.53 -18.47 -29.40 Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Palzer S. Photoacoustic-based gas sensing: A review Sensors 2020 20 2745 10.3390/s20092745 32403451 2. Walser S. Programmierbare Kapazitive MEMS-Mikrofone Ph.D. Thesis University of the German Federal Armed Forces Munich, Germany 2017 3. Hermawanto D. Ishikawa K. Yatabe K. Oikawa Y. Determination of frequency response of MEMS microphone from sound field measurements using optical phase-shifting interferometry method Elsevier Sci. Direct Appl. Acoust. 2020 170 107523 10.1016/j.apacoust.2020.107523 4. Zawaw S.A. Hamzah A.A. Majlis B.Y. Mohd-Yasin F. A Review of MEMS Capacitive Microphones Mircomachines 2020 11 484 10.3390/mi11050484 32397340 5. Wang H. Ma Y. Yang H. Jiang H. Ding Y. Xie H. Review MEMS Ultrasound Transducers for Endoscopic Photoacoustic Imaging Applications Mircomachines 2020 11 928 6. 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Polymers (Basel) Polymers (Basel) polymers Polymers 2073-4360 MDPI 36904380 10.3390/polym15051139 polymers-15-01139 Editorial Non-Covalent Interactions in Polymers Novikov Alexander S. 12 1 Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab., 7/9, 199034 St. Petersburg, Russia; [email protected] or [email protected] 2 Infochemistry Scientific Center, ITMO University, Kronverksky Pr., 49, bldg. A, 197101 St. Petersburg, Russia 24 2 2023 3 2023 15 5 113902 2 2023 23 2 2023 (c) 2023 by the author. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). Non-covalent interactions are one of the key topics in modern chemical science. These intramolecular weak interactions (e.g., hydrogen, halogen, and chalcogen bonds, stacking interactions and metallophilic contacts) have a significant effect on the properties of polymers. In this Special Issue, "Non-covalent interactions in polymers", we tried to collect fundamental and applied research manuscripts (original research articles and comprehensive review papers) focused on non-covalent interactions in polymer chemistry and related fields. The scope of the Special Issue is very broad: we welcome all the contributions that deal with the synthesis, structure, functionality and properties of polymer systems involving non-covalent interactions. pmcNon-covalent interactions are one of the key topics in modern chemical science. These intramolecular weak interactions (e.g., hydrogen, halogen, and chalcogen bonds, stacking interactions and metallophilic contacts) have a significant effect on the properties of polymers. This Special Issue of Polymers entitled "Non-covalent interactions in polymers" aims to address the most recent progress in the rapidly growing field of non-covalent interactions in polymer chemistry and related fields. Both experimental and theoretical studies, fundamental and applied research, application of machine learning and artificial intelligence in studies of non-covalent interactions in polymers and any forms of manuscripts (for example, reviews, mini-reviews, full papers, short communications, technical notes, and highlights) are welcome for consideration. The scope of the Special Issue is very broad: we welcome all the contributions that deal with the synthesis, structure, functionality and properties of polymer systems involving non-covalent interactions. This Special Issue will address the following bullet-point topics: experimental studies of non-covalent interactions in polymers; theoretical modeling of supramolecular polymeric systems; application of machine learning and artificial intelligence in studies of non-covalent interactions in polymers; development of polymer materials (1D, 2D, 3D) via non-covalent interactions; databases of non-covalent polymers. We welcome researchers focused on polymer science and related topics to contribute their research to our Special Issue. To date, there are many interesting publications in the field of fundamental studies of non-covalent interactions in polymers. In , authors observed that dihalomethanes CH2X2 (X = Cl, Br, I) can be co-crystallized with the isocyanide complexes trans-[MXM2(CNC6H4-4-XC)2] (M = Pd, Pt; XM = Br, I; XC = F, Cl, Br) to yield an extended series comprising fifteen X-ray structures of isostructural adducts featuring 1D metal-involving hexagon-like arrays linked via halogen bonding. In , the novel iodine-rich iodobismuthates(III), where the halometalate anionic fragments are linked by diiodine spacers into 2D-supramolecular polymeric systems, were discovered. In , the authors observed that reactions of chlorotellurates(IV) and Br2 afford the formation of one-dimensional supramolecular complexes of general formula Cat2{[TeCl6](Br2)} (Cat = Me3N+, PyH+, 4-MePyH+ and 1-MePy+) where dibromine fragments are "trapped" by [TeCl6] specific BrCl interactions (halogen bonding). In , 1D iodine-rich iodobismuthates(III) with the highest fraction of "captured" I2 molecules in the halometalates network (for p-elements) were reported. In , thermally stable supramolecular polymers of chloroplumbate(IV) and chlorostannate(IV) with Cl2 linkers were reported. In , authors found that oxochloroselenate with incorporated Cl2 units, (tetramethylammonium)3{[Se2O2Cl7](Cl2)}, features very strong halogen bonding in solid state and high thermal stability. In , three polymeric group 11 transition metal polymers featuring metallophilic interactions were obtained directly via the self-assembly of metal ions and 4-pyridinethiol ligands. In , the influence of non-covalent interaction on the self-healing of mechanical properties in supramolecular polymers was discussed. In , non-covalent interactions in polymer-graphene nanocomposites and their effects on electrical conductivity were analyzed. In , core/shell conjugated polymer/quantum dot composite nanofibers through orthogonal non-covalent interactions were presented. In , the importance of CH***X (X = O, p) non-covalent interactions in Cu(II) coordination polymers was highlighted. In , the effect of molecular structure on the chain mobility of dichalcogenide-based polymers with self-healing capacity was analyzed. In , the influence of non-covalent contacts on photoluminescence properties of Cd and Cd-Ln pentafluorobenzoates with 2,2':6',2'-terpyridine derivatives was investigated. In , the effect of non-covalent interactions on the 2, 3,5-dinitrobenzoate Eu-Cd Complex structures was discussed. In , chitosan functionalization via covalent and non-covalent interactions was reviewed. In , self-healing supramolecular hydrogels based on reversible physical interactions were introduced. In , surface plasmon resonance studies on molecular imprinting and the influence of non-covalent interactions on these processes were discussed. In , theoretical insight into the interaction between chloramphenicol and functional monomer (methacrylic acid) in molecularly imprinted polymers was introduced. In , advances in the multi-orthogonal folding of single polymer chains into single-chain nanoparticles were reviewed. In , enhancing the mechanical performance of a polymer material by incorporating pillar arene-based host-guest interactions was highlighted. In , a combined molecular dynamics and DFT simulation study of the molecular and polymer properties of a catechol-based cyclic oligomer of polyether ether ketone was performed. In , chemomechanical polymers as sensors and actuators for biological and medicinal applications involving non-covalent interactions were discussed. In , various applications of supramolecular gels were reviewed. In , electrically self-healing thermoset composites based on Diels-Alder cycloaddition and hydrogen bonds were reported. In , copolymers and hybrids based on carbazole derivatives and their nanomorphology investigation were discussed. Finally, in , phytosterol recognition via rationally designed molecularly imprinted polymers and non-covalent interactions was highlighted. I hope that other authors will follow my initiative and readers of this Special Issue of Polymers will have the opportunity to get acquainted with the achievements of researchers in this modern topic. Acknowledgments In commemoration of the 300th anniversary of St. Petersburg State University's founding. I am grateful to all my colleagues for fruitful collaboration. Institutional Review Board Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The author declares no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Kashina M.V. Kinzhalov M.A. Smirnov A.S. Ivanov D.M. Novikov A.S. Kukushkin V.Y. Dihalomethanes as bent bifunctional XB/XB-donating building blocks for construction of metal-involving halogen bonded hexagons Chem. Asian J. 2019 14 3915 3920 10.1002/asia.201901127 31550070 2. Adonin S.A. Usoltsev A.N. Novikov A.S. Kolesov B.A. Fedin V.P. Sokolov M.N. two-dimensional iodine-rich iodobismuthate(III) complexes: Structure, optical properties and features of halogen bonding in the solid state Inorg. Chem. 2020 59 3290 3296 10.1021/acs.inorgchem.9b03734 32037811 3. Usoltsev A.N. Adonin S.A. Novikov A.S. Abramov P.A. Sokolov M.N. Fedin V.P. Chlorotellurate(IV) supramolecular associates with "trapped" Br2: Features of non-covalent halogen***halogen interactions in crystalline phases CrystEngComm 2020 22 1985 1990 10.1039/C9CE01820D 4. Usoltsev A.N. Korobeynikov N.A. Novikov A.S. Plyusnin P.E. Kolesov B.A. Fedin V.P. Sokolov M.N. Adonin S.A. One-dimensional diiodine-iodobismuthate(III) hybrids cat3{[Bi2I9](I2)3}: Syntheses, stability, and optical properties Inorg. Chem. 2020 59 17320 17325 10.1021/acs.inorgchem.0c02599 33202124 5. Usoltsev A.N. Korobeynikov N.A. Kolesov B.A. Novikov A.S. Samsonenko D.G. Fedin V.P. Sokolov M.N. Adonin S.A. Rule, not exclusion: Formation of dichlorine-containing supramolecular complexes with chlorometalates(IV) Inorg. Chem. 2021 60 4171 4177 10.1021/acs.inorgchem.1c00436 33626273 6. Usoltsev A.N. Korobeynikov N.A. Kolesov B.A. Novikov A.S. Abramov P.A. Sokolov M.N. Adonin S.A. Oxochloroselenate(IV) with incorporated {Cl2}: The case of strong Cl***Cl halogen bonding Chem. Eur. J. 2021 27 9292 9294 10.1002/chem.202101024 33885201 7. Kolari K. Sahamies J. Kalenius E. Novikov A.S. Kukushkin V.Y. Haukka M. Metallophilic interactions in polymeric group 11 thiols Solid State Sci. 2016 60 92 98 10.1016/j.solidstatesciences.2016.08.005 8. Buaksuntear K. Limarun P. Suethao S. Smitthipong W. Non-Covalent Interaction on the Self-Healing of Mechanical Properties in Supramolecular Polymers Int. J. Mol. Sci. 2022 23 6902 10.3390/ijms23136902 35805906 9. Irzhak V.I. Uflyand I.E. Dzhardimalieva G.I. Self-Healing of Polymers and Polymer Composites Polymers 2022 14 5404 10.3390/polym14245404 36559772 10. 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J Revenue Pricing Manag Journal of Revenue and Pricing Management 1476-6930 1477-657X Palgrave Macmillan UK London 421 10.1057/s41272-023-00421-1 Research Article Does historical data still matter for demand forecasting in uncertain and turbulent times? An extension of the additive pickup time series method for SME hotels Heo Cindy Yoonjoung [email protected] 1 Viverit Luciano [email protected] 2 Pereira Luis Nobre [email protected] 3 1 EHL Hospitality Business School, HES-SO/ University of Applied Sciences and Art Western Switzerland, Lausanne, Switzerland 2 Hotelnet, Milan, Italy 3 grid.7157.4 0000 0000 9693 350X Research Centre for Tourism, Sustainability and Well-being & Escola Superior de Gestao, Hotelaria e Turismo, Universidade do Algarve, Faro, Portugal 11 3 2023 11 3 2023 15 17 10 2022 21 11 2022 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Demand forecast accuracy is critical for hotels to operate their properties efficiently and profitably. The COVID-19 pandemic is a massive challenge for hotel demand forecasting due to the relevance of historical data. Therefore, the aims of this study are twofold: to present an extension of the additive pickup method using time series and moving averages; and to test the model using the real reservation data of a hotel in Italy during the COVID-19 pandemic. This study shows that historical data are still useful for a SME hotel amid substantial demand uncertainty caused by COVID-19. Empirical results suggest that the proposed method performs better than the classical one, particularly for longer forecasting horizons and for periods when the hotel is not fully occupied. Keywords Hotel demand forecast Additive pickup Time series COVID-19 pandemic Small and medium-sized enterprises (SMEs) hotels Revenue management University of Applied Sciences and Arts Western Switzerland (HES-SO)Open access funding provided by University of Applied Sciences and Arts Western Switzerland (HES-SO) pmcIntroduction Forecasting hotel demand has always been challenging, because there are many external factors that can impact hotel demand. In particular, the COVID-19 pandemic has been a huge challenge for the hotel industry, because historical demand data has little value. Industry practitioners argue that even an RM system could not work well because there was no historical data to refer to. Most SME hotels have been struggling to manage the uncertainties of doing business in a world that has been turned on its head by the COVID-19 pandemic. Indeed, it is important that the chosen time series forecasting model can yield accurate forecasts for dates over a short-term forecasting horizon (1-4 weeks), regardless of the contextual factors. The forecasting approaches using advanced booking data are typically found in the RM literature and have been applied consistently over the years (e.g., Weatherford and Kimes 2003; Atiya and Gayar 2008; Tse and Poon 2015; Lee 2018; Fiori and Foroni 2019, 2020). Room reservations usually follow similar patterns of the past. Therefore, small hotels tend to forecast occupancy for a given day used to be the occupancy recorded for the same date of the previous year. However, an unprecedented demand environment caused by the pandemic has made the forecasting process even more difficult. Historical data lost some of its value and forecasting has become even more complex, as demands are changing quickly and unpredictably (Kourentzes et al. 2021). Thus, new hotel occupancy forecasting methods should be based not only on historical data but also on current booking status (i.e., reservations on hand). Several studies have compared the performance of different forecasting models for hotel demand. According to Weatherford and Kimes' study (2003), pickup methods and regression yielded the lowest error compared to the booking curve and combination forecasts. Ellero and Pellegrini (2014) found that forecasting models based on booking information performed better than historical ones and additive pickup models achieve the best results in the Italian market. In addition, they proposed to investigate possible variants of the pickup models. Following this approach, Fiori and Foroni (2020) extended the multiplicative pickup method based on generalized linear models and tested it with actual booking data from one Italian hotel. As traveler's booking patterns such as booking window has been dramatically change due to high uncertainty, using only methods strongly dependent on the "same day last year" booking data is not very relevant for hotel forecasting (Webb et al. 2020; Zhang and Lu 2022). While several scholars proposed and tested various demand forecasting models for hotels, no study has explored whether historical data and pickup forecasting models may work during the COVID-19 period. Therefore, this study focused on expanding on the additive pickup time series method for SME hotels and the efficacy of this method was tested using the real reservation data. Methodology Data The data used in this research are actual booking data from a small independent hotel on Isola d'Elba, a summer holiday destination in Italy, for six consecutive years (i.e., 2015-2020). The hotel is 3-star property with 32 rooms, open from April to September, which provided booking data. The time series of daily occupancy data is depicted in Fig. 1, which shows seasonal patterns. We show the annual average booking curve of the hotel per day of the booking window in Fig. 2. Since the high season of the destination is from the beginning of July until mid-September, we have decided to use this period in the empirical experiment. Data from 2015 to 2019 were used to feed the forecasting methods, while data from 1 July to 15 September 2020 were used to evaluate post-sample accuracy of forecasts up to 28 days ahead.Fig. 1 Room occupancy between 2015 and 2020 Fig. 2 Average booking curves between 2015 and 2020 Methods The classic additive pickup method predicts a "pickup average" of incremental bookings for each future day that is added to the current bookings on hand for a specific reading day to forecast hotel demand for future dates (Atiya and Gayar 2008; Fiori and Foroni 2019). Daily predictions of incremental bookings to be picked up from a given reading day until a future day of check-in are usually based on a fixed moving average of incremental bookings that have been observed for each specific number of days in advance in the current year (Fiori and Foroni 2019). As a result, forecasts of the number of rooms occupied do not take advantage of the information about the booking path of same calendar period in previous years. Thus, we propose an extension of the classic additive pickup method that predicts daily incremental bookings to be picked up using a moving average of k-neighbor periods of the future date of check-in and historical daily records on how bookings behaved in N previous years. Let bn,t,j represent the number of rooms booked for the t-th check-in day in year n (n = 0, ..., N) at least j days in advance (j = 0, 1, ..., J). The daily incremental rooms booked between lead times j and j-1, for j = 1, ..., J, is given by:an,t,j=bn,t,j-1-bn,t,j Assuming a moving average of k-neighbor periods, incremental bookings between lead times j and j - 1 in year n, for j = 1, ..., J and n = 1, ..., N, is given by:a n,t(j)=1ki=t-(k-1)/2t+(k-1)/2an,i,j while in the current year (n = 0) that quantity is computed by:a 0,d(j)=1ki=d-(k-1)+jd+ja0,i,j where k is a small and odd number of periods in a neighborhood of the future check-in day t. With an even number of periods the above moving averages are computed by averaging each pair of uncentered means. We propose that a prediction of incremental bookings between lead times j and j - 1, for a future check-in day t = d + j (j = 1, ..., J), made on a specific reading day d in the current year, and based on historical data from N previous years, is obtained from the following expression:a d(j)=1N+1a 0,d(j)+n=1Na n,t(j) Finally, the h-period-ahead forecast (h >= 1) of the total number of rooms occupied, Y, in that future check-in day is given by:y^d(h)=b0,t,h+l=0h-1a d(l) where h = t - d. Regarding the evaluation metrics, we resort to the mean absolute percentage error (MAPE), the root mean squared error (RMSE), and the symmetric mean absolute percentage error (SMAPE). The classic additive pickup method is used as a benchmark in the accuracy evaluation. Results Table 1 shows the post-sample forecasting accuracy of the three methods for multi-step forecasts from 1 to 28 days ahead. First, it is important to note that this table reports three accuracy measures revealing similar relative performance of the forecasting methods for all horizons. Results show that the moving average additive pickup method, with both 7 and 14 observations, appear to have the same forecast performance for the whole forecasting horizon. Although the forecasts for one to three days ahead generated by both methods perform similarly, the moving average additive pickup method outperforms the classic additive pickup method for forecasting horizons of at least seven days ahead. Forecasting accuracy gains of the moving average pickup methods are stronger for longer forecasting horizons.Table 1 Summary of accuracy measures of multi-step ahead forecasts for the test sample Accuracy measure Forecast horizon Forecasting method Ad Ad_MA7 Ad_MA14 RMSE 1 day 0.9 0.9 0.9 3 days 1.3 1.2 1.2 7 days 2.5 1.2 1.2 14 days 5.3 1.2 1.1 28 days 9.3 1.9 1.9 MAPE 1 day 2.3% 2.1% 2.1% 3 days 3.3% 3.1% 3.1% 7 days 5.5% 3.0% 2.9% 14 days 11.9% 3.1% 3.1% 28 days 23.9% 4.6% 4.7% sMAPE 1 day 2.3% 2.1% 2.1% 3 days 3.3% 3.1% 3.1% 7 days 5.8% 3.0% 2.9% 14 days 13.7% 3.1% 3.0% 28 days 29.9% 4.4% 4.4% Ad classical additive pickup, Ad_MA7 additive pickup using moving averages of 7 periods, Ad_MA14 additive pickup using moving averages of 14 periods Table 2 gives the forecasting accuracy results of the classical and the seven-day moving average pickup methods for multi-step forecasts from 1 to 28 days ahead, per month. Results are consistent with those presented in Table 1, since the moving average method performs better than the classic additive pickup method for longer forecasting horizons. The results also reveal that these accuracy gains are stronger in July and September than in August (which is the peak of high season).Table 2 Accuracy measures of multi-step ahead forecasts by month and forecasting method Accuracy measure Forecast horizon July August September Forecasting method Forecasting method Forecasting method Ad Ad_MA7 Ad Ad_MA7 Ad Ad_MA7 RMSE 1 day 0.8 0.9 0.7 0.5 1.4 1.4 3 days 1.2 1.2 1.0 0.9 2.0 1.7 7 days 2.5 1.3 1.1 1.0 4.1 1.2 14 days 6.3 1.1 2.3 1.2 7.4 1.0 28 days 12.6 2.0 3.6 2.1 9.6 1.5 MAPE 1 day 2.1% 2.3% 2.2% 1.5% 3.2% 3.1% 3 days 2.8% 3.1% 2.9% 2.6% 4.9% 4.2% 7 days 5.5% 2.9% 3.3% 3.0% 9.9% 3.0% 14 days 15.2% 2.9% 5.6% 3.7% 18.1% 2.4% 28 days 37.2% 4.5% 8.3% 5.4% 28.7% 3.3% sMAPE 1 day 2.1% 2.3% 2.2% 1.5% 3.3% 3.2% 3 days 2.9% 3.1% 2.9% 2.6% 5.1% 4.3% 7 days 5.9% 2.9% 3.3% 3.0% 10.9% 3.0% 14 days 17.8% 2.8% 5.8% 3.6% 21.6% 2.3% 28 days 48.4% 4.2% 9.1% 5.2% 34.5% 3.2% Conclusion Accurate demand forecasts allow hotels in managing room rates and inventories in a much more effective fashion. The Covid-19 pandemic disrupted tourism and hospitality sectors worldwide through border closures, social distancing measures, the cancelation of transportations, and changes in travelers' behavior. Indeed, Deya-Tortella et al. (2022)'s a longitudinal analysis revealed that the COVID-19 pandemic affected hotel guests' booking patterns such as booking window, distribution channel, and length of stay. Therefore, the demand forecasting models using a traditional approach without accounting for the new conditions caused by exogenous factor like the COVID-19 pandemic cannot estimate the demand correctly. In this research note, we present an extension of the additive pickup method using moving averages and using historical data. When exogenous factors affect overall tourism demand and hotel booking patterns, historical booking data have a value only when it is properly analyzed. This study shows that historical data are still useful even when there is a high degree of uncertainty because of demand volatility (i.e., COVID-19). Empirical results of our study suggest that the proposed moving average pickup method outperforms the classical one, particularly for longer forecasting horizons and for periods when the hotel is not fully occupied. Thus, we advise SME hotels to use the new moving average pickup method in their forecasting tasks, particularly in periods with strong volatility in hotel demand. This research note provides important practical implications for SME hotels, which are more threatened by increasing demand uncertainty and global competition than other hotels, and usually cannot afford for a subscription of a full revenue management system. First, this research note suggests a useful instrument for revenue managers maximizing revenue. The additive pickup time series method using moving averages generates accurate forecasts up to 28 days ahead of the date of arrival, and for periods when the hotel is not fully occupied, which is comprehensive and critical information for decision-makers regularly update their operational decisions related to price and inventory allocation. Second, the proposed method requires less data than traditional time-series approaches and can be easily implemented even in MS Excel. There characteristics are particularly pertinent for SME hotels, since they can empower their revenue management decisions with low resources. Finally, the extension of the pickup method is attractive for implementing by programmers of revenue management systems, since the formulae are straightforward, and the method is not computer-intensive. From a theoretical point of view, the proposed method closes the gap of classical pickup methods of not considering in the forecast incremental bookings that were observed for the same calendar period, in each specific number of days in advance, from previous years. Thus, the main contribution of this research note to the theory of revenue management relies on the use of historical information about the booking path of same calendar period in the additive pickup method, in order to improve accuracy of daily demand forecasts. Several limitations of the present research should also be noted. This study only applied the additive pickup using moving averages of 7 and 14 periods. The optimal periods of moving average and the moving average pickup method we proposed here may not work for some hotels which target different markets (e.g., business hotels in the major city). Also, the impact of COVID-19 on hotel demand was not shared equally around the world. The hotel we investigated in this study located in a summer holiday destination and enjoyed high occupancy during the summer of 2020 although the booking pattern changed significantly. However, many hotels in the major cities targeting mainly business segments had struggled during the summer of 2020. Further, the impacts of other exogenous factors on overall tourism demand and hotel booking patterns can be different from COVID 19. Therefore, we encourage future research to apply the proposed approach to various contexts and improve it further. For example, future research may consider applying the new additive pickup method per cluster of booking curves. Pattern similarity-based machine learning methods can be used to cluster booking curves. It would be interesting to compare hotel demand forecasting accuracy of this method with a cluster-based method that uses data of only similar stay days (i.e., belonging to the same cluster) to generate forecasts. Funding Open access funding provided by University of Applied Sciences and Arts Western Switzerland (HES-SO). Luis N. Pereira is pleased to acknowledge financial support provided by FCT - Foundation for Science and Technology through project UIDB/04020/2020. Declarations Conflict of interest The authors declare that they have no conflict of interest. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References Atiya A Gayar N A comparative study of the pickup method and its variations using a simulated hotel reservation data ICGST International Journal on Artificial Intelligence and Machine Learning 2008 8 15 21 Deya-Tortella B Leoni V Ramos V COVID-led consumption displacement: A longitudinal analysis of hotel booking patterns International Journal of Hospitality Management 2022 107 103343 10.1016/j.ijhm.2022.103343 36105783 Ellero A Pellegrini P Are traditional forecasting models suitable for hotels in Italian cities? 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Pan Afr Med J Pan Afr Med J PAMJ The Pan African Medical Journal 1937-8688 The African Field Epidemiology Network PAMJ-43-184 10.11604/pamj.2022.43.184.29628 Case Report Tumeurs parotidiennes negligees: rapport de cas Neglected parotid tumors: case reportRandrianandraina Patrick Maholisoa 1& Razanakoto Georges Franck Angelo 2 Valisoa Herimalalaniaina Angelo 3 Raotoson Herisitraka 4 Randrianirina Hery Henintsoa 5 Rakoto Fanomezantsoa Andriamparany 2 1 Service d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Centre Hospitalier Universitaire Professeur Zafisaona Gabriel Androva, Mahajanga, Madagascar, 2 Service d Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Centre Hospitalier de Soavinandriana, Antananarivo, Madagascar, 3 Service d Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale Centre Hospitalier Universitaire d Anosiala, Antananarivo, Madagascar, 4 Service de Stomatologie et Chirurgie Maxillo-faciale, Centre Hospitalier Universitaire Professeur Zafisaona Gabriel Androva, Mahajanga, Madagascar, 5 Service d Anesthesie-Reanimation, Centre Hospitalier Universitaire Professeur Zafisaona Gabriel Androva, Mahajanga, Madagascar & Corresponding author: Patrick Maholisoa Randrianandraina, Service d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Centre Hospitalier Universitaire Professeur Zafisaona Gabriel Androva, Mahajanga, Madagascar. [email protected] 08 12 2022 2022 43 18403 5 2021 15 5 2022 Copyright: Patrick Maholisoa Randrianandraina et al. 2022 The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Les tumeurs de la glande parotide peuvent se compliquer en absence de traitement. Nous rapportons trois premieres presentations cliniques et therapeutiques malgaches de tumeurs parotidiennes negligees. Ces cas survenaient chez deux femmes et un homme de 42, 47 et 51 ans, presentant des tumeurs evoluant respectivement depuis 4, 7 et 11 ans. Une tumeur maligne etait suspectee chez un patient devant la mise en evidence de necroses cutanees, confirmee par la cytoponction. Sur consentement des patients, une parotidectomie totale etait effectuee pour chaque cas. Un sacrifice du nerf facial avec evidement cervical ganglionnaire etait decide chez le patient presentant une tumeur maligne. Aucun incident peroperatoire n etait note. Les tumeurs parotidiennes peuvent se transformer en cancer en absence de traitement adequat. Des facteurs socio-economiques sont impliques dans le retard de consultation. Cependant, une consultation precoce devant toute tumeur parotidienne permettrait d eviter les aleas de la prise en charge. Tumors of the parotid gland can be challenging if left untreated. We report three cases of patients with initial clinical and therapeutic manifestations of neglected parotid tumours in Madagascar: two women and one man aged 42, 47 and 51 years, with tumours that had been developing for 4, 7 and 11 years respectively. One patient was suspected to have malignant tumour due to skin necrosis. The diagnosis was then confirmed by cytopuncture. After obtaining the informed consent, total parotidectomy was performed in all patients. Facial nerve sacrifice with cervical lymph node dissection was established in the patient with a malignant tumour. No intraoperative adverse events were reported. Parotid tumors can become cancerous without proper treatment. Socio-economic factors are involved in delayed consultation. However, early consultation in patients with parotid tumors would prevent management risks. Adenome pleomorphe tumeurs salivaires tumeurs parotidiennes cas clinique Pleomorphic adenoma salivary tumors parotid tumors case report pmcIntroduction Les tumeurs des glandes salivaires sont rares et representent moins de 3% des tumeurs cervico faciales . La glande parotide constitue le siege le plus frequent de ces tumeurs dans 70 a 80% des cas . Ces tumeurs d evolution lente, sont le plus souvent benignes, indolores et n entrainent que rarement des genes fonctionnels. Non traitees, elles peuvent devenir geantes et etre responsables d un gene esthetique ou meme se transformer en une tumeur maligne . A travers la presente etude, nous rapportons trois cas de tumeurs parotidiennes negligees a travers lesquelles nous mettons en evidence les aspects cliniques et therapeutiques associes a ce retard de prise en charge dans un centre de sante malgache. Patient et observation Observation 1 Informations relatives au patient: une femme de 51 ans s est presentee au service d ORL et de chirurgie cervico faciale du CHU Professeur Zafisona Gabriel de Mahajanga pour une masse latero-cervicale gauche evoluant depuis 11 ans. Cette vendeuse ambulante, sans antecedent particulier, consultait car, genee par le poids de la tumeur, elle ne pouvait plus porter ses marchandises sur la tete. Aucun traitement n a ete entrepris depuis selon la patiente, a part une notion de massage reguliere de la tumeur. Resultats cliniques: a l examen, elle etait en bon etat general, et presentait une tumefaction homogene, ferme de dimension 26cm x 21cm x 17cm, pendante a la partie laterocervicale gauche . La peau en regard etait normale, il n y avait ni de paralysie faciale, ni de dyspnee, ni gene a la deglutition, ni d adenopathie cervicale. L examen endobuccal et oropharynge etaient normaux. Figure 1 volumineuse tumeur parotidienne homogene gauche (observation 1) Demarche diagnostique: le scanner cervico facial n existait pas sur place, l echographie cervicale rapportait une tumeur mixte aux depens de la glande parotide gauche. Intervention therapeutique: une parotidectomie totale avec conservation du nerf facial etait effectuee sur consentement de la patiente. L hemostase etait assuree par la dissection et la ligature des pedicules vasculaires tumorales, permettant une stabilite des parametres vitaux pendant l intervention. A l issue de l extraction, la tumeur pesait 9,7kg et presentait une apparence jaunatre avec des micro calcifications. Suivi et resultats: les suites etaient simples, malgre une paresie faciale temporaire de grade II de Housse et Brackmann. La patiente a pu sortir au 5e jour post-operatoire. L examen histologique de la piece operatoire a confirme un adenome pleomorphe sans signe de malignite. Aucune recidive n est notee a 1 an post-operatoire. Observation 2 Informations relatives au patient: deux mois plus tard, une femme de 47 ans s est presentee dans le meme service pour une masse latero faciale droite evoluant depuis 7 ans. Cette patiente n avait aucun antecedent particulier, et n avait encore recu aucun traitement pour cette tumeur. Resultats cliniques: elle etait en bon etat general et presentait a l examen une tumefaction parotidienne droite ferme, polylobee, recouverte d une peau saine, mesurant 15cm x 11cm x 12cm . L examen endobuccal et l'examen oropharynge etaient normaux, il n y avait pas de paralysie faciale ni d adenopathie cervicale. Figure 2 volumineuse tumeur parotidienne polylobee droite (observation 2) Demarche diagnostic: aucun bilan d imagerie n avait ete effectue, faute de moyens financiers et d absence de scanner. Intervention therapeutique: une exerese chirurgicale etait effectuee avec consentement de la patiente. A l issue de cette parotidectomie totale avec dissection et preservation du nerf facial, et malgre l absence d examen extemporane, la tumeur pesait 1,9kg. Suivi et resultats: les suites operatoires immediates etaient simples, il n y avait pas de paralysie post operatoire ni d hematome du site operatoire. La patiente a pu sortir au 5e jour post-operatoire. L examen histologique de la piece operatoire a rapporte un adenome pleomorphe de la glande parotide sans signe de malignite. Aucune recidive n est retrouvee a 6 mois post operatoire. Observation 3 Informations relatives au patient: il s agissait d un homme de 42 ans qui s est presente en consultation, 6 mois apres le premier cas, pour une masse latero cervicale gauche evoluant depuis 4 ans. A l issue de seances de massages locaux, cette tumeur, indolore au depart, avait augmente de volume avec apparition de fistules, de necroses cutanees et de douleurs tumorales intermittentes, 9 mois auparavant, ayant motive cette consultation. Ce patient n avait aucun antecedent familial ni personnel particulier. Demarche diagnostic: a l examen, le patient etait en assez bon etat general, il presentait une masse parotidienne gauche, mesurant 21cm x 12,5cm x 9cm, ferme, necrosee et bourgeonnante, saignant facilement au contact. Les foyers de necroses etaient multiples entrecoupes d ilots de peau saine . L examen endobuccal et l'examen oropharynge etaient normaux. Il n y avait pas de paralysie faciale ni de gene a la deglutition et a la respiration, il n y avait pas d adenopathie cervicale palpee. En absence de scanner et d'imagerie par resonance magnetique (IRM) sur place, la radiographie de la face ne retrouvait pas d effraction osseuse. L echographie cervicale confirmait l origine parotidienne de la tumeur qui etait hypoechogene sans lesion kystique. Les gros vaisseaux etaient permeables. La cytoponction a l aiguille fine suspectait une tumeur maligne de la parotide. Il n y avait pas de signes de metastases viscerales. La tumeur etait alors classee T4aN0M0. Figure 3 tumeur parotidienne gauche ulcero-bourgeonnante avec necrose cutanee (observation 3) Intervention therapeutique: apres consentement du patient et information sur la probable paralysie faciale post-operatoire, une parotidectomie totale non conservatrice avec evidement ganglionnaire cervicale avait ete effectuee en un temps. La tumeur pesait 3,2Kg et l examen histologique extemporane etant indisponible sur place, l exerese cutanee respectait une marge de 2cm en zone saine emportant la tumeur avec reconstruction par lambeaux locaux. Suivi et resultats: une paralysie faciale totale etait effective en periode post operatoire, le patient a pu sortir au 7e jour post-operatoire. L examen histologique a confirme un carcinome invasif au sein d un adenome pleomorphe. Malgre une radiotherapie prevue, le patient n avait pas pu en beneficier. Une bonne cicatrisation cutanee ainsi qu une absence de recidive etaient notees a 6 mois post operatoire. Perspective des patients: a l issue du traitement hospitalier, les patients ont ete satisfaits car ils pouvaient reprendre leurs activites quotidiennes et une vie sociale normale, etant debarrasses des enormes tumeurs. Consentement eclaire: les patients ont ete informes des interets du rapport de leurs cas et de la particularite de la presentation de leurs pathologies. Ils ont volontairement donne leurs consentements pour permettre aux auteurs d utiliser leurs photos pour ce rapport de cas, en respectant l anonymat. Des consentements eclaires ont ete obtenus de chaque patient pour l utilisation de leurs photos. Discussion Les tumeurs parotidiennes geantes sont rares et sont le plus souvent rapportees sous formes de cas uniques . Les series de cas rapportees varient de 2 a 3 cas a 15 cas . Nous rapportons une premiere serie Malgache de tumeurs geantes de la glande parotide. L etiologie exacte de ces tumeurs parotidiennes est imprecise bien que certains auteurs aient rapporte une recrudescence tumorale apres 15 a 20 ans d irradiation ou en association a une infection virale . La duree d evolution des tumeurs negligees de la glande parotide avant la prise en charge hospitaliere varierait de 5 a 20 ans s il etait de 4 a 11 ans chez nos cas. Ce retard de consultation serait lie au bas niveau socio-economique dans les pays en developpement comme Madagascar, dans lesquels les couvertures sociales sont inexistantes, mais aussi aux difficultes d acces aux soins chez des patients vivants dans des villages recules, loin des centres de sante de references. Ces patients ne se deplaceraient pas dans des grandes villes devant cette tumeur qui est indolore, n entrainant aucun gene fonctionnel . Cependant, les tumeurs parotidiennes augmentent progressivement de volume en absence de prise en charge. Le seul gene provoque est esthetique, constituant les derniers soucis des patients vivants en zone rurale. Ils ne viennent consulter que lorsque la tumeur devient genante pour les activites quotidiennes ou lorsqu une douleur apparait. Le retard de consultation pourrait aussi s expliquer par une pratique courante dans les pays africains vis-a-vis des tumeurs de la face et du cou. Ces tumeurs y sont considerees comme etant des oeuvres de sorcelleries, si bien que les patients optent pour l automedication et la consultation chez le traditherapeute avant la consultation medicale. La glande parotide, pesant normalement de 0,015 a 0,021Kg avec une dimension de 5,8 x 3,4cm peut etre le siege de tumeurs pouvant mesurer jusqu a 35cm x 28cm et peser jusqu a 7,3kg . Les dimensions tumorales augmentent avec leur duree d evolution . Le massage cervical, de pratique courante a Madagascar, provoque des microtraumatismes sur la tumeur, pouvant etre responsable d une augmentation plus rapide du volume de la tumeur, voire de transformation maligne. Cette pratique a ete retrouvee chez nos patients. Cependant cette hypothese reste a verifier. La connaissance du diagnostic de nature en pre-operatoire est indispensable pour la decision therapeutique. Une tumeur maligne beneficiera d une parotidectomie totale sacrifiant le nerf facial avec evidement cervical ganglionnaire alors que si la tumeur est benigne, une parotidectomie superficielle serait suffisante . Ce diagnostic pre-operatoire est base sur la clinique et l IRM couplees a la cytoponction donnant une sensibilite de 100% et une specificite de 88% . L absence d IRM, d examen histologique extemporane ainsi que le niveau socio-economique bas etaient des obstacles a l accessibilite de ces examens chez nos cas, rendant la prise en charge delicate. L anatomopathologie des tumeurs parotidiennes geantes est representee par l adenome pleomorphe dans 60 a 70% des cas. Les tumeurs malignes de la parotide sont rares et representeraient moins de 10% des cas . D autre part, les adenomes pleomorphes peuvent se transformer en carcinomes dans 3 a 6% des cas . Ce risque varie avec le temps d evolution tumorale et atteint 9,5% pour une evolution de plus de 15 ans . Ces tumeurs malignes representent une hantise devant les tumeurs parotidiennes. Leur presentation clinique sous forme de masse ferme au sein de la glande parotide, differe de peu de la presentation clinique d un adenome pleomorphe. Le patient de l observation 3 avait presente une forme atypique de carcinome indifferencie de la parotide evolue, avec extension cutanee. Une perte d expression du gene de l adenome pleomorphe contrastant avec une surexpression du facteur de croissance epidermique serait responsable de la transformation des adenomes pleomorphes en tumeurs malignes . Des etudes genetiques sont necessaires pour confirmer cette hypothese. Le traitement des tumeurs parotidiennes geantes repose sur l exerese chirurgicale. Ce sont frequemment des tumeurs hyper vascularisees dont l exerese est associee a une hemorragie massive peroperatoire . Une embolisation du pedicule vasculaire est preconisee en pre-operatoire afin de limiter les pertes sanguines . Dans nos observations, malgre l absence de l embolisation pre-operatoire, une dissection meticuleuse associee a une ligature du pedicule vasculaire a permis d avoir un controle de l hemostase. Devant l insuffisance de l exploration pre-operatoire, afin d eviter tout risque de recidive et de reprise chirurgicale dans une loge parotidienne traversee par le nerf facial, une parotidectomie totale conservatrice etait decidee d emblee sauf en cas de tumeur maligne evidente. La reconstruction cervicale en cas de tumeur negligee de la parotide est facilitee par la presence d un exces de peau distendue par la tumeur, permettant la realisation de lambeaux locaux. Une radiotherapie post operatoire est indiquee en cas de tumeur maligne invasive de la glande parotide, necessitant ainsi un suivi au long cours. Le soulagement et la disparition de la tumeur en post operatoire associes a un contexte socioeconomique bas ont contribues aux difficultes de realisation des traitements complementaires post operatoires. Conclusion Les tumeurs parotidiennes peuvent etre tres volumineuses ou se transformer en cancer en absence de traitement chirurgical. Des facteurs socio-economiques sont impliques dans le retard de consultation. Malgre un plateau technique insuffisant, la chirurgie des tumeurs parotidiennes negligees, parfois compliquee d hemorragie ou de blessure du nerf facial en peroperatoire, peut etre realisee en respectant meticuleusement les temps operatoires. Cependant, une consultation precoce devant toute tumeur parotidienne permettrait d eviter ces aleas de la prise en charge. Conflits d'interets Les auteurs ne declarent aucun conflit d interets. Contributions des auteurs Patrick Maholisoa Randrianandraina: conception, redaction de l article, revision. Georges Franck Angelo Razanakoto, Herimalalaniaina Angelo Valisoa, Herisitraka Raotoson, Hery Henintsoa Randrianirina: acquisition des donnees, redaction, revision. Fanomezantsoa Andriamparany Rakoto: revision, approbation de la version finale. Tous les auteurs ont contribue a l elaboration et la mise en oeuvre de ce travail. Ils ont tous lu et approuve la version finale du manuscrit. Cite this article: Patrick Maholisoa Randrianandraina et al. Tumeurs parotidiennes negligees: rapport de cas. 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Pan Afr Med J Pan Afr Med J PAMJ The Pan African Medical Journal 1937-8688 The African Field Epidemiology Network PAMJ-43-190 10.11604/pamj.2022.43.190.30562 Perspectives Improving healthcare systems and services in the face of population ageing: policy considerations for middle-income countries Moeteke Nnamdi Stephen 1& 1 Delta State University Teaching Hospital, Oghara, Delta State, Nigeria & Corresponding author: Nnamdi Stephen Moeteke, Delta State University Teaching Hospital, Oghara, Delta State, Nigeria. [email protected] 13 12 2022 2022 43 19028 6 2021 30 11 2022 Copyright: Nnamdi Stephen Moeteke et al. 2022 The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Worldwide, the proportion and absolute numbers of over 60-year-olds in the population is rising: it was 1 billion in 2019 and is expected to get to 1.4 billion in 2030 and 2.1 billion by 2050, with the progression being more pronounced in developing countries. Degenerative and non-communicable diseases are more common with ageing, which means they would become the major disease problems for countries. Long-term care poses financial risks to individuals/families and governments. These warrant urgent policy and structural adjustments of health systems in middle-income countries to cater for the probable change in health needs and make their society more age-sensitive. There is the need for policymakers to begin to change focus from traditional models of healthcare delivery and give more attention to aged care and create separate financing mechanisms/programmes for the elderly, most of whom are already unemployed, to protect them from the effects of cream-skimming by private health insurers. Informed decisions on healthcare purchasing can be made using Economic Evaluation, as well as Programme Budgeting and Marginal Analysis, a presentation of discrete categories of healthcare expenditure (specialties, disease-groups, etc.) and the resources appropriated to each as an aid to reviewing subsequent resource allocation. Reforms in healthcare financing should pay particular attention to the elderly considering that technical efficiency concerns of the private sector may mean that they are discriminated against. There is need for retraining/reorientation of health workers on identification and comprehensive management of NCDs, including palliative care, in a culturally competent way, on the essence of shifting from an acute care model to a chronic care model, and on providing services to people within defined catchment areas. Population ageing health systems developing countries pmcPerspectives Introduction/problem statement Worldwide, the proportion/absolute numbers of over 60-year-olds in the population is rising: it was 1 billion in 2019, and is expected to get to 1.4 billion in 2030 and 2.1 billion by 2050, with the rise being more pronounced in developing countries . Population ageing, which arises from a progressive decrease in fertility and the size of younger age groups accompanied by increased longevity, has become a global public health concern because of its effects on healthcare and social policy. Increased survival means that people go through longer periods of ill-health and need for treatment, leading to increased health spending and pressure on health systems. Degenerative and non-communicable diseases are more common with ageing, which means they would become the major health problems for countries. With more people in the elderly bracket and fewer young adults, the latter would find themselves with few or no siblings to support in catering for elderly parents making institutionalised care a necessity . However, the resultant higher expenditures are not necessarily the fallout of ageing per se but the result of embracing new and expensive technologies and the re-organisation of the health system . Long-term care poses financial risks to individuals/families and governments. It has been projected that federal governments will eventually relinquish the financial burden to States and citizens . The elderly often are in rural areas where health services are most basic, and providers are poorly experienced/equipped in geriatric care since ageing is nascent in developing countries . There is also the possibility of failure to provide adequate access to quality care in other aspects of health and for other segments of the population arising from the competing demands for resources from technology-intensive therapies for advanced Non-Communicable Diseases (NCDs) . All these warrant urgent policy and structural adjustments of health systems in middle-income countries to cater for the probable change in health needs and make their society more age-sensitive . Health needs assessment: there is the need for policy-makers to begin to change focus from traditional models of healthcare delivery and give more attention to aged care, and create separate financing mechanisms/programmes for the elderly, most of whom are already unemployed, to protect from the effects of cream-skimming by private health insurers . Of priority is the elimination of long waiting lists for specialised ambulatory care, radiological investigations and surgical procedures, and transfer of cases of acute exacerbations to outpatient clinic, while ensuring adequate access to quality general out-patient services and basic surgical procedures by countering the competing demand for resources by high-technology interventions for advanced NCDs . As states assume increased responsibility for financing long-term care in the midst of dwindling federal allocations, they will have to device means to target resources and control costs. The latter can be more easily attained if the economic climate is made more favourable for private insurance for long-term care, employer-sponsored elder care programmes, and residential care alternatives. Individuals and families may increasingly find themselves left with no option but to foot the bills on their own via mechanisms such as long-term care insurance . Critical analysis of evidence and application of theory Health financing is the sum of mechanisms within the health system by which funds are collected, pooled, and used to purchase care for the intended population . It provides an essential nexus for collaboration between health managers/policy-makers, purchasers, providers, and users of services. The responsibility of the regulatory apparatus of government is, therefore, to create the enabling institutional framework for providers to deliver quality care and improve the system s responsiveness to the expectations of the populace . Generally, sources of funding include individuals, households, employees, employers (firms and corporate bodies), and donor agencies and organisations. Funds could be collected by government agencies, social security agency, community health insurance funds, private insurance funds, or direct payment to providers . The essence of pooling of funds is to evenly distribute financial risk among contributors to the pool . With the out-of-pocket payment method, there is no pooling of funds and distribution of risk, and therefore those who cannot afford care do not receive it or receive it catastrophically . Consumers aim to maximise utility relative to price, so demand increases with lower price and vice versa; producers aim to minimise cost relative to price, therefore, supply decreases with lower price and vice versa. The economic theory of consumer and producer choice can be applied to health and health care, and provides insights into consumer and producer behaviour, as well as causes of failure, in the market for health insurance. One cause of market failure in private health insurance is 'adverse selection'. It gives firms an incentive to engage in "cherry-picking", providing insurance only to people of low risk, and leaving the high-risk groups uncovered . The concept of scarcity stems from the fact that resources are insufficient to meet the wants of individuals/society . Health care resources are also scarce because, due to a fixed budget, there is a limit to the government's spending on health. Therefore, choices have to be made, in both production and consumption, about what amount and combination of health care to produce, how to produce it, who pays for it, and how it is distributed . Opportunity cost is the benefit not gained because of spending resources on the next best alternative . The opportunity cost of providing long-term care for the elderly and people with NCDs would, therefore, be other forms of healthcare and the utility that could have accrued from them. This brings to the fore the issue of allocative efficiency which is using the combination/deployment of resources that provides the maximum benefit to the whole population; and technical efficiency - the use of the least amount of resources to produce these health outcomes . Every health system aims at providing value for money, as far as is humanly possible, for everyone under the system, and should look at everybody, not just an individual or a group of persons. It would have to be ascertained if providing adequate care for the elderly and chronically ill would achieve allocative efficiency. Priority-setting is especially needed when health systems, as with developing countries, are faced with fixed budgets and heavy disease burden worsened by the epidemiological transition, making it pertinent to adopt health financing optimisation strategies. Informed decisions on healthcare purchasing can be made using Programme Budgeting and Marginal Analysis, a presentation of discrete categories of healthcare expenditure (specialties, disease-groups, etc.) and the resources appropriated to each as an aid to reviewing subsequent resource allocation . It organises information on spending patterns to serve as an economic framework for more efficient future health care resource allocation by comparing the outputs of health care services under broad categories/programmes bearing in mind health care objectives and priorities, underpinned by opportunity cost and marginal analysis . Economic evaluation, another tool of normative economics, entails a process of identifying competing interventions, assessing the costs and benefits of each, and comparatively analysing costs and benefits. For example, Cost Effectiveness Analysis (CEA) involves comparing relative trade-offs of cost and benefit in a bid to achieve production (economic) efficiency . Cost Utility Analysis (CUA), an extended form of CEA, uses Quality Adjusted Life Years (QALY) rather than natural units to measure benefits. These can be used in ascertaining what alternative gives the most output for a given cost. Recommendations and conclusion Many western countries like the United Kingdom have strategies in place, having crossed the threshold for aged societies (i.e. at least 14% of the population aged 65 or above) over four decades ago . Developing countries should consider the following in readiness for the imminent pan-global demographic and epidemiological transitions. a) Health policy reforms to cater for the aged have to be built into a broader framework of inter-sectoral action geared towards improvement in quality of life and socioeconomic wellbeing . b) Health promotion strategies can make a huge impact on the health status of the elderly as preventive interventions such as campaigns on healthy diet and control of tobacco use have been demonstrated to be far more cost-effective than a curative approach and "developing healthy lifestyles and environments for all age groups will mean fewer problems for tomorrow s aged" . c) Reforms in healthcare financing should pay particular attention to the elderly considering that technical efficiency concerns of the private sector may mean that they are discriminated against . d) There should be investments in a district-based primary healthcare system that integrates management of chronic diseases and cost-effective community-based prevention services into general health services alongside a formidable surveillance system, particularly as the major NCDs have common risk factors - smoking, physical inactivity, harmful use of alcohol, and an unhealthy diet - that are modifiable . e) There is need for retraining/reorientation of health workers on identification and comprehensive management of NCDs, including palliative care, in a culturally-competent way, on the essence of shifting from an acute care model to a chronic care model, and on providing services to people within defined catchment areas . f) Of importance is a change from the traditional paternalistic medical approach to patient-centred management against the backdrop of prolonged care and need for behavioural change and family/communal support . g) Subsidisation or free provision of basic medicines for NCDs such as hypertension, diabetes, osteoarthritis, asthma, etc. . h) Health technology assessment should be enhanced to provide a sound basis for the proper selection of new public health programmes and actions, and of new drugs, devices and diagnostic tests . Competing interests The author declares no competing interests. Authors' contributions The author read and approved the final version of the manuscript. Cite this article: Nnamdi Stephen Moeteke et al. Improving healthcare systems and services in the face of population ageing: policy considerations for middle-income countries. 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Pan Afr Med J Pan Afr Med J PAMJ The Pan African Medical Journal 1937-8688 The African Field Epidemiology Network PAMJ-43-189 10.11604/pamj.2022.43.189.36312 Case Report Clinico-radiological evaluation and management of type II radial ray defect in a young female from rural India: case report Sood Anshul 1 Dhande Rajasbala Pradeep 1 Nagendra Vadlamudi 1& Mishra Gaurav 1 Reddy Gopidi Nidhi 1 1 Department of Radiodiagnosis, Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha, Maharashtra, India & Corresponding author: Vadlamudi Nagendra, Department of Radiodiagnosis, Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha, Maharashtra, India. [email protected] 13 12 2022 2022 43 18926 7 2022 23 11 2022 Copyright: Anshul Sood et al. 2022 The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Radial Ray Defect (RRD) is a rare disorder, and the etiology of this disorder is still under discussion. RRD is associated with many medical conditions for which prenatal counselling is of paramount importance. Any association with the family history is still unknown. The patient is a 16-year-old female who came to the orthopaedic clinic complaining of tingling and weakness in the right forearm. On examination, there was a gross deformity in the right forearm with radial deviation of the hand. An X-ray revealed radial ray defect type-2. She previously had a history of perinatal infection during early childhood. Surgery was successfully achieved, and positive results were accomplished. Radial Ray Defect can be focal or associated with other clinical manifestations. The timing of antenatal ultrasound for detecting this musculoskeletal anomaly is crucial. When RRD is associated with other syndromes, counselling to the parents about the quality of life and morbidity comes into play. Treatment is primarily surgical. Radial ray defect radial dysplasia radial ray anomaly case report pmcIntroduction Radial dysplasia is significant when the structures on the radial side of the forearm (radius, carpals on the radial side and the thumb) fail to develop normally . It is rare, with an incidence of 1 in 30,000 live births . Radial ray syndrome is associated with hypoplasia or aplasia of the radius with/without deficient thumb and carpal bones. Radial ray syndrome and associated malformations range from unilateral to bilateral involvement. It can also have sporadic occurrences associated with multiple malformation syndromes. Isolated RRD comprises 8% to 30% of the cases, and the majority of the cases are associated with other anomalies . The aim of this case study was to report our experience with a young female from rural India with radial ray anomaly and its management. Patient and observation Patient information: a 16-year-old female child came to the orthopaedic clinic complaining of weakness and tingling sensation in the right forearm since one year. The patients mother noticed a deformity in the right forearm in the perinatal period. The patient had a history of perinatal infection of the right forearm associated with discharge at the age of 6 weeks which continued till five months. The patient was managed by surgery (documentation not available) and below the elbow brace, following which she was advised to follow up at 18 years. The patients mother had non-consanguineous marriage and had not undergone any antenatal ultrasound scans due to her low socio-economic status. There was no significant family history. Patient has no comorbidities. Clinical findings: on inspection, there was gross deformity with the prominence of the right ulnar head and the presence of a non-tender scar on the dorsolateral aspect of the right ulna. On physical examination of the right hand, done in a supine and sitting position, dorsiflexion was limited to 0-10, palmar flexion was limited to 0-10 with valgus deformity of 0-70 and radial deviation of 70-90. The supinator muscle was absent, and the forearm remained in pronation on rest. The patient was unable to make a fist and unable to flex the thumb. Timeline of current episode: January 2021: patient referral to the department of Radiology. X-ray and CT were conducted. March 2021: surgical correction was performed. October 2021: follow up. Diagnostic assessment: X-ray imaging of the right forearm revealed a grossly shortened radius, deformed radius and ulna and radio ulnar dislocation, as shown in Figure 1. C.T. scan revealed non-visualization of the proximal 1/3rd of the right radius, with the shaft of the ulna appearing curved and poorly supporting the wrist joint. Muscles of the right forearm appeared atrophied, as shown in Figure 2. On blood examination, TSH was raised, haemoglobin levels were low (11.1 mg/dl) with a peripheral smear showing normocytic hypochromic R.B.C.s with mild anisopoikilocytosis, few microcytes and pencil cells. Figure 1 X-ray antero-posterior view (A) and computed tomography 3D reconstruction (B) of right forearm showing grossly shortened radius, deformed radius and ulna with radio ulnar dislocation Figure 2 computed tomography coronal (A) and sagittal (B) view of right forearm showing non-visualization of the proximal 1/3rd of the radius with the shaft of ulna appearing curved and poorly supporting the wrist joint; muscles of the forearm show disuse atrophy Diagnosis: based on clinical and radiological examination, a diagnosis of radial ray defect type-2 was made. Deformity correction via operative procedure was advised after one week. Therapeutic intervention: after 1-week, a surgical fitness procedure of the patient was performed, and the following day surgical intervention was done in which deformity of the right radius and ulna was corrected by osteotomy. Alignment of the proximal ulna with distal radius with K-wire and bone grafting was performed under general anaesthesia and a brachial plexus nerve block, as shown in Figure 3. Patient was discharged after 2 weeks with post-operative cast for 6 months. Figure 3 post-operative (osteotomy of radius and ulna) X-ray antero-posterior (A) and lateral (B) view of right forearm showing reduction of the deformity using a fibular bone graft and k-wire stabilization Follow-up and outcome: postoperative X-ray revealed two K wires with bone graft in situ in the right forearm. On discharge, the patient was advised physiotherapy, limb elevation and hand exercises. On routine follow-up after 6 months, the patient is able to perform her day-to-day activities with minimal difficulties. Patients perspective: translated from the patients mothers own language. There was some noticeable defect in the right forearm of my child since birth. Later my child suffered a right forearm infection associated with discharge at the age of 6 weeks, for which surgery was done (documents not available). Post-surgery doctor advised a below elbow brace and asked to come back at 18 years of age to correct the deformity. At present, at the age of 16 years, she was having tingling sensation, pain and decreased movements in the right forearm. So, we came for further treatment. The doctor advised an X-ray and said that there was a defect in the right forearm bone and advised an operation. After successful surgery, I am happy to see my child do her day-to-day activities with minimal difficulties. Informed consent: informed and written consent was obtained from the patient. Discussion Focal musculoskeletal anomalies can be isolated or can be in association with clinical syndromes or can be affected by Central Nervous System (CNS) anomalies, genetic disorders, skeletal anomalies, and/or karyotype abnormalities . Radial dysplasia is significant when the structures on the radial side of the forearm (radius, carpals of radial side and the thumb) fail to develop normally . Radial ray syndrome is associated with hypoplasia or aplasia of the radius with/without deficient thumb and carpal bones. The distal end of the limb bud in the embryo has an Apical Ectodermal Ridge (AER) which covers proliferating mesenchyme known as the progress zone. The posterior border of this progress zone is known as the Zone of Polarising Activity (ZPA). Fibroblast Growth Factor type 4 (FGF 4) regulates the AER, which in turn controls limb growth in a proximal to distal fashion. However, the Sonic hedgehog (Shh) gene regulates the ZPA, which is responsible for limb patterning along the anterior to posterior axis . The underlying cause of RRD is still unknown. However, signals from the zone of polarising activity in the vertebrate limb bud are known to control the pattern of cellular differentiation in a radioulnar direction . Bayne and Klug classified Radial Ray Disease, which includes four types based on progressive radiographic severity of the deficiency of the radius. It adequately defines type 1 (deficient distal radial epiphysis), type 2 (deficient distal and proximal radial epiphyses), type 3 (partial radius dysplasia), and type 4 (complete absence of the radius) . Limbs develop by the end of 12 weeks. Hence should be visualised in the antenatal ultrasound scan scheduled for nuchal translucency (NT) scan at 11-13 weeks to detect any abnormality in the musculoskeletal system. This helps detect any association with the following syndromes, which may require prenatal genetic counselling such as: 1) Holt-Oram syndrome is associated with cardiac defects and congenital defects of the thumb; 2) Thrombocytopenia Absent Radius (TAR), which is autosomal recessive, comprises thrombocytopenia and absent radius; 3) Vertebral, Anal, Cardiac, Tracheoesophageal, Esophageal, Renal et Limb (VACTERL) association consists of vertebral, anal, and cardiac anomalies, trachea-oesophagal fistula, and radial and limb defects; 4) Chromosomal anomalies like trisomy 13 and trisomy 18; 5) Fanconi anaemia may be associated with hydrocephaly, abnormally shaped ears, kidney problems, and abnormal thumb and forearm. Fetal blood sampling is always advised to rule out the possibility of TAR syndrome or Fanconis anaemia . Management is surgical, but in infants, the management is conservative with the limited role of splint; hence initially, wrist and elbow range of movements with improving the radial and flexion deformities by stretching exercises is considered. To stretch the stiff structures, serial casts are used on the radial side to achieve longitudinal alignment, but the carpal malalignment cannot be corrected. The operative procedures include radialisation, in which the head of the ulna is brought under the radial carpal bones, and the hand is fixed in ulnar deviation with K wire. Another operative procedure is centralisation which attempts to re-align the 3rd metacarpal at the right angles to the plane of the distal ulnar epiphyseal plate is done. Conclusion Radial ray is a rare disorder associated with radial displacement of the phalanges and/or the carpal and metacarpal bones due to improper support to these bones with underdeveloped muscles on the radial side. It may present as an isolated defect or may be associated with other syndromes; hence, prenatal detection of this anomaly is of paramount importance. Counselling should be given to the parents about the postnatal complications and prognosis of the disorder. Postnatal X-ray is considered the best diagnostic technique. Correcting this deformity is best done by surgical approach, keeping centralization as its primary intention. Competing interests The authors declare no competing interests. Authors' contributions Patient management: Anshul Sood and Gopidi Nidhi Reddy. Data collection: Vadlamudi Nagendra and Rajasbala Pradeep Dhande. Manuscript drafting: Anshul Sood and Gaurav Mishra. Manuscript revision: Anshul Sood, Vadlamudi Nagendra, Rajasbala Pradeep Dhande, Gaurav Mishra and Gopidi Nidhi Reddy. All authors read and approved the final version of the manuscript. Cite this article: Anshul Sood et al. Clinico-radiological evaluation and management of type II radial ray defect in a young female from rural India: case report. Pan African Medical Journal. 2022;43(189). 10.11604/pamj.2022.43.189.36312 1 James MA McCarroll Jr HR Manske PR The spectrum of radial longitudinal deficiency: a modified classification J Hand Surg Am 1999 Nov 24 6 1145 55 10584934 2 Society for Maternal-Fetal Medicine (SMFM)Gandhi M Rac MW McKinney J Radial ray malformation Am J Obstet Gynecol 2019 Dec 221 6 B16 B18 3 Yang PY Yeh GP Hsieh CT Prenatal diagnosis of radial ray defects by ultrasound: a report of 6 cases Taiwanese Journal of Obstetrics and Gynecology 2018 Aug 1 57 4 598 600 30122586 4 Ryu JK Cho JY Choi JS Prenatal sonographic diagnosis of focal musculoskeletal anomalies Korean Journal of Radiology 2003 Dec 1 4 4 243 51 14726642 5 Pizette S Niswander L BMPs negatively regulate structure and function of the limb apical ectodermal ridge Development 1999 Mar 1 126 5 883 94 9927590 6 Tickle C Experimental embryology as applied to the upper limb J Hand Surg 1987 12B 294 300 7 Niswander L Jeffrey S Martin GR Tickle C A positive feedback loop coordinates growth and patterning in the vertebrate limb Nature 1994 Oct 13 371 6498 609 12 7935794 8 James MA McCarroll Jr HR Manske PR The spectrum of radial longitudinal deficiency: a modified classification The Journal of hand surgery 1999 Nov 1 24 6 1145 55 10584934 9 Kennelly MM Moran P A clinical algorithm of prenatal diagnosis of Radial Ray Defects with two and three dimensional ultrasound Prenatal Diagnosis 2007 Aug 27 8 730 7 17533626 |
Pan Afr Med J Pan Afr Med J PAMJ The Pan African Medical Journal 1937-8688 The African Field Epidemiology Network PAMJ-43-188 10.11604/pamj.2022.43.188.32982 Case Report Successful delivery in a woman with ventricular septal defect complicated with Eisenmenger syndrome: case report Souabni Sara Ait 1& Belhaddad El Habib 1 1 Cadi Ayyad University, Faculty of Medicine and Pharmacy of Marrakesh, Marrakesh, Morrocco & Corresponding author: Sara Ait Souabni, Cadi Ayyad University, Faculty of Medicine and Pharmacy of Marrakesh, Marrakesh, Morrocco. [email protected] 09 12 2022 2022 43 18826 12 2021 04 3 2022 Copyright: Sara Ait Souabni et al. 2022 The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Eisenmenger syndrome is a dramatic complication of certain heart diseases. It is an absolute contra-indication to pregnancy because it holds a high risk of maternal-fetal mortality. Nowadays, we dont see much of this condition, because congenital heart defects are diagnosed during childhood, infancy, or prenatally; and even if a pregnancy occurs, it is usually terminated as soon as it is diagnosed. Nevertheless, some women are willing to carry the risks that come with their condition. We report the case of a 26-year-old woman with an undiagnosed interventricular septal wall defect that evolved into Eisenmenger syndrome during her pregnancy. A successful elective C-section was done under epidural anesthesia and close monitoring. When facing this challenging situation, there are no clear guidelines, however, premature and elective delivery is paramount. Eisenmenger syndrome ventricular septal defect congenital heart disease high-risk pregnancy case report pmcIntroduction Maternal mortality due to cardiac disease is one of the leading causes of maternal death in developed countries . Congenital heart diseases are usually diagnosed since infancy, and women who have it can, with adequate management, have a successful pregnancy. However, some conditions still carry an important mortality risk and until now, remain contra-indications to pregnancy. Among these conditions, untreated left-right communications are one of the most dangerous ones, and pregnancy is usually terminated as soon as it is diagnosed . Therefore, the reported cases that discuss pregnancies that are carried out until the third trimester are very limited, and there is no standardized approach when facing this unique situation . In this article, we report the case of an otherwise healthy young primigravida that was carrying an undiagnosed ventricular septal wall defect, complicated by Eisenmenger syndrome. She presented with a rapidly progressing shortness of breath and cyanosis at 33 weeks + 2 days of gestational age. We describe our management and discuss the different therapeutic options. Patient and observation Patient information: we report the case of a 26-year-old primigravida, with no past medical history. She presented with stage III dyspnea that was developing for approximately 1 month and was progressively worsening. She was pregnant at 33 weeks + 2 days according to the first-trimester ultrasound. Clinical findings: on clinical examination, she was cyanotic, tachycardic (100 bpm) with a slightly elevated respiratory rate (22 cycles/min) and normal blood pressure (110/75mmHg). Saturation was at 82% in open-air and there was no visible retraction of the respiratory muscles. There was a loud P2 on cardiac auscultation, but no signs of right or left heart failure. The pulmonary examination was unremarkable. Diagnostic assessment: an ECG was performed and showed sinus tachycardia with electrical left ventricular hypertrophy and auricular hypertrophy. The cardiac ultrasound showed a large sub-aortic interventricular communication measuring 16mm with bidirectional shunt predominantly right-to-left shunt, dilated right cavities and hypertrophied left ventricle and left auricle with preserved function, severe pulmonary hypertension with aneurysmal pulmonary artery measuring 55mm and PAPS = 122mmHg . On the obstetrical side, the woman was at 33 weeks and 2 days of gestational age. She was not in labor. The ultrasound revealed a progressive mono-fetal pregnancy with breech presentation, with normal amniotic fluid quantity, fundal placenta, and estimated weight at 1931g 282g. Figure 1 transthoracic echocardiography showing ventricular wall defect with dilatation of the four cardiac cavities Figure 2 massive dilatation of the main pulmonary artery measuring 55mm Therapeutic interventions: we hospitalized her in the maternal intensive care unit and started her on diuretics, anticoagulation, and oxygen. Betamethasone for fetal pulmonary maturity was also administered. We performed an elective C-section under epidural anesthesia the next day. We did not perform a tubal ligation due to the couples refusal. Follow-up and outcome of interventions: the procedure went without incident, and there was minimal blood loss. No perioperative or postoperative complications were noted. The newborn was a male, 1kg900g weighing baby, with an APGAR score at 8/10 in 0 min and 10/10th at 5 minutes. He was hospitalized in a neonatal intensive care unit for further care. Informed consent: the patient reported her full consent to publish her case. Discussion Eisenmenger syndrome (ES) is a dramatic complication of untreated left-right communication, that was first described by Viktor Eisenmenger in 1897 . The increased pulmonary flow results in the progressive alteration of the pulmonary arterioles, which leads to the increased pulmonary resistance, that eventually becomes greater than systemic resistance, resulting in a reversal of the shunt with cyanosis. The fall in systemic vascular resistance (SVR) during pregnancy increases right to left shunting, originating in cardiac decompensation and low output . When it is diagnosed, patients should be sensitized to the dangers that pregnancy carries, and advised about the use of effective contraceptive methods . If pregnancy occurs anyway, pregnancy termination is recommended. It can be done by dilatation and evacuation, or by medication; ideally before 10 weeks gestation . If the patient chooses to preserve the fetus, she should be closely evaluated, with frequent monitoring in a tertiary care center . Early admission may be required . The medical management consists of digitalis, diuretics, vasodilators, anticoagulants, and oxygen . Oxygen should be given during delivery because it decreases right-to-left shunt by decreasing blood flow which accordingly increases O2 saturation. Diuretics are most beneficial when there is severe right heart failure. However, caution should be taken when it is associated with digitalis, so as not to have any toxicity . Although endothelin-receptor antagonists and phosphodiesterase 5 are medications that have proven to be effective in pulmonary hypertension, they are also teratogenic. Therefore, they are not used during pregnancy, but they can be utilized in the post-partum period . The administration of inhaled Nitric oxide during labor has proven to attenuate pulmonary arterial pressure, so it is now recommended . Regarding anticoagulation in ES patients, it should be used with caution, because of the existence of thrombocytopenia and hemoptysis risks, that add themselves to the risk of postpartum hemorrhage . That is why in every case, pros and cons should carefully be assessed . But generally speaking, low-dose heparin during bed-rest is reasonable . In all cases, early delivery is necessary because the hemodynamic condition of the mother can quickly deteriorate . Delivery before 32 weeks gestation seems to be beneficial , and the use of betamethasone for fetal pulmonary maturity can be done safely . However, the mode of delivery is not consensual yet. The options that present themselves are elective cesarian section or planned vaginal delivery. The European cardiac society recommends performing an elective C-section for patients with pulmonary hypertension, but they did not provide clear guidelines for Eisenmenger syndrome per se . Many authors are in favor of this option because it prevents emergency C-section that holds, in itself an increased risk of complications that are mainly due to less careful preparation . Also, the auto-transfusion phenomenon that occurs during each uterine contraction is an additional risk to consider . On the other hand, some argue that vaginal delivery is best because it is better tolerated in cardiac conditions, and there is a lower risk of general complications, especially those related to blood loss and thrombotic problems . When planned vaginal delivery is chosen, there should be short labor, with adequate anesthesia and avoidance of arduous expulsive efforts . This could be a possible indication for vacuum or forceps-assisted delivery . The best anesthetic option for ES during labor or delivery is epidural because it provides the best hemodynamic stability compared to other alternatives . Finally, some recent articles introduced the utility of preparing an ECMO during delivery, and having it available as a standby option in case of complications, because it could be, in some cases, a life-saving procedure . Strengths and limitations of our case report: our case gives a good description of the symptoms, the clinical findings, and the management of Eisenmenger syndrome during the third trimester of pregnancy, which adds to the scarcity of data about the subject. However, studies with a bigger sample are vital to be able to draw better conclusions. Conclusion There is limited information regarding the management of Eisenmenger syndrome during the third trimester of pregnancy. The management in a third-level hospital with a multidisciplinary team is always necessary. Elective and premature delivery, whether it is by vaginal delivery or cesarian section seems to improve maternal-fetal outcomes. Vasodilators that are used in pulmonary hypertension are teratogenic, and can only be used after delivery. The anesthesia during labor and delivery is best and more safely obtained via epidural. The availability of an ECMO nearby can sometimes be life-saving. Competing interests The authors declare no competing interests. Authors' contributions Collection of data, revision of the article: Sara Ait Souabni. Analysis, and interpretation of data: El Habib Belhaddad. Writing of the article: Sara Ait Souabni, El Habib Belhaddad. All the authors read and approved the final version of the manuscript. Cite this article: Sara Ait Souabni et al. Successful delivery in a woman with ventricular septal defect complicated with Eisenmenger syndrome: case report. Pan African Medical Journal. 2022;43(188). 10.11604/pamj.2022.43.188.32982 1 Bedard E Dimopoulos K Gatzoulis MA Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? European Heart Journal 2008 30 3 256 265 2 Cartago RS Alan PA Benedicto J Pregnancy outcomes in patients with severe pulmonary hypertension and Eisenmenger syndrome treated with sildenafil monotherapy Obstet Med 2014 7 1 40 42 27512419 3 Duan R Xu X Wang X Yu H You Y Liu X et al Pregnancy outcome in women with Eisenmengers syndrome: a case series from west China BMC Pregnancy Childbirth 2016 16 1 356 27852228 4 Mukhopadhyav P Bhattacharya P Begum N Successful pregnancy Outcome with Eisenmenger Syndrome J Obstet Gynecol India 2012 62 1 68 69 5 Trojnarska O Plaskota K Therapeutic methods used in patients with Eisenmenger syndrome Cardiol J 2009 16 6 500 506 19950085 6 Brossat H Fritz G Radojevic J Langer B Modalits du succs de la prise en charge thrapeutique dun syndrome dEisenmenger pendant la grossesse Gyncologie Obsttrique & Fertilit 2016 44 4 255 256 7 Griffiths MJD Evans TW Inhaled nitric oxide therapy in adults N Engl J Med 2005 353 25 2683 2695 16371634 8 European Society of Gynecology (ESG) Association for European Paediatric Cardiology (AEPC) German Society for Gender Medicine (DGesGM)Regitz-Zagrosek V Blomstrom Lundqvist C Borghi C et al ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC) Eur Heart J 2011 32 24 3147 3197 21873418 9 Rosenzweig EB Abrams D Biscotti M Kerstein D Drassinower D Brodie D et al Eisenmenger syndrome and pregnancy: Novel ECMO Configuration as a bridge to delivery and recovery utilizing a multidisciplinary team ASAIO Journal 2018 64 1 e8 e10 28195885 |
