Kikuchi-Fujimoto disease is a rare, idiopathic and generally self-limiting cause of lymphadenitis of unknow etiology with a low recurrence rate. The typical clinical signs are cervical lymphadenopathy, fever, and symptoms of respiratory infection, and less frequently chills, night sweats, arthralgia, rash, and weight loss.
Here we describe two case reports of Kikuchi Fujimoto disease presenting in Milan within the space of a few months. The first involved the recurrence of KFD in a young boy from Sri Lanka; the second was a rare case of severe KFD complicated by HLH.
Pediatricians must consider KFD in the differential diagnosis of fever of unknown origin in children, even in western countries. Although rare, recurrence and severe complications are possible. Where symptoms suggest KFD, a systematic diagnostic approach is key. Since no guidelines on the management of KFD are available, further studies should be conducted to investigate the therapeutic options and long term outcome in children.
Kikuchi-Fujimoto disease (FKD), also called histiocytic necrotizing lymphadenitis, is a rare, idiopathic and generally self-limiting cause of lymphadenitis. Prevalence of FKD is high among Japanese and other Asiatic individuals, but only isolated cases are reported in Europe. It was first described by the pathologists Kikuchi and Fujimoto in 1972 , but its etiology remains unclear, although the most likely theory suggests it is caused by one or more unidentified agents, probably viruses, that trigger a self-limiting autoimmune process in subjects with a genetic predisposition to autoimmune response [2, 3]. KFD is characterized by localized cervical lymphadenopathy, fever, and symptoms of upper respiratory tract infection, and less frequently chills, night sweats, arthralgia, rash, and weight loss. Lymph nodes are usually painful and tender; splenomegaly or hepatomegaly have sometimes been described. Although rare, KFD may present with neurologic involvement (both central and peripheral) . Laboratory findings include high inflammatory marker levels (C reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and mild cytopenia [5, 6].
This clinical scenario is non-specific and can be mistaken for viral infection (such as mononucleosis), bacterial adenitis (mainly tuberculosis or cat scratch disease), malignant lymphoma or systemic lupus erythematosus (SLE). Several authors have also reported an association between FKD and SLE . The diagnosis of KFD is confirmed by the histological analysis of an affected lymph node.
KFD is considered a benign disease, usually resolving within a few months. However, recurrences and complications including hemophagocytic lymphohistiocytosis (HLH) have been described in some patients. Here we report two cases of KFD presenting in Milan within the space of a few months. The first involved the recurrence of KFD in a young boy from Sri Lanka; the second was a rare case of severe KFD complicated by HLH.
A 12-year-old boy was admitted to our hospital with fever (38–39 °C) of 4 days' duration and bilateral cervical lymphadenopathy. Five years earlier, while living in Sri Lanka, he had been admitted to the local hospital for intermittent fever of 12 days' duration, mild cough, abdominal pain and significant bilateral cervical lymphadenopathy. Blood tests revealed very high LDH levels (2360 IU/L) and cytomegalovirus (CMV) antibodies (IgG and IgM). An abdomen ultrasound scan (US) was normal. Given the persistent fever and LDH levels, excisional biopsy of a cervical lymph node was performed, on the suspicion of a malignant lymphadenopathy. The histological analysis showed a lymphoid follicular hyperplasia with paracortical expansion and large areas containing immunoblasts, histiocytes and apoptotic cells, while atypical cells were absent. The clinical signs associated with the histological features suggested the diagnosis of KFD.
On his first examination after admission to our Emergency Pediatric Department, the patient was febrile and had a painful lymphadenopathy (3 cm in diameter) in the right side of the neck. His physical development was normal. Initial investigations revealed a mild increase in CRP (1.79 mg/dL) and hepatic enzymes (AST 51 IU, ALT 81 IU). Viral markers showed a past CMV infection while markers for Epstein Barr Virus (EBV), Toxoplasma gondii, Adenovirus and Parvovirus were negative. Angiotensin-converting enzyme (ACE) levels were normal. A chest X-ray was normal, while a neck US showed the presence of two hypoechoic and slightly inhomogeneous lymph nodes, with rich vascularized hilum and no evidence of colliquative phenomena. Some other small lymph nodes were also found in the submandibular region. Given the association of fever, cervical lymphadenopathies and mildly elevated inflammatory index, intravenous antibiotic therapy with cefotaxime (100 mg/kg/day) and analgesic oral therapy with paracetamol were started.
A tuberculin intradermal reaction was negative. As the blood tests confirmed the increase in hepatic enzymes, an abdomen US was performed, showing severe steatosis. Hepatitis B and C and HIV viral markers were negative; hepatic autoantibodies and LKM were negative, ANA and ASMA were mildly positive (ANA 1:80 homogeneous pattern, ASMA 1:80 vascular pattern), anti ds-DNA and the complement fraction (C3 and C4) were normal. Thyroid function, cholesterol (LDL and HDL) and A and B apolipoprotein were normal. Blood and urine copper and serum ceruloplasmin levels were normal. Urine galactose and fructose were normal.
Due to the persistence of intermittent fever, lymphadenopathy and the appearance of a diffuse erythematosus and itchy rash on the trunk, arms, and legs, an excisional lymph node biopsy was performed. The cytometric investigation showed B lymphocytes with non-malignant features, with just a reduced CD4 to CD8 lymphocyte ratio. The histologic exam revealed histiocytic necrotizing lymphadenitis, confirming the diagnosis of recurrent KFD (Fig. 1, Fig. 2). The microscopic and cultural exams were negative.
The intermittent fever lasted 15 days, then the patient's general condition improved, with progressive complete normalization of blood tests. The boy was discharged without therapy. Seven days later, at the follow-up visit, he was still afebrile and in good general condition.
The fever returned and progressive enlargement of the previous lymphadenopathies. An excisional cervical lymph node was performed.
A previously healthy 16-year-old Chinese girl came to the Emergency Pediatric Department with progressive fever, cough, headache and tender right cervical lymphadenopathy of four days' duration. She also complained of intense fatigue and dizziness and had had two episodes of syncope. She was initially treated at home with oral amoxicillin/clavulanate for four days, without improvement. On physical exam, she had a tender right retro-angulo-mandibular lymphadenopathy of 3 cm in diameter, without hepatosplenomegaly, and hyperemic pharynx. An initial US revealed the presence of multiple bilateral lymphadenopathies of different sizes (the largest 2.7 cm) with inflammatory characteristics (hypo-anechoic and hypervascularized nodes with perilesional hyperechoic tissues). CRP was 2.06 mg/dL (normal value < 0.5 mg/dL). A complete blood count revealed leukopenia with a white blood cell count (WBC) of 3690 cells/mm3. A broad-spectrum intravenous antibiotic therapy was started (cefotaxime 100 mg/kg/day), with partial regression of the lymphadenopathies and resolution of the fever. After six days, she recommenced having two daily fevers of up to 41 °C with progressive enlargement of the lymphadenopathies, which became extremely painful. New tender bilateral lymphadenopathies appeared in the inguinal and axillary areas. Blood tests revealed a worsening leukopenia with WBC 1930 cells/mm3, neutrophils 760 cells/mm3, ESR 33 mm/h (normal value < 20 mm/h), ferritin 1303 ng/dL, LDH 857 U/L. Due to persistent dry cough, oral clarithromycin was started (15 mg/kg/day). A thorax X ray and abdominal US were normal, while lymph node US was unchanged. EBV, human immunodeficiency virus (HIV), CMV and multiple other viral, bacterial and fungal serum tests were all negative. Mantoux and Quantiferon Test were negative. Autoimmune lymphoproliferative syndrome was ruled out, due to the absence of α/β double-negative T cells.
Given her history suspicious for hematological disorders, bone marrow aspiration was performed, which revealed a slightly hypocellular marrow, with focal evidence of hemophagocytosis. Flow cytometry was negative for lymphoproliferative disorders and cytogenetic testing was normal. Perforin gene mutations were absent. Due to the persistence of high fever and painful lymphadenopathies, cefotaxime was replaced by piperacillin/tazobactam (150 mg/kg/day) and vancomycin (40 mg/kg/day). After 24 h, there was regression of the fever by lysis and regression of the systemic lymphadenopathies, associated with an improvement in inflammatory markers, except for persistent neutropenia.
One week later, the fever returned and the patient reported intense fatigue, malaise and progressive enlargement of the previous lymphadenopathies, which were extremely painful and swollen. An excisional cervical lymph node biopsy was then performed, which was diagnostic for KFD (Fig. 3): as in case 1, the biopsy revealed wedge-shaped subcapsular necrotic foci composed of fibrinoid material with karyorrhectic debris, histiocytes with plasmacytoid features and crescentic nuclei, and several mitotically active immunoblasts; no granulocytic component was found. While in case 1 the finding was focal in the lymph node (that showed an overall preserved architecture with hyperplastic germinal centers) but extensive in the tissue fragments, in this case the lymph node was effaced by numerous necrotic foci. Immunohistochemistry revealed in both cases a T-cell phenotype (CD3+, CD2+, CD5+, CD7+, CD43+, CD8+ > CD4+) for the immunoblasts, along with focal and weak positivity for CD30, and a high proliferation index (Ki-67 / MIB-1 = 60%); ALK-1, EMA, CD25, CD56 and TdT were all negative. The B-cell markers CD20 and PAX5 highlighted only a few, scattered B-cells. Plasmacytoid histiocytes stained positively for CD68PG-M1 and CD123. In situ hybridization for Epstein-Barr virus was negative.
This histological picture suggested a T-cell neoplasm as the main differential diagnosis [6, 7]: however, the absence of T-cell antigen loss and of polyclonal T-cell receptor gamma chain rearrangement  were not indicative of a T-cell malignancy. Additionally, the clinical history, and the somewhat peculiar histological features (presence of a histiocytic component with typical plasmacytoid morphology in the background of fibrinoid necrosis, and absence of a granulocytic component), were indicative of KFD (relapsed in case 1) in the "proliferative" phase [9–12].
After 4 days, the fever spontaneously disappeared. However, inflammatory markers were still elevated, with alteration of liver enzymes and coagulation pattern (ALT 875 U/L, AST 342 U/L, LDH 1682 U/L, CRP 3.65 mg/dL, ferritin 9329 ng/mL, APTT 1.30, D-Dimer 2888 ng/mL, WBC 1500 cells/mm3, neutrophils 760 cells/mm3), suggestive of initial HLH. The patient was started on pulsed methylprednisolone therapy (1 g/day for 3 days) followed by prednisone (1.5 mg/kg/day) in combination with cyclosporine (4 mg/kg/day). A rapid improvement in her lymphadenopathies, fever and constitutional symptoms was seen soon after immunosuppressive therapy was started. A progressive normalization of blood analysis was also observed, with improvement of the leukopenia.
Although her symptoms improved with high doses of prednisone, the clinical course was complicated by the development of glucocorticoid-induced diabetes and hypertension. After four days of steroid treatment, the patient had a sudden rise in blood pressure (162/108 mmHg) associated with headache and malaise. Some hours later, she presented two generalized tonic-clonic seizures with cyanosis, requiring the administration of oxygen and intravenous diazepam. We performed an urgent computerized tomography (CT) brain scan, which was normal. Given the combination of generalized seizures, high blood pressure and immunosuppressive therapy, magnetic resonance imaging (MRI) of the brain was then performed, which showed pathological alterations suggestive of posterior reversible encephalopathy syndrome (PRES). An electroencephalogram (EEG) proved abnormal and antiepileptic therapy with Levetiracetam (750 mg/day) was started, achieving good control of the crisis. The hypertension was treated with amlodipine (10 mg/day). Follow-up brain MRI and EEG after 10 days showed a complete normalization of the previously described neurological alterations, thus confirming the diagnosis of PRES. Levetiracetam was then stopped and the anti-hypertensive therapy was gradually reduced. The patient continued high dose corticosteroids with a slow taper over several months in combination with cyclosporine and was discharged in good clinical condition.
Kikuchi-Fujimoto disease is a rare benign disease associated with histiocytic necrotizing lymphadenitis. It is endemic in Asia, especially among young women, but only isolated cases are reported in Europe and therefore its diagnosis may be difficult. FKD is characterized by lymphadenopathy with tenderness, night sweats and fever, less common manifestations include generalized lymphadenopathy, weight loss, splenomegaly, cutaneous rash, arthralgia, weight loss, nausea, vomiting and neurologic involvement. Although the lymphadenopathy usually affects the cervical lymph nodes, the axillary lymph nodes and other regions can also be affected. The affected lymph nodes are solid, movable, and painful but not suppurative; while the main affected node is usually solitary, multiple lymph nodes on both sides have been described [5, 6]. KFD is typically reported to have a self-limiting course, resolving within several months and with a recurrence rate of just 3 to 4% . In our first patient, a young boy of Asian origin, KFD recurred five years after its first manifestation.
KFD remains an enigmatic disease, not only for its rarity and non-specific manifestations, but also because its etiology and pathogenesis remain unclear and there are no clear diagnostic criteria. Even though it is a benign condition, correct diagnosis is fundamental to rule out other causes of lymphadenopathy. Cervical lymphadenopathy is in fact common in the pediatric population, with about 38 to 45% of otherwise healthy children having palpable lymphadenopathy. For this reason, KFD can be mistaken for other common or more serious conditions, such as lymphoma or systemic lupus erythematosus - another hard-to-diagnose disease in children due to its widely varying symptoms .