Pan Afr Med J Pan Afr Med J PAMJ The Pan African Medical Journal 1937-8688 The African Field Epidemiology Network PAMJ-43-181 10.11604/pamj.2022.43.181.36322 Case Report Positive myositis-specific autoantibodies during COVID-19: a case report Abdelkrim Asma Ben 1 Ghozzi Mariam 234& Saad Ghada 1 Melayah Sarra 245 Ach Taieb 1 Ghedira Ibtissem 2 Ach Koussay 1 1 Department of Endocrinology and Diabetology, University Hospital of Farhat Hached, Ibn Jazzar Avenue, 4031 Sousse, Tunisia, 2 Department of Immunology, Farhat Hached Hospital University, Ibn Jazzar Avenue, 4031 Sousse, Tunisia, 3 Research Laboratory for "Epidemiology and Immunogenetics of Viral Infections" (LR14SP02), Sahloul University Hospital, University of Sousse, Sousse, Tunisia, 4 Faculty of Pharmacy, Department of Immunology, University of Monastir, Monastir, Tunisia, 5 LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia & Corresponding author: Mariam Ghozzi, Department of Immunology, Farhat Hached Hospital University, Ibn Jazzar Avenue, 4031 Sousse, Tunisia. [email protected] 07 12 2022 2022 43 18113 7 2022 19 7 2022 Copyright: Asma Ben Abdelkrim et al. 2022 The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Viral infection is known to be a trigger of autoimmune diseases. Numerous cases of coronavirus disease 2019 (COVID-19) with autoimmune manifestations have been reported and several authors have highlighted the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and autoimmune diseases. Autoimmune myopathies being one of these manifestations. A 27-year-old diabetic woman was admitted for management of acido-ketosis decompensation of her diabetes secondary to SARS-CoV-2 infection. During hospitalization, she developed muscle weakness and increased creatine kinase levels, which led us to assay the autoimmunity pattern which became positive for myositis-specific autoantibodies against single recognition particle (anti-SRP). The patient was treated with intense hydration with clinical and biological improvement and anti-SRP disappeared two months later. Positive myositis auto-antibodies are one of the autoimmune complications that could be seen during and after the SARS-CoV-2 infection. COVID-19 myositis autoimmunity diabetes mellitus case report pmcIntroduction Coronavirus disease 2019 (COVID-19) is the first large-scale pandemic of the 21st century. It is caused by a pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 first appeared in Wuhan, China in the fall of 2019, hence the name of COVID-19. The clinical presentation ranges from no symptoms to severe forms of life-threatening respiratory distress. The most reported symptoms are fever, fatigue and otorhinolaryngological manifestations including anosmia, ageusia, cough and nasal congestion. Gastrointestinal, ocular, cardiac and neurological manifestations have also been reported . Viral infection is known to be trigger of autoimmune diseases. Numerous cases of the COVID-19 with autoimmune manifestations have been reported, and several authors highlighted the relationship between SARS-CoV-2 and autoimmune diseases . Autoimmune myopathies being one of these manifestations. Several viruses have been implicated as possible triggers of myositis. With regard to the current COVID-19 pandemic, 10% of those who are infected with SARS-CoV-2 present with myopathic complaints of myalgia, weakness, and elevated creatine kinase (CK), sometimes to very high levels, reminiscent of necrotizing autoimmune myositis . Here, we report a case of positive myositis auto-antibodies related to COVID-19 in a 27-year-old diabetic woman admitted for management of an acido-ketosis decompensation of her diabetes. Patient and observation Patient information: a 27-year-old woman was admitted to the emergency room with abdominal pain and vomiting for three days. Cough, dyspnea and other respiratory symptoms were not observed. She was obese with type 2 diabetes mellitus (T2D) since 2012 on oral anti-diabetics. Clinical findings: on admission, the patient was febrile at 40degC. She had a tachycardia at 100 beats per minute and a normal blood pressure at 11/7. She was eupneic at 18 cycles/minute with a peripheral oxygen saturation of 98%. The neurological and muscular examination was without abnormalities. Her weight was 77 kg with a height of 1.57 m (body mass index = 31.2 kg/m2). On day 4 of hospitalization the patient was apyretic, however, she presented muscle weakness and myalgia in the lower limbs that were disabling. The clinical examination showed a sensitivity of the lower limbs, with a decrease in muscle strength. Neurological and skin examinations were without abnormalities. Diagnostic assessment: finger glucose was elevated to 4.2 g/l and urinalysis revealed acetoneuria. An arterial gasometry was performed revealing an uncompensated metabolic acidosis: pH 6.97, HCO3-: 4 mmol/L, PaCO2: 16 mmHg, PaO2: mmHg, with a functional renal failure in biology (creatinine: 203 mmol/L urea: 22 mmol/L). C reactive protein (CRP) was slightly increased at 12 mg/L and CK normal at 102 IU/L. The patient performed COVID-19 swab, by Real Time Reverse Transcription-Polymerase Chain Reaction (rRT-PCR), which was positive. On day 4, urgent laboratory examinations indicated an increase in CK to 3730 UI/L (normal range 38-234 UI/L) and elevation of CRP to 102 mg/L (normal range <= 10 mg/L), lactate deshydroganase (LDH) was 441 UI/L (normal range 135-250 UI/L), aspartate aminotransferase (AST) was 103 UI/L (normal range 5-40 UI/L), alanine aminotransferase (ALT) was 99 UI/L (normal range 5-40 UI/L). Complete blood count was without abnormalities. The immunological workup showed positive myositis-specific autoantibodies against single recognition particle (anti-SRP). Autoantibodies were determined using a multiplexed Euroline profile autoimmune myositis kit (EUROIMMUN(r), Lubeck, Germany). Therapeutic intervention: the patient was put under antibiotic therapy, anticoagulation and intravenous insulin therapy and hydration, the acid-ketotic decompensation disappeared in 3 days with the following results: pH 7.43, HCOPaO3-: 19.7 mmol/L, PaCO2: 27 mmHg, PaO2: mmHg, creatinine: 55 mmol/l, urea: 22 mmol/l. In addition to the previous treatments, the patient was immediately treated with hydration with gradual improvement in myalgia and muscle weakness. On day 7 of hospitalization, she was again able to move her lower limbs freely and the CK level dropped to 1155 UI/L. Follow-up and outcomes: respiratory status was still stable, with a peripheral oxygen saturation of 98%. The patient s symptoms improved daily, and biochemistry indicators gradually returned to normal levels (Table 1). Throughout her hospital admission, she didn t present respiratory symptoms. The patient was discharged at day 13 of hospitalization on insulin therapy for her diabetes. Anti-SRP antibodies performed two months after her discharge were negative. Table 1 clinical and biological characteristics in the follow-up Day1 Day2 Day3 Day4* Day5 Day6 Day7 Day8 Day9 Day10 Day11 Day12 CK (38-234 UI/L) 102 ND ND 3738 3200 2500 1155 558 451 334 234 211 LDH1 (35-250 UI/L) ND ND ND 441 400 377 339 277 305 256 211 193 AST (5-40 UI/L) ND ND ND 103 90 82 63 ND 38 32 24 22 ALT (5-40 UI/L) ND ND ND 93 96 96 109 ND 82 61 50 40 CREAT (60 -120 mmol/l) 203 85 55 52 ND ND 34 39 43 ND ND ND CRP (<= 10 mg/L) 36 ND ND 102 ND ND 12 ND 5 ND ND ND pH (7.38-7.42) 6.97 7.26 7.40 7.43 7.42 ND ND ND ND ND ND ND * Rhabdomyolysis symptoms appeared on day 4 CK: creatine kinase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; CREAT: creatinine; CRP: C reactive protein; ND: not done Informant consent: written informed consent was obtained from the patient to publish anonymised information in this article. Diagnosis: a ketoacidosis decompensation of type 2 diabetes secondary to SARS-CoV-2 infection complicated with autoimmune manifestations was confirmed. Discussion We here report a case of a young woman admitted for ketoacidosis decompensation of her diabetes secondary to SARS-CoV-2 infection and who suffered during her infection from muscle pain and weakness. Anti-SRP antibodies were detected. SRP antibodies were found to be associated with high CK levels and can be detected in a subset of 4-6% of patients with myositis and almost 60% of patients with necrotic myositis . Recent studies revealed the presence of auto-antibodies in patients with infection by SARS-CoV-2 and demonstrated that auto-antibodies are correlated with the severity of COVID-19 . Our patient suffers from type 2 diabetes and obesity, which are well recognized determinants of increased severity related to acute COVID-19 . In fact, the elevated glucose levels in human monocyte supports SARS-CoV-2 replication and proliferation . During her infection, our patient suffers from myalgia. Despite that myalgia was described during COVID-19 in up to 50% of patients depending on the studies, myositis was only described in case reports . In some cases, no myositis-specific auto-antibodies has been detected . In our case, the patient had anti-SRP antibodies. Anti-SRP antibodies are associated with a low muscle strength score, a high CK levels and a severe degree of necrosis. Organ damage in COVID-19 was partly attributed to type I interferon, which is well known to play a major role in myofiber damage in myositis . Several mechanisms could explain autoimmune manifestations during SARS-CoV-2 infection. In fact, humoral and cellular auto reactivity during or succeeding a viral infection is due to molecular mimicry between viral antigens and auto-antigens. SARS-CoV-2 had at least one cross-reacting epitope with human proteins . Furthermore, in their study, Megremis S et al. identified three immunogenic linear epitopes with a high sequence identity to SARS-CoV-2 proteins in autoimmune dermatomyositis. These cross-reacting epitopes lead to the loss of tolerance to self peptides. Bystander activation and damage is another mechanism which could explain autoimmunity in viral infection. In fact, it starts with the migration of cytotoxic CD8 T cells to the infection site and the release of perforin and granzyme. CD4 T cells intervene by exerting proinflammatory cytokines, enhancing phagocytic activities. The ineffective clearance of killed cells exposes auto antigens, resulting in auto-immunity . Conclusion After almost three years of the emergence of this new coronavirus, several complications during and after the SARS-CoV-2 infection have been reported among which, the autoimmune complications take an important place. In our clinical case, we have reported one of these complications: positive myositis auto-antibodies related to COVID-19 which disappeared spontaneously after the acute phase of the infection. Competing interests The authors declare no competing interests. Authors' contributions Diagnosis and clinical management of the patient: Asma Ben Abdelkrim, Ghada Saad, Taieb Ach, Koussay Ach. Biological management of the patient: Mariam Ghozzi, Sarra Melayah. Writing the original draft: Asma Ben Abdelkrim, Mariam Ghozzi. Reviewing the report: Ibtissem Ghedira. All authors have read and agreed to the final manuscript. Cite this article: Asma Ben Abdelkrim et al. Positive myositis-specific autoantibodies during COVID-19: a case report. 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BMC Neurol BMC Neurol BMC Neurology 1471-2377 BioMed Central London 3125 10.1186/s12883-023-03125-6 Case Report Susceptibility weighted imaging can be a sensitive sequence to detect brain damage in neonates with kernicterus: a case report Lequin Maarten [email protected] 1 Groenendaal Floris [email protected] 1 Dudink Jeroen [email protected] 1 Govaert Paul [email protected] 2 1 grid.7692.a 0000000090126352 UMC Utrecht: Universitair Medisch Centrum, Utrecht, Netherlands 2 grid.417406.0 0000 0004 0594 3542 ZNA Middelheim, Antwerp, Belgium 11 3 2023 11 3 2023 2023 23 10420 6 2022 15 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Kernicterus in the acute phase is difficult to diagnose. It depends on a high signal on T1 at the globus pallidum and subthalamic nucleus level. Unfortunately, these areas also show a relatively high signal on T1 in neonates as an expression of early myelination. Therefore, a less myelin-dependent sequence, like SWI, may be more sensitive to detecting damage in the globus pallidum area. Case presentation A term baby developed jaundice on day three following an uncomplicated pregnancy and delivery. Total bilirubin peaked at 542 mmol/L on day four. Phototherapy was started, and an exchange transfusion was performed. ABR showed absent responses on day 10. MRI on day eight demonstrated abnormal high signal globus pallidus on T1w, isointense on T2w, without diffusion restriction, and high signal on SWI at globus pallidal and subthalamus level and phase image at globus pallidal level. These findings were consistent with the challenging diagnosis of kernicterus. On follow-up, the infant presented with sensorineural hearing loss and had a work-up for cochlear implant surgery. At 3 months of age, the follow-up MR shows normalization of the T1 and SWI signals and a high signal on T2. Conclusions SWI seems more sensitive to injury than the T1w and lacks the disadvantage of the T1w sequence, where early myelin confers a high signal. Keywords Susceptibility weighted imaging SWI Kernicterus Neonatal MRI issue-copyright-statement(c) The Author(s) 2023 pmcBackground Kernicterus, a clinicopathological term that describes the acute neonatal encephalopathy associated with brain toxicity due to unbound unconjugated bilirubin, stands out among other neonatal brain disorders by a characteristic multiregional damage pattern [1-4]: globus pallidus, nucleus subthalamicus, geniculate nuclei, dentate nuclei, inferior olive, nucleus gracilis and cuneatus, hippocampus, corpora mammillaria, nucleus ruber, substantia nigra, cranial nerve nuclei, colliculi, vermis cerebelli. A pallido-subthalamic pattern of injury is distinct from the thalamo-striate pattern that is typical of acute total asphyxia . The main effects of bilirubin on neurons are decreased oxygen consumption and increased release of calcium and caspase 3, resulting in apoptosis . A similar pattern is observed in oligodendrocytes, with increased apoptosis, oxidative stress, and reduced myelin synthesis. Microglia react to injury associated with bilirubin by releasing proinflammatory cytokines and metalloproteinase activity as cells manifest the phagocytic phenotype. Once the intracellular concentration of bilirubin exceeds a toxic threshold, a metabolic cascade leads to neurotoxicity. This means that the signature of kernicterus in the brain in the acute stage is region specific and characteristic of apoptosis. The neuronal swelling that alters diffusion characteristics in MR sequences in the acute phase after asphyxia is typically absent in kernicterus. However, more subtle alterations have been reported in the dentate to thalamus connections . Globus pallidus and nucleus subthalamicus are hyperintense on T1 weighted MRI in the acute stage, but this is only a gradient of the increased signal compared to normal and, therefore, not distinctive enough to be sure about the extent of neuronal death; after several weeks, only a fine fibrillary astrogliotic scar permanently marks globus pallidus on T2 weighted MRI . Many but not all infants with an acute encephalopathic presentation (day 1-2: stupor, hypotonia, poor feeding, apnea, convulsions; day 3-7: extensor hypertonia, fever, high pitched cry, tongue protrusion, 2w-3 m: hypotonia) go on to develop the typical outcome with dyskinetic cerebral palsy (extrapyramidal syndrome, vertical gaze palsy), dental dysplasia and hearing loss based on injury to the brainstem nuclei of the auditory system. Often, therefore, confirmation of the existence and extent of nuclear damage ("kern" icterus) is sought in acute neonatal MRI . Due to uncertain descriptions of the extent and severity of the neuronal injury, kernicterus is still a challenging disorder in neonatal imaging. Case presentation Our patient, a Caucasian male infant, was born via primary cesarean section at 41 2/7 weeks of gestation. Antenatal imaging and serology were normal, and there was no family history of neonatal jaundice. The infant was born in good condition with Apgar scores of 9 and 10 at 1 and 5 in, respectively, with a birth weight of 3705 g (p45). The patient was discharged from the local hospital in good clinical condition with no signs of jaundice on day two of life. After an uneventful day at home with the parents, where the baby was bottle-fed, the parents noticed their baby was jaundiced on day three after birth, and the midwife referred the patient to the hospital on day 4. Laboratory findings on admission to the local hospital revealed significant hyperbilirubinemia with a total bilirubin of 573 mmol/L and direct bilirubin of 38 mmol/L. (further lab: pH 7,44, PCO2 38 mmHg, pO2 95 mmHg, Act bic 25,6 mmol/L, BE 1 mmol/L, Sodium 139 mmol/L, Potassium 3,4 mmol/L, Ca-ion 1,22 mmol/L, Gluc 5,2 mmol/L, AF 152 U/L, yGT 34 U/L, ASAT 56 U/L, ALAT 14 U/L, LDH 922 U/L, Hb 6,9 mmol/L, Leucocytes 17,9 x 10^9/L, Trombocytes 346 x 10^9/L, PT 11,3 sec, Blood type A, Rhesus D pos, Direct Coombs positive.) The blood type of the mother was A and Rhesus positive. In his admission to the local hospital, he was presented with a weak general condition with a progressive opisthotonus. Triple phototherapy was started, and the patient was transferred to our NICU for an exchange transfusion. The patient had a successful exchange transfusion after arrival at our tertiary care center (posttransfusion total bilirubin of 223 mmol/L and direct bilirubin of 17 mmol/L). However, after the exchange transfusion, the patient had both clinical (apnea) and electrophysiological seizures, for which he was intubated and ventilated. The seizures were treated with phenobarbitone (2 x 10 mg/kg iv). After treatment, the (a) EEG returned to a normal background pattern, and the patient could be detubated. An ultrasound scan showed no significant abnormalities (e.g., hemorrhages). The ALGO and BERA showed no responses. Whole exome sequencing and variant analysis did not show protein-coding exons for hereditary hemolytic anemia. MR images in an 8-day-old term infant show abnormal high signal intensity at the globus pallidus level on SWI (Fig. 1). Fig. 1 MR images in an 8-day-old term infant. Upper row: Axial T2 (TR 6282 ms, TE 120 ms, slice thickness 2 mm, no gap) shows no high signal intensity at globus pallidus level (a). Axial 3D T1(TR 9,38 ms, TE 4,6 ms, slice thickness 2 mm) shows a high signal in the basal ganglia (b). SWI (spoiled T1 enhanced with TR 31 ms, TE first 7,2 ms, slice thickness 2 mm) shows a high signal at the subthalamus (c) and globus pallidus level (d). The Phase image at the level of globus pallidus level shows no abnormal signal compatible with calcifications or blood products (e) Axial DWI, b 1000 and ADC map (TR 4998 ms, TE 102 ms, slice thickness 3 mm) shows no abnormal increased signal in basal ganglia (f, g). Middle row: At three months of age, the followup MR shows normalization of the signal on T1 and SWI (i and j) and a high T2 signal at the globus pallidal level (h). Lower row: Term neonate as control scanned in the first week of life. A normal signal at the basal ganglia on Axial 3D T1(TR 9,38 ms, TE 4,6 ms, slice thickness 2 mm) (k) and SWI (spoiled T1 enhanced with TR 31 ms, TE first 7,2 ms, slice thickness 2 mm) (l) Discussion and conclusions Kernicterus is a rare and serious condition that gives rise to acute encephalopathy in the neonatal period and can cause long-lasting negative neurocognitive outcomes, including hearing loss and dyskinetic cerebral palsy . Close monitoring of bilirubin levels and timely treatment when bilirubin levels reach nationally defined treatment levels can prevent kernicterus. However, the clinical presentation of severe hyperbilirubinemia may not always be typical . It can be missed, and sometimes kernicterus can occur with bilirubin levels below those stated in the national treatment guidelines . The MRI findings in the disease's acute phase may aid in diagnosis. To date, neuroradiologists have had to rely on high-intensity signals (T1-weighted) at the level of the globus pallidum and subthalamic nuclei . However, determining kernicterus may not be straightforward due to the intrinsic T1-weighted hyperintensity signal in these areas, which is attributed to early myelination. Also, the extent of the neuronal injury could be hampered due to the inherent high signal on T1. Since our MR protocol for scanning neonates with encephalopathy includes an SWI sequence, we noticed an abnormally high signal at the globus pallidum region and less at the subthalamic region in the case of kernicterus. The signal is more conspicuous than the high signal on the T1 sequence. Moreover, these involved areas are not as high on SWI in normal neonatal controls, making it easier to recognize the damaged regions and may better delineate their extent and severity. Knowing that the main effects of bilirubin on neurons are decreased oxygen consumption and increased release of calcium and caspase 3, resulting in apoptosis , this may result in a high signal on the SWI sequence. This is important because other sequences lack discriminating power, like the commonly used sequences, DWI, and T2 sequences in the acute phase. The high signal on the magnitude image of the SWI sequence of our case is not due to a cluster of calcifications, looking at the normal signal on the phase image of the SWI sequence. Another explanation of the high signal in the globus pallidal region could be the influx of cells or edema as a response to the injury, best detected by the SWI due to its small flip angle, around 17 degrees, making the SWI images spin-density-weighted . When we had only the spin echo T2, the proton density image also showed a high signal at the globus pallidal region in kernicterus cases, suggesting increased proton density in these regions. Also, MRS seems to give contradictory results, though Groenendaal et al. reported a lactate peak at the globus pallidum area in some kernicterus cases . Our follow-up MR at 3 months of age shows normalization of the high signal on SWI and on T1, which has already been mentioned by Govaert et al. . In conclusion, we speculate that a high signal on SWI at the globus pallidum region is a promising imaging biomarker for recognizing kernicterus damage in the acute phase. Not applicable. Authors' contributions ML, JD, and PG, contributed to the writing of the manuscript. JD and FG investigate the kernicterus case's etiology, natural history, and management. All authors have read and approved the final manuscript. Funding The authors received no financial support for this article's study, authorship, and publication. Availability of data and materials The data supporting this case's findings are available at reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent for publication of this case report and any accompanying images were obtained from the patient's parents. A copy of the written consent is available for review by the Editor of this journal. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Larroche J-CL. Developmental pathology of the neonate. North Holland: Elsevier; 1977. 2. Leech RW, Alvord EC. Anoxic-ischemic encephalopathy in the human neonatal period. The significance of brain stem involvement. Arch Neurol. 19977;34:109-13. 3. Turkel SB Miller CA Guttenberg ME A clinical pathologic reappraisal of kernicterus Pediatrics 1982 69 267 272 10.1542/peds.69.3.267 7063283 4. Friede RL Developmental neuropathology 1989 Berlin Springer-Verlag 5. Hayashi M Satoh J Sakamoto K Clinical and neuropathological findings in severe athetoid cerebral palsy: a comparative study of globo-Luysian and thalamo-putaminal groups Brain and Development 1991 13 47 51 10.1016/S0387-7604(12)80297-X 2063998 6. Watchko JF Tiribelli C Bilirubin-induced neurologic damage N Engl J Med 2014 370 10 979 24597881 7. Wisnowski JL Panigrahy A Painter MJ Watchko JF Magnetic resonance imaging abnormalities in advanced acute bilirubin encephalopathy highlight -cortical pathways J Pediatr 2016 174 260 263 10.1016/j.jpeds.2016.03.065 27113379 8. Govaert P Lequin M Swarte R Robben S De Coo R WeisglasKuperus N James Barkovich changes in globus pallidus with (pre)term kernicterus case reports Pediatrics 2003 112 6 Pt 1 1256 1263 10.1542/peds.112.6.1256 14654594 9. Mohammad SS, Angiti RR, Biggin A, MoralesBriceno H, Goetti R, Perez-Duenas B, et al. Magnetic resonance imaging pattern recognition in childhood bilateral basal ganglia disorders. Brain Commun. 2020;2(2):fcaa178. 10. Hansen TWR Mechanism of bilirubin toxicity: clinical implications Clin Perinatol 2002 29 765 778 10.1016/S0095-5108(02)00053-2 12516745 11. Kemper AR Newman TB Slaughter JL Maisels MJ Watchko JF Downs SM Clinical practice guideline revision: Management of Hyperbilirubinemia in the newborn infant 35 or more weeks of gestation Pediatrics. 2022 150 3 e2022058859 10.1542/peds.2022-058859 35927462 12. Haller S Haacke EM Thurnher MM Barkhof F Susceptibility-weighted imaging: technical essentials and clinical neurologic applications Radiology. 2021 299 1 3 26 10.1148/radiol.2021203071 33620291 13. Groenendaal F van der Grond J de Vries LS Cerebral metabolism in severe neonatal hyperbilirubinemia Pediatrics 2004 114 1 291 294 10.1542/peds.114.1.291 15231949 |
BMC Cardiovasc Disord BMC Cardiovasc Disord BMC Cardiovascular Disorders 1471-2261 BioMed Central London 3133 10.1186/s12872-023-03133-x Case Report Myocardial tissue changes detected by cardiac MRI in a patient with suspected systemic sarcoidosis Vanchin Byambasuren 12 Ka Mame Madjiguene [email protected] 1 Arendt Christophe T. 1 Escher Felicitas 3 Nagel Eike 1 Puntmann Valentina O. 1 1 grid.411088.4 0000 0004 0578 8220 Institute for Experimental and Translational Cardiovascular Imaging, DZHK Centre for Cardiovascular Imaging, University Hospital Frankfurt, Frankfurt Am Main, Germany 2 grid.444534.6 0000 0000 8485 883X Department of Cardiology, School of Medicine, Mongolia-Japan Teaching Hospital, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia 3 grid.6363.0 0000 0001 2218 4662 Department of Cardiology, University Hospital Berlin Charite, Berlin, Germany 11 3 2023 11 3 2023 2023 23 13128 1 2022 19 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background The role of cardiac magnetic resonance imaging in the early management of chronic cardiac inflammatory conditions is growing. Our case enlightens the benefit of quantitative mapping in the monitoring and treatment guidance in systemic sarcoidosis. Case presentation We report about a 29-year-old man with an ongoing dyspnea and bihilar lymphadenopathy, suggesting sarcoidosis. Cardiac magnetic resonance showed high mapping values, but no scarring. In follow-ups, cardiac remodeling was noted; cardioprotective treatment normalized cardiac function and mapping markers. Definitive diagnosis was achieved in extracardiac lymphatic tissue during a relapse. Conclusion This case shows the role that mapping markers can play in the detection and treatment at early stage of systemic sarcoidosis. Keywords Systemic sarcoidosis Myocardial inflammation Cardiac remodeling Tissue mapping Scar Johann Wolfgang Goethe-Universitat, Frankfurt am Main (1022)Open Access funding enabled and organized by Projekt DEAL. issue-copyright-statement(c) The Author(s) 2023 pmcBackground Cardiac involvement is the leading cause of death in systemic sarcoidosis , due to fatal arrhythmias, conduction abnormalities or heart failure. The Heart Rhythm Society (HRS) and the Japanese Society of Sarcoidosis and other Granulomatous Disorders has both required the presence of late gadolinium enhancement (LGE) at CMR for the clinical diagnosis of cardiac sarcoidosis, among other criteria using different cardiac imaging tools (echocardiography, radionuclide scintigraphy, or cardiac catheterization). However, these techniques are mainly based on the detection of advanced structural and/or functional damages of heart muscle. Quantitative tissue characterization which is related to altered magnetization of myocardial properties is found to be more sensitive method and therefore, can allow an early recognition and treatment of cardiac sarcoidosis, before the detection of LGE. This case illustrates the role of quantitative tissue mapping in the early stages of the disease. Patient information A 29-year-old previously healthy man presented for an outpatient respiratory assessment of shortness of breath and vertigo lasting for a year. Both symptoms were limiting his professional performance, demanding physical fitness and a high degree of sensorimotor acuity. There were no chronic communicable and non-communicable diseases of note. A year prior, he had a bronchopulmonary infection with protracted symptoms but complete resolution. Clinical findings Clinical examination was normal. Timeline11 Diagnostic assessment The remarkable finding on initial investigations was bilateral hilar lymphadenopathy (BHL) at CMR, raising possibility of systemic sarcoidosis or hematological disease. Subsequent screen for neurological, dermatological and hemato-oncological involvement revealed no abnormalities. Mediastinal lymph node biopsy and bronchioalveolar lavage (BAL) were both normal. Cardiology review returned no ECG abnormalities and transthoracic echocardiography was normal. Cardiac magnetic resonance (CMR) was performed on a 3-T scanner (Magnetom Skyra; Siemens Healthineers), using Goethe CVI Approaches . Myocardial mapping was acquired in a single midventricular short-axis slice using Goethe CVI modified Look-Locker Imaging (MOLLI) sequence. Initial CMR (CMR 1) (Fig. 1) revealed normal biventricular volumes (age-gender-BSA indexed) and preserved left ventricular ejection fraction (LVEF 56%, normal values: 57-81%) . Right ventricular ejection fraction was normal too (RVEF 50%, normal values: 40-68%). Mildly increased native T1 (1106 ms) and normal T2 (36 ms) indicated diffuse myocardial fibrosis with no active myocardial inflammation (normal ranges: native T1 NPV <= 1106 ms; PPV >= 1136 ms; native T2 NPV <= 37.4 ms; PPV >= 39 ms). Late gadolinium enhancement (LGE) imaging (gadobutrol, 0.1 mmol/kg body weight Bayer AG, Leverkusen, Germany) revealed no regional myocardial pathology or scarring. Contrast-free follow-ups revealed progressive drop in LVEF and increase in left ventricular (LV) volumes (Fig. 2), native T1 and T2 values. RVEF remained within the normal range. Due to progressive dyspnea, LVEF decline and worsening of BHL (Fig. 3), together suggesting a high likelihood of systemic sarcoidosis, another round of tissue sampling was initiated, including endomyocardial biopsy (EMB), BAL and mediastinal lymph node biopsy. EMB was performed by sampling 6 tissue samples were harvested from left side of interventricular septum. Representative EMB images are provided in Fig. 4. Immunohistochemically stained sections were evaluated by light microscopy using a LEICA DMRD microscope (Leica; Bensheim, Germany). The image captured via a Sony 3-chip video camera (Sony 3CCD/color-red-green-blue/RGB video camera, Tokyo, Japan) using a Leica C-mount adapter (0.35 magnification) with a Matrox Comet 24-bit color graphics card was processed using the digital imaging analyzing (DIA) program designed on the platform of LUCIA G (V 3.52ab, Nikon, Dusseldorf, Germany). The DIA macros used consisted of three steps: (1) grabbing of image, (2) recognition of artefacts (areas not covered by cardiac tissue) for the calculation of the net myocardial area, and (3) recognition of colored cells. The images for the quantification of infiltrates were grabbed at 200x magnification.Fig. 1 Dynamics of the left ventricular volume, function and cardiac fibrosis, inflammation markers. The horizontal axis shows cardiac MRI scan timepoints, the red vertical line indicating sarcoidosis diagnosis and initiation of the treatment. A Left Ventricular End Diastolic Volume Index increased with time, and normalized after anti-remodeling, anti-inflammatory treatment. B Left ventricular ejection fraction was decreasing and sub-normalized after treatment. C Native T1 value increased drastically and sub-normalized after treatment. D. Native T2 value increased and normalized after treatment. Ppv-positive predictive value, npv-negative predictive value Fig. 2 Representative CMR long axis PSIR images. The long axis three-, views after injecting gadobutrol, revealing pericardial effusion (orange arrows) and increased LV volume without evidence of non-ischemic scar Fig. 3 Lymphadenopathy images. CMR localizer in axial plane showed enlarging lymph nodes (white arrows) in the hilar region on both sides over time, suggestive for the diagnosis of sarcoidosis. , artery, LL-Left lung, RL-right lung Fig. 4 Representative images of (immuno-)histological staining of Endomyocardial Biopsy. A Azan staining x200. The staining shows low fibrosis (blue). B HE staining x200. Staining shows regular cardiomyocytes without evidence of increased inflammatory cells or granulomas. C Immunohistological staining CD3-positive T lymphocytes (x200) without an increase of CD3-positive cells. D Immunohistological staining of CD45R0-positive t-memory cells (x200) without accumulation of CD45R0-positive cells Conventional morphology evaluation revealed no pathological changes of cardiomyocyte, including necrosis. The immunohistochemical characterization revealed no lymphocytic inflammatory infiltration (negative staining and counts for CD3, lymphocyte factor A-1, perforin, CD45R0 and MAC-1) or adhesion molecules (HDLA-DR). Azan staining revealed no relevant perimyocyte fibrosis. Moreover, no sarcoidosis-specific non-caseating granulomas were detected. Qualitative polymerase chain reaction (PCR) test for viral genomes was positive for parvovirus B19-specific DNA sequences, but absence of cDNA indicated no active viral replication. Patient complained hiccups and difficulty in swallowing for several months. Biopsy of mediastinal and hilar lymph nodes was performed using endobronchial ultrasound-guided transbronchial needle aspiration. The evidence of epithelioid and eosinophilic granulomas secured the definite cytopathological diagnosis of systemic sarcoidosis (Fig. 5).Fig. 5 Mediastinal lymph node specific cytochemical result. The images are showing different sizes of activated lymphocytes, epithelioid cells, epithelioid granulomas and eosinophilic granulomas indicating sarcoidosis. (A, B, C 400x magnification, D 600x magnification) Therapeutic intervention We initiated cardioprotective treatment with Ramipril 2.5 mg once daily to reduce inflammatory cardiac remodeling in July 2020. Short courses of prednisolone were introduced in December 2020 to control subsequent neurological manifestations (facial palsy). Follow-up and outcomes The result showed rebounding of LVEF and normalized native T1 and native T2 values in the 3 months' follow-up. Discussion and conclusions Systemic sarcoidosis is a chronic inflammatory condition characterized by histological evidence of non-caseous granulomas. Cardiac involvement with development of heart failure is the leading cause of death in systemic sarcoidosis . Cohort studies have shown that CMR using LGE can reveal non-ischemic patterns of cardiac involvement. LGE often marks an advanced stage of disease which is associated with poor prognosis . Current diagnostic criterion from the Heart Rhythm Society includes non-ischemic myocardial LGE as a diagnostic marker of cardiac involvement . CMR using quantitative mapping helps to inform on the diffuse inflammatory process outside the areas of scar, which can be also detectable in earlier stages of the disease . Informed by serial assessments, we were able to detect disease progression early ahead of scar development. The anti-remodeling effect of Ramipril is largely demonstrated . It explains why we used it in our case before having an accurate diagnosis of that cardiac inflammation with increased LV volumes and progressive drop in LVEF. But we also noticed that proactive cardioprotective treatment could potentially attenuate the myocardial inflammatory reaction with the reduction of parametric mapping values. This anti-inflammatory effect in the myocardium has been explored by some experimental animal studies in the context of post-myocardial infarction or rheumatoid arthritis . Further studies in this field should be considered to determine the role of Ramipril in reducing myocardial inflammation. The mismatch between clinical manifestations and normal results of EMB is common, as the sensitivity of EMB is very low from 19 to 32% . This low yield is probably due to sampling error: EMB is often performed in the right ventricle, whereas granulomas are mostly located in LV free wall or basal septum . In the present case, however, the EMB was left-ventricular. FDG-PET scanner is another key diagnosis and staging tool for cardiac sarcoidosis, very sensitive for early stages of inflammation . Whereas useful for initial diagnostic work-up, the accessibility, cost and radiation exposure make its use not suitable for follow-up in a young person. In cardiac sarcoidosis, regional scar formation is a late-stage consequence of myocardial injury. Quantitative CMR helps to detect diffuse fibrosis and inflammation using T1 and T2 mapping. Serial short contrast free examinations may help uncover early disease progression allowing cardioprotective treatment. Future studies are necessary to test the role of imaging markers in guiding therapy and improving cardiovascular outcomes. Learning Objectives 1. To understand the potential of quantitative tissue characterization using T1 and T2 mapping to detect early cardiac involvement of systemic sarcoidosis. 2. CMR is a vital tool to noninvasively inform on the diagnosis, progression and treatment response of cardiac sarcoidosis. Abbreviations BAL Bronchioalveolar lavage BHL Bilateral hilar lymphadenopathy CMR Cardiac magnetic resonance imaging EMB Endomyocardial biopsy FDG-PET Positron emission tomography with 18F-fluorodeoxyglucose HRS Heart Rhythm Society JSSOG Japanese Society of Sarcoidosis and other Granulomatous Disorders LGE Late gadolinium enhancement LV Left ventricular LVEF Left ventricular ejection fraction LVEDVi Left ventricular end-diastolic volume index NPV Negative predictive value PPV Positive predictive value Acknowledgements Dr Theodoros Topaladis from Cytological Institute of Hannover, Germany; Respiratory physicians of the Departments of internal Medicine, University Hospital Frankfurt. Author contributions BV, MMK, CA, FE and EN analyzed and interpreted the patient data regarding the cardiac MRI. BV, MMK, CA and VP were major contributors in writing the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. VP and EN have received speaker fees from Bayer AG and Siemens AG, as well as educational grants from Bayer AG and Neosoft limited. Availability of data and materials The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Declarations Ethics approval and consent to participate Ethics approval (T1 study 1/16) was obtained from the local ethics committee (Ethikkommission des Fachbereichs Medizin, Universitatsklinikum der Goethe-Universitat). Informed consent to participate in the study was obtained from the patient. Consent for publication Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for the Editor to review upon request. Informed consent Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. Competing interests Not applicable. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Byambasuren Vanchin, Mame Madjiguene Ka and Christophe T. Arendt have contributed equally References 1. Matsui Y Iwai K Tachibana T Clinicopathological study on fatal myocardial sarcoidosis Ann N Y Acad Sci 1976 278 1 455 469 10.1111/j.1749-6632.1976.tb47058.x 1067031 2. Birnie DH Sauer WH Bogun F HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis Heart Rhythm 2014 11 7 1304 1323 10.1016/j.hrthm.2014.03.043 3. Sakamoto N Sawahata M Yamanouchi Y Characteristics of patients with a diagnosis of sarcoidosis: a comparison of the 2006 and 2015 versions of diagnostic criteria for sarcoidosis in Japan J Rural Med 2021 16 2 77 82 10.2185/jrm.2020-022 33833832 4. 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BMC Cancer BMC Cancer BMC Cancer 1471-2407 BioMed Central London 36899363 10715 10.1186/s12885-023-10715-7 Editorial Advancing preclinical cancer models to assess clinically relevant outcomes Golebiewska Anna [email protected] 1Anna Golebiewska has expertise in preclinical modeling of brain tumors with use of patient-derived organoids, stem cell cultures and orthotopic xenografts. AG is member of the EurOPDX consortium. Fields Ryan C. 2Ryan C. Fields is a surgeon-scientist who applies novel pre-clinical cancer models to study cancer biology and immunobiology. 1 grid.451012.3 0000 0004 0621 531X NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, L-1210 Luxembourg, Luxembourg 2 grid.4367.6 0000 0001 2355 7002 The Alvin J. Siteman Comprehensive Cancer Ceter, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, USA 10 3 2023 10 3 2023 2023 23 23021 2 2023 7 3 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Cancer models are indispensable research tools for elucidating the mechanisms involved in tumor onset, progression and treatment resistance. They are key in evaluating therapeutics prior clinical trials. In this editorial, we invite contributions for a BMC Cancer's Collection of articles addressing 'Advances in pre-clinical cancer models' towards relivable outcomes at the preclinical stage. issue-copyright-statement(c) The Author(s) 2023 pmcCancers, in particular those of the aggressive nature, form very dynamic 'aberrant organs' that ultimately profit from their hosts to develop and survive. Although certain histopathological and genetic traits are common among cancers of the same (sub-)type, in essence each patient tumor is unique. The inherent inter-patient and intra-tumoral heterogeneity present at the cellular and molecular levels is a major hurdle for experimental cancer modeling. It is becoming clear that preclinical models recapitulating the dynamic tumor ecosystem, composed of tumor cells embedded in the adequate tumor microenvironment (TME), will be key for improving success rates of therapeutics in the clinic. Still, the research community will have to accept the intrinsic limitations of preclinical cancer modeling and develop a battery of protocols aiming at answering diverse questions step-by-step with models tailored best to each individual biological hypothesis. Preclinical cancer modeling came a long way since its infancy days as adherent 2D in vitro cell lines. Individual and collaborative international efforts over the years led to a large portfolio of in vitro cell lines derived from patient tumors, including thorough characterization at the genetic and pharmacological levels . Although very useful for mechanistic studies, such cell lines undergo selection and adaptation in culture, due to e.g. lack of physical and biological pressure from the TME and non-physiological media composition. Together with the ongoing genetic drift and cell line misclassifications , these parameters ultimately lead to inadequate responses to therapeutics . Numerous adaptations have emerged in recent years to improve in vitro conditions towards the 3D architecture and oxygen gradient. These include 3D growth as spheres, serum-free and physiological media, adapted oxygen levels as well as physical forces added by e.g. hanging drop cultures and bioreactor-based culture rotations . A significant step forward came with the rise of tumor organoids. Although definition of the term ''organoid'' is not clearly established, such cultures should represent a more complex organization than 3D spheres, allowing for a better preservation of the genetic and phenotypic heterogeneity. Importantly, organoids can be derived from less aggressive tumors, leading to an expanded diversity of patient-derived models . The ongoing efforts in developing cell printing and tumor-on-chip technologies , incorporating diverse cell scaffolds, extracellular matrix components and microfluidics towards physiological gradients of soluble factors and oxygen, will lead to improved phenotypes of tumor cells ex vivo. In vivo xenotransplantation of small tissue fragments in the flanks of rodents, i.e. patient-derived xenografts (PDXs), has been long considered as the most reliable option for the serial propagation of human tumors in vivo without a culture step . Similarly to tumor organoids, PDXs can be derived from more genetically diverse and less aggressive tumors . Orthotopic implantations (i.e. PDOXs) are currently more favorable in the research community due to the more suitable TME in the organ of origin. However, due to technical drawbacks, the majority of orthotopic models are nowadays based on the implantation of enzymatically dissociated cells or primary organoids cultured short-term ex vivo . If all steps of metastasis are essential, the implantation should be performed via blood or to the initial pre-metastatic organ, allowing for tumor cells to undergo a full process of cell migration from the primary site to distant organs. Importantly, most likely, these models will only be available in expert laboratories due to their high cost and advanced expertise. The ongoing challenge in the field is the robust incorporation of the adequate cellular components of the TME to current models. Any in vitro cultures, including organoids, lead to an inevitable loss of non-neoplastic cells upon passaging. Upon xenografting, TME cells are immediately replaced by the host counterparts. The obligatory use of immunodeficient animals for xenografting leads to lack of the adaptive immune system. The long-standing solutions for investigating the TME are animal models, including genetically-engineered mouse models (GEMMs), chemically induced models and allogenic transplantations of cultured tumor cells of animal origin. The application of embryonic stem cell-derived chimeras and the development of CRISPR-based gene editing technologies have recently boosted the field. Despite being widely used for testing novel immunotherapeutics at the preclinical stage, these models are currently highly criticized for the lack of resemblance to human disease. The breaking step would be the incorporation of not only gene mutations, but also genetic chromosomal copy-number alterations. Another promising option is the inclusion of missing TME components back to the preclinical models based on the patient tumor material. Numerous co-culture protocols are emerging allowing to integrate different types of non-neoplastic cells into tumor cultures or to integrate tumor cells into normal organoids . While technological advances allow for cells printing on sophisticated scaffolds and the introduction of immune cells via tubes resembling blood vessels, the ongoing challenge lies in the continuous source of relevant non-neoplastic cells and in finding a medium composition fitting all cell types in the co-culture system. In vivo, humanized mice bring an additional promise: while the PBMC-based models allow for the incorporation of mature allogenic or autologous tumor cells, humanized models based on the CD34 + hematopoietic stem cells allow a wider experimental window and the incorporation of immune cells from the early onset of the tumor growth . This includes newer humanized PDX models that are able to recapitulate the human immune system beyond T-cells, including components of the adaptive and innate immune system . These sophisticated models that rely on specific transgenic mice (e.g. MISTRG) come with limitations related to scalability, cost, and applicability across cancer types. Cancer models are key tools for assessing efficacy of novel therapeutics prior clinical trials. In the era of personalized medicine, in depth characterization of the models at the omics levels is crucial to link treatment outcomes to specific tumor profiles . Nowadays, advanced models allow for detailed molecular analyses upon treatment in time and space, an assessment that cannot be performed in patients. Still, the advancements of preclinical cancer modeling come at a price. Preclinical testing requires more advanced readouts as the model becomes more complex. Biochemical assays commonly applied in classical cell cultures are not appropriate for complex models. High-throughput readouts based on imaging combined with novel analytical algorithms will be instrumental in discriminating drug efficacy in tumor cells and associated TME components. While quoting a famous aphorism in statistics by George E. P. Box: ''All models are wrong, but some are useful", we expect that development of a plethora of preclinical models will allow us to tailor cancer modeling towards specific and clinically-relevant studies. In recognition of the important field, we are now welcoming submissions to our new Collection of articles titled 'Advances in pre-clinical cancer models'. More details can be found here: We hope that this Collection will provide a useful platform for novel protocols and discoveries advancing preclinical cancer modeling. We aim to discuss diverse modeling options in vitro, ex vivo and in vivo. Acknowledgements Not applicable. Authors' contributions AG conceived and drafted the Editorial, RCF revised the Editorial. 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34794 Pain Management Physical Medicine & Rehabilitation Orthopedics Utilization of Clinical Practice Guideline Interventions in the Conservative Management of Mechanical Neck Pain: A Retrospective Analysis Muacevic Alexander Adler John R Baumann Anthony 1 Youngquist Michelle 1 Curtis Deven 2 Chen Mingda 3 Baldwin Keith D 4 1 Rehabilitation Services, University Hospitals Cleveland Medical Center, Cleveland, USA 2 Medicine, Northeast Ohio Medical University, Rootstown, USA 3 Medicine, Case Western Reserve University, Cleveland, USA 4 Orthopedics, Children's Hospital of Philadelphia, Philadelphia, USA Anthony Baumann [email protected] 9 2 2023 2 2023 15 2 e347948 2 2023 Copyright (c) 2023, Baumann et al. 2023 Baumann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Introduction: Neck pain is a common musculoskeletal condition frequently treated by physical therapists. The American Physical Therapy Association (APTA) published a clinical practice guideline (CPG) in 2008 with a revision in 2017 to improve the diagnosis and treatment of neck pain. One subset of neck pain in the CPG is "Neck Pain with Mobility Deficits," also called mechanical neck pain. Little data exists on the adherence of physical therapists to the CPG-recommended treatments for neck pain as well as the outcomes associated with the utilization of the CPG. The purpose of this study is to examine both CPG treatment adherence and associated outcomes in patients treated for mechanical neck pain by physical therapists in the outpatient setting. Methods: Retrospective chart review of patients (n=224) who received physical therapy for neck pain between 2018 and 2022. Data ranges were chosen due to the publication of the CPG revision in 2017. Six interventions for mechanical neck pain from the CPG were examined: thoracic manipulation, cervical mobilization, transcutaneous electrical stimulation (TENS), dry needling, advice to stay active, and scapular resistance exercises. The exclusion criteria were a history of cervical spine surgery. Other data collected included age, sex, characteristics of the evaluating physical therapist, and the number of visits. Results: For CPG treatment adherence, 4.5% of patients received thoracic manipulation, 47.8% of patients received cervical mobilization, 12.5% of patients received TENS, 22.8% of patients received dry needling, 99.1% of patients received advice to stay active, and 89.3% of patients received scapular resistance exercises. There was no significant improvement in pain, range of motion (ROM), and function based on a number of CPG interventions used during the bout of physical therapy (p=0.17 to p=0.74). Patients who were evaluated by a physical therapist who was an Orthopedic Certified Specialist (OCS) were more likely to receive more interventions recommended by the CPG (p<0.01). Conclusion:CPG-recommended treatments are used with varying frequency by physical therapists when treating mechanical neck pain. Thoracic manipulation is rarely used while scapular resistance exercises are frequently used. There was no significant improvement in pain, ROM, or function based on the number of CPG-recommended treatments used during the bout of physical therapy. cervicalgia manual therapy clinical practice guidelines physical therapy neck pain The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Neck pain is a common musculoskeletal pathology treated by physical therapists around the world . Neck pain is one of the highest complaints in terms of years lived with a disability, increasing the relevancy of proper management by physical therapists . The overall prevalence of neck pain ranges from 10% to 20%, and the incidence of new neck pain ranging from 10% to 50% . In an effort to improve patient care, the American Physical Therapy Association (APTA) in 2017 recently updated the 2008 Neck Pain Clinical Practice Guideline (CPG) to help physical therapists diagnose and treat different subsets of neck pain . One subset of neck pain listed in the CPG is "Neck Pain with Mobility Deficits", otherwise called mechanical neck pain . Common signs and symptoms of mechanical neck pain as listed in the CPG include central and/or unilateral neck pain, limited cervical range of motion (ROM), neck pain that is reproduced at end ranges of ROM, and restricted cervical and thoracic segmental mobility . This diagnosis is in contrast to other subsets of neck pain in the CPG, such as "Neck Pain with Radiating Pain" and "Neck Pain with Movement Coordination Impairments" . While many different non-surgical interventions have been presented in the literature for the management of neck pain (such as manual therapy, exercise, patient education, and physical agents like ice and heat), the Neck Pain CPG strives to provide evidence-based recommendations regarding interventions for neck pain to allow clinicians to treat their patients in a more effective manner . However, little is known about the actual utilization rate or outcomes associated with using the CPG in clinic practice. One recent study found that utilization of neck and low back CPGs was about 70%; however, utilization was not associated with final pain or disability in the study cohort . A great deal of interest in the literature is focused on utilization of other clinical practice guidelines [5-8]. Much of the current data focuses on adherence to other CPGs, such as for low back pain or concussion . However, many of the studies that examine adherence to CPG recommendations are surveys or clinician interviews, which may cloud actual CPG adherence due to recall bias and unintentional positive view of one's own treatment plans . The purpose of the current study is to examine the adherence of physical therapists to recommended treatments within the CPG as well as outcomes associated with CPG utilization in patients with mechanical neck pain. Materials and methods The current study is a retrospective chart review of 224 patients from multiple outpatient clinics within a single hospital system from 2018 to 2022. The current study was approved by the University Hospitals Institutional Review Board (IRB) under IRB approval #20220542. Patient charts were gathered by the University Hospitals Clinical Research Center based on having a diagnosis of neck pain (ICD-10 code M54.2) as well as a physical therapy evaluation procedure code (97161, 97162, or 97163). Inclusion criteria include receiving physical therapy for neck pain, being older than 18 years old, attending at minimum two sessions of physical therapy (one evaluation session and at least one treatment session), and fitting best into the CPG category of "Neck Pain with Mobility Deficits" based on information in the patient chart. Exclusion criteria were a history of cervical spine surgery and fitting the CPG categories of "Neck Pain with Radiating Pain" or "Neck Pain with Movement Coordination Impairments." From a total of 1500 patient charts, 224 patients were found to meet inclusion and exclusion criteria. Data collected include age, sex, number of physical therapy visits, Orthopedic Certified Specialist (OCS) status of the evaluating physical therapist, and the presence or absence of six CPG-recommended interventions for mechanical neck pain (thoracic manipulation, cervical mobilization, TENS, dry needling, advice to stay active, and scapular resistance exercise). Advice to stay active was defined as any home exercise program (HEP) given to the patient. Each of the six CPG interventions was recorded as present if the intervention was performed at least once during the entire bout of physical therapy. Furthermore, other outcome data include pain before and after physical therapy, total cervical rotation active ROM before and after physical therapy, and Neck Disability Index (NDI) score (listed as a percentage) before and after physical therapy. Total cervical rotation ROM was created by adding up a both right and left rotation to help reduce errors in measuring rotation ROM. Because most post-therapy measurements are obtained in the final session of therapy-a session which was missing for many patients who abruptly discontinued therapy-we also performed a subgroup analysis on outcomes for pain, ROM, and disability as expressed by the NDI to help get a more complete picture. Statistical analysis was performed using SPSS software version 29.0. Frequency counts were used to determining the usage of CPG interventions among the cohort. One-way ANOVA with Tukey posthoc testing was used to compare patients receiving two or less, three, or four or more CPG interventions. The t-test was used to compare the number of CPG interventions used in comparison to the OCS status of the treating physical therapist. Results Patients (n=224) in the current study had an average age (standard deviation, SD) of 60.7 years (16.2 years) with 71.0% of patients (n=159) being female and 29.0% of patients (n=65) being male. Patients had an average (SD) number of PT visits of 7.1 visits (4.2 visits). Of the entire cohort, 76 patients (n=33.9%) had chronic neck pain, which we defined as pain lasting in duration equal to or longer than 180 days. For treatment selection, 4.5% of patients (n=10) received thoracic manipulation, 47.8% of patients (n=107) received cervical mobilization, 12.5% of patients (n=28) received TENS, 22.8% of patients (n=51) received dry needling, 99.1% of patients (n=222) received a HEP with advice to stay active, and 89.3% of patients (n=200) received scapular resistance exercises . Table 1 Frequencies (values and percentages) of CPG interventions used among the cohort. Abbreviations: TENS - transcutaneous electrical nerve stimulation, HEP - home exercise program. Received (n) Received (%) Did Not Receive (n) Did Not Receive (%) Thoracic Manipulation 10 4.5% 214 95.5% Cervical Mobilization 107 47.8% 117 52.2% TENS 28 12.5% 196 87.5% Dry Needling 51 22.8% 173 77.2% HEP 222 99.1% 2 0.9% Scapular Exercises 200 89.3% 24 10.7% Figure 1 Graph of the frequencies of the six CPG interventions examined in the current study. Abbreviations: TENS - transcutaneous electrical nerve stimulation, HEP - home exercise program For number of interventions used per patient, 3.1% of patients (n=7) received one intervention, 37.9% of patients (n=85) received two interventions, 41.5% of patients (n=93) received three interventions, 14.7% of patients (n=33) received four interventions, 2.7% of patients (n=6) received five interventions, and none of the patients received all six interventions (Table 2). Table 2 Frequency of number of CPG interventions used for the cohort during a bout of physical therapy. Frequency (n) Frequency (%) One CPG Intervention Received 7 3.1% Two CPG Interventions Received 85 37.9% Three CPG Interventions Received 93 41.5% Four CPG Interventions Received 33 14.7% Five CPG Interventions Received 6 2.7% Six CPG Interventions Received 0 0.0% For subgroup analysis, three subgroups based on outcomes were created: Pain (n=192), range of motion (n=96), and Neck Disability Index disability score (n=77). There was no significant difference in improvement in pain based on the number of CPG interventions used during the bout of PT (p=0.56). However, one-way ANOVA testing revealed a significant difference in the amount of PT visits used for pain outcomes (p<0.01). Patients who received four or more CPG interventions had significantly more visits than patients who received two or less CPG interventions during the bout of PT (p<0.01). There was no significant difference in improvement in ROM based on the number of CPG interventions used during the bout of PT (p=0.74). Furthermore, there was no significant difference in the amount of PT visits used based on the number of CPG interventions used (p=0.21). Finally, there was no significant difference in the improvement in disability per the Neck Disability Index based on the number of CPG interventions used during the bout of PT (p=0.17). However, patients who received four or more CPG interventions had significantly more PT visits with the same outcomes as compared to patients using three or two or less CPG interventions (p=0.02 and p<0.01). To further understand the different therapy utilization rates, patients were divided into groups depending on the OCS status of the treating physical therapist who did the evaluation. The OCS Group (n=16) and the Non-OCS group (n=174) had a significant difference in the amount of CPG interventions used (p<0.01), with the OCS group utilizing more CPG interventions (3.4 interventions compared to 2.7 interventions). Discussion Neck pain is a disabling condition that has received much attention in the literature in an effort to improve patient management via the creation and revision of a Neck Pain CPG by the APTA . The current study demonstrates that despite the significant effort to create recommended guidelines for the treatment of neck pain, CPG-recommended interventions are used with varying frequency. Some interventions, such as thoracic manipulation, are rarely used while other interventions, such as advice to stay active and scapular resistance exercises, are used for nearly every patient. Other studies in the literature have substantiated our findings, namely that CPGs are poorly utilized . In fact, there are multiple studies aimed at improving adherence to CPG and removing barriers to CPG utilization . One such strategy involves performing peer assessment to help improve awareness and reflection . However, even if such measures were successful and adherence were to improve, our data found that those improvements would not have actually been clinically significant in terms of improving patient outcomes. Our data showed that the number of CPG interventions used during the bout of physical therapy did not correlate with statistically significant improvement in pain, cervical ROM, and overall function. These outcomes are supported by a study in the literature that found that the use of a CPG for neck and low back pain was not associated with final pain and disability scores, but use was associated with a mild increase in physical therapy visits . Our data showed that as the number of therapy visits increased, so too did the number of CPG interventions used and that neither of those variables was associated with improvement in pain. There was also a significant association between the increased number of physical therapy visits and the increased number of CPG-recommended treatments utilized during the bout of physical therapy. Depending on the outlook, the increased visits could be a positive or a negative attribute. Increased visits could indicate greater attendance to physical therapy visits because of higher quality physical therapy care, or it could indicate greater waste if the outcomes are the same, despite the increase in visits. Interestingly, that study by Beneciuk et al. found that the overall CPG treatment adherence rate that was relatively high (71.2%), which is contrary to the current study . There are several limitations of the current study. First, the study has a relatively small sample size from a single hospital system. Therefore, the results may not be generalizable to physical therapists across different regions. Furthermore, while the study included patients from multiple outpatient clinics, it is unknown how many physical therapists or physical therapist assistants participated in the treatment of the 224 patients in the study. Therefore, it is unknown if the problem is more widespread among physical therapists or just represents consistent poor adherence among a smaller number of physical therapists. It is also possible that some physical therapists are simply not aware of the current CPG. Strengths of the current study include the retrospective nature of the study compared to the surveys, which has been the usual way of assessing CPG adherence in the literature . According to Maas et al., physical therapists have been shown to not hold realistic perceptions of their adherence to CPGs . Also, the current study attempted to be as conservative as possible when assessing CPG treatment adherence as the authors' hypothesis was that adherence to CPG-recommended treatments would be low. A treatment was counted as completed by the authors even if the treatment was only applied one time during the entire bout of physical therapy, which had an average of seven visits. Therefore, the current study does not comment on the quality and duration of the use of the CPG-recommended treatments, possibly indicating that the utilized CPG treatments may not have been used effectively. This fact would impact the overall outcomes and could explain why there was no significant difference in pain, ROM, or function based on the number of CPG used during the bout of physical therapy. If this assumption is true, the actual effective utilization of CPG-recommended treatments would be even lower than the current study proves. This may be why the literature shows that utilizing other CPGs, such as one for low back pain, leads to improved outcomes with lower costs . More research is needed to determine how the duration and overall use of the CPG impact patient outcomes. Conclusions CPG interventions are used with varying frequency in patients treated by physical therapists for neck pain with mobility deficits. Thoracic manipulation is rarely used whereas advice to stay active and scapular resistance exercises are a common part of PT treatment for mechanical neck pain. The number of CPG interventions used during the treatment session did not impact outcomes for pain, ROM, and function. Furthermore, increased CPG intervention usage was associated with increased patient visits, despite no significant improvement in outcomes. Patients treated by an evaluating PT who had their OCS were more likely to be treated with more CPG interventions. More research is needed to determine impact of CPG on outcomes as well as reasons for adherence or non-adherence to CPG interventions. Human Ethics Animal Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. University Hospitals Institutional Review Board issued approval 20220542 Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34796 Neurology Oncology Integrative/Complementary Medicine Spinal Metastasis Causing Dropped Head Syndrome in the Chiropractic Office: A Case Report Muacevic Alexander Adler John R Chu Eric Chun-Pu 1 Trager Robert J 2 Lee Wai Ting 1 Tam Damien Ming Yan 1 Kwok Ronald 1 1 New York Chiropractic and Physiotherapy Centre, New York Medical Group, Kowloon, HKG 2 Chiropractic, Connor Whole Health, University Hospitals Cleveland Medical Center, Cleveland, USA Robert J. Trager [email protected] 9 2 2023 2 2023 15 2 e347968 2 2023 Copyright (c) 2023, Chu et al. 2023 Chu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Dropped head syndrome is a rare disorder involving an inability to hold the head upright. It may be caused by a variety of neuromuscular disorders and occasionally by pathological vertebral fractures. A 79-year-old man presented to a chiropractor with a two-year history of gradual-onset chin-on-chest posture and increased thoracic kyphosis, which had failed to respond to physical therapy. The chiropractor ordered whole spine computed tomography which revealed extensive mixed lytic and sclerotic changes and multiple thoracic compression fractures suggestive of metastasis. The chiropractor promptly referred the patient to an oncologist, who performed a biopsy confirming prostate adenocarcinoma. The patient's health deteriorated, and he expired three weeks later. This case highlights that chiropractors should be aware that patients may present to their office with symptoms related to undiagnosed cancer, such as spinal deformity and dropped head syndrome. Chiropractors should order advanced imaging when patients have red flag signs or symptoms (e.g., older age, progressive symptoms despite care) and refer to an oncologist when clinical features or testing are suggestive of metastasis. prostate cancer neoplasms metastasis neck muscles kyphosis chiropractic The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Metastatic disease commonly affects the spinal column and may cause pathological vertebral fractures, leading to pain, abnormal posture, and neurological sequelae such as weakness or impaired balance . Dropped head syndrome is a rare disorder characterized by a severe kyphotic deformity of the cervicothoracic spine in both sitting and standing positions . The condition is typically seen in older adults and may be caused by a variety of conditions, including myopathy, spondylosis, spinal cord injury, and occasionally by vertebral fracture, which may be related to underlying spinal metastasis . Accordingly, providers who manage spinal complaints must be aware of dropped head syndrome, as it may be indicative of serious pathology. A systematic review including 129 patients presenting for treatment of dropped head syndrome found that the mean age of patients was 64 years (95% CI: 61-66) . The study reported that the most common causes of dropped head syndrome were isolated neck extensor myopathy (32%), Parkinson's disease (20%), myasthenia gravis (12%), and amyotrophic lateral sclerosis (7%). Some cases of dropped head syndrome were noted to result from radiotherapy (4%) , as this may be a late side-effect of the treatment for head and neck cancers . The review only listed a neoplastic cause of dropped head syndrome in 1% of cases . More recently, a limited number of case reports and series have described vertebral metastasis and/or fracture as etiology, suggesting that these are rare yet important causes of dropped head syndrome . Chiropractors are portal-of-entry healthcare providers who often evaluate patients with spinal disorders. As such, chiropractors may occasionally be faced with unusual case presentations which could be harbingers of serious underlying systemic disease . Therefore, early identification of metastasis is imperative not only to facilitate oncologic care but also to avoid any chiropractic treatment-related fractures among patients with compromised bone integrity . Despite it being important for chiropractors to identify metastasis, there is limited research on this topic . Chiropractors are trained to recognize red flags (i.e., warning signs and symptoms) that may be indicative of serious pathology such as cancer. Examples of red flags include older age, trauma, or a focal neurologic deficit with disabling or progressive symptoms . In such cases, chiropractors should order imaging and/or refer such patients for appropriate management without delay . We searched the literature on January 27, 2023, via PubMed, Google Scholar, and the Index to Chiropractic Literature, using the terms "dropped head syndrome," and "chiropractor," and recent review articles . We only identified one case report describing a patient with dropped head syndrome presenting to a chiropractor, which was caused by myopathy rather than metastasis . Given the limited research on this topic, we describe an elderly man with dropped head syndrome who presented to a chiropractor and was diagnosed with spinal metastasis. Case presentation Patient information A 79-year-old male with a past medical history of degenerative cervical spondylosis presented to a chiropractor with a two-year history of an inability to hold his head upright and stand up straight. He noted that his symptoms started gradually as fatigue of the neck and upper back. He also noted poor balance and required the use of a cane and assistance from a family member to ambulate. The patient noted having only mild neck and back pain, rated 1/10 on the numeric pain rating scale, and denied having any radiating pain, paresthesia, or numbness in the upper and lower limbs. He endorsed a 10-year history of nocturnal urinary urgency, however, his past serum prostate-specific antigen (PSA) test was reportedly within normal limits. Until two years prior he had been healthy, and he currently only took over-the-counter non-steroidal anti-inflammatory drugs for pain relief as needed. His World Health Organization Quality of Life score was 80%. Six months prior to presenting to the chiropractor, the patient visited his family physician for similar but slightly less severe symptoms. The provider referred him to a physiotherapist for muscle-strengthening exercises. However, his posture deteriorated regardless. Given the progressive worsening of symptoms, the patient sought a chiropractor for another opinion. Clinical findings Upon presentation, the patient was observed to have a chin-on-chest (i.e., dropped head) posture while seated and standing . He used a cane to maintain balance while standing. The dropped-head posture was partially improved upon lying in a supine position. Reduced muscle tone and grating sensations were evident upon nuchal palpation. The patient's active range of cervical extension was limited to 0deg, while passive cervical extension was likewise limited (20deg) and caused crepitus. Manual muscle tests of the upper limbs revealed diffuse weakness with each action graded 4 out of 5 (Medical Research Council scale). Upper and lower extremity reflex testing revealed diminished (1+) Achilles stretch reflexes bilaterally and a diminished left patellar reflex. A cranial nerve examination was normal, and no tremors, dysarthria, rigidity, hyperreflexia, or pathological reflexes (i.e., Babinski, Hoffmann) were present. Figure 1 The patient demonstrated an abnormal posture. The patient had a chin-on-chest/dropped-head posture in both sitting (A) and standing (B) positions. In addition, his head was rotated to the right and laterally flexed to the left, most notably when seated. Given the patient's worsening posture, diffuse weakness, lack of response to conservative care, and older age, the chiropractor considered thoracic spinal compression fracture as the working diagnosis, while cervical and lumbar radiculopathy were also considered. Central nervous system disorders (i.e., Parkinson's, amyotrophic lateral sclerosis) were considered less likely given the absence of typical upper motor neuron signs. The chiropractor recommended magnetic resonance imaging (MRI) to evaluate the entire spine, however, the patient preferred to obtain computed tomography (CT) due to its reduced cost and obtained it the same week of presentation. CT revealed extensive mixed lytic and sclerotic changes diffusely through the axial skeleton, including all spinal regions and several ribs, suggestive of extensive bone metastases . Also evident were severe dextro-convex kyphoscoliosis of the thoracic spine, collapsed T5, T8, and T11 vertebral bodies with anterior wedging, multiple bilateral rib fractures with callus formation suggestive of old fractures (right 5th-8th, left 4th, left 7th-11th), and a grade 1 spondylolisthesis at L2/L3 and L4/L5. A mild left pleural effusion, fibrotic changes at both lung bases, and enlarged prostate were also noted. No cervical fracture was evident, while cervical spondylosis and lytic/sclerotic changes were demonstrated. Considering the extensive mixed lytic/sclerotic changes and fractures, the chiropractor considered a working diagnosis of metastasis and immediately referred the patient to an oncologist at a nearby hospital. The patient also provided written informed consent for the publication of his case and any accompanying images. Figure 2 Sagittal (A) and three-dimensional reconstruction (B) of computed tomography (CT). This imaging revealed widespread mixed lytic/sclerotic changes, pathological anterior wedge compression fractures of the T5, T8, and T11 vertebral bodies (arrows), causing severe thoracic spine kyphoscoliosis (dotted line), several rib fractures (not indicated), and a grade 1 L2/L3 and L4/L5 spondylolisthesis (not indicated). The oncologist conducted a PSA test, which was normal. However, a biopsy of the prostate confirmed a diagnosis of adenocarcinoma, leading the oncologist to make a presumptive diagnosis of prostate metastasis to the spine. One week after the chiropractic consultation, the patient was admitted to a nearby hospital under suspicion of pneumonia. MRI further supported the diagnosis of vertebral metastasis. The patient's health rapidly deteriorated, and he passed away three weeks later. Discussion This case illustrates, to our knowledge, the first published case of a patient with dropped head syndrome secondary to undiagnosed spinal metastasis presenting to a chiropractor. As CT revealed multiple collapsed thoracic vertebral bodies and other findings suggestive of metastasis, the chiropractor promptly referred the patient to an oncologist who conducted prostate biopsy and diagnosed him with metastatic adenocarcinoma of the prostate. We suggest that the patient's pathologic thoracic fractures and severely increased kyphosis were the primary cause of his dropped head syndrome. Previous studies have likewise reported that thoracic spine fractures causing a kyphotic deformity led to dropped head syndrome . In one prior case series, the dropped head syndrome was reversed upon surgical correction of the thoracic kyphosis, leading the authors to suggest that the thoracic kyphosis caused stress on the cervical extensor muscles and impaired their function . We suspect that this mechanism was also involved in our present case. The two primary cervical extensor muscles (semispinalis cervicis and capitis) take origin from as low as the mid-thoracic spine . Such muscles, if stretched by a thoracic hyperkyphosis, could develop passive insufficiency wherein they are unable to function efficiently. Another mechanism that could have contributed to the current patient's dropped-head posture is the paraneoplastic syndrome of cancer-associated muscle weakness . This current case reinforces the diagnostic challenges of prostate cancer in men. While individuals with prostate cancer may have minimal symptoms, 19% of those with newly diagnosed prostate cancer already have bone metastases . These patients are typically older males (i.e., >60 years) and may present with back pain (93% of cases), nerve root pain (66%), neurologic deficits (25%), or bladder dysfunction (3%) . Providers should also be vigilant to detect any red flag signs or symptoms, such as progressively worsening neurological deficits, or symptoms that fail to improve with conservative care . In addition, chiropractors should be aware that men with undiagnosed prostate cancer may rarely present in their practice, as it is a common cause of spinal metastasis . For investigating suspected malignancy via imaging, CT and MRI are preferred over radiography . PSA testing is often used as part of the workup for suspected prostate cancer . However, as illustrated in the current case, the patient suffered from prostate cancer without having an elevated (abnormal) PSA. This may be explained in that the PSA test has a sensitivity of only 93% even when patients are symptomatic . Therefore, providers should be aware that a normal PSA test does not guarantee the absence of prostate cancer and should conduct further examination if they suspect malignancy. A previous case reported a 72-year-old male with dropped head syndrome presenting to a chiropractor caused by myopathy . Similarly, both the current and previous patients were elderly men who had a poor response to medication(s) and physical therapy. However, as the previous case showed improvement after chiropractic spinal manipulation (i.e., a manual therapy applied to the spine), the authors suggested that this treatment restored the function of involved joints and muscles . In contrast, spinal manipulation was contraindicated in the current case due to the presence of spinal metastasis . Instead, the priority was to refer the patient for oncologic management. The current case has certain limitations. While the findings were supported by extensive clinical evidence, imaging, and prostate biopsy results, we lacked electrodiagnostic testing and muscle biopsy which may have better characterized the patient's dropped head syndrome. However, these tests would not have been practical to obtain given the urgent priority of oncologic management. We were unable to describe the patient's previous primary care, physiotherapy, and PSA testing in greater detail due to a lack of supporting records. In addition, we were unable to obtain the patient's spinal MRI results and records from the outside hospital where he was admitted and expired. Availability of this imaging could have allowed us to better characterize or rule out any potential radiculopathy or myelopathy. Additionally, we could not ascertain the patient's specific cause of death. While the patient's clinical presentation can be described as dropped head syndrome (i.e., chin-on-chest position with cervicothoracic kyphosis and cervical extensor weakness), his posture could be more broadly described as severe/extreme kyphosis . The generalizability of this case may be limited, as chiropractors in certain regions may not have access to advanced imaging and might instead refer the patient immediately for further evaluation. Conclusions We describe an elderly male presenting to a chiropractor with dropped head syndrome, ultimately diagnosed as having prostate cancer metastasis to the spine. As dropped head syndrome can be caused by serious pathology, including vertebral fracture related to underlying malignancy, providers that manage spinal complaints should be familiar with this condition and conduct necessary investigations when indicated. When testing or imaging is suggestive of malignancy, providers should promptly refer the patient to an oncologist. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Vertebral fractures: clinical importance and management Am J Med Kendler DL Bauer DC Davison KS 1 10 129 2016 26205330 2 Dropped head syndrome: diagnosis and management Evid Based Spine Care J Martin AR Reddy R Fehlings MG 41 47 2 2011 23637681 3 Dropped head syndrome: a systematic review Clin Spine Surg Drain JP Virk SS Jain N Yu E 423 429 32 2019 30844858 4 Dropped head syndrome due to vertebral metastasis of breast cancer Neurol Clin Neurosci Ito H Okamoto H 340 341 8 2020 5 Dropped head syndrome: etiology and management J Am Acad Orthop Surg Sharan AD Kaye D Charles Malveaux WM Riew KD 766 774 20 2012 23203936 6 Dropped head syndrome caused by thoracolumbar deformity: a report of 3 cases JBJS Case Connect Kudo Y Toyone T Okano I 12 2022 7 Prevalence of serious pathology among adults with low back pain presenting for chiropractic care: a retrospective chart review of integrated clinics in Hong Kong Med Sci Monit Chu EC Trager RJ 28 2022 8 A retrospective analysis of the incidence of severe adverse events among recipients of chiropractic spinal manipulative therapy Sci Rep Chu EC Trager RJ Lee LY Niazi IK 13 2023 9 The chiropractic care of patients with cancer: a systematic review of the literature Integr Cancer Ther Alcantara J Alcantara JD Alcantara J 304 312 11 2012 21665878 10 Patients with cancer. Is there a role for chiropractic? J Can Chiropr Assoc Laoudikou MT McCarthy PW 32 42 64 2020 32476666 11 Guideline-concordant utilization of magnetic resonance imaging in adults receiving chiropractic manipulative therapy vs other care for radicular low back pain: a retrospective cohort study BMC Musculoskelet Disord Trager RJ Anderson BR Casselberry RM Perez JA Dusek JA 23 2022 12 Chiropractic case reports: a review and bibliometric analysis Chiropr Man Therap Trager RJ Dusek JA 29 2021 13 Isolated neck extensor myopathy associated with cervical spondylosis: a case report and brief review Clin Med Insights Arthritis Musculoskelet Disord Chu EC Wong AY Lin AF 13 2020 14 Is there a role for surgery in the management of dropped head syndrome? Br J Neurosurg Amin A Casey AT Etherington G 289 293 18 2004 15327235 15 Bracing to treat dropped head syndrome in cancer patients: a retrospective review J Prosthet Orthot Knowlton SE Zheng M Diamond Y Yakaboski M Ruppert LM 20 25 33 2021 36186001 16 Management of vertebral metastases in prostate cancer: a retrospective analysis in 119 patients Clin Prostate Cancer Cereceda LE Flechon A Droz JP 34 40 2 2003 15046682 17 Defining and measuring imaging appropriateness in low back pain studies: a scoping review Eur Spine J Yates M Oliveira CB Galloway JB Maher CG 519 529 29 2020 31938944 18 Presumptive prostate cancer presenting as low back pain in the chiropractic office: two cases and literature review Cureus Chu EC Trager RJ Lai CR Leung BK 14 2022 19 Imaging of spinal metastatic disease Int J Surg Oncol Shah LM Salzman KL 2011 2011 20 Systematic review and meta-analysis of the diagnostic accuracy of prostate-specific antigen (PSA) for the detection of prostate cancer in symptomatic patients BMC Med Merriel SW Pocock L Gilbert E Creavin S Walter FM Spencer A Hamilton W 54 20 2022 35125113 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34798 Internal Medicine Pulmonology Therapeutics Rituximab-Induced Immune Dysregulation Leading to Organizing Pneumonia, Bronchiectasis, and Pulmonary Fibrosis Muacevic Alexander Adler John R Ayyad Mohammed 1 Azar Jehad 2 Albandak Maram 1 Sharabati Haneen 1 Salim Hamza 3 Jaber Yasmin 4 Al-Tawil Mohammed 1 1 Internal Medicine, Al-Quds University, Jerusalem, PSE 2 Respiratory Institute, Cleveland Clinic, Cleveland, USA 3 Department of Medicine, An-Najah National University, Nablus, PSE 4 Internal Medicine B, Hadassah Ein Kerem Hospital, Jerusalem, ISR Mohammed Ayyad [email protected] 9 2 2023 2 2023 15 2 e347989 2 2023 Copyright (c) 2023, Ayyad et al. 2023 Ayyad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We present a case of rituximab-induced organizing pneumonia (OP) along with bronchiectasis and pulmonary fibrosis, in a patient with a history of granulomatosis with polyangiitis (GPA), on long-term maintenance therapy with rituximab. T-cell dysregulation and B-cell depletion associated with the chronic use of rituximab often lead to a profound immunosuppressed state with hypogammaglobulinemia and unbalanced T-cell response. This acquired immunodeficient state with severe immune dysregulation predisposed this patient to recurrent pulmonary infection and ultimately led to bronchiectasis and pulmonary fibrosis. hypogammaglobulinemia immunosuppression therapy granulomatosis with polyangiitis pulmonary fibrosis humoral immunity bronchiectasis rituximab The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Rituximab is a monoclonal antibody targeting the antigen CD20 and causing the depletion of CD20+ B-cells . B-cell dysfunction leads to hypogammaglobulinemia, which in turn increases the susceptibility to severe pulmonary infections. Rituximab is also associated with the development of acute fibrinous organizing pneumonia (OP) . Rituximab-induced OP is very rare and has only been described in a few case reports [2-5]. Moreover, rituximab is known to cause drug-induced pneumonitis with fibrosis, as well as hypersensitivity pneumonitis. In this report, we present a case of rituximab-induced hypogammaglobulinemia with subsequent repeated infections, resulting in concurrent bronchiectasis and pulmonary fibrosis. Case presentation We present the case of a 60-year-old male with a history of granulomatosis with polyangiitis (GPA). It manifested as recurrent sinusitis and was associated with end-stage renal disease requiring hemodialysis, despite prior adequate treatment with pulse steroid therapy and rituximab. Consequently, the patient underwent renal transplantation, with subsequent graft dysfunction. Since his diagnosis, the patient had also suffered from recurrent episodes of pneumonia responsive to antibiotics; the patient had continued to undergo steroid therapy as part of his immunosuppressive regimen. Baseline high-resolution CT (HRCT) at the time of GPA diagnosis had revealed no signs of bronchiectasis, consolidation, or interstitial lung disease . However, HRCTs done over the subsequent two years had shown evidence of progressive bronchiectasis, migrating peripheral and broncho-centric consolidations, as well as bilateral fibrotic changes in the form of reticulation, traction bronchiectasis, architectural distortion, and volume loss , which are findings atypical to pulmonary GPA. Figure 1 High-resolution CT findings at the time of GPA diagnosis The image shows no signs of interstitial lung disease, bronchiectasis, or consolidation CT: computed tomography; GPA: granulomatosis with polyangiitis Figure 2 High-resolution CT findings two years after GPA diagnosis High-resolution CT of the chest two years after GPA diagnosis, on rituximab, shows bilateral ground-glass opacities and broncho-centric consolidation, with reversed halo sign (atoll sign) in the left lower lobe (red arrow). It also shows traction bronchiectasis and peripheral reticulation CT: computed tomography; GPA: granulomatosis with polyangiitis Figure 3 High-resolution CT findings 30 months after GPA diagnosis High-resolution CT chest 30 months after GPA diagnosis, on rituximab, shows bilateral peripheral reticulation (blue arrows), patchy areas of ground-glass opacities and broncho-centric consolidation in the left lower lobe (orange arrow), and traction bronchiectasis associated mild architectural distortion/volume loss (green arrows) CT: computed tomography; GPA: granulomatosis with polyangiitis Based on the patient's clinical and radiological picture, the IgG level test was ordered and was found to be reduced at 530 mg/dL (normal range: 700-1,600 mg/dL). Bronchoalveolar lavage was performed and showed neutrophilic predominance with negative viral, bacterial, and fungal cultures. Pulmonary function tests showed restrictive disease with a moderately reduced diffusing capacity for carbon monoxide (DLCO). Based on these findings, we suspected that the patient's immunosuppression was responsible for his recurrent pulmonary infections, bronchiectasis, and fibrosis. Furthermore, the broncho-centric and migratory distribution of the pulmonary consolidation, in addition to the reversed halo sign on HRCT, raised concerns for OP secondary to rituximab therapy and/or repeated chest infections. Due to the lack of clinical improvement after multiple courses of broad-spectrum antibiotics, and the fact that his underlying GPA was deemed to be in a state of remission, the decision was made to resume rituximab therapy at a lower dose, bridged with IVIG supplementation and steroid therapy. This resulted in immunomodulation with B-cell repletion, normalization of immunoglobulin, and T-cell functional recovery. These interventions broke the vicious cycle of immune dysfunction that had led to repeated infection with ultimate bronchiectasis and fibrosis. On follow-up, HRCT was done and showed resolution of OP as well as marked clinical improvement. GPA continued to be in remission and both bronchiectasis and pulmonary fibrosis were stable with no signs of progression. Additionally, it was recommended to check his IVIG levels regularly, with supplementation as required. Discussion Cryptogenic OP is diagnosed by both radiological and clinical presentation. OP, on the other hand, is the histopathological diagnosis . OP can be secondary when associated with conditions known to induce OP, or cryptogenic when the cause is unknown. Secondary OP is associated with viral and bacterial respiratory infections, malignancy, organ transplantation, autoimmune disease, drugs, radiation, and environmental exposure . The classic presentation of OP is a nonproductive cough, malaise, fever, dyspnea, and weight loss, with a preceding mild flu-like illness. This presentation often delays the diagnosis and even makes it difficult to differentiate between secondary infection, preceding infection, and cryptogenic-type OP. In most cases, patients typically receive various courses of antimicrobial agents without clinical improvement, which should indicate the diagnosis of OP. The pathogenesis of OP is poorly understood . However, T-cell dysregulation appears to be substantially related to OP . It is possible that chronic B-cell depletion induced by rituximab causes an unbalanced T-cell response, which triggers the emergence of OP, especially if the patient is taking other immunomodulating agents . Bronchoalveolar lavage is done to exclude other etiologies, mainly infection, which usually shows differential lymphocytosis. The classic radiological presentation of OP is extensive airspace disease in the form of patchy lower lung zone-predominant consolidation and ground-glass opacities with peri-broncho-vascular and/or subpleural distribution. These are typically bilateral and peripheral and are often migratory, as seen in our case. The atoll sign, which is also known as the reversed halo sign, often seen in cases of OP, is characterized by a central ground-glass opacity surrounded by dense airspace consolidation in the shape of a crescent or a ring. Atoll sign is nonspecific to OP and has been reported in association with a wide range of pulmonary diseases, including invasive pulmonary fungal infections, tuberculosis, community-acquired pneumonia, and GPA . Surgical lung biopsy is the gold standard for diagnosis; however, transbronchial biopsy often shows the diagnostic histopathological findings of excessive fibrotic tissue deposition within alveolar sacs extending into alveolar ducts and bronchioles, as well as intraluminal granulation tissue deposition known as Masson bodies . Rituximab-induced OP is rare but has gained interest and recognition recently among physicians given the emerging cases. To the best of our knowledge, there are only a few reported cases of rituximab-induced OP in the literature [2-5]. All of them were treated by withholding rituximab and corticosteroid courses, with subsequent clinical recovery. Bronchiectasis, on the other hand, is a progressive lung disease characterized by irreversible destruction of the airway due to a combination of immunological dysfunction and recurrent bacterial infection. This leads to progressive bronchiolar dilatation, ciliary dyskinesia, and bacterial colonization and invasion . The original cycle theory of recurrent infections disrupting the integrity of the airway has formed the basis for an emerging version known as the "vicious vortex". This theory proposes that airway inflammation may be due to a dysregulated cytokine network . Similarly, rituximab's side effects are related to its ability to deplete B-cells causing hypogammaglobulinemia with a subsequent susceptibility to infection, as well as immune dysregulation, triggering cytokine imbalance . In our case, we believe that rituximab caused bronchiectasis by the synergistic effect of two mechanisms: immunomodulation and recurrent bacterial infections. To our knowledge, this sequela of rituximab involving the concurrent development of OP, bronchiectasis, and fibrosis has never been reported before. Moreover, pulmonary fibrosis has been rarely reported as a consequence of long-term rituximab therapy . We suspect that rituximab-induced fibrosis in our patient most likely relates to recurrent infections with a vicious cycle of lung injury and healing with fibrotic tissue deposition. Conclusions Rituximab is a B-cell-depleting agent, and it has detrimental effects on the humoral immune system leading to B-cell depletion with hypogammaglobulinemia and T-cell qualitative dysfunction, with subsequent immune dysregulation. Impaired respiratory mucosal immunity triggers a cascade of recurrent severe pulmonary infections resulting in bronchiectasis and progressive pulmonary fibrosis. Based on our literature review, rituximab is rarely associated with OP. A decision to halt the use of rituximab might be difficult due to the high rates of relapse of the primary illness. Consequently, treating rituximab-associated complications while continuing its administration might be the only feasible approach, with regular evaluation of immunoglobulin levels and supplementation. Steroids or other steroid-sparing agents are used to treat rituximab-induced OP. Airway clearance with bronchopulmonary hygiene, bronchodilation, mucolytics, eradication of pseudomonas colonization, and systemic antibiotics in case of exacerbation are the main treatment modalities for bronchiectasis. Anti-fibrotics should be prescribed if the criteria for progressive pulmonary fibrosis are met. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases Br J Haematol Cooper N Arnold DM 3 13 149 2010 20151975 2 Rituximab-induced lung disease: a systematic literature review Eur Respir J Liote H Liote F Seroussi B Mayaud C Cadranel J 681 687 35 2010 19608586 3 Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) Blood Byrd JC Peterson BL Morrison VA 6 14 101 2003 12393429 4 Bronchiolitis obliterans organizing pneumonia in a patient with non-Hodgkin's lymphoma following R-CHOP and pegylated filgrastim Leuk Lymphoma Macartney C Burke E Elborn S 1523 1526 46 2005 16194900 5 Bronchiolitis obliterans with organizing pneumonia after rituximab therapy for non-Hodgkin's lymphoma Hematol Oncol Biehn SE Kirk D Rivera MP Martinez AE Khandani AH Orlowski RZ 234 237 24 2006 16948177 6 Pathologic aspects of bronchiolitis obliterans organizing pneumonia Chest Colby TV 38 43 102 1992 7 An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias Am J Respir Crit Care Med Travis WD Costabel U Hansell DM 733 748 188 2013 24032382 8 T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors Haematologica Ditschkowski M Elmaagacli AH Trenschel R Peceny R Koldehoff M Schulte C Beelen DW 558 561 92 2007 17488669 9 Cryptogenic organizing pneumonia after rituximab therapy for presumed post-kidney transplant lymphoproliferative disease Pediatr Nephrol Bitzan M Ouahed JD Carpineta L Bernard C Bell LE 1163 1167 25 2010 20140460 10 The concept of "organizing pneumonia" Chest Sulavik SB 967 969 96 1989 2805864 11 Cryptogenic Organizing Pneumonia Chandra D Maini R Hershberger DM Treasure Island, FL StatPearls Publishing 2022 12 Pathophysiology and genetics of bronchiectasis unrelated to cystic fibrosis Lung Nikolic A 383 392 196 2018 29754320 13 Bronchiectasis diagnosis and treatment Dtsch Arztebl Int Rademacher J Welte T 809 815 108 2011 22211147 14 Common variable immunodeficiency disorder - an uncommon cause for bronchiectasis Lung India Panigrahi MK 394 396 31 2014 25378851 15 Complement activation plays a key role in the side-effects of rituximab treatment Br J Haematol van der Kolk LE Grillo-Lopez AJ Baars JW Hack CE van Oers MH 807 811 115 2001 11843813 16 Rituximab-induced acute pulmonary fibrosis Mayo Clin Proc Leon RJ Gonsalvo A Salas R Hidalgo NC 949 79 2004 15244399 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34800 Cardiology Dermatology Internal Medicine Generalized Drug Eruption Secondary to Ticagrelor: A Case Report and Review of the Literature Muacevic Alexander Adler John R Akdogan Raziye E 1 Chen Jennifer 1 Varon Alberto 1 Muradova Elnara 2 Fusco Joseph 3 1 Internal Medicine, University of Connecticut School of Medicine, Farmington, USA 2 Dermatology, University of Connecticut School of Medicine, Farmington, USA 3 Internal Medicine, St. Francis Hospital, Hartford, USA Raziye E. Akdogan [email protected] 9 2 2023 2 2023 15 2 e348008 2 2023 Copyright (c) 2023, Akdogan et al. 2023 Akdogan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Currently, guidelines recommend ticagrelor over clopidogrel as part of dual antiplatelet therapy with aspirin in treating individuals with acute coronary syndrome. As there is an increased usage of ticagrelor, it is important to keep in mind uncommon adverse events, including hypersensitivity skin reactions. To date, only a few studies have been published regarding ticagrelor-induced skin eruptions. Additionally, there is no consensus on antiplatelet therapy management after a hypersensitivity reaction to antiplatelet agents. Hereinafter, we describe a case of an 81-year-old female who presents with a diffuse erythematous hypersensitivity eruption, including palms and soles, secondary to ticagrelor use. Ticagrelor transitioned to clopidogrel, and the patient was started on steroid taper with an antihistamine. The patient's rash progressively improved after the treatment. Our case demonstrates a rare adverse effect of ticagrelor, which needs prompt diagnosis and switching to one of the thienopyridines to prevent thrombosis. thienopyridines antiplatelets hypersensitivity rash drug-eruption ticagrelor hypersensitivity The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Ticagrelor is a relatively new antiplatelet medication introduced in 2011, which has increased in practice after many guidelines recommended using ticagrelor over clopidogrel for acute coronary syndromes . This recommendation was communicated after the Platelet Inhibition and Patient Outcomes (PLATO) study , which demonstrated that ticagrelor had a 16% relative risk reduction in major adverse coronary events and a 22% relative risk reduction in all-cause death compared with those treated with clopidogrel. Ticagrelor's common side effects include dyspnea, bleeding, and bradyarrhythmias while skin-related adverse events are limited. Upon a literature search, we are only able to identify six cases describing a hypersensitivity skin reaction after the initiation of ticagrelor. In this case report, we describe an 81-year-old female with a new diffuse erythematous rash involving the palms and soles secondary to ticagrelor use. Case presentation An 81-year-old Caucasian female with a past medical history of coronary artery disease, hypertension, hypothyroidism, osteoarthritis, gastroesophageal reflux disease, and recurrent urinary tract infections presents to the emergency department with a one-day history of pruritic generalized erythematous tender eruption involving bilateral acral surfaces. Ten days prior to the onset of the rash, the patient was admitted for non-ST elevation myocardial infarction and had a drug-eluting stent placed in the circumflex artery. She was then started on ticagrelor. The patient denied any other new medications, over-the-counter supplements, and new detergents or soaps. Additionally, the patient denied any fever, arthralgia, blisters, dyspnea, facial edema, difficulty swallowing, or dysuria. Her vitals showed a systolic blood pressure in the 70s mmHg, which improved after fluid resuscitation. She was afebrile with a heart rate in the 60s. For laboratory work-up, she had an increased WBC count to 18.1 (K/mL) with a left shift without eosinophilia. Her chemistries showed creatinine at 1.2 mg/dl, sodium at 132 meq/ L, potassium at 3.1 meq/L, estimated glomerular filtration rate (eGFR) at 43.1 ml/min, and a sedimentation rate of 45 mm/h. On physical examination, erythematous non-blanching coalescing macules, papules, and patches were localized on the face, trunk, and extremities, as well as bilateral palms and soles. There was no mucosal involvement . A skin biopsy of the left lateral thigh demonstrated perivascular lymphocytic spongiotic dermatitis with scattered eosinophils and rare necrotic keratinocytes, consistent with a drug eruption . Figure 1 Anterior and posterior cutaneous findings Generalized erythematous non-blanching coalescing macules, papules, and patches, involving the bilateral palms and soles. Figure 2 H&E skin biopsy from the left lateral thigh Perivascular lymphocytic spongiotic dermatitis with scattered eosinophils (red circle) and rare necrotic keratinocytes (black spiral), consistent with a drug eruption. For management, ticagrelor was switched to clopidogrel, and she was started on steroids (methylprednisolone IV followed by a tapering dose of oral prednisone) and an antihistamine (IV diphenhydramine). Over a three-day hospital course, the patient's eruption and pruritus gradually improved, starting at the palms and soles. Discussion This is the first case of generalized drug-induced eruption involving bilateral palms and soles, secondary to ticagrelor hypersensitivity. To the best of our knowledge, there were only six other case reports published regarding ticagrelor hypersensitivity skin reactions. Two of the case reports demonstrated maculopapular rash that mainly involved only the central trunk as opposed to our case, which involved the entire body, including palms and soles . The case reported by Quinn et al. demonstrated very similar skin biopsy findings showing perivascular lymphocytic infiltrates compared to our patient but did not comment on necrotic keratinocytes as seen in our biopsy . The four other reports showed different dermatological reactions with one case of exanthematous pustulosis , one case of eccrine hidradenitis , one case of a bullous fixed drug eruption , and a case of Sweet syndrome . These cases are described in Table 1. Table 1 Case reports of ticagrelor-induced hypersensitivity skin reactions Age Gender Cutaneous Findings Biopsy Findings Treatment Reference 65 M Pruritic exanthematous rash Perivascular lymphocytic infiltrate Discontinuation of the offending drug Quinn et al. 2014 68 M Pruritic and exanthematous eruptions None provided Switched to warfarin due to clopidogrel resistance Dai et al. 2017 65 F Generalized erythroderma with scattered sloughing, with accentuation on the abdomen and thighs Acute generalized exanthematous pustulosis Did not mention Maybrook et al. 2015 73 M Multiple painful hemorrhagic bullae on the palms of both hands Neutrophilic infiltrate consistent with Sweet Syndrome Switched to clopidogrel Ikram and Kandasamy 2017 66 M Painful erythematous papulonodules on both palms Revealed dermal edema and infiltration of eccrine gland coils and ducts by a dense neutrophilic and eosinophilic infiltrate Switched to clopidogrel Bishnoi et al. 2019 44 M Translucent bullous lesions with surrounding erythema on the distal flexor aspect of the right forearm None performed Switched to clopidogrel and rivaroxaban Kawall et al. 2021 81 F Erythematous maculopapular rash involving her palms and soles Perivascular lymphocytic dermatitis, spongiotic type, with scattered eosinophils and rare necrotic keratinocytes Switched to clopidogrel Our case Symptomatic management with antihistamines and steroids and discontinuation of the offending agent are the mainstays of the treatment. In addition, antithrombotic therapy should continue to prevent further ischemic events by switching to another class of antiplatelet agents. Among these seven cases reported, including ours, four were successfully transitioned to clopidogrel without recurrence of skin lesions. Notably, one case was ultimately changed to warfarin due to recurrent thrombosis after switching to clopidogrel . Although clopidogrel and ticagrelor are both antiplatelets that are P2Y12 adenosine diphosphate (ADP) receptor blockers, they are structurally different. P2Y12 ADP receptor blockers are split into two categories based on their chemical structures: thienopyridines and cyclopentyl-triazole-pyrimidines (CTP). Thienopyridines irreversibly inhibit platelet activation by binding ADP receptors and include clopidogrel, prasugrel, and ticlopidine. CTP reversibly binds ADP receptors, that is, ticagrelor and cangrelor . Therefore, cross-reactive hypersensitivity is less likely to occur when changing from a CTP to thienopyridines, as observed in the analyzed cases above. Identified skin adverse events from ticagrelor appear to be at a much lower incidence compared to clopidogrel, as up to 6% of patients will develop a clopidogrel-induced rash . Although these dermatological events appear to be uncommon in patients receiving ticagrelor, it may be due to its more recent introduction, and we might expect to see an increase in these events as ticagrelor utilization continues to rise . Conclusions This case highlights the importance of considering ticagrelor as a potential cause of a pruritic generalized erythematous hypersensitivity rash of the whole body, including palms and soles. Prompt identification allows for a quick replacement of the CTP offending agent with one of the thienopyridines. Cross-reactive hypersensitivity is rare given CTP, and thienopyridines are structurally different. This will allow for the resolution of the hypersensitivity as well as the continuation of antithrombotic therapy to prevent a catastrophic ischemic event. We thank Dr. Jeffrey Sussman for his final diagnosis and photos of the skin biopsy slides. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Increase in ticagrelor use over time is associated with lower rates of ischemic stroke following myocardial infarction BMC Cardiovasc Disord Henriksson R Ulvenstam A Soderstrom L Mooe T 51 19 2019 30832574 2 Association of ticagrelor vs clopidogrel with major adverse coronary events in patients with acute coronary syndrome undergoing percutaneous coronary intervention JAMA Intern Med Turgeon RD Koshman SL Youngson E Har B Wilton SB James MT Graham MM 420 428 180 2020 31930361 3 First report of hypersensitivity to ticagrelor Can J Cardiol Quinn KL Connelly KA 957 954 30 2014 4 Hypersensitivity to ticagrelor and low response to clopidogrel: a case report Asia Pac Allergy Dai J Lyu S Ge C 51 53 7 2017 28154807 5 Ticagrelor-induced acute generalized exanthematous pustulosis Int J Cardiol Maybrook RJ Fischer R Deibert B 11 12 191 2015 25965589 6 Ticagrelor induced neutrophilic eccrine hidradenitis: a unique adverse effect of a new antiplatelet drug Postgrad Med J Bishnoi A Daroach M Aggarwal D Radotra BD Panda P Parsad D 279 280 95 2019 30926720 7 Suspected ticagrelor-induced bullous fixed drug eruption Cureus Kawall T Seecheran R Seecheran V Persad S Seecheran NA 0 13 2021 8 Ticagrelor-induced Sweet syndrome: an unusual dermatologic complication after percutaneous coronary intervention Cardiovasc Interv Ther Ikram S Veerappan Kandasamy V 244 246 32 2017 27146134 9 Ticagrelor versus clopidogrel in patients with acute coronary syndromes N Engl J Med Wallentin L Becker RC Budaj A 1045 1057 361 2009 19717846 10 Management of clopidogrel hypersensitivity without drug interruption Am J Cardiol Campbell KL Cohn JR Fischman DL Walinsky P Mallya R Jaffrani W Savage MP 812 816 107 2011 21247516 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34797 Neurology Otolaryngology Infectious Disease Gradenigo's Syndrome With Septic Lateral Sinus Thrombosis Muacevic Alexander Adler John R Branco Tiago 1 Marques Catarina 2 Santos Vera C 3 Lopes Joao M 1 1 Servico de Medicina 2, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, Lisboa, PRT 2 Internal Medicine, Hospital Jose Joaquim Fernandes, Beja, PRT 3 Servico de Medicina Intensiva, Hospital Prof. Doutor Fernando Fonseca, Amadora, PRT Tiago Branco [email protected] 9 2 2023 2 2023 15 2 e347979 2 2023 Copyright (c) 2023, Branco et al. 2023 Branco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Gradenigo's syndrome (GS) is a rare but life-threatening complication of acute otitis media (AOM). It is classically defined as a clinical triad of acute otitis media, ipsilateral sixth (abducens) nerve palsy, and pain in the distribution of the first and second branches of the trigeminal nerve. Another rare but serious complication of AOM is venous sinus thrombosis, which is often associated with GS. The diagnosis of these conditions requires clinical suspicion, sound interpretation of signs and symptoms, and the use of the correct imaging techniques. Here, we present the case of an 81-year-old man with a previous history of recurrent otitis media, who presented with GS and septic lateral sinus thrombosis. The clinical presentation, physiopathology, and management of these conditions are discussed. gradenigo's syndrome chronic suppurative otitis media septic thrombosis otitis media complication lateral sinus thrombosis The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Gradenigo's syndrome (GS) is a clinical triad of acute otitis media (AOM), ipsilateral sixth (abducens) nerve palsy, and pain in the distribution of the first and second branches of the trigeminal nerve, first described by Professor Giuseppe Gradenigo in 1904 . Classically, these symptoms are assumed to be a consequence of the inflammation of the petrous apex of the temporal bone and Dorello's canal, a condition termed apical petrositis (or petrous apicitis) usually caused by medial extension of AOM into a pneumatized apex located near the trigeminal ganglion and sixth cranial nerve . After the introduction of antibiotics in the early 20th century, the incidence of GS has diminished, and is now considered a rare, but still life-threatening condition . It is more frequent in adults . The incidence of apical petrositis is reported to be two per 100,000 children with AOM . GS can be associated with other complications, such as meningitis and venous sinus thrombosis . Septic venous sinus (lateral, cavernous, or sagittal) thrombosis is also a serious complication of AOM with high mortality, particularly in elderly patients . Chronic or untreated AOM may result in the spreading of the infection to the mastoid air cell, leading to thrombosis of the lateral sinus, which may then propagate to the internal jugular vein and other dural sinuses . The infection usually reflects the polymicrobial nature of otitis media. Physical findings may include fever, which is less prominent in those associated with chronic otitis media , and, when present, GS provides strong evidence for lateral sinus thrombosis or petrous apex inflammation . Prompt administration of large-spectrum antibiotics is paramount, and in the absence of rapid defervescence, surgery is indicated . Case presentation An 81-year-old man with a previous history of hypertension, cerebrovascular disease, and type 2 diabetes was admitted to the emergency department for a three-week course of nausea, vomiting, headache, and ataxia. The headache was described as affecting mainly the left parietal and temporal regions, with mention to left retro-orbital pain. Investigation of clinical history revealed recurring otitis media infections with previous complaints of headache, vertigo, and ataxia along with left imbalance for the last six months. On physical examination, he presented with left hearing loss, peripheral vertigo, left gait ataxia, and left external oculomotor ophthalmoplegia, with no meningeal signs. A slightly elevated C-reactive protein (CRP) (4.4 mg/dL; normal <0.9 mg/dL) was the only relevant finding on blood tests. Diabetes was reasonably controlled (HbA1c 7.6%). Head CT showed only ischemic lesion sequelae and left middle ear and mastoid filling . Figure 1 Head CT showing ischemic lesion sequelae. Figure 2 Head CT showing left middle ear and mastoid filling. Upon admission to the ward, blood cultures were drawn and empirical antibiotherapy was started with intravenous (IV) ceftriaxone 2 g every 12 hours. Further investigation with ear CT revealed skull base osteomyelitis and left otomastoiditis . Figure 3 Ear CT revealing skull base osteomyelitis and left otomastoiditis. Additional findings of infectious collections in the cerebellopontine angle and retropharyngeal space were also documented. Antibiotherapy was then changed to meropenem (2 g every eight hours) to improve antibiotic penetration and add coverage to Pseudomonas aeruginosa. Neurology and neurosurgery opted for a conservative approach and discarded surgical control of the cerebellopontine and retropharyngeal collections. The case was then discussed with the otolaryngology department and surgical intervention was decided. Prior to the surgery, a head MRI confirmed left otomastoiditis, labyrinthitis, and documented septic left lateral sinus thrombosis with pachymeningeal inflammation . Figure 4 T2-weighted head MRI documenting left otomastoiditis with pachymeningeal inflammation. Figure 5 T1-weighted MRI with gadolinium documenting septic left lateral sinus thrombosis with apical petrositis. It was decided not to start anticoagulation at this point, considering that it could increase hemorrhagic risk and hematogenous infection dissemination. The patient was then submitted to exploratory tympanostomy, closed technique mastoidectomy, and myringotomy with Shepard tympanostomy tube insertion in the left ear. During the procedure, samples were collected for cytochemical, bacterial, mycobacterial, and anatomopathological studies. Samples were also collected for 16s rRNA gene sequencing. No microorganism was isolated or identified in any of the samples. The patient then began a long recovery process adjuvanted by physical therapy. At this point, anticoagulation with enoxaparin in a prophylactic dose was started. Only partial symptomatic recovery was achieved, with persistent sixth nerve palsy two months after the surgery. Subsequent MRI studies revealed the persistence of the infectious cerebellopontine and retropharyngeal collections and lateral sinus thrombosis. The need for long-term IV antibiotics (at least six months) conditioned discharge, but the patient was eventually able to go back home under a domestic hospitalization protocol. Three months later, he suffered a fatal ischemic stroke, affecting the right precentral gyrus. Although the lesion was consistent with an embolic etiology, the relationship of this event with lateral sinus thrombosis remains unclear. Discussion Septic lateral sinus thrombosis is a rare complication of otitis media, and GS is an exceedingly rare presentation of otitis media complications. The time interval between the onset of otitis media and the clinical presentation of Gradenigo's triad of symptoms is variable. Despite sharing otitis media as the common etiology, each symptom results from different physiopathological processes. In a 40-year review of apical petrositis cases, only 13.6% presented all the GS triad's symptoms . A recent review of all reported cases over the last 50 years found only 45 cases of classic GS presentation and proposed a new classification of incomplete GS and GS mimicking other presentations of apical petrositis . In general, the petrous apex is composed of dense bone and bone marrow. In only one-third of the cases, petrous apexes are well pneumatized and communicate with the middle ear cleft , making it more susceptible to obstruction, opacification, inflammation, and infection. This is the same process by which the pneumatized mastoid segment is also vulnerable to middle ear infection and the reason why it is usually associated with GS. However, GS can also occur on a background of previous radical mastoidectomy . The petrous apex is located at the central part of the temporal bone. A fold of medial dura mater of the petrous apex forms Dorello's canal, in which the sixth nerve rises toward the cavernous sinus . The proximity of the Gasserian ganglion, from which the ophthalmic and maxillary branches of the trigeminal nerve arise, can cause AOM patients to experience retro-orbital pain. This symptom was present in 54.6% of the cases according to the review by Gadre and Chole and can be one of the earliest signs of GS . Development of abducens nerve palsy varies from one week to two to three months after the initial infection and is present in only 15.9% of patients with apical petrositis . The average time to presentation from symptom onset for classic GS is 14.9 days . In the present case, ear CT revealed skull base osteomyelitis and left otomastoiditis, triggering further investigation with MRI. Although CT scans are adequate for describing bone anatomy and bone destruction, other methods are preferred for diagnosing central nervous system pathologies and the composition of the lesion in the bone. In a series of 49 patients, head CT failed to identify 14% of the patients with central venous thrombosis, whereas venous CT or MRI venography could provide positive identification of abnormalities in all cases . Clinical presentation may be atypical and high clinical suspicion may be needed to prompt image investigation . In cases of infectious petrositis, MRI shows hypointensity on T1-weighted and hyperintensity on T2-weighted images. In cases of abscess formation, a rim of gadolinium enhancement and diffusion-weighted imaging hyperintensity may be observed . Identification of infectious agents was not possible in the presented case, but recent reviews found the microbiology of the AOM infections leading to GS surprising, for the preponderance of aerobic gram-positive cocci, and the relative paucity of Streptococcus pneumonia and Haemophilus influenza, common pathogens in otitis media and mastoiditis . Infectious petrositis is equivalent to osteomyelitis, which needs intensive and prolonged IV antibiotic treatment to avoid relapse . Many cases of successful conservative treatment with IV antibiotics have been reported. However, if the patient deteriorates, or in the absence of rapid improvement, immediate surgery is indicated . This approach, when considered, should remove as much of the infected temporal bone as possible with preservation of hearing and facial nerve functions, including mastoidectomy and the exposition of petrous apex by media fossa . The benefit of anticoagulation treatment in this condition is debatable and remains controversial. In a series of five cases involving septic lateral sinus thrombosis under long-term anticoagulation with low-molecular-weight heparin, there was only one reported complication of a non-life-threatening intracranial hemorrhage . A Cochrane review designed to assess the effectiveness and safety of anticoagulant therapy in patients with confirmed non-septic cerebral venous sinus thrombosis suggested that anticoagulant drugs are probably safe and may be beneficial for people with sinus thrombosis, with a potentially important reduction in the risk of death or dependency. The results, however, did not reach statistical significance due to the limited evidence available . In the present case, after consultation with several specialties, it was decided not to introduce therapeutic anticoagulation, which may have contributed to a fatal outcome. Conclusions GS and lateral sinus thrombosis are rare but life-threatening complications of acute and chronic otitis media. Clinical interpretation of the signs and symptoms can be challenging as the time interval between the onset of otitis media and the clinical presentation of Gradenigo's triad of symptoms is variable, and not all patients present with the classical syndrome. Imaging studies should include venous CT or MRI venography to exclude cerebral venous thrombosis. The use of anticoagulation treatment remains controversial but is probably safe and may be beneficial. Prompt treatment with large-spectrum IV antibiotics is paramount, and in the absence of rapid improvement, immediate surgery is indicated. The presented case highlights the pivotal role of internal medicine in the management of a complex condition that required continuous consultation with several surgical and non-surgical specialties (neurology, neurosurgery, otolaryngology, neuroradiology, ophthalmology, and infectiology). Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Uber circumscripte Leptomeningitis mit spinalen Symptomen und uber Paralyse des N. abducens otitischen Ursprungs Arch Ohrenheilk Gradenigo G 255 270 62 1904 2 Gradenigo's syndrome secondary to chronic otitis media on a background of previous radical mastoidectomy: a case report J Med Case Rep Plodpai Y Hirunpat S Kiddee W 217 8 2014 24957520 3 Petrous apicitis. Clinical considerations Ann Otol Rhinol Laryngol Chole RA Donald PJ 544 551 92 1983 6660745 4 The changing face of petrous apicitis-a 40-year experience Laryngoscope Gadre AK Chole RA 195 201 128 2018 28378370 5 Intratemporal complications of acute otitis media in infants and children Otolaryngol Head Neck Surg Goldstein NA Casselbrant ML Bluestone CD Kurs-Lasky M 444 454 119 1998 9807067 6 Gradenigo's syndrome in a patient with chronic suppurative otitis media, petrous apicitis, and meningitis Am J Case Rep Taklalsingh N Falcone F Velayudhan V 1039 1043 18 2017 28955030 7 Cerebral vein and dural sinus thrombosis in elderly patients Stroke Ferro JM Canhao P Bousser MG Stam J Barinagarrementeria F 1927 1932 36 2005 16100024 8 Diagnosis and management of lateral sinus thrombosis Otol Neurotol Manolidis S Kutz JW Jr 1045 1051 26 2005 16151357 9 Nonseptic and septic lateral sinus thrombosis: a review Indian J Otolaryngol Head Neck Surg Viswanatha B Thriveni CN Naseeruddin K 10 15 66 2014 24533354 10 Gradenigo's syndrome with lateral venous sinus thrombosis: successful conservative treatment Eur J Pediatr Scardapane A Del Torto M Nozzi M Elio C Breda L Chiarelli F 437 440 169 2010 19697060 11 How well do we know Gradenigo? A comprehensive literature review and proposal for novel diagnostic categories of Gradenigo's syndrome Int J Pediatr Otorhinolaryngol McLaren J Cohen MS El Saleeby CM 109942 132 2020 32065876 12 Gradenigo syndrome without acute otitis media Pediatr Neurol Gibier L Darrouzet V Franco-Vidal V 215 219 41 2009 19664541 13 Gradenigo syndrome: case report and review of literature Neurobiologia Neto ARS Bezerra MJ Galvao AR 143 147 72 2009 14 The forgotten syndrome? Four cases of Gradenigo's syndrome and a review of the literature Strabismus Jensen PV Hansen MS Moller MN Saunte JP 21 27 24 2016 26979620 15 [Cerebral venous thrombosis: retrospective analysis of 49 cases] Acta Med Port Santos GR Andre R Pereira SL Parreira T Machado E 21 28 24 2011 21672438 16 Sigmoid sinus thrombosis as a complication of acute otitis media in a 6-year-old male Ear Nose Throat J Poutoglidis A Tsetsos N Keramari S Skoumpas I Vlachtsis K Kilmpasanis A Fyrmpas G 1455613211015752 2021 33993776 17 Otogenic lateral sinus thrombosis: case series and controversies Int J Pediatr Otorhinolaryngol Funamura JL Nguyen AT Diaz RC 866 870 78 2014 24680135 18 Anticoagulation for cerebral venous sinus thrombosis Cochrane Database Syst Rev Coutinho J de Bruijn SF Deveber G Stam J 0 2011 2011 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.36018 Endocrinology/Diabetes/Metabolism Emergency Medicine Genetics A Young Female With Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD): A Case Report Muacevic Alexander Adler John R Yusuf Ibidapo Q 1 Venkatesan Aadithiyavikram 2 Okafor Faith C 2 Yasin Athar 2 Oyibo Samson O 3 1 General Medicine, Peterborough City Hospital, Peterborough, GBR 2 Emergency Medicine, Peterborough City Hospital, Peterborough, GBR 3 Diabetes and Endocrinology, Peterborough City Hospital, Peterborough, GBR Samson O. Oyibo [email protected] 11 3 2023 3 2023 15 3 e3601811 3 2023 Copyright (c) 2023, Yusuf et al. 2023 Yusuf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is a rare autosomal recessive inborn error of mitochondrial fatty acid oxidation. MCAD is essential for fatty acid b-oxidation during hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores are exhausted during extended fasting and periods of increased energy demand. The inability to metabolize these fatty acids results in hypoketotic hypoglycemia and the accumulation of toxic partially metabolized fatty acids. Intercurrent infection, extended fasting, excessive alcohol intake, vomiting, or diarrhea can lead to serious illness, including encephalopathy and even sudden death. Young people with MCADD are followed up on a regular basis by their metabolic disease specialist, and they are informed about risk factors as they advance through adolescence and adulthood. They should also carry along a written emergency management plan and relevant contact numbers. We describe a case of a 17-year-old female who attended her local emergency care center complaining of severe abdominal pain, vomiting, muscle ache, and poor oral intake. She was known to have MCADD; however, her emergency care plan had a date from eight years ago. She made a rapid recovery after receiving intravenous glucose and other therapies. The patient's concerns and knowledge about MCADD were not fully appreciated at the initial stage due to the rare nature of the disease. This in combination with the absence of current notes on the system, an emergency care plan dated from eight years ago, and the need to obtain specialist advice led to a slight delay in commencing specific therapy. This case report serves as a reminder of the emergency presentation of young people with MCADD, emphasizing the importance of effective communication between the patient, their parents, and the treating clinicians, obtaining the emergency care plan and recommendations, and communicating with the metabolic disease specialist. medium-chain acyl-coa dehydrogenase deficiency medium-chain acyl-coa dehydrogenase acyl-coa dehydrogenase metabolic crisis emergency care plan exercise training sports injury surgery rhabdomyolysis hypoketotic hypoglycemia mcadd The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is a rare autosomal recessive inborn error of mitochondrial fatty acid oxidation characterized by a rapidly progressive metabolic crisis, often presenting with hypoketotic hypoglycemia, lethargy, vomiting, seizures, and coma . MCADD is caused by mutations in the ACADM gene, which encodes the mitochondrial MCAD protein and is located on chromosome one (1p31) . Fatty acid b-oxidation fuels hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores become depleted during extended fasting, and during periods of increased energy demand . People with MCADD are unable to go through this process. Instead, they develop hypoketotic hypoglycemia and accumulate toxic partially metabolized fatty acids in their kidneys, liver, muscles, and brain. Intercurrent infection, prolonged fasting, excessive alcohol intake, vomiting, or diarrhea can lead to encephalopathy and even death. Symptomatic individuals should seek prompt medical assistance, which should include an intravenous 10% glucose infusion (2 ml/kg per hour) to maintain their blood glucose level above 5.0 mmol/L, to prevent hypoglycemia and the accumulation of toxic partially metabolized fatty acids. This treatment should be started even if the initial blood glucose level is in the normal range . People with MCADD will be admitted to their local emergency care center in the event of illness for urgent treatment to prevent a metabolic crisis. We discuss a case of a young female with MCADD who presented to her local emergency care center for emergency treatment. This case report serves as a reminder of the emergency presentation of young people with MCADD, emphasizing the importance of effective communication between the patient, their parents, and the treating clinicians, obtaining the emergency care plan and recommendations, and communicating with the metabolic disease specialist. Case presentation Medical history and demographics A 17-year-old female presented with a four-day history of severe, intermittent abdominal pain and vomiting, and a one-day history of aching and mild weakness in her lower limbs. She had been managing little amounts of glucose drinks to maintain her calorie intake, but this became intolerable from the day before the presentation. She had sustained a right knee injury during rugby training five months prior to this presentation and had been taking non-steroidal anti-inflammatory drugs (NSAIDs; ibuprofen and naproxen) for pain relief since then. She had no urinary symptoms, and her menstrual cycle was complete. She was known to have MCADD since childhood and had regular follow up at a pediatric metabolic disease center. She was transferred to the adult metabolic disease team responsible for her region. She had an MCADD emergency care plan with her, but this was dated eight years ago. Aside from the NSAIDs listed above, she was not taking any additional medication. She was allergic to co-amoxiclav, dairy products, and coconut oils. She did not smoke or drink alcohol. She participated in rugby, horse riding, swimming, netball, and regular gymnasium workouts. On examination, she had a Glasgow Coma Scale score of 15, with a blood pressure of 120/75 mmHg, heart rate of 66 beats per minute, respiratory rate of 18 breaths per minute, and oxygen saturation of 99% on room air. Abdominal examination revealed severe tenderness in the epigastric and umbilical area, but no guarding or rigidity. Bowel sounds were normal. She weighed 82 kg. Investigations Her initial bedside capillary blood glucose level was 5.3 mmol/L. Further investigation demonstrated normal full blood count, renal function, and liver function. Her C-reactive protein, venous pH, and venous lactate levels were normal. A pregnancy test was negative. The patient's creatinine kinase and lactate dehydrogenase levels were slightly elevated, indicating mild rhabdomyolysis (Tables 1, 2). Electrocardiography was normal. Table 1 Initial hematology results Hematology blood test Results Reference range White cell count (x 109/L) 8.2 4-11 Hemoglobin (g/L) 143 115-165 Platelets (x 109/L) 284 150-400 Neutrophils (x 109/L) 6.4 1.8-7.7 Lymphocytes (x 109/L) 1.2 1.4-4.8 Fibrinogen (g/L) 3.0 2.0-4.5 Prothrombin time (seconds) 13 9-16 Activated partial thromboplastin time (seconds) 29 24-36 Table 2 Initial biochemistry results Results on admission demonstrated slightly elevated creatinine kinase and lactate dehydrogenase levels. Biochemistry blood test Results Reference range C-reactive protein (mg/L) <1 <5 Creatinine kinase (U/L) 515 25-200 Glucose (mmol/L) 5.6 3.9-7.0 Thyroid-stimulating hormone (mU/L) 3.62 0.3-4.2 Free thyroxine (pmol/L) 15.8 12-22 Sodium (mmol/L) 137 133-146 Creatinine (mmol/L) 74 45-84 Potassium (mmol/L) 4.5 3.5-5.3 Urea (mmol/L) 3.1 2.5-7.8 Chloride (mmol/L) 103 95-108 Anion gap (mmol/L) 6 4-16 Alkaline phosphatase (U/L) 81 30-130 Albumin (g/L) 49 35-50 Total bilirubin (mmol/L) 23 <21 Alanine transferase (U/L) 22 10-60 Amylase (U/L) 52 0-100 Adjusted calcium (mmol/L) 2.3 2.2-2.6 Inorganic phosphate (mmol/L) 0.71 0.8-1.5 Magnesium (mmol/L) 0.7 0.7-1.0 Lactate dehydrogenase (U/L) 262 <250 Ferritin (mg/L) 29 30-400 Vitamin B12 (pg/ml) 655 270-1132 Folate (mg/L) 7.3 >3 Venous pH 7.34 7.31-7.41 Venous bicarbonate (mmol/L) 28 23-30 Venous lactate (mmol/L) 1.07 0.2-1.8 Base excess (mmol/L) 1.2 -2 to +2 Treatment We determined that the patient had NSAID-induced gastritis accompanied by mild rhabdomyolysis, based on the symptoms and biochemistry. As her blood glucose levels were in the normal range, an intravenous infusion of 0.9% sodium chloride was commenced for rehydration. She was also given an antiemetic to relieve her vomiting and an analgesic to relieve her pain. After consultation and evaluation of her emergency care plan, she was then commenced on specific therapy according to the emergency care plan: an intravenous infusion of 10% glucose (2 ml/kg per hour) to provide energy and prevent hypoglycemia. She was also given a proton-pump inhibitor to treat her gastritis. She had hourly monitoring of her capillary blood glucose levels while on the glucose infusion. She restarted her glucose polymer drinks and feeding once able to tolerate oral intake. Outcome and follow-up The patient made a rapid recovery and was discharged the following day on pantoprazole 40 mg daily and a liquid antacid for gastritis. Her serum creatinine kinase levels returned to normal three days after discharge. She was provided with an up-to-date emergency care plan, and a notification was put in her electronic records in case of future admissions. Discussion We have presented a case of a young female known to have MCADD who presented to the emergency care center with the inability to keep up calorie intake because of NSAID-induced gastritis. She also had symptoms and biochemical features suggestive of mild rhabdomyolysis. Our hospital records for this patient relating to MCADD and her personal emergency care plan were dated eight years ago. Because her blood glucose level was normal, she was initially commenced on an intravenous 0.9% sodium chloride infusion. Once the emergency care plan was validated, the patient was commenced on an intravenous 10% glucose infusion, and she made a rapid recovery. The patient's concerns and knowledge about MCADD were not fully appreciated at the initial stage due to the rare nature of the condition. This in combination with the absence of current notes on the system, an emergency care plan dated from eight years ago, and the need to obtain specialist advice led to a slight delay in starting specific therapy. The global birth prevalence of MCADD is around 1/14,000 . Affected children are monitored on a regular basis by their metabolic disease pediatrician. As they grow into teens and adults, they are educated about the risk factors and potential dangers associated with hypoglycemia. Risk factors include weight-reducing regimens, competitive sports, and surgery as well as pregnancy and delivery, and the use of alcohol and illicit drugs. People with MCADD should carry along a written emergency management plan and relevant contact numbers . With proper care, there is no reason why people with MCADD cannot live a normal, healthy, and active life. Rhabdomyolysis has been reported as a presenting feature both at diagnosis and during a metabolic crisis in patients with fatty acid oxidation disorders, namely, MCADD and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) . Rhabdomyolysis is characterized by acute and often severe skeletal muscle damage resulting in the release of intracellular muscle components into the bloodstream frequently resulting in myoglobinuria and, in severe cases, acute renal failure . Causes of rhabdomyolysis can be divided into acquired and genetic. The diverse etiologies share a common final pathway, involving increased intracellular free ionized calcium and muscle cell death through the activation of several detrimental mechanisms such as enzymatic activation and prolonged muscle fiber contraction . Patients present with muscle aches, weakness, and, in some cases, dark urine. Triggers for rhabdomyolysis in patients with MCADD include fasting, extreme exercise, alcohol, and illicit drugs . Our patient had symptoms and biochemical features of mild rhabdomyolysis, which could have got worse if emergency treatment was not promptly commenced. Living with MCADD is challenging for both young people and their parents. Parental challenges include preventing and managing illness, dietary monitoring, schooling, excursions, and exercise. These concerns and anxieties increase as the child gets older . Young people with MCADD perceive a burden of responsibility that they must maintain appropriate energy input to stay safe . The importance of self-management and continued support for young people with MCADD and their parents cannot be overemphasized. People with MCADD may require interim follow-up, medication advice, prescriptions, and blood tests at their local clinic, especially if they have other comorbidities. The rare coexistence of MCADD and type 1 diabetes has been described in a case report. Where the goal of therapy is to achieve optimal glycemic control to reduce the risk of long-term complications, there is an increased risk of insulin-induced hypoglycemia, which can be catastrophic in the presence of MCADD . We have previously described the challenges involved in managing a patient with coexisting MCADD, type 1 diabetes, and pregnancy, where the blood glucose control was kept even tighter for optimum fetal development and pregnancy outcome . The importance of continued liaison between the local hospital team and the metabolic disease specialist cannot be overemphasized. Conclusions People with inborn errors of metabolism, such as MCADD, are at risk of metabolic crisis and will attend their local emergency care center in the event of illness. This case report serves as a reminder of the emergency presentation of young people with MCADD, emphasizing the importance of effective communication between the patient, their parents, and the treating clinicians, obtaining the emergency care plan and recommendations, and communicating with the metabolic disease specialist. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 The portal for rare diseases and orphan drugs (Orphanet). Medium chain acyl-CoA dehydrogenase deficiency 2 2023 2014 2 Medium-chain acyl-coenzyme A dehydrogenase deficiency GeneReviews Merritt JL 2nd Chang IJ Seattle, WA University of Washington 2023 3 British Inherited Metabolic Disease Group (BIMDG). Adult emergency management: medium chain fat oxidation disorders 2 2023 2018 4 The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population J Inherit Metab Dis Schatz UA Ensenauer R 513 520 33 2010 20532824 5 Adult-onset very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) Eur J Neurol Fatehi F Okhovat AA Nilipour Y 2257 2266 27 2020 32558070 6 Rhabdomyolysis: a genetic perspective Orphanet J Rare Dis Scalco RS Gardiner AR Pitceathly RD 51 10 2015 25929793 7 Recurrent exercise-induced rhabdomyolysis CMAJ Hannah-Shmouni F McLeod K Sirrs S 426 430 184 2012 22311949 8 Parental experiences of raising a child with medium chain acyl-COA dehydrogenase deficiency Glob Qual Nurs Res Piercy H Machaczek K Ali P Yap S 4 2017 9 "It's just always eating": the experiences of young people growing up medium chain acyl-CoA dehydrogenase deficiency Glob Qual Nurs Res Piercy H Nutting C Yap S 8 2021 10 Coexistence of medium chain acyl-CoA dehydrogenase deficiency (MCADD) and type 1 diabetes (T1D): a management challenge BMJ Case Rep Afreh-Mensah D Agwu JC 0 14 2021 11 Blood glucose control in a pregnant female with type 1 diabetes and medium-chain acyl-CoA dehydrogenase deficiency (MCADD) Endocr Abstr Wilson D Brown A Gumma AD Oyibo SO 0 50 2017 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34806 Dentistry Oral Medicine Integrative/Complementary Medicine Management of Oral Squamous Papilloma Using Annona squamosa (Custard Apple) Leaves: A Novel Case Muacevic Alexander Adler John R Yadav Shikha 1 1 Department of Dentistry, All India Institute of Medical Sciences, Mangalagiri, Mangalagiri, IND Shikha Yadav [email protected] 9 2 2023 2 2023 15 2 e348069 2 2023 Copyright (c) 2023, Yadav et al. 2023 Yadav et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from This report presents the case of a 36-year-old male who was diagnosed with oral squamous papilloma in the palatal region. Excision was planned. The patient in the meantime chewed upon custard apple leaves and reported that the lesion prolapsed over the next few days. On examination, the site showed no signs of scarring or contracture and presented with healthy palatal tissue. The patient was prevented from requiring surgery, which would have shown a longer healing period with heavy reliance on an expensive resource base. This novel observation highlights the benefits of custard apple (Annona squamosa) leaves and warrants that its hepatoprotective, anticancer, antidiabetic, antioxidant, antibacterial, anti-obesity, and lipid-lowering properties are studied in an astute scientific setup with a well-drawn-out research plan. herbal medicine complementary medicine t/cam annona squamosa leaves human papilloma virus oral papilloma custard apple squamous papilloma The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Oral squamous papilloma (OSP) is a benign tumour seen in all age groups, more commonly in individuals aged 30-50 years. It is usually found on the tongue, palatal complex (higher predilection), uvula, and gingiva. Some of these tumours have been linked to human papillomavirus (HPV) 6 and HPV 11, making them one of the most prevalent benign epithelial tumours . It is unknown if all oral papillomas are caused by viral infection. The preferred course of treatment for these lesions is surgical excision, which can alternatively be accomplished with electrocautery, cold-steel excision, laser ablation, cryosurgery, or intralesional interferon injections . It has been extensively documented how traditional medicine and complementary and alternative medicine (T/CAM) are becoming more and more popular among the general people. T/CAM is now frequently used by almost half of the population in several industrialised nations (United States, 42%; Australia, 48%; France, 49%; Canada, 70%), and is widely used in many developing nations (China, 40%; Chile, 71%; Colombia, 40%; up to 80% in African nations) . Custard apple (Annona squamosa) leaves (ASL) have been investigated for their health advantages, which are attributed to a wide variety of phytochemicals. The biological effects of ASL extracts, including their hepatoprotective, anticancer, antidiabetic, antioxidant, antibacterial, anti-obesity, and lipid-lowering properties, have been investigated . No publication mentioning the use of ASL for the management of oral squamous papilloma was discovered after an extensive search of scientific databases. This case presentation is an example of this novel observation. Case presentation A 36-year-old male presented with a raised whitish-pink lesion on the left side of the palatal mucosa. According to the patient, the lesion's size had progressively grown over the past year without any obvious cause for aggravation or relief, and the patient had not taken any special measures to treat it. A firm, single, well-defined exophytic sessile growth with a rough verrucous surface was found on the intersection of the hard and soft palates, originating along the cervical margins of 27 and extending up to 24, roughly the size of 2.5 X 1.5 cms, according to an intraoral examination . There were no palpable lymph nodes. No accompanying pain, paresthesia, or discomfort during speech or deglutition existed for the patient. There were no other lesions on the body with a comparable appearance. Figure 1 Oral squamous papilloma on the left maxillary palatal region The patient was a known diabetic and was under management for it. No personal information on their usage of any substances, such as alcohol, tobacco, or other drugs was provided. The patient did not have a multi-partner/high-risk/unsafe sexual history. Upon a thorough haematological evaluation, all parameters aside from blood sugar levels were found to be within normal ranges. HCV, HIV, and hepatitis B surface antigen (HBsAg) viral indicators all tested negative. The provisional diagnosis of OSP was given on the basis of clinical information, and it was distinguished from other common benign and malignant diseases present in the oral cavity, such as fibromas, verruciform xanthomas, papillary hyperplasia, and condyloma acuminatum. After receiving written informed consent, a biopsy was carried out under local anaesthesia, and tissue measuring 0.5 X 0.2 X 0.1 cm was sent in 10% formalin for histopathological analysis. The histopathological section showed squamous epithelium-lined fragments thrown into the shape of papillae and a central fibrovascular core with sparse lymphocytic infiltration and a few thin-walled blood vessels. Mild hyperkeratosis and inflammatory cell infiltrates were visible in the surface epithelium, although the surface maturation was intact. The area that was investigated revealed no dysplasia or cancer, providing the impression of a squamous papilloma, which was compatible with the provisional clinical diagnosis. Electron microscope analysis reveals viral particles. In situ hybridization, immunohistochemistry, and polymerase chain reaction (PCR) procedures are the additional detection methods . There was no viral genetic typing done. We decided that no additional testing was required because neither dysplasia nor neoplasia was visible. The patient was slated for excision. After a gap of one month, the patient returned to the department, and during examination, it was discovered that the squamous papilloma had entirely disappeared. Following an in-depth conversation with the patient, we concluded that neither any other medical professional had performed any surgical procedures nor had the patient used any medicines targeting the OSP. The only thing he did was that on the advice of a sibling, he utilized ASL. The lesion spontaneously prolapsed during the course of a few days after the patient chewed on a few ASLs and spit the remainder out. There were no obvious surgical scars nor any signs that a cauterization had occurred. This strengthened his claim . Figure 2 Healthy palatal tissue after self-prolapsed oral squamous papilloma Recurrence is uncommon, with the exception of people who are HIV-positive . However, the patient was advised regular follow-ups to check for recurrence. Discussion According to WHO, squamous cell papilloma is a benign hyperplastic exophytic localized proliferation with a verrucous or cauliflower-like morphology. Squamous cell papillomas may be pedunculated or sessile. The pedunculated lesions are composed of a cluster of finger-like fronds and may be white or mucosal in colour, depending on the degree of keratinisation . It is a non-tender exophytic growth that resembles a lesion with a roughened, verrucous, or cauliflower-like surface and is composed of numerous tiny sharp or blunted finger-like projections. Depending on the level of keratinization, the colour may appear white or raspberry-like/pink. The size is typically tiny, with a diameter of a few millimetres to less than 1 cm, although occasionally, enormous growths up to 3 cm in diameter can be found . It is made of a supporting core of connective tissue and a tiny quantity of benign epithelium. OSP was initially described as a "gingival wart" by Tomes in 1848 . HPV 6 and HPV 11 may be linked to it since it is most usually detected on the tongue, palate, uvula, and gingiva. Up to 50% of oral papillomas have been found to contain the HPV 6 and 11 strains . Papilloma is the fourth most common oral soft tissue lesion, accounting for 3-4% of all biopsied lesions . Males are significantly more likely to develop it than females, and the White race is more likely to do so than other races . Smoking, concurrent infections, nutritional deficits, and hormonal shifts all affect the likelihood of developing these lesions . The first line of treatment is surgical removal, with a suggested clearance of 1 mm from the base to the depth of the submucosa. Other options include electrocauterization, cryosurgery, laser surgery, and interferon injections. Topical cidofovir in patients who are HIV positive needs to be explored further . Salicylic acid and vitamin A have both been suggested as topical treatments . It must be carefully removed from highly vascular areas while keeping other critical structures such as nerves and blood vessels in mind. OSPs normally do not turn malignant or recur after surgical removal . Plants and the bioactive components these contain have been used for medicine since the dawn of humanity. Herbal medicines are a gift from nature to humans. The potential of natural products and phytochemicals produced from plants in the treatment of oral disorders has been documented by various writers in recent years . A sizable fraction of the world's population uses traditional medicines to treat a range of illnesses. The term "home" or "folk" remedies is used to describe T/CAM in developing countries where it has been used for a long time both inside and outside the current healthcare system. By 2018, 124 WHO Member States had passed legislation governing herbal remedies, 109 had put national T/CAM laws or regulations forward, and 98 had created national T/CAM policies . In addition to safety and efficacy concerns, regulation has also been a point of concern for WHO in past in the matter related to T/CAM . Anthocyanins, ginseng, curcumin, lycopene, and artemisinin are a few of the possible substances that have demonstrated promise in the treatment of oral squamous cell carcinoma (OSCC) and other tumours . The custard apple (Annona squamosa), of the family Annonaceae, is a popular tropical fruit known for its health benefits. The West Indies, South and Central America, Ecuador, Peru, Brazil, India, Mexico, the Bahamas, Bermuda, and Egypt all farm this significant tropical fruit . The health advantages of ASL, which are attributable to a wide variety of phytochemicals, have been examined and are used as a folk remedy. These substances include phenol-based substances, such as proanthocyanidins, which are made up of 18 different phenolic substances. The majority of these are total phenolic compounds, which also include flavonoids, alkaloids, phenols, saponins, and tannins. The biological effects of ASL extracts, including their hepatoprotective, anticancer, antidiabetic, antioxidant, antibacterial, anti-obesity, and lipid-lowering properties, have been investigated . The protective effects of polyphenolic compounds against a number of chronic diseases, including cancer, diabetes, cardiovascular, and neurological diseases, have been established by epidemiological studies . In Japan, the herbal medicine keishibukuryogan-ka-yokuinin (KBGY) is used to treat different skin conditions, including viral warts. KBGY is a combination of keishibukuryogan, which is made up of five medicinal plants , and yokuinin (coix seeds extract) . Yokinin may be antiviral while keishibukuryogan may be helpful for skin or oral mucosal remodelling, and the impact of KBGY on papillomas is therefore positive . Studies have found that garlic (Allium sativum), which is frequently used in traditional and alternative medicine, has potent antiviral effects. Many different forms of warts, including verruca plana, are treated by pounding garlic into a paste and applying it topically; however, an inappropriate application might have unfavourable effects like the Koebner phenomenon . Examples of ethical problems that may occur include difficulties with patient recruiting, randomization, and retention, as well as the identification of permissible placebo therapies. Furthermore, the ready availability of nutritional supplements and other complementary interventions on the free market considerably increases the potential of "cheating" by the control group should patients agree to randomization. Despite these challenges, carefully thought-out clinical trials are still possible, including in-depth analyses of entire T/CAM systems. Observational studies provide a useful way to tackle particular types of issues, such as the assessment of occasional unfavourable occurrences. People who maintain that the evidence for T/CAM can legitimately be weaker than mainstream care will need to reevaluate their views. Integrating T/CAM practitioners within settings of traditional medicine is essential. This was done in India by incorporating AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy) clinics within standard conventional medical facilities. The National Health Policy 2017 has provided significant support for AYUSH's potential within a varied system of integrative healthcare . Conventional healthcare practitioners need to learn as much as they can about T/CAM in order to make sure that their patients feel comfortable discussing their usage of T/CAM with them. Natural dietary phytoconstituents will continue to be an intriguing and vibrant study subject in the coming years. Large-scale, meticulously supervised clinical trials are required to examine the efficacies, side effects, and safety of promising phytochemicals derived from plants. Comparisons of alternative and conventional medicine are necessary for the treatment of specific diseases. In addition to specific biomedical outcomes, comparative studies could assess the viability, affordability, and environmental impact. Our report's obvious limitation is that it only considers one specific example. But to believe that there is a seed of truth in a patient's words is a starting point. Conclusions This report is unique because our search of scientific literature turned up no published works in which the use of ASL for OSP treatment was highlighted. In order to establish the repeatability of our novel observation with ASL on papillomas, well-drawn-out research with a larger sample size is required. Given their lower cost and less reliance on an expensive resource base, these food-based drugs may be more readily accepted. Reduced healing time or less wound contracture/scarring may also lessen patient anxiety. There is an urgent need for local health traditions to be globally revived in a more uniform way. The future is an amalgamation of all streams, and perhaps this will be decided by objective scientific analysis. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Prevalence of human papillomavirus (HPV) in oral cavity and oropharynx Braz J Otorhinolaryngol Castro TP Bussoloti Filho I 272 282 72 2006 16951865 2 An update on oral human papillomavirus infection Indian J Sex Transm Dis AIDS Bharti AH Chotaliya K Marfatia YS 77 82 34 2013 24339456 3 A public health agenda for traditional, complementary, and alternative medicine Am J Public Health Bodeker G Kronenberg F 1582 1591 92 2002 12356597 4 Custard apple (Annona squamosa L.) leaves: nutritional composition, phytochemical profile, and health-promoting biological activities Biomolecules Kumar M Changan S Tomar M 614 11 2021 33919068 5 Annonas: Underutilized species as a potential source of bioactive compounds Food Res Int Anaya-Esparza LM Garcia-Magana ML Abraham Dominguez-Avila J Yahia EM Salazar-Lopez NJ Gonzalez-Aguilar GA Montalvo-Gonzalez E 109775 138 2020 33292953 6 Oral squamous papilloma management with diode laser: a case report Int J Contemp Med Res Jose RM K RB Jayapal N David CM Nanaiah P Gowda VA 0 7 6 2019 7 Oral squamous papilloma: clinical, histologic and immunohistochemical analyses J Oral Sci Carneiro TE Marinho SA Verli FD Mesquita AT Lima NL Miranda JL 367 372 51 2009 19776503 8 WHO Classification of Head and Neck Tumours, 4th Edition Lyon, France IARC Publications 2017 9 Human papillomavirus and oral disease - emerging evidence: a review Aust Dent J Prabhu SR Wilson DF 2 10 58 2013 10 Diode laser treatment of an oral squamous papilloma of soft palate J Dent Lasers Rakhewar PS Patil HP Thorat M 114 117 9 2015 11 The clinical and histopathologic features of a series of 464 oral squamous cell papillomas Oral Surg Oral Med Oral Pathol Abbey LM Page DG Sawyer DR 419 428 49 1980 6154913 12 The management of oral human papillomavirus with topical cidofovir: a case report Cutis DeRossi SS Laudenbach J 191 193 73 2004 15074348 13 Oral squamous papilloma mimicking oral verrucous leukoplakia Cureus Tebcherany H Grandhi A Khocht A 0 14 2022 14 Plant-based antioxidant extracts and compounds in the management of oral cancer Antioxidants (Basel) Prakash S Radha Radha Kumar M 1358 10 2021 34572990 15 WHO global report on traditional and complementary medicine WHO Global Report On Traditional And Complementary Medicine 2019 Geneva, Switzerland World Health Organization 2019 16 Flavonoid epimers from custard apple leaves, a rapid screening and separation by HSCCC and their antioxidant and hypoglycaemic activities evaluation Sci Rep Zhu H Chen L Yu J 8819 10 2020 32483211 17 The traditional Japanese formula keishibukuryogan inhibits the production of inflammatory cytokines by dermal endothelial cells Mediators Inflamm Yoshihisa Y Furuichi M Ur Rehman M Ueda C Makino T Shimizu T 804298 2010 2010 21253500 18 Effects of Yokuinin on the therapeutic efficacy of a new benzoxazinorifamycin KRM-1648 against Mycobacterium avium infection Int J Antimicrob Agents Shimizu T Tomioka H Sato K Sano C Yamada Y Shibata H Higashi N 69 74 11 1999 10075281 19 Prolapsed tongue papilloma cured by administration of the traditional Japanese (Kampo) herbal medicine, keishibukuryogan-ka-yokuinin: a case report J Integr Med Sakata M Watanabe J 535 538 18 2020 32980289 20 Topical garlic treatment for verruca plana triggers Koebner phenomenon: a case report J Cosmet Dermatol Yu T Che J Song J Duan X Yang J 1 3 2022 21 AYUSH for new India: vision and strategy J Ayurveda Integr Med Shankar D Patwardhan B 137 139 8 2017 28923183 |
Contemp Clin Trials Commun Contemp Clin Trials Commun Contemporary Clinical Trials Communications 2451-8654 Elsevier S2451-8654(23)00054-6 10.1016/j.conctc.2023.101108 101108 Article An evidence double standard for pharmacological versus non-pharmacological interventions: Lessons from the COVID-19 pandemic Hoeg Tracy Beth [email protected] * Prasad Vinay K. Department of Epidemiology and Biostatistics, University of California-San Francisco, 550 16th St 2nd floor, San Francisco, CA, 94158, USA * Corresponding author. [email protected] 11 3 2023 6 2023 11 3 2023 33 1011084 1 2023 24 2 2023 10 3 2023 (c) 2023 The Authors 2023 This is an open access article under the CC BY license ). Keywords Medical evidence Public health COVID-19 Pharmacological interventions Non-pharmacological interventions pmcThroughout the COVID-19 pandemic, a wide range of interventions have been deployed with the goal of slowing viral spread or lessening harmful impacts of the virus after exposure or infection. These included either individual or society-wide interventions, and non-pharmacological or pharmacological interventions. For pharmacological interventions, such as pills or injectable compounds, bioplausibility was derived from biochemical or in-vitro studies. For behavioral or non-pharmacological interventions, bioplausibility might have relied upon physics, aerosol science or simply that the intervention seemed logical. Interventions can be embraced to different degrees. While some are merely recommended, others may be required or mandated. In general, there is a discrepancy in supporting evidence: Pharmacological interventions typically require numerous randomized studies before (or at least ongoing with) any recommendation, whereas non-pharmacological interventions were often untested prior to widespread adoption. A review completed in August of 2021 found only around 1% of registered clinical trials on COVID-19 globally were for non-pharmaceutical interventions. This might be justifiable if pharmaceutical or pharmacological interventions had greater side effects or downsides, but this is often not the case. For example, downsides of school closures have included but are not limited to increased school dropout rates , decreased academic achievement and decreased lifetime earnings . Downsides of sports closures may include weight gain and negative effects on emotional well-being . Downsides of interventions such as carbon dioxide (CO2) monitors or sensors may include money diverted from other evidence-based public health interventions, technological dependency, where focus is on the device rather than on situational awareness , heightened sense of anxiety about disease or, conversely, a false sense of security for those who are high risk . For pharmacological interventions, side effects are predominately biological and often detectable, particularly in a randomized fashion. Conversely, for non-pharmacological interventions, the scope and magnitude of downsides are more difficult to quantify and may involve social, emotional, educational and often more delayed or difficult-to-define biological effects. Because most biologically plausible interventions, even those supported by some observational data, are eventually shown to be ineffective in real-world conditions , we should presume the net harms of non-pharmacological and pharmacological interventions alike outweigh the benefits until high-quality evidence can be shown to the contrary. As we look back on the COVID-19 pandemic, it is our obligation to identify ways we can improve our public health response in the future. While pharmacological interventions were more readily accepted or rejected based on rapidly completed high-quality trials, many non-pharmacological interventions with known or obvious harms and weak evidence at best continued to be recommended for years if not to this day. In this essay, we contrast the varying response to two interventions: the use of ivermectin vs. C02 monitors against COVID-19 as examples of this evidentiary double standard. We then discuss the broader implications of this double standard during the COVID-19 pandemic highlighting why gathering high quality data quickly, preferably through randomized trials, should be required to guide public health recommendations and avoid policies with net societal harms in the future. 1 Ivermectin Ivermectin is an FDA approved anti-parasitic drug. It has biological plausibility against SARS-CoV-2 because of its in vitro effects against RNA virus replication, including very promising in vitro effects against SARS-CoV-2. Ivermectin relies on a chemical mechanism of action, and has been tested repeatedly in randomized trials, which thus far have rarely found significant benefits and have predominantly been negative. There have been few [ , , ], double blind, placebo-controlled RCTs that have found clinical benefit of ivermectin alone vs placebo. The vast majority of trials have been negative. Most trials have been underpowered to detect reductions in hospitalization or death of less than 30-50%. For example, the TOGETHER trial found 17%, 23% and 12% reductions in hospitalization, mechanical ventilation and death, respectively, but none was significant. One systematic review and meta-analysis from June of 2022 failed to identify benefit against severe disease or recovery time, but found, based on low certainty, it may reduce mortality (log OR -0.67[95% CI, -1.20 to -0.13]). Another systematic review of 25 randomized studies failed to identify a benefit against mortality or requirement for mechanical ventilation . The ACTIV-6 trial identified no significant clinical benefits of ivermectin, though it was completed in a setting of very high degree of population immunity. None of the randomized studies identified major safety issues with Ivermectin. Cost of individual ivermectin treatment would typically be less than $100. The FDA , CDC , NIH and other public health and medical organizations have not only not recommended ivermectin, but warned against its use for COVID-19. 2 CO2 monitors Numerous experts have advocated for the use of personal CO2 monitors without randomized or high-quality data supporting their use against COVID-19. For example, one Chair of Atmospheric Chemistry, has advocated for , carrying a "CO2 sensor to determine where to sit in airports ..." and has also recommended "measur[ing] CO2 levels when classes are running w[ith] people present ... levels need to be < 800 ppm." Additional infectious disease experts have recommended using personal CO2 devices to reduce the risk of COVID-19, admitting to carrying their own device. One coronavirus researcher explained he has a phone CO2 device which alarms when levels rise above a certain point, a sign ventilation is not sufficient to decrease his chance of getting COVID-19, at which point he puts on a mask . Beyond the advice of experts to the public, some public schools in California are now, for the purposes of maintaining safety related to the COVID-19 pandemic, required to use CO2 sensors in some classrooms . 10.13039/100004956 Minnesota Department of Health recommends their use in high-occupancy classrooms . The CDC supports the use of portable CO2 monitors and recommends portable air cleaners for readings above 800 ppm . CO2 monitors have been proposed as a way to minimize risk of contracting (or spreading) COVID-19. These monitors work through indirect mechanisms to estimate the amount of CO2 in the air. CO2 concentrations increase in an indoor space related to the number of people in a room, ventilation and, in certain circumstances such as during wildfires, surrounding environmental levels. The effectiveness of a CO2 monitor against COVID-19 relies on 1. Accurately measuring CO2 levels, 2. CO2 levels correlating with risk of infection, 3. A person's ability to react to a reading that is above their predetermined threshold of risk and 4. Assumes CO2 monitors give you information about an indoor environment you don't already know. The monitors vary in terms of quality. To date, no randomized studies exist of rates of COVID-19 infection or transmission in different CO2 levels. One randomized trial in a hospital found CO2 monitors placed in patient rooms with instructions to staff to keep CO2 levels below 800 parts per million did not result in significantly less time per day at elevated levels in the invention arm. The staff cited patient discomfort from cold with windows open as a major barrier to decreasing CO2 levels. This study demonstrates the important principle that even very plausible interventions will only work insofar as people can comply with them. Additional side effects of using CO2 monitors to determine or estimate COVID-19 infection risk include the need to change plans due to CO2 levels, increase in anxiety, false sense of security and potentially unnecessary expenses of an upgraded building ventilation system when an arbitrary CO2 threshold cannot be maintained. Higher quality personal CO2 monitors such as the ARANET4 recommended by one researcher cost around $250. 3 Recommendations and mandates of non-pharmacological interventions by public health authorities Other non-pharmacological interventions have not only been recommended by public health authorities but, at times, mandated. In the United States, for example, the CDC ordered mask requirements for public transportation and required testing prior to international travel into the United States. The CDC also made recommendations for indoor masking and for certain conditions to be met for schools or businesses to reopen, which were then mandated on a local level. 4 Contrasting required levels of evidence for pharmacological vs non-pharmacological interventions We conducted PubMed search on Feb 15th, 2023, to identify published randomized trials and a US National Library of Medicine search on ClinicalTrials.gov for ongoing/active randomized trials assessing the effects of ivermectin, hydroxychloroquine, convalescent plasma, CO2 monitors, masking, school, sports or business closures, and ventilation system changes against COVID-19. We excluded trials where the select interventions were studied only in combination with another intervention, where the outcomes did not include a measurement of efficacy against a COVID-19 endpoint or where the study was in preprint form only. We chose specifically not to use COVID-19 vaccines for comparison due that intervention's need for additional evidence to guide recommendations for different doses and in different populations. In Table 1 and Fig. 1, we list pharmacological interventions, for which the medical community implicitly understands the importance of validation studies. It is not sufficient to have a mechanism of action; indeed it is merely a prerequisite. When it comes to non-pharmacological interventions, we do not extend the same scrutiny.Table 1 Randomized investigation, mandates, risks and benefits of select non-pharmacological and pharmacological interventions against COVID-19. Table 1Non-pharmacological interventions Ongoing RCTs Completed RCTs Ever mandated? Benefits demonstrated in randomized trials Documented or theoretical risks CO2 monitors 0 0 Yes, in some settingsa Noneb Anxiety from being unable to decrease CO2 levels in certain situations, uncomfortable room temperatures due to need to open windows, cost, potentially needless upgrade to improved ventilation systems Masks vs. no masks 2 2 Yes 1 RCT negative; 1 with modest surgical mask benefit only significant among >=50 age groupc Interpersonal communication, word acquisition, comfort, anxiety about disease School/sports closures 0 0 Yes Noneb Educational disruption, decreased lifetime earning potential, loss of safe environment outside of home, loss of fitness and socialization, disruption of physical, speech and other therapies School/building ventilation system upgrades 0 0 Yes Noneb Cost to society/schools, increased energy demand compared with natural ventilation and potential movement away from outdoor air exposure Business closures 0 0 Yes Noneb Loss of current and future earning potential, psychological stress of loss of business and productivity, unemployment costs and supply chain disruptions, delayed care, decreased life expectancy Pharmacological interventions Ivermectin (alone) 8 24 No Small minority of RCTs finding clinical benefit Generally safe at recommended dosages Hydroxychloroquine (alone) 8 34 No No significant benefit found in existing RCTs Generally safe at recommended dosages Convalescent plasma 16 40 No No significant benefit found in existing RCTs Typically mild; similar to blood transfusion w/rare risk of infection or allergic reaction a All public schools in California receiving CALShape grant money ). b Randomized evidence entirely lacking. c This benefit has been called into question due to imbalances between treatment and control groups ). Fig. 1 Ongoing and Published Randomized Controlled Trials for Select Non-Pharmacological vs Pharmacological Interventions for COVID-19. Fig. 1 Besides CO2 monitors, other examples include, but are not limited to, mask mandates, ventilation systems and school, sports and business closures. School closures, for example, were a massive societal intervention with numerous harms undertaken with a lack of evidence of effectiveness. Researchers from Norway famously called for randomized studies of the intervention, which were not done, and their country's school closures were brief. For mask mandates in children, social and educational harms have been suspected and are now beginning to be documented . It is not that randomized studies of non-pharmacological interventions cannot be done; they can, but are simply not expected or required by the medical and public health communities. We contend this is a dangerous and expensive double standard; we should require the same level of evidence for non-pharmacological interventions as pharmacological. High quality studies should be undertaken within weeks of a new pandemic to avoid unnecessary harms from ineffective interventions. Although non-pharmacological interventions have side effects that are more difficult to quantify and study, they should not be assumed to be of less importance and, in most cases, have wider societal consequences. Funding None. Declaration of competing interest The authors report no conflicts of interest. Both authors had access to the data and a role in writing this Commentary. References 1 Hirt J. Janiaud P. Hemkens L.G. Randomized trials on non-pharmaceutical interventions for COVID-19: a scoping review BMJ Evid Based Med 27 6 2022 Dec 334 344 10.1136/bmjebm-2021-111825 Epub 2022 Jan 27 2 Center for Global Development Learning loss and student dropouts during the COVID-19 pandemic: a review of the evidence two years after school shut down March 14 2022 3 Goldhaber D. National center for analysis of longitudinal data in education research. The consequences of remote and hybrid instruction during the pandemic May 2022 4 McKinsey Company COVID-19 and student learning in the United States: the hurt that could last a lifetime June 1, 2020 5 Raimondi S. Cammarata G. Testa G. Bellerba F. Galli F. Gnagnarella P. Iannuzzo M.L. Ricci D. Sartorio A. Sasso C. Pravettoni G. Gandini S. The impact of sport activity shut down during the COVID-19 pandemic on children, adolescents, and young adults: was it worthwhile? Int. J. Environ. Res. Publ. Health 19 13 2022 Jun 28 7908 6 Donaldson S.J. Ronan K.R. 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Markowitz J.S. Navaeifar M.R. Hosseinzadeh F. Movahedi F.S. Rezai M.S. Effects of ivermectin in patients with COVID-19: a multicenter, double-blind, randomized, controlled clinical trial Clin. Therapeut. 43 6 2021 Jun 1007 1019 13 Aref Z.F. Bazeed S.E.E.S. Hassan M.H. Hassan A.S. Ghweil A.A. Sayed M.A.A. Rashad A. Mansour H. Abdelmaksoud A.A. Possible role of ivermectin mucoadhesive nanosuspension nasal spray in recovery of post-COVID-19 anosmia Infect. Drug Resist. 15 2022 Sep 19 5483 5494 36164334 14 Reis G. Silva E.A.S.M. Silva D.C.M. Thabane L. TOGETHER investigators. Effect of early treatment with ivermectin among patients with covid-19 N. Engl. J. Med. 386 18 2022 May 5 1721 1731 35353979 15 Shafiee A. Teymouri Athar M.M. Kohandel Gargari O. Ivermectin under scrutiny: a systematic review and meta-analysis of efficacy and possible sources of controversies in COVID-19 patients Virol. J. 19 2022 102 35698151 16 Marcolino M.S. Meira K.C. Guimaraes N.S. Motta P.P. Chagas V.S. 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34810 Internal Medicine Hematology An Unusual Case of Catastrophic Antiphospholipid Syndrome in an Elderly Man Muacevic Alexander Adler John R Lam Kayla 1 Selim Mohammad 1 1 Internal Medicine, Creighton University School of Medicine, Omaha, USA Kayla Lam [email protected] 9 2 2023 2 2023 15 2 e348109 2 2023 Copyright (c) 2023, Lam et al. 2023 Lam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Antiphospholipid syndrome (APS) is a condition in which the body produces antiphospholipid antibodies, resulting in arterial and venous thrombosis. Catastrophic antiphospholipid syndrome (CAPS) is a rare APS subtype characterized by acute thrombotic microangiography. Antiphospholipid antibodies cause thrombosis through activating and inhibiting properties. CAPS is caused by conditions or factors that trigger the production of antiphospholipid antibodies: genetics that increases the risk of antiphospholipid antibody-associated thrombosis, infection, surgery, medications, and malignancy. We present a unique case of CAPS in a 63-year-old male patient. catastrophic apls apls aps antiphospholipid syndrome catastrophic aps catastrophic antiphospholipid antibody syndrome(caps) caps The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Antiphospholipid syndrome (APS) is a condition in which the body produces antiphospholipid antibodies, resulting in arterial and venous thrombosis, most commonly impacting the lower limbs and cerebral arterial circulation . Catastrophic antiphospholipid syndrome (CAPS) is a rare, life-threatening subtype of APS (<1% APS patients), characterized by acute thrombotic microangiography that can result in multi-organ failure in a short period of time . This case study describes an unusual patient with CAPS, which occurs in a 63-year-old male. CAPS has been noted to occur in middle-aged females . Case presentation A 63-year-old male with a history of hypertension presented to the emergency department (ED) with a two-day history of increasingly worse shortness of breath (SOB) and chest tightness. The patient's SOB was minimal at rest but aggravated with exertion. Lung sounds were clear bilaterally, albeit slightly reduced. The skin was noted to be pale. The serum troponin level was increased from 66 ng/L to 150 ng/L over the course of 45 hours (male normal range <=77 ng/L). Doppler ultrasound showed deep vein thromboses (DVTs) in the right femoral, popliteal, and peroneal veins . Figure 1 Doppler venous ultrasound demonstrating thromboses in the right (A) femoral, (B) popliteal, and (C) peroneal veins The orange arrow is pointing at the thrombus within the femoral vein. Dashed orange lines outline the popliteal vein. The red arrow is indicating an extensive, active thrombus within the peroneal vein. The green arrow is pointing at an old thrombus within the peroneal vein. The electrocardiogram (EKG) was unremarkable, and the complete blood count (CBC) showed a low platelet count of 35,000/uL (no previous history of thrombocytopenia), serum creatinine was 2.2 (previous levels for the past two years were 1.41-1.47 mg/dL), blood urea nitrogen (BUN) was 33, and the congestive heart failure (CHF) peptide was 10,000 pg/mL. The echocardiogram showed severe right ventricular (RV) dilatation and reduced RV function. The interventricular septum flattened during diastole. A computed tomography (CT) with angiogram was ordered and showed sub-massive bilateral pulmonary embolism (PE), spanning from the right and left main pulmonary arteries into the lobar and segmental branches and indicating a cause for the right heart failure . Figure 2 CT chest angiogram demonstrating pulmonary emboli in (A) the left main pulmonary artery, (B) the right main pulmonary artery and right lobar branches, and (C) the left lobar and segmental branches. Red arrows indicate pulmonary emboli. Catheter-directed thrombolysis was done to resolve the pulmonary embolism. Serum creatinine levels and BUN were repeated four hours later and found to have decreased to 1.6 and 28, respectively. On the fourth day of admission, the platelet count decreased to 27,000/uL, and there were no signs of hemolysis. The patient was then switched from low-dose heparin to apixaban. Due to the combination of acute thrombosis and thrombocytopenia, APS was suspected. Because the patient was in post-catheter-directed thrombolysis status, the drop in platelet count could not be attributed to deep vein thrombosis (DVT) or pulmonary embolism (PE). Tests for antiphospholipid antibodies, anticardiolipin, and anti-BGP-1 came back positive. Disseminated intravascular coagulation (DIC) and heparin-induced thrombocytopenia (HIT) were deemed less likely due to a low score based on the International Society on Thrombosis and Haemostasis (ISTH) criteria for disseminated intravascular coagulation (DIC) and based on the low 4T-score for the HIT pretest probability . Consequently, HIT antibodies were not measured. On day five of admission, the patient was switched over to warfarin. The patient was discharged on the sixth day of admission with prednisone and warfarin prescribed. Six weeks later, he was still positive for antiphospholipid antibodies. As a result, this patient was diagnosed with antiphospholipid syndrome and further suspected of having catastrophic APS. Discussion Antiphospholipid syndrome has been under-researched in terms of epidemiology, and the first population-based study on the epidemiology of APS itself was just recently published in 2019 . Antiphospholipid syndrome presents with arterial and venous thrombosis, most commonly impacting the lower limbs and cerebral arterial circulation . Less than 1% of patients present with catastrophic antiphospholipid syndrome, a rare, life-threatening subtype of APS characterized by acute thrombotic microangiography that can result in multiorgan failure in a short period of time . The antiphospholipid antibodies cause thrombosis through activating and inhibiting properties. For activation, the antibodies target endothelial cells, platelets, immune cells, and complement, inducing inflammation and thrombosis. The antibodies also inhibit anticoagulants and deter fibrinolysis. CAPS is caused by conditions or factors that trigger the production of antiphospholipid antibodies: genetics that increase the risk of antiphospholipid antibody-associated thrombosis (ex: coagulation factor mutations), infection (ex: Borrelia burgdorferi, treponema, HIV, Leptospira), surgery, medications (ex: chlorpromazine, procainamide, quinidine, phenytoin), and malignancy . Furthermore, CAPS is often associated with autoimmune disorders, with systemic lupus erythematosus (SLE) being the most common (40%) . Regarding the patient population, 72% of CAPS patients are women, ranging in age from 11 to 60 years old, with a mean age of 37 . In this case, the patient was a man, on the far upper end of the age spectrum, at the age of 63, which is unusual in terms of both age and sex. As for the criteria to diagnose CAPS, all four of the following requirements must be fulfilled for a definitive diagnosis: (1) involvement of at least three organs; (2) development of manifestations in less than a week; (3) histological evidence of intravascular thrombosis; and (4) presence of antiphospholipid antibodies on two occasions, six weeks apart . CAPS is probable but not definitive if any subset of the criteria occurs in the following manner: 1, 2, 4; 1, 3, 4, but the third event occurs between a week and a month even with anticoagulation; 1-4, but only two organs are affected; and 1-4, but the second antiphospholipid antibodies assay could not happen at least six weeks after the first due to patient death . In our case, the patient fulfilled one, but only two organs: the heart (elevated serum troponin levels and right heart strain) and kidneys (elevated creatinine and BUN until they dropped post-thrombolysis) were affected. He also fulfilled requirements three and four. Thus, the suspicion of CAPS was confirmed. Regarding treating CAPS, the consensus is to employ anticoagulants and corticosteroids in all patients . While there are no randomized-controlled trials (RCTs) on specific types of anticoagulants in CAPS specifically due to low prevalence, there have been several recent studies on APS in general showing that warfarin prevents anticoagulation more efficaciously than direct oral anticoagulants (DOACs) and that DOACs increase the risk of thromboses compared to warfarin . Hence, the patient was switched from apixaban to warfarin upon the suspected diagnosis of CAPS. Conclusions Based on this unusual instance of CAPS, there is a need to keep an open mind when diagnosing and not be limited by the common patient presentation. Considering that CAPS is not as frequently seen as typical APS and yet is also life-threatening, this unusual appearance of CAPS in a more elderly male rather than the typical middle-aged female calls for the need to screen all patients with evidence of intravascular thrombosis for CAPS in order to treat CAPS earlier and reduce mortality from this disease. Additional studies should be done to further identify differences in risks between CAPS and generic APS to help prompt earlier prevention or intervention, especially since this patient had no prior medical history besides hypertension. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Antiphospholipid Syndrome Bustamante JG Goyal A Singhal M Treasure Island, FL StatPearls [Internet] 2022 2 Catastrophic antiphospholipid syndrome: a clinical review J Nephropathol Nayer A Ortega LM 9 17 3 2014 24644537 3 The diagnosis and clinical management of the catastrophic antiphospholipid syndrome: a comprehensive review J Autoimmun Cervera R Rodriguez-Pinto I Espinosa G 1 11 92 2018 29779928 4 The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview J Thromb Haemost Toh CH Hoots WK 604 606 5 2007 17096704 5 Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis Blood Cuker A Gimotty PA Crowther MA Warkentin TE 4160 4167 120 2012 22990018 6 The epidemiology of antiphospholipid syndrome: a population-based study Arthritis Rheumatol Duarte-Garcia A Pham MM Crowson CS 1545 1552 71 2019 30957430 7 Epidemiology of antiphospholipid syndrome in the general population Curr Rheumatol Rep Dabit JY Valenzuela-Almada MO Vallejo-Ramos S Duarte-Garcia A 85 23 2022 34985614 8 Treatment of catastrophic antiphospholipid syndrome Curr Opin Rheumatol Kazzaz NM McCune WJ Knight JS 218 227 28 2016 26927441 9 A difficult and rare case of warfarin refractory antiphospholipid syndrome presenting with catastrophic antiphospholipid syndrome complicated by gastrointestinal bleeding Cureus Lim W Kaur A Munoh Kenne F Shulimovich M 0 13 2021 10 Direct oral anticoagulants use in antiphospholipid syndrome: are these drugs an effective and safe alternative to warfarin? A systematic review of the literature Curr Rheumatol Rep Dufrost V Risse J Zuily S Wahl D 74 18 2016 27812956 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34814 Otolaryngology Pediatrics Pediatric Surgery Congenital Laryngeal Hemangioma: A Case Report of a Rare Presentation Muacevic Alexander Adler John R Appiah-Thompson Peter 12 Hanson Nana Andoh M 2 Quansah Kofi 2 Edzie Emmanuel Kobina Mesi 3 Babatunde Jimah Bashiru 3 1 Surgery/Otolaryngology, School of Medical Sciences, University of Cape Coast, Cape Coast, GHA 2 Surgery/Otolaryngology, Cape Coast Teaching Hospital, Cape Coast, GHA 3 Radiology, School of Medical Sciences, University of Cape Coast, Cape Coast, GHA Peter Appiah-Thompson [email protected] 9 2 2023 2 2023 15 2 e348148 2 2023 Copyright (c) 2023, Appiah-Thompson et al. 2023 Appiah-Thompson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Pediatric vascular anomalies are classified into vascular malformations and vascular tumors. While vascular malformations are generally anomalous vessels, vascular tumors arise from endothelial cells characterized by abnormal proliferation. Vascular tumors, also called hemangiomas, are subdivided into infantile and congenital hemangiomas. The differentiation of these anomalies can be challenging, and immunohistochemical staining is often employed for this purpose. The GLUT-1 (erythrocyte-type glucose transporter protein) stain is positive for the infantile type. Hemangiomas are usually found in the head and neck region. Their occurrence in the laryngeal region in infants tends to manifest in the subglottic region. Hemangiomas in the larynx mostly do not cause any symptoms until they are large enough to cause dyspnea, stridor, or hoarseness of voice. They are mostly treated in infants with propranolol or surgical excision. We report a case of an eight-day-old female infant who presented with a mass that recurrently protruded out of the mouth when she cried. The mass stopped protruding out of the mouth when the baby became restless, had respiratory distress, and refused feeds. Endoscopy of the pharynx and larynx showed a pedunculated hemorrhagic mass attached by a stalk to the left arytenoid. With cautery, the stalk of the lesion was severed from its attachment. The baby was discharged on the fourth postoperative day and histology reported a cavernous hemangioma. Seven months after the surgery, the baby is growing normally. Yearly follow-up endoscopies have been scheduled to evaluate for recurrence or residual disease. congenital haemangioma vascular tumours vascular malformations vascular anomalies supraglottic subglottic capillary cavernous infantile laryngeal haemangioma The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Pediatric vascular anomalies are classified into vascular malformations and vascular tumors. The vascular malformations generally comprise anomalous vessels, while the vascular tumors arise from the endothelial cells characterized by abnormal proliferation. The vascular malformations, though present at birth, grow slowly and mostly become enlarged due to hormonal activity (such as at menarche or during pregnancy) or in the setting of trauma or surgery. Vascular tumors, also called hemangiomas, are subdivided into infantile and congenital hemangiomas. The differentiation of these anomalies can be very difficult, and immunohistochemical staining is helpful for their differentiation. The GLUT-1 (erythrocyte-type glucose transporter protein) stain is positive for the infantile type. Infantile hemangiomas are generally not present at birth, and, if they do occur, they only appear as a reddened or pale area where the lesion subsequently appears. The congenital type, which involves high-flow vascular tumors, manifests at birth. The congenital type can involute over a period of a year or may persist . Hemangiomas are the most common tumors of infancy and are mostly found in the head and neck region . These lesions tend to be more common in children as compared to adults . The usual locations of these tumors are the subglottic region for the infantile laryngeal type and the supraglottic region for the adult laryngeal type . They rarely transform into malignancies even in adults . In children, the presence of congenital laryngeal hemangiomas may cause stridor or dyspnea due to their subglottic location in most cases . The diagnosis of these lesions is usually made in newborns based on the observation of the aforementioned clinical features. The clinical presentation of these lesions tends to be dependent on their size. In adults, they might not cause any symptoms until they are incidentally noted on endoscopy, e.g., during direct laryngoscopy . CT scans or MRIs would be able to reveal the exact locations and sizes of these lesions. Even though a detailed history, examination, flexible nasolaryngoscopy, and CT scanning may point to the lesion as being a vascular anomaly, histology is needed to confirm the diagnosis of hemangioma. Case presentation An eight-day-old baby girl was referred to our tertiary healthcare facility, with a history of intermittent protrusion of a fleshy swelling out of the mouth since birth. The baby had a normal cry but was noted to have difficulty feeding when the swelling returned to the throat. The examination showed a pink, healthy baby with a reddish mass that periodically protruded out of the mouth when she cried, as shown in Video 1. Video 1 Reddish mass protruding out of the mouth of the baby when she cries A tentative diagnosis of a pharyngeal mass was made with a differential diagnosis of a lingual thyroid gland. An initial ultrasound of the neck found a normal thyroid gland. A nasogastric tube was blindly passed with caution and tube-feeding was started since breastfeeding was difficult for the baby. During admission, the baby developed a fever, which was managed with IV cefazolin and IV paracetamol. While awaiting a CT scan report, the baby became restless and started crying excessively, and the mass no longer protruded from the oral cavity. Emergency examination of the pharynx and larynx under anesthesia was then done after successful endotracheal intubation. The intraoperative findings were as follows: i) a pedunculated reddish mass with a pedicle attached to the superior surface of the left arytenoid region with the mass completely buried in the esophagus, and ii) a normal oral cavity, pharynx, and laryngeal structures (apart from the left arytenoid). The reddish lesion was then teased out of the esophagus with forceps and the pedicle was severed with diathermy under direct laryngoscopy with a Chevalier Jackson laryngoscope. The specimen, i.e. the lesion as seen in Figure 1, was then sent for histopathology. Figure 1 Reddish laryngeal mass after excision The baby recovered well after surgery and was discharged on the fourth postoperative day. The CT scan, which was received after the surgery, showed a poorly differentiated mass located in the left half of the nasopharynx, as shown in Figure 2. Figure 2 Axial CT scan of the paranasal sinuses and pharynx showing a mass in the left half of the nasopharynx (encircled) CT: computed tomography Histology reported the following findings: sections show proliferation of thick and thin-sized blood vessels in the dermis of varying sizes admixed with lobules of fat. The overlying epithelium was ulcerated. Diagnosis: cavernous hemangioma. Seven months after surgery, the baby continues to grow very well. Discussion Vascular anomalies have been grouped into vascular malformations and vascular tumors. Vascular malformations are present at birth in most cases but grow slowly and are challenged to grow more by trauma and hormones. Vascular tumors, which result from endothelial hyperplasia, are classified into the infantile type and the congenital type. The infantile type is differentiated from all other vascular anomalies by the positive GLUT-1 staining , which, unfortunately, is not available in our country. Laryngeal hemangiomas are mostly found in the subglottic region in infants with the adult type being found attached to supraglottic structures such as epiglottis, aryepiglottic folds, arytenoids, and false and true vocal cords . In our case, unlike the mostly reported location, the lesion was attached by a stalk to the left arytenoid in a baby. Laryngeal hemangiomas occur in different forms, i.e., cavernous, capillary, or mixed types. The capillary type tends to have larger vascular channels with deeper infiltration into the submucosa while the cavernous types are well-circumscribed and less infiltrative . Our case was a cavernous type. Management of these lesions depends on their size. Small lesions may be treated with observation and follow-up. Larger lesions causing symptoms may require intralesional injections of corticosteroids, carbon dioxide laser or potassium-titanyl-phosphate laser, or surgical excision . Generally, due to the risk of residual disease and recurrence, laryngeal lesions must be followed up with endoscopy and biopsy . We hope to follow up with our patient yearly with flexible laryngoscopy to avoid missing any residual disease or recurrence.Hemangiomas in children have been shown to respond to propranolol as well , though in this case, due to the bulky nature of the lesion and the negative impact it was having on the baby's health, a complete surgical excision was carried out to prevent death. Awaiting improvement for days with propranolol, as reported in other cases , was not feasible in our case as we could have lost the baby due to respiratory distress. It has been argued that radical surgical excision of hemangioma is necessary when the lesion is circumscribed and attached only to the submucosal layer. This is believed to prevent recurrence and possible later complications as the structures of phonation are mostly spared . The lesion in our case was excised without injuring the underlying tissues. Conclusions Congenital laryngeal hemangioma may or may not present any significant clinical features. Babies born with masses in the oral cavity should undergo careful endoscopy to evaluate for such lesions and clinicians should maintain a high index of suspicion for laryngeal hemangioma. Surgical excision is an effective method of treatment for laryngeal hemangiomas causing respiratory distress or other obstructive symptoms. We acknowledge the role of doctors and nurses of the Paediatric Ward and ENT Clinic of our hospital who helped with the management of this case. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. Cape Coast Teaching Hospital Ethical Review Board issued approval Not Applicable. No conflicts of interest declared. Our institution does not require review board approval for case reports. Informed consent was obtained from the father of the baby for this publication. References 1 Cummings Pediatric Otolaryngology Lesperence MM Philadelphia, PA Elsevier 2021 2 Venous malformation and haemangioma: differential diagnosis, diagnosis, natural history and consequences Phlebology Lee BB 176 187 28 2013 23482556 3 Postcricoid hemangioma of childhood: report of four cases Ann Otol Rhinol Laryngol Awwad RJ Mortelliti AJ 191 194 115 2006 16572608 4 Adult laryngeal haemangioma; a rare entity J Pak Med Assoc Akhtar S Shamim AA Ghaffar S Ahmed MS Ikram M 173 174 62 2012 22755385 5 Vocal cord hemangioma Med J Malaysia Prasad SC Prasad KC Bhat J 419 420 63 2008 19803307 6 Malignant transformation in a laryngeal hemangioma Ann Otol Rhinol Laryngol McRae RD Gatland DJ McNab Jones RF Khan S 562 565 99 1990 2195963 7 Laryngeal hemangioma Braz J Otorhinolaryngol Martins RH Lima Neto AC Semenzate G Lapate R 574 72 2006 17143442 8 Strategies and controversies in the treatment with carbon dioxide laser of laryngeal hemangioma: a case series and review of the literature Ear Nose Throat J Mesolella M Allosso S Mansueto G Fuggi M Motta G 326 331 101 2022 32921178 9 Adult laryngeal hemangioma Tzu Chi Med J Lin YH Ho HC 237 240 4 2010 10 Twenty-year experience with salvage total laryngectomy: lessons learned J Laryngol Otol Tsetsos N Poutoglidis A Vlachtsis K Stavrakas M Nikolaou A Fyrmpas G 729 736 135 2021 34219631 11 Subglottic hemangioma in an infant: a case report Int Arch Otorhinolaryngol Carvalho H Nikolay P Medeiros LA Sabel BR Cimolin LC Rauber P 21 26 2022 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34813 Gastroenterology Esophagomediastinal Fistula Closed Endoscopically in a Young Patient With Tuberculosis and Human Immunodeficiency Virus Muacevic Alexander Adler John R Wong Vincent 1 Ahmed Ahmed 2 Manoharan Anjella 1 Wang Weizheng 2 1 Internal Medicine-Pediatrics, Rutgers University New Jersey Medical School, Newark, USA 2 Gastroenterology and Hepatology, Rutgers University New Jersey Medical School, Newark, USA Vincent Wong [email protected] 9 2 2023 2 2023 15 2 e348139 2 2023 Copyright (c) 2023, Wong et al. 2023 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Tuberculosis is a primary lung disease that can spread to the lymph nodes, vertebrae, and gastrointestinal tract. The esophagus can be affected by mediastinal lymphadenitis, mostly in immunocompromised patients, leading to the formation of esophagomediastinal fistulas. They can cause dysphagia, pleuritic chest pain, and choking coughs from recurrent aspiration. The treatment is surgery but endoscopic interventions using over-the-scope endoclips, stents, medical adhesives, and sutures are successful alternatives. We present a case of an esophagomediastinal fistula in a patient with tuberculosis and human immunodeficiency virus that was successfully treated with through-the-scope endoclips. mediastinal lymph node immunocompromised patient tb - tuberculosis esophageal fistulas upper endoscopy The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Tuberculosis (TB) is a primary lung disease affecting 10 million people worldwide . Extrapulmonary manifestations affect the lymph nodes, vertebrae, and gastrointestinal tract . The esophagus is the least commonly involved and can manifest as fistulas with the trachea, bronchus, and mediastinum . These are very rare complications but are seen in immunocompromised patients, such as those with human immunodeficiency virus (HIV) . We present a case of a patient with TB and HIV who developed an esophagomediastinal fistula which was treated with through-the-scope endoclips. Case presentation A 29-year-old male with recently diagnosed HIV and TB presented with worsening dysphagia for the past month. His symptoms started suddenly with difficulty swallowing solids and thin liquids as if the food was getting stuck in his throat. He had to forcefully swallow his meals but that led to pleuritic chest pain, violent coughing fits, and post-tussive emesis. He denied any recent fevers, chills, hemoptysis, palpitations, abdominal pain, hematuria, melena, or hematochezia. Two months prior, the patient was found to have HIV with CD4 of 185 cells/mL at an outside hospital. CT scan also showed mediastinal lymphadenopathy which was biopsied percutaneously and diagnosed as TB. He was started on antiretroviral and anti-tuberculosis therapies at the time. On presentation, his vitals were stable, and his basic labs were within normal limits. On physical exam, he was cachectic and in no acute distress with a healed scar below the sixth rib at the biopsy site. His respiratory exam was significant for diminished breath sounds in the right lower lung field with decreased effort due to chest pain upon inspiration. CT scan of the chest showed trace extra-luminal contrast to the right of the esophagus with a small focus of gas in a walled-off non-rim enhancing area of soft tissue within the mediastinum, concerning for an esophagomediastinal fistula . Figure 1 CT scan showing contrast extravasation (blue arrow) into mediastinal mass (1.42x). Esophagogastroduodenoscopy (EGD) was done which revealed esophagitis without bleeding and a fistula in the middle third of the esophagus . Six through-the-scope endoclips were placed to close the defect . A follow-up gastrograffin study one day post-procedure did not show any contrast extravasation . Figure 2 Fistula seen (blue arrow) in the middle third of the esophagus on EGD. Figure 3 Fistula in the middle third of the esophagus with clips closing the defect on EGD. Figure 4 Esophagram showing no signs of contrast extravasation after endoscopic clips were applied to close the fistula. The patient had a percutaneous jejunostomy tube placed to optimize nutrition and fistula healing. He was discharged on antiretroviral therapy (Efavirenz, Emtricitabine, Tenofovir), anti-tuberculosis medications (Rifampin, Isoniazid, Pyrazinamide, Ethambutol), Pyridoxine, Bactrim for prophylaxis, and Pantoprazole for reflux esophagitis. At his outpatient follow-up two months later, the patient's symptoms resolved and repeat EGD showed that the fistula had completely closed. Discussion Esophagomediastinal fistulas are rare in patients with tuberculosis, reported in approximately 20 cases over the last 30 years [2-12]. They form as a consequence of lymphadenitis, which occurs in about 17.6% of patients with tuberculosis and up to 35% in those with concomitant HIV [3-5]. Tracts develop from ruptured caseating necrotic lymph nodes that compress and erode into adjacent organs, either spontaneously or from iatrogenic procedures [2-4,13,14]. Fistulas can connect the esophagus with the mediastinum and lead to repeated episodes of aspiration . Patients initially present with a choking cough from eating or drinking . The diagnosis can be made using an esophagram, high-resolution CT, or EGD . The mainstay of treatment is to close the defect, control the infection, and improve nutritional status . These types of fistulas are usually surgically ligated or excised . However, they can be closed endoscopically using clips, metal stents, medical adhesives, and stitches [6,7,13-20]. In the literature, over-the-scope (OTS) endoclips have been used to close fistulas in patients that have larger defects of up to 3 centimeters (cms), with a success rate of 89% . However, they require additional setup time to load onto the endoscope, and removal of the clips is often difficult . Metallic or plastic self-expanding stents can be used with up to 83% success rate but carry risks for stent migration (10%-30%) and luminal perforation (3%) . Fibrin glue is another modality for fistula closure but there are reports of the glue clotting inside the injection catheter, and being aspirated into the airway . Endoscopic suturing can close defects larger than 2 cm and has a greater than 95% success rate but is technically challenging to perform and can reopen in 65% of patients . On the contrary, through-the-scope (TTS) clips have mainly been used for hemostasis and perforations less than 2 cm provided that the surrounding mucosa is healthy . With recent technology, they are easy to load, rotatable, reusable, and can be maneuvered into difficult-to-reach areas . The use of TTS endoclips described in this case demonstrates their effectiveness in closing esophagomediatinal fistulas . Our patient developed an esophagomediastinal fistula shortly after his diagnosis of tuberculosis. Based on the timing of his symptoms, the etiology is likely multifactorial. TB could have caused lymphadenitis, which was further exacerbated by the biopsy, and subsequent remodeling in the setting of a compromised immune system likely led to fistula formation. Through-the-scope endoclips were used in this case because it was easy to load into the endoscope and rapidly deployable. A jejunostomy tube was placed to maximize nutrition in our cachectic patient but also to prevent worsening reflux that can affect the healing process. The patient was compliant with his antiretroviral and antituberculosis medications. His fistula closed after two months making it one of the first cases of a successfully treated TB-related esophagomediastinal fistula with through-the-scope endoclips . Conclusions For immunocompromised patients with tuberculosis who present with dysphagia, a thorough history and physical exam should be done to determine the presence of an esophagomediastinal fistula. They can be treated either surgically or endoscopically, but this case suggests that through-the-scope endoclips can be another alternative. They are minimally invasive, easy to load, quick to deploy, low risk, low cost, and can lead to complete fistula closure. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 World Gastroenterology Organisation Global Guidelines. 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Case Rep Cardiol Case Rep Cardiol CRIC Case Reports in Cardiology 2090-6404 2090-6412 Hindawi 10.1155/2023/6646715 Case Report Late Incidental Discovery of Compression of the Left Anterior Descending Coronary Artery by an Endocardial Defibrillator Lead Scripcariu Alex [email protected] 1 2 Gaty Denis 2 Maury Philippe 1 3 1Department of Cardiology, University Hospital Rangueil, Toulouse, France 2Department of Cardiology, Hospital of Carcassonne, Carcassonne, France 3Unite INSERM U 1048, Toulouse, France Academic Editor: Anca Daniela Farcas 2023 4 3 2023 2023 664671530 11 2022 2 2 2023 25 2 2023 Copyright (c) 2023 Alex Scripcariu et al. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Coronary artery compression/damage by cardiac pacing/defibrillation leads is very rare and often an unknown complication of pacemaker implantation. Here, we present the case of a 71-year-old woman with late discovery of an asymptomatic compression of the left anterior descending (LAD) coronary artery by a defibrillation lead implanted ten years before. This dissuaded us in removing this now malfunctioning lead with high threshold, and an additional right ventricular (RV) lead was implanted along with atrial and left ventricular (LV) leads for allowing resynchronization therapy. Based on the published data, a majority of RV leads are currently implanted in the "anteroseptal area," which is neighboring the course of the LAD. pmc1. Clinical Case A 71-year-old woman came to our hospital for aggravated dyspnea and atypical chest pain. Twenty years before, she presented with an anterior wall infarction, which prompted angioplasty of the left anterior descending (LAD). She had been implanted seven years later for primary prevention with a single chamber defibrillator (EVERA S VR DF1, Medtronic, Minneapolis, MN, USA) on the right side connected to a ventricular lead (Saint Jude Medical Durata) with active fixation to the interventricular septum. During follow up, the can glided into the axillary fossa, prompting multiple interventions until a pocket was eventually created by a Plastic Surgeon in the right mammary region . Device interrogation showed a remaining battery life of 4 years, the absence of any ventricular or supraventricular arrhythmia in the last year, but a dysfunctioning right ventricular (RV) lead with normal detection and impedance but with a high pacing threshold of 5 V at 0.6 ms. The threshold had been steadily increasing over the past years. The Electrocardiogram (ECG) showed regular sinus rhythm with first degree atrioventricular block, complete right bundle branch block, and left axis deviation with a QRS duration of 180 ms . Transthoracic echocardiography found a severely altered left ventricle ejection fraction of 20% with a very thin and almost aneurysm-like akinetic area in the apical and anterolateral regions. Minor to moderate functional mitral regurgitation and dyskinesia of the septum were also present. As some evolution was suspected concerning her coronary disease, a coronary artery angiography was performed , showing lack of new stenosis, but a compression of the distal LAD coronary artery at the implantation site of the RV lead. Chest pain was not considered to be caused by myocardial ischemia because of the likely lack of viability regarding the thin aneurism like apex, lack of significant Thrombolysis in Myocardial Infarction (TIMI) score alteration, and lack of collaterality. Computed Tomography (CT) scan was not performed due to the high artefacts expected to be caused by the defibrillation lead. As recommended by the European Society of Cardiology (ESC) guidelines , the patient underwent an upgrading intervention. A decision was made not to extract the dysfunctioning RV lead because of its old age (15 years since implantation) and its dangerous proximity to the LAD. We proceeded to the implantation of a new IS1 RV lead (Ingevity, Boston Scientific, Marlborough, MA, USA), an IS4 left ventricular (LV) lead (Attain, Medtronic), and an IS4 Atrial lead (Tendril, Saint Jude Medical/Abbott, Abbott Park, IL, USA), leaving in place the ancient Durata DF1 lead (Saint Jude Medical/Abott) for its shocking coil. The choice to not implant a new DF 4 Lead was due to the restricted intravascular space. A new pocket was formed in the proximity of the subclavian region to optimize the defibrillation vector, and the ancient DF 1 lead was tunneled after careful dissection. The new Medtronic CRT-D IS1/DF1 device was thoroughly attached to the pectoral muscle fascia to prevent migration. The following day chest X-ray showed no lead displacement and the ECG revealed satisfactory resynchronization pattern . 2. Discussion Although device implantation has some potentially fatal complications (see Table 1) , procedure-related death is exceptionally rare (0-0.1%). Damage to the coronary arteries and related structures from pacemaker and implantable cardioverter-defibrillator leads is an even more rarely reported complication, which can lead to myocardial infarction and pericardial tamponade, which can occur acutely or even years later . Incidence of this type of complication is probably very low, and reported cases are exceptional among the literature. Hints could be chest pain that appears close to the intervention and increase of pacing threshold, especially in unipolar configuration [4-6] as for other types of perforation. Usually, management is diverse, and case by case discussion is needed as lead revision is of potential devastating consequence. There have been identified several factors increasing the risk for lead perforation, such as an older age, a female gender, a Body Mass Index (BMI) <20, higher LV ejection fraction, heart failure, left bundle branch block, previous temporary pacing, small diameter ICD leads, active fixation leads, longer fluoroscopy time, and also factors decreasing the risk, such as BMI >35, previous cardiac surgery, higher implantation procedure rate, diabetes mellitus, and atrial fibrillation . In an imaging study, Pang et al. sought out to better identify the actual incidence of coronary artery damage albeit in a subclinical presentation and to better understand the anatomical relationship between the pacemakers/defibrillators lead implantation sites and the coronary vasculature. In their CT-scan series, leads in the RV antero-septal area were only a few millimeters (median 4.7 mm) away from the LAD, which lies in the anterior interventricular groove. This is due to the fact that implantation is done through fluoroscopy, which is a two-plane imaging method, and leads expected to be in the RV septum in left anterior oblique (LAO) view are actually more at the junction with the RV anterior wall and thus closer to the interventricular groove . The same group suggested a more detailed approach to implantation, describing a technique to better target the true inter-ventricular septum away from the LAD. This would be achieved not only using a leftward shift of the lead in the LAO view but also by using the right anterior oblique view and targeting the middle of the cardiac silhouette together with a paced-QRS duration <140 ms . Data Availability The data used to support the findings of this study are included within the article. In addition, some data analyzed in this study were a re-analysis of existing data, which are openly available at locations cited in the reference section. Consent Informed consent was obtained from the study participant. Conflicts of Interest The author(s) declare(s) that they have no conflicts of interest. Figure 1 (a) Right thoracic anatomy and (b) anteroposterior chest X-ray. Figure 2 ECG at admission. Figure 3 Coronary angiography in the 30deg left anterior oblique (a) and 20deg right anterior oblique (b) views, showing compression of the LAD. Of note, in the right anterior oblique view, the implantation site is distal to the heart silhouette, suggesting a very anterior position. Figure 4 Anteroposterior fluoroscopic view showing the final placement of the leads and of the can. Figure 5 ECG after resynchronization. Table 1 Device-related complications. Procedure-related mortality 0-0.1% 30-day mortality 0-0.6% Pneumothorax 0.4-2.8% Clinically relevant perforation 0.1-1.5% Pericardial effusion 10.2% Tamponade 0.5-1.5% Pocket hematoma 0.2-16% Infection 0.6-3.4% Lead dislodgement 1.2-3.3% Other: arrhythmias, pleural effusion, haemothorax, aortic root perforation, lung perforation, pneumopericardium, constrictive pericarditis, air embolism, myocardial infarction, diaphragmatic or intercostal pacing, stroke, brachial plexus palsy, phrenic nerve palsy, acute access vein thrombosis, pulmonary embolism, and tricuspid valve damage <0.5% 1 Glikson M. Nielsen J. C. Kronborg M. B. 2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy European Heart Journal 2021 42 35 3459 3460 10.1093/eurheartj/ehab364 2 Burri H. Starck C. Auricchio A. EHRA expert consensus statement and practical guide on optimal implantation technique for conventional pacemakers and implantable cardioverter-defibrillators: endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), and the Latin-American Heart Rhythm Society (LAHRS) Europace 2021 23 7 983 1008 10.1093/europace/euaa367 33878762 3 Pang B. J. Barold S. S. Mond H. G. Injury to the coronary arteries and related structures by implantation of cardiac implantable electronic devices Europace 2015 17 4 524 529 10.1093/europace/euu345 2-s2.0-84926649395 25564549 4 Nishiyama N. Takatsuki S. Kimura T. Implantation of the right ventricular lead of an implantable cardioverter-defibrillator complicated by apical myocardial infarction Circulation 2012 126 10 1314 1315 10.1161/CIRCULATIONAHA.112.097527 2-s2.0-84865839978 22949541 5 Majauskiene E. Aucina G. Semeniene P. Jurkuvenas P. Serpytis P. Myocardial infarction caused by active-fixation atrial pacing lead screwed into the anterior descending coronary artery International Journal of Cardiology 2018 12 p. e68816 6 Occetta E. Bortnik M. Marino P. Ventricular capture by anodal pacemaker stimulation Europace 2006 8 5 385 387 10.1093/europace/eul013 2-s2.0-33745414761 16636000 7 Hsu J. C. Varosy P. D. Bao H. Dewland T. A. Curtis J. P. Marcus G. M. Cardiac perforation from implantable cardioverter-defibrillator lead placement: insights from the national cardiovascular data registry Circulation. Cardiovascular Quality and Outcomes 2013 6 5 582 590 10.1161/CIRCOUTCOMES.113.000299 2-s2.0-84884484236 24002030 8 Mahapatra S. Bybee K. A. Bunch T. J. Incidence and predictors of cardiac perforation after permanent pacemaker placement Heart Rhythm 2005 2 9 907 911 10.1016/j.hrthm.2005.06.011 2-s2.0-25444441460 16171740 9 Pang B. J. Joshi S. B. Lui E. H. Proximity of pacemaker and implantable cardioverter-defibrillator leads to coronary arteries as assessed by cardiac computed tomography Pacing and Clinical Electrophysiology 2014 37 6 717 723 10.1111/pace.12330 2-s2.0-84902536501 24372320 10 Pang B. J. Joshi S. B. Lui E. H. Validation of conventional fluoroscopic and ECG criteria for right ventricular pacemaker lead position using cardiac computed tomography Pacing and Clinical Electrophysiology 2014 37 4 495 504 10.1111/pace.12301 2-s2.0-84898538631 24215477 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34821 Physical Medicine & Rehabilitation Oncology Integrative/Complementary Medicine Lung Cancer With Vertebral Metastases Presenting as Low Back Pain in the Chiropractic Office: A Case Report Muacevic Alexander Adler John R Chu Eric Chun-Pu 1 Trager Robert J 2 Lee Wai Ting 1 Cheong Benjamin Kah Chun 1 Hei Steve Yun Ming 1 1 New York Chiropractic and Physiotherapy Centre, New York Medical Group, Kowloon, HKG 2 Chiropractic, Connor Whole Health, University Hospitals Cleveland Medical Center, Cleveland, USA Robert J. Trager [email protected] 9 2 2023 2 2023 15 2 e348219 2 2023 Copyright (c) 2023, Chu et al. 2023 Chu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Lung cancer commonly metastasizes to the skeletal system, and when affecting the spine, it may initially be mistaken for a typical musculoskeletal source of back pain. We report a previously healthy 52-year-old male non-smoker with an eight-week history of low back pain that radiated into his left thigh and recent weight loss, yet no respiratory symptoms. Initially, the patient visited his primary care physician, who suspected a musculoskeletal condition and prescribed a nonsteroidal anti-inflammatory drug and muscle relaxant, then referred the patient to the chiropractor. Based on the patient's pain pattern, limited mobility, and other features, the chiropractor suspected a lumbar disc herniation. However, the patient's condition worsened during a one-week trial of care, so the chiropractor ordered magnetic resonance imaging (MRI) and, as the findings suggested vertebral metastasis, promptly referred the patient to an oncologist, who confirmed a diagnosis of lung adenocarcinoma via positron emission tomography (PET)/computed tomography and biopsy. Chiropractors should be aware of warning signs of malignancy, such as unexplained weight loss or progressive worsening despite treatment. If providers suspect spinal metastasis, they should order advanced imaging such as an MRI and refer patients to an oncologist for timely care. intervertebral disc displacement low back pain adenocarcinoma neoplasms lung cancer chiropractic The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Lung cancer is one of the most prevalent forms of cancer globally . In Hong Kong, the site of the current study, it is the most common type of cancer and the leading cause of cancer-related deaths in men and women . Adenocarcinoma is the most common type of primary lung cancer, accounting for approximately 40% of all cases . Symptoms of lung adenocarcinoma may include cough, shortness of breath, systemic symptoms (e.g., weight loss), or various other symptoms related to potential sites of metastasis (e.g., bone pain) . Lung cancer often has a poor prognosis when it metastasizes . Bone is one of the most common metastatic sites in lung cancer , with 39% of patients with adenocarcinoma developing bone metastasis . While lung cancer can metastasize throughout the skeletal system, it frequently affects the thoracic and thoracolumbar spine . Pain related to vertebral (spinal) metastasis may begin at a mild intensity and then rapidly worsen . At later stages, vertebral metastasis can manifest with dull, continuous bone pain, pathological fractures, spinal cord compression, cachexia, and hypercalcemia . Chiropractors are healthcare providers who often encounter patients with musculoskeletal complaints, back pain being the most common . Given the potential for spinal metastasis to cause back pain, patients may seek chiropractic providers while being unaware of the serious source of their symptoms. Chiropractors rarely encounter patients with undiagnosed, serious pathology such as cancer. One study in Hong Kong, which included 7,221 adults, found that malignancy was the most common serious undiagnosed pathology that chiropractors encountered, which was found in 0.25% of patients seen for a new episode of low back pain . Despite metastasis being an uncommon presentation in the chiropractic office, it is critical for these providers to promptly recognize and refer such patients to improve their care outcomes. Here, we describe a rare case of metastasis from lung cancer causing low back pain and presenting to the chiropractic office. Moreover, we emphasize the role of chiropractors in identifying patients with metastases and referring them for appropriate follow-up care. Case presentation Patient information A 52-year-old man without a previous medical history of illness or significant pain presented to a chiropractor upon referral with an eight-week history of constant low back pain radiating into the left anterior thigh, which he rated 6 out of 10 on the numeric pain rating scale. The patient described his pain as dull and deep and noted that it was exacerbated by transitional movements and lifting. The patient also endorsed having pain at night and noted having severe morning stiffness. The patient was a nonsmoker and social drinker and denied any history of trauma, cough, shortness of breath, or cancer. He acknowledged having an increased nocturnal urinary frequency for over a year, as well as a weight loss of 2 kg over the past month due to a decreased appetite. His father had a myocardial infarction and dementia; however, there was no family history of cancer. The patient worked as an engineer. His World Health Organization Quality of Life score was 86%. Eight weeks prior, the patient had initially consulted his primary care physician for his back pain, who ordered a metabolic panel and a serum prostate-specific antigen test, both of which were within normal limits. The physician's initial differential diagnosis included sciatica and lumbar strains. The primary care physician prescribed the patient baclofen, a muscle relaxant, and diclofenac, a nonsteroidal anti-inflammatory medication, which provided some relief. The primary care provider then referred the patient to a chiropractor for conservative management. Clinical findings During the initial chiropractic evaluation, the patient was observed to walk with a swayback posture. Palpation revealed restricted intersegmental motion with tenderness at the T7/8, L1/2, L2/3, and L5/S1 spinal segments. Muscular hypertonicity was identified bilaterally in the erector spinae, rectus femoris, and iliopsoas muscles. All active and passive lumbar spine ranges of motion were severely limited and painful. A left lumbar extension-rotation test and straight-leg raise each exacerbated his low back pain with radiation to the left anterior thigh. Motor, sensory, and muscle stretch reflexes were normal. Given the patient's symptoms of radiating low back pain and neural tension signs, the chiropractor considered a working diagnosis of lumbar disc herniation with L4 radicular pain. The patient consented to a trial of care with three visits over the span of a week consisting of lumbar flexion-distraction (a gentle type of manipulation used to restore lumbar motion), which only transiently relieved his pain. After one week, a re-examination identified a worsening of the straight leg raise test, with symptoms exacerbated at a lower degree of leg raising. Given the lack of improvement and other red flags (urinary frequency, slight weight loss, pain at night/rest), the chiropractor, therefore, ordered lumbar magnetic resonance imaging (MRI), which the patient obtained that week. The MRI revealed heterogeneous marrow signals within several vertebral bodies and compression fractures at T8 and T11 . Also noted were degenerative disc changes at L4/5 . As the vertebral fractures and marrow changes were highly suggestive of metastases, the chiropractor promptly referred the patient to an oncologist for further evaluation of suspected metastases. Figure 1 Mid-sagittal magnetic resonance imaging including a scout view (A) and T1-weighted image of the lumbar spine (B) The scout view (A) demonstrates compression fractures of T8 and T11 (triangles), with each level having 20% loss in anterior vertebral body height. In the T1-weighted view (B), heterogeneous marrow signal is evident within multiple vertebral bodies, with hypointense areas indicated in the sacrum, L4, L3, L2, L1, and T11 (arrows), suggestive of spinal metastases. Although there is mild retropulsion at T11 (not indicated), there is no significant narrowing of the central spinal canal. Figure 2 T2-weighted axial lumbar magnetic resonance image at the level of the L4/5 intervertebral disc A left-sided posterior annular fissure (arrowhead) is evident, while a disc bulge impresses the thecal sac and causes mild left neural foraminal stenosis (arrow). The oncologist conducted an ultrasound-guided biopsy of a right posterior neck triangle lymph node, which was performed using a 16G TemnoTM biopsy needle for four passes. Cytological and histopathological analysis confirmed the diagnosis of adenocarcinoma. F18-fluorodeoxyglucose (FDG) whole-body positron emission tomography/computed tomography (PET-CT) revealed numerous hypermetabolic bone lesions, some of them expansile and lytic, throughout the axial and appendicular skeleton, suggestive of multifocal bony metastases . These involved multiple levels of the cervical to lumbar spine, multiple bilateral ribs, the sternum, the right clavicle, the right scapula, and bilateral pelvic bones. A hypermetabolic subpleural lung mass was also noted at the medial left upper lobe, measuring 2.5 cm x 2.2 cm, consistent with primary lung carcinoma. Hypermetabolic lymph nodes of the left hilum, bilateral mediastinum, and right posterior neck were also evident. The patient was treated via targeted therapy using erlotinib. He provided written consent for the publication of this case report and its related images. Figure 3 Coronal F18-fluorodeoxyglucose (FDG) whole body positron emission tomography/computed tomography (PET-CT) Increased FDG uptake is evident throughout several sites. Select representative lesions are highlighted with their corresponding maximum standardized uptake values (SUVmax) listed including the vertebrae (arrowheads) T11 (18.01) and L4 (20.42), right scapula (arrow; 20.69), right seventh rib (asterisk; 19.28), left ilium (dotted line; 25.17), and left medial upper lung lobe (triangle; 15.86). Discussion This case describes a 52-year-old man who was referred to a chiropractor for treatment of suspected sciatica by his primary care provider. After a lack of success with a brief trial of care, the chiropractor ordered an MRI, which was suggestive of multiple bone metastases, ultimately leading to a diagnosis of lung adenocarcinoma by an oncologist. The patient's low back pain can be primarily explained by the presence of vertebral metastases causing cancer-related bone pain. However, his degenerative disc changes at L4/5 may have also contributed to some of his symptoms (i.e., thigh pain) and examination findings (i.e., neural tension), leading to a misleading clinical presentation. A case-control study found that initial respiratory symptoms were common among those ultimately diagnosed with lung cancer . Cough was the most common presenting symptom, affecting 65% of patients, followed by shortness of breath (56%), and chest or rib pain (42%). In this study, 34% of patients were current or ex-smokers . In contrast, bone pain is less common and occurs in up to 25% of patients, while systemic symptoms such as weight loss are variable in frequency . Our patient did not have any of the common respiratory symptoms of lung cancer and was a non-smoker. Instead, he only had bone pain and systemic symptoms. This case illustrates the challenges of recognizing metastatic bone disease in the context of what otherwise appears to be a musculoskeletal complaint. As in the current case, radiating low back pain can easily be mistaken for a common degenerative spinal condition . While the current patient did not report any respiratory symptoms related to lung cancer, he did report weight loss, loss of appetite, and increased urinary frequency, which are all red flags for potential serious pathology such as cancer . Chiropractors and other healthcare providers should therefore be aware that symptoms of metastasis can be misleading and should conduct further investigation given the presence of red flags or systemic symptoms. In the current case, the chiropractor's primary goal was to refer the patient to an oncologist after identifying a potential malignancy via MRI. While a trial of chiropractic treatment is often recommended for low back pain, when the practitioner becomes suspicious of serious pathology, manual treatment should be halted until further investigations are conducted . Fortunately, forceful spinal manipulation was not used in the current case, considering this type of treatment can potentially fracture already-weakened bones . Other cases of patients presenting to a chiropractor with musculoskeletal complaints ultimately caused by lung cancer have been published previously [13-18]. In some of these cases, the patient presented with spinal pain and was eventually diagnosed with skeletal and/or vertebral metastasis . In the current and previous cases, each malignancy was identified using imaging. However, providers should be aware that conventional radiography has a poor sensitivity to detect skeletal metastasis and should consider advanced imaging such as MRI or computed tomography as a first-line investigation when suspecting malignancy . This case has some limitations. We were unable to obtain histology slides or detailed follow-up information, including the response to chemotherapy, as the patient was referred to an outside hospital for treatment. The current case report may not be broadly generalizable. There are regional differences in the scope of chiropractic practice, and it is possible that other chiropractors may not be able to order advanced imaging. Given the patient's red flag symptoms, ordering an MRI could have been justified even sooner, for example, at the initial chiropractic visit rather than a week later. Conclusions This case describes an adult man who visited a chiropractor with low back pain and was ultimately diagnosed as having skeletal metastasis from adenocarcinoma of the lung. Chiropractors may encounter patients with undiagnosed metastasis who present with back pain. These providers should therefore be vigilant to recognize any warning signs during the initial history-taking and examination and monitor patients' responses to care. If vertebral metastasis is suspected, providers should request advanced imaging, such as an MRI, and refer the patient to an oncologist for timely care. Human Ethics The authors have declared financial relationships, which are detailed in the next section. Robert J. Trager declare(s) royalties from Integrated Clinics, LLC. Robert J. Trager declares he has received royalties from authoring two texts on the topic of sciatica. 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screening was completed by two authors (SG and GA) independently, in duplicate, and conflicts were resolved by a third author (MTS). Full-text screening was completed by MTS. Data extraction was performed independently and in duplicate by authors SG and MTS. Data items included the study design, patient population, type of intervention, comparison group (when available), outcome, and any additional information felt useful to describe the literature. Synthesis of results Results were summarized by intervention type, including the following categories:Changes to ventilator settings, such as PEEP, tidal volume (Vt), respiratory rate, or ventilator mode Prone position ventilation (PP) Inhaled pulmonary vasodilators Intravenous or oral medications ECLS. Outcome summarization could not be reported uniformly due to heterogeneous use of technologies and parameters to assess RV function. Therefore, we reported the outcomes provided by the individual studies, which typically included transthoracic or transesophageal echocardiographic measurements of RV size and function and/or pulmonary artery catheterization (PAC) determinations. Given the heterogeneity of the literature, no formal synthesis or analyses were performed. Results Selection of sources of evidence A total of 1430 studies were assessed for abstract review after removing duplicates. After exclusion of 1317 due to irrelevance, 113 full-text studies remained. In total, 62 studies were further excluded after a full-text review (Additional file 2: Fig. S1). We report the data on 1526 patients from the remaining 51 studies. Characteristics of sources of evidence We identified 27 (53%) non-randomized experimental studies, 8 (16%) case reports, 5 (9.8%) prospective cohort studies, 4 (7.8%) retrospective cohort study, 3 (5.9%) case series, 3 (5.9%) randomized controlled trials (RCT), and 1 (2%) cross-sectional study. Fifteen studies (29.4%) evaluated ventilator settings, 17 (33.3%) studied inhaled medications, 7 (13.7%) each tested ECLS and IV/PO medications, and 5 (9.8%) tested prone position ventilation. The median number of patients enrolled in all studies was 13 (interquartile range [IQR] 8-20); by intervention: ECLS (n = 6, IQR 1-16), inhaled medications (n = 12, IQR 8-16), IV/PO medications (10, IQR 8-26), PP (18, IQR 9-42), and ventilator settings (n = 16, IQR 12-20) (Fig. 1 and Additional file 2: Table S1). Only 14 studies (27%) were conducted with the goal of treating RVD; 50% of these assessed the effect of inhaled medications, with 29% and 21% assessing IV/PO medications or ECLS, respectively. No studies were conducted with the goal of preventing right ventricular dysfunction. Interventions studied by year are detailed in Fig. 2. Study design by year is detailed in Additional file 2: Fig. S2. A total of six studies (11.8%) reported on patients with COVID-19.Fig. 1 Interventions studied, by study design. IV = intravenous, PO = by mouth Fig. 2 Interventions studied by year. IV = intravenous, PO = by mouth RV function was assessed by various means, the most common of which was by PAC measurements (n = 31, 60.7%), followed by transthoracic echocardiography (TTE) (n = 16, 31.4%) and transesophageal echocardiography (TEE) (n = 11, 21.6%) (Additional file 2: Table S2). Other means of RV function assessment included cardiac magnetic resonance imaging, central venous catheter pressure measurements, invasive pressure-volume loop measurements, and transpulmonary thermodilution systems. Ventilator settings Out of the 15 studies testing ventilator settings, 9 tested the effect of PEEP on RV function. Full details of the studies are listed in Additional file 2: Table S3. Four studies showed increasing PEEP led to RVD by observing unfavorable responses such as decreased stroke volume (SV), increased right ventricular end diastolic volume (RVEDV), decreased tricuspid annular plane systolic excursion (TAPSE), and decreased cardiac index (CI) [12-15]. One study showed no statistically significant impact of PEEP on CI . Another compared PEEP set to best respiratory system compliance to PEEP set using the lower inflection point of P-V curve, demonstrating better RV function with best compliance PEEP compared to PEEP set using the lower inflection point . One study examined recruitment maneuvers, including a sustained insufflation to 45 cmH2O for 40 s, and showed decreased CI and increased mean pulmonary artery pressure (mPAP) during the maneuver . Two other studies evaluating the impact of recruitment maneuvers in this patient population found that although the RV Tei index, cardiac output (CO), and TAPSE were lower at time of the maneuver, they returned to baseline with decremental PEEP titration to best respiratory compliance . Three studies evaluated high-frequency oscillatory ventilation (HFOV), showing a reduction in CI, increased right ventricular end diastolic area (RVEDA): left ventricular end diastolic area (LVEDA), increased mPAP, and pulmonary vascular resistance (PVR) index during HFOV compared to standard ventilator settings [21-23]. Another investigation compared inverse ratio, pressure control ventilation to volume control ventilation, showing a significant increase in CI in inverse ratio ventilation compared to volume control with no significant change in mPAP . Another study evaluated the impact of various plateau pressures on the incidence of acute cor pulmonale (ACP). It is found that the incidence of ACP as well as mortality was highest in patients with plateau pressures > 35 cmH2O. It is also noted that in patients with plateau pressures ranging from 18 to 26 cmH2O, the presence of ACP did not confer increased mortality compared to those without ACP . One study attempted to measure the impact of respiratory rate on RVD, showing a higher respiratory rate resulted in a lower CI and pulmonary artery (PA) velocity time integral (VTI) . This was due in part to higher alveolar dead space, as well as increase in intrinsic PEEP. Prone positioning Out of the 5 studies testing prone positioning, 3 showed improvement in RV function by a reduction in RVEDA:LVEDA ratio and increased CI (Additional file 2: Table S4) [27-29]. In contrast, a case report showed a decrease in SV and RV EF, and increased mPAP as measured with invasive pressure-volume loops . Another study demonstrated no significant impact of prone positioning on RV function as measured by TTE . Inhaled pulmonary vasodilators Of the 17 studies evaluating inhaled pulmonary vasodilators, 15 tested inhaled nitric oxide (iNO), 3 tested nebulized prostacyclin analogues, and 2 tested nebulized alprostadil (Additional file 2: Table S5). A wide range of iNO doses were used, ranging from 5 to 40 parts per million (ppm). Eleven of the studies with iNO showed a reduction in mPAP and/or PVR/PVRi [32-42], 3 showed improvement in RV EF , and 4 showed improvement in CO [37, 41-43]. In contrast, 6 studies failed to find a statistically significant impact of iNO on CO [32-34, 39, 40, 44]. Two investigations reported reduced mortality in patients who responded to iNO (40% vs 67% in one study and 50% vs 65% in the other) , and another noted return to baseline hemodynamic measurements postdiscontinuation of iNO . Three studies evaluating nebulized prostacyclin demonstrated a reduction in mPAP. Two of those also showed a reduction in PVR. There was no change in CO/CI in any of the studies . Two studies investigating nebulized alprostadil showed no significant change in CI as measured by PAC, although one showed a decreased in right ventricular end systolic and end diastolic volume index . Intravenous and oral medications Two studies evaluating enteral sildenafil found a decreased PVR with an increase in CO . Two studies tested IV almitrine; one demonstrated a decrease in mPAP and PVR, an increase in CI, and an improved RV global longitudinal strain at a dose of 4 mg/kg/min . The other investigation found that almitrine increased mPAP, PVRi, and reduced RV ejection fraction (EF) without a significant change in CI at a dose of 16 mg/kg/min . An investigation of IV epoprostenol showed a reduction in mPAP and PVRi, and an increase in RV EF (in patients with abnormal baseline values) and CI . Another study explored the use of IV norepinephrine with iNO compared to iNO alone and found that there was a greater decrease in mPAP, PVR index and right ventricle stroke work (RVSWI) in patients receiving norepinephrine with iNO compared to iNO alone . A single RCT in 35 patients demonstrated that levosimendan decreased mPAP, PVR index, and increased CI (from 3.8 L/min/m2 to 4.2) as well as RVEF . See Additional file 2: Table S6. Extracorporeal therapies Three out of the seven studies exploring the impact of ECLS evaluated veno-venous extracorporeal membranous oxygenation (VV-ECMO). These works have heterogeneous findings, with one showing decreased central venous pressures (CVP) and mPAP without a significant change in CO , while another case report showed decreased interventricular septal flattening immediately after VV ECMO cannulation, which normalized at time of ICU discharge . Another investigation demonstrated that VV-ECMO combined with ultra-protective tidal volumes (driving pressures of 10 cm H2O) reduced PA systolic pressures; however, it did not result in significant differences in RV size and systolic dysfunction as measured by TTE . In a case series, the addition of an intra-aortic balloon pump (IABP) to VV-ECMO resulted in increased PA pressures and reduced CVP . A case report displayed a reversal of septal flattening and improved RV systolic function on conversion to VAV-ECMO from VV-ECMO . Two studies examined the impact of extracorporeal CO2 removal (ECCO2R) on RV function. One found that ECCO2R decreased RVEDA, improved RVEDA:LVEDA ratio, and increased CO . The second study investigated the impact of ECCO2R with ultra-protective TV (4 ml/kg of ideal body weight) and found no detectable change in CVP, right ventricular end diastolic diameter to left ventricular end diastolic diameter ratio, or PA systolic pressures; however, it did show improvement in TAPSE, see Additional file 2: Table S7 . Discussion To our knowledge, this is the first scoping review of the literature on the effect of clinical interventions on RV function in ARDS. Despite over 50 years of ARDS research, we found only 51 citations meeting inclusion criteria, only 27% of which intended to directly influence RV function. The strength of evidence overall is low, given the low number of enrolled patients and a paucity of randomized controlled trials only three in this study. The majority of more recent studies were case reports, case series, or otherwise observational in nature. The sole pharmacologic RCT on RVD in ARDS occurred in 2006 . Overall, the literature on RVD in ARDS suffers from a lack of standardization in definitions, treatment targets, and patient-centered outcomes. Significant heterogeneity in the included literature precludes meaningful pooling and systematic synthesis of these results. Many of the interventions tested were applied at different doses and durations with differing inclusion and exclusion criteria. A significant proportion of studies tested inhaled pulmonary vasodilators, which have been repeatedly shown to improve oxygenation, with uncertain effect on pulmonary artery pressures, and no clear mortality benefit . Over the past decade, extracorporeal life support modalities have been tested with increasing frequency, but there is still considerable heterogeneity in the configurations used as well as the quality of evidence. Furthermore, methods of RV assessment and the definition of RVD differed across studies. The most common assessment was via pulmonary artery catheterization, which largely reflects the era in which most of these studies were completed. Currently, pulmonary artery catheters are used infrequently in patients with ARDS in many centers around the world. While transthoracic echocardiography has become increasingly available across intensive care units, the challenges of acquiring adequate images for RV assessment in patients with ARDS may limit its utility. Furthermore, approximately 30% of included studies were completed before the lung protective ventilation era, where higher tidal volumes (and thereby distending pressures) were used. This may have predisposed to higher rates of RVD , perhaps in ways which could modify responsiveness to any of the tested therapies compared to a contemporary cohort. Priorities In order to enroll patients in high-quality prospective studies, consensus definitions of RVD and specifically, RVD in ARDS, are needed . These metrics ideally should account for both functional and structural changes in the right ventricle, incorporating features such as systolic and diastolic function, size, morphology, as well as measures of right ventricular pulmonary artery coupling . Reproducible definitions of RVD may be aided by improved cardiovascular phenotyping in ARDS . While the incidence of RVD in ARDS is estimated to be 20-50% , both the etiology and the natural history of RVD in ARDS are incompletely understood and could have time-varying characteristics. Given the mortality risk associated with RVD in ARDS, this review highlights several priority areas for scientific inquiry. There is a clear need for randomized controlled trials of all the major categories of treatments detailed in this review. A "RV-protective ventilation" strategy has been described and would be a low-cost intervention bundle with potentially high benefit. Patients at increased risk for RVD in ARDS (by established acute cor pulmonale risk scores ) could be selectively enrolled in trials, even as a preventative strategy. While patients with moderate to severe ARDS seem to benefit from a higher PEEP strategy , optimal PEEP strategy may differ in patients at increased risk for RVD. While pulmonary vasodilator medications have not shown benefit in unselected ARDS patients, it may be worthwhile to conduct RCTs in patients with established RVD as a predictive enrichment strategy. Although previous investigations examining the use of extracorporeal support in ARDS have yielded tepid results , RVD is not typically an explicit therapeutic target for ECLS. However, RVD is associated with increased mortality in this group . In addition to the included studies on ECLS, a retrospective analysis of 15 patients with COVID-19 ARDS demonstrated improvement in RV echo parameters after VV-ECMO cannulation (published after our systematic search). In patients who are already receiving ECLS, there are still opportunities for prospective physiologic studies to mitigate RVD, using adjunctive management such as pharmacologic therapies as well as different mechanical ventilation strategies. One recently published retrospective analysis demonstrated an improvement in RVD and hemodynamic parameters when PEEP was optimized to a slightly positive transpulmonary pressure using esophageal manometry . Finally, there may be differences in right ventricular outcomes based on cannulation strategy , which should be further investigated in prospective studies. Rescue strategies (including changes to cannulation strategy, among other interventions) for persistent RVD despite ECLS deserve further study but may be challenging to perform systematically across a small number of heterogeneous patients and centers. Secondly, there are several areas of ARDS management which were unexplored in this review of the literature. For instance, the specific role of tidal volume was not studied. This may be a priority area since it has been demonstrated that higher tidal volumes increase RV afterload even outside of ARDS . The effect of tidal volume on mortality in ARDS may depend on respiratory system elastance , and it is unknown if any of this effect is due to impact on RV function. While some alternative modes of ventilation were studied, including inverse-ratio pressure control, no studies on airway pressure release ventilation were found. Finally, the effect of commonly used vasoactive agents which may have varying effects on pulmonary vascular resistance (such as vasopressin and phenylephrine) as well as inotropic agents (such as dobutamine and milrinone) was not specifically assessed. Limitations This review has limitations. We systematically and exhaustively searched multiple databases, but relevant articles may have been missed if the broad search criteria did not capture them. Extraction of data from individual studies proved challenging given heterogeneous reporting, which limited our own reporting to a descriptive format. Conclusions Given the prevalence of RV dysfunction in ARDS and its association with mortality, the dearth of high-quality research in this area is concerning. The existing literature is characterized by small sample sizes, inconsistent application of treatments across studies, and variable reporting of results. Prospective trials aimed at treating or preventing RV dysfunction should be a research priority for the ARDS scientific community. Supplementary Information Additional file 1. PRISMA-ScR Checklist. Additional file 2. Search Strategy, Supplemental Tables and Figures. Abbreviations RVD Right ventricular dysfunction ARDS Acute respiratory distress syndrome RV Right ventricle PEEP Positive end expiratory pressure ECLS Extracorporeal life support PP Prone position ventilation SV Stroke volume RVEDV Right ventricular end diastolic volume TAPSE Tricuspid annular plane systolic excursion CI Cardiac index mPAP Mean pulmonary artery pressure CO Cardiac output HFOV High-frequency oscillatory ventilation RVEDA Right ventricular end diastolic area LVEDA Left ventricular end diastolic area ACP Acute cor pulmonale PA Pulmonary artery VTI Velocity time integral iNO Inhaled nitric oxide PVR Pulmonary vascular resistance PAC Pulmonary artery catheter VV-ECMO Veno-venous extracorporeal membranous oxygenation ICU Intensive care unit IABP Intraaortic balloon pump CVP Central venous pressure ECCO2R Extracorporeal CO2 removal TV Tidal volume RCT Randomized controlled trial TTE Transthoracic echocardiography TEE Transesophageal echocardiography EF Ejection fraction RVSWI Right ventricular stroke work index Author contributions SG performed screening of abstracts, data extraction, drafting and critical revision of manuscript. GA performed abstract screening and critical revision of the manuscript. MS and MTS devised search strategy. MH, AT, and AD performed critical revisions of the manuscript. MTS conceived the original idea, performed full-text screening, data extraction, and drafting and critical revision of the manuscript. All authors read and approved the final manuscript. Funding No funding was received for this work. Availability of data and materials All data related to this work are included in the main text or the supplementary materials. For pre-registered search strategy, please see Declarations Ethical approval and consent to participate This work is exempt from IRB review as it is a synthesis of published literature. Competing interests The authors have no financial or non-financial competing interests to report. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
BMJ Glob Health BMJ Glob Health bmjgh bmjgh BMJ Global Health 2059-7908 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 36882220 bmjgh-2023-011815 10.1136/bmjgh-2023-011815 Commentary 1506 Recognising stillbirth as a loss of life and not a baby born without life Dandona Rakhi 12 Solberg Carl Tollef 3 1 Public Health Foundation of India, Gurugram, Haryana, India 2 Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA 3 Centre for Medical Ethics, Department of Health and Society, University of Oslo, Oslo, Norway Correspondence to Dr Rakhi Dandona; [email protected] 2023 7 3 2023 8 3 e01181519 1 2023 22 2 2023 (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. 2023 This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: Child health Health policy Maternal health Public Health Bill and Melinda Gates Foundation INV-004506 special-featureunlocked pmcSummary Stillbirths and their families continue to be neglected despite several calls to address preventable stillbirths. The dichotomy between stillbirth and neonatal death in the quantification of loss does not comply well with the societal burden of perinatal deaths or with the philosophical accounts of death's individual harm. Grief is a natural emotional consequence of attachment and loss, whether the loss of a limb, country, employment, marriage or other crucial relationships. We argue that giving birth to a baby bearing no signs of life is grief unlike any other. Grieving for death must be rebalanced to include stillbirths. Recognising stillbirth as a loss of life and not a baby born without life is important for the global child survival initiatives to be effective in reducing preventable stillbirths. The proposition of the Lancet Commission on the Value of Death is that our relationship with death and dying needs rebalancing because how people die has changed radically over recent generations as death comes later in life for many and dying is often prolonged, and has moved from a family and community setting to primarily the domain of health systems.1 They argue that rebalancing death and dying will depend on changes across death systems the many interrelated social, cultural, economic, religious and political factors that determine how death, dying and bereavement are understood, experienced and managed. We support this rebalancing of death and dying and suggest a broader scope for it by the inclusion of stillbirths babies born dead. The incident of 'death' (loss of one's life) impacts the friends and family left behind in addition to the individual who loses his/her own life. We argue that this type of impact is also true for stillbirths because a stillbirth is still a birth. Despite several calls to address preventable stillbirths, the acknowledgement that these babies 'die' and hence are born dead, and that some of them could and should have been born alive continues to be neglected by health practitioners, policy makers and in health metrics indicators.2 3 The recent UNICEF-IGME report estimated nearly 2 million stillbirths globally in 2021, defined as fetal death at or after the 28th gestational week but before birth.3 In comparison, an estimated 2.4 million neonatal deaths occurred globally in 2019, which is the death of a newborn (live birth) between birth and the first 28 days of postpartum life.4 The most disability-adjusted life-years (DALYs), approximately 86 DALYs, in the Global Burden of Disease Study arise from neonatal death, most of which are early neonatal deaths that occur at birth (intrapartum complications) or within the first 6 days postpartum. Notably, many neonatal deaths result from preterm birth that is, birth earlier than 37 weeks of gestation. Therefore, in terms of the burden of disease, a baby born alive and prematurely at the 24th gestational age who dies at birth or right after birth is registered as the worst possible tragedy with 86 DALYs. In contrast, the death of a baby in the womb at 40th week of gestation just before birth (stillbirth) is not assigned any disease burden.5 Today's majority view for contemporary philosophers is that death is comparatively harmful to the individual who dies,6 7 and the years of life lost component of the DALY relies on such counterfactual reasoning.8 9 In this philosophical reasoning, death implies a loss of a future, and generally, death at a young age results in losing a more extensive future than death at an older age. If taken seriously, such a comparative account of the harm of death implies that neonatal death is considered not just death of the neonate but death of 'a future like ours' with all that life has to offer. That is to say, the death of a baby implies the loss of not only the baby itself but also the child and adult person that it could have been had it not died. However, the dichotomous view that birth itself constitutes the difference between a seemingly morally insignificant event (ie, stillbirth) and the worst tragedy we can think of (ie, neonatal death) neither complies well with the philosophical perspective nor with the empirical literature on the societal burden of perinatal deaths.6 10 There is also no birth dichotomy in perinatal medicine but rather a set of overlapping pathologies that can occur both before and after birth. The built-in ethical tension of perinatal deaths is also well reflected in the etymology of 'burden' itself, which can mean both 'to bear children' and 'that is borne'. Thus, we believe that our concept of disease burden should ideally reflect not only the harm of perinatal deaths that occur after birth but also those that occur before birth. The babies who are stillborn are real babies, and just because they died before birth does not mean they did not exist. And yet stillbirths are also overlooked in fertility indicators such as the crude birth rate which is based only on livebirths,11 and in vital registration systems in many countries.12 The Lancet Commission describes grief as the natural emotional consequence of attachment and loss, whether the loss of a limb, country, employment, marriage or other crucial relationships and mourning as the public face of this grief.1 Similarly, the devastating incomprehension of giving birth to a baby bearing no signs of life is unexplainable. There is no greater pain that a parent can feel than leaving the hospital with empty arms without the baby and coming home to a house prepared for a baby that did not make it home. However, the invisibility of stillbirths is apparent even in grief and mourning, as individual feelings of guilt or shame prevent public mourning of their loss.10 This lack of opportunity to publicly grieve fuels the cycle of stillbirths being considered of less consequence and without merit of grieving, contributing to their invisibility. Furthermore, bereavement refers to losing an important relationship through death and can be associated with many physical and mental health problems. The loss of a baby born dead reaches far beyond the loss of life. The psychological costs, including maternal depression and its impact on fathers, family and siblings, are profound and long-lasting.10 13 During the COVID-19 pandemic, the world saw people dying alone and families unable to say goodbye and being prevented from coming together in grief.14 This has been the case since long for many stillborn babies as they are not given proper burial or goodbyes.13 The birth of a dead baby impacts families, and the most impact is on the mother. She enters the hospital pregnant but leaves with a box or empty arms. With women traditionally viewed as caregivers at times of ill health and dying, it is estimated that women contribute almost 5% of the global gross domestic product through health caring.15 However, caregiving support is not always available to the mother of a baby born dead, who feels undervalued and unsupported having given birth to a baby born dead.16 If current trends continue, an additional 20 million stillbirths are estimated to occur before 2030, placing an immense burden on women, families and society.3 Therefore, there are reasons to argue that death's harm to others implies that there should be no prebirth and postbirth dichotomy for either quantifying the disease burden or being able to grieve and be supported. The world suffered an estimated 48 million stillbirths in the past two decades. The health community recognises the urgent need to prevent stillbirths, and stillbirth prevention has become an essential part of global child survival initiatives.3 The UN-IGME report has highlighted urgent actions to prevent an estimated 20 million more stillbirths by 2030.3 Importantly, this death toll could likely be higher because of the impact of COVID-19.17 The Lancet Commission emphasises that grieving must be rebalanced and calls on the society to respond to this challenge.1 We respectfully extend this challenge and call on society to embrace stillbirths as the death of a baby, many of whom should have been born alive, which is essential not only for the global child survival initiatives to be effective in preventing further loss of lives but also for providing support for those grieving the loss of lives of their babies. In conclusion, real progress in stillbirth prevention can be made by simply recognising stillbirth as a loss of life and not a baby born without life. There is still a pregnancy, still a baby, still a mother, still a father a stillbirth is still a birth. Let's grieve for a whole life lost. Data availability statement No data are available. Ethics statements Patient consent for publication Not applicable. Handling editor: Seye Abimbola Contributors: RD and CTS contributed equally to this work. Funding: This work was supported by the Bill & Melinda Gates Foundation. Disclaimer: The funder had no role in the writing of the report or in the decision to submit the paper for publication. Competing interests: RD is on the Board of the International Stillbirth Alliance. Provenance and peer review: Not commissioned; externally peer reviewed. References 1 Sallnow L, Smith R, Ahmedzai SH, et al . Report of the lancet commission on the value of death: bringing death back into life. Lancet 2022;399 :837-84. 10.1016/S0140-6736(21)02314-X 35114146 2 de Bernis L, Kinney MV, Stones W, et al . Stillbirths: ending preventable deaths by 2030. Lancet 2016;387 :703-16. 10.1016/S0140-6736(15)00954-X 26794079 3 Danzhen H, Lucia M, Anu B, et al . A neglected tragedy: the global burden of stillbirths. 2020. Available: [Accessed 28 Mar 2022]. 4 Temmerman M, Lawn JE. Stillbirths count, but it is now time to count them all. The Lancet 2018;392 :1602-4. 10.1016/S0140-6736(18)32342-0 5 GBD 2015 Child Mortality Collaborators. Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the global burden of disease study. The Lancet 2016;388 :1725-74. 6 Gamlund E, Solberg CT, eds. Saving people from the harm of death. 1st ed. Oxford University Press, 2019. Available: [accessed 28 Oct 2021]. 7 Broome J. Weighing lives. 5 Aug 2004. 10.1093/019924376X.001.0001 8 Anand S, Reddy SG. The construction of the DALY: implications and anomalies. SSRN Journal 2019. 10.2139/ssrn.3451311 9 Murray CJL. Rethinking dalys. In: Murray CJL, ed. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020; summary. Cambridge: Harvard School of Public Health [u.a.]. Global burden of disease and injury series, 1996: 1-98. 10 Burden C, Bradley S, Storey C, et al . From grief, guilt pain and stigma to hope and pride - a systematic review and meta-analysis of mixed-method research of the psychosocial impact of stillbirth. BMC Pregnancy Childbirth 2016;16 :9. 10.1186/s12884-016-0800-8 26785915 11 World Health Organization. Crude birth rate. the global health observatory [internet]. 2023. Available: www.who.int/data/gho/indicator-metadata-registry/imr-details/1139#:~:text=Definition%3A,year%2C%20usually%20multiplied%20by%201%2C000 12 Lawn JE, Blencowe H, Waiswa P, et al . Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 2016;387 :587-603. 10.1016/S0140-6736(15)00837-5 26794078 13 Heazell AEP, Siassakos D, Blencowe H, et al . Stillbirths: economic and psychosocial consequences. Lancet 2016;387 :604-16. 10.1016/S0140-6736(15)00836-3 26794073 14 Wakam GK, Montgomery JR, Biesterveld BE, et al . Not dying alone - modern compassionate care in the covid-19 pandemic. N Engl J Med 2020;382 :e88. 10.1056/NEJMp2007781 32289215 15 Langer A, Meleis A, Knaul FM, et al . Women and health: the key for sustainable development. Lancet 2015;386 :1165-210. 10.1016/S0140-6736(15)60497-4 26051370 16 Pollock D, Ziaian T, Pearson E, et al . Understanding stillbirth stigma: a scoping literature review. Women Birth 2020;33 :207-18. 10.1016/j.wombi.2019.05.004 31296472 17 Chmielewska B, Barratt I, Townsend R, et al . Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis. Lancet Glob Health 2021;9 :e759-72. 10.1016/S2214-109X(21)00079-6 33811827 |
ga1 Keywords SARS-CoV-2 Charge adaptation Codon usage adaptation Ka/Ks evolution Spike protein pmc1 Introduction The SARS-CoV-2 virus has been causing COVID-19 pandemic for more than three years. During the pandemic, the virus is rapidly accumulating mutations. The three major variants, namely alpha, delta and omicron, caused significant waves of infection worldwide in early 2021, mid 2021 and early 2022. Each infection wave is much more serious than the initial outbreak in Wuhan, China around early 2020, and the infections in each wave increased dramatically . With the mitigation of quarantine policies in many countries, the transmission will be booming, and the transmission between human and animals may become more frequent. Thus, omicron should not be the last variant of SARS-CoV-2. The main evolutionary force of the viral mutations includes infectivity, reproduction efficiency and immune evasion. The earliest infectivity-increasing mutations were observed in China (V367F, W436R and D364Y), where strict isolation policies were deployed; in contrast, the other early mutations in the rest of the world did not show increased affinity of S-RBD and human ACE2 because of relaxed quarantine measures , . The worldwide massive vaccination was also a driving force of virus evolution. The major variants emerged soon after such massive vaccination, causing immune evasion and significantly reduces the effectiveness of vaccines , . However, little was known about the mutations on the reproduction efficiency, i.e. the adaptation on the viral protein synthesis. The epidemiology indicated that the SARS-CoV-2 virus is adapting human for co-existence due to the increasing infectivity and decreasing mortality. However, many studies showed that the SARS-CoV-2 is under strong purifying selection , . This normally means that the functional mutations are being excluded, which is counteracting the adaptation . Such a contradiction needs more clarification. In this study, we focused on the translational adaptation of the SARS-CoV-2 virus and the surface properties of the spike protein to provide more insights on the abovementioned questions, and depict the major trend of the SARS-CoV-2 evolution during the evolution. 2 Materials and methods 2.1 Sequencing data analysis The original RNA-seq and Ribo-seq data (Calu3 cells infected with SARS-CoV-2 for 7 h) were downloaded from Gene Expression Omnibus database (GEO) under accession number GSE149973 , In brief, all raw sequencing data low quality reads and linker were removed using fastp . For the quantification of SARS-CoV-2 gene expression, FANSe3 program was used to align the clean reads to human refmRNA (UCSC) to remove human reads , , after human reads removal, the remaining reads mapped to the Wuhan Hu-1 (NCBI Accession NC_045512.2. Mapping parameter, Ribo-seq: -S10 -E1 -U1, RNA-seq: -S12 -E2), reads per kilobase per Million mapped reads (RPKM) of each gene were calculated in golang program. 2.2 Proteomic and RNC-seq expression data analysis Proteomic (quantitative technique: DIA, A549 cells were infected with SARS-CoV-2 for 24 h) and RNC-seq (human HBE cell line) expression data were extracted from two independent studies supplementary materials, respectively , . 2.3 SARS-CoV-2 genomes data analysis SARS-CoV-2 genomes for temporal evolution analysis were downloaded from NCBI SARS-CoV-2 database at 2023/01/29 ), with a list of over 2.9 million SARS-CoV-2 genomes, only sequences with length longer than 29500 and having zero N bases will be included in the subsequent analysis. Genomes for CAI and ITE evolution analysis were downloaded from GISAID database (www.epicov.org). Protein-coding sequences were exracted by using Exonerate2.2 with affine:local model, ), which perform gapped alignment against a database, this model equivalent to the classic Smith-Waterman-Gotoh type of alignment. Lineage assignment using Pangolin lineage command line tool ) with standard model . 2.4 Ka/Ks and charge evolution analysis Due to high closely related (identity ~ 99%) of SARS-CoV-2 genomes, we used MAFFT v7 as multiple sequence aligner . Each cds Ka/Ks calculation was performed by Ka/Ks calculator2.0 using YN method , . For charge evolution, Protein translation and net charge calculations were performed using gotranseq v0.3.0 ) and peptides v1.2.2 ) , respectively. 2.5 Codon adaptation analysis CAI (Codon Adaptation Index), ITE (Index of Translation Elongation) and RSCU (Relative Synonymous Codon Usage) were calculated using DAMBE7, CAI is a measure of the host codon adaptation for a gene sequence. ITE is similar to CAI, which incorporates both tRNA-mediated selection and background mutation bias and fits protein production better than CAI , , . 2.6 Electrostatic energy and surface electrostatic potential calculations The complex structure of the SARS-CoV-2 RBD and ACE2 complex (PDB: 6M0J), SARS-CoV-2 Spike with furin cleavage site structure (PDB: 7FG7) and Human furin structure (PDB: 5MIM) were obtained from the PDB database. The three-dimensional structures of three variants (alpha, delta and omicron) were generated by in silico mutation using UCSF chimera software v1.15 (Dunbrack backbone-dependent rotamer library method) , , all site mutations selected the most probable isoforms. PyMol was used to calculate the surface electrostatic potential by Adaptive Poisson Boltzmann solver (APBS), the color scale range was set from - 1.0-1.0 kT/A. We used delphi force webtool ) to calculate the electrostatic energy of the RBD and ACE2 binding domain, the required PQR file was generated by delphiPKa ) , . DelphiPKa calculation was used charmm force field, pH and salt concentration were set to 7 and 0.15 M, respectively, other setting uses standard mode, delphiforce calculation uses the Gaussian-smoothed mode, the Grid Resolution uses 2.0 A, and the salt concentration is set to 0.15 M. 3 Results 3.1 The S-gene is the only gene undergoing stepwise positive selection We used Ka/Ks to evaluate the selection of the SARS-CoV-2 sequences from the end of 2019 to January 2023. Ka/Ks> 1 means that the gene is undergoing positive selection and drives the adaptation. Ka/Ks< 1 indicates purifying selection, which stabilizes the gene. It is noted that the Ka/Ks of the S-gene was below 1 till February 2021, showing that in the first year of pandemic, S-protein was under purifying selection in general, indicating that the selective pressure was not that significant. However, the Ka/Ks surpassed 1 from February 2021 and is constantly increasing, showing that the S-protein is undergoing an increasingly stronger positive selection (Fig. 1A). In the era of Omicron pandemic, the Ka/Ks of the S-protein suddenly increased to more than 5. The Ka/Ks analysis of omicron sublineages showed that the Ka/Ks tend to increase over the time: the early omicron BA.1 lineage showed Ka/Ks between 2 and 8; the BA.2 lineage started from Ka/Ks= 4 and increased to 8-9 in early 2023; the BA.4, BA.5 and BQ.1 lineages showed Ka/Ks about 7-8; the latest XBB lineage had Ka/Ks over 10 (Supplementary Fig. S1B). This echoed much faster evolution of omicron variants than the earlier variants.Fig. 1 Ka/Ks analysis of SARS-CoV-2 evolution. Ka/Ks of each gene was calculated using the SARS-CoV-2 genome sequences. The data was averaged in a day-wise manner. (A) Temporal Ka/Ks analysis of annotated canonical CDS. The background colors indicate the major lineages (Wild-type, alpha, delta and omicron) and their approximate pandemic timespan. E protein, ORF7B, ORF6 and ORF10 were not shown due to insufficient data. Cyan dashed line showed the threshold of Ka/Ks= 1. (B) Ka/Ks evolutionary trends of major variants. Fig. 1 The M protein, which encodes the most abundant membrane protein, was undergoing purifying selection until the omicron variant. In the omicron variant, the Ka/Ks of M gene was approximately 1.1 (Fig. 1A), indicating that it was undergoing neutral selection. In contrast, the other important and highly expressed genes, such as the N-gene as structural genes, the orf1ab gene for viral replication, the orf3a and orf7a genes that mediates cell inflation, were undergoing purifying selection, because their Ka/Ks were almost constantly below 1. The Ka/Ks of N-gene was transiently above 1 between February and September 2021 and then dropped back below 1, suggesting that the mutations generated in this period were not the primary factor to maintain pandemic. These results showed that the S-gene was the only SARS-CoV-2 gene that underwent positive selection. Such positive selection may be driven by the massive vaccination worldwide and preexisting antibody due to natural infection, because most COVID-19 vaccines include or produce S-protein. Interestingly, the stepwise elevation of the positive selection coincides temporally with the major SARS-CoV-2 variation types (alpha, delta, omicron. Fig. 1A). However, within one variant type, the Ka/Ks of S-gene has a long term continuous upward or downward trend (Fig. 1B). This indicated that the mutations were accumulated stepwise. 3.2 SARS-CoV-2 codon usage did not evolve towards more efficient translation in human Adaptation to the host translation system is needed for efficient viral protein production and replication of the virus. Such adaptation is largely represented by similar codon usage in the host cells. Using the CAI (codon adaptation index) and ITE (index of translation elongation) to represent the codon adaptation, we showed that the SARS-CoV-2 genes (demonstrated using the original strain Wuhan Hu-1) with higher CAI and ITE were expressed in a significantly higher level (Fig. 2A). This trend was also visible in Ribo-seq data (Fig. 2B), but CAI and ITE do not correlate to mRNA expression level at all (Fig. 2C). These results showed that the protein expression preference towards the codon adaptation happened indeed in the translation process of SARS-CoV-2. However, SARS-CoV-2 CAI and ITE were significantly lower than that of the human cells and other well-known human viruses, respectively, while the human viruses have comparable CAI and ITE against the human cells (Fig. 2D). Compared to the other coronaviruses that can infect human (SARS-CoV, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-NL63 and HCoV-OC43), the CAI and ITE of the SARS-CoV-2 is comparable to the SARS-CoV, and slightly lower than the other coronaviruses but without statistical significance (P > 0.05). Note that the other coronaviruses have been shown to infect multiple species other than human. Coincidently, the CAI and ITE of these coronaviruses were significantly lower than that of the human cells and other well-known human viruses (Fig. 2D). Here, we used the genomic data to calculate the CAI and ITE for all virus, and we used the RNC-seq (sequencing of the translating mRNAs) data of the human lung cell line A549 to reflect the actual codon demand in human lung cells, which was the primary infection host of SARS-CoV-2. These results showed that the SARS-CoV-2 were not fully adapted to human in terms of codon usage.Fig. 2 SARS-CoV-2 codon adaptation analysis. (A, B, C) Correlation of CAI/ITE values against the proteome proteomic, Ribo-seq and RNA-seq gene expression level in SARS-CoV-2 infected cells. Spearman correlation coefficient. (D) CAI and ITE value calculated for SARS-CoV-2 genes, RNC-HEG (Translating highly expressed genes in HBE cells), common viruses and ERV (Human endogenous retroviruses) sequence. (E) CAI and ITE values of each gene grouped by variant. (F) Box plot of Spike protein RSCU values grouped by variant. Human RSCU was compared as negative control. (G) Evolutionary trends of SARS-CoV-2 5'UTR MFE. Fig. 2 To assess the evolutional trend of the codon adaptation of SARS-CoV-2 during the pandemic, we calculated the CAI and ITE of the typical strains of the wild-type (the original strain in Wuhan) and the major variants alpha, delta and omicron (Fig. 2E). Most genes showed a constant CAI and ITE during the pandemic. Only the orf7b gene showed an increase in CAI and ITE. However, the orf7b was lowly expressed, indicating the limited biological impact of its increase in codon adaptation. The S-gene, which is the only gene underwent positive selection, showed a decrease in CAI and ITE from the original strain to delta variant, and minimally increased in omicron variant. Such a minimal increase may not cause any visible biological effect. We also calculated the RSCU of the S-gene of all collected virus sequences. Compared to condensed RSCU distribution of human genes, S-genes of all major variants showed a wide scatter of S-gene RSCU values (Fig. 2F), indicating that the optimal codon usage was not a selective force during the pandemic. Translation efficiency is determined by translation initiation and translation elongation, while CAI, ITE and RSCU can only reflect translation elongation efficiency. According to previous research, 5'UTR minimum free energy (MFE) characterizes translation initiation efficiency. We calculated the SARS-CoV-2 5'UTR MFE between end of 2019 to January 2023, it can be seen that there was no continuous upward trend in three years 5'UTR evolution (Fig. 2G), and there was only a brief and small increase before July 2021 and January 2022, indicating that the translation initiation efficiency did not have sign of enhancement. In sum, the SARS-CoV-2 virus did not mutate towards optimal translation efficiency. We need to investigate the evolutional advantage from other aspects. 3.3 S-gene accumulated positive charges during pandemic Electrostatic force is a major force to guide protein-protein interactions. Compared to van der Waals force, the electrostatic force decays much slower against distance, which facilitates the binding of virus to other proteins in various important processes. We analyzed the changes of charges (at pH=7) and found similar pattern as the Ka/Ks analysis. The S-gene showed a steady increase in positive charge, and this increase was remarkably speeded up since June 2021, which was the time when delta variant was leading the pandemic. The charges of other genes did not apparently change during the pandemic in general (Fig. 3A). The accumulation of the positively charged amino acid residues were mainly found in the RBD and furin domains (Fig. 3B). The net charge in RBD domain increased from 1.5 to 4, and the net charge in furin domain increased from 3 to 4. The increase in the charge at the furin cleavage site can theoretically increase the cleavage efficiency, but it has been verified in previous studies that omicron furin has a lower cleavage efficiency, It is related to allosteric modulations of the linoleic acid binding pocket . Overall, these results indicated that these changes may be functionally meaningful.Fig. 3 The charge of SARS-CoV-2 proteins during evolution. (A) Net charge evolution of SARS-CoV-2 proteins. (B) Net charge of local region of the spike protein: RBD (333-527), RBM (438-506) and Furin cleavage site (675-695) , . (C, D) Electrostatic surfaces of the spike protein RBD region and human ACE2 protein. (E) Electrostatic energy of ACE2 binding S-RBD. (F) Electrostatic surfaces of the spike protein furin cleavage site and human furin. Fig. 3 Indeed, the human ACE2 protein is largely negatively charged in surface, especially in the region that binds SARS-CoV-2 S-RBD domain (Fig. 3C). The increasing positive charge in RBD (Fig. 3D) obviously elevated the electrostatic affinity, confirmed by energy computation on the structure of the RBD-ACE2 binding state (Fig. 3E). This is also supported by other investigations . Similarly, the furin enzyme active site is highly negatively charged. The furin cleavage site in S-gene accumulated positive charges during evolution (Fig. 3F), which should increase the binding efficiency and accelerate the enzymatic cleavage. 4 Discussion Our results may provide novel insights on the SARS-CoV-2 evolution. It has been shown that the narrow-spectrum +ssRNA viruses evolve their codon usage matching their hosts' tRNA better than the broad-spectrum viruses. Such adaptation is to optimize their protein expression , . In our analyses, we showed that the SARS-CoV-2 did not evolve towards optimized codon usage in human lung cells, indicating that it maintains the translation ability to adapt multiple hosts expression system. It has been experimentally shown that the SARS-CoV-2 virus infects deers, hamsters, North American raccoons, striped skunks, white-tailed deer, raccoon dogs, fruit bats, deer mice, domestic European rabbits, bushy-tailed woodrats, tree shrews and multiple non-human primate species . Evidence were also demonstrated that cats, ferrets, fruit bats, hamsters, dogs, deer mice and white-tailed deer can transmit the virus within the species , , . Such ability facilitates formation of a natural reservoir of virus. Even with the strictest lockdown policy, the reservoir serves and animals as a refuge of SARS-CoV-2 and may transmit to human again when possible. Indeed, SARS-CoV-2 transmission from mink and pet hamsters to humans has been confirmed , . Analyses also suggested that the progenitor of omicron variant jumped from human to mice and jumped back to humans and caused the omicron outbreak . Maintaining a broad spectrum of hosts is inferred to facilitate the survival of SARS-CoV-2, especially in the regions deploying "dynamic zero-COVID policy" like China. In other countries where not so strict policies were applied, the massive vaccination also drives the virus to maintain the ability to infect other species to survive. Therefore, it is understandable that the major evolutionary driving force is applied on the infectivity, i.e. the spike protein. Coincidently, we showed that the S gene is the only gene which underwent the strong positive selection. Other genes exhibit only weak or temporary positive selection. Since the infection is conducted via the binding of S-RBD and human ACE2, two major ways can enhance this affinity: increasing the electrostatic interaction and mutating specific residues to from more stable van der Waals force on the interaction interface. Electrostatic force decreases far slower than the van der Waals force against distance, making it more suitable to serve as guide force of the two molecules. Indeed, van der Waals energy between S protein and human ACE2 barely increased in omicron variant compared to the initial wild type . ACE2 is highly conserved in mammals ,and has a negatively charged surface in the RBD binding region for multiple species(Fig. S1C). Therefore, the increase of electrostatic interaction is the major factor of the increasing binding affinity during the evolution , . Increasing the electrostatic interaction is also universal for all species, and thus could potentially beneficial for a broad host spectrum. The occurrence of the same mutation in variants is a sign of convergent evolution. Nevertheless, our omicron sublineage analysis shows that the direction of evolution is deviate from the convergent evolution for the past three years, due to XBB lineage has the lowest net charge among all omicron lineages (-2.5 net charge). The XBB lineage also showed the highest Ka/Ks analysis, XBB has higher Ka/Ks, which means under stronger positive selection (Fig. S1A-B). The convergence and divergence of the evolution simultaneously occurred in the virus, illustrating the multifaceted and complex evolutionary scenario. There are other interesting studies showing different conclusions , synonymous substitutions in SARS-CoV-2 adapted towards human codon usage patterns over time. To be noted, the global analysis of this study includes both synonymous and non-synonymous mutations in codon and translation adaptation, showing that there is no significant adaptation towards human codon usage in general, indicating that the evolutionary force may not come always from the human host. With the average reported R0 = 9.5 , the SARS-CoV-2 omicron variant is already among the most infectious viruses in the human history. However, since the accumulation of positive charges in its S-RBD and Furin digestion site is the key aspect of the high infectivity, it can be used as druggable target. Polar reagents which neutralize the charges may counteract the infectivity. In another aspect, the positive charges cover almost the entire interaction surface of the S-RBD and Furin digestion site of the omicron variant, showing that there's only restricted potential to accumulate more positive charges in these interfaces, which indicates that the infectivity of SARS-CoV-2 may approach to a limit. Funding This work has been supported by the 10.13039/501100012166 National Key Research and Development Program of China (2017YFA0505000), Guangdong Key R&D Program (2019B020226001) and the 10.13039/501100012226 Fundamental Research Funds for the Central Universities . CRediT authorship contribution statement Xialong Lu: Conceptualization, Methodology, Visualization, Data curation, Writing - original draft. Yang Chen: Data curation, Writing - review & editing. Gong Zhang: Supervision, Funding acquisition, Data curation, Writing - original draft, Writing - review & editing. Conflict of interest The authors declare no conflict of interest. Appendix A Supplementary material Supplementary material . Data availability statement The data presented in this study are available on accession number. Appendix A Supplementary data associated with this article can be found in the online version at doi:10.1016/j.csbj.2023.03.010. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.36036 Pediatrics Osteopathic Medicine Integrative/Complementary Medicine Conservative Management of Low Back Pain and Scoliosis in a Patient With Rheumatoid Arthritis: Eight Years Follow-Up Muacevic Alexander Adler John R Chu Eric Chun-Pu 1 Cheng Hay Yeung 1 Huang Kevin 2 Yao Kristy 3 Zhao Jason 1 1 New York Medical Group (NYMG) Chiropractic Department, EC Healthcare, Hong Kong, HKG 2 New York Medical Group (NYMG) Chiropractic Department, EC Healthcare, Yuen Long, HKG 3 New York Medical Group (NYMG) Chiropractic Department, EC Healthcare, Taikoo, HKG Eric Chun-Pu Chu [email protected] 12 3 2023 3 2023 15 3 e3603612 3 2023 Copyright (c) 2023, Chu et al. 2023 Chu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Scoliosis in patients with rheumatoid arthritis (RA) can cause significant pain and disability. RA has been extensively studied in relation to the cervical spine, yet the pathology of the thoracic and lumbar spine in RA patients has been largely overlooked. A 66-year-old woman, with longstanding RA and severe scoliosis, presented to the chiropractic clinic with a five-month history of exacerbated low back pain radiating to the right lower limb. The patient was treated with a combination of full-spine mechanical spinal distraction, spinal manipulative therapy, mechanical distraction of the cervical spine, and soft tissue treatment (scraping therapy). Thereafter, the patient recovered from the pain and radiculopathy and showed improvements in the radiological parameters, walking gait, and postural balance. Radiography was performed at the 12-month, four-year, and eight-year follow-up appointments and revealed improvements in symptoms, posture, and scoliosis. Although the treatment for RA-related scoliosis is similar to that for other types of scoliosis, due to the nature of RA, treatment should be tailored to individual patients. This case report highlights the importance of considering chiropractic therapy for the management of lumbar scoliosis in patients with RA, as a comprehensive treatment plan resulted in improved spinal balance, mobility, gait, posture, and quality of life. chiropractic management chiropractic therapy inflammatory disease scoliosis rheumatoid arthritis The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease characterized by the widespread swelling joints of multiple joints, including the atlantoaxial ligament of the cervical spine. The craniocervical junction is composed solely of ligaments and synovial joints, making it susceptible to the inflammatory process of RA . Inflammatory processes in RA can cause asymmetric arthritis of the facet joints, costovertebral joints, and vertebral bodies, resulting in spinal deformities . RA has been extensively studied in relation to the cervical spine, yet the pathology of the thoracic and lumbar spine in RA patients has been largely overlooked. It is estimated that between 30-50% of RA patients experience back pain, leading to greater levels of disability and depression compared to those who do not experience back pain . Recent studies have revealed that individuals with RA suffer from a higher rate of disc narrowing, subluxation, osteoporosis, and apophyseal destruction of the lumbar spine in comparison to individuals who do not have RA. These conditions can lead to long-term complications and severe pain in the lower back region. Early diagnosis, prompt medical treatment, and lifestyle modifications are essential to ensure the best possible outcomes . The treatment for RA-related scoliosis is similar to that for other types of scoliosis and includes bracing, physical therapy, and surgery. However, due to the nature of RA, treatment should be tailored to individual patients. Chiropractors are healthcare providers who use manual therapy to treat neuromusculoskeletal conditions . Many case reports have suggested that chiropractic therapy may help manage spinal conditions related to the symptoms of RA . Chiropractic care includes hands-on spinal manipulation and mobilization for alleviating pain and improving range of motion, as well as the prescription of rehabilitative exercises. Most existing literature focuses on cervical spine involvement in RA, but this patient had severe thoracolumbar scoliosis. The effects of RA on the lower spine and management of resulting scoliosis deserve more study. This highlights the importance of our case report, which provides an eight-year follow-up of the clinical presentation and chiropractic care of thoracolumbar spine pathology in a patient with RA, contributing to the current knowledge of patient management. Case presentation A 66-year-old female office administrator presented with a five-month history of exacerbated low back pain, and longstanding RA and scoliosis. She experienced sharp, radiating pain extending to her right sacroiliac joint and down her right leg. The pain pulled on her leg and limited her mobility, often requiring her to use a cane. Even with a cane, she could only walk for approximately 20 min before being limited by severe pain. These symptoms negatively impacted her sleep quality and social life. She rated her average pain severity as 6 out of 10 and stated that the symptoms were stress-related. Her World Health Organization Quality of Life (WHOQOL) assessment score was 70%. Radiography and MRI showed degenerative disc disease, severe scoliosis, and spondylolisthesis at L3/4. She was administered pain medication and acupuncture with minimal improvement. Her orthopedist recommended surgical intervention. She sought a second opinion and non-surgical options to help manage the pain and complications from worsening scoliosis. Figure 1 Full-spine radiograph and lumbar magnetic resonance image A) Full-spine radiograph revealing degenerative changes in the thoracic and lumbar regions, shoulder and pelvic imbalance (dash white line), and abnormal thoracic and lumbar scoliotic curves. The Cobb angle was measured at 60 deg (red lines) B) At L4-5 (white arrows), there are spondylolisthesis, posterior bulging disc, and marked bilateral facet joint degeneration, in the right facet joint and ligamentum flavum hypertrophy causing mild indentation of the thecal sac. Diffuse bulging disc and osteophytes at L2-3 causing mild indentation of the thecal sac, mild right lateral recess and mild bilateral foraminal stenosis. No nerve root compression is seen. Her medical history revealed that she had osteoporosis, RA, and insomnia. The moderately severe RA, which required continued treatment with leflunomide, methotrexate, and prednisone, was discovered 20 years earlier. Her scoliosis over the course of 10 years progressively worsened by 10 degrees at the same time as her RA diagnosis. Additionally, she underwent a thyroidectomy for hyperthyroidism six years prior, and levothyroxine was prescribed for post-thyroidectomy care. She denied having saddle anesthetic or losing control of her bladder, despite having a family history of scoliosis and RA. She had been swimming once a week to keep her musculoskeletal system in good shape. The patient provided written authorization for the use of her photographs, and the study received approval from the appropriate ethics committee. On physical examination, she weighed 65 kg and measured 160 cm in height, with an abnormal kyphotic posture that caused an imbalance, shoulder heaviness, and constant tightness across her upper back. Heberden and Bouchard's nodes were observed on her fingers . She had a limited range of motion in all planes in her lumbar spine due to pain and stiffness. Palpable muscle spasms and tenderness were present over the lumbar spine and right sacroiliac joint. Neurologically, the sensation was intact and reflexes were equal bilaterally. She had a negative straight leg raise test. The results of her Adam's test showed abnormal kyphotic curvature with an elevated right shoulder, uneven waistline, and rib hump, indicating asymmetrical trunk rotation. Her lower extremities showed no edema and normal muscle tone/strength, although her right ankle jerk reflex was diminished. She had decreased sensation on her right distal leg and ankle, and tenderness over her right greater trochanter and lateral knee. Standing posture and limb position measurements indicated a shortened right leg and pelvic tilt. On palpation, spinal intersegmental dysfunction was identified from T3-5, T7-T8, and L1-L2. Bilateral hypertonicity was observed at the quadratus lumborum, rectus femoris, and erector spinae. Functionally, she ambulated with a limp, favoring her right leg, and used a cane for prolonged walking and community mobility. She mobilized in and out of a chair slowly and with caution due to her limited spinal range of motion, which impacted her daily tasks. Based on her clinical history and radiological results, she is diagnosed with degenerative scoliosis complicated by spondylolisthesis and rheumatoid arthritis. Figure 2 Photo of patient's hands Her hands show Heberden (yellow arrow) and Bouchard nodes (red arrow) on the fingers. Chiropractic intervention was used to address the patient's scoliosis, as well as any associated shoulder and pelvic imbalances. The treatment involved a combination of techniques, including full-spine mechanical spinal distraction, spinal manipulative therapy, the mechanical spinal distraction of the cervical spine, and soft tissue treatment (scraping therapy). During the sessions, the chiropractor applied manipulation at the apex of the scoliotic curve and to the restricted vertebral segments to correct the spinal curvature. Mechanical spinal distraction is used to restore the restore scoliotic curves and scraping therapy on the hypertonic soft tissues to stabilize the spine. The patient received three treatment sessions per week for the first month and was given lifestyle coaching to help them maintain proper posture and spinal alignment. The range of motion in her back improved after four weeks of treatment, and specific tight muscle stretching was performed in each session. The treatments were continued twice per week for an additional five months, resulting in improved spinal mobility, gait, and trunk posture. Continued chiropractic care and custom foot orthotics were administered to improve abnormal motion within the pelvis and correct leg length discrepancy. Figure 3 Mechanical spinal distraction demonstration on scoliosis The patient is positioned in supine on the distraction device (Spine MT, Shinhwa Medical, Korea) with the head, thoracic, and pelvis stabilized via straps. The knees are in flexed position. A distraction and rotation force (20% of the body weight) is applied for 15 minutes. At 12 months, radiographs revealed normalized spinal curvature and posture and halted scoliosis progression . The patient reported symptom resolution, and her WHOQOL score improved to 98% (from 70%). The patient's treatment schedule was reduced to monthly maintenance appointments to preserve the spinal alignments . Follow-up radiographs at four and eight years confirmed a stable spinal curvature, and the patient was symptom-free . Her WHOQOL score remained at 98% and no adverse events were observed. Figure 4 Full-spine radiographs at the 12th month and eighth year re-evaluations A) At the 12th month, radiographs showed improved spinal curvature and posture, as well as halted scoliosis progression. Shoulder is more balanced, and the Cobb angle was reduced from 60 deg to 50deg (red lines) B) At the 8th year, the thoraco-lumbar scoliosis and shoulder (dash white line) and pelvic imbalances showed improvement. The Cobb angle was stable at 48 deg (red lines) Discussion In total, 32.0% of patients with RA have lumbar scoliosis . The severity of scoliosis in patients with RA depends on disease duration and severity, the pattern of joint involvement, genetics, osteoporosis, weight, fatigue, and muscle weakness. Longer duration and higher disease activity or severity of RA increase the risk of joint damage, leading to scoliosis . If the joints and ligaments connecting the spine to the pelvis are severely affected, the risk of spinal instability and deformity increases . Family history may play a role in the developmental risk of scoliosis from RA . Chronic inflammation in RA can lead to osteoporosis, which causes bone fragility . Chronic pain and fatigue due to RA can lead to decreased mobility and muscle weakness, contributing to scoliosis . The presence of RA in patients with scoliosis can exacerbate spinal curve progression, leading to increased pain, disability, and decreased quality of life. Additionally, immunosuppressive medications commonly used in the management of RA, such as methotrexate and prednisone, can weaken vertebral bodies and contribute to the progression of scoliosis . As our patient had a family history of scoliosis and RA, it was crucial for her healthcare practitioners to closely monitor spinal health in osteoporosis and chronic pain and fatigue symptoms to prevent or manage spinal curve progression and improve overall health outcomes. Chiropractic treatment has been shown to be effective in managing RA-related symptoms. Several studies have reported significant improvements in pain, joint mobility, and overall health-related quality of life in patients with RA undergoing chiropractic care . Evidence from a systematic review of alternative medicine for RA indicates that many therapies may be useful for treating rheumatic diseases . In addition, physical therapy modalities, such as exercise, can improve muscle strength and flexibility, reducing the risk of joint damage and improving overall joint function in older adults with RA . These findings suggest that chiropractic care can be complementary to traditional medical management of patients with RA, providing significant improvements in low back pain and overall health outcomes. Chiropractors also manage scoliosis-related symptoms including spinal subluxation and low back pain. Several studies have reported significant improvements in pain, posture, and overall spinal alignment in patients with scoliosis undergoing chiropractic care . Spinal manipulative therapy has been shown to reduce pain and improve spinal alignment in patients with scoliosis . In addition, corrective and therapeutic exercise can improve function and reduce symptoms in patients with scoliosis, thereby reducing the risk of spinal injury and improving overall spinal function . Adult patients with scoliosis with mild-to-moderate (17-26deg) curve magnitudes can have mild reductions in unusually high thoracic curves , and adolescent idiopathic scoliosis can have more reduction through chiropractic care . These findings suggest that chiropractic care can be an effective alternative to traditional medical management for scoliosis in patients with RA, providing significant improvements in pain and overall spinal health. Conclusions This case report highlights the effectiveness of a comprehensive treatment strategy during an eight-year follow-up, which included chiropractic care, the prescription of orthotics, and lifestyle changes, in the successful management of lumbar scoliosis in a patient with RA. More research is required to demonstrate the efficacy of this method in a wider patient group due to the limitations of a single case report. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. Chiropractic Doctors Association of Hong Kong issued approval CDA20230223. The committee approved the study and grant the request for a waiver of written informed patient consent. References 1 Craniocervical instability associated with rheumatoid arthritis: a case report and brief review AME Case Rep Chu EC Wong AY Lee LY 12 5 2021 33912801 2 Characteristics of lumbar scoliosis in patients with rheumatoid arthritis J Orthop Surg Res Ohishi M Miyahara H Kondo M 30 9 2014 24767138 3 Impact of low back pain on functional limitations, depressed mood and quality of life in patients with rheumatoid arthritis Pain Kothe R Kohlmann T Klink T Ruther W Klinger R 103 108 127 2007 16982148 4 Rheumatoid arthritis of the lumbar spine Ann Rheum Dis LA JS SH J BA J BI F 205 217 23 1964 14156623 5 Neck pain and headache after pinealectomy: improvement with multimodal chiropractic therapies Am J Case Rep Chu EC Trager RJ 0 23 2022 6 Successful interprofessional treatment of juvenile rheumatoid arthritis: a case report Integr Med (Encinitas) Boothby J Coffman S Turnbull T 55 60 16 2017 30881239 7 Use of spinal manipulation in a rheumatoid patient presenting with acute thoracic pain: a case report J Can Chiropr Assoc Chung CL Mior SA 143 149 59 2015 26136606 8 Reducing cervical retrolisthesis with long-term monthly chiropractic maintenance care: a case report J Med Cases Chu EC 359 364 13 2022 35949943 9 Lumbar scoliosis in rheumatoid arthritis: epidemiological research with a DXA cohort Spine (Phila Pa 1976) Makino T Kaito T Fujiwara H Yonenobu K 0 43 38 2013 10 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Ann Rheum Dis Aletaha D Neogi T Silman AJ 1580 1588 69 2010 20699241 11 Diagnosis and treatment of inflammatory joint disease Hip Pelvis Kim Y Oh HC Park JW 211 222 29 2017 29250494 12 Epidemiology and genetics of rheumatoid arthritis Arthritis Res Silman AJ Pearson JE 0 72 4 Suppl 3 2002 13 Osteoporosis and fractures in rheumatoid arthritis Curr Opin Rheumatol Wysham KD Baker JF Shoback DM 270 276 33 2021 33651725 14 Muscle weakness in rheumatoid arthritis: the role of Ca2+ and free radical signaling EBioMedicine Yamada T Steinz MM Kenne E Lanner JT 12 19 23 2017 28781131 15 Incidence of and risk factors for spondylolisthesis, scoliosis, and vertebral fracture in rheumatoid arthritis J Bone Miner Metab Yamada K Suzuki A Takahashi S 120 131 40 2022 34424413 16 Complementary and alternative medicine for rheumatic diseases: A systematic review of randomized controlled trials Complement Ther Med Phang JK Kwan YH Goh H Tan VI Thumboo J Ostbye T Fong W 143 157 37 2018 29609927 17 Effects of aerobic and resistance exercise in older adults with rheumatoid arthritis: a randomized controlled trial Arthritis Care Res (Hoboken) Lange E Kucharski D Svedlund S Svensson K Bertholds G Gjertsson I Mannerkorpi K 61 70 71 2019 29696812 18 Changes in radiographic parameters following chiropractic treatment in 10 patients with adolescent idiopathic scoliosis: A retrospective chart review Clin Pract Pu Chu EC Chakkaravarthy DM Huang KH Ho VW Lo FS Bhaumik A 1258 10 2020 32952984 19 The reduction of high thoracic scoliosis in adults by mirror image((r)) blocking: a chiropractic biophysics((r)) case series J Phys Ther Sci Oakley PA Kallan SZ Harrison DE 467 472 34 2022 35698559 20 Bridging the gap between observation and brace treatment for adolescent idiopathic scoliosis J Family Med Prim Care Pu Chu EC Kai Huang KH 447 449 6 2017 29302566 21 Effects of corrective, therapeutic exercise techniques on adolescent idiopathic scoliosis. A systematic review Arch Argent Pediatr Ceballos Laita L Tejedor Cubillo C Mingo Gomez T Jimenez Del Barrio S 0 9 116 2018 |