The non-specific presentation requires numerous investigations. Excisional lymph node biopsy is the only reliable means of establishing a diagnosis, but a systematic approach is fundamental to exclude other causes of persistent fever and lymphadenitis and identify when biopsy is necessary. The starting diagnostic point is a collection of a careful medical history and a thorough physical examination. It is important to consider all symptoms (such as fever, anorexia, weight loss, night sweats, fatigue), their onset and duration, any insect bites, any changes in mass size, other recent illnesses or travel, exposure to animals, treatments (such as antibiotics) and response to them, vaccinations, family history, and the patient's origins. Associated systemic symptoms, such as weight loss, night sweats, unexplained fever, or fatigue, suggest the need for further workup for possible malignancy or chronic inflammatory conditions. A careful examination should then be conducted to identify the number of masses, their location, size, mobility, tenderness, and characteristics of the masses on palpation and of the overlying skin. A complete physical examination of all body systems is necessary: infection is the most common cause of pediatric cervical lymphadenopathy and a benign reactive lymphadenopathy with infectious origin may be suggested by an associated illness (viral or bacterial) such as an upper respiratory infection, pharyngitis, tonsillitis, or otitis media .
While these data could orient towards a diagnosis, they are not unequivocal. The signs and symptoms of KFD are often enigmatic, especially in the early stages, and only their persistence can lead to diagnosis. For these reasons, some investigations need to be performed. Initial tests comprise complete blood cell count with WBC differential, erythrocyte sedimentation rate, liver enzymes and lactate dehydrogenase (significantly associated with malignancy), and inflammatory markers. Blood markers for virus infections that could cause lymphadenitis (CMV, HBV, Herpes virus, HIV, Adenovirus) and bacterial infections (Toxoplasma gondii, Bartonella henselae, Borrelia burgorferi) are also important . Tuberculin skin test and Interferon-gamma release assay (IGRA), a pharyngeal swab and nasopharyngeal aspirate should also be performed.
A chest X-ray and neck US should be performed as a first step. Abdomen US could be useful to exclude the involvement of abdominal lymph nodes. In our patients, neck US features indicated benign or reactive lymph nodes. Fatty liver was found in case 1; this has never before been described in the manifestation of KFD. A cohort study should be conducted to evaluate hepatic US of these patients, although this finding was probably independent of the underlying disease.
If the initial investigation is inconclusive, or if indicated, additional investigations could include testing for Listeria monocytogenes and Francisella tularensis and ACE assay to exclude sarcoidosis. If, such as in our patients, symptoms persist and no definitive diagnosis has been arrived at, excisional lymph node biopsy should be performed .
In our first patient, biopsy was performed at an early stage because his history (a first occurrence of KFD five years before) and clinical course were very similar to the previous episode. However, other possible causes of lymphadenitis must be ruled out: since a low KFD recurrence rate is described in the literature, more frequent causes of lymphadenopathy should also be considered.
Yoo IH et al. found that a past history of other systemic illnesses and a higher Absolute Lymphocyte Count (ALC) despite a reduced WBC count were significantly associated with recurrent KFD, but there are insufficient data to predict recurrence . Some data suggest that removal of the affected lymph node is not only diagnostic but also potentially therapeutic: after excisional lymph node biopsy some patients improve quickly , as did case 1 reported herein.
KFD has a wide clinical spectrum and is generally self-limiting. However, some patients suffer from prolonged systemic symptoms during the course of the disease, sometimes with severe complications. These include, especially in western countries, a few cases of secondary HLH, also known as hemophagocytic syndrome (HS) [13, 19–23]. HS is a histiocytic reactive process found in cases of strong immunologic activation such as severe infection, malignancy, autoimmune diseases, and metabolic diseases. It is characterized by histiocytic proliferation, hemophagocytosis, fever, hepatosplenomegaly, generalized lymphadenopathy, hypertriglyceridemia, and hypofibrinogenemia. KFD seems to be a hyperimmune reaction of immune cells to unidentified agents; too much stress could then lead to HLH [24–26]. The prognosis and therapeutic strategy for KFD in association with HS remains unclear. As Kim et al. conclude, childhood KFD is more frequently associated with HS and seems to have a less aggressive course and better prognosis than in adults .
No clear therapeutic guidelines are available on how to shorten the clinical course of KFD. Little information is available about the use of hydroxychloroquine or glucocorticoids [28, 29]. While we decided not to treat our first patient, who returned to good health after three weeks of fever, our second patient required prompt treatment because KFD associated with HLH has a potentially fatal outcome [27, 30]. It should be borne in mind that during the prolonged course of KFD, children suffer from impaired school performance, numerous medical visits and hospital admissions, and/or acute deterioration of health: further studies should be conducted to clarify possible therapeutic choices. Unfortunately, no clinical features that significantly affect the duration of KFD have been clearly identified, although some authors hypothesized that detection of atypical lymphocytes in peripheral blood may be a predictor for its duration [31, 32].
Pediatricians must consider KFD in the differential diagnosis of fever of unknown origin in children, even in western countries: prelevalence of KFD is high among Asiatic individuals but until now only very rare cases are reported in Europe, however the immigration from Asian countries is likely to cause an increase of KFD cases. Although rare, recurrence and severe complications are possible. Where symptoms suggest KFD, a systematic diagnostic approach is key. Since no guidelines on the management of KFD are available, further studies should be conducted to investigate the therapeutic options and long term outcome in children.
This case report was funded by the Italian Ministry of Health (Grant RC 2018 850/02).
Mara Lelii, Senatore Laura and Ilaria Amodeo drafted the manuscript; Raffaella Pinzani, Samantha Bosis and Sara Torretta performed the diagnosis, managed the patients and gave a support in the follow-up of the children; Stefano Fiori performed the hystological diagnosis; Paola Marchisio and Samantha Bosis revised the manuscript and made substantial scientific contributions. All authors read and approved the final manuscript.
Written informed consent for publication of their clinical details and/or clinical images was obtained from the parent of the patient.
Sopena B, Rivera A, Vazquez-Trinanes C, Fluiters E, Gonzales-Carrero J, Del Pozo M, et al. Autoimmune manifestations of Kikuchi disease. Semin Arthritis Rheum. 2011; https://doi.org/10.1016/j.semarthrit.2011.11.001.


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Home> GreenerCars Ratings> How to Use GreenerCars
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redpajama_set_name: RedPajamaCommonCrawl


Yeah, well this week the former First Lady will about the moment with Ellen DeGeneres—and even revealed what was inside said Tiffany box. To quote: "It was a frame."
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У нашей организации популярный web-сайт про направление https://sellmax.com.ua.


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@Mike_Pence Actually, you did. You started a war with your own people, pitting neo-Nazis, white nationalists, and a… twitter.com/i/web/status/1… 10 hours ago
storiesbywilliams	in News, Space	 September 1, 2013 544 Words
News From Space: 12 Asteroids to Mine
Last year, the private space exploration company Planetary Resources announced that they intended to being prospecting and mining asteroids in the near future. And while they are certainly not alone in their intention to make this happen (Deep Space Industries has the same intention), many have asked if humanity is ready to begin extracting resources from the Asteroid Belt, at least as far as our level of technology is concerned.
In response, a group of astronomers at the University of Strathclyde in the UK did their own study and concluded that it is indeed possible with current rocket technology. What's more, they conducted a survey of the Asteroid Belt and identified 12 near-Earth asteroids that could be easily retrieved and mined, and which are believed to contain high concentrations of precious and industrial metals.
Already, it has been estimated that an asteroid as small as one-kilometer in diameter could contain upwards of two billion tons of iron-nickel ore, which is three times the global yield on Earth. Then there is the likely presence of gold, platinum, and other rare substances. Planetary Resources claims a 30-meter object of the right composition could contain $25 to $50 billion in platinum.
These numbers spurred the University of Strathclyde team, led by Garcia Yarnoz, to pour over the astronomical data on near-Earth objects to see if any of them could actually be snared. To their surprise, they found 12 small asteroids that pass close enough to Earth that they could be corralled into the L1 or L2 Lagrangian points for mining operations. The researchers dubbed these asteroids Easily Retrievable Objects (EROs).
Lagrange points refer to points where the gravity of Earth an another celestial object balance out. If anything enters one of these areas, it stays put, which is precisely what you want to do if you are looking to study it, mine it, or just keep it where its accessible. The L1 and L2 Lagrangian points are where the gravity of Earth and the sun are at a draw, roughly 1.6 million km (1 million miles) from Earth and about four times the distance to the moon.
The 12 candidate asteroids all have orbits that take them near the L1 or L2 Lagrangian points, so they would need only a small push to get them to the right spot. Yarnoz and his team estimate that changing the velocity of these objects by less than 500 meters per second would be sufficient, and this could be completed as early as 2026.
One of the important criteria in selected 12 mineable asteroids from the database of 9,000 near-Earth objects was size. Nudging a larger asteroid safely to a Lagrange point is simply not feasible with the current state of technology. In fact, most of the EROs that were identified in the study range between two to 20 meters, but that's still large enough to contain substantial resources.
These 12 objects are probably a small fraction of EROs floating around near Earth. We know where many more of the big space rocks are because they're much easier to see, but there might be a wealth of resource-rich small asteroids near the Lagrangian points ripe for the picking. And with time, and more orbital telescopes to spot them with, we can expect the list of mineable asteroids to grow.
Source: extremetech.com
asteroid mining
asteroid prospecting
deep space industries
Easily Retrievable Objects (EROs)
L1 or L2 Lagrange Points
Lagrange Points
planetary resources
Detroit's New Robocop Statue
The Future is Here: Nanofibre Heart Patches


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Spilt MilkArchives
A Stranger Asked Me If I Was Okay, And I Knew I Wasn't
By Leanne Simpson
Let me take you back to yesterday afternoon.
I cried so much on my way to the psychiatrist that my contact folded in half inside my eyelid – yep, it was as gross as it sounds – and I could barely read the hospital signs as I made my way to his office. The waterworks didn't stop there, either. I pulled myself together long enough for him to ask how things had been, and then I returned to my natural state as a human puddle. Depression sucks.
But the thing about depression is that it's monotonous.
I forgot how hard it is. My mood tends to swing towards the manic side of things, which has its own pitfalls to avoid. But the thing about depression is that it's monotonous. It's dogged. It follows you around like a dandelion fluff in the wind, sticks to your clothes, and grows weeds all over you (okay, that's not how dandelions work at all, but you get the picture). It snuck up on me at a time where everything was going right on the surface, and I felt silly – ungrateful, even – saying that life was any less than perfect. But there's a difference between being sad and being depressed. With depression, there doesn't have to be a reason.
A couple months ago, I had a bad reaction to lithium, threw up all over Queen Street, went unconscious and hit my head, and wound up in the hospital. I've been trying a new medication since then – Latuda, a weight neutral miracle that has given back most of my functioning and allows me to work a normal person job for the first time in my life. The last time I saw my therapist, she asked me if it was making me a little flat. I didn't think so at the time, but over the past few weeks the light's been getting dimmer. I've been creating less, sharing less, feeling a little less like myself without suffering any tangible losses.
There always seems to be a catch with these things.
He decided to up my dose, and I was instantly wary of the side effects. There always seems to be a catch with these things, like "You'll feel better but lose 20% of your hair," or "You'll feel better but fit in none of your clothes." Then people tell you to exercise to fix that problem, and you're just like, "It's literally a God-given miracle that I have shuffled out of bed to buy this Jamba Juice. Please leave me alone now."
"I wouldn't change the dosage if I didn't think it would work," he said. I know he's got my best interests at heart but sometimes I feel more like a science experiment than a human, like a game of Operation gone so horribly wrong that the only thing left to remove from my body is tears. I have to change my garbages when people come over so they can't spot the evidence of how much I've cried. "Look at this beautiful view," I always say, and then shove my Kleenex mountain down the crack of my bed while they're not looking. It's pretty crafty.
The other reason I went to see my psychiatrist was to get a letter for a mental health yoga program recommended to me by a friend from SickNotWeak. I've been on a yoga kick but had to take a break since I hurt my back learning how to twerk (I really wish I was kidding). It's a great form of exercise because a) a lot of the time they let you lay on the floor b) it's another excuse to shop at lululemon and c) it forces me to remember how to breathe. The program felt like a life preserver in the middle of my tear-fueled ocean (join with me! http://blumatterproject.com/).
I realized that the worst thing about treatment is time.
He wrote me a new prescription and asked if there was anything else I wanted to talk about, and I realized that the worst thing about treatment is time. Everything takes time. Even if I took the upped dose that night, I would have to wait to feel better. And I'm lucky enough that I'm not in a bad enough place not to wait – but for those who are, where do they find the time? The will? The thing that keeps them going? That's when a passerby looked at my face, and saw what I had been trying to hide. Waving him off, I sat on a picnic bench outside the hospital and called my parents. I needed help getting home.
DHead
I can empathize. After years of settling with one medication it's drastically and radically changing. I got so mad. Like why hadn't they figured it out? Had I changed so much 10 years?
Then the inevitable time. Take this, wait 2 weeks, let's see what happens.


Dr. Johnson, an army veteran originally from Massillon, Ohio, specializes in general ophthalmology and oculoplastic surgery. He completed his fellowship in Ophthalmic Plastic & Reconstructive Surgery after attending Case Western Reserve University School of Medicine in Cleveland, Ohio. Dr. Johnson holds clinical privileges at UHHS Geauga Regional Hospital in Chardon, the Center for Advanced Eye Surgery in Youngstown, and Novamed Surgery Center in Sandusky. He is Board Certified in Ophthalmology and is a Clinical Instructor at Case Western Reserve University. Dr. Johnson has received many honors including the 2009 Case Western Reserve University Professionalism in Ophthalmology Award. In his spare time, he enjoys cooking, cycling, and traveling with his wife and young children.


Some of you may find this very interesting, Bloomberg a team of statistic scientists decided to create a 'predicted' Premier League table. This table was created by creating thousands of different scenarios of results and put an average point tally. The team considered the strength of each team in this data.
From the table Aston Villa are predicted in 12th place. The table also includes the percentage of likely hood that a team can finish in the top 4, Champions, top 10 or in relegation. I like this table a lot, you can find more information about this table in this sub-reddit linked down below.
Not realistic really, when you think the 3 teams promoted will be relegated by prediction !


The Church's Music Director, Mrs. Christina Roberts, leads all the choirs. Mrs. Roberts can be reached at 616.949.8890 (her office) or via email at croberts@oursavior-gr.org.
The adult vocal choir is open to all confirmed Church members. The choir rehearses on Thursday evenings at 7:30 pm to 9:00 pm, September through May, at the Church. The adult choir sings many Sundays and at selected special Church services.
The bell choir is open to all Church members. The choir rehearses on Thursday evenings at 6:15 pm to 7:30 pm, September through May, at the Church. The bell choir plays on selected Sundays and at some special Church services.
The junior vocal choir is open to Church members in the first through fourth grades. The choir rehearses on Wednesdays from 3:45 pm to 4:30 pm, September through May, at Our Savior Lutheran Church. The junior choir sings many Sundays and at selected special Church services.
The Schola Cantorum is a junior high choir open to Church members in the fifth through the eighth grades. The choir rehearses on Wednesdays from 3:45 pm to 5:00 pm, September through May, at Our Savior Lutheran Church. The Schola Cantorum choir sings many Sundays and at selected special Church services.
The musical instrument talents of Church members are frequently used in the Church's services. Contact the congregations Music Director, Mrs. Roberts, if you play an instrument and are interested in participating in Church services.