Philos Trans A Math Phys Eng Sci Philos Trans A Math Phys Eng Sci RSTA roypta Philosophical transactions. Series A, Mathematical, physical, and engineering sciences 1364-503X 1471-2962 The Royal Society 36907206 10.1098/rsta.2022.0359 rsta20220359 100973Introduction Introduction Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper: part 2 Taylor-Couette and related flows on the centennial of Taylor's seminal philosophical transactions paper: part 2 Hollerbach Rainer Writing - original draft Writing - review & editing 1 Lueptow Richard M. Writing - original draft Writing - review & editing r-lueptow@northwestern 2 Serre Eric Writing - original draft Writing - review & editing 3 1 School of Mathematics, University of Leeds, Leeds LS2 9JT, UK 2 Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, USA 3 M2P2, Aix Marseille University, Cent. Marseille, CNRS, Marseille, France One contribution of 16 to a theme issue 'Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical transactions paper (part 2)'. 1 5 2023 May 1, 2023 13 3 2023 March 13, 2023 13 3 2023 March 13, 2023 381 2246 Theme issue 'Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper (part 2)' compiled and edited by Richard M. Lueptow, Rainer Hollerbach and Eric Serre 2022035919 1 2023 January 19, 2023 19 1 2023 January 19, 2023 (c) 2023 The Authors. 2023 Published by the Royal Society under the terms of the Creative Commons Attribution License which permits unrestricted use, provided the original author and source are credited. In 1923, the Philosophical Transactions published G. I. Taylor's seminal paper on the stability of what we now call Taylor-Couette flow. In the century since the paper was published, Taylor's ground-breaking linear stability analysis of fluid flow between two rotating cylinders has had an enormous impact on the field of fluid mechanics. The paper's influence has extended to general rotating flows, geophysical flows and astrophysical flows, not to mention its significance in firmly establishing several foundational concepts in fluid mechanics that are now broadly accepted. This two-part issue includes review articles and research articles spanning a broad range of contemporary research areas, all rooted in Taylor's landmark paper. This article is part of the theme issue 'Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper (part 2)'. Taylor-Couette flow , stability analysis cover-dateMay 1, 2023 pmcIn a remarkable paper published in the Philosophical Transactions A a century ago, G. I. Taylor connected theory and experiment in his ground-breaking investigation of flow between differentially rotating concentric cylinders . The paper is sometimes described as the first convincing proof of the applicability of mathematical approaches to predict stability as well as proof of the fundamental correctness of the Navier-Stokes equations and the no-slip boundary condition , which are foundational concepts in modern fluid mechanics. Taylor's 1923 paper has inspired several generations of researchers in fields ranging from nonlinear dynamics to astrophysics. Not only does Taylor-Couette flow display remarkable vortical patterns that are easily generated and visualized, it is a test bed for studies probing fundamental aspects of fluid flow as well as practical engineering applications. Part 1 of this two-part theme issue explored contemporary topics related to Taylor-Couette flow including turbulent, convective and two-phase flows as well as extensions to magnetohydrodynamic, ferrofluidic and viscoelastic flows and flow geometries that are closely related to the Taylor-Couette problem [3-18]. Part 2 of this theme issue continues with review articles and research articles having their origin in Taylor's 1923 paper. Like Part 1, contributions in Part 2 come from an international community of leading researchers studying fluid flows that all connect back to Taylor's 1923 pioneering work published in the Philosophical Transactions. This issue starts with several papers that consider much the same problem as Taylor did, but with an emphasis on turbulence rather than the linear onset of instability. Feldmann et al. review the different routes to turbulence in the classical problem. Wang et al. present numerical results in the supercritical turbulent spiral regime. Merbold et al. conduct experiments in a relatively unexplored parameter space, namely the very wide gap case with cylindrical radius ratio ri/ro=0.1. Most of their resulting flow states are also turbulent. As in Part 1, we have several papers on the interaction of Taylor-Couette flow with convection, but with one crucial difference. The papers in Part 1 imposed a temperature gradient in the cylindrically radial direction, which corresponds to a radial force field playing a role like that of gravity. By contrast, the papers here impose gradients in the axial direction, matching gravity in a typical laboratory setting. Lopez et al. review Taylor-Couette flows in stably stratified configurations. Closely related to this is the paper by Meletti et al. , who present numerical work on the so-called strato-rotational instability. This is an intriguing phenomenon whereby the imposed differential rotation can be in the Rayleigh-stable regime, and the stratification by itself would also be stable, but the combination of the two is nevertheless unstable. By contrast, Masuda et al. impose unstable axial temperature gradients, and then study how the resulting convection interacts with the underlying Taylor-Couette flows. Ji & Goodman present a review of magnetohydrodynamic Taylor-Couette flows, with a particular emphasis on the magnetorotational instability and attempts to obtain various versions of it in liquid metal experiments. Both the magnetorotational instability and the strato-rotational instability are believed to be important in understanding the dynamics of astrophysical accretion discs, so experiments specifically targeting this regime are of considerable interest. As was the case in Part 1, the Taylor-Couette problem can be extended by considering fluids that are more complex than Newtonian fluids. Bai et al. and Moazzen et al. both present experimental results using viscoelastic fluids. Lopez & Altmeyer consider viscoelastic fluids numerically, and obtain arrow-shaped rotating waves. Panwar et al. conduct experiments involving oil-in-water emulsions in Taylor-Couette flows. Kang & Mirbod present a numerical study of non-colloidal suspensions in a Taylor-Couette flow. Finally, and again as in Part 1, there are a variety of systems and geometries that are not strictly Taylor-Couette flows as such, but are nevertheless closely related. Nagata presents theoretical comparisons of very narrow gap Taylor-Couette flow and rotating plane Couette flow. Krivonosova et al. consider spherical Couette flow, the flow between differentially rotating spheres. After a brief review of the subject, they investigate the effect of noise on some of the resulting flow states. Sharma et al. numerically study two lid-driven flow systems and confirm the presence of a Taylor-Gortler-like instability in those geometries. This two-part theme issue is a fitting tribute to celebrate the centennial of Taylor's foundational paper in the Philosophical Transactions. It is clear that the study of Taylor-Couette flow will continue to provide a basis for a broad range of important and fundamental research topics for many decades to come. Acknowledgements We are grateful to the many researchers who have contributed to this theme issue. We appreciate their enthusiasm for this project and the high quality of the articles they contributed. Thanks to the Royal Society Publishing and in particular the Editorial Office of the Philosophical Transactions of the Royal Society A. Specifically, we thank the Commissioning Editor, Alice Power, for help, advice and leadership throughout the process of assembling this theme issue. Finally, thanks to Randall Tagg for helpful discussions in preparing this theme issue. Authors' contributions R.H.: writing-original draft, writing-review and editing; R.M.L.: conceptualization, project administration, writing-original draft, writing-review and editing; E.S.: writing-review and editing. All authors gave final approval for publication and agreed to be held accountable for the work performed therein. Conflict of interest declaration This theme issue was put together by the Guest Editor team under supervision from the journal's Editorial staff, following the Royal Society's ethical codes and best-practice guidelines. The Guest Editor team invited contributions and handled the review process. Individual Guest Editors were not involved in assessing papers where they had a personal, professional or financial conflict of interest with the authors or the research described. Independent reviewers assessed all papers. Invitation to contribute did not guarantee inclusion. Funding No funding has been received for this article. Data accessibility This article has no additional data. References 1. Taylor GI. 1923 Stability of a viscous liquid contained between two rotating cylinders. Phil. Trans. R. Soc. Lond. A 223 , 289-343. (10.1098/rsta.1923.0008) 2. Donnelly RJ. 1991 Taylor-Couette flow: the early days. Phys. Today 44 , 32-39. (10.1063/1.881296) 3 Lueptow RM, Hollerbach R, Serre E. 2023 Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper: part 1. Phil. Trans. R. Soc. A 381 , 20220140. (10.1098/rsta.2022.0140)36709771 4 Crowley CJ, Pughe-Sanford JL, Toler W, Grigoriev RO, Schatz MF. 2023 Observing a dynamical skeleton of turbulence in Taylor-Couette flow experiments. Phil. Trans. R. Soc. A 381 , 20220137. (10.1098/rsta.2022.0137)36709779 5 Wiswell H, Snow B, Tricouros FA, Smits AJ, Van Buren T. 2023 End effects in low aspect ratio Taylor-Couette flow. Phil. Trans. R. Soc. A 381 , 20220118. (10.1098/rsta.2022.0118)36709777 6 Jeganathan V, Alba K, Ostilla-Monico R. 2023 Exploring the origin of turbulent Taylor rolls. Phil. Trans. R. Soc. A 381 , 20220130. (10.1098/rsta.2022.0130)36709783 7 Oishi JS, Baxter M. 2023 Generalized quasi-linear approximation and non-normality in Taylor-Couette spiral turbulence. Phil. Trans. R. Soc. A 381 , 20220122. (10.1098/rsta.2022.0122)36709784 8 Kang C, Yoshikawa HN, Ntarmouchant Z, Prigent A, Mutabazi I. 2023 Solitary-like and modulated wavepackets in the Couette-Taylor flow with a radial temperature gradient. Phil. Trans. R. Soc. A 381 , 20220117. (10.1098/rsta.2022.0117)36709773 9 Meyer A, Yoshikawa HN, Szabo PSB, Meier M, Egbers C, Mutabazi I. 2023 Thermoelectric instabilities in a circular Couette flow. Phil. Trans. R. Soc. A 381 , 20220139. (10.1098/rsta.2022.0139)36709772 10 Baroudi L, Majji MV, Peluso S, Morris JF. 2023 Taylor-Couette flow of hard-sphere suspensions: overview of current understanding. Phil. Trans. R. Soc. A 381 , 20220125. (10.1098/rsta.2022.0125)36709780 11 Alam M, Ghosh M. 2023 Unified torque scaling in counter-rotating suspension Taylor-Couette flow. Phil. Trans. R. Soc. A 381 , 20220226. (10.1098/rsta.2022.0226)36709774 12 Yi L,Wang C, Huisman SG, Sun C. 2023 Recent developments of turbulent emulsions in Taylor-Couette flow. Phil. Trans. R. Soc. A 381 , 20220129. (10.1098/rsta.2022.0129)36709776 13 Blaauw LJ, Lohse D, Huisman SG. 2023 Sodium chloride inhibits effective bubbly drag reduction in turbulent bubbly Taylor-Couette flows. Phil. Trans. R. Soc. A 381 , 20220127. (10.1098/rsta.2022.0127)36709775 14 Guseva A, Tobias SM. 2023 Transition to chaos and modal structure of magnetized Taylor-Couette flow. Phil. Trans. R. Soc. A 381 , 20220120. (10.1098/rsta.2022.0120)36709782 15 Altmeyer SA. 2023 Ferrofluidic wavy Taylor vortices under alternating magnetic field . Phil. Trans. R. Soc. A 381 , 20220121. (10.1098/rsta.2022.0121)36709786 16 Boulafentis T, Lacassagne T, Cagney N, Balabani S. 2023 Experimental insights into elasto-inertial transitions in Taylor-Couette flows. Phil. Trans. R. Soc. A 381 , 20220131. (10.1098/rsta.2022.0131)36709781 17 Song J, Zhu Y, Lin F, Liu N, Khomami B. 2023 Turbulent Taylor-Couette flow of dilute polymeric solutions: a 10-year retrospective. Phil. Trans. R. Soc. A 381 , 20220132. (10.1098/rsta.2022.0132)36709785 18 Martinand D, Serre E, Viaud B. 2023 Instabilities and routes to turbulence in rotating disc boundary layers and cavities. Phil. Trans. R. Soc. A 381 , 20220135. (10.1098/rsta.2022.0135)36709778 4. Feldmann D, Borrero-Echeverry D, Burin MJ, Avila K, Avila M. 2023 Routes to turbulence in Taylor-Couette flow. Phil. Trans. R. Soc. A 381 , 20220114. (10.1098/rsta.2022.0114)36907218 5. Wang B, Mellibovsky F, Ayats R, Deguchi K, Meseguer A. 2023 Mean structure of the supercritical turbulent spiral regime in Taylor-Couette flow. Phil. Trans. R. Soc. A 381 , 20220112. (10.1098/rsta.2022.0112)36907214 6. Merbold S, Hamede MH, Froitzheim A, Egbers C. 2023 Flow regimes in a very wide-gap Taylor-Couette flow with counter-rotating cylinders. Phil. Trans. R. Soc. A 381 , 20220113. (10.1098/rsta.2022.0113)36907212 7. Lopez JM, Lopez JM, Marques F. 2023 Stably stratified Taylor-Couette flows. Phil. Trans. R. Soc. A 381 , 20220115. (10.1098/rsta.2022.0115)36907216 8. Meletti G, Abide S, Viazzo S, Harlander U. 2023 A parameter study of strato-rotational low-frequency modulations: impacts on momentum transfer and energy distribution. Phil. Trans. R. Soc. A 381 , 20220297. (10.1098/rsta.2022.0297)36907220 9. Masuda H, Nakagawa K, Iyota H, Wang S, Ohmura N. 2023 Thermo-fluid dynamics and synergistic enhancement of heat transfer by interaction between Taylor-Couette flow and heat convection. Phil. Trans. R. Soc. A 381 , 20220116. (10.1098/rsta.2022.0116)36907208 10. Ji H, Goodman J. 2023 Taylor-Couette flow for astrophysical purposes. Phil. Trans. R. Soc. A 381 , 20220119. (10.1098/rsta.2022.0119)36907209 11. Bai Y, Latrache N, Kelai F, Crumeyrolle O, Mutabazi I. 2023 Viscoelastic instabilities of Taylor-Couette flows with different rotation regimes. Phil. Trans. R. Soc. A 381 , 20220133. (10.1098/rsta.2022.0133)36907219 12. Moazzen M, Lacassagne T, Thomy V, Bahrani SA. 2023 Friction dynamics of elasto-inertial turbulence in Taylor-Couette flow of viscoelastic fluids. Phil. Trans. R. Soc. A 381 , 20220300. (10.1098/rsta.2022.0300)36907211 13. Lopez JM, Altmeyer SA. 2023 Arrow-shaped elasto-inertial rotating waves. Phil. Trans. R. Soc. A 381 , 20220227. (10.1098/rsta.2022.0227)36907207 14. Panwar V, Varga CN, Dutcher CS. 2023 Dispersion and mixing dynamics of complex oil-in-water emulsions in Taylor-Couette flows. Phil. Trans. R. Soc. A 381 , 20220128. (10.1098/rsta.2022.0128)36907205 15. Kang C, Mirbod P. 2023 Transitions in Taylor-Couette flow of concentrated non-colloidal suspensions. Phil. Trans. R. Soc. 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Environmental regimes (or environmental legacy or historical legacy) are the dynamics of environmental characteristics over a given (either long or short) time period, such as frequency of mean or extreme events and rate of change, which might be absent by using only contemporary variables. We present SER, an R package for estimating environmental regimes for different environmental variables. Using the data included in the package, several examples are shown. SER is suitable for any type of environmental or biotic variables, including nutrient concentration, light, and dissolved oxygen. In addition, by changing the argument "days_bf," it is possible to compute environmental regimes over any time period, such as days, months, or years. Our case study showed that the inclusion of environmental regimes increased the explained variation of temporal b-diversity and its components. Environmental regimes are expected to advance the "environment-community" relationships in ecological studies. They can further be implemented in other subjects such as social science, socioeconomics, and epidemiology. We present a new R package to compute environmental regimes over a certain period, which has important implications for basic and applied ecology, as well as other subjects. environmental legacy environmental variables historical legacy R package regime SER National Natural Science Foundation of China 10.13039/501100001809 52279068 source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:12.03.2023 Wu, N. , Guo, K. , Zou, Y. , He, F. , & Riis, T. (2023). SER: An R package to characterize environmental regimes. Ecology and Evolution, 13 , e9882. 10.1002/ece3.9882 Kun Guo contributed equally as first author. pmc1 INTRODUCTION A sound understanding of environment-community relationships is a central topic in ecology. Scientists have been endeavoring to find suitable environmental variables or indices that have potential impacts on community compositions and distributions. Traditionally, snapshot contemporary environmental variables that were collected simultaneously with biological samples, such as in situ parameters and nutrient concentrations, are often employed. However, such snapshot neglects the fact that the biological community responds not only to contemporary environmental conditions but also to historic environmental (also called historic legacy) characteristics (Su et al., 2022). For example, Oliveira et al. (2020) found that current environmental variables were weak predictors of fish community structure, but the predictive power substantially increased when using dataset obtained in a previous time period. In response, new indices that integrate long-term environmental records were proposed. For instance, hydrologic indicators for characterizing streamflow regimes (i.e., flow regimes) using long-term flow records have been developed to represent biologically relevant streamflow attributes (Olden & Poff, 2003). Another example is the 19 standard bioclimatic indices, which integrate climate data from 1970 to 2000 (available in WorldClim 2 database; Fick & Hijmans, 2017). In addition, historical legacies (i.e., past climate and geography: temperature anomaly during the quaternary period, past temperature trend, past precipitation trend, past climate-change velocity, basin median latitude, and the endorheic/exorheic status of the river) were computed and used to explore their roles in shaping functional diversity of global freshwater fishes (Su et al., 2022). The results showed that the historical legacies significantly imprinted the functional dispersion and functional identity patterns. FIGURE 1 Schematic figure showing 3 scenarios of environmental conditions over a certain time period (within curly brackets) before snapshot samples (indicated by black arrows). Scenario a: environmental variable being constant; b: weak fluctuations in the environmental variable; and c: strong fluctuations in the environmental variable over the whole time period (i.e., from time 0-30). Commonly used indices such as instant value, simple mean, or median values do not sufficiently represent the environment regimes/fluctuations prior to the sampling date in scenarios b and c. The utility of these historical environmental regime indices (e.g., hydrologic indicators, bioclimatic indices) has resulted in tremendous applications in ecological research and also other lines of research (e.g., De Pauw et al., 2022; Nguyen et al., 2021; Su et al., 2022; Tonkin et al., 2018; Tornes et al., 2021; Xu et al., 2022). However, there are several constraints to the currently used historical environmental regime indices: (1) The currently available indices are limited to hydroclimatic variables, such as flow, temperature, and precipitation. There is no available R package to integrate all environmental variables with consideration of any biotic and abiotic factors such as pH, turbidity, dissolved oxygen, and chlorophyll a; (2) these aforementioned indices are mostly based on long-term intervals, e.g., 30 years for bioclimatic variables. Given that some organisms, particularly microorganisms, may show quick responses to environmental changes, the aforementioned indices might fail to link with biotic changes, and a shorter time period may be more relevant. In addition, different organisms (e.g., algae, macroinvertebrates, fish, macrophytes, or even terrestrial plants) have a distinct extent of response to historical environmental regimes. For instance, recent studies found that flow regimes over a short-term period (e.g., 7 or 14 days) played a vital role in riverine algae and biofilm communities (Guo et al., 2020; Guo et al., 2021; Qu et al., 2019; Wu et al., 2018). By contrast, macroinvertebrate and fish communities may show a good response to environmental changes over a longer time period (e.g., 4 weeks, 1 year) (Schneider & Petrin, 2017). Therefore, to differentiate the distinct responses of different organisms, we should derive community-specific indices that describe environmental patterns over relevant time periods. Unfortunately, no R package so far provides a function to calculate indices over a required time period. Prompted by the importance of environmental characteristics over a certain time period and their research scarcity in this field, we here propose a new term for "environmental regime" (or environmental legacy or historical legacy). Unlike the traditional environmental variables, these new environmental regime indices are defined as the environmental dynamic characteristics during a given (either long or short) time period, which might be absent by using contemporary environmental variables or simple average or median values . With the facilitation of science and technology, high resolution (measured by daily, sub-daily, hourly, or even finer scale) environmental variables (e.g., nutrient concentration, dissolved oxygen) are available nowadays. An increasing number of studies have used data from high-frequency measurements, e.g., water temperature and dissolved oxygen in lakes (Meinson et al., 2015) or soil greenhouse gas fluxes (Courtois et al., 2019). These data provide scientists a chance to explore research questions at time scales that were not possible earlier. Further, high-frequency data allow computing environmental regimes that can be potential variables to increase the explained variation of biological communities (e.g., Guo et al., 2020; Wijewardene, Wu, Gimenez-Grau, et al., 2021; Wu et al., 2019). Therefore, this study aims to facilitate the computation of those indices by providing a common and extensible platform. 2 THE SER PACKAGE: SHORT-PERIOD ENVIRONMENTAL REGIME The SER package aims to compute environmental regimes over a certain time period. In total, 11 elementary indices that focus on variations of environmental factors over a given short period were developed (Table 1). These indices, inspired by Olden and Poff (2003), elucidate three aspects, i.e., the magnitude, the frequency, and the rate of change of environmental variables over a given time period. The magnitude contains four indices: mean, median, coefficient of variation, and skewness of the variables over a given time period before the snapshot sampling; frequency demonstrates the number of environmental low or high pulses over a given time period before the snapshot sampling; rate of change how fast the environmental variable changed (i.e., positive or negative change) within the given time period before the snapshot sampling. TABLE 1 Definition of the 11 elementary indices for environmental regimes. Code Unit Definition Magnitude of environmental data MA1 Depends Mean of the environmental variable over a given time period (N) MA2 Depends Median of the environmental variable over a given time period (N) MA3 % Coefficient of variation over a given time period (N) MA4 - Skewness of the environmental variable for a given time period (N) Frequency of environmental data ML1 Temporal unit Number of low pulse events over a given time period (N): numbers of occurrences where the magnitude of an environmental variable drops below the 25th percentile of all values for the given time period MH1 Temporal unit Number of high pulse events over a given time period (N): numbers of occurrences where the magnitude of an environmental variable is above the 75th percentile of all values for the given time period EL1 Temporal unit Number of extreme low pulse events over a given time period (N): numbers of occurrences where the magnitude of an environmental variable drops below the 10th percentile of all values for the time period EH1 Temporal unit Number of extreme high pulse events over a given time period (N): numbers of occurrences where the magnitude of an environmental variable is above the 90th percentile of all values for the time period Rate of change of environmental data RC Depends Rate of change over a given time period (N) RH1 Temporal unit Numbers of events with rising change over a given time period (N), i.e., numbers of positive change RL1 Temporal unit Numbers of events with declining change over a given time period (N), i.e., numbers of negative change Note: Depends: the unit depends on the variables; -: no unit; Temporal unit: the given temporal units, e.g., days, months, or years. N can be defined as any interested time period, by default N = BetwSamT (days between two successive sampling dates). Currently, the package is developed with regarding days, months, and years as the interested period, more features are under development. To be consistent with a previous study (Olden & Poff, 2003), we choose 25th/10th and 75th/90th percentile as low/extreme low and high/extreme high values for the frequency indices. 2.1 Package overview The SER package contains one main function SER and two data files, i.e., hydro_df and sample_date. The two data files are derived from Guo et al. (2020) and are used to illustrate how the main function works. The hydro_df is a data frame that contains daily discharge in a stream, while sample_date is a vector containing 13 dates, first of which is the date when the experiment was initialized while the rest 12 are snapshot biological sampling dates. The SER package is written in R (R Core Team, 2021) and require a standard installation of R and the "tidyverse" and "lubridate" packages. The development version of SER is hosted on GitHub at The package can be installed with the following codes: if(!require(devtools))install.packages("devtools"). devtools::install_github(" build_vignettes = TRUE). 2.2 Example analyses As an example, the embedded data are used to illustrate how SER works with discharge data. By default, days between two successive sampling dates were used as the focal short period. The R codes are shown below: # load required packages library(SER) # inspect the discharge data str(hydro_df) # inspect the sample dates str(sample_date) # calculate short-period hydrological indices hydro_ser<-SER(hydro_df$Date, hydro_df$Discharge, sample_date, days_bf = NULL) str(hydro_ser) The function SER returned a data frame, in which, the first column "SampleDate" contains the 12 biological sampling dates, while the rest 11 columns represent the short-period environmental regimes, i.e., short-period hydrological indices for each sampling date . The indices' names were constructed as the combination of short period and names of the elementary indices, for example, BetwSamT.MA1 and BetwSamT.RC stand for the mean of the daily average flow and mean rate of change in days between two successive sampling days, respectively. FIGURE 2 Boxplots (median, first, and third quantiles) and violin plots illustrate the distribution of 11 short-period hydrological indices calculated in the example of SER package. These indices decipher the three facets, i.e., magnitude, frequency, and rate of change, of flow regime over the time between two successive samplings. See Table S1 for the definition of each index. Indices generated with new data or new time period should be interpreted with a full understanding of the 11 elementary indices and expertise in a given area. 3 A CASE STUDY: ENVIRONMENTAL REGIMES PLAY AN IMPORTANT ROLE IN TAXONOMIC AND FUNCTIONAL TEMPORAL b-DIVERSITY OF RIVERINE DIATOMS To examine whether the inclusion of environmental regimes advances our understanding of environment-biota relationships, daily samples of riverine diatom communities over a 1-year period were collected at a German lowland catchment (Wu, Wang, et al., 2022). Concurrently, three categories of abiotic factors were obtained: (a) hydrological variables (Hyd) included daily discharge (Q), discharge skewness (Sk), precipitation (Prec), and antecedent precipitation index (API); (b) metal ions (Met) contained six parameters (Cl-, K+, Ca+, Na+, Mg2+, and Si2+); and (c) nutrients (Nut) included ammonium-nitrogen (NH4-N), nitrate-nitrogen (NO3-N), orthophosphate (PO4-P), and sulphate (SO4 2-). In addition, environmental regimes of both flow (using Q) and nutrient (using NH4-N, NO3-N, PO4-P, and SO4 2-) were computed with SER package. Therefore, we have two extra abiotic factors: Hyd + (i.e., hydrology + flow regimes) and Nut+ (i.e., nutrient + nutrient regimes) (Wu, Wang, et al., 2022). Furthermore, both taxonomic and functional temporal b-diversity of riverine diatoms were computed (for details see Wu, Wang, et al., 2022). Using distance-based redundancy analysis (db-RDA; with capscale function in R package vegan) (Oksanen et al., 2019) and variation partitioning analysis (VPA; with varpart function in R package vegan), we investigated the relationships between abiotic factors and temporal b-diversity of riverine diatoms (for details see Wu, Wang, et al., 2022). To detect the role of environmental regimes in explaining the variation of both taxonomic and functional temporal b-diversity, we compared the explained variations between without and with environmental regimes. VPA results demonstrated that the addition of environmental regimes (i.e., flow and nutrient regimes) increased the explained variations of both taxonomic and functional temporal b-diversity . Specifically, taxonomic total b-diversity increased by 3.0%, while functional total b-diversity increased by 13.3%. Interestingly, the inclusion of flow regimes (i.e., Hyd+) played a less important role in taxonomic temporal b-diversity than functional temporal b-diversity. By contrast, the addition of nutrient regimes (i.e., Nut+) increased explained variations in both taxonomic and functional temporal b-diversity . Regardless of the potential reasons, which warrant further investigations, these results supported our hypothesis that the addition of environmental regimes could dramatically advance our understanding of environment-biota relationships. FIGURE 3 Comparison (between without and with environmental regimes) of the explained variations to taxonomic and functional temporal b-diversity of riverine diatoms. Hyd, hydrology without flow regimes; Met, metal ions; Nut, nutrients; Hyd+, hydrology with flow regimes; Nut+, nutrients with nutrient regimes. The adjusted R 2 is shown. ***p < .001, **p < .01, *p < .05. The figure was modified from Wu, Wang, et al. (2022). 4 CONCLUSION AND REMARKS SER is a promising tool to facilitate the calculation of environmental regimes over a given time period. As a holistic term, it is suitable for any type of environmental or biotic parameters, such as nutrient concentration, pH, conductivity, light, dissolved oxygen, and chlorophyll a. Furthermore, by changing the argument "days_bf," it is possible to compute environmental regimes over any given time period, such as months or years, as long as the records are measured in a corresponding manner. Being a completely open-source tool, it is open for further extension and examination. We envisage that SER is greatly helpful for both basic and applied ecological studies from mesocosm experiments to field surveys. Environmental regimes (e.g., thermal, nutrient, flow), particularly short-term environmental regimes, can be robust variables in understanding the "community-environment" relationships of different organisms in various ecosystems (e.g., aquatic, forest, terrestrial ecosystems), being complementary predictors for model simulation and prediction. A recent study found that severe changes in the thermal regimes of Austrian rivers under climate change reinforced physiological stress and supported the emergence of diseases for brown trout (Borgwardt et al., 2020). Moreover, exploring responses of different organisms to environmental regime shifts can be used for management and policy-making. For instance, by exploring the relationships between the occurrence of cyanobacterial blooms and water-level regimes, management of water-level can be a potential mitigation strategy for cyanobacterial blooms (Bakker & Hilt, 2016). Particularly, we would like to emphasize SER's potential in experimental biology or mesocosm experiments, which often last for a relatively short period but could have high-frequency measured data, e.g., temperature and light. High-frequency data (at 15-min interval) of light and water temperature were measured in a microcosm study, and the results indicated light and temperature emerged as significant variables on phytoplankton community attributes (Wijewardene, Wu, Hormann, et al., 2021). To a broad extent, environmental regimes can be used in other subjects such as social sciences, socioeconomics, and epidemiology. For example, a recent study (Wu, Wen, et al., 2022) found that increasing temperature variability (calculated as the standard deviation of the average of the same and previous days' minimum and maximum temperatures) has caused a higher human heat-related mortality. Another example showed that a shift in a temperature regime caused by climate changes may facilitate a pathogen's survival, development, and spillover and have an effect on transmission chains. Pandemic forecasting models (such as COVID-19) were recommended to integrate these effects, alongside human behavior and awareness (Rodo et al., 2021). A third example is about crop yield in relation to weather regimes. Altered temperature and rainfall regimes, such as unusually cool and wet spring, is reducing global production of staples (e.g., rice, wheat), while, by contrast, some more drought-tolerant crops (e.g., sorghum) have benefited from such changes (Ray et al., 2019). Developing an empirical model linking crop yield to weather regimes may inform local people with proper crops under future climate scenarios. AUTHOR CONTRIBUTIONS Yi Zou: Writing - review and editing (equal). Tenna Riis: Funding acquisition (supporting); writing - review and editing (equal). Naicheng Wu: Conceptualization (lead); funding acquisition (lead); methodology (lead); project administration (equal); visualization (lead); writing - original draft (lead). Kun Guo: Data curation (equal); formal analysis (equal); methodology (equal); software (lead); writing - original draft (lead). Fengzhi He: Writing - review and editing (equal). CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. Supporting information Table S1: Click here for additional data file. ACKNOWLEDGMENTS This study was supported financially by the National Natural Science Foundation of China (No. 52279068) and the Humboldt fellowship for the experienced researcher. DATA AVAILABILITY STATEMENT The SER package can be downloaded from GitHub ). An online tutorial is available for this package on the same GitHub repository. SER depends on two existing R packages: tidyverse and lubridate. |
statements Reporting of results in abstracts We extracted 278 claims that reported non-significant results of NHST. Of these, 174 (63%) were classified as claiming evidence of no effect, 71 (26%) as making formally correct statements that there were no statistically significant differences between groups or conditions, 17 (6%) as making claims about an effect being 'similar' between groups or conditions, or as describing a small effect size, and 16 (6%) were classified as ambiguous. Table 5 provides examples of these claims. 10.7717/peerj.14963/table-5 Table 5 Examples of claims about the sample in the abstracts of articles following non-significant NHST classified as "No Effect", "Similar or Small Effect Size", "Non-Significant" or "Ambiguous". No Effect N = 174, 63% "Levels of individuals sitting with their back to the window was unaffected by visitor number or noise." Hashmi & Sullivan (2020) "The groups did not differ in their ability to follow human signals" Lazarowski et al. (2020) Similar or Small Effect Size N = 17, 6% "Pair members demonstrated comparable responses towards a male 'intruder', as latency to respond and proximity scores were very similar between pair members in the majority of pairs examined" DeVries, Winters & Jawor (2020) "We found that individuals called back to sympatric and allopatric calls within similar amounts of time," Wu et al. (2021) Non-Significant N = 71, 26% "Nutcrackers...did not significantly change their caching behaviour when observed by a pinyon jay." Vernouillet, Clary & Kelly (2021) "No significant correlations between degree of laterality and behavioral interest in the stimuli were found" Lilley, De Vere & Yeater (2020) Ambiguous N = 16 (6%) "We also found no conclusive evidence that either the visual or the vibratory sensory modalities are critical for prey capture." Meza, Elias & Rosenthal (2021) "No systematic variations on space allocation were observed in neither experiment" Ribes-Inesta, Hernandez & Serrano (2020) Interpretations of results in abstracts We extracted 63 statements that were interpretations of statistically non-significant results in relation to substantive claims. Of these, 45 (71%) were classified as caveated and 18 as claiming that there was no effect (29%). Table 6 provides examples of these claims. 10.7717/peerj.14963/table-6 Table 6 Examples of claims about populations in the abstracts of articles following non-significant NHST classified as "No Effect" and "Caveated, Ambiguous or Similar". No Effect N = 18 (29%) "Partial rewarding does not improve training efficacy" Cimarelli et al. (2021) "Our findings show that H. horridum does not respond to hypoxic environments" Guadarrama et al. (2020) "Oviposition site choice is not by-product of escape response" Kawaguchi & Kuriwada (2020) Caveated, Ambiguous, or Similar N = 45 (71%) "These results suggest capuchin monkeys do not engage in indirect reciprocity" Schino et al. (2021) "These results suggest that shoal composition may not be an important driver of shoal choice in this system" Paijmans, Booth & Wong (2021) "...suggesting that size is not a determinant factor for feral horse society." Pinto & Hirata (2020) Result text In the results sections, 276 non-significant results of NHST were coded. Of these, 140 (52%) were classified as reporting the results as "Non-Significant", 113 (41%) as reporting that there was "No Effect", 12 (4%) as reporting groups or conditions being "Similar", 10 (4%) were classified as "Ambiguous", and one (0.4%) as reporting a "trend" in the opposite direction to the prediction. Table 7 provides examples of the different types of result reporting. 10.7717/peerj.14963/table-7 Table 7 Examples of statement reporting the results in the results sections of articles using non-significant NHST classified as "No Effect", "Similar or Small Effect Size", "Non-Significant" or "Ambiguous". No Effect N = 113 (41%) During farrowing, No Effect of the treatments was seen on the percentage of time spent (3.22% vs. 1.90%, P = 0.372) on the nest-building behaviour" Aparecida Martins et al. (2021) "There were no differences between treatments in the frequency or duration of birds flying between walls" Stevens et al. (2021) Similar or Small Effect Size N = 12 (4%) "The average time yaks spent grazing was similar among shrub coverage groups ( P = 0.663)" Yang et al. (2021) "The number of sessions required to reach criterion didn't reliably differ between groups" O'Donoghue, Broschard & Wasserman (2020) Non-Significant N = 140 (52%) "Comparing the pooled data of all crows, no significant increase in the number of mark-directed behaviors during the mirror mark condition was found compared with the no-mirror sham condition." Brecht, Muller & Nieder (2020) "There was no significant effect of removal type on changes in display strength in either dominant males or subordinate males." Piefke et al. (2021) Ambiguous N = 10 (4%) "As can be seen in Figure 1D, there was no difference in response rates after R andNR trials across days for rats under reward uncertainty." [where in Figure 1D the bars on the graph look almost identical) Anselme & Robinson (2019) "It showed that there was a significant main effect of session, but no main effect of CS" Harris & Bouton (2020) Notably, if a sentence reporting the results in the results section was classified as "No Effect", it was more likely that this statistical test would also be reported as "No Effect" in the abstract, compared to when the result was classified as "Non-Significant" (kh2(1, N = 211) = 21.65, p < .0001). Limiting the data to just those with responses in the abstract and results classified as "Non-Significant" or "No Effect", of the 92 statements in the results classified as "No Effect", 80 (87%) of the corresponding statements reporting the results in the abstract were classified as "No Effect". In contrast, of the 119 statements in the results classified as "Non-Significant", only 67 (56%) were reported as "No Effect" in the abstract. Nevertheless, the "No Effect" phrasing when reporting results in the abstracts was absolutely the most likely classifications for both "No Effect" and "Non-Significant" phrasings in the results section. p-value distributions In total, 202 of the 283 articles reported exact p-values, with the other 81 reporting either inequalities or not reporting the p-values at all. Of these 202 p-values, four were below .05 and non-significant due to a lower a level. The distribution of the 198 non-significant p-values in the interval .05-1 is displayed in Fig. 2. This distribution significantly differs from a uniform distribution (two-sided Kolmogorov-Smirnov test, D = 0.12, p = .0087). 10.7717/peerj.14963/fig-2 Figure 2 Distribution of non-significant p-values from result sections of 198 articles in animal cognition and related fields, with a density distribution overlaid in pink. The dotted line shows the average density. Figure 3 contrasts the distribution of Fig. 2 with the four simulated distributions of bodies of research performed where 80% of alternative hypotheses were correct, and studies had either 10, 33, 50 or 80% statistical power to detect the true effect size of H1 if it was true. Notably, p-values in the interval from .05 to .10 were underrepresented in the manually extracted data, making up only 5.6% of observations compared to 8.2% (10% power simulation), 15% (33% power simulation), 19% (50% power simulation), and 20% (80% power simulation). Similarly, very high p-values (.95-1.0) were overrepresented in our manual dataset (7.6% of observations, compared to 4.3%, 3.2%, 2.4% and 3.4% for the 10, 33, 50 and 80% power simulations respectively), which likely reflects either the use of multiple correction procedures, or small sample non-parametric statistics that produce non-uniform distributions under the null hypothesis. 10.7717/peerj.14963/fig-3 Figure 3 The observed p-value distribution of 198 p-values > .05, compared to three simulated distributions where 80% of alternative hypotheses were correct. The observed p-value distribution was manually extracted from results corresponding to negative claims present in the abstracts of animal cognition articles. The observed p-value distribution was compared to three simulated distributions where 80% of alternative hypotheses were correct, with studies performed at either 10%, 33%, 50% or 80% statistical power. Discussion We extracted and classified how animal cognition researchers reported and interpreted the results of non-significant null hypothesis significance tests in 253 articles between 2019 and 2021. Across titles, abstracts, and results, we classified non-significant results as being reported with the "No Effect" phrasing that has often been labelled as erroneous in 84% of titles with a statistically non-significant result, in 63% of abstracts reporting a statistically non-significant result and in 41% of results sections reporting a statistically non-significant result. Reporting statistically non-significant results as "Non-Significant" was less common in titles and abstracts, but as prevalent as "No Effect" phrasings in the result sections (titles: 16%; reporting of results in abstract: 26%; result text: 52%). The other, albeit less frequently classified method of reporting statistically non-significant results was to comment on the similarity between groups or conditions (reporting of results in abstracts: 6%; result text: 4%). Overall, these results demonstrate considerable heterogeneity in how animal cognition researchers report and interpret non-significant results in published articles. However, we often found it difficult to categorize results due to the heterogeneity in how statements referring to statistically non-significant results were phrased. Despite this heterogeneity, our results suggest that statistically non-significant results are at risk of being misreported and misinterpreted in animal cognition publications. It remains a question, however, what the consequences of such misreporting might be, i.e., how readers of scientific articles interpret "No Effect" statements, and this could be studied through analyzing how these studies are cited, in other publications but also in media reports and student essays. A good example for the different ways in which the same phrasing can be interpreted by different researchers within the same research community are the three instances in which authors phrased the results of an ANOVA term as "no main effect", which we classified as "Ambiguous" as per our Coding guidelines. However, during the review process, one of the reviewers stated that they treat "no main effect" as formally equivalent to "no effect". The reason for our original classification was that referring to "no main effect" gives the reader more information about the statistical analysis used and thus may be more likely to be interpreted by readers correctly as the analysis yielding a non-significant main effect compared as when "no effect" is used. However, the reviewer's interpretation is as justifiable, and this example clearly illustrates the importance of investigating how researchers interpret and cite original findings in their own publications. Possibly encouragingly, when researchers extended "No Effect" statements from reporting their study's results to interpreting them in relation to a substantive claim, they routinely opted for qualifiers to caveat inference to the populations (e.g., "...these results suggest that there is no effect at the population level"). However, such qualified statements lack precision and are open multiple interpretations they make only a vague suggestion that the strength of the evidence for the claim might be low, a claim that can often be explored in a quantitative and precise manner. Moreover, it is likely that such caveating is not unique to statistically non-significant results but also used to caveat significant findings, too. If that is correct, then the caveating may have more to do with researchers being critical of, or attempting to appear critical, of their results in general, and acknowledging that there may be alternative conceptual interpretations of their results (Farrar & Ostojic, 2019), rather than being specific to recognising the lack of information associated with studies with low power of statistical tests. However, more research is needed to pinpoint precisely how such statements are interpreted and implemented by scientists and the wider community. As already noted, one way in which researchers might reduce the ambiguity of their negative statements would be to use more formal methods of assessing evidence against informative null hypotheses, such as by testing against theoretically interesting effect sizes using as equivalence tests or comparing plausible null and alternative hypotheses using Bayes factors. Although beyond the scope of the current project, Lakens (2017) provides a detailed tutorial for equivalence testing in psychological research, and Rose et al. (2018) in animal behavior, and Rouder et al. (2009) provide an introduction to Bayes Factors. In addition, we would like to refer the reader to a competence model developed by Edelsbrunner & Thurn (2020) for all researchers who are involved in teaching statistics and mentoring students in the field of animal behavior science. Notably, our coding team found it difficult to identify whether interpretations of a study's results in relation to a substantive claim in the abstracts were based on a statistically non-significant result and thus also to classify them in the next step. This difficulty likely reflects the distance between the theoretical claims researchers wish to test and the actual statistical hypotheses that are tested, i.e., rarely can a theoretical prediction about an animal's cognition be reduced to a single decision between a null and alternative hypothesis in a null hypothesis significance test. Finally, we classified the formally incorrect reporting of results and interpretations of results as "No Effect" more commonly in abstracts and titles than "No Effect" reporting of results in the results section. That is, authors who have written out "Non-Significant" results in the results section nevertheless used the "No Effect" phrasing for reporting and interpreting the results in the abstracts and titles. This could be due to two factors, namely word limits and incentives to make bolder claims. If this is correct, then the former should be considered by journal editorial boards when setting their policy. The p-value distribution likely differed from a uniform distribution for two reasons: the cumulative frequency was greater in the observed distribution for smaller p-values (p < .3) and was also greater for large p-values (p >.95). The larger density of smaller p-values is consistent with research with low-powered statistical tests in which the null hypothesis was incorrect, but which produces p-values that did not reach statistical significance. The density of very large p-values is consistent with researchers applying corrections that might increase p-values, such as Bonferroni corrections, or by using statistical tests with small sample sizes that produce non-uniform p-value distributions under the null hypothesis. An interesting contrast between the observed and simulated p-value distributions is that, unlike in the manual distribution, p-values in the range .05 to .10 were much more common than p-values in the range .10 to .15 in the simulated distributions. This is likely because we extracted results that we as coders had interpreted as being statistically non-significant for the manual dataset, but p-values in the range .05-0.1 are often interpreted by the original authors as "trends" or "marginally significant" and may therefore lead to author interpretations as if there had not been a statistically non-significant result. Conclusions This study explored reporting and interpretation of statistically non-significant results in animal cognition literature through classification by other researchers in the field. In line with previous studies in other disciplines (Aczel et al., 2018; Fidler et al., 2006), we found that statistically non-significant results were often reported as if there were no differences observed between groups or conditions, and this was the case in the titles, abstracts and result sections of papers, although it was most frequent in the titles and abstracts. These results suggest that incorrect theoretical inferences based on non-significant results in animal cognition literature are common. However, because of the distance between statistical hypotheses and theoretical claims, and uncertainty around how no difference statements are interpreted, the consequences of this putative error are uncertain but may be grave. Nevertheless, these findings suggest that researchers should pay close attention to the evidence used to support claims of absence of effects in the animal cognition literature, and prospectively seek to, (i) report non-significant results clearly and formally correct, and (ii) use more formal methods of assessing the evidence against theoretical predictions. Supplemental Information 10.7717/peerj.14963/supp-1 Supplemental Information 1 Supplemental Material Click here for additional data file. We would like to thank Balazs Aczel for discussions and clarifications about previous research in this area Additional Information and Declarations Competing Interests Author Contributions Data Availability Ljerka Ostojic is an Academic Editor for PeerJ. Benjamin G. Farrar conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft. Alizee Vernouillet performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Elias Garcia-Pelegrin performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Edward W. Legg performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Katharina F. Brecht performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Poppy J. Lambert performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Mahmoud Elsherif performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Shannon Francis performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Laurie O'Neill performed the experiments, authored or reviewed drafts of the article, and approved the final draft. Nicola S. Clayton conceived and designed the experiments, authored or reviewed drafts of the article, and approved the final draft. Ljerka Ostojic conceived and designed the experiments, performed the experiments, authored or reviewed drafts of the article, and approved the final draft. The following information was supplied regarding data availability: The data are available at OSF: Farrar, Benjamin G. 2022. "Non-Significant Results in Animal Cognition." OSF. October 30. osf.io/gdp6f. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34838 Cardiology Rheumatology A Case of Spontaneous Multivessel Coronary Artery Dissection Muacevic Alexander Adler John R Lisevick Alexa B 1 Kumar Manish 2 Mahmut Asiya 3 1 Surgery, Medical College of Wisconsin, Milwaukee, USA 2 Cardiology, Pat and Jim Calhoun Cardiology Center, UConn Health, Farmington, USA 3 Cardiology, Trinity Health of New England, Hartford, USA Manish Kumar [email protected] 10 2 2023 2 2023 15 2 e3483810 2 2023 Copyright 2023, Lisevick et al. 2023 Lisevick et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Spontaneous coronary artery dissection (SCAD) is a non-traumatic separation of the epicardial coronary arterial wall leading to luminal obstruction with subsequent myocardial ischemia andinfarction. Herein, we describe an interesting case of acute coronary syndrome due to multivessel SCAD without an underlying susceptibility or trigger, and review the literature for SCAD management. coronary heart disease (chd) younger women myocardial infarction with no obstructive coronary atherosclerosis non st-elevation acute coronary syndrome spontaneous coronary artery dissection The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Spontaneous coronary artery dissection (SCAD) is a non-traumatic separation of the epicardial coronary arterial wall occurring via intramural hematoma formation compressing the true lumen, leading to ischemia and acute myocardial infarction . This report presents a compelling case of SCAD with a literature review of the condition. Case presentation A 38-year-old female with a history of hypertension, migraine, obesity (BMI 36 kg/m2), and nonischemic cardiomyopathy with recoveredejection fraction (EF) presented to the emergency department (ED) with severe, substernal chest heavinessthat started suddenly while she was driving after brushing snow off of her vehicle. She reported accompanying nausea, dyspnea, and diaphoresis. She had two similar prior episodes of mild, self-resolvingchest discomfort within the past month. Upon arrival at the ED, the patient was asymptomatic and hemodynamically stable. The physical examination was within normal limits. An initial electrocardiogram (ECG) demonstrated normal sinus rhythm with new T wave inversions in V1 through V6 . Figure 1 Initial electrocardiogram showing diffuse T wave inversions (red circles) suggestive of myocardial ischemia Lab work demonstrated a high-sensitivity troponin level of 374 ng/L (normal 0-14 ng/L). While in the ED, she experienced two additional episodes of similar chest discomfort responsive to sublingual nitroglycerin. These episodes were associated with dynamic T wave changes on the ECG. She was given antiplatelet medications,aspirin, and ticagrelor, andheparin infusion for non-ST-segment elevation myocardial infarction (NSTEMI). Because of ongoing pain, a coronary angiogram was done urgently that revealed spontaneous coronary artery dissectionof multiple vessels including the mid-left anterior descending (LAD), circumflex obtuse marginal arteries, right marginal artery, and posterior descending artery . Figure 2 (A) RAO cranial view showing the left anterior descending artery that is initially angiographically normal until the mid-to-distal segment followed by an abrupt change in caliber with a long, smooth tapering progressing to severe diffuse narrowing consistent with SCAD. (B) RAO caudal view showing the smaller first marginal that has severe diffuse narrowing and the second obtuse marginal with moderate diffuse narrowing extending to the distal branches, consistent with diffuse SCAD of the left circumflex system. (C) RAO cranial view showing dissected distal RCA branches including posterior descending artery and posterolateral branches (red arrows denote areas of vessel dissection) RAO, right anterior oblique;SCAD, spontaneous coronary artery dissection; RCA, right coronary artery The left ventriculogram showed a left ventricular (LV) EF of 35% with mid to apical anterior, apical, and contiguous apical inferior hypokinesis. Patient's pain had resolved during the procedure and no coronary intervention was done. Heparin was continued for 48 hours in addition to dual antiplatelet therapy (DAPT) and guideline-directed medical therapy (GDMT) for heart failure. Troponin peaked at 1825 ng/L (normal 0-14 ng/L) with a subsequent downtrend. She remained asymptomatic, and was discharged after72 hours of hospitalization. Discussion SCAD is an acute coronary event in which an intramural hematoma, with or without an intimal tear, leads to the separation of the walls of epicardial coronary arteries . It is a non-traumatic, non-iatrogenic, and non-atherosclerotic cause of acute coronary syndrome (ACS) accounting for 1%-4% of ACS cases overall. It typically affects middle-aged women and younger individuals, as demonstrated in this case; however, SCAD can be seen in patients in their late teens to the ninth decade of life irrespective of underlying coronary atherosclerosis . SCAD tends to occur in individuals with pre-existing risk factors, such as fibromuscular dysplasia (FMD), pregnancy and multiparty, connective tissue disorders, exogenous hormone replacement therapy (including oral contraceptives), systemic inflammatory diseases, andmigraine headaches . A hereditary or genetic component may further account for the predisposition to SCAD . Unlike in our case, patients commonly experience a triggering event initiatingdisruption of the vasa vasorum causing dissection.The triggers are broad, but typically are a source of either extreme physical or emotional stress . Men more commonly report a physical stressor, such as intensive exercise, vomiting, or heavy lifting, whereas women more frequently report an emotionally stressful precipitant[1-3]. Patients with SCAD-driven ACS present similarly to atheroscleroticACSwith characteristic symptoms, ECG changes, and cardiac biomarker elevation.Pregnant patients can have more extensive coronary involvement resulting in severe presentations, such as LV dysfunction, ventricular arrhythmia, or cardiogenic shock due to left main or proximal LADartery involvement. SCAD has a predilection for the mid to distal coronary arteries, usually involving the LAD artery, though any artery can be affected. Multivessel SCAD can be seen in 9%-23% of the cases,but widespread, diffuse dissection and involvement of distal branches, in the absence of pregnancy, as seen in this case, is rare . Coronary angiography is the gold standard for the diagnosis of SCAD, and three distinct dissection morphologies have been described . The most common, Type 2, appears as a long, smooth narrowing affecting a long segment, usually greater than 20 mm with distal tapering of the termination branches. Type 1 appears as a double radiolucent lumen with arterial wall staining as seen in the LAD artery in this case . Type 3 is focal tubular stenosis similar to atherosclerotic plaque rupture. In cases where the diagnosis is uncertain, noninvasive imaging including optical coherence tomography or intravascular ultrasoundcan be considered with caution for the risk of propagation of dissection and abrupt vessel closure[1-3]. Acute medical therapy Extensive evidence-based data for the management of SCAD is lacking; thus, the majority of guidelines are based on expert opinion. The use of heparin and antiplatelet agents in the acute management of SCAD is not well established. However, these agents are routinely used in the managementto resolve overlying thrombus at the site of intimal tear balanced against the risk of worsening intramural hematoma and dissection extension. Heparin is usually discontinued once the diagnosis of SCAD is made unless there is an intraluminal thrombus or other indications of systemic anticoagulation. Some experts recommend dual antiplatelet therapy for at least one year following SCAD, especially in those who receive percutaneous coronary intervention (PCI), while others recommend one to three months of DAPT followed by long-term or lifelong aspirin therapy . Given the lack of consensus regarding the use and duration of DAPT and aspirin in these patients, further research is needed to assess the risk-benefit of DAPT in this subset of patients. Beta-blockers can be used for LV dysfunction as indicated by the guidelines. Theoretically, beta-blockers reduce shear stress on the coronary arteries and may reduce SCAD recurrence; however, studies are needed for validation and to understand the complex hemodynamiceffects on coronary circulation . Revascularization SCAD lesions heal over time with conservative therapy and recover near-normal coronary architecture; therefore, revascularization is typically not utilized given the risk of dissection propagation and risk of graft or stent failure . This approach is in contrast to the invasive revascularization for acute ACS due to plaque rupture or erosion where stenting reduces the risk of recurrence and adverse events . Clinically stable patients with SCAD should be managed conservatively with inpatient monitoring for three to five daysto monitor for signs and symptoms of recurrent MI that may occur in 5%-10% of conservatively managed patients, typically within the first seven days . Revascularization should be considered in patients experiencing ongoing ischemia, hemodynamic instability, or high-risk anatomies, such as dissection involving the left main or two proximal vessels. PCI in these patients is technically challenging, andoften has suboptimal outcomes with a higher rate of complications, such as iatrogenic dissection, abrupt vessel occlusion, hematoma propagation, and strut malposition after healing . Urgent coronary artery bypass graftingshould be considered in patients with failed PCI, or those with high-risk anatomy . Long-term management The long-term medical management of SCAD should be directed towards the prevention of SCAD recurrence, identifying extra-coronary vascular abnormalities, and improving quality of life. All patients who have ACS should receive cardiac rehabilitation. In consideration of recurrence, patients with hypertension should be closely managed; specifically, beta-blockers may help to reduce SCAD recurrenceand should be initiated first . Furthermore, the use of statins is limited given that SCAD is not atherosclerosis mediated; patients who do not have underlying hyperlipidemia are unlikely to benefit fromstatin therapy. As SCAD may be the first manifestation of underlying vascular abnormalities, patients should receive arterial cross-sectional CT or MR angiography from the brain to the pelvis . Tailored exercise in patients with SCAD is safe and effective, and these patients should be referred for cardiac rehabilitation. SCAD has a recurrence rate of17%-18% within three to four years and mayinflict tremendous psychosocial stress on young patients raising the importance of addressing patient psychosocial well-being. Moreover, female patients should be cautioned about the risks of pregnancy after SCAD and oral contraceptive use; women who wish to become pregnant after SCAD should be referred for preconception counseling . Conclusions SCAD is a non-traumatic, non-iatrogenic, and non-atherosclerotic acute coronary event thatpredominantly affects women and younger patients. While the underlying mechanism is not fully understood, it is traditionally considered to occur in patients with an underlying susceptibility and an inciting event. Diffuse, multivessel SCAD isuncommon, except in pregnant patients where multivessel involvement can be seen. Despite presenting similarly to atherosclerotic-driven ACS, patients with SCAD should be managed conservatively in the vast majority of cases and emphasis should be given to long-term management of this highly recurrent disease. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Spontaneous coronary artery dissection: JACC state-of-the-art review J Am Coll Cardiol Hayes SN Tweet MS Adlam D Kim ES Gulati R Price JE Rose CH 961 984 76 2020 32819471 2 Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association Circulation Hayes SN Kim ES Saw J 0 57 137 2018 3 Spontaneous coronary-artery dissection N Engl J Med Kim ES 2358 2370 383 2020 33296561 4 Hereditary spontaneous coronary artery dissection J Case Rep Studies Kumar M Chaturvedula ST Meng J 1 5 6 2018 5 Insights into spontaneous coronaryarterydissection: can recurrence be prevented? J Am Coll Cardiol Tweet MS Olin JW 1159 1161 70 2017 28838365 6 Natural history of spontaneous coronaryartery dissection with spontaneous angiographic healing JACC Cardiovasc Interv Hassan S Prakash R Starovoytov A Saw J 518 527 12 2019 30826233 7 Spontaneous coronary artery dissection: latest developments and new frontiers Curr Atheroscler Rep Yang C Alfadhel M Saw J 49 22 2020 32734349 8 Stent embolization in spontaneous coronary artery dissection and its deployment at the right radial artery Cureus Batta A Agstam S Ghosh S Kumar B 0 13 2021 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34832 Internal Medicine HIV/AIDS Oncology Immune Reconstitution Inflammatory Syndrome Presenting as Disseminated Kaposi Sarcoma Muacevic Alexander Adler John R Ruzgas Gabriele 1 Eshan Shayet Hossain 2 Ramanathan Shrungavi 2 Gotimukul Ashwini 2 Bodapati Rohan K 3 1 Family and Community Medicine, University of Illinois Chicago, Chicago, USA 2 Internal Medicine, Ascension Saint Joseph - Chicago, Chicago, USA 3 Internal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, USA Gabriele Ruzgas [email protected] 10 2 2023 2 2023 15 2 e348329 2 2023 Copyright (c) 2023, Ruzgas et al. 2023 Ruzgas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We present a patient who was previously diagnosed with HIV and had multiple violaceous skin lesions at the time of his diagnosis. Following the initiation of antiretroviral therapy (ART), the number of lesions increased significantly and he developed shortness of breath, which prompted hospital admission for further workup. Biopsy of the skin lesions confirmed the diagnosis of Kaposi sarcoma (KS). Bronchoscopy with biopsy revealed KS lesions in his respiratory system. Imaging and biopsy confirmed KS invasion of lymph nodes. Due to widespread KS, he was diagnosed with immune reconstitution inflammatory syndrome (IRIS). Because of the lack of improvement on ART alone, he was started on chemotherapy, which decreased the size of existing skin lesions, stalled the development of new skin lesions, and led to symptom improvement. As a result of this case, we recommend that treatment teams have close follow-ups of patients started on ART and that they remain mindful of the possibility of IRIS. Disseminated KS may warrant a prompt response with chemotherapy to improve outcomes. doxorubicin antiretroviral therapies art iris disseminated kaposi sarcoma pulmonary kaposi sarcoma kaposi sarcoma hiv The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Kaposi sarcoma (KS) is a well-known AIDS-defining illness caused by human herpesvirus-8 (HHV-8) that has been less frequently observed since the development of antiretroviral therapy (ART) . Regardless, it remains a critical malignancy to identify and treat early, given the potential for visceral involvement; this includes pulmonary KS, which has been documented to have a poor prognosis . Dissemination of KS may occur in the setting of immune reconstitution inflammatory syndrome (IRIS), a condition in which there is a worsening of pre-existing conditions following initiation of ART. There are no universally accepted diagnostic criteria for the condition, therefore diagnosis typically requires a temporal relationship between ART initiation and worsening of pre-existing conditions, while still maintaining a positive response to ART. IRIS may be classified as either "unmasking," meaning an asymptomatic pre-existing condition becomes clinically evident, or "paradoxical," meaning that a symptomatic pre-existing condition clinically worsens . Of note, disseminated KS in the setting or IRIS may occur regardless of the patient's CD4 count prior to initiation of ART . This case will highlight the importance of screening patients for opportunistic infections prior to ART initiation, surveilling patients after ART initiation to monitor for IRIS, including pulmonary KS as a differential for respiratory symptoms in patients with HIV, and promptly considering chemotherapy for treatment of disseminated KS. Case presentation Presentation An African American non-Hispanic male in his late 20s with a past medical history of HIV, hepatitis B, and asthma was admitted for shortness of breath and diffuse skin lesions. Four months prior to this admission, the patient tested positive for HIV during incarceration, at which time he had already had the presence of maculopapular skin lesions, but he was not started on ART. Two months prior to this admission, he underwent repeat testing for HIV, which revealed a viral load of 115,000 copies/mL and CD4 count of 556; he was subsequently started on ART with Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide). Additionally, the patient's hepatitis B viral load was 120000 IU/mL. Tests for gonorrhea and chlamydia (urine, rectal, and throat), HCV antibody, QuantiFERON-TB (QIAGEN N.V., Hilden, Germany), and cytomegalovirus (CMV) DNA polymerase chain reaction (PCR) were all negative. His most recent CD4 count one week prior to admission was 547. Following the initiation of ART, the patient noted that his skin lesions multiplied in number. On admission, there were widespread, violaceous, painless papules, plaques, and nodules ranging in size from 2 mm up to 18 mm with some of the smaller lesions coalescing. There were also occasional vesicles overlying the papules and plaques . He also noted a prominent oropharyngeal lesion that he felt with swallowing, though it did not cause any dysphagia or odynophagia . Figure 1 Kaposi sarcoma lesions on the patient's back. Figure 2 Kaposi sarcoma lesions on the patient's right upper arm. Figure 3 Kaposi sarcoma lesions on the patient's right lower arm. Figure 4 Suspected Kaposi sarcoma lesion in the left oropharynx. Additionally, he had prominent non-tender lymphadenopathy and swelling on presentation. Visual inspection revealed one firm, non-fluctuant right upper anterior cervical lymph node measuring approximately 8 mm and another firm, non-fluctuant right lower posterior cervical lymph node measuring approximately 3 mm . His right arm, bilateral legs, and genitalia were significantly edematous. This edema caused discomfort, although he could still ambulate and urinate appropriately. Figure 5 Two non-tender enlarged lymph nodes on the patient's right neck. Workup and diagnosis We began prompt and concurrent workup of the patient's skin lesions, lymphadenopathy, and shortness of breath. A skin biopsy of a lesion on his left thigh was positive for HHV8, confirming the highly suspected diagnosis of KS. An initial chest x-ray revealed bilateral pneumonic infiltrates, with associated bilateral pleural effusions, worse on the right side . At this point, the primary team considered a number of pathogens that could cause pneumonia, including opportunistic pathogens; the differential also included concurrent pulmonary KS given the patient's widespread skin lesions and lymphoma, and Castleman disease given the patient's diffuse lymphadenopathy. Figure 6 Patient's initial chest x-ray on admission. We proceeded to obtain coronavirus disease 2019 (COVID-19) PCR, respiratory virus panel, QuantiFERON-TB test, histoplasmosis antibody labs, blastomycosis antibody labs, histoplasmosis urine antigen, blastomycosis urine antigen, cryptococcal serum antigen, and bacterial and fungal blood cultures. He tested positive for coronavirus variant OC43 but was negative otherwise. The 1,3-b-D-glucan test (Fungitell(r), Associates of Cape Cod, Inc., Falmouth, Massachusetts, United States) was positive, as was the repeat test several days later, despite no apparent signs of fungal infections and negative fungal workup. Therefore, we decided to defer systemic antifungals due to the possible side effects associated with this therapy. We decided to conduct thoracentesis for both diagnostic and therapeutic purposes. Pleural fluid analysis revealed negative Gram stain and culture, negative acid-fast bacteria (AFB) culture, and negative fungal culture. Cytology was negative for malignancy. However, the pleural fluid met 1/3 Light's criteria and was therefore exudative. Following this initial workup, we planned to obtain additional imaging and perform broncho-alveolar lavage (BAL) for additional pathogen testing. Given the patient's pulmonary findings and widespread lymphadenopathy, we proceeded with CT imaging of the neck, chest, and abdomen. Chest CT showed diffuse areas of ground glass opacities throughout the lungs and bilateral pleural effusions . Neck and abdomen CT imaging showed enlarged and necrotic lymph nodes of the neck, a necrotic lymph node in the right axilla, mediastinal lymphadenopathy, and several enlarged inguinal lymph nodes. Imaging did not reveal any hepatic, gallbladder, pancreatic, renal, or gastrointestinal lesions. Of note, we did not obtain CT imaging of the head given the patient did not have any neurologic symptoms or neurologic deficits on exam. Figure 7 Cross-section of patient's chest CT showing ground glass opacities, air space opacities, and bilateral pleural effusions. Given our wide differential and CT imaging that showed significant lymphadenopathy, we decided to proceed with bronchoscopy for BAL, lymph node biopsy, and lung biopsy. BAL culture and Gram stain, AFB smear, and fungal culture were all unremarkable. The sample was also negative for legionella, aspergillus, and pneumocystis. Fine-needle aspiration via bronchoscopy of the right paratracheal lymph node revealed spindle cell proliferation and HHV8+ staining consistent with KS. Transbronchial biopsy of the right middle and upper lobes showed fibroblast-like proliferation and HHV8+ cells, consistent with KS, which confirmed a diagnosis of pulmonary KS. Of note, we did not biopsy the patient's oropharyngeal lesion per the otolaryngology team's recommendations, given the risk of the lesion being highly vascular and a biopsy possibly causing excessive bleeding or respiratory compromise. Given the patient's disseminated KS lesions, the oropharyngeal lesion remained highly suspicious of KS. The patient's shortness of breath was most likely caused by concurrent COVID-19 infection and pulmonary KS. Given the rapid dissemination of KS lesions following the initiation of ART, while still maintaining a positive response to ART supported by the maintenance of CD4>500, the patient was diagnosed with disseminated KS secondary to paradoxical IRIS. Treatment and outcomes For symptomatic treatment, we administered 2-4 L supplemental oxygen via nasal cannula for shortness of breath, which achieved sufficient O2 saturation levels and therefore did not require escalation. We also administered loop diuretic therapy to reduce fluid volume that may contribute to lymphedema, and multimodal analgesics for pain management. He underwent thoracentesis to drain the bilateral pleural effusions. Unfortunately, this procedure was complicated by pneumothorax, so a chest tube was put into place to treat this complication. We eventually performed pleurodesis, given continued drainage from the chest tube. The patient was continued on his home ART regimen throughout his admission. However, the patient's clinical condition not only failed to improve on ART alone, but continued to worsen; new skin lesions were developing, the edema was causing increasing discomfort, and his shortness of breath was not resolving. He was started on doxorubicin therapy after a thorough discussion with the patient regarding benefits and risks. Following the first cycle of chemotherapy, he had a positive response; his skin lesions and cervical lymph nodes regressed in size . Additionally, there was a significant decrease in swelling of his extremities and genitals. Figure 8 Kaposi sarcoma lesions on the patient's back following doxorubicin therapy. The patient was discharged home due to clinical improvement. He was connected with home services to assist him with activities of daily living (ADLs) and instrumental ADLs (IADLs) and he was scheduled for routine outpatient follow-up and outpatient chemotherapy. Discussion This case highlights the interesting relationship between pre-existing KS and the development of IRIS and disseminated KS. In one retrospective study, researchers found that patients with KS on presentation had the highest percentage of IRIS following ART initiation compared to other AIDS-defining illnesses . One randomized control trial found that almost 60% of individuals with pre-existing KS developed IRIS after initiating therapy, which can then lead to the rapid expansion of the lesions . KS can disseminate to the musculoskeletal, lymphatic, gastrointestinal, and pulmonary systems, sometimes even in the absence of cutaneous lesions . KS of the respiratory structures has a poor prognosis; one cohort study found that patients with lung involvement had a median survival time of approximately 1.6 years . Interestingly, recent studies investigating outcome predictors in KS showed that interleukin (IL)-5 levels are higher in patients with a positive clinical response to ART (lesion regression), while levels of IL-6 and IP-10 (interferon-gamma inducible protein of 10 kDa) are higher in patients with negative clinical response to ART (lesion progression) . Therefore, healthcare professionals may consider measuring these markers prior to and following ART initiation to supplement their monitoring of treatment response and disease progression in their patients. Additionally, there are treatment options for those with significant KS lesions. A randomized, controlled, open-label trial found that dual treatment with ART and chemotherapy significantly reduced KS lesions within a year . In the patient discussed in the current report, the initiation of chemotherapy showed rapid clinical improvement. Therefore, while this condition may be clinically rare, it has significant clinical outcomes and, therefore, requires the clinician's awareness when treating individuals with HIV. Conclusions This case report presents several important implications in HIV care. One is that healthcare professionals should carefully screen patients with HIV for opportunistic infections prior to ART initiation. Healthcare professionals should then closely monitor their patients after ART initiation for signs of IRIS, especially in individuals with pre-existing AIDS-defining illnesses such as KS. Both these first two suggestions may also include measurement of IL-5, IL-6, and IP-10 to predict disease outcomes following ART initiation, if clinic or hospital resources allow such. Additionally, it is important to include pulmonary KS in the differential diagnosis for patients with HIV presenting with pulmonary signs and symptoms. This is important since, as mentioned previously, visceral organs may be involved in the absence of skin lesions. Lastly, a diagnosis of disseminated KS may warrant prompt consideration of chemotherapy to prevent the significant morbidity and mortality associated with this condition. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults J Natl Cancer Inst 1823 1830 92 2000 11078759 2 Pulmonary Kaposi sarcoma in the era of highly active antiretroviral therapy HIV Med Palmieri C Dhillon T Thirlwell C 291 293 7 2006 16945073 3 Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort Clin Infect Dis Haddow LJ Easterbrook PJ Mosam A Khanyile NG Parboosing R Moodley P Moosa MY 1424 1432 49 2009 19788360 4 Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma J Clin Oncol Bower M Nelson M Young AM 5224 5228 23 2005 16051964 5 Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection Clin Infect Dis Achenbach CJ Harrington RD Dhanireddy S Crane HM Casper C Kitahata MM 424 433 54 2012 22095568 6 Kaposi's sarcoma-associated immune reconstitution inflammatory syndrome (KS-IRIS) in Africa: initial findings from a prospective evaluation Infect Agent Cancer Martin J Laker M Kambugu A 0 4 2009 7 Kaposi's sarcoma of internal organs. A multiparameter study of 86 cases Cancer Ioachim HL Adsay V Giancotti FR Dorsett B Melamed J 1376 1385 75 1995 7882289 8 Outcome markers of ART-treated HIV+ patients with early stage Kaposi's sarcoma PLoS One Ngalamika O Tso FY Lidenge S Munsaka S Shea D Wood C West J 0 15 2020 9 A randomized controlled trial of highly active antiretroviral therapy versus highly active antiretroviral therapy and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa J Acquir Immune Defic Syndr Mosam A Shaik F Uldrick TS 150 157 60 2012 22395672 |