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Il castello di Craigievar è una fortificazione situata ad Alford, nell'Aberdeenshire in Scozia.

Era la sede del Clan Sempill e la famiglia Forbes risiedette qui per 350 anni fino al 1963, quando la proprietà fu data al National Trust for Scotland da William Forbes-Sempill, Lord Sempill. L'ambientazione è tra le colline pedemontane delle Grampian Mountains. Il contrasto tra la struttura massiccia del piano inferiore, le torrette multiple finemente scolpite, i gargoyle e il lavoro ad alte altezze creano un classico aspetto da fiaba.

Storia
Un eccellente esempio dell'originale architettura baronale scozzese, il grande castello di sette piani fu completato nel 1626 dal mercante di Aberdon, William Forbes, antenato dei baroni di Forbes di Craigievar e fratello del vescovo di Aberdeen, Patrick Forbes del castello di Corse. Forbes acquistò la struttura parzialmente completata dalla famiglia Mortimer nel 1610. Forbes fu soprannominato Danzig Willy, un riferimento al suo abile successo commerciale internazionale con gli stati baltici.

Il figlio di William divenne un baronetto della Nuova Scozia su iniziativa di Carlo I e questo titolo è tuttora esistente. La Forbes Baronetcy, di Craigievar nella contea di Aberdeen, fu creata nel Baronetage della Nuova Scozia il 20 aprile 1630 per William Forbes. Era anche un discendente di Patrick Forbes, terzo figlio del secondo Lord Forbes, e il nipote del primo baronetto della creazione del 1628. Il quarto baronetto rappresentava l'Aberdeenshire nella Camera dei comuni. Il 5° baronetto sposò Sarah Sempill, la figlia maggiore di Hugh Sempill, dodicesimo Lord Sempill. Il loro nipote, l'ottavo baronetto, successe come diciassettesimo Lord Sempill nel 1884. I titoli rimasero uniti fino alla morte di suo nipote, il diciannovesimo Signore e il decimo baronetto, nel 1965.

Progettato con pianta a "L", come lo era il castello di Muchall, che si trova nella stessa regione, Craigievar è noto per i suoi soffitti in cartongesso eccezionalmente lavorati. Craigevar, castello di Muchall e castello di Glamis sono generalmente considerati i tre controsoffitti più belli della Scozia. La famiglia del Clan Forbes era amica del Clan Burnett di Leys, che costruì sia il castello di Crathes che il castello di Muchalls. I soffitti presentano figure in gesso dei Nove Worthies e altri emblemi della famiglia.

All'inizio del XIX secolo, la torre era caduta in rovina. Sir John Forbes aveva preso in considerazione la demolizione della torre e consultato l'architetto della città di Aberdeen, John Smith, che sconsigliò questa linea d'azione, affermando che la torre era: "uno dei migliori esemplari nel Paese dell'epoca e dello stile in cui è stato costruito". Le riparazioni del tetto sono state intraprese e hanno comportato la ricostruzione di quasi l'intero piano superiore. Le finestre, l'harling esterno e il puntamento sono stati sostituiti ed è probabile che anche Smith abbia progettato la casetta del giardiniere.

Il castello in origine aveva più elementi difensivi tra cui un cortile murato con quattro torri rotonde; solo una delle torri rotonde rimane oggi. Nella porta ad arco di quella torre sono conservate le iniziali intagliate di Sir Thomas Forbes, figlio di William Forbes. C'è anche un enorme portone in ferro o un cancello che copre la porta d'ingresso che viene chiamata Yett.

L'interno del castello vanta una corte che ha le insegne Stuart sopra il camino, una galleria di musicisti; una scala segreta che collega l'alta torre alla corte; camera da letto della regina; gli alloggi dei domestici e naturalmente alcuni splendidi soffitti in stucco. All'interno vi è una collezione di ritratti della famiglia Forbes e una considerevole quantità di arredi dei Forbes risalenti ai secoli XVII e XVIII. Il castello ospita anche due ritratti originali di Henry Raeburn completi di ricevute originali.

La famiglia Forbes possedeva anche una grande casa in granito a Fintray, vicino ad Inverurie, nell'Aberdeenshire. Questa divenne la residenza principale della famiglia per un certo numero di anni fino alla seconda guerra mondiale. Durante questo periodo, la Fintray House fu utilizzata come ospedale per i soldati belgi feriti.

Note

Altri progetti

Collegamenti esterni

Aberdeenshire
Craigievar

redpajama_set_name: RedPajamaWikipedia


text:
Greenlight Dispensaries hopes to open five locations across southern West Virginia – WOAY-TV
MC News January 11, 2022 Greenlight Dispensaries hopes to open five locations across southern West Virginia – WOAY-TV2022-01-11T06:47:42+00:00 Oregon Marijuana News No Comment
LEWISBURG, WV (WOAY) – Medical marijuana is an up and coming industry in West Virginia. The state's first ever dispensary opened in Morgantown late last year, and now southern west Virginia will soon be home to several dispensaries.
Greenlight Dispensaries is a company with locations in four different states, and is now expanding to West Virginia. They're getting locations ready and plan to open several in the coming months, including one in Lewisburg.
The dispensary is currently holding interviews to staff the upcoming store, and hopes to fill the positions with West Virginia locals.
"I find that people from the area tend to do much better than bringing in people from other parts of the country," Casey Efting, Greenlight Director of Retail Operations said. "Because we can teach you about cannabis. We can't teach you how to be a leader in your community."
Medical marijuana is a new concept for West Virginia. It was passed by the state legislature in 2018, and for the past few years, the newly created Office of Medical Cannabis has been writing regulations for the new industry.
Now Greenlight, as well as other dispensaries, are hoping to
« Advocates working to clean records of marijuana-related offenses – Spectrum News
Planning Board approves permit for medical marijuana dispensary – Dartmouth Week »