s, Library, and Information Science & Technology Abstracts. Databases will be searched using the following terms: "living librar*" OR "human librar*", applied in each database to 'title', 'abstract', and where available 'keywords' fields. Grey literature will be searched using: ProQuest (theses/conference documents), British Library via Ethos (theses), International Clinical Trials Registry Platform (clinical trials), Overton.io (UK health policy), Bielefeld Academic Search Engine (articles/these/conference documents), Google.com*. We will conduct google searches of the following domains for websites that included the words "human library" or "living library". - Inurl: ac (academic institutions) - Inurl: edu (academic institutions) - Inurl: gov (government-published) - Inurl: org (non-governmental organisations) - Inurl: nhs (UK National Health Service). We will test the sensitivity of the search strategy by ensuring it picks up five key papers identified from our literature scoping in each of the electronic databases that includes the paper. We will include a wide range of data sources including primary data, reviews, commentaries, manuals and detailed lived experience accounts. Inclusion and exclusion criteria are listed in box 1. Box 1 Inclusion criteria for living library systematic search screening Inclusion criteria Full text available in English. Published since 2000 (inception of the human library concept). Relates to human or living library (as per the aforementioned definition). Any study type is permitted. Written text only (excluding audiovisual content). All identified documents will be uploaded to EndNote and duplicates will be removed. Deduplicated records will be uploaded into Rayyan39 to facilitate a two-step screening process. In step 1, all documents will be screened by title and abstract with 20% screened by a second reviewer to check reliability. Any uncertainties will be discussed and refinements will be made to criterion descriptors as needed. At stage 2, full texts will be read, first to check the inclusion criteria are met, and second to assess the additional criteria of rigour and relevance. Rigour will be assessed by the overall quality of the study or the theoretical arguments being put forward, and the confidence we have in the conclusions being drawn. Relevance will be assessed by the extent to which the document tells us anything useful to refine, refute or elaborate our programme theories.40 Only studies considered to be relevant and of sufficient rigour for us to trust the implications for our theory development will be included. We will not use formal assessment of methodological quality tools often used in systematic reviews. The value of individual studies to the development of the programme theory in a realist synthesis depends not only on the methodological rigour but also on what the document can tell us that is relevant to building our theory, and the conceptual thinking of the authors. We will conduct hand searches of reference sections (backward searching) and citations (forward searching) of eligible documents included in the review after this full-text screening stage. We will also consult members of our expert advisory group for any additional materials that may have been missed by our search strategy. Data extraction Using a proforma designed for the study, we will extract details about each included study including publication details (authors, date and title); study details (location, design and sample characteristics); and intervention details (where applicable, format of the intervention). Reading the full paper in detail and extracting data from all sections, we will extract any data that pertains to any of our identified theory areas and code these extracts into our NVivo framework. We do not anticipate identifying full explicit CMO configurations but will use inductive, deductive and abductive reasoning to work back from what is being said and infer what the underlying CMO configurations may be and code the data accordingly.41 Where data relevant to our theory are identified but are not easily coded into our theory areas, we will refine and add to our framework. At this point, data from both workstreams will be integrated. Field notes and online interactive whiteboards created during the EBCD workshops will also be coded into the NVivo framework and will continue to inform the theory development throughout the rest of the study. Data analysis A detailed analysis of each theory area will be done using retroductive reasoning. This involves working back from the data to identify the context-dependent mechanisms underlying the impacts described in the data that can help us to understand the impacts of living libraries across a range of different contexts and why these impacts are occurring. Analysis will focus on refining, reconfiguring, elaborating, refuting and consolidating each of the theory areas described in the NVivo framework. Here we will draw on several strategies including Comparing instances in which a living library has been used in very different contexts to understand how and why the outcomes are different. Examining extreme cases where very positive or very negative outcomes are reported for a library or any specific individuals within the library. Examining unintended and unexpected outcomes to determine what contextual factors may have triggered mechanisms to generate these. Using counterfactual thinking and thought experiments to consider whether a particular outcome could have occurred without a specific contextual factor being present, what it is about this contextual factor that leads to the outcome and imagining how the outcome might have been different if a specific aspect of context was modified. We hope this process will refine our initial programme theories, but we anticipate it will also generate further questions. Drawing on formal theories To further elaborate our theories and fill in any gaps in our CMO configurations, we will draw on formal theories that can explain how a LoLEM might work by theorising relevant mechanisms at a level of abstraction above the specifics of the living library model. For example, at the individual (micro) and interpersonal (meso) levels, these may include intergroup contact theory,42 43 social identity theory,44 social learning theory45 and personal recovery.46 Additional theories at the organisational (macro) level may also be relevant, such as the theory of health empowerment.47 At this stage, and consistent with the iterative nature of realist synthesis methodology, we may conduct additional theory-driven literature searches for further formal theories that augment the theory development process. The selection and use of formal theories will be guided by the extent to which each theory helps us to further develop our programme theories. Stakeholder interviews Our second strategy to elaborate and refine our theories, will be to use realist interviewing48 with key stakeholders. We will sample through snowballing techniques, initially drawing on the networks of our broad research team, expert group and key individuals identified through our literature searching. Early interviews will inform the development of our initial programme theories, but as our theories develop, the focus of the interviews will evolve into a more specific focus on filling in gaps in our theories and testing competing theories. Sampling will become more purposive to select interviewees with relevant knowledge and expertise. Those willing to take part will be sent a participant information sheet and asked to provide consent online. Interviews will be done flexibly (to maximise participation) using individual/group interviews, online/face-to-face/telephone media, and topic guides designed to test our explanatory theories. Data will be recorded and transcribed, and coded and analysed within the theory framework in NVivo as described in steps 5 and 6. Synthesising final theories In the final stage of the synthesis, we will use iterative discussion within our research team and expert group to consolidate our programme theories into a final framework that articulates how a LoLEM works, for whom, and in what contexts. This will draw on data derived from literature searches, realist interviews, and the EBCD workshops described further. Workstream 2: EBCD of a LoLEM guide Informed by the EBCD approach,49 we will adapt the process to meet the specific needs of this project. Key steps are outlined as follows. Gathering experiences from stakeholders to understand key issues to be addressed In EBCD, these are referred to as 'touchpoints' and are identified through interviews, observations or group discussion. In this project, we will use the data from steps 1-3 of the realist synthesis to identify key features of living libraries that need to be codesigned. Setting up the codesign process Participants will be recruited through NHS Trusts, peer support charities and existing user involvement networks across the North of England to take part in a series of monthly codesign workshops. Participants will include people with experience of using their mental health experiences to support others or to inform research and development in health services and mental health professionals with expertise in supporting peer workers. All participants will be sent a participant information sheet and will be asked to consent to data from the workshops being used to inform study outputs. Participants will be paid in accordance with guidance from the National Institute of Health Research50 and will be offered access to individual support from the research team. Workshops will be run online to maximise engagement geographically and through pandemic restrictions. They will be cofacilitated by an experienced trainer in peer support interventions whose work is grounded in lived expertise (KM), our PPI lead for the project (CL) and an artist (GC) with experience in codelivering and capturing codesign processes using creative visual tools. The process will be supported by other members of the research team. Running the codesign workshops The content of each workshop will be responsive to our developing programme theories and agreed in consultation with participants during the process. The initial plan consists of four phases to the process: Building rapport and trust within the group through experiences of story sharing which are fundamental to the living library model. Applying the experiences of story sharing to generate further understanding of the living library model and to identify barriers and facilitators to success. Applying the understanding of the barriers and facilitators to develop fundamental guidelines and key considerations for running a living library in a range of settings. Agreeing on the format of production of the guidelines and next steps. Generating a LoLEM guide for how to set up and run a LoLEM across a range of contexts The aim is not to write a 'recipe book' but to identify key things to consider when setting up a library and to understand how different decisions are likely to lead to different outcomes. These will be described using text and artistic impressions. Key issues anticipated include what the library is for, where and how the library is hosted, how books are defined, recruited, trained, reimbursed, and supported; who the readers are, and how the library is offered to them; how the role of the librarian is set up; and how a LoLEM should be evaluated. Celebrating and sharing outputs A celebration event will be held to share the final draft of the protocol and to review the process of codesign. Patient and public involvement (PPI) statement Lived expertise is embedded at every level of the project. During the study design, and prior to applying for funding, we held an online consultation with four service users from our Spectrum Centre Advisory Panel at Lancaster University,51 which informed the idea of a living library (two had been living books). Perceived benefits were that this approach can be engaging, non-stigmatising and draws on a familiar and non-threatening metaphor. It has the potential to involve a wide range of books and readers due to flexibility in time/location/what is shared/ways of sharing, and the opportunity for in-depth dialogue. Challenges identified were the need for adequate training, supervision and support for books, as well as ensuring empowerment, ownership and control by people with lived experience. While designing the study, we hosted an online stakeholder event (n=8) with services users and mental health service staff across the region. Additional considerations identified in this process included the need to accentuate the library as additional to (rather than alternative to) PSW roles, and the need to increase diversity and access to a broad range of living books across age, ethnicity, gender, sexuality and types of experience. The research team includes two PPI leads with lived experience (CL and KM). They contributed to the design of the study and application for funding. They are involved in strategic management meetings and practical delivery in both workstreams, including cofacilitating the EBCD workshops. They will be authors on all outputs and involved in dissemination including presentations, and as coapplicants for future grants. Our expert group includes two people with lived expertise. One is a service user who has been a reader (or book) in a living library, and the other is a carer who has a lot of experience in service development at an advisory level. Knowledge mobilisation Outputs from this study will include an expert informed theory of how a LoLEM could work to improve outcomes for books and readers, and a theory-informed codesigned protocol for setting up and running a LoLEM. These will be openly shared in open access journals, following RAMESES reporting guidelines52 and through Lancaster University and Lancashire and South Cumbria NHS websites. Any amendments made to the protocol will be explained in the outcome paper on completion of the study, and updated on PROSPERO. We also aim to have established a network of people with lived experience and mental health support providers who are motivated to use the study outputs to establish a library. We will host a dissemination event to present the findings of the study to stakeholders including commissioners. We will invite mental health support providers, commissioners, health professional trainers and other organisations who may benefit from hosting a LoLEM. We hope to use this to build a collaborative twice daily for further research funding to conduct a realist evaluation of a series of LoLEMs across different contexts. Ethics and dissemination In the same way that a poorly designed LoLEM could be disempowering, stressful and even traumatising for books, and could confirm rather than challenge existing stigma and prejudice, this could also be true for the process of codesigning the library guide. To mitigate against this, we will conduct the study within a university (rather than NHS) context; ensure all EBCD workshops will be cofacilitated with people who have lived expertise; and ensure all participants will have access to one to one support from the research team throughout the process as required. EBCD group members will be purposively sampled to ensure a diverse range of views and minimise any power issues. We will encourage exploration of the role of a LoLEM within the broader social context of mental health support, as well as more detailed design features of the library. All data will be provided with informed written consent and will be collected and stored securely. The detailed and personal nature of the EBCD workshop data makes it impossible to fully anonymise, so these data will not be shared openly. However, all outputs will be published in open access journals. Plain English summaries will be made available on the Lancaster University website. Supplementary Material Reviewer comments Author's manuscript MS acknowledges the support of the NIHR Nottingham Biomedical Research Centre. Data availability statement No data are available. n/a. Ethics statements Patient consent for publication Not applicable. Ethics approval This study involves human participants and was approved by Ethical approval was granted by Coventry and Warwick National Health Service (NHS) Research Ethics Committee (REC) on 29th December 2021 (REF: 305975). Participants gave informed consent to participate in the study before taking part. Twitter: @fionalobban, @stackingbooks, @kmachin, @DrSarahPowell1 Contributors: FL is the guarantor; led the design and funding application, and co-led the running of the project. PM is an early career researcher who led the ethics application and the realist synthesis and integration of theory between the workstreams; and co-led the management of the study. JB advised on the search strategy. GC cofacilitated EBCD workshops and produced artistic impressions of the developing theory. ZG, PJ, RJ and LW will help with the running of the EBCD workshops, and RJ also screened papers and extracted data in the realist synthesis. CL and KM will cofacilitate the EBCD workshops, with KM leading the codesign process and Cl supporting public and patient involvement. JR-M provided methodological guidance and input into the realist synthesis. SHJ was organisational lead for the EBCD workstream and was consulted on theory development in the realist synthesis. SF, CI, HK, SP, EM and MS provided strategic guidance to the design of the study. All authors contributed to and approved the final version of all protocols. Funding: The study was funded by the National Institute of Health and Care Research (NIHR), Research for Patient Benefit programme (NIHR203476). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The study is sponsored by Lancashire and South Cumbria NHS Foundation Trust. Competing interests: None declared. Patient and public involvement: Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the Methods and analysis section for further details. Provenance and peer review: Not commissioned; externally peer reviewed. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34828 Neurology Allergy/Immunology Oncology Thymoma and Myasthenia Gravis: An Examination of a Paraneoplastic Manifestation Muacevic Alexander Adler John R Itani Mira 1 Goldman Gollan Yarden 2 Ezell Kristin 3 Mohanna Mohamed 4 Sabbagh Saad 4 Mears Caoimhin 5 Mears Katrina A 5 Dominguez Barbara 4 Feinsilber Doron 4 Nahleh Zeina 4 1 Hematology-Oncology, Cleveland Clinic Foundation, Weston, USA 2 Hemaology-Oncology, Ross University School of Medicine, Weston, USA 3 Hematology-Oncology, Ross University School of Medicine, Weston, USA 4 Hematology-Oncology, Cleveland Clinic Florida, Weston, USA 5 Ophthalmology, Retina Consultants of Southwest Florida, Fort Myers, USA Mira Itani [email protected] 10 2 2023 2 2023 15 2 e348289 2 2023 Copyright (c) 2023, Itani et al. 2023 Itani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Thymoma is a rare type of malignancy but is considered one of the most common neoplasms that occur in the anterior mediastinum. A large proportion of thymomas are associated with paraneoplastic syndromes, such as myasthenia gravis. Whenever feasible, the standard of care for the treatment of thymoma should focus on the control of paraneoplastic syndromes, surgical resection, and adjuvant therapy if appropriate. A 36-year-old female patient with a significant past medical history of obesity and iron deficiency anemia who underwenten bloc resection of thymoma three months prior now presented to the benign hematology clinic to establish care for the management of anemia. Upon review of systems, the patient incidentally reported fatigue, weakness with repetitive motion, occasional blurred vision, headaches, and exertional dyspnea. Physical examination was positive for horizontal nystagmus. Given the patient's history and clinical findings, suspicion of myasthenia gravis was high. Further work-up demonstrated anti-acetylcholine receptor titers of 5.70 nmol/L (normal < 0.21 nmol/L), supporting a diagnosis of myasthenia gravis in this patient. She was subsequently started on pyridostigmine. Often, patients with thymoma experience paraneoplastic syndrome-related symptoms prior to thymectomy, and in many cases thymectomy is curative. However, in the case presented, we examine a patient that was asymptomatic prior to surgery and subsequently reported the onset of symptoms following what we suspect was an exacerbation due to general anesthesia and pain control medications. We argue that all patients with thymoma should undergo systematic evaluation and treatment of paraneoplastic syndromes, regardless of clinical symptoms and prior to surgery, in order to improve patient quality of life and hospital outcomes. thoracic surgery oncology neurology case report paraneoplastic syndrome myasthenia gravis (mg) thymoma The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Thymomas are malignant cancers of the thymus, a primary lymphoid organ of the anterior mediastinum where T-lymphocytes mature immunologically . It is known that the thymus naturally involutes with age and decreases in functionality while retaining some capacity to regenerate; however, there is no well-defined age at which it begins this process . In some cases, the epithelium of the thymus undergoes abnormal cell proliferation and creates thymic epithelial neoplasms . The thymoma is one such neoplasm and is made of both lymphocytes and epithelial cells, giving rise to multiple classes of thymoma depending on the varying degrees of each . Although rare, with an incidence of around 1.5 cases per million, this cancer accounts for around 20% of malignancies in the adult mediastinum . The prevalence of thymomas is comparable between males and females and the median age of diagnosis differs between races, with 48 years in Black patients and 58 in White patients . The Masaoka Staging System allows for tumor staging, prognostic predictions, and treatment guidance of thymomas . Treatment modalities available are surgical resection, systemic treatments, radiotherapy, and chemotherapy depending on each case . Thymomas are often associated with other conditions such as myasthenia gravis (MG), pure red cell aplasia, immunodeficiency, and multi-organ autoimmunity . Myasthenia gravis is a common paraneoplastic syndrome related to thymomas . MG is an autoimmune disorder that presents with weakness on repetitive use of certain muscle groups, such as ocular, bulbar, proximal muscles of the extremities, and respiratory muscles to varying degrees and in varying combinations . The variable, fatigable weakness present in MG is a manifestation of autoimmune IgG antibodies targeted against muscle nicotinic acetylcholine receptors (AChR) disrupting postsynaptic neuromuscular transmission . The incidence rate of MG as a paraneoplastic syndrome in thymoma is estimated at around 0.25-2 cases per million, with a trend of increasing prevalence suspected to be due to increased life expectancy as a result of effective treatment . MG is diagnosed clinically by history and physical exam findings. Diagnosis can be aided by electrophysiological studies and serum autoantibody titers, most commonly the AChR antibodies. Treatment is chosen on a case-by-case basis according to each patient's profile and personal wishes . Herein, we present a case of MG in a 36-year-old female with a previously resected thymoma who initially presented for iron deficiency anemia. Case presentation Thymoma In January 2022, the patient, a 36-year-old female with a significant past medical history of obesity, vitamin D deficiency, chronic left shoulder pain, intermittent asthma, and iron deficiency anemia acquired a coronavirus disease (COVID-19) infection, which led her to develop dyspnea and chest pain. She presented to the emergency department for worsening symptoms and underwent an extensive work-up, including a computed tomography (CT) scan of the chest. The patient was incidentally found to have a left upper lobe (LUL) lung mass measuring 2.8 cm x 4.4 cm x 3.6 cm that was directly bordering the pulmonary artery. On follow-up with pulmonology, a CT-guided biopsy and positron emission tomography (PET)-CT scan were ordered to evaluate the LUL lung mass. In February 2022, the patient underwent PET-CT scan imaging, which re-demonstrated a metabolically active LUL lung mass with a maximum standardized uptake value of 11.3, indicating potential cancerous involvement. She proceeded to undergo a CT-guided biopsy. Images from the CT-guided biopsy are supplied in Figures 1-3. On pathologic examination, the biopsied sample was found to have features most consistent with thymoma, with predominant lymphoid tissue. The biopsied sample had low cell yield and thus was not ideal for flow cytometry immunophenotypic testing. The patient was then referred to cardiothoracic surgery. Figure 1 The lesion abuts the third left costal cartilage without invasion or erosion. It also, medially abuts the main pulmonary artery with a thin fat plane of separation. Figure 2 A second view of how the lesion abuts the third left costal cartilage without invasion or erosion, while also medially abutting the main pulmonary artery with a thin fat plane of separation. Figure 3 Well-defined solid left anterior mediastinal mass measuring 4.5 x 2.8 cm. There is no calcification, fat or cystic changes. At the end of March 2022, the patient underwent left robotic thoracoscopy with a plan for complete thymectomy. Intra-operatively, the tumor was upstaged from a modified Masaoka Stage II to a Stage III thymoma due to visualized extension into the lung parenchyma. It was decided to proceed with extended resection of the thymoma en bloc, including complete removal of the LUL of the lung, and partial resection of the left phrenic nerve and pericardium. Complete resection was achieved, with negative surgical margins of 0.5 mm. Diagnosis of thymoma was confirmed on pathologic examination. The mass was found to demonstrate World Health Organization (WHO) B2 and B3 components and measured 5.2 cm in greatest dimension. One lymph node was dissected and was found to be negative for malignant disease. Following surgery, the patient was prescribed paracetamol and gabapentin for pain control. In April 2022, a thoracic oncologist evaluated the patient and referred her to radiation oncology, as she was a candidate for radiotherapy according to the National Comprehensive Cancer Network (NCCN) guidelines . The radiation oncologist recommended adjuvant radiotherapy for this patient and currently, the patient will begin said regimen in the near future. Myasthenia gravis In June 2022, the patient visited her hematologist for follow-up on iron-deficiency anemia. The patient reported that she was feeling fatigued and was experiencing weakness with repetitive motion on review of systems. Other symptoms present were headaches, dysphagia and blurred vision. The physician noted that the patient had horizontal nystagmus and appeared fatigued during the physical exam. MG was suspected and anti-acetylcholine receptor (anti-AChR) antibody titers were ordered. Titers were elevated with a result of 5.70 nmol/L with the institutional reference range being <0.21 nmol/L for normal results. Gabapentin prescribed to the patient following her surgery was discontinued and the patient was counseled about the effects of certain medication classes on MG, prescribed pyridostigmine, and was then referred to neurology. In July 2022, the patient presented to the neurology clinic, where she reported experiencing vision loss, blurriness, facial drooping, difficulty swallowing, dyspnea, and fatigue for the past four months. The timeline of symptom appearance overlaps with the post-thymectomy period. Physical exam findings, including a comprehensive neurological exam, were normal with the exception of bilateral eyelid ptosis that worsens with sustained upward gaze. The patient initially did not improve after the prescription of pyridostigmine due to non-compliance, as reported by the patient. Pyridostigmine was continued by neurology with dose modification for better tolerance. Discussion Thymoma and MG mechanisms Thymomas and MG are quite interlinked: 50% of thymoma patients develop MG and 10%-20% of MG patients are found to have thymomas . This interconnection is due to the link between the function of thymic tissue and the pathogenesis of myasthenia gravis. Immunological maturation takes place when the T cells interact with cell surface proteins on the thymic tissue cells in order to be able to differentiate between self and non-self-antigens . In the case of thymoma-associated MG, it is hypothesized that thymomas hold epitopes that can cross-react with certain skeletal muscle proteins. These epitopes are the ryanodine receptor (RyR), titin, and acetylcholine receptor . The most implicated antibody in the pathogenesis of MG is the anti-AChR antibody; however, the majority of paraneoplastic thymoma-associated MG cases also have anti-titin or anti-RyR antibodies . Due to the nature of the autoantibodies present in MG, certain drugs could be detrimental to the patient's health and could induce a myasthenic crisis . These drugs include neuromuscular blockers, inhalation anesthetics, and gabapentin . We suspect that the use of gabapentin may have caused our patient to have an increase in MG symptoms since the time of the surgical resection when it was prescribed to her for pain control. The patient underwent surgical resection under general anesthesia, which may have also caused an exacerbation of symptoms. Here, we highlight the importance of awareness of MG as a common paraneoplastic syndrome in thymoma. Our purpose for presenting these findings is to optimize patient care and improve quality metrics. Surgery and anesthesia recommendations There are no formal guidelines or recommendations for patients undergoing surgery with general anesthesia that are known to have a thymoma but have an unknown myasthenia gravis status. Decisions regarding MG workup in patients with confirmed thymomas pre-thymectomy are largely institution-based and vary in purpose, with some being used to guide further management and others being used to monitor trends [17-19]. For patients with known MG undergoing surgery, the standard of care is to employ plasmapheresis or intravenous immunoglobulin (IVIG) infusions prior to surgery in order to extract complex pathogenic autoantibodies from the patient's sera . This is done to keep the patient safe during general anesthesia and to protect them from post-thymectomy MG symptom exacerbation or crisis . In our patient's case, the titer status was unknown and, thus, she received no prophylactic pre-operative intervention against an exacerbation of symptoms or a crisis. Although MG is typically a clinical diagnosis, this case highlights the importance of maintaining a high index of suspicion in patients with thymoma with or without clinical manifestations prior to undergoing surgery. In many cases, surgical resection greatly reduces MG symptoms or MG may go into remission. However, we argue that patients should be monitored following surgery due to the potential for exacerbation of MG. Quality improvement and safety The purpose of presenting this case is to emphasize the need for better safety and quality improvement practices. The lack of guidelines or recommendations for pre-operative workup and peri-operative management of MG in patients with thymomas could lead to deleterious effects, especially given the context of general anesthesia and the stress of surgery. We believe that it would be beneficial to have a guideline in place that mandates the testing of common MG-associated antibodies prior to thymectomy, and as part of pre-operative management in the case of a patient with thymoma. Antibody testing is generally cost-efficient. Additionally, it is important to obtain a neurology consult for a comprehensive clinical exam and confirmation of clinical signs. We believe systematic evaluation of paraneoplastic MG in patients with thymoma would improve patient safety and allow for optimal medical management. Conclusions Myasthenia gravis as a paraneoplastic disease in patients with thymoma requires careful attention. Identifying these patients prior to undergoing surgery and general anesthesia is paramount in ensuring proper management and care. In this case, we highlight the importance of screening for MG in a thymoma patient before thymectomy and the need for guidelines to be set in place. Avoiding myasthenic crises and complications helps in ensuring a better quality of life for patients and in ensuring satisfactory health outcomes. Further cross-team collaboration in this area is important in the care of such patients, and for health, institutions to establish guidelines that guarantee no patient falls in between the cracks of missed conditions. We thank Dr. Leandro Singerman, MD (Cleveland Clinic Florida) and Dr. Ian Drexler, MD (Cleveland Clinic Florida) for assisting us with obtaining the radiological images and annotations. Mira Itani, MD, would like to acknowledge the training received under the Scholars in HeAlth Research Program (SHARP) that set the foundations for a career in clinical and translational research. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Thymus and aging: morphological, radiological, and functional overview Age (Dordr) Rezzani R Nardo L Favero G Peroni M Rodella LF 313 351 36 2014 23877171 2 Postnatal involution and counter-involution of the thymus Front Immunol Cowan JE Takahama Y Bhandoola A Ohigashi I 897 11 2020 32477366 3 The 2021 WHO classification of tumors of the thymus and mediastinum: what is new in thymic epithelial, germ cell, and mesenchymal tumors? J Thorac Oncol Marx A Chan JK Chalabreysse L 200 213 17 2022 34695605 4 Polyparaneoplastic manifestations of malignant thymoma: a unique case of myasthenia, autoimmune hepatitis, pure red cell aplasia, and keratoconjunctivitis sicca Cureus Feinsilber D Mears KA Pettiford BL 0 9 2017 5 Prognostic factors for cure, recurrence and long-term survival after surgical resection of thymoma J Thorac Oncol Safieddine N Liu G Cuningham K 1018 1022 9 2014 24926546 6 Epidemiology of thymoma and associated malignancies J Thorac Oncol Engels EA 0 5 5 2010 7 The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms J Thorac Oncol Detterbeck FC Nicholson AG Kondo K Van Schil P Moran C 0 6 6 2011 8 Paraneoplastic syndromes and thymic malignancies: an examination of the International thymic malignancy interest group retrospective database J Thorac Oncol Padda SK Yao X Antonicelli A 436 446 13 2018 29191778 9 Frequency of synaptic autoantibody accompaniments and neurological manifestations of thymoma JAMA Neurol Zekeridou A McKeon A Lennon VA 853 859 73 2016 27135398 10 Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society J Neurol Melzer N Ruck T Fuhr P 1473 1494 263 2016 26886206 11 A systematic review of population based epidemiological studies in myasthenia gravis BMC Neurol Carr AS Cardwell CR McCarron PO McConville J 46 10 2010 20565885 12 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(r)) - Thymomas and Thymic Carcinomas 11 2022 Network Network N.C.C N.C.C 2022 13 Myasthenia gravis as a prognostic marker in patients with thymoma J Thorac Dis Cacho-Diaz B Salmeron-Moreno K Lorenzana-Mendoza NA Texcocano J Arrieta O 2842 2848 10 2018 29997948 14 Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol Meriggioli MN Sanders DB 427 438 8 2012 22882218 15 Drugs that induce or cause deterioration of myasthenia gravis: an update J Clin Med Sheikh S Alvi U Soliven B Rezania K 1537 10 2021 33917535 16 Uncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use J Community Hosp Intern Med Perspect Chien JL Baez V Mody HR 371 372 9 2019 31528296 17 Measurement of antiacetylcholine receptor antibody in patients with thymoma without myasthenia gravis complications Jpn J Thorac Cardiovasc Surg Sakuraba M Onuki T Nitta S 690 692 49 2001 11808089 18 The importance of measuring acetylcholine receptor antibodies in thymomas Mediastinum Marcuse F Hochstenbag M Hoeijmakers J Maessen J De Baets M 0 2 2018 19 Relationship between anti-acetylcholine receptor antibodies and the development of post-thymectomy myasthenia gravis in patients with thymoma: a single-center experience Gland Surg Nabe Y Hashimoto T Tanaka K 2408 2413 10 2021 34527552 20 Plasma exchange for myasthenia gravis Cochrane Database Syst Rev Gajdos P Chevret S Toyka K 0 2002 2002 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34841 Genetics Obstetrics/Gynecology Pediatrics Prenatal Diagnosis of Williams-Beuren Syndrome Based on Suspected Fetal Hypotonia in Early Pregnancy Muacevic Alexander Adler John R Tsagkas Nikolaos 1 Katsanevakis Emmanouil 2 Karagioti Natalia 3 Perdikaris Panagiotis 4 Billis Michail 5 1 Obstetrics and Gynaecology, General Hospital of Agrinion, Agrinion, GRC 2 Obstetrics and Gynaecology, United Lincolnshire Hospitals NHS Trust, Nottingham, GBR 3 Fetal Medicine, Private Practice, Ioannina, GRC 4 Obstetrics and Gynaecology, General University Hospital of Patras, Patras, GRC 5 General Surgery, General Hospital of Lefkas, Lefkas, GRC Nikolaos Tsagkas [email protected] 10 2 2023 2 2023 15 2 e3484110 2 2023 Copyright (c) 2023, Tsagkas et al. 2023 Tsagkas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from In this report, we describe a rare case of prenatal diagnosis of Williams-Beuren syndrome (WBS). While the prenatal diagnosis of WBS is very rare, in the current case, WBS was diagnosed in early pregnancy. The key element was the detection of fetal hands hypotonia and generalized fetal hypotonia at 17 weeks of gestation. This led to the diagnosis of WBS by molecular karyotyping, specifically array comparative genomic hybridization (arrayCGH) of the fetal DNA. The genetic material was acquired by extraction from the fetal cells which are abundant in the amniotic fluid drawn by amniocentesis. Clinical hypotonia of the affected individuals is a clinical characteristic that is widely associated with WBS; however, fetal hypotonia has not been described as a diagnostic criterion for the prenatal diagnosis of WBS. prenatal genetic testing fetal medicine specialist first trimester scan fetal hypotonia williams-beuren syndrome The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction The examination of the fetal anatomy by ultrasound in early pregnancy is invaluable because it can help with the early detection of fetal abnormalities. This could serve as the basis for informed choices and possibly early termination of pregnancy, which in many cases is the optimal choice. Early rather than late termination can be the optimal management in terms of women's health, both physically and from a psychological perspective . Williams-Beuren syndrome (WBS) is a chromosome microdeletion syndrome of a specific locus at chromosome 7 that includes the elastin (ELN) gene . Its diagnosis is clinical and the first cases were described in the years 1961-1962 . Individuals with WBS are diagnosed postnatally and a prenatal diagnosis is considered to be highly unlikely, albeit not impossible . In this report, we present a rare case of prenatal diagnosis of WBS and we highlight the idea of prenatally diagnosing WBS based on suspected fetal hypotonia during a prenatal scan. In the literature, studies on "normal fetal motility patterns" exist and the authors consider fetal motility as abnormal when immobility exceeds 13 minutes before 20 weeks of gestation . Case presentation A primigravida aged 27 years with type 1 diabetes underwent a routine first-trimester scan by a fetal medicine specialist. The results of the first trimester tests are presented in Table 1. Table 1 Summary of blood test results and ultrasound and karyotype findings WBS: Williams-Beuren syndrome; HCG: human chorionic gonadotropin: PAPPA: pregnancy-associated plasma protein A; NT: nuchal translucency First-trimester biochemical test Case WBS Beta HCG 45.71IU/l, 1.262 MoM PAPPA 7.710IU/l, 2.441 MoM NT 1.5 mm Gestational age at scan and findings 17 weeks of gestation, fetal hypotonia Karyotype findings Deletion of ~3,73 MB of the chromosomal region 7q11.22q11.23 (chr7:70,400,155-74,133,332) Significance of findings WBS (associated with cardiac anomalies, dysmorphic features, hypotonia, and neurodevelopmental delay) Due to the history of diabetes, a follow-up scan was booked at 17 weeks of gestation for the optimal assessment of the fetal heart and the spinal cord. Anatomically, the fetus appeared normal but there was a strong impression of fetal hypotonia, more profound in the upper extremities. The movements of the fetal core, extremities, and fingers appeared to be fewer than expected for the specific week of gestation. Based on extensive scanning (duration: >4 hours, over two consecutive appointments) and after a detailed discussion with the parents, it was decided to perform an amniocentesis. Fetal hypotonia is a nonspecific finding and a multidisciplinary team (MDT) approach was decided. The clinical geneticist in the MDT advised that the array comparative genomic hybridization (arrayCGH) analysis should be the method of choice in the presented case. Indeed, the arrayCGH analysis revealed a deletion of ~3,73 MB of the chromosomal region 7q11.22q11.23, where 30 genes are registered on the gene database OMIM (Online Mendelian Inheritance in Man), with the gene ELN being among them (*130160 in OMIM). This specific finding is linked to WBS (#194050 in OMIM), which is characterized by cardiac anomalies, dysmorphic features, hypotonia, and neurodevelopmental impairment. A summary of the blood test results, ultrasound, and arrayCGH findings can be found in Table 1. Following consultation, the couple opted for the termination of pregnancy. Termination was successfully performed by the "medical management pregnancy termination protocol", which is based on the use of misoprostol tablets. The procedure was successful and uneventful; there was no need for admission to the surgical theater and no need for a blood transfusion. An en bloc fetoplacental specimen was produced and the woman was discharged home after spending 48 hours in the hospital. Discussion In this report, we described a case of fetal hypotonia that led to the diagnosis of WBS early in pregnancy. The absence of fetal movements is considered abnormal when it exceeds 13 minutes before 20 weeks of pregnancy and the nonspecific finding of reduced fetal motility/hands hypotonia, led to a rare identification and diagnosis of WBS prenatally. The incidence of the typical presentation of the syndrome is approximately 1/10,000 live births but atypical forms, of unknown incidence, have also been described . In our literature search, we identified only nine cases of WBS that have been diagnosed prenatally (eight associated with deletion and one with duplication of genetic material). A summary of these studies and the indication for referral for invasive testing and molecular karyotyping are presented in Table 2. Table 2 Literature search: cases of prenatal diagnosis of WBS WBS: Williams-Beuren syndrome; IUGR: intrauterine growth restriction; NT: nuchal translucency Cases of prenatal diagnosis of WBS Referral reason - indication for prenatal invasive testing References WBS deletion IUGR 20 weeks of gestation Marcato et al., 2013 WBS deletion IUGR 32 weeks of gestation Marcato et al., 2013 WBS deletion Omphalocele 13 weeks of gestation - IUGR 18 weeks of gestation Marcato et al., 2013 WBS deletion Hydrops, polyhydramnios, absence of umbilical diastolic blood flow 30 weeks of gestation von Dadelszen et al., 2000 WBS deletion Ventricular septal defect 23 weeks of gestation Kontos et al., 2008 WBS deletion Symmetrical IUGR 20 weeks of gestation Krzeminska et al., 2009 WBS deletion IUGR 25 weeks of gestation Popowski et al., 2011 WBS deletion IUGR 33 weeks of gestation Maeda et al., 2018 WBS duplication Increased NT 13+4 weeks of gestation, absence of nasal bone, inversion of a wave of ductus venosus Marcato et al., 2013 WBS is usually diagnosed during childhood (median age: four years) and the diagnosis is clinical; the criteria include characteristic facial features that vary as per severity. Children often present with a flat nasal bridge, short upturned nose, periorbital puffiness, long philtrum, everted lower lip (dropping lower lip), widely spaced teeth, and delicate chin, whereas older patients have slightly coarse features, with full lips, wide mouth, and a full nasal tip . In the present case, bulbous nasal tip, long philtrum, malar hypoplasia, pointed chin, and large earlobes were observed in the affected WBS fetus . Figure 1 En bloc specimen: fetoplacental unit of the affected WBS fetus Personal archive of current case: Nikolaos Tsagkas MD, MSc; Consultant OB/GYN WBS: Williams-Beuren syndrome Figure 2 Profile of the affected WBS fetus: facial deformities Personal archive of current case: Nikolaos Tsagkas MD, MSc; Consultant OB/GYN WBS: Williams-Beuren syndrome Common medical conditions that coexist with WBS include cardiovascular, endocrine, and nervous system abnormalities. Of note, 75% of WBS cases present with clinical cardiac disease, with supravalvular aortic stenosis and pulmonary artery stenosis being the most common findings. Mental retardation, developmental delay, learning disability, and hypotonia are also among the common neurological features of WBS . Furthermore, it has to be mentioned that the differential of hypotonia except for the WBS include T21/DOWN syndrome, T13/PATAU syndrome, Prader-Willi syndrome, Tay-Sachs disease, achondroplasia, and spinal muscular atrophy . In our case, the pregnant woman was routinely offered first-trimester scanning by a fetal medicine specialist as per local practice. At the first trimester scan, the nuchal translucency and the maternal serum screening tests [beta chorionic gonadotropin (bHCG) and pregnancy-associated plasma protein A (PAPPA)] were normal, together with first-trimester anatomical scanning. Fetal crown-rump length (CRL) was showing a small-for-date fetus and, due to the mother being a type 1 diabetic, a 17-week scan was booked to re-evaluate for cardiac anomalies. During the scan and, specifically when scanning for the anatomy of the digits of the hands, the hand movements seemed to be very reduced for the gestational age. After scanning that lasted more than four hours on two consecutive days, there was a strong, albeit nonspecific, impression of inactivity of the fetal hands and overall hypotonia of the fetus. Invasive prenatal testing was decided to be performed after counseling, and the repeat scan before termination of the pregnancy at 19 weeks classified the baby at the ninth centile of the growth chart (evidence of intrauterine growth restriction). As for the genetic procedure, the actual molecular genetic analysis was performed by arrayCGH analysis as mentioned above. In more detail, the microarray used was the "8Kh60K G3 ISCA V2" (Agilent Technologies, Santa Clara, CA) and the software Cytogenetics (Agilent Technologies). The specific platform detects imbalances (deletions/duplications) of ~500kbases in the whole genome and imbalances of 50kbases in ~240 genetic regions of known clinical significance, which are related to ~512 genetic conditions according to OMIM. This includes numerical anomalies (trisomies 21, 18, 13), microdeletion syndromes, duplication syndromes, and imbalanced structural chromosomal abnormalities . Conclusions Our report introduced a novel scientific question in the field of fetal medicine and prenatal scanning and diagnosis. We described a case of WBS, which, while diagnosed postnatally in a vast majority of cases, was successfully diagnosed in early gestation based on scanning for fetal motility. The question to be addressed in future research is whether fetal inactivity/hypotonia in early gestation is a feature that requires more attention by obstetricians and sonographers (as it can be associated with a spectrum of severe fetal abnormalities) or if the diagnosis of the syndrome in our case was a matter of pure luck? Human Ethics The authors have declared that no competing interests exist. 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Quantitative aspects Early Hum Dev de Vries JI Visser GH Prechtl HF 99 120 12 1985 3905353 11 Williams-Beuren syndrome N Engl J Med Pober BR 239 252 362 2010 20089974 12 Prenatal phenotype of Williams-Beuren syndrome and of the reciprocal duplication syndrome Clin Case Rep Marcato L Turolla L Pompilii E 25 32 2 2014 25356238 13 De novo 46,XX,t(6;7)(q27;q11;23) associated with severe cardiovascular manifestations characteristic of supravalvular aortic stenosis and Williams syndrome Am J Med Genet von Dadelszen P Chitayat D Winsor EJ 270 275 90 2000 10710222 14 Prenatal diagnosis of a fetus with 7q11.23 deletion detected by multiplex ligation-dependent probe amplification (MLPA) screening Prenat Diagn Kontos H Manolakos E Malligiannis P 556 558 28 2008 18509863 15 Prenatal diagnosis of Williams syndrome Ultrasound Obstet Gynecol Maeda K Kaji T Nakaoku D Yamasaki M Kondo A Morine M Hinokio K 3 7 52 2018 16 Hypotonia: National Institute of Neurological Disorders and Stroke 2 2023 2023 17 Easychip 8x15k: a new tool for detecting chromosome anomalies in low risk pregnancies, supporting and integrating standard karyotype J Genet Syndr Gene Ther Alesi V Bernardini L Goidin D 1 6 7 2016 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34836 Cardiac/Thoracic/Vascular Surgery Cardiology Radiology Left Pulmonary Artery Aneurysm: A Post-stenotic Pulmonary Aneurysm Related to Pulmonary Valve Stenosis Muacevic Alexander Adler John R Bhattad Pradnya Brijmohan 1 Yukselen Zeynep 2 Bhasin Mohit 3 Roumia Mazen 1 1 Cardiovascular Medicine, Saint Vincent Hospital, UMass Chan Medical School, Worcester, USA 2 Internal Medicine, Saint Vincent Hospital, Worcester, USA 3 Cardiology, Innovation Cardiology, Norfolk, USA Pradnya Brijmohan Bhattad [email protected] 10 2 2023 2 2023 15 2 e348369 2 2023 Copyright (c) 2023, Bhattad et al. 2023 Bhattad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Aneurysms of the pulmonary artery are uncommon vascular pathologies that are associated with congenital structural cardiac anomalies, pulmonary hypertension, vasculitis, neoplasm, iatrogenic, and infection. PAAs are commonly asymptomatic and accidentally diagnosed, however, if symptomatic, clinical features are generally non-specific and depend on the etiology of PAA. CT pulmonary angiography remains the gold standard imaging modality and other diagnostic imaging tests include transthoracic echocardiography and right heart catheterization. Definitive treatment of PAA is surgery, however, conservative management with close monitoring should be practiced in patients with poor surgical candidates or surgery is unlikely to improve survival. Here, we report a case of pulmonary artery aneurysm secondary to congenital pulmonary valve stenosis as well as a brief review of the literature regarding pulmonary artery aneurysms. dilating vascular disease ct pulmonary angiography adult congenital heart disease (achd) pulmonic valve stenosis pulmonary artery aneurysm The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Pulmonary artery aneurysms (PAAs) are rare vascular pathologies compared to aortic aneurysms, the estimated incidence of being one in 13,696 necropsies according to a study of 109,571 autopsies published by Mayo clinic . PAAs are classified as true or pseudoaneurysms. A true PAA results from the dilatation of all three layers of vascular walls (intima, media, and adventitia) whereas pseudoaneurysms only involve tunica media and adventitia of the pulmonary artery. Pulmonary artery pseudoaneurysms (PAPs) are uncommon but potentially lethal compared to true PAA as pseudoaneurysms have a higher risk of rupture than true aneurysms . PAAs can be proximal (or central) or peripheral based on the anatomic locations. While proximal PAAs arise from the main pulmonary artery, peripheral PAAs arise from segmental or subsegmental arteries. PAA is defined by a dilation of the pulmonary artery to at least 1.5 times the normal diameter, involving all three layers of the vessel wall , and is highly associated with pulmonary artery hypertension (PAH). Proximal PAAs are generally asymptomatic unless complications develop from PAH causing rupture, dissection, or sign of compressions . On the other hand, peripheral PAAs are located on an intrapulmonary artery, thus, even unruptured aneurysms can be life-threatening for instance dissection of PAA can be fatal . The diagnosis of a PAA is often an incidental finding on imaging, however, in suspected cases, echocardiography is the first choice. Transthoracic echocardiography (TTE) is an important tool to reveal the presence of proximal saccular PAA but has a limited role in evaluating peripheral PAA. CT pulmonary angiography is the gold standard to evaluate the morphology and the location of PAAs and it can also differentiate from other vascular pathologies, such as pulmonary arteriovenous malformation (AVM) . PAA is classified as acquired and congenital due to its etiology. In this case report, we present a case of PAA secondary to congenital pulmonic valve stenosis status post-pulmonic valve surgical repair and balloon valvuloplasty where careful monitoring and conservative management were practiced. Case presentation A 64-year-old male with a history of coronary artery disease, hypertension, dyslipidemia, known pulmonic stenosis and PAA presented with worsening dyspnea, peripheral edema, and volume overload. He had open pulmonic valve surgical repair at the age of 29 for his congenital heart disease with pulmonic stenosis and subsequent balloon valvuloplasty at age 56. He underwent angioplasty with stent placement in the proximal right coronary artery at the age of 56. His family history was negative for any congenital diseases including congenital heart disease. As he presented with biventricular heart failure with severe right ventricular systolic dysfunction, he underwent further evaluation by a echocardiogram (TTE) and computed tomography angiography (CTA) of the chest with contrast. A TTE revealed a left ventricular ejection fraction of 40% with a paradoxical septum, increased left ventricular wall thickness with normal left ventricular cavity size, dilated right ventricular size, normal left atrial size, reduced right ventricular global systolic function, dilated right atrium, with a right ventricular systolic pressure 46 mmHg. Valvular pulmonic stenosis with a maximum pressure gradient of 20 mmHg and a mean pressure gradient of 12.8 mmHg with mild pulmonic regurgitation was noted. The dilated and aneurysmal pulmonary artery at 6 cm, pulmonary arterial hypertension, and severe right heart enlargement were notable findings on the TTE. Further evaluation with CTA chest was remarkable for a large 6.5 cm main PAA, enlarged right ventricle, enlarged right atrium with prominent crista terminalis, and a dilated coronary sinus from right atrial hypertension. The pulmonic valve cusps are mildly calcified. A prominent dilated coronary sinus of 16 mm in diameter, secondary to right atrial hypertension. The aortic arch and descending aorta exhibit grade II atheromatous disease, particularly at the ostium of the left subclavian. Also, there is a stent in the proximal right coronary artery with an occluded large ecstatic vessel . Figure 1 Severe pulmonary artery aneurysmal dilation up to 6.5 cm in diameter Figure 2 3D reconstruction of CTA showing pulmonary artery aneurysm Figure 3 Severe PAA as visualized on 3D CTA Figure 4 PAA as seen on CTA Figure 5 Aneurysmal pulmonary artery as seen on CTA Figure 6 Pulmonary artery aneurysm Figure 7 PAA as seen on 3D reconstruction CTA Figure 8 Severe pulmonary artery aneurysm as visualized on CTA with 3D reconstruction Right ventriculography showed a dilated right ventricle with an ejection fraction of 30% with no evidence of infundibular stenosis. There was the visible restriction of pulmonic valve leaflets and a turbulent jet extruding from the right ventricle which filled a massively dilated pulmonary artery. His right heart catheterization revealed mild pulmonic stenosis by a peak gradient of 10 mmHg and a mean gradient of 4 mmHg and moderate pulmonic stenosis by the valve area of 1 cm2. He was managed medically given his multiple comorbidities and biventricular heart failure making him a poor surgical candidate for any surgical interventions per multimodal evaluation by cardiology and cardiothoracic surgery. Discussion PAAs can either be acquired or congenital. Common congenital etiologies are structural cardiac abnormalities and connective tissue abnormalities. Historically congenital structural abnormalities causing Eisenmenger's syndrome that increase blood flow to pulmonary circulation was a common acquired cause of PAA. Gupta et al. reviewed 41 patients with PAA caused by congenital heart abnormalities due to Eisenmenger's syndrome. The most common cause was patent ductus arteriosus (PDA). Other congenital abnormalities they identified were tetralogy of Fallot (TOF), TOF with absent pulmonary valve, atrial septal defect (ASD), ventricular septal defect (VSD), transposition of great arteries (TGA), and Loeys-Dietz syndrome . Even though rarely published as a case report, pulmonary valve abnormalities are also a significant cause of the congenital etiology of PAAs. In a review shared the outcome of surgical repair of PAA, the most common pathology (>50%) in 38 patients with PAA was pulmonary valve regurgitation (29%), followed by pulmonary valve stenosis (16%), both pulmonary valve stenosis and regurgitation (16%) . In our patient, after excluding mentioned risk factors, congenital pulmonic valve stenosis is likely the leading etiological factor. Historically, infections such as syphilis and tuberculosis (Rasmussen's aneurysms) were the primary causes of acquired PAAs, which are less common today. Infective endocarditis is another infectious cause of PAAs that complicates mycotic aneurysms in peripheral pulmonary arteries, which are commonly seen in immunocompromised patients or intravenous drug users. Other acquired PAA pathologies include PAH, vasculitis, neoplasm, (i.e., Hughes-Stovin syndrome Bechet's syndrome, Takayasu arteritis), trauma, and pregnancy-related or iatrogenic injuries [1,6-9]. In the literature, there are only a few case reports of PAAs secondary to congenital PVS [7,10-12]. Even though the exact mechanism of post-stenotic pulmonary artery dilation is unknown, it was suggested that pulmonary valve stenosis causes PAA due to the turbulent blood flow through the pulmonary artery distal to the stenotic area by weakening of the vessel wall. This phenomenon is also known as the Venturi effect (Bernoulli effect) which refers to an increase in velocity and decrease in pressure when a fluid flows through a constricted section of a tube causing dilation . This effect has been demonstrated in a study to explain the mechanism of the development of aneurysms. In 1954, a study demonstrating the physiology of post-stenotic dilation showed that mild dilation appeared beyond the stenosis after 19 hours of pumping against the rubber tubing with two points of stenosis and dilation subsided when the pumping stopped . PAAs are usually asymptomatic and diagnosed as an incidental finding due to the increased use of CT chest. For symptomatic patients, the clinical manifestations of PAA are usually nonspecific and some of the manifestations include cough, dyspnea, pleuritic chest pain, and hemoptysis . According to a review, among 19 patients with PAAs associated with pulmonary valvular abnormalities, only 11 patients were asymptomatic on the first presentation. In symptomatic patients, the most commonly seen symptom was dyspnea (n=6), followed by exercise intolerance (n=2). Chest pain or angina-like symptoms were also reported in some patients . Similarly, our patient also presented with worsening dyspnea. Visualization of PAAs on chest x-ray depends on the location and the size of the aneurysm, however, if it appears, it presents as mediastinal or hilar enlargement. If PAA is suspected, CT chest is usually the next step to confirm the diagnosis. TEE should be performed in suspected cases to obtain PA pressures and diagnose PAH . CTA is an important tool for both detection and follow-up of PAAs as it provides the size, location, and characteristics of aneurysms such as saccular or fusiform aneurysm types. Another advantage of CTA is being helpful to reveal the underlying etiology of an aneurysm . Usually, surgery is the preferred treatment for PAA, but a conservative approach should be practiced when the surgery is not feasible due to comorbidities, as seen in our patient. If the patient is asymptomatic without PAH, conservative management can also be practiced . Conclusions PAAs are uncommon aneurysms that are usually asymptomatic and diagnosed as incidental findings in imaging tests. CTA remains the choice of imaging modality. Surgery is the definitive treatment; however, management depends on the patient's symptoms and concomitant comorbidities. We describe the clinical presentation and imaging findings of a patient with a PAA secondary to congenital pulmonic valve stenosis which had been rarely published in the literature. Pulmonary valve stenosis causes pulmonary dilation likely due to turbulent blood flow through the pulmonary artery distal to the stenotic region by weakening of the vessel wall. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Aneurysm of the pulmonary artery; review of the literature and report of a case Am Heart J Deterling RA Jr Clagett OT 471 499 34 1947 20266464 2 Acquired pulmonary artery pseudoaneurysms: a pictorial review Br J Radiol Guillaume B Vendrell A Stefanovic X 20160783 90 2017 28337922 3 Pulmonary artery dissection in patients without underlying pulmonary hypertension Histopathology Inayama Y Nakatani Y Kitamura H 435 442 38 2001 11422480 4 Pulmonary artery aneurysms: four case reports and literature review Int J Angiol Theodoropoulos P Ziganshin BA Tranquilli M 143 148 22 2013 24436601 5 Pulmonary artery aneurysm secondary to patent arterial duct and infection: a case report and review Echocardiography Zhang L Li Y Lv Q 1878 1881 35 2018 30267632 6 Pulmonary artery aneurysm: a review Pulmonary Circulation Gupta M Agrawal A Iakovou A 2045894020908780 10 2020 32166017 7 Outcome of surgical repair of pulmonary artery aneurysms: a single-center experience with 38 patients Annals Thorac Surg Reisenauer JS Said SM Schaff HV 1605 1610 1 2017 8 Aneurysms of the pulmonary arteries Chest Bartter T Irwin RS Nash G 1065 1075 94 1988 3053058 9 Acquired peripheral pulmonary artery aneurysms: morphological spectrum of disease and multidetector computed tomography angiography findings cases series and literature review. La Radiol Medica Valente T Abu-Omar A Sica G 664 675 123 2018 10 Extreme dilation of pulmonary artery: a literature review Case Reports Shafiq A Bokhari A Nahin I 2013202223 25 2014 11 Pulmonary artery aneurysm due to severe congenital pulmonic stenosis: case report and literature review Angiology Tami LF McElderry MW 383 390 45 1994 8172386 12 Pulmonary artery aneurysm secondary to congenital pulmonic valve stenosis Southwest Respir Crit care Chron Audra Schwalk MD Berdine G 32 35 5 2017 13 The obscure physiology of poststenotic dilatation: its relation to the development of aneurysms Journal of Thoracic Surgery Holman E 109 133 28 19541 13184533 14 Brief review: pulmonary artery aneurysms and pseudoaneurysms Int J Cardiovascular Imag Kalra-Lall A Donaldson J Martin C 1357 1364 35 2019 15 Congenital and acquired pulmonary artery anomalies in the adult: radiologic overview Radiographics Castaner E Gallardo X Rimola J 349 372 1 2006 16 Aneurysms of the pulmonary artery Circulation Kreibich M Siepe M Kroll J 310 316 131 2015 25601950 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34834 Anesthesiology Pain Management Allergy/Immunology Urticaria After Lidocaine Use for Pecto-Intercostal Nerve Block Muacevic Alexander Adler John R Ambai Vats T 12 Atawala Neel 3 Kalava Arun 4 1 Department of Anesthesiology, Emory University School of Medicine, Atlanta, USA 2 Graduate Medical Education, Northside Hospital Gwinnett, Lawrenceville, USA 3 Medical Education, Mercer University School of Medicine, Savannah, USA 4 Department of Anesthesiology/Pain Medicine, University of Central Florida College of Medicine, Orlando, USA Neel Atawala [email protected] 10 2 2023 2 2023 15 2 e3483410 2 2023 Copyright (c) 2023, Ambai et al. 2023 Ambai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Urticaria within one hour of lidocaine injection is a sign of type I (immediate) hypersensitivity to lidocaine, yet most patients suspected of having a lidocaine allergy do not exhibit urticaria. Aside from being a sign of a rare lidocaine allergy, urticaria can also be a symptom of COVID-19. COVID-19 patients who experience urticaria after receiving lidocaine require careful evaluation to determine the cause. Here, we present a case of a patient exhibiting urticaria one hour after a lidocaine injection for the Pecto-intercostal nerve block to treat COVID-19-induced costochondritis. urticaria case report allergy regional anesthesia lidocaine The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction True immunologically mediated allergic reactions to lidocaine are rare and represent only 1% of all adverse reactions . A commonly seen symptom of true allergic hypersensitivity to lidocaine is an urticarial rash [1-4]. Rashes such as these are not specific to lidocaine allergies. They have been documented in various other disease processes, including cases of COVID-19, obscuring the determination of whether the patient is experiencing a reaction to lidocaine or suffering from the residual effects of a nonallergic process . This is a case report of a patient experiencing urticaria one hour after an injection of lidocaine for a Pecto-intercostal nerve block to treat COVID-19-induced costochondritis. Case presentation Consent to share information regarding this case was obtained directly from the patient. A 38-year-old female with no significant past medical history was diagnosed with COVID-19 in March 2020 and developed left-sided pleurisy and costochondritis five weeks later. This resulted in shortness of breath with exertion, prompting clinical evaluation. Physical exams, multiple laboratory tests, and diagnostic investigations, including pulmonary function tests, chest X-ray, CT angiogram, and xenon gas MRI revealed no findings. The patient continued to experience significant discomfort and presented for evaluation at a transitional pain clinic. Her allergy history was significant only for cat dander, which caused conjunctival injection and wheezing. She had no history of acute or chronic urticaria. She had received lidocaine twice in the past, once for a dental procedure and another time for the removal of plantar warts, both of which were uneventful. Family history of allergic reactions included a father with an allergy to sulfa-containing drugs and a mother with an allergy to cat dander. She had no relevant psychosocial history. During her treatment at the transitional pain clinic, she consented to a left Pecto-intercostal nerve block. This procedure occurred one year after her COVID-19 diagnosis and was performed after cleaning the injection sites with alcohol and using 15 mL of preservative-free 1% lidocaine without epinephrine as the injectate. At no point during the procedure was the patient exposed to latex, chlorhexidine, antibiotics, non-steroidal anti-inflammatory drugs, steroids, opiates, or additives in the lidocaine solution. The patient tolerated the procedure well and experienced no adverse events in the immediate period following the injection. She was subsequently discharged home and developed a skin rash one hour after injection. The rash appeared as numerous, slightly elevated, non-pruritic, erythematous wheals with irregular borders spanning 1-3 cm in length. Her skin findings spanned the left side of her body, extending across her arm, shoulder, chest, neck, jaw, and cheek . The rash lasted one to three hours after the initial lidocaine injection. It did not have associated pruritus, edema, changes in vital signs, anxiety, perioral numbness or tingling, dizziness, sympathetic stimulation signs, psychomotor reactions, vasovagal symptoms, or other signs of systemic toxicity. Because this reaction occurred at home, the patient could not be monitored for changes in vital signs. She reported that the rash resolved on its own after three hours without using any medications. Figure 1 Skin findings one hour after left Pecto-intercostal lidocaine injection. (A) left face, (B) left shoulder, (C) left forearm. An allergen-skin test to guide future local anesthetic administration was recommended. Upon follow-up several months later, no allergen testing was completed. However, the patient had received lidocaine in a different medical setting without experiencing any type of urticarial rash, anaphylactic symptoms, or vasovagal symptoms. Discussion In this case, a patient who was treated with a left Pecto-intercostal nerve block using lidocaine developed an urticarial rash one hour after injection. In evaluating this patient's findings, immediate hypersensitivity (type I), delayed hypersensitivity (type IV), nonallergic hypersensitivity, and IgE-mediated response to COVID-19 infection were all considered. Immediate hypersensitivity reactions occur within one hour and are associated with urticaria in locations away from the lidocaine injection site . They typically occur upon subsequent exposure to an allergen and are dose-independent . Delayed hypersensitivity reactions are experienced between two and three days after exposure and have been shown to exhibit skin findings localized to the site of lidocaine injection . Nonallergic hypersensitivity reactions often occur on first exposure and can be dose-dependent . Characteristics of nonallergic hypersensitivity reactions include widespread exanthematous rashes, psychomotor reactions, and vasovagal symptoms [1, 3-5]. Urticarial rashes related to COVID-19 typically appear in the prodromal and acute periods of COVID-19 infection and are not currently known to appear one year after infection . A previously published case of a 16-year-old female who received a spinal lidocaine injection demonstrated the manner in which lidocaine hypersensitivity may present. The patient developed erythematous plaques away from the injection site on the neck and trunk, as well as mild edema of the eyelids and lips . These symptoms of a hypersensitivity reaction to lidocaine injection appeared within minutes and were later confirmed by positive intradermal skin testing . In another case, a 26-month-old boy underwent a dental procedure involving lidocaine injections into the buccal mucosa for local anesthesia . That patient returned home without complications but later presented to the ED with angioedema at the injection site. Skin prick test with lidocaine was positive after 15 minutes and confirmed a hypersensitivity response to lidocaine. Based on the timing of the case, the patient's presentation after lidocaine injection, distribution of skin findings, and lack of other systemic symptoms, type I hypersensitivity to lidocaine is a rare consideration. It is more likely that the patient experienced an anaphylactoid urticarial reaction to the lidocaine, as this is known to primarily be a dose-dependent reaction, with cutaneous symptoms being the most common presenting feature . Anaphylaxis and anaphylactoid reactions may both present with elevated histamine and tryptase levels. However, histamine has been shown to decline to baseline within 60 minutes, whereas tryptase may stay elevated between 15 minutes to 3 hours . Thus, it may be more clinically useful to check serum tryptase in the acute setting if a true allergy is suspected . Patients suspected of having adverse reactions to lidocaine should be counseled to avoid the class of amino-amide local anesthetics overall. They may benefit from the use of the amino-ester group of local anesthetics instead . If not possible to avoid using lidocaine and other amino-amides, pre-treatment with a local injection of 1% diphenhydramine has been shown to provide an adequate amount of anesthesia for up to 30 minutes, comparable to 1% lidocaine . Additionally, diphenhydramine does not exhibit cross-reactivity with the "caine" anesthetics, eliminating the risk of allergic reactions . Conclusions Symptoms of a true type I hypersensitivity to lidocaine may include urticaria, but the presence of urticaria alone is not diagnostic of a true allergic reaction. When suspected, positive results on skin testing with an allergist can provide a definitive diagnosis. The patient in this case report experienced a rare urticarial reaction after a lidocaine injection that was not challenged with allergen testing. Subsequent administration of lidocaine without the appearance of any allergic symptoms makes it extremely unlikely that she has a true allergy to lidocaine. This case displays the rarity and complexity of attempting to diagnose lidocaine hypersensitivity. To avoid misdiagnosing a patient's lidocaine-related urticaria, it is essential to complete a thorough history and physical exam and understand the characteristics of a true hypersensitivity reaction. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Allergic reactions to local anesthetics 4 2021 2021 2 A pharmacologic review of anaphylaxis Plast Surg Nurs Yunker NS Wagner BJ 183 189 34 2014 25461639 3 Hypersensitivity to local anaesthetics update and proposal of evaluation algorithm Contact Dermatitis Thyssen JP Menne T Elberling J Plaschke P Johansen JD 69 78 59 2008 18759873 4 Risk of immediate-type allergy to local anesthetics is overestimated - results from 5 years of provocation testing in a danish allergy clinic J Allergy Clin Immunol Pract Kvisselgaard AD Mosbech HF Fransson S Garvey LH 1217 1223 6 2018 28988784 5 Twenty years' experience with anaphylaxis-like reactions to local anesthetics: genuine allergy is rare J Allergy Clin Immunol Pract Trautmann A Goebeler M Stoevesandt J 2051 2058 6 2018 29655774 6 Caution in the time of rashes and COVID-19 J Am Acad Dermatol Vesely MD Perkins SH 0 83 2020 7 COVID-19: Cutaneous manifestations and issues related to dermatologic care 4 2021 Feldman S Freeman E 2021 2021 8 [Allergy to lidocaine: case report.] Rev Bras Anestesiol Araujo LM Amaral JL 672 676 54 2004 19471776 9 Hypersensitivity to local anesthetics: a case report J Korean Acad Pediatr Dent Rah Y Lee J Ra J 365 369 31 2017 10 Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients Int Arch Allergy Immunol Sala-Cunill A Cardona V Labrador-Horrillo M 192 199 160 2013 23018683 11 Diphenhydramine as an alternative local anesthetic agent J Clin Aesthet Dermatol Pavlidakey PG Brodell EE Helms SE 37 40 2 2009 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34843 Emergency Medicine Internal Medicine Neurology Simultaneous Presentation of Brainstem and Cerebellar Posterior Reversible Encephalopathy Syndrome With Acute Cerebral Infarction Muacevic Alexander Adler John R Maruyama Hajime 12 Fujikawa Hirohisa 31 Takimiya Ryuichi 14 Sato Hiroki 5 1 Department of Internal Medicine, Suwa Central Hospital, Nagano, JPN 2 Department of Internal Medicine, Fujimi-Kogen Hospital, Nagano, JPN 3 Department of Medical Education Studies, International Research Center for Medical Education, Graduate School of Medicine, The University of Tokyo, Tokyo, JPN 4 Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, JPN 5 Department of Neurosurgery, Suwa Central Hospital, Nagano, JPN Hirohisa Fujikawa [email protected] 10 2 2023 2 2023 15 2 e348435 2 2023 Copyright (c) 2023, Maruyama et al. 2023 Maruyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Posterior reversible encephalopathy syndrome (PRES) and cerebral infarction are both caused by hypertension, but they rarely occur together. If they do coexist, the selection of a management strategy is difficult because of their pathologic differences. Here, we present an uncommon case of brainstem and cerebellar PRES combined with acute lacunar infarction. For this patient, we used an aggressive blood pressure-lowering regimen during the acute phase of his condition. Once the cerebral edema caused by PRES began to improve, antiplatelet therapy was initiated. The treatment was ultimately successful, and the patient was discharged home. A return to work is now planned. Given the rarity of this combination of conditions and a lack of published evidence for management, our report will contribute to the literature concerning the treatment for this combination of conditions. hypertension antiplatelet therapy blood pressure management acute cerebral infarction posterior reversible encephalopathy syndrome (pres) The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Hypertension is a major public health issue and a risk factor for cardiovascular and cerebrovascular diseases throughout the world . Although both cerebral infarction and posterior reversible encephalopathy syndrome (PRES) are caused by poorly controlled hypertension, the two conditions are completely different and rarely occur together. If both develop in the same patient, management becomes challenging . Here, we present a successfully treated case of the brainstem and cerebellar PRES coexisting with cerebral infarction. Case presentation A 53-year-old man with a history of untreated hypertension presented with a lean to the left and a headache. Several hours after the onset of the symptoms, the patient visited our hospital. On examination, his blood pressure and heart rate were 214/145 mmHg and 84 bpm, respectively. A neurologic examination revealed dysarthria; weakness of the left quadriceps and hamstrings, with manual muscle testing of 4/5; and bilateral cerebellar ataxia. Blood tests showed high low-density lipoprotein cholesterol (201 mg/dL) and mildly elevated serum creatinine (1.13 mg/dL). Liver function, fasting blood glucose, and hemoglobin A1c tests were all within the normal range. Cranial magnetic resonance imaging (MRI) produced two significant findings. First, a lesion extending from the right centrum semiovale to the posterior limb of the internal capsule showed a high diffusion-weighted imaging (DWI) signal and a low apparent diffusion coefficient (ADC) signal, indicating an acute-phase lacunar infarction . Second, fluid-attenuated inversion recovery (FLAIR) images and ADC revealed extensive hyperintense lesions in the brainstem and bilateral cerebellar hemispheres, indicating PRES . The patient was admitted for a suspected lacunar infarction coexisting with PRES. Figure 1 Cranial magnetic resonance imaging at admission (A,B) Diffusion-weighted imaging (DWI) shows a high signal, and the apparent diffusion coefficient (ADC) map shows a low signal extending from the right centrum semiovale to the posterior limb of the internal capsule (red arrows). (C,D) Fluid-attenuated inversion recovery (FLAIR) images and (E,F) the ADC map both show a high signal in the pons (yellow arrows) and bilateral cerebellar hemispheres (white arrows). Upon admission, intravenous nicardipine was administered to lower the patient's systolic blood pressure to less than 140 mmHg. On day 11 of admission, the patient's antihypertensive therapy was switched from intravenous nicardipine to oral nifedipine with azilsartan. Considering the risk of hemorrhage from the PRES lesions, antiplatelet agents were not started immediately. On day 4 of admission, FLAIR images on MRI revealed a reduction in the high signal in the brainstem and cerebellum that had suggested PRES ; antiplatelet therapy was therefore initiated. For secondary prevention, rosuvastatin was administered from day 1 of admission. Figure 2 Magnetic resonance imaging of the head during hospitalization (A,B) Cranial magnetic resonance imaging on day 4 of admission. Fluid-attenuated inversion recovery (FLAIR) images show lightening of the high signal in the pons and cerebellum. (C,D) Cranial magnetic resonance imaging on day 21 of admission. On FLAIR images, the high-signal lesions have disappeared. On day 21 of admission, cranial MRI showed clear improvement in the bilateral cerebellar hemispheric and brainstem lesions, a course consistent with PRES . The patient's final management regimen consisted of nifedipine 20 mg, azilsartan 40 mg, aspirin 100 mg, and rosuvastatin 2.5 mg daily, which maintained the patient in stable condition, without recurrence of the PRES and infarction or development of any intracranial hemorrhage. After an intensive course of rehabilitation, the patient was discharged home. Two months after discharge from our hospital, the patient is doing well, with no recurrence. He is planning a gradual return to work. Discussion Reports of the brainstem and cerebellar PRES occurring together with cerebral infarction are few, and only a little evidence for a management strategy has been developed. The present case posits a management approach for this rare condition. PRES is characterized by clinical symptoms such as headache, altered mental status, seizures, and visual abnormalities. Although details of its pathogenesis remain unknown, the precipitating factor is believed to be vasogenic edema. Causes of vasogenic edema include impaired cerebral autoregulation from severe hypertension, vascular endothelial dysfunction from sepsis, bone marrow transplantation and chemotherapy, and increased permeability of the blood-brain barrier related to immune system activation . On imaging, PRES generally presents as subcortical and cortical edema of the cerebral hemispheres, with the parietal and occipital lobes most frequently being involved. However, deep structures and other areas can also be affected. A high signal on T2-weighted MRI and FLAIR sequences is more sensitive for detecting PRES lesions . The hallmark vasogenic edema in PRES presents with a iso-intense signal on DWI and high ADC values. In contrast, the main pathologic change in early cerebral infarction is cytotoxic edema, which presents with marked hyperintensity on DWI and low ADC values . PRES generally has a good prognosis: it is frequently fully reversible within a period of days to weeks if treated early and adequately (i.e., with the removal of the triggering factor and appropriate blood pressure control) . However, PRES can also result in death and permanent neurologic disability . Death can occur as a result of progressive cerebral edema, intracerebral hemorrhage, or underlying disease . Cerebral hemorrhage is reported to occur in about 15% of PRES cases . Microbleeds are reported to occur even more often . Early diagnosis and management of bleeding risks are therefore vital. PRES lesion sites typically include the occipital lobe (98.7%), posterior frontal lobe (78.9%), and temporal lobe (68.4%). Atypical sites, accounting for approximately 4% of lesions, include the cerebellum, basal ganglia, brainstem, and deep white matter . Finding PRES lesions in the brainstem, cerebellum, and basal ganglia without parietal or occipital involvement, as in this case, is rare . However, it is important to note that brainstem and cerebellar PRES can cause acute posterior fossa circulation failure and thus obstructive hydrocephalus . Brainstem lesions are considered a poor prognostic factor . In a previous report with a summary of 16 cases of brainstem PRES, the authors stated that no clear explanation for the mechanism that leads to PRES lesions being more prominent in the brainstem than in the occipital lobes had been presented . However, two hypotheses have been proposed. The first suggests that the distal part of the vertebrobasilar artery system (the parieto-occipital region) might be preserved because of extensive fluid leakage in the brainstem. The second hypothesizes that the preservation of this region relates to its richness in sympathetic nerves and blood flow from the anterior circulation via the posterior communicating artery . The combination of cerebral infarction and PRES is rare, and Table 1 summarizes the few reported cases [2,14-16]. Only one prior case of cerebral infarction combined with brainstem and cerebellar PRES has been published, and the PRES lesion, in that case, was confined to the infratentorial region, as in our patient . In general, the brainstem is not vulnerable to hypertensive conditions, but an unexpectedly rapid elevation of blood pressure might cause a brainstem lesion. In our case, the patient had a history of hypertension. The onset of his cerebral infarction was assumed to cause a sudden elevation in blood pressure, which was thought to lead to the development of PRES. Table 1 Characteristics of patients with posterior reversible encephalopathy syndrome coexisting with cerebral infarction HTN: Hypertension; PRES: Posterior reversible encephalopathy syndrome. Author (year) [Ref.] Patients Site of lesions Treatment Age (years) Sex Past medical history PRES Cerebral infarction Kamada et al. (2014) 46 Male HTN Brainstem, cerebellum Basal ganglia, posterior limb of the internal capsule Antihypertensive medication from day 1 of admission (nicardipine -> combination of five drugs); no antithrombotic therapy Kazahari et al. (2018) 48 Male HTN White matter of the fronto-temporoparietal lobes, pons Corona radiata Antihypertensive medication from day 1 of admission (nicardipine -> amlodipine); aspirin, atorvastatin (start date unknown) Liu and Zhang (2020) 36 Male None Pons, hippocampus Thalamus Nifedipine, aspirin, and atorvastatin from day 1 of admission Suzuki et al. (2022) 66 Male None Cerebral cortex, thalamus Medulla oblongata Nicardipine only on days 1-2 of admission; anticoagulants from day 2 of admission (argatroban -> edoxaban) No clear management strategy for brainstem and cerebellar PRES combined with cerebral infarction has been established. Individually, these conditions have different management strategies. Moreover, the treatments for hypertension and the timing for introducing antithrombotic drugs are controversial when the two conditions are combined. In PRES of the brainstem and cerebellum, bleeding at the lesion site can be fatal; therefore, while choosing the treatment, particular consideration must be given to the risk of bleeding. In our case, the choice was to begin with antihypertensive therapy to treat the PRES. Antithrombotic therapy, a treatment for cerebral infarction, was not initially used. Antithrombotic therapy was initiated after improvement of the cerebellar and brainstem edema was demonstrated on MRI . It has been reported that antihypertensive therapy for acute lacunar infarction does not worsen the functional prognosis . A management strategy that prioritizes blood pressure control to reduce bleeding risk could therefore be appropriate. Furthermore, antithrombotic therapy is believed to increase bleeding in PRES . In reports of PRES with edema and intraparenchymal hemorrhage, the hemorrhage was reported to have occurred in the same location as the edema or within a similar vascular distribution in all patients; hemorrhage was not observed in areas without edema . Thus, in the present case, we initiated antiplatelet drugs after the cerebral edema improved; however, there is still insufficient evidence in this regard, and the risks and benefits should be fully considered in shared decision-making with patients. Conclusions Herein, we report a rare case of PRES coexisting with acute cerebral infarction. Our management strategy was to aggressively lower the blood pressure in the acute phase and to initiate antiplatelet therapy when the vasogenic edema of PRES abated. We hope that this report can be useful to other clinicians encountering this combination of conditions. Additional case reports and further research on this topic are required. The authors thank Dr. Satoshi Mizuma, Department of Internal Medicine, Suwa Central Hospital, for his contribution to patient care. The authors also thank Enago for the English language review. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 High blood pressure and cardiovascular disease Hypertension Fuchs FD Whelton PK 285 292 75 2020 31865786 2 Posterior reversible encephalopathy syndrome coexists with acute cerebral infarction: challenges of blood pressure management Quant Imaging Med Surg Liu L Zhang L 2356 2365 10 2020 33269231 3 Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema AJNR Am J Neuroradiol Bartynski WS 1043 1049 29 2008 18403560 4 Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome: clinical and radiological considerations Front Neurol Pilato F Distefano M Calandrelli R 34 11 2020 32117007 5 Imaging of atypical and complicated posterior reversible encephalopathy syndrome Front Neurol Saad AF Chaudhari R Wintermark M 964 10 2019 31551919 6 A reversible posterior leukoencephalopathy syndrome N Engl J Med Hinchey J Chaves C Appignani B 494 500 334 1996 8559202 7 Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions Lancet Neurol Fugate JE Rabinstein AA 914 925 14 2015 26184985 8 Imaging characteristics associated with clinical outcomes in posterior reversible encephalopathy syndrome Neuroradiology Schweitzer AD Parikh NS Askin G 379 386 59 2017 28289809 9 Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features AJNR Am J Neuroradiol Hefzy HM Bartynski WS Boardman JF Lacomis D 1371 1379 30 2009 19386731 10 The clinical and radiological spectrum of posterior reversible encephalopathy syndrome: the retrospective Berlin PRES study J Neurol Liman TG Bohner G Heuschmann PU Endres M Siebert E 155 164 259 2012 21717193 11 Hypertensive posterior reversible encephalopathy syndrome causing posterior fossa edema and hydrocephalus J Clin Neurosci Grossbach AJ Abel TJ Hodis B Wassef SN Greenlee JD 207 211 21 2014 24126039 12 Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images AJNR Am J Neuroradiol Covarrubias DJ Luetmer PH Campeau NG 1038 1048 23 2002 12063238 13 Hypertensive brainstem encephalopathy without parieto-occipital lesion two case reports Neurol Med Chir (Tokyo) Doi Y Kimura F Fujiyama T 75 79 46 2006 16498216 14 Posterior reversible encephalopathy syndrome with lacunar infarction: a case report [Article in Japanese] Tokushima Red Cross Hospital Medical Journal Kamada S Kiuchi T Hajime KN 35 38 19 2014 15 Symptomatic lacunar infarct accompanied with posterior reversible encephalopathy syndrome: a case report Tokai J Exp Clin Med Kazahari S Honma K Kawamura R Uesugi T Nagata E Takizawa S 64 67 43 2018 29961934 16 A case of medullary infarction with posterior reversible encephalopathy syndrome [Article in Japanese] Jpn J Stroke Suzuki I Otsuka Y Furuya Y Akazawa S Takeuchi Y Yoneda Y Kageyama Y 295 299 44 2022 17 Imaging pattern of intracranial hemorrhage in the setting of posterior reversible encephalopathy syndrome Neuroradiology Sharma A Whitesell RT Moran KJ 855 863 52 2010 19956935 18 Antihypertensive therapy in acute ischemic stroke: where do we stand? J Hum Hypertens Georgianou E Georgianos PI Petidis K Athyros VG Sarafidis PA Karagiannis A 799 807 32 2018 30232398 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34835 Internal Medicine Medical Education Infectious Disease Tick-Borne Rhabdomyolysis: A Rare Case of Rhabdomyolysis and Acute Kidney Injury Due to Anaplasmosis Muacevic Alexander Adler John R Dogra Megha 1 Thakur Manish 2 Kumar Amrat 1 Thakur Garima 3 1 Internal Medicine, Mary Imogene Bassett Hospital, Cooperstown, USA 2 Internal Medicine, Cayuga Medical Center, Ithaca, USA 3 Internal Medicine, Indira Gandhi Medical College, Shimla, IND Megha Dogra [email protected] 10 2 2023 2 2023 15 2 e3483510 2 2023 Copyright 2023, Dogra et al. 2023 Dogra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Anaplasmosis is a tick-borne illness commonly seen in the northeastern states of the United States. The most common presenting signs are fever, malaise, and body aches accompanied by leukopenia, thrombocytopenia, and transaminitis. Rhabdomyolysis and acute kidney injury are rare presentations that can lead to significant morbidity. We present the case of a patient who presented with non-specific symptoms of malaise, fatigue, and body aches and was found to have rhabdomyolysis and acute kidney injury on laboratory workup. A presumptive diagnosis of anaplasmosis was made, and the patient was started on treatment for the same. The patient recovered successfully. Our case highlights the rare presentation of anaplasmosis with rhabdomyolysis and acute kidney injury. Physician awareness is needed for early diagnosis and preventing morbidity. tick borne infections infectious disease pathology infectious disease aki anaplasmosis The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Anaplasmosis is a tick-borne disease caused by the bacterium Anaplasma phagocytophilum. This disease was previously known as human granulocytic ehrlichiosis (HGE). Constitutional symptoms, leukopenia, thrombocytopenia, and elevated liver function tests are known to be the typical presentations . Rhabdomyolysis and acute kidney injury have been rarely reported as the initial presenting complaints. Case presentation A 69-year-old male presented to the hospital in October with malaise, fatigue, dizziness, and body aches. He did not have any known chronic medical conditions, was not taking any chronic medications, and was a resident of upstate New York. On arrival, vitals were: blood pressure of 104/84 mm Hg, a pulse of 98 beats per minute, a temperature of 36.2C (97.1 F), respiratory rate of 20 per minute, and SpO2 of 95% on room air. There was no rash or eschar. The following abnormalities were discovered during the lab workup: high-sensitivity Troponin I of 141.4 pg/ml (ref range = 20 pg/ml), creatine phosphokinase (CPK) of 24,078 U/L (122-218 U/L), creatinine (Cr) of 1.3 (baseline Cr of 0.8), blood urea nitrogen (BUN) of 30 mg/dl (7-25 mg/dl), bicarbonate of 19 mmol/L (21-31 mmol/L). The patient did not have any complaints of chest pain. No history of known coronary artery disease. The electrocardiogram showed a normal sinus rhythm with no changes to suggest ischemia. An echocardiogram showed a left ventricular ejection fraction of 55%and no wall motion abnormalities. The patient denied having any recent falls, new medication use, or seizure episodes. He was started on intravenous fluids. Lab workup on the second day of admission showed worsening leukopenia (1.5 x 10E3 cells/uL), thrombocytopenia (25 x 10E3 cells/uL), and Transamnitis (Aspartate aminotransferase/alanine aminotransferase: 442/100, alkaline phosphatase: 61, total bilirubin: 1.3). Given the high prevalence of tick-borne illnesses in the geographic location, polymerase chain reaction (PCR) for tick-borne diseases was obtained. While waiting for the PCR results, the patient was started on Doxycycline 100 mg twice daily. The following day, the patient reported improvement in his symptoms, which was accompanied by an improvement in his lab abnormalities. Table 1 shows laboratory workup on day 1, day 2, and day 4. Table 1 Laboratory workup on days 1, 2, and 4 CPK:Creatine phosphokinase, CO2:Bicarbonate, BUN:Blood urea nitrogen, ALT:Alanine transaminase, AST:Aspartate aminotransferase, MCV:Mean corpuscular volume, MCH:Mean corpuscular hemoglobin, MCHC:Mean corpuscular hemoglobin concentration Investigations Day 1 Day 2 Day 4 Reference Ranges Unit Troponin I 141.4 138.2 120 <= 20.0 pg/ml CPK 24,078 19,515 997 122-218 U/L Sodium 132 136 139 136-145 mmol/l Potassium 4 3.8 3.6 3.5-5.1 mmol/l Chloride 102 109 113 98-110 mmol/l Glucose 109 105 83 70-139 mg/dl CO2 19 20 19 21-31 mmol/l Anion gap 11 7 7 6-14 mmol/l BUN 30 27 24 7-25 mg/dl Creatinine 1.3 0.9 0.8 0.7-1.3 mg/dl ALT 321 442 383 7-72 U/L AST 67 100 90 13-39 U/L Alkaline phosphatase 53 61 54 34-104 U/L Total bilirubin 0.8 1.3 0.9 0.3-1.0 mg/dl white cell count 4.9 1.5 10.2 3.7-10.6 x 10E3 cells/uL hemoglobin 14.2 13.2 13 11.5-18.0 g/dl hematocrit 42.2 38.9 36.8 35.0-50.0 % MCV 89.8 89.6 86.8 81.0-99.0 fL MCH 30.2 30.4 30.3 27-33.5 pg MCHC 33.6 33.9 34.8 31.5-35.5 g/dl platelet count 47 25 39 140-425 x 10E3 cells/uL Serial troponins were138.2, 120 pg/ml, CPK improved with hydration, and Creatinine improved to 0.8. On day four of admission, PCR resulted positive for anaplasmosis phagocytophilum, which confirmed the suspicion of anaplasmosis, as shown in Table 2. Table 2 Tick-borne panel polymerase chain reaction result Component Result Babesia microti negative Babesia duncani negative Babesia divergens/MO-1 negative Anaplasma phagocytophilum positive Ehrlichia chaffeensis negative Ehrlichia ewingii/canis negative Ehrlichia muris eauclairensis negative Borrelia miyamotoi PCR, B negative The patient was discharged with instructions to complete 10 days of doxycycline. After two weeks, the patient was evaluated in the clinic and had a complete resolution of symptoms, as well as normalization of lab abnormalities. Discussion Anaplasmosis is a systemic, tick-borne illness. In the eastern United States, the black-legged tick (Ixodes scapularis) and the western coast black-legged tick (Ixodes pacificus) are the primary vectors. Ixodes scapularis is also known to transmit other pathogens (e.g., Borrelia burgdorferi), and co-infections have been reported. White-tailed deer and white-footed mice are the most common reservoirs. Less commonly, there have been cases of disease transmission by blood transfusion as well as organ transplant . Anaplasmosis was first recognized as a human disease in the mid-1990s and became nationally notifiable by 1999. The number of cases reported to the centers for disease control and prevention (CDC) annually has been steadily increasing since the disease became reportable. There were 348 reported cases in 2000, followed by 5,762 in 2017 and 5,655 in 2019 . In the United States of America (USA), the highest incidence has been reported in the northeastern states, including Connecticut, New York, Rhode Island, and Wisconsin . Figure 1shows the annual incidence of anaplasmosis per million population reported in 2019. Figure 1 Annual incidence (per million population) of reported Anaplasmosis in United States Adapted from the Centers for Disease Control and Prevention website . This geographic location corresponds to the prevalence of ticks. The peak seasons of transmission coincide with seasonal variations due to an increase in arthropod vectors and vertebrate host reservoirs . Most cases are seen between June and November. Two peaks are generally seen, with the first peak occurring during June-July and a smaller peak during October-November.Simultaneous infections with Babesia and B. burgdorferi have been reported after a single tick bite, as the tick I. scapularis is a known vector for both of these organisms . Patients are known to develop signs of illness within one to two weeks of the tick bite. The typical symptoms include fever, malaise, myalgia, and headache, and are seen in 25% to 50%of the patient population. The clinical manifestations can range from mild illness to severe disease, including septic shock. Patients with compromised immunity (old age, immunosuppressive drugs, malignancy, chronic illness) are more likely to develop severe disease . Severe diseases with complications, including acute kidney injury, rhabdomyolysis, disseminated intravascular coagulopathy, and acute respiratory distress syndrome, require hospitalization and intensive care unitadmission. Rhabdomyolysis and acute kidney injuryare rarely encountered complications of anaplasmosis. On review of the available literature, two instances with similar presentations have been reported. Jeong Min Cho et al. describea patient who presented with systemic signs of rickettsial disease and was found to have rhabdomyolysis and AKI on lab work, which resolved with 10 days of doxycycline . Zainab Shahid et al. describea case of a 72-year-old male who was suspected to have septic arthritis and was found to have rhabdomyolysis and AKI on workup. He later tested positive for Anaplasmosis and responded well to doxycycline . The mechanism of rhabdomyolysis remains unknown. Increased activation of macrophages and increased release of cytokines are considered to be associated with anaplasmosis-induced rhabdomyolysis . A presumptive diagnosis of Anaplasmosis can be made in patients with appropriate epidemiologic exposures and unexplained systemic febrile illness with no alternative explanation. Given the risk for rapid progression to severe systemic disease, the CDC recommends starting treatment whenever the infection is clinically suspected without waiting for definitive diagnostic test results. PCR, serology, and peripheral blood smear examination are all definitive tests. PCR-based testing has high sensitivity and specificity during the first week of an illness . A peripheral blood smear can help identify morulae in the neutrophils, which are seen in 20%to 80%of patients . Serological tests measure titersof specific immunoglobulin M (IgM) and immunoglobulin G (IgG) levels, and a definitive diagnosis requires at least a fourfold change in the IgG titer between the acute and convalescent stages, with at least one of the IgG titers being at least 1:64 to 1:80 . The treatment of choice for both adult and pediatric populations is doxycycline. For pregnant patients, rifampin is an alternative treatment option . The CDC recommends 100 mg of doxycycline twice daily for 10 to 14 days to cover the possibility of concurrent Lyme disease infection. Within the first 24-48 hours after starting antimicrobial therapy, there is a rapid clinical response . Conclusions Anaplasmosis can manifest as a mild, self-limiting illness in healthy individuals or as a severe disease in patients with risk factors for diminished host defense mechanisms, like old age, an immunosuppressed state, human immunodeficiency virus infection, organ transplantation, and cancer. In rare cases, it can present with rhabdomyolysis and acute kidney injury. Our case highlights the importance of making a presumptive diagnosis of anaplasmosis based on constitutional symptoms and laboratory abnormalities like leukopenia, thrombocytopenia, and transaminitis in patients living in endemic areas and starting empiric treatment while awaiting confirmatory results, which can lead to rapid improvement and resolution of the condition. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Human granulocytic anaplasmosis Infect Dis Clin North Am Bakken JS Dumler JS 341 355 29 2015 25999228 2 Transfusion-transmitted anaplasmosis from a leukoreduced platelet pool Transfusion Fine AB Sweeney JD Nixon CP Knoll BM 699 704 56 2016 26645855 3 Ehrlichiosis and Anaplasmosis among Transfusion and Transplant Recipients in the United States Emerg Infect Dis Mowla SJ Drexler NA Cherry CC Annambholta PD Kracalik IT Basavaraju SV 2768 2775 27 2021 34670661 4 Centers for Disease Control and Prevention (CDC): Anaplasmosis 1 2023 2021 5 Tick-borne emerging infections: Ehrlichiosis and anaplasmosis Clin Lab Med Ismail N McBride JW 317 340 37 2017 28457353 6 "Ticking bomb": The impact of climate change on the incidence of Lyme disease Can J Infect Dis Med Microbiol Dumic I Severnini E 5719081 2018 2018 30473737 7 Epidemiology and impact of coinfections acquired from Ixodes ticks Vector Borne Zoonotic Dis Belongia EA 265 273 2 2002 12804168 8 Human granulocytic anaplasmosis combined with rhabdomyolysis: a case report BMC Infect Dis Cho JM Chang J Kim DM Kwak YG Cho CR Song JE 1184 21 2021 34823480 9 Rhabdomyolysis: An unusual complication of anaplasmosis Jr Hos Med Shahid Z Golamari R Cai A Hussein R Jain R 2020 10 Human granulocytic anaplasmosis and macrophage activation Clin Infect Dis Dumler JS Barat NC Barat CE Bakken JS 199 204 45 2007 17578779 11 Evaluation of a novel high-definition PCR multiplex assay for simultaneous detection of tick-borne pathogens in human clinical specimens J Clin Microbiol Shakir SM Mansfield CR Hays ED Couturier MR Hillyard DR 58 2020 12 Serial measurements of hematologic counts during the active phase of human granulocytic ehrlichiosis Clin Infect Dis Bakken JS Aguero-Rosenfeld ME Tilden RL 862 870 32 2001 11247709 13 Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis United States: a practical guide for physicians and other health-care and public health professionals MMWR Recomm Rep Chapman AS Bakken JS Folk SM 1 27 55 2006 14 The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America Clin Infect Dis Wormser GP Dattwyler RJ Shapiro ED 1089 1134 43 2006 17029130 |