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Arts at UCF
UCF MusicTheatre UCFVisual Arts and GalleryUCF Celebrates the ArtsAll College Events
College of Arts & HumanitiesSchool of Performing ArtsSchool of Visual Arts & Design
Locations, Directions and ParkingTicketing
UCF Celebrates the Arts 2016
Nine days of free events at the Dr. Phillips Center for Performing Arts!
The second annual presentation of UCF Celebrates the Arts features the art and performances of more than 1,000 university students and 100 faculty members.
Two more days of events have been added to this year's festival, including performances under the direction of renowned composers Hans Zimmer (Pirates of the Caribbean, The Dark Knight, and more than 150 films), and Patrick Doyle (Harry Potter and the Goblet of Fire, Bridget Jones's Diary, and more than 45 other films).
The festival showcases the talents of the university's artists and practitioners in theatre, dance, orchestra, choirs, big band, chamber music, cabaret, concert bands, opera, visual arts, studio art, gaming, animation, photography and film. There's even a concert that organizers think may be the first of its kind: a presentation geared exclusively for expectant parents.
Ongoing • Lobbies and public spaces throughout the center
SVAD Banner Art
Massive prints of artworks, from ceramics to paintings, are on display throughout the Center.
SVAD Mixed Media Event "Multiples"
Theatre UCF Costume Exhibits
SVAD Arcade Cabinets
Friday, April 8, 2016, 6:00 p.m. • DeVos Family Room
A collaborative project with the Alive Inside Foundation, demonstrating how music affects the minds of Alzheimer patients.
Friday, April 8, 2016, 7:30 p.m. • Walt Disney Theater
Theatre UCF presents Dance 10
In celebration of ten years of dance, eighty dancers take the stage for UCF's biggest and most elaborate dance concert to date!
Friday, April 8, 2016, 8:00 p.m. • Alexis & Jim Pugh Theater
SVAD Animation Showcase
An entertaining and artful display of computer animation by UCF's Character and Experimental Animation Programs.
Saturday, April 9, 2016, 10:30 a.m. • Alexis & Jim Pugh Theater
EAT (it's not about food)
A play for and about teens and their struggle with food.
Saturday, April 9, 2016, 2:30 p.m. • Alexis & Jim Pugh Theater
The "Life is a Dream" Project
A contemporary one-act inspired by Pedro Calderón de la Barca's play Life is a Dream, performed in Spanish.
April 9 – April 15, 2016 • Lobbies and public spaces throughout the center
Tableaux vivants
Saturday, April 9, 2016, 5:00 p.m. • Seneff Arts Plaza
Jill's Cashbox
Hosted by the Dr. Phillips Center for the Performing Arts, this Florida Blue Concert features a 6-piece band with an affinity for country music.
Saturday, April 9, 2016, 7:30 p.m. • Walt Disney Theater
The Warped Side of the Universe with Hans Zimmer, Paul Franklin, and Kip Thorne
A collaborative presentation about science and music, with internationally acclaimed special guests Hans Zimmer, Paul Franklin, and KipThorne
SVAD Film Student Showcase
A showcase of narrative, documentary, and experimental shorts from UCF's Film programs.
Sunday, April 10, 2016, 12:00 p.m. • DeVos Family Room
"We All Can Dance!" Kinderdrama Session
A special event for kids aged 2-4 with their parents.
Sunday, April 10, 2016, 2:00 p.m. • DeVos Family Room
Clashes in Theatre History
A panel of theatre history students demonstrate their research projects.
Sunday, April 10, 2016, 3:00 p.m. • Walt Disney Theater
Wind Ensemble and Symphonic Band Concert
Enjoy UCF Music's premier band ensembles in a beautiful concert setting.
SVAD Faculty Talk
Sunday, April 10, 2016, 5:00 p.m. • Alexis & Jim Pugh Theater
The Miracle of Music and Your Baby's Development
A special concert, designed specifically for expectant moms and dads.
UCF Choral Concert: I Dream a World
UCF's three choirs sing music from around the world.
Monday, April 11, 2016, 7:30 p.m. • Alexis & Jim Pugh Theater
Stravinsky's "Histoire du soldat (The Soldier's Tale)"
The story of a soldier who trades his prized possession, a violin, to the devil in exchange for promises of riches.
Tuesday, April 12, 2016, 5:00 p.m. • DeVos Family Room
Women Playwrights Panel
Theatre UCF playwrights discuss the challenges and rewards of writing for the stage and screen.
Tuesday, April 12, 2016, 7:00 p.m. • Alexis & Jim Pugh Theater
Theatre UCF presents Stephen³
A cabaret celebrating three of the most prolific modern musical theatre composers: "Stephens" Sondheim, Schwartz, and Flaherty.
Tuesday, April 12, 2016, 7:00 p.m. • Walt Disney Theater
UCF Middle and High School Choir Invitational
Drop in anytime to watch a workshop or enjoy a performance by UCF and Central Florida high school students.
Wednesday, April 13, 2016, 1:00 p.m. • Walt Disney Theater
Percussion Festival: Michael Burritt Guest Artist Masterclass
Guest composer and percussionist Michael Burritt leads a performance masterclass with UCF percussion majors and area high school students.
Percussion Festival: High School Percussion Ensemble Showcase
A day of workshops with university and high school students culminates in a giant celebration of percussion.
Wednesday, April 13, 2016, 5:00 p.m. • Alexis & Jim Pugh Theater
UCF K-12 Fine Arts Showcase
Wednesday, April 13, 2016, 6:00 p.m. • DeVos Family Room
SVAD Digital Media Showcase
Highlighting interactive student creations from digital media's Game Design and Web Design programs.
Percussion Festival: The Music of Michael Burritt
April 14 – April 16, 2016 • Alexis & Jim Pugh Theater
Donizetti's "L'elisir d'amore (The Elixir of Love)"
"Elixir" combines a touching love story and hilarious comedy with beautiful music, including one of the most beautiful and recognizable arias in all of opera.
Friday, April 15, 2016, 5:30 p.m. • Lobbies and public spaces throughout the center
How Games Are Made
Through interactive exhibits featuring virtual reality and real-time motion capture, visitors will see how video games are made.
Friday, April 15, 2016, 7:30 p.m. • Walt Disney Theater
Patrick Doyle's "Music of Shakespeare"
Patrick Doyle presents his greatest works as the composer for Kenneth Branagh's Shakespeare movies (Hamlet, Much Ado About Nothing, Henry V, and more). Conducted by acclaimed maestro James Shearman (Brave, Thor, Harry Potter and the Goblet of Fire), the UCF Orchestra and choir perform songs and underscores from the best scenes in the films with actors from Prague Shakespeare Company and Orlando Shakespeare Theater playing the roles.
Saturday, April 16, 2016, 4:30 p.m. • Alexis & Jim Pugh Theater
"Interior": A Talk and Screening with Filmmaker Zachary Beckler
UCF alumnus and filmmaker Zachary Beckler shows his award-winning film "alternative" horror film and discusses new digital technologies.
Saturday, April 16, 2016, 8:00 p.m. • Walt Disney Theater
The Flying Horse Big Band Swings! (and has a funky good time).
Central Florida's ultimate big band brings a swingin' end to the Celebration!
UCF Celebrates the Arts, a festival showcasing creativity, innovation and collaboration from Orlando's hometown university, occurs annually at Dr. Phillips Center for the Performing Arts in April. The event is hosted by the UCF College of Arts and Humanities and features the faculty and students from the School of Performing Arts and the School of Visual Arts and Design, as well as work from the humanities departments and other units from around the university. Partnership, one of UCF's long-standing values, is brought front-and-center at UCF Celebrates the Arts, with many events showcasing the collaborative nature of the university and demonstrating how UCF is both in and of the Central Florida community.
Browse the program book or download with the link below.
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Download 2016 Program Book
boxoffice@ucf.edu
4000 Central Florida Blvd. Orlando, Florida, 32816 | 407.823.2000


It is so hard to believe that real people are saying things such as the ones quoted in the newsletter of "Emily's List" for Summer of 2013. They are living in a time warp and have no connection to this century. Here are some of the quotes and the people who said them.
What in the world is going on in the minds of people like them!! Surely they are smarter than that, but maybe not. Not all conservative people are that ignorant and unlearned about life, but there are too many of them who are.
"The dance of the love of God cannot be danced alone." This sentence is copied from Dorothee Soelle"s book, The Silent Cry, Mysticism and Resistance. This is the third time I have read this book and each time her spirituality ignites my own some more. This sentence and others throughout the book strike me because I like to be alone. Not all the time, but more alone than not. When I can concentrate on the feeling of God in my heart. I can shed tears because of the swelling feeling of God in my heart.
On Sunday mornings when Norm has choir practice before worship I go to Burger King that is near our church. I order an iced coffee mocha and then I read whatever spiritual enriching book I am meditating on. God lives in that Burger King! How odd. How odd that I should feel God so strongly in a place lacking any "sacred" ambiance! Some Sundays when my 45 minutes at BK is over and it is time to go to church, I don't want to go. I want to stay in my solitude in this very public place. It is a place where, for me, God dwells.
I don't mean to say that I don't find God in the sanctuary of my church. What I mean to say is that I enjoy having God all to myself. Most times there is some act of community worship in which God touches me as She does at BK. But I really like to be alone with Her.
Then I read Soelle's strong statement: "The dance of the love of God can't be danced alone." I want to dance alone. When I get to church to worship after my sacred time in BK drinking iced coffee mocha, and I find my seat among the people of God gathered to worship, I do feel the dance of the love of God. I need those people. Without them I would be so alone in my faith.
The Virginia State Legislature and those of several other states that have a law mandating transvaginal ultrasounds before all abortions probably don't realize that they are clinging, in the 21st century, to logic that was proposed in the 4th century by Aristotle. He wrote, "It is the best for all tame animals to be ruled by human beings. For this is how they are kept alive. In the same way, the relationship between the male and the female is by nature such that the male is higher, the female lower, that the male rules and the female is ruled.' Aristotle, Politica, ed. Loeb Classical Library, 1254 b 10-14.
Therefore, men should make all the important decisions. There is no way to tell what Aristotle would have said about TVU but mandating it it fits right in with his understanding of the inferiority of women. A concept which some male legislators heartily endorse, not only endorse but enact into law. The men in the Virginia state legislature passed a bill that requires a woman to have a transvaginal ultrasound before she can have an abortion. Governor Bob McConnell said it is a good law because it gives a woman information before she decides to have an abortion. That's why men alone should not be making decisions about women's choices. The governor has not a clue about the emotions and the thoughts that a woman who needs it terminates a pregnancy goes through.
Part of the law requires that the woman look at the pictures from the ultrasound. The men say they want to know the gestational age of the fetus. What they really want and hope for is that an emotionallly driven woman will look at the fetus and see a human being and be moved to spare its life. They want women to be intimidated into rejecting an abortion. Aristotle would love that–a woman can't make a decision based on logic so appeal to her emotions. Evidence indicates that women forced to see the ultrasound images opt to teminate the pregnancy anyway. So much for the 21st century men who want to ccontrol women based on a 4th century logic.
Since I wrote this blog the Virginia Legislature has delayed action on the law. Their retreat is due the uproar from women and the press. We need to keep that uproar loud to prevet further enfringement on women's rights.
My newly published book, From Heaven to My Heart, God's Journey With Me, could be classified as "memoirs." But I would label it instead a "spiritual autobiography." Memoirs belong to famous people, people who have been big players in the course of world events. If the events of my life are interesting to people who don't know me, it is because they are interested in the experience of living life with God. I've not done things that made me famous. What I have done is write a prayer almost every day of my life for more than thirty years.
This book contains some of those prayers, commentary on them, quotes from the Bible and from other books on prayer that have enriched my spiritual journey. My journey started from a place where I was asking God for things, basically telling Her what was best for any one for whom I prayed. The journey has not ended yet, but by the end of the book, From Heaven to My Heart, it became apparent that prayer for me is fellowship with God.


Syfy's new series The Expanse premiered this week, and the network has released a Q&A video with the cast.
The Expanse is based on the book series by James S.A. Corey and stars Thomas Jane as a detective tasked to track down a missing woman in a solar system set 200 years in the future.
In the series, humans have colonized both Mars and the surrounding Asteroid belt.
Dominique Tipper, who plays ship engineer Naomi Nagata, says what drew her to the series is how it handles female characters.
What do you think? Did you see the premiere of The Expanse? Will you keep watching?
The first few shows were confusing. I am caught on the show now. I think it is confusing as to where the entire show is going and how all the various characters are related. I am still excited to watch each episode to see what happens.
There was nothing special in the first episode. Just a mashup of stories from other shows. The editing: jumping from one storyline to another was bad. The music as louder than the conversation -Why? No need to watch another episode.
Expanse was a great show last night I loved it I can't wait to see the show for tonight at the plot is excellent the writing is great I just hope its just not a tonight miniseries it needs to be a full series.