Signal Transduct Target Ther Signal Transduct Target Ther Signal Transduction and Targeted Therapy 2095-9907 2059-3635 Nature Publishing Group UK London 36906601 1356 10.1038/s41392-023-01356-0 Research Highlight Tumor-draining lymph node-derived tumor-specific memory CD8+ T cells: a key player in PD-1/PD-L1 immunotherapy Yin Enzhi 12 Sun Nan [email protected] 12 He Jie [email protected] 12 1 grid.506261.6 0000 0001 0706 7839 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 2 grid.506261.6 0000 0001 0706 7839 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 11 3 2023 11 3 2023 2023 8 1111 12 2022 10 1 2023 5 2 2023 (c) The Author(s) 2023 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Subject terms Cancer microenvironment Immunotherapy issue-copyright-statement(c) The Author(s) 2023 pmcA new study by Huang et al. in Cell identified the presence of tumor-specific memory CD8+ T cells in tumor-draining lymph nodes (TdLNs) and confirmed the critical role of this population in PD-1/PD-L1 immune checkpoint therapy for cancer.1 The work enriched our understanding of tumor-specific CD8+ T cell subsets and further refined the spatiotemporal mechanism of the antitumor effects of PD-1/PD-L1 immune checkpoint blockade (ICB). PD-1 and PD-L1 ICB have made remarkable achievements in antitumor therapy. A traditional theory represents the major mechanism by which PD-1/PD-L1 ICB reactivates exhausted CD8+ T cells (TEX) in tumor microenvironment (TME), thereby restoring the autologous antitumor immunity.2 However, this theory cannot explain why only a portion of TEX can response to PD-1/PD-L1 ICB and even "cold" tumors responses to ICB. More recently, accumulating studies point out that immune microenvironment of TdLNs may be a theoretical supplement for TME.3 At present, the study on the role of TdLNs in immunotherapy has just started. Huang's work provides us with a new perspective on studying TdLNs. Utilizing orthotopic and subcutaneous tumor mouse models, Huang et al. detected a group of memory CD8+ T cells in TdLNs that expressed TCF1+ -1low. This group of identified CD8+ T cells was consistent in features of memory T cells, such as high expression of canonical memory-associated markers (CD127, CD122, and CD62L), semblable transcriptome and epigenome characteristics, as well as low expression of PD-1. Therefore, they named these cells tumor draining lymph node derived tumor-specific memory T cells (TdLN-TTSM). Significantly, compared with progenitor of exhausted T cells (TPEX) in TdLN and TME, TTSM had a greater proliferation potential comparable to that of memory cells and exhibit an increased capability on antitumor. Remarkably, authors next demonstrated that TdLN-TTSM also existed in tumor draining lymph nodes from patients who suffered hepatocellular carcinoma. According to T cell receptor clonal comparison and pseudotime trajectory analysis, TdLN-TTSM showed a developmental trajectory of TPEX cells differentiated into tumor infiltrates and exhausted T cells, suggesting that TdLN-TTSM may also play an important antitumor role in cancer patients. To further investigate the antitumor effects of TdLN-TTSM, TdLN-TTSM and other two tumor-specific CD8+ T cell subsets including TME-TEX and TPEX were adoptively transferred into tumor-bearing mice respectively. TdLN-TTSM cells showed the most significant effect on inhibiting tumor growth. Notably, TdLN-TTSM was shown to be a key response cell for PD-1/PD-L1 ICB therapy compared with TdLN-TPEX cells through both in vivo and in vitro experiments. Further, lymphadenectomy resulted in the failure of PD-L1 blocking antibody-mediated immunotherapy before or during PD-L1 ICB treatment. However, this effect was able to be restored by denovo transfusion of TdLN-TTSM cells, which further verified that TdLN-TTSM was a bona fide cell subgroup responding to PD-L1 ICB. In summary, these data established the presence and role of the TdLN-TTSM in generating primary antitumor immune responses following anti-PD-1/PD-L1 ICB, besides providing insights into the spatio-temporal mechanism of PD-1/PD-L1 ICB against tumor (Fig. 1a). Importantly, this work led us to profound reflection.Fig. 1 a The mechanism of tumor draining lymph nodes-tumor specific memory T cells (TdLN-TTSM) response to PD-1/PD-L1 immune checkpoint blocking. As a precursor of TdLN-progenitor of exhausted T cells (TPEX), TTSM is located upstream of differentiation and persistently recruit various exhausted T cell subpopulation located in the tumor microenvironment (TME). The antitumor effect of PD-1/PD-L1 antibody is dependent on TTSM cell subsets. The prerequisite for antitumor effect of PD-1/PD-L1 antibody is to first amplify TTSM cell in draining lymph nodes, meanwhile promoting the differentiation into TPEX which subsequently differentiate into exhausted CD8+ T cells (TEX). Finally, the progeny of these cells enters TME through peripheral circulation and plays an antitumor role. Created with BioRender.com. b A summary of published studies on stemlike memory CD8+ T cells which have similar functions to TdLN-TTSM. TdLN-TTSM tumour-draining lymph nodes-tumor specific memory T cells, N.S. nothing special, TSL stem-like T cells, LCMV lymphocytic choriomeningitis virus, NSCLC non-small cell lung cancer, TPEX progenitor of exhausted T cells, ICB immune checkpoint blockade First, to dig into stemlike memory CD8+ T cells, we summarized previous literature that confirmed the presence of intra or extra-tumoral stemlike memory T cell which had broadly similar functions to TdLN-TTSM (Fig. 1b). In contrast to cells from other research, TdLN-TTSM were shown to be free of exhaustion associated epigenetic scars, suggesting this population was a steady resident in TdLN. It is well known that tumor escape caused by T cell exhaustion is the main cause limiting the efficacy of chimeric antigen receptor (CAR) T cell therapy.4 This study implied that TdLN-TTSM may be a promising candidate of CAR T cell therapy, correspondingly, TdLN which removed by surgery may become a more suitable source of CAR T cell in place of peripheral blood (PB). Next, as a bona fide cell responding to PD-1/PD-L1 ICB, proportion of TTSM in TdLN may be a novel predictable biomarker of effect after ICB to enable identification of patients in need of alternative treatment strategies. Future studies should focus on confirming the particular marker and existence of TTSM on various tumor types, as well as investigating a potential role in progression and outcome of different pathological types and stages. Moreover, the percentage of TTSM in TdLN, non-TdLN and PB should also be detected in future work. More importantly, based on the impressive data from adoptive transfer study of TdLN-TTSM in animal model, TdLN-TTSM was a potential choice of adjuvant or combination therapy. Clinical application of immunotherapy by utilizing this population from TdLN should be more explored to potentiate ICB therapy in a real-world setting. Last not least, this work led us to a renewed look at the effect of TdLN in oncological surgery. To prevent the spread of tumor cells in patients undergoing surgical treatment, complete lymphadenectomy has been well accepted as a traditional clinical practice. However, assisted by the development of ICB therapy, especially PD-1/PD-L1 ICB, reassessment of optimal strategy of lymphadenectomy is clearly warranted. A study from Fear et al. indicated that LN resection may impair the efficacy of adjuvant immunotherapy in a pre-clinical model.5 According to Huang's research, we inferred leaving tumor-free lymph nodes intact during operation may enable patients to benefit from PD-1/PD-L1 ICB therapy. Further study needs to be performed to verify speculation mentioned above. Acknowledgements This work was supported by the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-050). Author contributions E.Y. participated in writing the manuscript and drawing the figure. N.S. and J.H. participated in the research design and oversaw the study. All authors have read and approved the article. Competing interests The authors declare no competing interests. References 1. Huang Q The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes Cell 2022 185 4049 4066.e25 10.1016/j.cell.2022.09.020 36208623 2. Ribas A Wolchok JD Cancer immunotherapy using checkpoint blockade Science 2018 359 1350 1355 10.1126/science.aar4060 29567705 3. Connolly KA A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response Sci. Immunol. 2021 6 eabg7836 10.1126/sciimmunol.abg7836 34597124 4. Chow A Perica K Klebanoff CA Wolchok JD Clinical implications of T cell exhaustion for cancer immunotherapy Nat. Rev. Clin. Oncol. 2022 19 775 790 10.1038/s41571-022-00689-z 36216928 5. Fear VS Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used Cancer Immunol. Immunother. 2021 70 3249 3258 10.1007/s00262-021-02934-3 33835222 |
J Med Case Rep J Med Case Rep Journal of Medical Case Reports 1752-1947 BioMed Central London 36906591 3813 10.1186/s13256-023-03813-4 Case Report Melanoma of unknown primary origin with skeletal muscle metastasis: a case report Andrianandrasana Ny Ony Tiana Florence 1 Randrianarisoa Rova Malala Fandresena [email protected] 2 Navoly Patty 1 Ranaivoson Mirana Andoniaina Christiana 1 Vololontiana Hanta Marie Danielle 2 Rafaramino Florine 1 1 Oncology Department, Joseph Ravoahangy Andrianavalona Hospital, Antananarivo, Madagascar 2 Department of Internal Medicine, Joseph Raseta Befelatanana Hospital, Antananarivo, Madagascar 12 3 2023 12 3 2023 2023 17 9015 7 2022 8 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Melanoma is usually discovered from an irregular skin patch or a modification of a preexisting patch. Cutaneous and lymph node metastases are common. Muscle metastases are rare. We report a case of melanoma with infiltration of the gluteus maximus, which had normal dermatological examination. Case presentation A 43-year-old Malagasy man with no history of skin surgery was admitted with progressively worsening dyspnea. On admission, he presented with superior vena cava syndrome, painless cervical lymphadenopathy, and a painful swelling in the right buttock. Skin and mucous membrane examination did not reveal any abnormal or suspicious lesions. The biology was limited to a C-reactive protein of 40 mg/L, a white blood cell count of 23 G/L, and a lactate dehydrogenase level of 1705 U/L. The computed tomography scan showed several lymphadenopathies, compression of the superior vena cava, and a tissue mass at the expense of the gluteus maximus. Cervical lymph node biopsy and cytopuncture of the gluteus maximus were consistent with a secondary melanoma location. A stage IV melanoma of unknown primary origin, and with stage TxN3M1c associated with lymph node metastases and extension to the right gluteus maximus, was suggested. Conclusions Melanoma of unknown primary origin accounts for 3% of diagnosed melanomas. Diagnosis is difficult in the absence of a skin lesion. Patients are diagnosed with multiple metastases. Muscle involvement is unusual and may suggest a benign pathology. In this context, biopsy remains essential for diagnosis. Keywords Biopsy Melanoma Melanoma of unknown primary origin Muscle metastasis issue-copyright-statement(c) The Author(s) 2023 pmcBackground Melanoma is one of the most aggressive forms of skin cancer, accounting for about three-quarters of all deaths. Over the past two decades, the incidence of melanoma has been steadily increasing . According to the Global Cancer Observatory, the incidence was 3.4 cases per 100,000 population in 2020, with 57,043 deaths . The diagnosis of melanoma is usually made in the presence of an irregular skin patch, or a change in a preexisting patch. The diagnosis is then based on histological examination. Cutaneous and lymph node metastases are common. Hematogenous spread is possible, often involving the lungs, liver, and brain . Striated muscle metastases are unusual . In the absence of a skin lesion, melanoma represents a diagnostic challenge that can delay therapeutic management. We report a case of melanoma with infiltration of the right gluteus maximus, which had a normal dermatological examination. Our objectives are to discuss the frequency, pathophysiological mechanism, and prognosis of this type of melanoma in relation to the literature. Case presentation A 43-year-old man of Malagasy nationality with phototype V (Fitzpatrick) skin was admitted to the oncology department for dyspnea, which had been evolving for a few weeks with progressive worsening. He reported dysphonia, dysphagia, and associated episodes of dry cough. He had asthenia and weight loss without fever. He was followed by the thoracic surgery team for a right cervical lymphadenopathy, which had been evolving for 4 months and for which the histological result of the biopsy was pending. He had a history of alcoholism and chronic weaned smoking. He had no history of skin pigmentation or skin surgery, and no personal or family history of cancer. On admission, hemodynamic parameters were stable. General condition was impaired with a World Health Organization performance status score of 3. Examination revealed facial edema and venous collateral circulation in the neck. He had painless right cervical lymphadenopathy and a swelling in the right buttock that was painful to palpation and firm in consistency (Fig. 1). Careful examination of the skin and mucous membranes did not reveal any abnormal or suspicious lesions. The rest of the examination was normal.Fig. 1 Muscle swelling in the patient's right buttock The blood count showed a white blood cell count of 23 g/L with a predominance of neutrophils. The C-reactive protein was 40 mg/L. Serum ionogram, calcium, and creatinine levels and liver function tests were normal. Human immunodeficiency virus (HIV) and hepatitis B and C serologies were negative. The lactate dehydrogenase level was 1705 U/L. The carcinoembryonic antigen test was negative. The thoracic-abdominal-pelvic computed tomography scan revealed cervical, mediastinal, and retroperitoneal lymphadenopathy and compression of the superior vena cava (Fig. 2). The mass in the right buttock was well-limited and heterogeneous, measuring 63 x 127 mm, and was located at the expense of the gluteus maximus muscle with low enhancement (Fig. 3).Fig. 2 CT scan with injection in axial (A) and coronal (B) sections. Mediastinal lymph node complex and compression of the right superior vena cava Fig. 3 CT scan in axial (A) and coronal (B) sections. Mass at the expense of the gluteus maximus muscle The result of the histological examination of the cervical lymph node biopsy showed invasion of the lymph node and capsular architecture by globular cells with abundant cytoplasm, cytonuclear atypia, and melanin pigments (Fig. 4). A cytopuncture of the gluteus maximus was performed and cytology showed an infiltration of neutrophils and macrophages, tattooed with melanin pigments.Fig. 4 Histology of lymph node biopsy. Cell infiltration and melanin pigments [hematoxylin and eosin (HE) x 40] BRAF V600 mutation testing could not be performed due to the technical platform. A stage IV malignant melanoma with lymph node metastases and extension to the right gluteus maximus was suggested. No primary skin site was identified. This is equivalent to stage TxN3M1c. The dyspnea was related to the superior vena cava syndrome, secondary to lymph node compression. A brain scan was performed and showed no secondary lesions. Corticosteroid therapy with methylprednisolone and preventive anticoagulation with enoxaparin were taken for superior vena cava syndrome. After multidisciplinary discussion, mediastinal radiotherapy for decompression was started in the first instance. Treatment with dacarbazine was planned, depending on the availability of chemotherapy molecules. The short-term course was marked by rapid regression of the superior vena cava syndrome and improvement in respiratory symptomatology. No suspicious skin patches appeared during follow-up. Discussion and conclusions In 2019, Andrianarison et al. reported 47 cases of skin cancer over an 8-year period in Madagascar. Squamous cell carcinoma was predominant, followed by melanoma, found in 17 cases (37%) and 10 cases (21%), respectively . The rarity of melanoma is explained by the limited number of diagnostic and therapeutic centers, underestimating the data. It is also explained by the darker skin (phototype V and VI) of the Malagasy population, making them less likely to develop melanoma. Melanoma is an aggressive melanocyte tumor with easy and early metastasis. In the case of a metastatic melanoma, a primary lesion must be rapidly identified to allow tumor classification and therapeutic orientation. Assessment should include a full dermatological examination and anorectal, genital, and ophthalmological examination. The primary lesions commonly present as skin, mucous membrane, or ocular lesions. In some cases, it is not identified and is referred to as a melanoma of unknown primary (MUP) origin. The first entity of MUP was proposed by Das Gupta et al. in 1963 . It is defined by the presence of histologically confirmed melanoma in skin/subcutaneous tissue, lymph nodes, or viscera, without manifestation of a primary lesion. MUP is rare, accounting for approximately 3% of diagnosed melanomas . It usually occurs in people in their 40s and 50s, with a male predominance. The pathophysiological mechanism of MUP is not fully understood. Two hypotheses have been suggested: complete spontaneous regression of the primary lesion after metastasis and primary origin from ectopic melanocytes in lymph nodes or viscera . The spontaneous regression hypothesis is the most supported, secondary to an immunological response . Metastases from MUP may be subcutaneous, lymph node, or visceral . Lymph node metastases are the most common, occurring in 60% of cases. Muscle metastases are rare and solitary forms occur in 0.8% of cases . This low incidence may be attributed to the hostile environment of the muscles for cancer progression. In small series and single case reports, muscle metastases from melanoma often manifest as a palpable and painful mass. The paravertebral and proximal limb muscles are most affected . Some cases were initially misdiagnosed as a lipoma . However, the certainty of diagnosis is anatomopathological, obtained from a muscle or lymph node biopsy. Due to the lack of precision in the American Joint Committee on Cancer staging system, the authors classified MUP as stage III or IV . Patients with lymph node, skin/subcutaneous, or soft tissue metastases are classified as stage III. Other forms are classified as stage IV. In our case, the melanoma was classified as stage IV. According to the TNM staging, our case can be classified as TxN3M1c. The prognosis of MUP has been shown to be better than melanoma of known origin at the corresponding stage . In other studies, the clinical outcome is worse for patients with MUP . These results remain inconclusive as the data are contradictory. Furthermore, treatment depends on the staging of the lesion and is generally similar in both forms of melanoma. The diagnosis of melanoma is difficult in the absence of a skin lesion. MUP is thus evoked. Patients are diagnosed with subcutaneous, lymph node, or visceral metastases. Invasion of striated muscles is rare in melanoma, but also in cancer in general. Muscle metastases usually present as a painful mass and may suggest a benign pathology. Biopsy plays an important role in the certainty of diagnosis and should be performed systematically for any adenopathy or muscle mass. Abbreviation MUP Melanoma of unknown primary Acknowledgements The authors would like to thank all the staff of the Oncology, Thoracic Surgery, Pathological Anatomy and Cytology and Medical Imaging departments of the Joseph Raseta Befelatanana Hospital, Antananarivo, Madagascar. Author contributions ANOTF: patient follow-up, visualization, critical revision. RRMF: patient follow-up, writing. NP, RMAC: patient follow-up, clinical data collection. VHMD, RF: validation, monitoring. All authors read and approved the final manuscript. Funding The authors declare that they do not have a grant from any specific organization. Availability of data and materials All data generated are included in this published article. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no conflicts of interest. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. O'Neill CH Scoggins CR Melanoma J Surg Oncol 2019 120 5 873 881 10.1002/jso.25604 31246291 2. World Health Organization. Melanoma of skin. Global Cancer Observatory 2020. Accessed 02 Jul 2022. 3. Gershenwald JE Scolyer RA Hess KR Sondak VK Long GV Ross MI Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual Cancer J Clin 2017 67 6 472 492 10.3322/caac.21409 4. Gomez-Leon N Pacheco-Barcia V Ballesteros AI Fraga J Colomer R Friera A Skeletal muscle and solitary bone metastases from malignant melanoma: multimodality imaging and oncological outcome Melanoma Res 2018 28 6 562 570 10.1097/CMR.0000000000000466 29975212 5. Andrianarison M Tika L Ranaivo IM Razakanaivo M Ramarozatovo LS Rafaramino F Pan Afr Med J 2019 34 167 10.11604/pamj.2019.34.167.19269 32153707 6. Das Gupta T Bowden L Berg JW Malignant melanoma of unknown primary origin Surg Gynecol Obstet 1963 117 341 345 14080349 7. Verver D van der Veldt A van Akkooi A Verhoef C Grunhagen DJ Louwman WJ Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population-based study Int J Cancer 2020 146 1 26 34 10.1002/ijc.32229 30801710 8. Song Y Karakousis GC Melanoma of unknown primary J Surg Oncol 2019 119 2 232 241 10.1002/jso.25302 30481368 9. Cervinkova M Kucerova P Cizkova J Spontaneous regression of malignant melanoma - is it based on the interplay between host immune system and melanoma antigens? Anticancer Drugs 2017 28 8 819 830 10.1097/CAD.0000000000000526 28609309 10. Grech A Mercieca N Calleja-Agius J Abela R Metastatic malignant melanoma of unknown primary in temporalis muscle J Surg Case Rep 2020 2020 6 1 3 10.1093/jscr/rjaa202 11. Balch CM Gershenwald JE Soong SJ Thompson JF Atkins MB Byrd DR Final version of 2009 AJCC melanoma staging and classification J Clin Oncol 2009 27 36 6199 6206 10.1200/JCO.2009.23.4799 19917835 12. Bae JM Choi YY Kim DS Lee JH Jang HS Lee JH Metastatic melanomas of unknown primary show better prognosis than those of known primary: A systematic review and meta-analysis of observational studies J Am Acad Dermatol 2015 72 1 59 70 10.1016/j.jaad.2014.09.029 25440435 13. van der Ploeg AP Haydu LE Spillane AJ Scolyer RA Quinn MJ Saw RP Melanoma patients with an unknown primary tumor site have a better outcome than those with a known primary following therapeutic lymph node dissection for macroscopic (clinically palpable) nodal disease Ann Surg Oncol 2014 21 9 3108 3116 10.1245/s10434-014-3679-5 24802907 14. Milton GW Shaw HM McCarthy WH Occult primary malignant melanoma: factors influencing survival Br J Surg 1977 64 11 805 808 10.1002/bjs.1800641114 588977 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34846 Cardiac/Thoracic/Vascular Surgery Cardiology Pulmonology Balloon Pulmonary Angioplasty for Recurrent Lesions Six Years Following Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension Muacevic Alexander Adler John R Tamura Hiroto 1 Hosokawa Shinobu 1 Takahashi Takefumi 1 Kishi Koichi 1 1 Cardiology, Tokushima Red Cross Hospital, Tokushima, JPN Hiroto Tamura [email protected] 10 2 2023 2 2023 15 2 e3484629 1 2023 Copyright (c) 2023, Tamura et al. 2023 Tamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Pulmonary endarterectomy (PEA) is the standard treatment for chronic thromboembolic pulmonary hypertension (CTEPH). However, repeating surgery in recurrent cases is generally deemed high-risk. Balloon pulmonary angioplasty (BPA), an alternative treatment for organized thrombotic lesions of the peripheral pulmonary artery, has also shown a good prognosis in cases of inoperable CTEPH. Here, we report the case of a 65-year-old woman who presented with dyspnea. She had been admitted to our hospital in 2015 and diagnosed with University of San Diego (USD)-California classification CTEPH of level II. PEA had been performed, which resolved her respiratory discomfort, and her WHO functional class had improved from IV to I. Post-surgery pulmonary angiography had shown several residual lesions; nonetheless, pulmonary hypertension had not been noted, and the patient had not experienced dyspnea thereafter. We had decided to continue medical therapy; however, the patient stopped taking anticoagulation and pulmonary vasodilators due to the absence of symptoms. In 2021, dyspnea recurred, and she was hospitalized for examination. Chest radiography showed no cardiomegaly, and heart failure and tricuspid regurgitation were absent on echocardiography. The six-minute walk test distance was 565 m, and the lowest oxygen saturation during the test was 92%. Right heart catheterization demonstrated a mean pulmonary arterial pressure (PAP) of 15 mmHg without pulmonary hypertension; however, pulmonary angiography showed new organized thrombotic lesions in the left segments of the lower lobe. Based on the advancement of the lesions, we speculated that they were the cause of the symptoms even without concurrent pulmonary hypertension. Therefore, we performed two additional BPA procedures. Subsequently, the mean PAP decreased further to 13 mmHg. The patient's symptoms improved, the six-minute walk test distance increased to 656 m, and the WHO functional class returned to I. In conclusion, BPA for recurrent lesions after surgery for CTEPH can improve the patient's symptoms and exercise tolerance. right heart catheterization pulmonary endarterectomy pulmonary hypertension balloon pulmonary angioplasty chronic thromboembolic pulmonary hypertension The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as Group 4 pulmonary hypertension (PH) . CTEPH can be diagnosed if the mean pulmonary arterial pressure is 20 mmHg or higher and organic thrombotic lesions are present in the pulmonary arteries, even when using anticoagulants for more than three months . Pulmonary endarterectomy (PEA) is the standard treatment for CTEPH . Balloon pulmonary angioplasty (BPA), which is an alternative treatment for organized thrombotic lesions of the peripheral pulmonary artery, has demonstrated a good prognosis in cases of inoperable CTEPH . In our case, the patient had undergone PEA for CTEPH six years prior and experienced recurrent dyspnea. Therefore, we decided to perform BPA. Here, we describe how the patient was successfully treated with BPA. Case presentation A 65-year-old woman presented with dyspnea and was referred to our department for careful investigation in 2021. She had been diagnosed with CTEPH in 2015 and had experienced progressive dyspnea. Lung perfusion scintigraphy revealed multiple wedge-shaped defects . Right heart catheterization (RHC) revealed a PAP of 75/25 mmHg with a mean pressure of 45 mmHg, pulmonary arterial wedge pressure (PAWP) of 10 mmHg, cardiac output (CO) of 4.75 L/min, and pulmonary vascular resistance (PVR) of 7.37 Wood units (Table 1). Pulmonary angiography (PAG) revealed organized thrombi in several segments bilaterally despite continued anticoagulation therapy of edoxaban . Figure 1 Lung perfusion scintigraphy revealed multiple wedge-shaped defects (red arrows). (A) Anterior (B) Posterior Table 1 Right heart catheterization results. s/d/m, systolic/diastolic/mean; BPA, balloon pulmonary angioplasty; CO, cardiac output; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PEA, pulmonary endarterectomy; PVR, pulmonary vascular resistance Pre-PEA Post-PEA Pre-BPA Post-BPA PAP (s/d/m) (mmHg) 75/25/45 34/18/22 23/10/15 18/10/13 PAWP (mmHg) 10 13 7 9 CO (L/min) 4.75 4.44 6.39 4.41 PVR (wood units) 7.37 2.03 1.25 0.91 Figure 2 Pulmonary angiography before pulmonary endarterectomy showing organized thrombi (red arrowheads) in several bilateral segments. Pulmonary artery of the (A) right upper, (B) left upper, (C) right lower, and (D) left lower lobes. The patient had undergone a pulmonary endarterectomy (PEA). Post-surgery PAG revealed a reduction in thrombi , with significant improvement in symptoms. Postoperative lung perfusion scintigraphy revealed multiple residual wedge-shaped defects . Figure 3 Pulmonary angiography after pulmonary endarterectomy revealing decreased organized thrombotic lesions (red arrows), especially in the right pulmonary artery. Pulmonary artery of the (A) right upper, (B) left upper, (C) right lower, and (D) left lower lobes. Figure 4 Postoperative lung perfusion scintigraphy revealed residual multiple wedge-shaped defects (red arrows). (A) Anterior (B) Posterior The patient self-terminated anticoagulation therapy in 2019 due to the absence of symptoms. On current admission, her blood pressure was found to be 106/62 mmHg; pulse rate, 85 bpm; oxygen saturation, 97% on room air; and body temperature, 36.9degC. The World Health Organization (WHO) functional class was identified to be II. The six-minute walk test distance was 565 m. Echocardiography revealed a normal ejection fraction of 68%, normal wall motion, and transtricuspid pressure gradient (TRPG) of 20 mmHg. RHC revealed a PAP of 23/10 mmHg with a mean pressure of 15 mmHg, PAWP of 7 mmHg, CO of 6.39 L/min, and PVR of 1.25 Wood units (Table 1). PAG revealed new organized thrombotic lesions in the left segments of the lower lobe compared with postoperative PAG . Figure 5 Pulmonary angiography six years after pulmonary endarterectomy showing residual thrombotic lesions in the right segments of the lower lobes (yellow arrowheads) and new thrombotic lesions in the left segments of the lower lobes (red arrowheads). Pulmonary artery of the (A) right upper, (B) left upper, (C) right lower, and (D) left lower lobes. Even though pulmonary hypertension did not recur, a total occlusion lesion in the left segments of the lower lobe and residual organized thrombotic lesions in multiple other segments were evident. After a discussion with our cardiology team, BPA was proposed. The seven segmental pulmonary arteries on the right (A1, A2, A3, A8, and A9) and the left (A4 and A5) were dilated during the first BPA session . The four segmental pulmonary arteries on the right (A1) and left (A8, A9, and A10) were dilated during the second BPA session. The patient developed hemoptysis after dilation of the left segment (A9). Pulmonary arterial injury was suspected ; therefore, balloon inflation was performed for 10 minutes, causing the hemoptysis to subside. Figure 6 Balloon pulmonary angioplasty procedure. (A) Pulmonary angiography image showing a thrombotic lesion (blue arrowheads) in the right A9 segment. (B) Dilation with a 4-mm semi-compliant balloon. (C) Improved pulmonary flow after the dilation (blue arrowheads). (D) Pulmonary angioplasty showing a thrombotic lesion (yellow arrowheads) in the left A9 segment. (E) Dilation with a 5-mm semi-compliant balloon. (F) Improved pulmonary flow after dilation and pulmonary vessel injury (red arrow). After two BPA sessions, the patient's symptoms improved. Her six-minute walk test distance improved to 656 m. After three months, RHC revealed a PAP of 18/10 mmHg with 13 mmHg of mean pressure, PAWP of 9 mmHg, CO of 4.41 L/min, and PVR of 0.91 Wood units (Table 1). The patient's hemodynamics further improved. PAG revealed improved bilateral pulmonary arterial flow; however, an organized thrombotic lesion remained in the left segments of the lower lobe . We speculated that the lesion persisted because of a massive thrombus. The patient did not experience any subsequent dyspnea; therefore, we decided against performing an additional BPA. The dyspnea has not recurred to date, two years following the BPA. Figure 7 Pulmonary angiography after balloon pulmonary angioplasty showing improved pulmonary flow (red arrowheads) and residual organized thrombotic lesions (blue arrowheads) in the left segments of the lower lobe. Pulmonary artery of the (A) right upper, (B) left upper, (C) right lower, and (D) left lower lobes. Discussion The gold standard for CTEPH treatment is PEA, which reduces the thrombotic volume . The patient had undergone PEA, which significantly improved the symptoms; however, these symptoms recurred, probably due to the termination of anticoagulation therapy. Lifelong therapeutic anticoagulation is recommended for patients with CTEPH because recurrent pulmonary thromboembolism accompanied by insufficient clot resolution is a key pathophysiological feature of this disease . It is important that patients, especially those without symptoms, are informed of this after their treatment. Araszkiewicz et al. reported that 17% of patients developed recurrent or persistent pulmonary hypertension after PEA . In such cases, repeating the surgical treatment is generally high risk. Therefore, we consulted the cardiology team, and BPA was proposed. If the peripheral thrombotic lesion persists even after PEA, the compression of peripheral thrombotic lesions can increase the pulmonary bed. Taniguchi et al. reported that additional BPA after PEA further decreases PAP and results in a good prognosis . The mean PAP of the patients who underwent combination treatment of PEA and BPA improved from 42.4 mmHg to 17.9 mmHg. All patients who received the combination therapy were shown to survive for five years. Some patients do not have pulmonary hypertension but an organized pulmonary thrombus. This pathophysiology is called "chronic thromboembolic pulmonary disease (CTEPD) without pulmonary hypertension" , for which BPA has been also reported to be effective . In the present case, BPA was effective, even six years post-PEA. The patient's mean PAP was 15 mmHg without pulmonary hypertension and further decreased to 13 mmHg after BPA, which is sufficiently low. In addition, the patient's symptoms improved significantly. The PAG after BPA revealed an organized thrombotic lesion in the left segments of the lower lobe, which appeared to be a slight aggravation immediately after the two BPA sessions. The anticoagulation therapy the patient received was direct oral anticoagulants (DOACs). Recurrent venous thromboembolism rates are higher in patients receiving DOACs . Switching medication from DOAC to warfarin can improve pulmonary artery flow while dissolving massive thrombi . Conclusions In this report, we demonstrate that BPA can improve the functional state of patients who have undergone PEA and have recurrent symptomatology, even without concomitant pulmonary hypertension. Although in our case the patient rejected the suggestion, we strongly recommend switching to warfarin administration in such cases, where the thrombotic lesion recurs following treatment. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Eur Heart J Humbert M Kovacs G Hoeper MM 3618 3731 43 2022 36017548 2 Current status of long-term prognosis among all subtypes of pulmonary hypertension in Japan Int J Cardiol Kozu K Sugimura K Ito M 228 235 300 2020 31813677 3 Balloon pulmonary angioplasty for the treatment of residual or recurrent pulmonary hypertension after pulmonary endarterectomy Int J Cardiol Araszkiewicz A Darocha S Pietrasik A 232 237 278 2019 30409735 4 The role of balloon pulmonary angioplasty and pulmonary endarterectomy: Is chronic thromboembolic pulmonary hypertension still a life-threatening disease? 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Eur J Nucl Med Mol Imaging Eur J Nucl Med Mol Imaging European Journal of Nuclear Medicine and Molecular Imaging 1619-7070 1619-7089 Springer Berlin Heidelberg Berlin/Heidelberg 36907901 6175 10.1007/s00259-023-06175-7 Image of the Month Rabbit fever: granulomatous inflammation by Francisella tularensis mimics lung cancer in dual tracer 18FDG and 68Ga-FAPI PET/CT Meetschen Mathias [email protected] 1 Sandach Patrick 2 Darwiche Kaid 3 Theegarten Dirk 4 Moter Annette 56 Schaarschmidt Benedikt Michael 1 Herrmann Ken 2 Fendler Wolfgang P. 2 Hautzel Hubertus 2 Opitz Marcel 1 1 grid.5718.b 0000 0001 2187 5445 Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany 2 grid.5718.b 0000 0001 2187 5445 Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany 3 grid.410718.b 0000 0001 0262 7331 Department of Pulmonary Medicine, Section of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, Essen, Germany 4 grid.5718.b 0000 0001 2187 5445 Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany 5 grid.6363.0 0000 0001 2218 4662 Institute of Microbiology, Infectious Diseases and Immunology, Biofilmcenter Charite-Universitatsmedizin Berlin, Berlin, Germany 6 Moter Diagnostics, Berlin, Germany 13 3 2023 13 3 2023 2023 50 8 25672569 23 1 2023 24 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Universitatsklinikum Essen (8912)Open Access funding enabled and organized by Projekt DEAL. issue-copyright-statement(c) Springer-Verlag GmbH Germany, part of Springer Nature 2023 pmcA 39-year-old hunter presented with chills, headache, limb pain, tachycardia, hypertension, ventricular extrasystoles, elevated inflammatory values, and persistent chest pain. A CT scan revealed a mass on the left hilus (A). Due to suspicion of lymphoma or lung cancer 1 week later, an 18FDG (B-D) plus a 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT scan (E-G) were performed. The hilar mass increased in size (B, E) and demonstrated both intense 18FDG uptake (SUVmax 24.5) (C, D) and 68 Ga-FAPI accumulation (SUVmax 23.2) (F, G) strongly indicating malignancy. However, subsequent EBUS-TBNA and EUS-B yielded necrotizing granulomatosis (H). Finally, a bone-hard mass on the left hilus discharging creamy pus was resected by VATS. Pathological and microbiological workup evidenced Francisella tularensis infection by FISHseq analysis (Fluorescence in situ hybridization combined with 16S rRNA gene amplification and sequencing ), ELISA, and Western blot. Postoperative bronchoscopy demonstrated re-established bronchus patency (I). After antibiotic therapy with gentamicin and ciprofloxacin, no recurrence was detectable on CT control 20 weeks later (J). 18FDG PET/CT is one of the diagnostic mainstays in oncology and standard imaging in patients with lung mass. However, its specificity is impaired due to inflammation-induced uptake. In tularemia, a granulomatous inflammation, 18FDG PET/CT revealed an uptake pattern indicative for lung cancer in more than 50% of all cases . 68Ga-FAPI emerged as an alternative tracer for tumor imaging, as FAP is expressed in > 90% of epithelial cancers . 68Ga-FAPI shows high uptake and tumor-to-background ratio in primary lung cancer and in metastatic lesions of other tumor types located in the lung [5-9]. Although promising data on this new radiotracer are increasing, false-positive results in non-malignant diseases with FAP uptake have been reported . Also, chronic infections like tuberculosis might occasionally demonstrate increased 68Ga-FAPI . On the other hand, in a head-to-head comparison (sub)acute inflammation in lymph nodes after COVID-19 vaccination induces no 68Ga-FAPI accumulation besides a positive FDG signal . Our case adds tularemia to the scope of potential granulomatous inflammation-induced pitfalls in hybrid imaging coming along with increased high FDG uptake but also high FAP expression. However, given an already known diagnosis of granulomatous disease like tularemia, 68Ga-FAPI PET/CT might be suitable to assess extent and activity of chronic inflammation. Funding Open Access funding enabled and organized by Projekt DEAL. Declarations Wolfgang P. Fendler reports fees from SOFIE Bioscience (research funding), Janssen (consultant, speaker), Calyx (consultant), Bayer (consultant, speaker, research funding), Parexel (image review), Novartis (speaker), and Telix (speaker) outside of the submitted work. Benedikt M. Schaarschmidt received a research grant from PharmaCept for an undergoing investigator-initiated study not related to this paper. Ken Herrmann reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, personal fees from Aktis Oncology, personal fees from Theragnostics, personal fees from Pharma15, personal fees from Debiopharm, personal fees from AstraZeneca, personal fees from Janssen, outside the submitted work. Mathias Meetschen was supported as a Junior Clinician Scientist within the University Medicine Essen Academy (UMEA) program. Annette Moter reports honoraria for lectures by BioMerieux and Chiesi and holds shares in MoKi Analytics GmbH and Moter Diagnostics private practice. Ethical approval This is a case presentation of the ongoing 68Ga-FAPI PET observational trial conducted at the University Hospital Essen (NCT04571086). Evaluation of data was approved by the ethics committee of the University Duisburg-Essen (20-9485-BO and 19-8991-BO). All studies involving human participants were conducted in accordance with the ethical standards of the relevant committee and the 1964 Helsinki Declaration and its later amendments. Consent to participate Written informed consent was obtained from individual participant included in the study. Conflict of interest The authors declare no competing interests. This article is part of the Topical Collection on Image of the month Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. 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Fibroblast activation protein positron emission tomography and histopathology in a single-center database of 324 patients and 21 tumor entities. J Nucl Med. 2022. 10.2967/jnumed.122.264689. 10. Kessler L Ferdinandus J Hirmas N Zarrad F Nader M Kersting D Pitfalls and common findings in (68)Ga-FAPI PET: a pictorial analysis J Nucl Med 2022 63 890 896 10.2967/jnumed.121.262808 34620730 11. Sun R Huang Z Wei J Zeng C Chen X 68Ga-FAPI and 18F-FDG PET/CT findings in a patient with pancreatic tuberculosis mimicking malignant tumor Clin Nucl Med 2022 47 653 654 10.1097/rlu.0000000000004099 35261359 12. Demmert TT Maric I Pomykala KL Lueckerath K Siveke J Schaarschmidt BM Novel (68)Ga-FAPI PET/CT offers oncologic staging without COVID-19 vaccine-related pitfalls J Nucl Med 2022 64 3 368 371 10.2967/jnumed.122.264872 36396454 |
] OR hypothyroidism in pregnancy[Title/Abstract] OR hypothyroidism during pregnancy[Title/Abstract] OR subclinical hypothyroidism in pregnancy[Title/Abstract] OR thyroid hormones during pregnancy[Title/Abstract] OR thyroid disorders in pregnancy[Title/Abstract] OR overt hypothyroidism during pregnancy[Title/Abstract] OR maternal thyroid deficiency[Title/Abstract] OR maternal hypothyroidism[MeSH Terms] OR hypothyroidism[MeSH Terms]) AND (fetal development[Title/Abstract] OR fetal neurological development[Title/Abstract] OR foetal development[Title/Abstract] OR foetal neurological development[Title/Abstract] OR fetal development[MeSH Terms] OR foetal development[MeSH Terms]). Screening and the number of articles included in the final review are summarized in Figure 1. Figure 1 Screening and the number of articles included in the final review. Thyroid hormone in fetal development About 20 years ago, many endocrinologists brought the effects of maternal thyroid hormone deficiency to public attention . In 1999, it was demonstrated that a child's neurodevelopment might be severely affected if hypothyroidism is left untreated in pregnant women . For normal fetal development, an adequate quantity of thyroid hormone is necessary . By 10-12 weeks of gestation, the fetal thyroid gland develops and produces the thyroid hormone. Until the fetus reaches 36 weeks of gestation, thyroid hormone levels in serum do not reach the levels of an adult . As the thyroid hormone can cross the placenta in the first trimester, the fetus depends on its mother for hormone transport . During the early phase of pregnancy, the hCG hormone has a weak stimulatory effect on the thyroid gland . As a result, the maternal serum thyrotropin (TSH) levels decrease, which then subsequently increase. Consequently, maternal serum thyrotropin (TSH) levels fall, followed by a rise in free thyrotropin levels . If the mother is a known case of hypothyroidism throughout the pregnancy, then there is a very high risk of low-birth-weight babies being born . TSH receptor-stimulating antibodies and TSH receptor-blocking antibodies are the two types of TSH receptor antibodies. The capacity of maternal TSH receptor antibodies to penetrate the placenta results in impaired fetal thyroid function . Figure 2 depicts thyroid hormone regulation in the thyroid gland of the fetus. Figure 2 Thyroid hormone regulation in the fetus. Figure Credits: Arundhati Pande (Author) Factors associated with the development of maternal hypothyroidism and its metabolism during pregnancy The following are major risk factors for developing maternal hypothyroidism: history of thyroid dysfunction, goiter, thyroid antibody positive, age above 30 years, type 1 diabetes mellitus, previous thyroid surgery, autoimmune thyroid disease in the family, obesity, drugs such as amiodarone or lithium, and geographical iodine deficiency . The maternal thyroid gland produces the thyroid hormone, which crosses the placenta through a thyroid hormone transporter that is more selective for free thyroxine (fT4). Maternal fT4 is transformed into triiodothyronine (T3) and reverse triiodothyronine (rT3) in the presence of placental deiodinases. Then, before the embryonic thyroid grows, maternal T3 enters the fetal tissues . Thyroid hormones hence significantly impact central nervous system development . Mechanism of physiological changes of thyroid function in pregnancy and challenges Throughout the first trimester, there is a rise in thyroxine-binding globulin (TBG) which is maintained at the same levels during the second trimester. This augmentation of TBG synthesis is caused by higher maternal estrogen levels, which also causes sialylation and, more critically, because of reduced clearance by the liver . Because of an increase in maternal thyroid hormone production, there is an increase in concentration, resulting in a rise in total T3 and T4 levels, also causing a boost in the thyroid hormone production in the mother. Iodide is cleared from the kidneys when the maternal glomerular filtration rate increases. This clearance, together with enhanced thyroxine metabolism, leads to a drop in plasma iodide levels. Due to increased placental deiodinases, T4 metabolism is boosted in the second and third trimesters . During pregnancy, the placenta is critical in reacting to and regulating the mother's thyroid hormones . These alterations in levels of hormones induce changes in the size of the thyroid gland, which eventually reverts to its previous size after the baby is delivered. As a result, the measures used to assess hypothyroidism throughout pregnancy vary depending on the trimester and the remainder of the pregnancy . Along with the thyroid gland, the placenta accumulates iodine. Iodine is required for the fetus to manufacture its thyroid hormones. Iodine is therefore taken up by iodine absorption from the mother . Iodine inflow is assumed to be controlled by the sodium/iodine symporter (NIS), whereas outflow is controlled by pendrin . Maternal hypothyroidism is linked to newborn growth, development, and intellect The thyroid hormone promotes fetal development by promoting protein synthesis, RNA, DNA, and specific enzymes . It also plays a vital role in tissue formation, maturation, and differentiation. The thyroid hormone is required for brain cell growth. Before the 20th week of pregnancy, brain development primarily relies on the mother's thyroid hormone. The brain proliferates throughout the first and second trimesters of pregnancy. Because fetal thyroid follicular epithelial cells are immature and cannot make thyroid hormone initially, this hormone is delivered to the fetus by transplacental administration . Maternal thyroid hormone insufficiency in the latter stages of pregnancy may induce neurodevelopmental abnormalities, albeit the effects may be less severe than maternal thyroid shortage in the first trimester. Inadequacy is also found in levels of physical and intellectual development and response to environmental stimuli compared to children born to women with normal thyroid functioning throughout their pregnancy. Thyroid hormones are also responsible for forming long bones and teeth . Outcomes of maternal hypothyroidism Some symptoms of hypothyroidism, such as exhaustion, anxiety, constipation, muscular cramps, and weight gain, may be mimicked during pregnancy. Consequently, diagnosing hypothyroidism during pregnancy becomes more challenging . Thyroid dysfunction may result in mental impairment and neurological disorders . Pregnancy loss (miscarriage, intrauterine death, fetal loss), preterm labor (onset of labor before or after 37 weeks of gestation), preterm delivery (delivery before or after 37 weeks of gestation), gestational hypertension, preeclampsia, eclampsia, gestational diabetes, placental ligation performed by abruption (premature separation of a typically implanted placenta), and placenta previa may be some unfortunate expected outcomes. There has been evidence of poor response in terms of attention, language, reading motor, and visual-spatial skills in infants born to hypothyroid mothers . One of the most prevalent outcomes in one of the cohort studies was neonatal jaundice. Reports of hypocalcemia, respiratory distress, down syndrome, cardiovascular abnormalities, and urogenital malformations have also been observed . In addition, the offspring's decreased cognitive and motor functioning has also been seen . Assessment Hypothyroidism is thus a condition of an increased thyroid-stimulating hormone concentration with standard blood thyroxin (T4) levels (either total or free) or an elevated TSH concentration above 10mlU/L . Multiple studies have been conducted across the globe to understand the effects of maternal hypothyroidism on fetal development; implications from certain such studies are put forth in Table 1. Table 1 Implications from various studies (systemic review, meta-analysis, cohort study, prospective study, etc.) regarding effects of maternal hypothyroidism on fetal development. Serial number Name of author, month and or year (if any), citations Type of Study Objectives of the study Implications (1) Lee et al., December 2022 Case report To analyze dysfunction in the thyroid gland during pregnancy. To avoid difficulties in fetal neurodevelopment, pregnant women with hypothyroidism must be treated with LT4. (2) Derakshan et al., June 2020 A systemic review and individual data meta-analysis To assess the association of maternal thyroid functioning with birthweight. Hypothyroidism in mothers during pregnancy is responsible for small gestational age and low birth weight in babies. (3) Parizad Nasirkandy et al., September 2017 Systemic review and meta-analysis To assess the correlation of subclinical hypothyroidism during pregnancy and preterm birth. Preterm birth was most commonly seen in mothers with subclinical hypothyroidism compared to euthyroid mothers. (4) Prezioso et al., 2018 Mini review To analyze the dependency of neurodevelopment of fetus on thyroid hormones. Maternal low thyroid functions are responsible for poor intellectual quotients and developmental retardation in infants. It is also linked to slower cognitive development in these infants. (5) Xu, Zhong, March 2022 Cohort study To analyze and observe the association of hypothyroidism during pregnancy and its effect on fetal growth and development. Hypothyroid mothers have a high risk of premature delivery, which may affect intellectual and psychomotor development in their infants. (6) Kankanamalage et al., May 2021 Randomized controlled trials To understand the manner of development of gestational hypothyroidism. Iodine deficiency during pregnancy and changes in estrogen in circulation is one of the common reasons that cause gestation hypothyroidism. (7) Kiran et al., September 2021 Cross-sectional retrospective study To analyze and understand the anomalies caused in infants born to mothers with hypothyroidism. The most common congenital anomalies included cardiovascular defects. Other abnormalities included low birth weight and neonatal jaundice. (8) Lucaccioni et al., September 2020 Prospective study To assess the results seen in infants born to mothers having an abnormal functioning of the thyroid gland. Maternal thyroid dysfunction may lead to fetal thyroid gland being dysfunctional with altered metabolism. (9) Ahmed, February 2015 A systemic review To understand the effect of hypothyroidism in mothers on the brain development of their infants. Lack of thyroid hormone in mothers during pregnancy is responsible for the retardation in brain development and decreased intelligence quotient in infants. Treatment and management During pregnancy, it is necessary to check the thyroid gland functions every 6 to 8 weeks . Hypothyroidism in this condition should be treated to prevent obstetric complications and neurodevelopmental adversities in infants. Treatment includes administration of levothyroxine (LT4) sinceT3 cannot cross the placenta. Using T3 or a combination of T3 and T4 therapy may result in insufficient fetal thyroid hormone availability . Pregnant women suffering from pre-existing hypothyroidism need to increase their pre-pregnancy dose of T4 to maintain the normal functioning of the thyroid gland . Levothyroxine thyroid hormone (LT4) injection can be administered rarely and only in the setting of profound coma or impaired oral feeding after adjusting the dose . Asymptomatic pregnant mothers in some countries are frequently screened for hypothyroidism . Autoimmune hyperthyroidism is medically treated with methimazole or propylthiouracil, both anti-thyroid medications. Anti-thyroid medications may pass the placenta during pregnancy. If LT4 is appropriately dosed, most fetuses will get enough thyroid hormone levels throughout pregnancy. Maternal thyroid autoantibodies may cross the placenta but do not affect fetal or neonatal thyroid function. Neonates born to mothers with autoimmune hyperthyroidism may develop central hypothyroidism due to high fetal thyroid hormone concentrations inhibiting the hypothalamus-pituitary-thyroid axis . Increased maternal iodine consumption is essential during pregnancy to provide adequate iodine levels for both mother and baby. With pregnancy, the recommended dietary allowance rises from 150 mcg to 250-300 mcg daily . Thyrotropin, commonly known as TSH, is produced by the pituitary gland. It increases thyroid hormone synthesis and its release by the gland. Serum TSH levels rise when thyroid hormone concentrations are low and fall when concentrations are high. It is the standard screening test for thyroid dysfunction because it is a highly sensitive indicator of thyroid function . Conclusions Hypothyroidism during pregnancy is a significant threat not only to the mother but also to her infant. There is a considerable risk of developmental anomalies and hindrances in the growth of infants in terms of intelligence and physical well-being. Since a pregnant mother can be diagnosed with hypothyroidism which can be present before she conceives or may develop it during her pregnancy, known as gestational hypothyroidism, it is necessary to identify the signs and symptoms as early as possible and get the required treatment. In cases of females who have had hypothyroidism since before must get treated before they plan to conceive. They must wait till the thyroid hormone levels get back to normal. After their levels reach the desired limit, women must wait for some time before they can conceive and get pregnant to prevent any harmful reactions that may hinder the baby's growth due to the presence of the drugs consumed for treatment. Mothers who develop gestational hypothyroidism must get treated as soon as they are diagnosed. Iodine is recommended for people living in areas with severe deficiency of iodine because of the inability and non-feasibility of salt iodization in such areas. Mothers must be educated and made aware of the importance of thyroid hormones and their functioning for their infant's proper growth and development. The knowledge about recognizing the early signs in themselves is of utmost importance. Regularly checking for normal levels of hormones in the blood should be encouraged, especially during the early phase of pregnancy. Monitoring and regulating the doses of prescribed medicines and maintaining normal functioning must be enabled. The authors have declared that no competing interests exist. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34849 Otolaryngology Pediatrics Neurosurgery Acute Bacterial Sinusitis With Epidural and Subdural Involvement Muacevic Alexander Adler John R Arcalas Chelsea-Jane E 1 Reich Daniel A 1 Blair Samari A 1 Paradise Black Nicole M 21 1 College of Medicine, University of Florida, Gainesville, USA 2 Department of Pediatrics, University of Florida, Gainesville, USA Daniel A. Reich [email protected] 10 2 2023 2 2023 15 2 e3484910 2 2023 Copyright (c) 2023, Arcalas et al. 2023 Arcalas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Sinusitis is a common childhood infection with potential for rare intracranial complications. These neurologic sequelae can lead to serious morbidity and mortality if not addressed promptly. We describe a case of suspected sinusitis in a 13-year-old male complicated by a superior sagittal sinus thrombosis along with subdural and epidural empyemas. intracranial epidural abscess pediatric headache rhinosinusitis intracerebral abscess subdural empyema The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Pediatric sinusitis is generally considered a mild infection and is commonly found in the setting of viral or bacterial etiologies . Classic symptoms of congestion, nasal obstruction, and facial pressure overlap with those of viral upper respiratory infections, making diagnosis a challenge. Symptoms usually resolve with conservative management in the setting of a viral etiology; however, oral antibiotics are warranted when the condition worsens . Although rare, extracranial and intracranial complications may occur, with orbital complications including orbital cellulitis and abscess formation being some of the most frequently reported. Intracranial complications including subdural empyema, epidural abscess, meningitis, or cerebritis are particularly important to recognize due to the possible rapid clinical deterioration and significant morbidity and mortality associated with this condition . Similar intracranial complications may also present in the setting of otitis media, another highly prevalent infection in childhood . Common intracranial complications of acute otitis media are otitic hydrocephalus, extradural abscess, and lateral sinus thrombosis. Those of chronic otitis media include the aforementioned as well as meningitis, cerebral abscess, and encephalitis . It is noted in the literature that intracranial complications may account for 30% of all complications of otitis media. Aside from these rare conditions, acute mastoiditis is consistently reported as the most frequent complication of otitis media in the pediatric population, with a majority of cases occurring at around ages two to three years old . Predictably, associated intracranial complications of acute mastoiditis are similar to those of sinusitis and otitis media. In one retrospective review, the top two conditions of this category were reported to be sigmoid sinus thrombosis and intracranial abscess. Subperiosteal abscess was reported as the most common complication overall . This case report describes an older pediatric patient who developed a superior sagittal thrombosis, subdural empyema, and epidural empyema after a suspected sinus infection. We describe his clinical course as well as his unique neurologic recovery. Case presentation A 13-year-old male with no significant past medical history presented to the pediatric emergency department (ED) with a five-day history of a right-sided frontal headache, decreased appetite, intermittent subjective fevers, and right orbital swelling. Per the child's mother, the patient never complained of headaches before the presentation and attributed them to the cessation of routine energy drink consumption. The patient subsequently developed intermittent fevers and was treated supportively at home with acetaminophen. He had an associated decrease in appetite but was tolerating clear liquids. The mother also noticed decreased activity, as the child did not seem interested in playing sports as much as usual. On the morning of the presentation, the patient had transient numbness of the left upper and lower extremities that lasted approximately five minutes before spontaneously resolving. Approximately 10 minutes later, the patient had another episode of numbness in the same distribution, which also resolved spontaneously. These two transient episodes of numbness along with progressive right eye swelling prompted the mother to bring the patient to the ED. In the ED, the patient was febrile to 39.1degC and received acetaminophen. The patient was started on maintenance intravenous fluids and empiric antibiotics consisting of clindamycin and piperacillin-tazobactam. Initial laboratory workup showed the following elevated lab values: a C-reactive protein of 225 (normal <10 mg/L), an international normalized ratio of 2.1 (normal </= 1.1), a prothrombin time of 24 (normal 11-13.5 seconds), and an erythrocyte sedimentation rate of 43 (normal 0-22 mm/hr). There was no leukocytosis. Because of presenting symptoms of headache and numbness, a computed tomography (CT) angiography scan of the head and neck with and without contrast was obtained promptly. The study was notable for a chronic appearing, multifocal, nonocclusive thrombus in the superior sagittal sinus. It also showed moderate paranasal sinus mucosal changes with pneumatized secretions in the right maxillary sinus and posterior ethmoid air cells as well as chronic osteitis changes in the right maxillary sinus walls. Because of these sinus findings, radiology suggested that these were secondary to acute on chronic sinusitis. Pediatric neurology recommended further imaging given the concerns for thrombosis and meningitis. Initial magnetic resonance imaging (MRI) revealed mild right frontal leptomeningeal enhancement, subtotal opacification of the frontal sinuses and right maxillary sinus with air-fluid levels, and severe mucosal inflammatory changes of the anterior ethmoid air cells bilaterally. There were also concerns for a small right frontal subdural empyema and subocclusive filling defects in the superior sagittal sinus. These MRI findings are demonstrated in Figures 1A-1C. Lumbar puncture was obtained due to concerns for meningitis, revealing the following: glucose of 74 (normal 50-80 mg/100mL), protein of 27 (normal 15-60mg/dL), white blood cells of 4 (normal 0-5 cells/mL), and red blood cells of 12 (20-40 mg/dL). The patient was admitted to the pediatric hospital medicine service for continued antibiotics and further management. Figure 1 (A-C) Initial brain magnetic resonance imaging with early formation of a right frontal, maxillary, and ethmoid sinusitis and concerns for superior sagittal sinus thrombosis, small subdural empyema, and mild right frontal leptomeningeal enhancement The following morning, the patient had acute neurologic changes, including left cranial nerve VI and VII palsies as well as 2/5 left upper extremity grip weakness. Several consults were placed including neurosurgery (NSGY), infectious disease (ID), ophthalmology, otolaryngology (ENT), and hematology/oncology. He was subsequently transferred to the pediatric intensive care unit (PICU) given the acute neurological changes and the need for frequent neurological exams. NSGY did not recommend surgical intervention at this time due to the small size of the empyema. ENT recommended sinus aspiration for culture and possible drainage. The hematology and oncology team recommended anticoagulation following the sinus aspiration/drainage. In the PICU, the patient was transitioned to vancomycin, ceftriaxone, and metronidazole per ID recommendations. A repeat CT showed progression of the subdural empyema with an increase in soft tissue swelling. On hospital day three, ENT performed a functional endoscopic sinus surgery, which included a bilateral total ethmoidectomy and sphenoidectomy, frontal sinusotomy, and maxillary antrostomy. On hospital day five, NSGY performed a right frontal subdural empyema evacuation. The patient was started on Lovenox treatment for superior sagittal sinus thrombosis with a therapeutic goal of anti-Xa levels of 0.5-1 units/mL. Cultures drawn during the NSGY evacuation grew Klebsiella spp. from the sinuses and Gamella moribilum from the empyema. ID switched his antibiotic regimen from vancomycin to linezolid and continued metronidazole and ceftriaxone. Inflammatory markers gradually improved, as did a leukocytosis that developed during the hospitalization. The patient was transferred from the PICU to the general inpatient service on hospital day five for further management. Repeat brain MRI on hospital day 14 showed an increasing size of the right subdural empyema and a new midline frontal epidural empyema, as well as new surrounding vasogenic edema and parenchymal enhancement . Based on this imaging, he underwent needle aspiration of the two intracranial empyemas. Following surgery, the patient continued to show clinical improvement with full recovery of the left cranial nerve VI and VII palsies. He started working with physical and occupational therapy three times a week to regain strength. A repeat brain MRI on hospital day 21 showed near complete resolution of the intracerebral abscess with residual vasogenic edema . He was discharged home with a peripherally inserted central catheter for long-term antibiotic therapy with ceftriaxone and metronidazole and subsequent outpatient follow-up with ID, ENT, and NSGY. Figure 2 (A-C) Brain magnetic resonance imaging on hospital day 14 revealed a collection overlying the right frontotemporal lobe that increased in size, new surrounding vasogenic edema, and parenchymal enhancement. Figure 3 Final brain magnetic resonance imaging on hospital day 21 before the patient was discharged home. Imaging revealed continued improvement in the areas of involvement from the midline over the high frontal convexity and multiloculated over the right frontal lobe. Discussion Previous literature of case reports/series demonstrates that most patients with neurologic involvement secondary to complicated sinusitis show eventual resolution of neurological deficits . However, patients with certain complications, including subdural empyemas and dural sinus thromboses, often suffer from significant morbidity [8-10]. This includes residual motor neurological deficits, cognitive and behavioral problems, or persistent seizures, potentially affecting up to 50% of survivors . Mortality and long-term neurological deficits still occur frequently despite advancements in workup and treatment . In a case series published by the Journal of the American Medical Association in 2006, researchers at the Children's Hospital of Philadelphia followed 25 children with intracranial complications secondary to sinusitis who were treated between January 1, 1999, and April 30, 2004 . Most of the patients in this series were male (76%, n=19), with a mean age of 13.5 years. All patients were healthy at presentation, with a median duration of 12 days of symptoms including headache, fever, nausea, and/or vomiting. Fifty-eight percent of patients had some form of neurological deficit at the time of presentation, with altered mental status being the most common. The presence of neurologic signs and symptoms at the time of presentation was correlated with the type of sinusitis complication as well as prognosis. In the patients with no central neurologic findings, nearly all patients had an epidural abscess. In contrast, patients presenting with at least one neurologic finding were more likely to have a more serious complication including meningitis, encephalitis, cerebral abscess, subdural empyema, and dural sinus thrombosis. In addition, patients in this group were more likely to have short-term sequelae including seizures and hemiparesis. Eight patients had to be placed on prophylactic phenytoin of various duration; six of these patients were identified as having subdural empyema. Epidural abscesses have a more favorable prognosis because they progress more slowly in comparison to subdural empyema. The subdural empyema spreads rapidly and freely within a preformed space, typically resulting in a more fulminant, acute presentation with earlier development of neurologic deficits. In a more recent retrospective study also conducted at the Children's Hospital of Philadelphia in 2021 , researchers looked at 54 patients admitted for operative management of sinusitis with intracranial extension. Like the older case series, there was a male predominance among the patients, and the average age was 11 years. The median duration of symptoms before hospitalization was seven days and less than one-third of patients reported neurological symptoms at the time of presentation. It is important to note that in this study, nearly all (89%) of patients had a healthcare visit in the days leading up to admission, and 50% were prescribed antibiotics. Those who had a subdural empyema proved to have a poorer prognosis and/or further complications; those who required repeat surgery were significantly more likely to have been diagnosed with a subdural empyema. The uniqueness of this case arises from the multiple self-resolving episodes of focal neurologic deficits and, ultimately, full neurologic recovery. There is limited information detailing the progression and spontaneous resolution of simultaneous neurological deficits, cranial nerve palsies and hemiparesis, after having multiple areas of involvement. There are no standard guidelines or recommendations for the management of intracranial complications of sinusitis; treatment varies by the clinical institution. While most pediatric patients with intracranial complications underwent some form of neurosurgical and otolaryngological intervention, gold-standard surgical management has not been fully established . Conclusions The current case and prior literature emphasize the importance of providers having a high index of suspicion for complications in patients with known sinusitis who present with symptoms greater than one week. This is especially true for those who do not improve despite appropriate antibiotic treatment. Providers should have a low threshold for obtaining prompt neuroimaging with CT or MRI, as symptoms of infection extension may be subtle. Simultaneously, broad-spectrum intravenous antibiotics should be initiated after prompt recognition. This case demonstrates that care of these patients should be multidisciplinary, with a team of hospitalists, intensivists, neurologists, neurosurgeons, otolaryngologists, infectious disease specialists, and hematologists in the event of thrombosis, as well as rehabilitation (physical, occupational, and speech therapists) for those with residual neurological deficits. We hope this case report adds to the literature of intracranial complications following pediatric sinusitis and provides further guidance for subsequent management of these complications. Chelsea-Jane Arcalas and Daniel Reich contributed equally to this work and should be considered co-first authors. Human Ethics The authors have declared that no competing interests exist. 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34789 Dermatology Family/General Practice Rheumatology Confusion With Presentations of Calcium Pyrophosphate Dihydrate Disease: A Report of Two Cases Mistaken for Cellulitis Muacevic Alexander Adler John R Rana Masooma S 1 Raza Mahanoor 2 Arif Mobeena 2 Akinpelu Taofeek 2 Waheed Abdul 34 1 Family Medicine, Aga Khan University Hospital, Karachi, PAK 2 Family Medicine, WellSpan Good Samaritan Hospital, Lebanon, USA 3 Family Medicine, Wellspan Good Samaritan Hospital, Lebanon, USA 4 Family and Community Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, USA Abdul Waheed [email protected] 8 2 2023 2 2023 15 2 e347898 2 2023 Copyright (c) 2023, Rana et al. 2023 Rana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Both pseudogout and cellulitis are diseases that may mimic one another in clinical practice. We discuss two cases of acute calcium pyrophosphate dihydrate (CPPD) arthritis mistaken for cellulitis in the emergency department. Both patients experienced significant improvement after management was changed to treat CPPD. These cases highlight how it is essential for physicians to consider CPPD as a differential diagnosis for a patient that is presenting with signs of inflammation in any joint. pseudogout crystal arthropathy pseudocellulitis cellulitis cppd arthritis calcium pyrophosphate dihydrate crystal deposition The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Pseudogout is a crystal-induced arthropathy resulting from acute calcium pyrophosphate dihydrate (CPPD) crystal deposits in the joints. Pseudogout can have multiple presentations, ranging from asymptomatic to more severe destructive polyarticular arthritis . Patients may present with fevers and chills lasting weeks, and lab results may be nonspecific for inflammatory or infectious etiologies . Cellulitis is a much more common cause of inflammation caused by a break in the skin barrier resulting in bacterial infection of the skin's subcutaneous and deep dermis layers . Systemic involvement is also present, and patients may have leukocytosis, elevated C-reactive protein levels, and increased erythrocyte sedimentation rate . Due to its non-specific symptomology, cellulitis can mimic many other conditions, including gout, osteoarthritis, septic arthritis, and pseudogout . Despite multiple reports of gout misdiagnosed as pseudo-cellulitis, few studies have compared these diseases [5-8]. This report describes two cases initially misdiagnosed as cellulitis and later identified as CPPD and successfully treated. Case presentation Case 1 An 83-year-old female presented to the Good Samaritan Hospital (Lebanon, USA) emergency room via emergency medical services on August 8, 2021, with complaints of bilateral leg swelling and pain lasting two days. She described a burning, non-radiating, dull ache, which was worse in the left foot. The pain, rated 8/10 on the pain scale by the patient, was exacerbated by ambulation. Her left foot was extremely tender on palpation. A blister also was present on the left foot. She had a medical history of hypertension, type 2 diabetes with insulin use, mixed hyperlipidemia, glaucoma, left foot fracture and metal plate insertions, right nephrectomy in 2014 for renal cell carcinoma, anemia of chronic disease, parathyroidectomy for parathyroid adenoma in 2015, and open reduction and internal fixation of right femur in 2020. The patient was also diagnosed with CPPD in April 2019 after discovering intracellular pyrophosphate crystals in a fluid analysis of a left ankle joint aspiration. However, the patient did not follow up with rheumatology, and appropriate treatment was not sought. On admission, she was taking amlodipine, metoprolol, hydralazine, lovastatin, and multiple eye drops. A review of systems was positive for bilateral edema and negative for trauma, fevers, chills, chest pain, and shortness of breath. On arrival, the patient was vitally stable with a blood pressure of 134/59 mmHg, heart rate of 89 beats per minute, respiratory rate of 18 breaths per minute, a temperature of 37.7 degC (99.9 degF), and oxygen saturation (SaO2) of 96% on room air. On examination, she appeared uncomfortable with limited lower extremity motion, marked left ankle swelling with warmth and erythema, and a bulla on the dorsal aspect of the left foot . Her sensation, strength, and distal pulses were intact and equal in the bilateral lower and upper extremities. Given the unclear initial picture and the patient's complex medical history, a broad list of differential diagnoses including cellulitis, venous insufficiency, myxedema, nephrotic syndrome, deep venous thrombosis of the lower extremity, and pseudogout were considered. Figure 1 Lower extremity physical findings showing left ankle swelling and a bulla on the dorsal aspect of the left foot Initial laboratory results were significant for troponin elevation of 0.04 ng/mL, which increased to 0.11 ng/mL (reference range: <0.03 ng/mL); B-type natriuretic peptide of 277 pg/mL, which increased to 380 pg/mL (reference range: <100 pg/mL), C-reactive protein of 134.9 mg/L (reference range: <10 mg/L); and sedimentation rate of 73 mm/hr (reference range: 0-30 m/hr). An electrocardiogram (EKG) showed a new left anterior fascicular block and new nonspecific ST and T wave abnormalities . A plain-film chest radiograph showed mild cardiomegaly. A bilateral lower extremity ultrasound was unremarkable. The X-rays of the left foot and ankle showed a small calcaneal spur, degenerative changes in tarsal metatarsal joints, and soft tissue swelling . Figure 2 Electrocardiogram in sinus rhythm with left anterior fascicular block and nonspecific ST and T wave abnormalities Figure 3 X-rays of the left foot and left ankle show a metallic plate with screws along the distal diaphysis of the third metatarsal bone (green arrow), a small calcaneal spur (red arrow), some osteopenia, degenerative changes in tarsal metatarsal joints, and soft tissue swelling The patient was initially treated with cefepime for cellulitis, but after a thorough chart review and discovery of the previous diagnosis of CPPD in her left ankle, antibiotics were stopped and prednisone and colchicine started instead. The patient found instant relief in symptoms after this medication adjustment. Cardiology was consulted due to the elevated troponin and EKG changes, but the patient's symptoms were not considered true acute coronary syndrome due to the absence of classic symptoms. She was thus treated conservatively for type 1 versus type 2 myocardial infarction (MI) with aspirin, metoprolol, and lovastatin. The patient was discharged on August 24, 2021, to acute rehab with a prednisone taper and continued colchicine for pseudogout prophylaxis. Colchicine was discontinued after discharge from acute rehab. Case 2 A 73-year-old male with a medical history significant for atrial fibrillation, cardiomyopathy, chronic obstructive pulmonary disease, previous deep venous thrombosis, hypertension, hyperlipidemia, and stage III adenocarcinoma of the lung was referred to the Good Samaritan Hospital emergency room from the orthopedic clinic on February 20, 2022, for atraumatic left wrist pain and swelling. The patient first noticed atraumatic left thumb pain two days earlier after receiving chemotherapy through a right upper extremity port. Over the next few days, he noted an increase in pain and swelling in his left hand tracking proximally into his wrist. He rated the pain as 6/10 overall, periodically increasing to 10/10. There was associated warmth and erythema, but he denied trauma to the area, fevers, chills, and any history of inflammatory arthritis or gout. He was taking hydrocodone and acetaminophen in combination on an as-needed basis, providing mild relief for his pain. During the in-office orthopedics evaluation, potential differential diagnoses for his symptoms were discussed, including trauma, cellulitis, septic arthritis, flexor tenosynovitis, and inflammatory arthritis. The orthopedics team felt he was demonstrating signs of cellulitis in the left hand and would benefit from evaluation in the emergency department, along with required lab work and a medicine consult for possible admission for IV antibiotics. In the emergency department, the patient's vital signs were within normal limits, and he was afebrile. His physical exam was remarkable only for diffuse swelling of the left wrist and hand without any obvious soft tissue injury. There was warmth but no erythema and acute tenderness of the triangular fibrocartilage complex, scaphotrapeziotrapezoid joint, and thumb extensor retinaculum. Strength was intact in the upper and lower extremities. The sensation of the median, radial and ulnar nerves was intact on the left hand, with easily palpable radial and ulnar pulses. Initial laboratory results were significant for elevated creatinine from his baseline, indicating a possible acute kidney injury. Additionally, he had low hemoglobin and platelets but was at his baseline given his cancer history. His C-reactive protein was 38.3 mg/L (reference range: <10 mg/L) and the sedimentation rate was 34 mm/hr (reference range: 0-30 mm/hr), representing an inflammatory process. The X-rays of the left hand and wrist showed mild soft tissue calcification of the wrist in the triangular fibrocartilage complex and between the lunate and triquetral bones. Figure 4 X-rays of the left hand show mild soft tissue calcification of the wrist in the triangular fibrocartilage complex (green arrow) and between the lunate and triquetral bones (red arrow) Figure 5 X-rays of left wrist showing mild soft tissue calcification of the wrist in the triangular fibrocartilage complex (Green Arrow) and between the lunate and triquetral bones (Red Arrow) Sepsis was considered as tachycardia may be masked by the beta-blocker, and fever may be masked by acetaminophen. His white blood cell count also may have been falsely normal due to his immunocompromised state, but clinically the patient did not appear septic. We initiated intravenous fluids and antibiotics for 24 hours for possible cellulitis and stopped when blood cultures came back negative. Due to localized tenderness of the joints, pseudogout was suspected. A loading dose of colchicine and 40 mg of prednisone were initiated. The next day, the swelling had subsided. The patient was instructed to continue taking 40 mg prednisone for three more days to complete a total of five days and to take 0.6 mg colchicine twice daily for the next 14 days, and then take 0.6 mg once daily until seen by rheumatology. Discussion We describe two cases of CPPD initially suspected to be other conditions. Upon diagnosis, both patients' symptoms were relieved. These two cases highlight how CPPD can be misdiagnosed because its symptomology mimics other more common diagnoses for acute inflammation, such as cellulitis. Cellulitis has an estimated prevalence of 14 million cases annually . Despite its prevalence, there is no established gold standard or reference for diagnosis. Moreover, symptoms of cellulitis are often nonspecific and observed in several non-infectious conditions, including CPPD, which can have multiple presentations and lab results that are nonspecific for inflammatory or infectious etiologies . Thus far, attempts to establish a definitive diagnosis lack specificity, feasibility, or sufficient evidence to be used in a healthcare setting . Misdiagnosis is a particular concern in the geriatric population due to the significant risk of morbidity. In the United States, about 30% of cellulitis diagnoses in the emergency department are misdiagnosed, contributing to antibiotic resistance and unnecessary healthcare costs . A retrospective cross-sectional study by Weng et al. looked at the consequences of misdiagnosing lower-extremity cellulitis and found that 79 of 269 (30%) emergency department patients were incorrectly managed; of those, 85% did not require any hospitalization and 92% received unneeded antibiotic treatment . The study estimates that more than 44,000 patients with pseudo-cellulitis are exposed to unnecessary antibiotics annually in the United States, leading to readmission rates of up to 13% and multiple complications such as GI distress, anaphylaxis, nosocomial infections, and antibiotic resistance . Cellulitis frequently affects older adults, with incidence increasing by 43% with every additional decade of age . Geriatric patients who are correctly diagnosed with pseudo-cellulitis are 86% less likely to experience complications of treatment . In a study by Bailey et al., 17% of patients with suspected cellulitis were found to have other conditions, most commonly stasis dermatitis, gout, pseudogout, and hematoma . Moreover, 8.9% of the pseudo-cellulitis cases were found to have gout or pseudogout. Warmth at the site may be a good predictor for true cellulitis, with a 2.2-fold increase in likelihood, whereas erythema, tenderness, and edema are not seen to be good predictors . Predisposing risk factors (e.g., diabetes, malignancy, and IV drug use) also show a 90% increased likelihood of true cellulitis . Patients with CPPD may have negative x-rays, and about 40% of patients have no radiological findings . Nevertheless, positive birefringent rhomboid-shaped crystals in the affected joint's synovial fluid indicate a definitive diagnosis of pseudogout. Pseudogout also may be suspected in patients with localized inflammation around one or more joints with a severely limited range of motion. The distribution of joint involvement and prior history of pseudogout can assist in forming a diagnosis . A dermatological consult also may be useful in cases with an unclear diagnosis. A clinical trial by Arakaki et al. found that outpatient dermatological consultations can help rule out cellulitis and thus reduce unnecessary antibiotic use . Further studies should be conducted to determine how to definitively diagnose cellulitis to reduce confusion between the disease and other causes of inflammation. Improving these diagnostic criteria will allow for appropriate integration of antibiotic stewardship, reduce hospital costs, and prevent hospital-acquired complications. Conclusions Gout and pseudogout represent challenging diagnoses, particularly in elderly populations due to atypical presentations and underlying comorbidities. It is therefore important to consider pseudo-cellulitis presentations such as CPPD as possible diagnoses for any patient presenting with cardinal signs of inflammation in any joint. Early and accurate diagnoses help physicians provide adequate and timely patient care to avoid unnecessary hospitalization and antibiotic use. It is essential that healthcare providers understand the underlying pathophysiology of CPPD to differentiate it from other forms of inflammatory arthritis and soft tissue inflammation. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Treatment and management of pseudogout: insights for the clinician Ther Adv Musculoskelet Dis Macmullan P McCarthy G 121 131 4 2012 22870500 2 Calcium pyrophosphate crystal deposition disease: diagnosis and treatment Open Access Rheumatol Rosales-Alexander JL Balsalobre Aznar J Magro-Checa C 39 47 6 2014 27790033 3 Cellulitis mimics in the geriatric patient Curr Geri Rep Blake AK Cruzval-O'Reilly E Sayed C 192 198 9 2020 4 The impact of dermatology consultation on diagnostic accuracy and antibiotic use among patients with suspected cellulitis seen at outpatient internal medicine offices: a randomized clinical trial JAMA Dermatol Arakaki RY Strazzula L Woo E Kroshinsky D 1056 1061 150 2014 25143179 5 Epidemiology of suspected wrist joint infection versus inflammation J Hand Surg Am Skeete K Hess EP Clark T Moran S Kakar S Rizzo M 469 474 36 2011 21186086 6 Gemcitabine-induced pseudocellulitis: a case report and review of the literature Curr Oncol Bami H Goodman C Boldt G Vincent M 0 26 2019 7 An unusual case of acute chondrocalcinosis in wrist joint presenting as cellulitis Cureus Awan R Ghazanfar H Martes Pena KA Farkhad RI 0 9 2017 8 The red leg dilemma: a scoping review of the challenges of diagnosing lower-limb cellulitis Br J Dermatol Patel M Lee SI Thomas KS Kai J 993 1000 180 2019 30422315 9 Cellulitis: a review JAMA Raff AB Kroshinsky D 325 337 316 2016 27434444 10 What diagnostic strategies can help differentiate cellulitis from other causes of red legs in primary care? BMJ Edwards G Freeman K Llewelyn MJ Hayward G 0 368 2020 11 Costs and consequences associated with misdiagnosed lower extremity cellulitis JAMA Dermatol Weng QY Raff AB Cohen JM 141 146 153 2017 27806170 12 Outcomes of early dermatology consultation for inpatients diagnosed with cellulitis JAMA Dermatol Li DG Xia FD Khosravi H 537 543 154 2018 29453874 13 Predictors Help Differentiate Cellulitis From Its Imitators | MDedge Family Medicine 9 2022 2011 14 European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis Ann Rheum Dis Zhang W Doherty M Bardin T 563 570 70 2011 21216817 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34844 Infectious Disease Neurosurgery Orthopedics Acute Lumbar Pyogenic Spondylitis With Multiple Abscesses Complicated by a Septic Shock That Required Emergency Surgical Open Drainage: A Case Report Muacevic Alexander Adler John R Kurita Takumi 1 Tatsumura Masaki 1 Eto Fumihiko 1 Funayama Toru 2 Yamazaki Masashi 2 1 Department of Orthopaedic Surgery and Sports Medicine, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, JPN 2 Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, JPN Masaki Tatsumura [email protected] 10 2 2023 2 2023 15 2 e348442 2 2023 Copyright (c) 2023, Kurita et al. 2023 Kurita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We treated a patient with pyogenic spondylitis complicated by septic shock, who was saved by emergency surgery. The patient was a 75-year-old man with back pain, fever, and weakness in the lower limbs four days before. Upon admission to our hospital, he had tachycardia, tachypnea, fever, and fluctuating vital signs. His quick sequential organ failure assessment (SOFA) score was 2. Emergent magnetic resonance imaging showed scattered intramuscular abscesses and an epidural abscess. Gram-positive cocci were detected in a blood sample. He was diagnosed with pyogenic spondylitis complicated by sepsis. Intravenous antimicrobial therapy with cefepime, vancomycin, and clindamycin was added. However, he developed tachycardia and hypotension three hours after arrival at our hospital, so he received a blood transfusion and noradrenaline and underwent emergent surgical open drainage since percutaneous drainage was difficult to perform because of scattered abscesses. Paralysis of the proximal lower extremities was recovered after surgery. Postoperatively, the causative organism was found to be methicillin-susceptible Staphylococcus aureus and intravenous antimicrobial therapy for 81 days. Three years after surgery, the patient remains free of recurrence with improvement in the activity of daily living to the extent that he could walk. The outcome of our patient suggests that surgery may be a lifesaving measure in cases whose uncontrollable vital signs by pyogenic spondylitis are complicated by sepsis. Preoperative judgment is extremely important in difficult-to-control cases because surgical invasion can be lethal. a lethal case open drainage a case report successful treatment emergency surgery septic shock epidural abscess intramuscular abscesses pyogenic spondylitis acute phase The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction The number of patients with pyogenic spondylitis has increased in recent years. The reasons for the increase in such patients include an aging population, lifestyle-related diseases, and drug-induced immunodeficiencies . The basic treatment strategy for pyogenic spondylitis consists of broad-spectrum antimicrobial agents given early during the diagnostic workup, with reviewing and de-escalation of the agents based on the results of blood cultures. In most cases, conservative treatment should be effective. If it is not effective, percutaneous drainage or surgery may be used. The surgical option is commonly used after the patient has stable vital signs because vital signs are unstable in the acute phase of septic shock . In this report, we describe a patient in the acute stage of pyogenic spondylitis complicated by septic shock, who received life-saving emergency surgery. Some physicians may abandon emergency surgery for such systemic infectious diseases because it may not be life-saving. We hope that they will be encouraged by our successful experience, which we hope will lead to saving lives. Case presentation The patient was a 75-year-old man with an unremarkable past medical history. He had no history of diabetes and was in good health with no regular medication prior to this pyogenic spondylitis complicated by sepsis. He had been admitted to a previous hospital with chief complaints of back pain, fever, and weakness of the lower limbs. Four days after admission he developed problems with defecation and was referred to our hospital because an intestinal obstruction was suspected. Upon admission to our hospital, the patient was disorientated, with tachycardia at 130 beats/min, tachypnea at 34 breaths/min, fever of 38.7degC, and fluctuating vital signs. His quick sequential organ failure assessment (SOFA) score was 2. Physical examination revealed loss of the rectoanal reflex, motor paralysis of the lower extremities, and grade 2 on the manual muscle test (MMT). The results of blood tests showed the following: white blood cells 23,300 cells/mL, C-reactive protein 35.7 mg/dL, and lactate 4.14 mMol/L. The patient was considered critical because of the severe inflammatory findings. His platelet count was low (67,000 cells/mL), and his coagulation capacity was slightly decreased (prothrombin time international normalized ratio 1.14 and activated partial thromboplastin time 43.0 sec) (Table 1). Emergent lumbar magnetic resonance imaging (MRI) showed intradiscal edema, scattered intramuscular edema near the spinous processes, and epidural edema which were considered abscesses . Gram-positive cocci were detected in a blood sample. Table 1 Results of blood testing at the time of admission. The results of blood tests showed the following: white blood cells 23,300 cells/mL, C-reactive protein 35.7 mg/dL, and lactate 4.14 mMol/L. The patient was considered critical because of the severe inflammatory findings. His platelet count was low (67,000 cells/mL), and his coagulation capacity was slightly decreased (prothrombin time international normalized ratio 1.14 and activated partial thromboplastin time 43.0 sec). Category Test Unit Result Reference Values Biochemical Blood Test Albumin (g/dL) 1.7 3. Nitrogen (mg/dL) 52 8.0-22 Creatinine (mg/dL) 1.3 -1.2 Sodium (mEq/L) 140 136-147 Chloride (mEq/L) 101 98-109 Potassium (mEq/L) 3.8 3.6-5.0 Creatine Kinase (IU/L) 2,455 57-197 C-reactive Protein (mg/dL) 35.7 -0.3 Blood Cell Count White Blood Cell (cells/mL) 23,300 3,100-8,400 Hemoglobin (g/dL) 13.4 13.1-16.3 Platelet Count (cells/mL) 67,000 145,000-329,000 Coagulation Test Prothrombin Time International Normalized Ratio 1.14 0.90-1.15 Activated Partial Thromboplastin Time (sec) 43.0 20-40 Blood Gas pH 7.514 7.35-7.45 Partial Pressure of Carbon Dioxide (mmHg) 30.7 35-45 Partial Pressure of Oxygen (mmHg) 63.3 carbonate Ion (mMol/L) 24.2 22-26 Lactate (mMol/L) 4.14 0.4-1.6 Figure 1 Preoperative lumbar magnetic resonance imaging (MRI). a: Sagittal slice Magnetic resonance imaging (MRI) showed intradiscal edema (white arrowheads) and epidural edema that were considered abscesses and compressed the dural sac (white arrows). b, c: T2-weighted image of axial slice. MRI showed scattered intramuscular edema (white arrows) and epidural edema that were considered abscesses and compressed the dural sac (white arrowheads). Altogether, the patient's findings were diagnosed as pyogenic spondylitis complicated by sepsis. The patient began receiving intravenous antimicrobial therapy that consisted of cefepime (CFPM) (2 g twice daily), vancomycin (VCM) (1 g twice daily), and clindamycin (CLDM) (600 mg four times daily), which commenced 15 minutes after the patient arrives at the hospital. However, he developed tachycardia and hypotension three hours after arrival at our hospital, so he received a blood transfusion and noradrenaline for serious shock vital and underwent emergent surgical open drainage since percutaneous drainage was difficult to perform because of scattered abscesses. Incision of the lumbodorsal fascia allowed white-colored pus to drain from the paraspinal muscles , and necrotic fatty tissue was observed around the dural sac . Because of a large volume of bleeding during the surgical approach, the epidural vein was enlarged and coagulated. Platelets and fresh-frozen plasma transfusions were also administered during the procedure because of the patient's low platelet count and coagulation dysfunction. Figure 2 Intraoperative findings. a: Surgical site after splitting the lumbodorsal fascia white-colored pus was observed (black arrows). b: Surgical site after laminectomy. Necrotic adipose tissue was present around the dural sac (black arrows). On the first postoperative day, the patient's vital signs became stabilized, and noradrenaline was discontinued. On the second postoperative day, the organism in the blood culture was identified as methicillin-susceptible Staphylococcus aureus, and the CFPM was changed to cefazolin (CEZ) 2 g four times a day intravenously. Blood samples were taken for culture every three days and turned negative 12 days after surgery. An MRI performed 81 days after surgery appeared to show the resolution of the abscess, and intravenous antimicrobial therapy was stopped . Figure 3 Antimicrobial therapy and C-reactive protein (CRP) after arrival at the hospital. The patient's antimicrobial agents were changed after the identification of the causative organism. Thereafter, there was neither increase in CRP nor a recurrence of signs and symptoms, and antimicrobial therapy was continued for 81 days after surgery when the abscess was found to have disappeared. CRP: C-reactive protein, VCM: Vancomycin, CFPM: Cefepime, CLDM: Clindamycin, CEZ: Cefazolin, S. Aureus: Staphylococcus aureus MMT of the proximal lower extremities was recovered to grade 5 bilaterally in the iliopsoas muscles and 4 bilaterally in the quadriceps muscles. But MMT of the distal lower extremities showed poor recovery in the tibialis anterior muscles (grades 2 right and 1 left) and 0 bilaterally in the extensor digitorum longus, flexor digitorum longus, and gastrocnemius muscles. Three years after surgery, the patient remains free of recurrence with improvement in the activity of daily living to the extent that he could walk for approximately 20 minutes with the use of a short leg brace. Discussion Although there are no guidelines for the treatment of pyogenic spondylitis complicated by sepsis, there are reports of good outcomes achieved by treatments that were based on the practice guidelines for the treatment of sepsis . The guidelines for sepsis state that an early diagnosis of sepsis by the SOFA or the quick SOFA followed by lifesaving measures that include resuscitation are the highest priorities . Recommendations include the initiation of broad-spectrum antimicrobial therapy after specimens are obtained for culture, and attempts to control the infected lesions should be performed without the use of invasive procedures. Echo-guided and CT-guided drainage have been found to be less invasive and more effective . Invasive surgery is recommended for the treatment of intra-abdominal infections and soft tissue infections after the patient's general conditions improve . In our patient, the quick SOFA was used to make a prompt diagnosis of sepsis upon his arrival at our hospital, and antimicrobial agents were started after blood culture specimens were obtained. Even after antimicrobial agents were started, the patient's vital signs worsened, which included decreased blood pressure and worsening tachycardia; and the patient received support for his hypotension. After physical examination showed findings consistent with a spinal lesion, we found multiple small abscesses on MRI. Urgent open drainage was performed to control infection since a puncture was difficult to perform for drainage because of small and multiple abscesses. Rutges et al. reported that S. aureus is the most common causative organism of pyogenic spondylitis, and has high rates of complication and mortality . They recommended eight weeks of antimicrobial therapy for the treatment of S. aureus pyogenic spondylitis. Their findings suggest that pyogenic spondylitis caused by S. aureus is more frequent than pyogenic spondylitis due to other organisms, and is more likely to be severe. For our patient, we planned to administer antimicrobial therapy for six weeks after his blood cultures became negative. However, resolution of the abscesses was not achieved, and 81 days of antimicrobial therapy were required until the abscesses disappeared. The duration of therapy should be determined based on diagnostic imaging. Although it has been reported that the addition of surgical treatment does not improve the long-term prognosis , the cases of Rutges et al. that required surgical treatment may have been more severely affected than the patients who were treated conservatively . The impact of surgery on outcomes warrants further study. Early surgical intervention is recommended for cases of pyogenic spondylitis that are resistant to conservative treatment or are complicated by severe bone destruction, neuropathy, or spinal instability [5-7]. Anemia, hypoalbuminemia, multiple intervertebral lesions, and epidural abscesses have been reported as factors associated with resistance to conservative treatment . Our patient showed neuropathy, hypoalbuminemia, and an abscess in the epidural space; findings that were consistent with the recommendation for emergent surgical treatment. However, since previous reports have not reported detailed vital signs, we believe that it is essential to take the acute phase treatment of the disease to the individual patient. Additionally, with regard to pyogenic spondylitis, a previous study on the outcomes of patients with epidural abscesses found that neurological outcomes were significantly better when interventional treatment was initiated within 36 hours and significantly worse with diffuse lesions . The same study also reported that two of 27 patients died, and only 40% of the patients had resolution of their signs and symptoms even with appropriate therapeutic intervention, which is a very poor study outcome . The risk factors for death included older age, medical comorbidities, elevated white blood cell counts, low platelet counts, low albumin levels, septic shock before and after surgery, cardiac arrest, pneumonia, multiple blood transfusions, and the presence of motor dysfunction . Most of these factors are associated with the presence of chronic comorbidities and the patient's poor condition, making it difficult to intervene after the onset of the condition. With regard to motor dysfunction, however, making an appropriate diagnosis immediately after the onset of the disorder is very important, because that allows early treatment and may improve outcomes. Our patient's risk factors included problems with mobility apparent four days before surgery and disturbed intestinal motility. Septic shock developed on the day of surgery. Although the patient had risk factors for death and poor functional prognosis because several days elapsed from the onset of his signs and symptoms to intervention, we were able to save the patient's life. Risks of the recurrence of the condition include a history of intravenous drug injection, disordered intestinal motility at presentation, and local infection after surgery . Our patient did not develop recurrence, and his general condition and motor paralysis improved over time. Although emergency surgery is sometimes recommended in septic shock, many physicians hesitate to perform spine surgery because of the invasive procedure and the difficulty in accessing the lesion. However, there are cases that can be saved through collaboration among spine surgeons, anesthesiologists, intensive care physicians, and infectious disease physicians. There is a concern when cases similar to our case are encountered. Our patient's vital signs were controlled with the use of vasopressor agents, but preoperative judgment is extremely important in difficult-to-control cases because surgical invasion can be lethal. In addition, the use of vasopressor agents in surgery and postoperative systemic management requires the cooperation of many specialists, including anesthesiologists, emergency room physicians, and infectious disease specialists. Thus there may be patients for whom the treatments we used would be difficult to administer in different hospitals based on the available specialties of each hospital. Conclusions We treated a patient with pyogenic spondylitis complicated by septic shock, who was saved by emergency surgery and comprehensive treatment including antimicrobial administration. The outcome of our patient suggests that surgery may be a lifesaving measure in cases whose uncontrollable vital signs by pyogenic spondylitis are complicated by sepsis. Preoperative judgment is extremely important in difficult-to-control cases because surgical invasion can be lethal. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study. The Institutional Review Board of Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital issued approval 21-16. All procedures including the review of the patient record used in this research were approved by the Institutional Review Board of Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital. Verbal informed consent was obtained from the patient and her parents to participate in this study. References 1 Preventing and treating discitis: cephazolin penetration in ovine lumbar intervertebral disc Eur Spine J Walters R Rahmat R Fraser R Moore R 1397 1403 15 2006 16830132 2 2015 Infectious Disease Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults Clin Infect Dis Berbari EF Kanj SS Kowalski TJ 0 46 61 2015 3 A comprehensive treatment strategy for severe pyogenic spondylitis, including orthopedic surgery, in compliance with Surviving Sepsis Campaign Guidelines [Article in Japanese] J Spine Res Koakutsu T Onoda Y Oyanagi T Aizawa T 110 118 13 2022 4 Outcome of conservative and surgical treatment of pyogenic spondylodiscitis: a systematic literature review Eur Spine J Rutges JP Kempen DH van Dijk M Oner FC 983 999 25 2016 26585975 5 Early surgery with antibiotic medication was effective and efficient in treating pyogenic spondylodiscitis BMC Musculoskelet Disord Guo W Wang M Chen G 288 22 2021 33736624 6 A study of pyogenic spondylitis requiring emergency surgery [Article in Japanese] J West Jpn Res Soc Spine Baba H Adachi K Tsuda K 87 90 34 2008 7 Treatment of thoracolumbar pyogenic spondylitis with minimally invasive posterior fixation without anterior lesion debridement or bone grafting: a multicenter case study J Clin Med Gamada H Funayama T Yamaji A 932 12 2023 36769580 8 Predictors of conservative treatment for pyogenic spondylitis Spine Surg Relat Res Kugimiya F Muraki S Nagakura D Umekoji H Oda H Takahashi K 135 139 1 2017 31440624 9 Spinal epidural abscess: report on 27 cases Surg Neurol Int Khursheed N Dar S Ramzan A 240 8 2017 29026676 10 Spinal epidural abscess: diagnosis, management, and outcomes J Am Acad Orthop Surg Schwab JH Shah AA 0 38 28 2020 11 Independent predictors of spinal epidural abscess recurrence Spine J Shah AA Yang H Ogink PT Schwab JH 1837 1844 18 2018 29649612 |
BJA Open BJA Open BJA Open 2772-6096 Elsevier S2772-6096(23)00010-2 10.1016/j.bjao.2023.100131 100131 Case Report Perioperative fatal thrombotic complication after elective meningioma resection in asymptomatic SARS-CoV-2 BA.5.2 (Omicron variant) infection Lavinio Andrea [email protected] 1* Cammarano Cinzia 2 1 Neurosciences and Trauma Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 2 Department of Anaesthesia, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK * Corresponding author. [email protected] 13 3 2023 6 2023 13 3 2023 6 1001311 12 2022 6 2 2023 6 3 2023 (c) 2023 The Author(s) 2023 This is an open access article under the CC BY license ). SARS-CoV-2 infection is associated with hypercoagulability, heparin resistance, and increased perioperative mortality and morbidity. Recommendations on screening and postponement of elective surgery after SARS-CoV-2 infection are being relaxed worldwide. We present a case of fatal thrombotic complication in an asymptomatic incidental SARS-CoV-2 infection (Omicron BA.5.2 variant, first isolated in May 2022) in a triple-vaccinated patient undergoing elective resection of frontal meningioma. The assumption that asymptomatic infection with more recent SARS-CoV-2 variants does not add any perioperative risk remains to be demonstrated. Based on the presented case of unexpected fatal thrombotic perioperative complication in a triple-vaccinated, asymptomatic BA.5.2 SARS-CoV-2 Omicron infection, it would seem prudent to continue to screen for asymptomatic infection and to systematically audit perioperative outcome. Evidence-based perioperative risk stratification of elective surgery in asymptomatic patients with Omicron or future COVID variants relies on reporting of perioperative complications and prospective outcome studies, which would rely on continued systematic preoperative screening. Keywords elective surgery neuroanaesthesia perioperative death SARS-CoV-2 thrombosis Handling Editor: Phil Hopkins pmcSARS-CoV-2 infection, whether symptomatic or not, is associated with a three-fold increase in perioperative mortality risk throughout 6 weeks after infection. Viral variants differ in terms of their transmissibility, the severity of illness they cause, and their ability to infect vaccinated patients.1 The Omicron SARS-CoV-2 variant, in particular, is characterised by less severe symptoms; increased transmissibility; and the potential to evade immunity acquired through previous SARS-CoV-2 infection, vaccination, or both.2 Limited data are currently available on perioperative risk stratification in vaccinated patients with asymptomatic infection by the Omicron variant. Therefore, previous recommendations that, where possible, patients should avoid elective surgery within 7 weeks of SARS-CoV-2 infection remain, unless the benefits of proceeding exceed the risk of waiting.3 Case report This case report is published with the written consent of the patient's next of kin. A 72-yr-old female with a background of Type 2 diabetes and hypertension treated with metformin and ramipril, respectively, presented with a history of worsening mild left-sided weakness and frequent falls. The patient had also suffered a nondisplaced right ankle fracture approximately 4 months before surgery, which had been treated conservatively and had not restricted her ability to mobilise with the support of a frame. External examination on admission to hospital did not reveal lower-limb swelling, residual pain, or any other signs of deep vein thrombosis. Brain imaging revealed a right frontal meningioma of approximately 5 cm in diameter with perilesional oedema and mass effect. The patient was admitted to Addenbrooke's Hospital, Cambridge, UK for elective resection of the tumour. Her neurological status on admission was Glasgow Coma Scale (GCS) 15, with mild left-sided weakness affecting upper and lower limbs. The patient was triple-vaccinated against Covid-19 and was deemed to be immunocompetent, and her admission SARS-CoV-2 polymerase chain reaction (PCR) screening test was negative. Hospital screening policies have evolved and changed throughout the SARS-CoV-2 pandemic in accordance with WHO directives. At our hospital, routine screening was stopped in September 2022 for all asymptomatic patients admitted for elective and non-elective procedures, unless immunocompromised. As the SARS-CoV-2 screening testing policy had just changed for hospital admission, a SARS-CoV-2 PCR test was performed. This returned a negative result. Because of significant perilesional oedema, a decision was made to postpone surgery until 6 days after admission for preoperative treatment with dexamethasone 4 mg twice daily. Prophylactic dalteparin 5000 units was administered subcutaneously daily from the day of admission until the evening before surgery. Non-pharmacological prophylaxis consisted of Thrombo-Embolus Deterrent Stockings through hospitalisation and intermittent pneumatic calf compressors during surgery. On the morning of surgery, preoperative vital signs and blood results were within expected ranges, with the exception of a slightly reduced activated partial thromboplastin time of 23.7 s (reference: 26.7-35.7 s) and prothrombin time of 10.0 s (reference: 10.3-12.9 s). A second SARS-CoV-2 screening sample was taken on the morning of surgery. The result of this second test was still pending at the time of anaesthetic induction, and surgery proceeded in accordance with local policy, which did not require a repeated negative sample. After uneventful induction of general TIVA, the patient was established on intermittent positive-pressure ventilation in the supine position and the head secured in a Mayfield clamp. Mannitol 10%, 100 ml was administered shortly after induction. Stealth navigation was set up. This was followed by bicoronal scalp incision. The myocutaneous flap was raised. After craniotomy, a frontal bone flap was raised. Despite stable heart rate and blood pressure, the early intraoperative course was characterised by a significant base deficit (base excess [BE] -11.1 mmol L-1 at baseline, after anaesthetic induction) and metabolic acidosis with a mild lactic acidaemia (lactate 2.6 mmol L-1) of unclear cause, which improved transitorily and incompletely with fluid resuscitation (4 L crystalloids and 2 units of packed red blood cells). Pulmonary gas exchange remained normal throughout surgery. The tumour was exposed and debulked uneventfully, and the bone flap was replaced with plates and screws and the scalp closed in layers. Emergence from anaesthesia appeared to be uneventful, and the trachea was extubated approximately 5 h after induction with stable vital signs and neurology (GCS E3V4M6). The base deficit before extubation had reduced to BE -6.0 mmol L-1. Sudden neurological deterioration occurred approximately 15 min after extubation (GCS E1V2M5) with pupils equal and reactive. The patient was re-anaesthetised with propofol and remifentanil, and the airway was secured with maintenance of normal vital signs throughout. Around this time, the SARS-CoV-2 PCR test that had been sampled in the morning was returned as positive and sequenced as a BA.5.2 2019 nCOV Omicron variant, first isolated May 2022.2 Emergency postoperative CT demonstrated unexpected left frontal haemorrhagic infarct, likely to represent a venous infarction, pneumoencephalus, and subdural haematoma and also hypodensities of the posterior circulation. Under general anaesthesia, the previous incision was reopened and the craniotomy flap raised, revealing a tense brain. The small subdural haematoma was evacuated, and an intraparenchymal intracranial pressure (ICP) monitor was placed to facilitate postoperative management and neuroprotection. The time trend of plasma fibrinogen indicated an acquired hypercoagulability state, with fibrinogen increasing from normal concentrations (reference range: 1.5-3.3 g L-1) preoperatively to 4.2 g L-1 postoperatively and peaking at 6.5 g L-1 during the neuroscience intensive care unit stay. Despite maximal medical treatment, the multifocal intracranial infarcts detected by the CT head performed at admission to neuroscience critical care progressed to hypodense lesions affecting bilateral frontal, occipital, and temporal lobes and of the basal ganglia, with resulting bilateral uncal herniation compressing the midbrain (Fig 1c).Figure 1 (a) Preoperative MRI: 5 cm right frontal meningioma with associated oedema. (b) Postoperative CT (Day 0): unexpected left frontal haemorrhagic infarct likely to represent venous infarction and new posterior circulation bilateral hypodensities. (c) Postoperative CT (Day 5): evolution of multifocal infarcts with obliterated basal cisterns and sulci, and uncal herniation. Figure 1 Refractory ICP with ICP >80 mm Hg and diabetes insipidus developed, indicating fatal and irreversible neurological injury. Active care was withdrawn, and death was confirmed on the 12th day after surgery. Discussion We present a case of unexpected fatal venous and arterial thrombotic complications of an asymptomatic incidental SARS-CoV-2 infection (Omicron BA.5.2 variant) in a triple-vaccinated patient undergoing elective resection of a frontal meningioma. Since the first wave of the pandemic, it became evident that symptomatic SARS-CoV-2 infection was associated with profound hypercoagulability and heparin resistance.4,5 Asymptomatic SARS-CoV-2 infection was also associated with a significant increase in perioperative morbidity and mortality, leading to recommendations to postpone elective surgical procedures for at least 7 weeks after infection.2 In view of widespread vaccination, milder symptoms associated with more recent Omicron variants, and the significant backlog of patients awaiting surgery, there might be an opportunity to safely relax such recommendations. It is important to note that for oncology patients undergoing surgery, requiring expedited surgery, delayed surgical treatment during non-pandemic and pandemic settings has been shown to be associated with worse overall survival when compared with timely surgical treatment.6,7 As such, the balance between the risk of postoperative complications associated with SARS-CoV-2 infection and the risk of worse overall survival associated with delayed surgical treatment should be carefully discussed at a multidisciplinary level and implemented in a patient-shared decision-making pathway. The near-complete cessation of elective surgery worldwide and the curtailment of all but the most urgent and emergency cases attributable to the SARS-CoV-2 pandemic have burdened health systems for years to come. Barie and colleagues7 estimated that the backlog of cases was already more than 28 million in June 2020 worldwide. They suggested that the temptation to sacrifice rigor for speed in resuming elective surgery must be avoided. Crucial elements of a resumption programme include awareness of the status of the pandemic and testing, globally and locally.7 Based on proportionate review of medical records and after coronial review, SARS-CoV-2 was included in the medical certificate of cause of death as a 'causative factor' (1b) for our patient. This conclusion was based on otherwise unexpected cerebral venous and arterial infarcts leading to a fatal outcome despite adequate pharmacological thromboprophylaxis, and a concomitant increase in fibrinogen concentrations, typically associated with severe COVID-19. A post-mortem was not held. Whilst this causative link is probabilistic rather than deterministic, it seems reasonable to conclude that the assumption that asymptomatic or mildly symptomatic infection does not add risk remains to be demonstrated. Evidence-based guidelines to safely restore surgical activity are urgently needed. Based on the present case of unexpected fatal thrombotic perioperative complication in a triple-vaccinated, asymptomatic BA.5.2 n-SARS-CoV2 (Omicron) infection, it would seem prudent to continue perioperative screening for asymptomatic SARS-CoV-2 infection. Whilst it may be safe to perform surgery on asymptomatic or recently recovered patients, robust risk stratification must rely on prospective screening and perioperative outcome monitoring. Authors' contributions Writing, editing of the case study, discussion and figures, and clinical care: both authors. Declarations of interest The authors declare they have no conflicts of interest. Acknowledgements The authors acknowledge the family of the patient for allowing them to publish this article. The authors also thank the Department of Anaesthesia, the Department of Neurosurgery, and the Medical Examiner Service at Cambridge University Hospitals NHS Foundation Trust for their support. References 1 Bhattacharyya R.P. Hanage W.P. Challenges in inferring intrinsic severity of the SARS-CoV-2 Omicron variant N Engl J Med 386 2022 e14 35108465 2 Khan K. Farina Karim F. Ganga Y. Omicron BA.4/BA.5 escape neutralizing immunity elicited by BA.1 infection Nat Commun 13 2022 4686 35948557 3 El-Boghdadly K. Cook T.M. Goodacre T. Timing of elective surgery and risk assessment after SARS-CoV-2 infection: an update. A multidisciplinary consensus statement on behalf of the association of anaesthetists, centre for perioperative care, federation of surgical specialty associations, royal college of anaesthetists, royal college of surgeons of England Anaesthesia 77 2022 580 587 35194788 4 White D. MacDonald S. Bull T. Heparin resistance in COVID-19 patients in the intensive care unit J Thromb Thrombolysis 50 2020 287 291 32445064 5 Thomas W. Varley J. Johnston A. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom Thromb Res 191 2020 76 77 32402996 6 Deng J.Z. Chan J.S. Potter A.L. The risk of postoperative complications after major elective surgery in active or resolved COVID-19 in the United States Ann Surg 275 2022 242 246 34793348 7 Barie P.S. Ho V.P. Hunter C.J. Surgical Infection Society guidance for restoration of surgical services during the coronavirus disease-2019 pandemic Surg Infect (Larchmt) 22 2021 818 827 33635145 |
Front Surg Front Surg Front. Surg. Frontiers in Surgery 2296-875X Frontiers Media S.A. 10.3389/fsurg.2023.1094387 Surgery Case Report A simple combined approach using anterior transpetrosal and retrosigmoid approach: A case report Tamura Ryota * Ueda Ryo Karatsu Kosuke Sayanagi Taichi Takahara Kento Hino Utaro Iwama Takashi Nogawa Hirotsugu Nakaya Masato Horiguchi Takashi Toda Masahiro Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan Edited by: Thanasis Paschalis, Cambridge University Hospitals NHS Foundation Trust, United Kingdom Reviewed by: Ishu Bishnoi, Maharaja Agrasen Medical College, India Marcio S. Rassi, Santa Casa of Sao Paulo, Brazil * Correspondence: Ryota Tamura [email protected] Specialty Section: This article was submitted to Neurosurgery, a section of the journal Frontiers in Surgery 27 2 2023 2023 10 109438710 11 2022 07 2 2023 (c) 2023 Tamura, Ueda, Karatsu, Sayanagi, Takahara, Hino, Iwama, Nogawa, Nakaya, Horiguchi and Toda. 2023 Tamura, Ueda, Karatsu, Sayanagi, Takahara, Hino, Iwama, Nogawa, Nakaya, Horiguchi and Toda This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background A combined transpetrosal approach (CTP) is often used for large lesions in the posterior cranial fossa (PCF). Although CTP provides a wide surgical corridor, it has complex and time-consuming bony work of mastoidectomy and cosmetic issues. Here, we describe a simple combined surgical technique to approach the supratentorial region, anterolateral surface of the brainstem, petroclival region, and foramen magnum by drilling only the petrous apex with a combination of retrosigmoid approach (RA). Clinical presentation A 27-year-old female was referred with extra-axial left cerebellopontine angle space-occupying epidermoid cyst extending to the prepontine cistern, anterior to the basilar artery, superior to the chiasma, and caudally to the foramen magnum. A one-stage surgical procedure using the anterior transpetrosal approach (ATP) and RA was performed after one-piece temporal-suboccipital craniotomy. These two approaches complemented each other well. Near-total removal was achieved. Conclusion A one-stage surgical procedure using ATP and RA provides the wider viewing and better visualization of the PCF with minimal technical difficulty. anterior transpetrosal approach retrosigmoid approach lateral suboccipital approach combined transpetrosal approach posterior cranial fossa skull base pmcIntroduction The anterior transpetrosal approach (ATP) is a skull base surgical procedure that can provide an operative view of the petroclival and supratentorial region (1). However, this surgical approach is not appropriate for lesions located around the lower cranial nerves (LCN) and the hypoglossal nerve (2). Posterior transpetrosal approaches, including the retrolabyrinthine, translabyrinthine, and transcochlear approaches, are based on the standard mastoidectomy, which is mainly used for large lesions in the posterior cranial fossa (PCF) from the top of the clivus to the jugular foramen (3). Furthermore, wide surgical exposure of the cerebellopontine angle (CPA) and petroclival region can be obtained via the combinational approach of anterior and posterior transpetrosal procedures (4). A combined transpetrosal approach (CTP) can minimize cerebellar and temporal lobe retraction (5). However, it may have complex and time-consuming bony work of mastoidectomy and cosmetic issues (5). The retrosigmoid approach (RA) is indicated for resection of infratentorial tumors (6). RA is simple and quick, and it does not need temporal lobe retraction. The disadvantage is the limited access to the prepontine and supratentorial regions (6). Anterior petrosectomy can overcome the limitations associated with RA (7). Therefore, the combination of ATP and RA has the possibility to result in many options for obtaining wide surgical exposure of the PCF and overcome the complex procedure of mastoidectomy. In this report, we describe a simple one-stage operation to approach the anterolateral surface of the brainstem, petroclival region, and foramen magnum (FM) by drilling only the petrous apex with a combination of RA. Case presentation Patient characteristics A 27-year-old female presented with a 4-month history of left trigeminal neuralgia and left hearing impairment followed by dizziness and headache. Fast imaging employing steady-state acquisition (FIESTA) showed an extra-axial left CPA space-occupying lesion extending to the prepontine cistern, anterior to the basilar artery, superior to the chiasma, and caudally to the FM . Tumor extended through the left internal auditory canal (IAC). It has a lobulated outline with low T1-weighted imaging (T1WI), high T2WI, and heterogeneous fluid-attenuated inversion recovery (FLAIR) signals with evident diffusion restriction . No post-contrast enhancement was seen. Preoperative axial computed tomography (CT) scan showed the development of air cells in the petrous apex. The peritubal air cell tract connecting around the Eustachian tube from the apical area of the petrous apex was identified (8). A one-stage surgical procedure using ATP and RA was planned. Figure 1 Preoperative radiographic findings. (A) FIESTA demonstrates an extra-axial lobulated mass at the left CPA, extending to the prepontine/interpeduncular cisterns as well as the ipsilateral FM, compressing the brainstem, and cranial nerves. There is also an extension into the ipsilateral IAC with encasement of the basilar artery. White arrow: tumor. (B) Axial DWI image shows bright signals in the CPA cistern. CPA, cerebellopontine angle; FM, foramen magnum; IAC, internal auditory canal. Skin incision and craniotomy The head was placed in the horizontal position, with the body in the lateral position . The skin incision began 1 cm anterior to the tragus, went cranially until the superior temporal line, turned posteriorly, then turned caudally approximately 6 cm posterior to the external auditory canal, and ended around the FM . The skin flap was elevated off the temporal muscle, pericranium, and suboccipital muscles. A temporalis fascia flap was harvested to aid subsequent dural closure. The temporal muscle was elevated and retracted anteriorly. The suboccipital muscles were elevated and retracted laterally. Figure 2 Intraoperative findings of the ATP. Microsurgical maneuvers of the ATP are shown. (A) Skin incision and patient's position (Park bench) are shown. (B) Burr-hole placement for the one-piece temporal-suboccipital craniotomy is shown. (C) Surgical field of the ATP is shown (1). The MCF dura is elevated toward the petrous ridge. The middle meningeal artery is coagulated and divided. After the GSPN is preserved, the landmarks for drilling Kawase's quadrangle are identified (2). The tentorium is opened exposing the trigeminal nerve superior to petroclival tumor. Trochlear nerve is exposed coursing over tumor before entering tentorium (3). Trigeminal nerve is compressed by tumor (4). Tumor removal of the prepontine cistern and supratentorial region is done. BA, brainstem (5), and oculomotor nerve (6) are identified. The lower limit of this exposure is the abducens nerve (7). Trigeminal nerve decompression is done (8). ATP, anterior transpetrosal approach; MCF, middle cranial fossa; AE, arcuate eminence; BA, basilar artery; EAC, external auditory canal; GSPN, greater superficial petrosal nerve; KT, Kawase's triangle; T, tumor; TI, trigeminal impression; TS, transverse sinus; SS, sigmoid sinus. A neuronavigation system was used for outlining the transverse and sigmoid sinuses. Multiple burr holes were placed as described in Figure 2B. Once the one-piece temporal-suboccipital craniotomy was completed, the bone flap was lifted off, exposing part of the supratentorial dura, PCF dura, transverse sinus, and sigmoid sinus. The squamous temporal bone was drilled flat to the middle cranial fossa (MCF) floor. Sigmoid sinus was carefully skeletonized. Anterior transpetrosal approach Microsurgical maneuvers of the ATP are shown in Figure 2C. The MCF dura is elevated toward the petrous ridge. The middle meningeal artery was coagulated and divided. Interdural temporal elevation was performed to preserve the greater superficial petrosal nerve. Dura propria overlying the trigeminal nerve was incised sharply, and dural elevation was carried out progressively. After dural elevation was turned posteriorly toward the arcuate eminence, the petrous ridge was reached. The landmarks for drilling Kawase's quadrangle were identified. Petrous apex was removed to gain access to PCF. The temporal dura matter was opened parallel to superior petrosal sinus (SPS). PCF dura matter was opened below SPS. The SPS was coagulated and cut. The tentorium was opened exposing the trigeminal nerve superior to petroclival tumor component, preserving the trochlear nerve. The porus trigeminus was opened to expose trigeminal ganglion in Meckel's cave. Near-total resection with cyst capsules of prepontine and supratentorial tumor was achieved, preserving oculomotor, trochlear and trigeminal nerves, basilar artery, superior cerebellar artery, and brainstem. The lower limit of this surgical exposure around abducens nerve was exposed. A small amount of tumor remained around the optic chiasm. Retrosigmoid approach Microsurgical maneuvers of the RA are shown in Figure 3. FM decompression was performed to increase the volume of the PCF. The dura was incised along the inferior border of the transverse sinus, and then it was carried inferiorly posterior to the sigmoid sinus. The operative corridor was widened by retracting the petrosal surface of the cerebellum. A smooth dissection was applied to detach the capsule of epidermoid cyst from facial/vestibulocochlear nerves, LCN, and hypoglossal nerve. Complete resection with cyst capsules of CPA and foramen magnum was achieved. After the IAC decompression, tumor component in the IAC was removed. Figure 3 Intraoperative findings of the LSO. Microsurgical maneuvers of the LSO are shown. Surgical field of the LSO is shown. SS is skeletonized. Foramen magnum decompression is performed (1). The dura is incised in a C-shape fashion, and the cerebellar hemisphere is gently retracted to expose the cerebellomedullary cistern (2). Tumor removal around the trigeminal nerve (3), facial/vestibulocochlear nerves (4), and LCN (5) is done. Tumors growing below vertebral artery (VA) and hypoglossal nerve are removed (5). Tumor extending into the IAC is gently removed with curette (6). The decompression is achieved by removing bone posterior and inferior to the IAC. The one-piece temporal-suboccipital bone flap is replaced and attached to the surrounding bone with titanium plates and screws (7). IAC, internal auditory canal; FM, foramen magnum; IAA, internal auditory artery; JF, jugular foramen; LCN, lower cranial nerves; T, tumor; TS, transverse sinus; SS, sigmoid sinus. This surgery took 10 h 33 min in total (ATP: 3 h 15 min; RA: 4 h 25 min; other general procedures: 2 h 53 min). Postoperative course Postoperative Diffusion-weighted imaging (DWI) displayed near-total tumor removal . FIESTA showed that the decompression of all cranial nerves is achieved in the PCF . Craniotomy size is shown in Figure 4C. Trigeminal neuralgia, headache, and dizziness were completely reduced. Abducens nerve palsy has occurred following the operation, which completely improved 1 month after the operation. The patient was discharged 10 days after the operation. Figure 4 Postoperative radiographic findings. (A) Postoperative DWI shows near-total removal of epidermoid cyst in the supra/infra tentorial regions. A small amount of tumor remains around the optic chiasm. (B) Postoperative FIESTA shows that the decompression of trochlear nerve, trigeminal nerve, facial/vestibulocochlear nerves, LCN, and hypoglossal nerve is achieved. (C) Head CT bone window images show the one-piece temporal-suboccipital craniotomy (left panel: axial view, right panel: three-dimensional reconstruction). (D) Schematic diagram illustrating the difference between this approach and CTP. FIESTA, fast imaging employing steady-state acquisition; LCN, lower cranial nerves; CTP, combined transpetrosal approach; ATP, anterior transpetrosal approach; IAC, internal auditory canal; PTP, posterior transpetrosal approach; RA, retrosigmoid approach; SC, semicircular canal. Discussion In general, CTP is used for large lesions in the PCF. Although some authors simplified CTP by minimizing the petrosectomy and mastoidectomy (9, 10), most neurosurgeons may not be familiar with these complex procedures. The RA, with which most neurosurgeons are familiar, is versatile for the treatment of different pathologies in PCF (6). This procedure facilitates the rapid identification of the neurovascular structures in CPA. However, RA could not provide an adequate exposure to the clivus and anterior/superior part of the brainstem (6). Because anterior petrosectomy can overcome the limitations associated with RA, a two-stage approach with ATP and RA has been already performed (11). In this report, a one-stage surgical procedure using ATP and RA was proposed. This approach may be simple and quick for most neurosurgeons compared with CTP. Because mastoidectomy is not required in this approach, we may avoid sigmoid sinus-associated complications. The inferior portions of the CPA are much more clearly observed via this approach than via the CTP . Furthermore, for hypervascular tumors such as meningioma, we recommend the RA procedure after the ATP, because the early coagulation of feeding arteries (the tentorial artery and the middle meningeal artery) can be performed during the ATP. However, there may be disadvantages with this approach. During the present simultaneous procedures, the microscope's visual axis has to be tilted considerably. The operator needs to change the standing position during the operation. With conventional equipment, this procedure may force the surgeon into an uncomfortable position for the manipulation of RA. The best view can be obtained through bed rotation in both directions and will mitigate the surgeon's fatigue at the same time in this combined approach. An exoscope permits us to perform stable microsurgery in a comfortable posture regardless of the angle of the operative visual axis (12). In addition to the potential hearing loss, other RA-related morbidities include cerebellar edema from retraction and venous congestion from venous thrombosis or sacrifice. Intraoperative use of an endoscope may extend the view to the corner looking at the perforator that could not be provided by microscopic view, preventing the complications (13). Further studies are warranted to confirm the merits of this combined strategy. This is a case report and thus should be further assessed using clinical studies to evaluate the practical advantages and disadvantages of this approach. Conclusions A one-stage surgical procedure using ATP and RA provides wider viewing and better visualization of the PCF with minimal technical difficulty. This simple combined procedure may be versatile for the treatment of PCF pathology. Data availability statement The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author. Ethics statement Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article. Author contributions RT conceptualized, designed, and performed the study and wrote the manuscript. RU, TS, MN, KT, KK, UH, HN, and TI assisted in the acquisition of data. TH and MT assisted with discussion and review of the manuscript. All authors contributed to the article and approved the submitted version. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Kawase T Toya S Shiobara R Mine T . Transpetrosal approach for aneurysms of the lower basilar artery. J Neurosurg. (1985) 63 :857-61. 10.3171/jns.1985.63.6.0857 4056899 2. Tomio R Horiguchi T Borghei-Razavi H Tamura R Yoshida K Kawase T . Anterior transpetrosal approach: experiences in 274 cases over 33 years. Technical variations, operated patients, and approach-related complications. J Neurosurg. (2021) 136 :413-21. 10.3171/2020.12.JNS204010 34388716 3. Gross BA Tavanaiepour D Du R Al-Mefty O Dunn IF . Evolution of the posterior petrosal approach. Neurosurg Focus. 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Hassaan SA Tamura R Morimoto Y Kosugi K Mahmoud M Abokerasha A Surgical outcomes of anterior cerebellopontine angle meningiomas using the anterior transpetrosal approach compared with the lateral suboccipital approach. Acta Neurochir (Wien). (2020) 162 :1243-8. 10.1007/s00701-020-04236-6 32056016 8. Tamura R Tomio R Mohammad F Toda M Yoshida K . Analysis of various tracts of mastoid air cells related to CSF leak after the anterior transpetrosal approach. J Neurosurg. (2018) 130 :360-7. 10.3171/2017.9.JNS171622 29547085 9. Morisako H Ohata H Shinde B Nagahama A Watanabe Y Goto T . Minimal anterior and posterior combined transpetrosal approach for large petroclival meningiomas. J Neurosurg. (2021) 19 :1-10. 10.3171/2020.8.JNS202060 10. Fava A di Russo P Passeri T Camara B Paglia F Matano F The mini-combined transpetrosal approach: an anatomical study and comparison with the combined transpetrosal approach. Acta Neurochir (Wien). 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Data Brief Data Brief Data in Brief 2352-3409 Elsevier S2352-3409(23)00138-5 10.1016/j.dib.2023.109020 109020 Data Article Data of worldwide observational studies of adults with accelerometry-measured physical activity and sedentary behavior Evenson Kelly R. [email protected] a* Scherer Elissa b Cuthbertson Carmen C. c Peter-Marske Kennedy M. a Madson Gabriel J. b Eckman Stephanie b a Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States b RTI International, Research Triangle Park, North Carolina, United States c Department of Health Education and Promotion, East Carolina University, Greenville, North Carolina, United States * Corresponding author. [email protected] 28 2 2023 4 2023 28 2 2023 47 10902011 11 2022 14 2 2023 21 2 2023 (c) 2023 The Author(s) 2023 This is an open access article under the CC BY license ). A compendium of observational studies of adults that collected accelerometry to assess physical activity and sedentary behavior (i.e., physical behaviors) could facilitate cross-study comparisons, meta-analyses, and future research collaborations. Therefore, we performed a systematic search to identify observational studies, including surveillance systems, that collected accelerometry-measured physical activity and sedentary behavior among adults. We performed a search using PubMed, Web of Science, and SPORTDiscus for studies published on or before June 1, 2021. After screening 5686 abstracts and 1027 full text articles, we included 155 unique studies that collected accelerometry on at least 500 adults 18 years or older. Most studies used one accelerometer (n=146), although eight studies used two accelerometers and one study used four accelerometers. The country of data collection, age range, and accelerometer characteristics were abstracted and checked by a second reviewer. These datasets summarizing relevant observational studies of adults can be a resource to researchers seeking to identify data sources for accelerometer-measured physical activity and sedentary behavior from around the world. Keywords Accelerometer Cohort Epidemiology Physical behavior Sitting Surveillance Wearable device Abbreviations NA, not applicable NI, not indicated pmc Specifications Table Subject Epidemiology Specific subject area Observational studies of adults that collected accelerometry-measured physical activity and sedentary behavior Type of data Table How the data were acquired Data were acquired through systematic searches of PubMed, Web of Science, and SPORTDiscus databases, and were reviewed and abstracted by at least two coders. Data format Raw Description of data collection Included surveillance, cross-sectional, and cohort studies were published in English and collected accelerometry to measure physical activity and sedentary behavior on at least 500 adults. Excluded studies included those of hospitalized or institutionalized populations, those that used pedometers, and those that were experimental (e.g., randomized controlled trial or intervention). Data source location Studies from around the world identified through three databases: PubMed, Web of Science, and SPORTDiscus Data accessibility Repository: University of North Carolina - Chapel Hill Dataverse Cohort level dataset : Accelerometer level dataset : Related research article Evenson KR, Scherer E, Peter KM, Cuthbertson CC, and Eckman S. Historical development of accelerometry measures and methods for physical activity and sedentary behavior research worldwide: A scoping review of observational studies of adults. PLOS One. 2022 Nov 21;17(11): e0276890. Value of the Data * The datasets can serve as a compendium of observational studies that measured physical activity and sedentary behavior using accelerometry among adults at least 18 years of age. * The datasets can be used to facilitate future data harmonization analyses, systematic reviews, and meta-analyses of correlates and determinants of physical activity and sedentary behavior, as well as associations of accelerometry metrics (e.g, time in moderate-to-vigorous physical activity, steps per day) with health outcomes. * The datasets could be expanded to include health outcomes and data availability across studies. * The datasets include the country location(s) of participants to facilitate cross-country comparisons. * The ethical and governance issues to accessing and using each data source is not included in the dataset and would need to be further investigated by the potential user. * The datasets can provide a historic perspective on the field over the past 22 years (i.e., the time since accelerometry measures were integrated into epidemiologic studies). 1 Objective Accelerometers are device-based sensors that can be used to measure physical activity and sedentary behavior. These devices are often integrated into surveillance and epidemiologic studies of health. With the rise in the use of accelerometry, a comprehensive review on key aspects of the devices and processing decision rules would aid the field. Therefore, we conducted a scoping review of the literature to identify studies with accelerometry measured physical activity or sedentary behavior on at least 500 adults . This article describes the cohort and accelerometer level datasets and provides data dictionaries for both to aid users of these resources. The research supports the call from several groups for a more complete reporting of accelerometer methodology to enhance future harmonization . 2 Data Description There are two datasets associated with the project: a cohort level and an accelerometer level dataset. The cohort level dataset contains 155 observational studies that collected accelerometry on adult participants identified from the systematic searches. Each row of data contains a different study, with an ID variable, study name, description of study (e.g., distributed data, study design, waves of data collection, study years, start year), description of the sample (e.g., country, gender), and number of accelerometers used. Table 1 provides more detail on each variable in the cohort level or study level dataset.Table 1 Variables and description of the cohort level dataset . Table 1Variable (Column Header Name) Description Cohort ID (IDCOHORT) An unique identification number is assigned for each study; Surveillance studies with multiple waves received unique study ID numbers; cohort studies with multiple waves received one unique ID number. PubMed Identifier (PMID) Main published study from PubMed that we used to abstract information; note that for some studies, other articles were also used, as well as information obtained by contacting the study directly. Study name (NAME) Name of study. When not specified, for most studies we named it using the format <Unnamed-Country-Cohort-Year>. Specifically for distributed data studies, the format was <Unnamed-Distributed-Company name-Cohort-Year>. Distributed (DISTRIBUTED) "YES" indicates that the participant provided data indirectly through wearing an activity tracker and agreeing to the terms of use. Study years (YEARS) Years of accelerometry data collection; when multiple waves were collected, only the first study wave is indicated. Start year (STARTYEAR) Year that accelerometry data collection began. Country (COUNTRY) Country the participants lived in. Gender (GENDER) Gender breakdown as either male, female, or male and female as reported by the studies. Sample size (SAMPLESIZE) Analytic sample size provided in the papers reviewed. Sometimes the numbers were in conflict across papers, so we chose the most reasonable one. This does not represent the starting sample size of the study. Logbook (LOGBOOK) Whether a logbook was used in the study, indicated by yes, no, or NI (not indicated). Population-based study (POPBASED) Whether or not the study was population-based considering only the paper(s) we reviewed. Sample weights (WEIGHTS) Whether or not sample weights were used in the paper(s) we reviewed. Number of accelerometers (ACCNUM) Number of accelerometers that the study used in the data collection period. Most studies used one accelerometer (n=146), although eight studies used two accelerometers and one study used four accelerometers. Therefore, we developed a separate accelerometer level dataset (n=166). Each row of data contains a different study*accelerometer, with an ID variable, study name, description of the accelerometer (e.g., brand, model), and features of the study protocol. Table 2 provides more detail on each variable in the accelerometer level dataset.Table 2 Variables and description of the accelerometer level dataset . Table 2Variable (Column Header Name) Description Accelerometer ID (IDACC) An unique identification number is assigned for each study by accelerometer. Each row of data represents a single accelerometer. For example, if a study used two accelerometers, then it would be represented in the dataset with two rows. ID's with a number after the decimal point indicate that they used more than one accelerometer. Cohort ID (IDCOHORT) An unique identification number is assigned for each study; Surveillance studies with multiple waves received unique study ID numbers; cohort studies with multiple waves received one unique ID number. Study name (NAME) Name of study. When not specified, for most studies we named it using the format <Unnamed-Country-Cohort-Year>. Specifically for distributed data studies, the format was <Unnamed-Distributed-Company name-Cohort-Year>. Brand (BRAND) Brand name of the accelerometer. Model (MODEL) Model name of the accelerometer; NI is not indicated. Epoch (EPOCH) Epoch length used for data collection; NI is not indicated and in some cases the accelerometer did not have this setting. Sampling frequency (SAMPLEFREQ) Sampling frequency of the accelerometer; NI is not indicated and in some cases the accelerometer did not have this setting. Location (LOCATION) Location of accelerometer wear; NI is not indicated. Side (SIDE) Side of accelerometer wear; NI is not indicated. Attachment (ATTACH) Attachment method for the accelerometer; NI is not indicated. Distribution method (DIST) Distribution method of the accelerometer; NI is not indicated; NA is not applicable and applies to the distributed data studies. Return method (RETURN) Return method of the accelerometer; NI is not indicated; NA is not applicable and applies to the distributed data studies. Days of collection (DAYS) Number of days of accelerometer data collection from the participants; NI is not indicated. Weekend days (WEEKEND) Weekend days required as specified in the paper abstracted; N is no; W indicated two work days were required. Wear protocol (WEAR) Accelerometer wear protocol for wake only or a 24-hour period; NI is not indicated. 3 Experimental Design, Materials and Methods Three databases (PubMed, Web of Science, SPORTDiscus) were searched on June 1, 2021, with the search strategy describe elsewhere (see Supplement 2 in Evenson et al. ). After removing duplicate citations, two authors independently screened all titles and abstracts before subsequently reviewing full-text articles for eligibility. Both title/abstract and full-text screening were conducted using Covidence software (Veritas Health Innovation, Melbourne, Australia). Discrepancies between authors were resolved by consensus. In our search strategy we included observational studies, including surveillance studies, with analytical sample sizes of at least 500 community-dwelling adults 18 years and older. The participant must have worn an accelerometer for the purposes of collecting physical activity, sedentary behavior, or both. We included only full-length, peer-reviewed papers published in English. If there was more than one publication identifying a single study that met the inclusion criteria, then we included only one publication to represent the study, using the study that provided the most information we were abstracting. If needed, we sought missing information from other publications captured by the search. We excluded studies of hospitalized or institutionalized adults, or samples that gave consent by proxy, as well as studies of youth (children or adolescents <18 years of age). We excluded intervention studies (i.e., randomized trials, quasi-experimental trials), unless there was a new consent process that enrolled participants into an observational study. We excluded publications in the grey literature, as well as abstracts, dissertations, and conference proceedings. We excluded studies that used spring-levered pedometers, but included pedometers that used accelerometry. Studies that collected accelerometry, but did not report on physical activity or sedentary behavior, were also excluded. After removing duplicate papers captured from the databases, 5686 titles and abstracts were screened for inclusion. Among those, 1027 full-text studies were further screened and 157 studies were included. Further detail can be found in Evenson et al. . Several caveats to the completeness and accuracy of the databases should be noted. First, we based the information on a primary publication so it is possible that missing abstracted fields may be available in other publications. Second, we attempted to capture data availability, but found this was inconsistently reported. Therefore, the database does not include this information. Despite these caveats, the accelerometer-level datasets may be useful to researchers seeking to identify data sources for accelerometer-measured physical activity and sedentary behavior from around the world. Ethics Statements This scoping review did not directly collect information on human subjects. CRediT Author Statement Kelly R. Evenson: Conceptualization, Data curation, Writing - Original Draft, Funding acquisition; Elissa Scherer: Conceptualization, Data curation, Writing - review and editing, Funding acquisition; Carmen C. Cuthbertson: Conceptualization, Data curation, Writing - review and editing; Kennedy M. Peter-Marske: Data curation, Writing - review and editing; Gabriel J. Madson: Data curation, Writing - review and editing; Stephanie Eckman: Conceptualization, Data curation, Writing - review and editing. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Data availability Cohort level dataset (Original data) (Dataverse). Accelerometer level dataset (Original data) (Dataverse). Acknowledgements and Funding The authors gratefully acknowledge the input from Dr. Robert Furberg. The project was supported by the 10.13039/100006108 National Center for Advancing Translational Sciences , 10.13039/100000098 National Institutes of Health (NIH) grant #UL1TR002489. Kennedy M. Peter-Marske was supported by the NIH National Heart, Lung, and Blood Institute National Research Service Award (T32-HL007055). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. References 1 Evenson KR. Cohort level dataset: observational studies of adults with accelerometry measured physical activity and sedentary behavior through June 1, 2021. 10.15139/S3/ZYVHUO, UNC Dataverse. 2022. 2 Evenson KR. Accelerometer level dataset: observational studies of adults with accelerometry measured physical activity and sedentary behavior through June 1, 2021. 10.15139/S3/8GPGJZ, UNC Dataverse. 2022. 3 Evenson KR Scherer E Peter KM Cuthbertson CC Eckman S. Historical development of accelerometry measures and methods for physical activity and sedentary behavior research worldwide: a scoping review of observational studies of adults PLOS One 17 11 2022 Nov 21 e0276890 4 Wijndaele K Westgate K Stephens SK Blair SN Bull FC Chastin SF Utilization and harmonization of adult accelerometry data: review and expert consensus Med. Sci. Sports Exerc. 47 10 2015 2129 2139 25785929 5 van Hees VT Thaler-Kall K Wolf KH Brond JC Bonomi A Schulze M Challenges and opportunities for harmonizing research methodology: raw accelerometry Methods Inf. Med. 55 6 2016 525 532 27714396 |
Data Brief Data Brief Data in Brief 2352-3409 Elsevier S2352-3409(23)00129-4 10.1016/j.dib.2023.109011 109011 Data Article A hierarchical dataset of vegetative and reproductive growth in apple tree organs under conventional and non-limited carbon resources Reyes F. [email protected] a* Tagliavini M. b Gianelle D. c a University of Studies of Modena and Reggio Emilia, Life Science Department, via Amendola 2, 42122, Reggio Emilia, Italy b Free University of Bozen-Bolzano, Faculty of Science and Technology, Piazza Universita, 5, 39100, Bozen-Bolzano, Italy c Forest Ecology Unit, Research and Innovation Centre, Fondazione Edmund Mach, Via E. Mach 1, San Michele All'adige, 38010 Trento, Italy * Corresponding author [email protected] 27 2 2023 4 2023 27 2 2023 47 10901127 12 2022 27 1 2023 20 2 2023 (c) 2023 The Authors. Published by Elsevier Inc. 2023 This is an open access article under the CC BY license ). A monitoring of apple fruit, shoot and trunk growth was performed on 15 trees, equally split according to three treatments, which determined heavily contrasting carbon assimilate availability: unmanipulated trees (FRU), thinned trees (THI) and defruited trees (DEF). Several variables describe the vegetative growth on FRU and DEF trees (shoot length, base diameter, number of fruits on shoot, and height, diameter, pruning intensity and number of fruits of the branch carrying the shoot; trunk circumference), as well as the fruit growth on FRU and THI trees (3 fruit diameters). Additional measurements from ancillary shoots (apical diameter, number of leaves, leaf dry weight, stem dry weight, fresh mass, volume) and fruits (3 diameters, dry weight) from trees undergoing the same treatments, provide a more complete (destructive) characterization of organs growth, thanks to several measurements performed across the growing season. Organs are provided with categorical variables indicating the treatment, tree, canopy height, orientation (for both shoots and fruit), as well as branch and shoot identifiers, so that hierarchical modeling of the dataset can be performed. The dataset is completed with dates and day of the year of the measurements and the accumulated growing degree days from full bloom. Data can be used to calculate apple tree absolute and relative growth rates, maximum potential growth rates, as well as shoot growth responses to thinning and pruning. The dataset can also be used to calibrate allometric relationships, estimate structural apple tree growth parameters and their variability. Keywords Shoot Fruit Trunk Hierarchical sampling Growth parameters Maximum potential growth Carbon availability Modeling pmc Specifications Table Subject Agronomy and Crop Science Specific subject area Temperate fruit tree crops Type of data Table How the data were acquired Tree organs morphology monitoring via manual instruments: caliper, tape measure, precision scale after oven drying, submersion in graduated cylinder. Data format Raw Description of data collection Data were collected from trees with greatly different fruit load: notably from trees completely defruited or heavily thinned three weeks after bloom, and from trees in normal commercial field conditions. Data source location Location: an organic commercial orchard City: Caldaro, Bolzano/Bozen province, Trentino Alto Adige region Country: Italy Latitude and longitude collected samples/data: 46deg 21' N, 11deg 16' E, Altitude 240 m Period: May-November 2014 Data accessibility Repository name: Mendeley Data Data identification number: 10.17632/852r5dnzd5.1 Direct URL to data: Related research article F. Reyes, T. DeJong, P. Franceschi, M. Tagliavini, D. Gianelle, Maximum growth potential and periods of resource limitation in apple tree, Frontiers in Plant Science 7 (2016). doi:10.3389/fpls.2016.00233 Value of the Data * The dataset allows analysis of the impact of fruit load, on vegetative and reproductive growth, also in respect to pruning severity, branch diameter and height in the canopy. * The dataset can be used to infer maximum potential growth curves, periods of resource limitation for reproductive and vegetative organs. * The dataset can be used to calibrate allometric relationships and extract several additional growth parameters. * The structure of the dataset allows for hierarchical data analysis. * The presented data can be used by field scientists, statisticians and modelers working on tree growth. 1 Objective This paper reports a dataset obtained comparing the impact of contrasting carbon assimilate availability on the growth of different apple tree organs. Fifteen trees were divided in three groups: trees in normal field conditions (FRU), trees with low competition for carbohydrates thanks to heavy thinning (THI), trees in which the competition for carbohydrates was reduced to a minimum via the complete removal of the reproductive organs (DEF). Growth analysis of the dataset permitted the assessment of the resource limited growth periods for organs under normal field conditions. Growth data were also used to estimate maximum potential growth parameters, such as maximum potential absolute and relative growth rates . This information is essential to calibrate source-sink carbon allocation models (such as in ), as well as to estimate several allometric relationships and plant growth parameters. 2 Data Description The dataset is composed by an ensemble of eight spreadsheets concerning the seasonal growth of the apple tree (Malus domestica, Fuji Variety grafted on M9 rootstock) organs growing under three sharply different carbon assimilate availability conditions (trees in normal field conditions, FRU; in which fruit competition for carbohydrates was minimized by heavy thinning, THI; and in which vegetative competition was minimized by complete fruit removal, DEF), in the Trentino Alto Adige apple production area, Northern Italy (Fig. 1). The dataset covers both primary and secondary shoot growth, secondary trunk growth, fruit growth. It includes monitoring of tagged plant organs and a concurrent characterization of analogous sampled organs, following the same treatments (Table 1, Fig. 2). Both the monitored and sampled organs contain information useful for hierarchical data treatment, such as tree, branch and shoot numbers or canopy level (Low, Middle, High). The spreadsheets are provided in the CSV format and include treatment, sampling date, the day of the year of the measurements, and the corresponding daily accumulated growing degree days, calculated from air temperature.Fig. 1 Tree treatments (DEF, complete fruit removal; THI, heavy fruit thinning; FRU, normal field conditions) and sequential numbering of tagged organs (Modified from Fig. 1 in ). Fig 1 Table 1 Variables measured in tagged and sampled organs. Table 1Variables measured in tagged and sampled organs. Organ Tagged/sampled Numerical Variable Total nb observations Nb Dates Fruit Tagged 3 diameters 1333 16 Sampled 3 diameters 413 16 dry weight 413 16 Shoot Tagged length 4209 9 base diameter 354 4 number of fruits on shoot 251 1 number of fruits on carrying branch 251 1 height of carrying branch 449 1 diameter of carrying branch 440 1 pruning intensity of carrying branch 449 1 Sampled length 182 6 base diameter 182 6 apical diamater 182 6 number of leaves 182 6 leaf dry weight 182 6 stem dry weight 182 6 sampled at end of growing season fresh mass 40 1 volume 40 1 Trunk Tagged circumference 70 7 Fig. 2 Measurement and sampling dates for the different organs from year 2014 (squares) and 2015 (triangles). Fig 2 2.1 Spreadsheets name and content Tagged_Fruit: contains measurements of three orthogonal diameters for nine fruits from each of five FRU and five THI trees in 16 dates. Sampled_fruits: contains measurements of three orthogonal diameters, dry weight and canopy level for 413 fruits, sampled in 6 dates (of which 238 FRU and 175 THI; 358 from ancillary trees and 55 tagged fruits after harvest). It contains also estimates of fruit volume and density. Fruit_yield: contains yields for five FRU and five THI trees. Tagged_Shoot: contains measurements of length for about 20% shoots of five FRU and five DEF trees (468 shoots) in 9 dates. It also includes: a monitoring of the basal diameters for about 10 shoots per tree in four dates, shoot orientation (North/South); the number of fruits present on individual shoots and on their carrying branch as for one date in early June; the height of the carrying branch at its insertion point into the trunk, its diameter and a measure of pruning intensity evaluated after the end of the growing season. Sampled_shoots: contains length, basal and apical diameter, number of leaves, leaf and shoot dry weight and canopy level of 182 shoots sampled from ancillary FRU trees on 6 dates. Sampled_shoots_End_Growing_season: contains shoot fresh mass, volume and the calculated density of 40 shoots (20 FRU and 20 DEF) sampled after the end of the growing season. Tagged_Trunk: contains measurements of trunk circumferences of five FRU and five DEF trees in 7 dates. DegreeDays: contains the growing degree days and accumulated growing degree days from the date of full bloom, after cut off of temperatures below 5degC and below 35degC, for year 2014 in the study site. 3 Experimental Design, Materials and Methods 3.1 Field description Field monitoring and sampling was performed in an intensive orchard located in the apple production area of the Adige river floodplain, Caldaro municipality, Trentino Alto Adige region, Italy (46deg 21' N, 11deg 16' E; 240 m a.s.l.). Trees were planted in year 2000, trained as spindelbush and spaced 1 m along the tree rows and 3 m between the rows. Orchard management followed organic guidelines, including winter pruning and tree topping at 3.6 m. A superficial water table and a drip irrigation system assured no water stress, while the availability of soil phosphorous, nitrogen and exchangeable potassium was at optimal levels . Fifteen trees were selected along a tree row and randomly split in three classes: unmanipulated trees (FRU), thinned trees (THI) and defruited trees (DEF). FRU trees followed common practices for commercial orchard and hold an average of 0.47 fruits per shoot or spur. Both THI and DEF trees underwent fruit thinning on 23rd April 2014 (150 GDD - Growing Degree Days after bloom). THI trees were heavily thinned, so that about 10-15 fruits were left per tree, with no more than one fruit per bourse shoot or spur. Conversely, fruits were completely removed in DEF trees. Mean FRU tree yield (26.2 kg/tree) was above the average yield at orchard level in previous years (Max = 22.3 kg/tree in years 2009-2012). A meteorological station was installed in the field, measuring mean daily air temperature at 2 m height. 3.2 Fruit growth Nine fruits were tagged along a vertical transect comprising the whole tree height, on each FRU and THI tree. Three orthogonal largest diameters were measured on each tagged fruit using a digital caliper: the largest transversal diameter, a second transversal diameter obtained by turning the fruit by about 90 degrees along its longitudinal axis, and a diameter passing from the petiole to the fruit bottom, so that the fruit dimensions could be acquired similarly across different fruits and dates. Measurements were repeated about weekly. Fruits volume was estimated using the formula for a rotational spheroids (Volume = 4/3 p r1 r2 r3). About 15 or more additional fruits were sampled from the different canopy levels on each date, alternately from additional FRU or THI ancillary trees. Finally, tagged fruits were also collected at harvest time. Sampled fruit diameters, volumes and dry weights (after petiole removal) were determined using a precision scale, after drying at 70 degC until constant weight was reached. 3.3 Shoot growth For each tree, the trunk was marked at 1.20 and 2.40 m height, dividing it horizontally in three levels (Low, Medium, High). From the lower part to the top of each level, one first order branch every five was tagged and numbered sequentially. On each tagged branch, from the insertion point in the main axis to the branch apex, every shoot and spur were tagged and lettered sequentially. The length of each tagged shoot/spur, from its insertion point in the carrying branch to its apex, was measured with a tape measure, every about two weeks from April to July and once a month in August and September in year 2014. Secondary shoot growth was monitored on about 10 tagged shoots for each DEF and FRU trees, by measuring the basal diameters, respectively above the shoot bases on four dates (mid-July, mid-August, early-September and after the end of the growing season). About 30 vegetative shoots were also sampled from additional FRU trees according to a stratified sampling, taking into account level, orientation and shoot length. Sampling occurred in six dates (DOY 148, 162, 188, 205, 234, 251) from years 2014 and 2015. Leaves were separated from their shoots by means of a lancet and counted. The shoot basal diameters were measured 1 cm above their bases, by means of a digital caliper. Leaves and shoots fresh weight were determined. They were then dried in a stove at 70 degC until constant weight was reached, brought to room temperature in a desiccator and weighted again. Shoots and leaves dry weights were obtained using a precision scale. 20 additional shoots per treatment were also sampled after fruit harvest. Their volume was obtained by submersion in water in a graduated cylinder, and their dry weight obtained after oven drying at 70 degC. Shoot density was calculated as the ratio between shoot dry weight and volume. The number of fruits present on each tagged branch and on the monitored shoot/spur contained in them was also counted on 18th June 2014. The height and diameter of each tagged branch were respectively measured with a tape measure and a digital caliper by the end of the vegetative season. On the same date, the branches/shoots cross sections left exposed after the winter pruning from previous years were visually compared to the cross section of the carrying branch. Branches were then classed according to four pruning intensities: 1, 2 and 3 for cross section areas respectively smaller, equal and larger than the area of the cross section of the carrying branch; 0 for no evidences of pruning. Diameters were measured next to the insertion point into the main axis (< 1 cm far), except when pruning had occurred next to the basis of the branch. In this latter case, measurements were made just following the pruning. The dataset presents a few missing measurements: lengths and diameters (< 1 %) when shoots/spurs were difficult to find because of occlusion due to the high leaf density; branch diameters, when they originated directly from the tree main axis, or were difficult to reach because too high in the canopy. 3.4 Trunk growth Each DEF and FRU tree was equipped with a trunk collar, mounted at 10 cm above the grafting point (about 40 cm above the ground). Measurements of trunk circumference were also taken every two weeks. Ethics Statements The authors declare that there are no ethical issues with the data presented, nor with the work performed to acquire them. The authors also declare that no humans or animals, nor any social media platform were subjects of this work. CRediT Author Statement Francesco Reyes: Conceptualization, Methodology, Investigation, Data Curation, Writing. Massimo Tagliavini: Supervision, Funding acquisition. Damiano Giannelle: Resources, Supervision, Funding acquisition. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability A hierarchical dataset of vegetative and reproductive growth in apple tree organs under conventional and non-limited carbon resources (Original data) (Mendeley Data). Acknowledgments The authors thank Damiano Zanotelli, Marilu Solas, Mathilde Erfurt, Roberto Zampedri, Mauro Cavagna, and Leonardo Montagnani for field assistance. This work was funded by the FIRST FEM doctoral school, which is funded by the Autonomous Province of Trento, Italy. References 1 Reyes F. DeJong T. Franceschi P. Tagliavini M. Gianelle D. Maximum Growth Potential and Periods of Resource Limitation in Apple Tree Front. Plant Sci. 7 2016 10.3389/fpls.2016.00233 2 Reyes F. Pallas B. Pradal C. Vaggi F. Zanotelli D. Tagliavini M. Gianelle D. Costes E. MuSCA: a multi-scale source-sink carbon allocation model to explore carbon allocation in plants. An application to static apple tree structures Ann. Bot. 126 2020 571 585 10.1093/aob/mcz122 31642506 3 Reyes F. Tagliavini M. Gianelle D. A hierarchical dataset of vegetative and reproductive growth in apple tree organs under conventional and non-limited carbon resources Mendeley Data v1 2023 10.17632/852r5dnzd5.1 |
Iperception Iperception IPE spipe i-Perception 2041-6695 SAGE Publications Sage UK: London, England 10.1177/20416695231162010 10.1177_20416695231162010 Short and Sweet Connecting the beholder with the artwork: Thoughts on gaining liveliness by the usage of paraphernalia Carbon Claus-Christian Department of General Psychology and Methodology, University of Bamberg, Bavaria, Germany; Research Group EPAEG (Ergonomics, Psychological Aesthetics, Gestalt), Bamberg, Germany; Bamberg Graduate School of Affective and Cognitive Sciences (BaGrACS), Bamberg, Germany; Claus-Christian Carbon, Department of General Psychology and Methodology, University of Bamberg, Bavaria, Germany. Email: [email protected] 9 3 2023 Mar-Apr 2023 14 2 2041669523116201010 12 2022 20 2 2023 (c) The Author(s) 2023 2023 SAGE Publications Ltd. Manuscript content on this site is licensed under Creative Commons Licenses This article is distributed under the terms of the Creative Commons Attribution 4.0 License ) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ). When we attend sculptures in museums, they might fascinate us due to the mastery of the material, the inherent dynamics of body language or due to contrapposto or the sheer size of some of these statues such as Michelangelo's David. What is less convincing, however, is the life-alikeness of the face. Actually, most visitors experience dead faces, dead eyes, and static expressions. By merely adding paraphernalia to a face (e.g., a facemask or sunglasses), such unalive sculptures gain vividness and liveliness. This striking effect is demonstrated by applying a facemask and sunglasses to a sculpture on public display in Bamberg, but it can easily be demonstrated on any available sculpture. This simple method might help connect people with sculptures or artworks, in general, to lower the barrier between the beholder and artwork and increase their interaction. perception empirical aesthetics sculptures paraphernalia face masks sunglasses gestalt vividness like-alikeness vivid eyes typesetterts19 cover-dateMarch-April 2023 pmcHuman sculptures often appear dead with some exceptions, for instance, wax figures that are mainly created to shock, provocate, or even horrify the beholders. That is no surprise; actually, sculptures are not alive. Artworks, however, do not have to be alive to appear vivid (instead of dead) and invite their beholders to connect with them. A lot of human sculptures throughout art history were created to provide a vivid representation or reference to living persons for instance, to a beloved one, like in the case of Antinous, who probably was the favourite lover of the Roman emperor Hadrian . Artists have developed sophisticated techniques to make lively characters and to enable or even deepen the connection between artwork and the beholder for hundreds of years. One important method in this respect was to drill a little hole or etch circles in sculptured eyeballs to create the illusion of a pupil, giving a more lively impression . But this technique also bears the risk of creating a staring expression, as often attributed to Michelangelo's Proculus (1494-1495) and as Figure 1b and c indicates. Using eye inlays made of marble and glass, as realized in many Greek and Roman Imperial statues (Steiner, 2001), allows for greater realism. Yet, the results often remain unconvincing since the material fixation of the eyes' position and the gaze bring about mostly static expressions. Figure 1. (a) Roman marble bust of Antinous as Dionysus from about 130 CE. Louvre Museum in Paris, France. (b) Roman marble bust of Antinous from 130 to 138 CE, Galleria degli Uffizi Florence, Italy. (c) Commercial plaster bust of W. A. Mozart on the display of a tourist shop in Vicenza, Italy. Photos were taken by CCC in October 2010, March 2015, and June 2014, respectively. So, how to achieve an inviting impression of activity and vividness in a static object? Typical techniques for depicting motion in paintings, such as blur, action lines, or arrows (Cutting, 2002), are not easily applicable in sculptural works. The well-known method to impose vividness in human sculptures via contrapposto might work for larger movements of the body's extremities (Pazhoohi et al., 2020), but not for the face. Another attempt to render human sculptures more vivid and approachable that was already used in ancient times is polychromy (Brinkmann, 2008). Today's recipients partly show a rejective attitude towards polychrome ancient sculpture, especially if they are not sufficiently familiarized with such versions (cf. Carbon & Hesslinger, 2014). On the other hand, there are also works that are appreciated primarily for their vivid polychromy such as the hyperrealistic sculptures by Duane Hanson (1925-1996) which the artist created from casts of actual individuals using different materials. Hansons's approach is, of course, very different from that of most classical sculpturors who stuck to a single kind of material and a singular sculptural technique (Duby & Daval, 2010). There is a very simple option that probably works for portraits as well, but is especially effective for sculptures. I found this simple method accidentally when visiting a sculptural work in Bamberg and it seems there were others who played with that already, for example, sculptor Isa Genzken equipped copies of the Nefertiti with paraphernalia in her 2015 Nefertiti series. The artwork I attended in 2020 during the COVID-19 pandemic consists of eight bronze casts that are sitting in a circle . Although the whole group as a Gestalt makes quite a vivid impression, the single characters lack liveliness . Figure 2. (a) This is the group of sculptures called "meeting" on Schonleinsplatz, Bamberg/Bavaria, which was created by Chinese artist Wang Shugang for an exhibition in 2013. The group consists of eight red-painted bronze casts. Important note: the figures were originally not equipped with face masks but were temporarily covered by them as a spontaneous reaction to the COVID-19 pandemic. (b) Part of the original sculpture, (c) temporarily equipped by the author with a face mask, and (d) sunglasses, respectively. Photos were taken by CCC in October 2020. As a reaction to the anti-COVID measures that demanded the wearing of face masks in 2020, visitors to the sculpture equipped some of the bronze casts with surgical masks which drew my attention . This little addition had a remarkable effect actually, heads with a facemask appeared much more vivid and "real," and when I played around equipping one figure selectively with a face mask and with sunglasses such simple additions increased the life-alikeness substantially. What happened due to this intervention? Covering parts of the facial information seems to have triggered perceptual completion that resulted in an imaginary Gestalt compatible with a very vivid proxy of a real human. Imagination obviously does not create a lifeless object but a living creature. Empirical evidence. To test whether this first impression of more liveliness in artworks by equipping them with unusual paraphernalia is empirically observable, we conducted an online study (N = 35, based on an a priori power test with a proposed effect size of f = 0.25, and set alpha = .05 and beta = .20 yielding a minimum sample size of 28, which we overpowered by 20% to cope with potential data loss; we gained an actual power of .81) with four different sculptures with four different presentation conditions (none, original; SunG, sunglasses; Mask, facemask; Mask&SunG, facemask and sunglasses together) each. Each participant was exposed to all 4 [sculptures] x 4 [presentation conditions] versions, one by another, in a fully randomized order. To cover a broader spectrum of relevant variables of aesthetic experience, we used three different measures that were asked for each version in the following order: (a) how lively does the sculpture appear, (b) how thought-provoking is the sculpture, and (c) how interesting is the respective sculpture? The mean total length of the study was 7.5 min. As shown in Figure 3, we detected the strongest effects on liveliness when applying sunglasses; applying a face mask plus sunglasses was the most thought-provoking, but only for the classic sculptures of Plato and Aristotle. Applying a face mask had apparent positive effects on the variables lively and thought-provoking. Figure 3. Results for four different sculptures (Socrates, Plato, Aristotle, and Red Sculpture) with four different presentation conditions (none, original; SungG, sunglasses; Mask, facemask; Mask&SunG, facemask and sunglasses together) each. The rows show the results for the three dependent variables, that is, lively, thought-provoking, and interesting. *p < .05, ***p < .001, ****p < .0001, based on t-tests comparing conditions with the none-condition. Coda. We can easily give dead sculptures back their life (sculptures were unalive all their life, true, but at least at the beginning of their career, the artist breathed life into the unaddressed chunk of raw material, whether marble, plaster, or wood). The effect is appealing, and artworks emerge more lively and thought-provoking; similar effects are intuitively used by kids equipping their snowmen with scarves, branches, and carrots. This mixture might change our perspective and probably invite us to rethink our established evaluations and associations with artworks of all kinds what an excellent opportunity to have more vivid and engaged interaction with artworks. Acknowledgement I am very thankful for the comments by Marco Bertamini on a previous version of this manuscript. How to cite this article Carbon, C.C (2023). Connecting the beholder with the artwork: Thoughts on gaining liveliness by the usage of paraphernalia. i-Perception, 14(2), 1-5. Author Contribution: Claus-Christian Carbon: Conceptualization; Data curation; Formal analysis; Formal analysis; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing - original draft; Writing - review & editing. The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author received no financial support for the research, authorship, and/or publication of this article. ORCID iD: Claus-Christian Carbon References Brinkmann V. (2008). The polychromy of ancient Greek sculpture. In Panzanelli R. Schmidt E. D. Lapatin K. (Eds.), The color of life: Polychromy in sculpture from antiquity to the present (pp. 18-39). The J. Paul Getty Museum and the Getty Research Institute. Carbon C. C. Hesslinger V. M. (2014). Stable aesthetic standards delusion: Changing "artistic quality" by elaboration. Perception , 43 (9 ), 1006-1013. 10.1068/p7709 25420339 Cutting J. E. (2002). Representing motion in a static image: Constraints and parallels in art, science, and popular culture. Perception, 31 (10 ), 1165-1193. 10.1068/p3318 12430945 Duby G. Daval J.-L. (2010). Sculpture: From antiquity to the present day. Taschen. Pazhoohi F. Arantes J. Kingstone A. Pinal D. (2020). Becoming sexy: Contrapposto pose increases attractiveness ratings and modulates observers' brain activity. Biological Psychology, 151 , 107842. 10.1016/j.biopsycho.2020.107842 31958547 Steiner D. T. (2001). Images in mind. Statues in archaic and classical Greek literature and thought: Princeton University Press. |
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