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A multi-centre, non-inferiority, randomised controlled trial to compare a cervical pessary with a cervical cerclage in the prevention of preterm delivery in women with short cervical length and a history of preterm birth – PC study
Bouchra Koullali1Email authorView ORCID ID profile,
Liselotte E.M. van Kempen1,
Maud D. van Zijl1,
Christiana A. Naaktgeboren2,
Ewoud Schuit2,
Dick J. Bekedam3,
Maureen T.M. Franssen4,
Sebastiaan W.A. Nij Bijvank5,
Marieke Sueters6,
Marchien van Baal7,
Marjon A. de Boer8,
Angelo B. Hooker9,
Brenda B.J. Hermsen10,
Toon A.A.M. Toolenaar11,
Joost J. Zwart12,
David P. van der Ham13,
Flip W. van der Made14,
Federico Prefumo15,
Begoña Martinez de Tejada16,
Dimitri N.M. Papatsonis17,
Anjoke J.M. Huisjes18,
Liesbeth H.C.J. Scheepers19,
Marion E. van Hoorn20,
Tom H.M. Hasaart21,
Nico W.E. Schuitemaker22,
Karlijn C. Vollebregt23,
Moira A. Müller24,
Inge M. Evers25,
Marinka S. Post26,
Karin de Boer27,
Henricus Visser28,
Nico A. Mensing van Charante29,
Josje Langenveld30,
Nicole Y.C. Steemers31,
Ben W.J. Mol32,
Martijn A. Oudijk1 and
Eva Pajkrt1
Preterm birth is in quantity and in severity the most important contributor of perinatal morbidity and mortality both in well- and low-resource countries. Cervical pessary and cervical cerclage are both considered as preventive treatments in women at risk for preterm birth. We aim to evaluate whether a cervical pessary can replace cervical cerclage for preventing recurrent preterm birth in women with a prior preterm birth due to cervical insufficiency or in women with a prior preterm birth and a short cervix in the current pregnancy.
A nationwide open-label multicentre randomised clinical trial will be set up to study women with a singleton pregnancy and a prior preterm birth before 34 weeks of gestation. Women are eligible in case of previous preterm birth based on cervical insufficiency (primary intervention, <16 weeks) or in case of previous preterm birth and a short cervical length in current pregnancy ≤25 mm (secondary intervention, <24 weeks). Eligible women will be randomised to either cervical pessary or cervical cerclage. Both interventions will be removed at labour or at 36 weeks of gestational age, whatever comes first. The primary outcome will be delivery before 32 weeks. Secondary outcomes will be gestational age at birth, preterm birth rate before 24, 28, 34 and 37 weeks of gestation (overall and stratified by spontaneous or indicated delivery), premature rupture of membranes, use of tocolysis and/or corticosteroids during pregnancy, mode of delivery, maternal infections, maternal side effects, neonatal and maternal hospital admissions, and a composite of adverse perinatal outcomes including both morbidity and mortality. We assume an event rate of 20% preterm birth before 32 weeks for cerclage and use a non-inferiority margin of 10% for the cervical pessary. Using an alpha of 0.05 and power of 0.80 we need 2 groups of 200 women each.
The outcome of this study will indicate the effectiveness and the cost-effectiveness of a cervical cerclage and of a cervical pessary.
Netherlands Trial Registry, NTR 4415. Date registered: 29th of January 2014.
Preterm birth
Cerclage
Preterm birth is defined as delivery before 37 completed weeks of gestational age (GA). The incidence of preterm birth varies between countries with a range of 5–13% and results in 15 million preterm deliveries worldwide each year. Preterm birth is a major contributor to perinatal mortality. Of all perinatal mortality, 50–70% is associated with preterm birth [1].
Approximately 75% of all preterm births occur spontaneously, starting with either contractions or preterm pre-labour rupture of membranes (PPROM). Preterm birth is the leading cause of neonatal morbidity, mostly due to respiratory immaturity, intracranial haemorrhages and infections. These conditions can result in long-term neurodevelopmental sequelae such as intellectual impairment, cerebral palsy, chronic lung disease, deafness and blindness [2]. Thus, prevention of spontaneous preterm birth remains one of the biggest challenges in obstetric care.
An important risk factor for preterm birth is a prior preterm birth. Women with a prior spontaneous preterm birth before 34 weeks have an average risk of 20% (range between 15.8% and 30.2%) of recurrence of spontaneous preterm birth before 37 weeks and 15% before 34 weeks [3, 4]. Women with a previous preterm birth before 34 weeks of gestation are usually advised to use progestagens, either 17-hydroxy progesterone caproate or vaginal progesterone, in a following pregnancy. Additionally, women with a prior preterm birth due to cervical insufficiency can be offered a primary cervical cerclage, i.e. history based cerclage. Cervical insufficiency is characterized by progressive shortening and dilatation of the cervix before 24 weeks of gestation without signs of preterm labour, and is associated with mid-trimester pregnancy loss and early preterm birth. Screening for cervical shortening by transvaginal ultrasound before 24 weeks of gestation is recommended in women with a prior preterm birth without (clear) diagnosis of cervical insufficiency in prior pregnancies. In case of a short cervix ≤25 mm before 24 weeks of gestational age, these women can be offered a secondary cervical cerclage, i.e. ultrasound indicated cerclage [5].
A cervical cerclage is a surgical procedure that involves occlusion of the cervix by means of a cervical suture or stitch which is performed under general or spinal anaesthesia proposed by Shirodkar in 1955 [6] and by McDonald in 1957 [7]. A primary cerclage is considered to be effective in the prevention of preterm birth in women with cervical insufficiency and is usually offered before 16 weeks of gestational age. The largest trial published in 1993 included 1292 women with singleton pregnancies, and showed a significant reduction in preterm birth before 33 weeks of gestation (13% versus 17%; P = 0.03) [8]. A meta-analysis from 2003 demonstrates that primary cervical cerclage has a significant effect in preventing spontaneous preterm birth before 34 weeks of gestation [9]. The effectiveness of a secondary cerclage has been studied in a meta-analysis from 2011. This meta-analysis found that in these women the risk of delivery before 32 weeks' gestation was 19% in women with cerclage as compared to 30% in those without cerclage (RR 0.66 95% CI 0.48–0.91) [10].
Placement of cervical cerclages has proven to be effective in some women at risk for recurrent preterm birth. However, the disadvantage of cervical cerclage is the potential harm. Complications of cervical cerclage include PPROM, preterm labour, infection, suture displacement, and bleeding [11]. In addition, cerclage is associated with an increased risk of cervical laceration, both in nulliparous (OR 3.7, 95% CI 1.1–12.8) and multiparous women (adjusted OR 12.7, 95% CI 5.7–28.2) [12].
The cervical pessary is a soft and flexible silicone device known since 1959 when it was used in women with recurrent miscarriage [13]. Although the exact mechanism of the cervical pessary remains unknown, it has been hypothesised that the pessary relieves direct pressure on the internal cervical ostium by changing the position of the cervical canal and distributing the weight of the pregnant uterus [14]. Another possible mechanism is that the pessary might support the immunological barrier between chorioamnion-extraovular space and the vaginal microbiological flora [15]. Recently, several randomised trials showed that the cervical pessary may be potentially effective as a treatment for preterm birth prevention. The Spanish Pesario Cervical para Evitar Prematuridad (PECEP) trial from 2012 compared treatment with a pessary in women with a short cervix with expectative management and showed a significant decrease in preterm birth before 34 weeks of gestation (OR 0.19; 95% CI 0.12–0.30) and improvement of neonatal outcome (RR 0.14; 95% CI 0.04–0.39) in the intervention (pessary) group. In this study, 11% of 385 women included had at least one prior preterm birth, however, no subgroup analysis was performed for women with a previous preterm birth [15]. The same group performed a similar trial in twin pregnancies and observed a reduction in spontaneous preterm birth before 34 weeks of gestation in the pessary group (16.2% versus 25.7%; p 0.0001) [16]. Another randomised controlled trial performed by Liem et al. in 2014 comparing a pessary with no treatment in twin pregnancies showed similar results in a subgroup with short cervix [17]. Two randomised trials coordinated by the Fetal Medicine Network from the United Kingdom could not confirm these results of the pessary, both in singleton and multiple pregnancies with short cervix [18, 19]. The most frequently reported side effect of a pessary is vaginal discharge. Less common reported complications during the use of a pessary are vaginal blood loss or pelvic pain. Cervical laceration as complication is rarely seen in the use of pessary, this chance seems smaller than 0.1%.
Since a cervical pessary can be positioned in an outpatient setting, it is less expensive than placing a surgical cerclage and is therefore potentially more attractive than a cerclage. In addition, a cervical pessary is a non-invasive method contrary to a cervical cerclage which is an invasive procedure. Although both interventions have been available for over 55 years now, both interventions have been compared directly only once. A randomised study performed in 1986 in Germany in women with a prior preterm birth included 242 women and did show comparable outcomes in women using a pessary and women having cerclage (37 + 5 weeks of gestational age at delivery in the cerclage group versus 37 + 1 weeks in the pessary group, p value not significant) [20].
We propose to compare the cervical pessary and cervical cerclage in a head-to-head comparison and hypothesise that the use of a cervical pessary will be equally effective in preventing preterm birth as cervical cerclage. The outcome of the proposed study will indicate the relative effectiveness of cervical pessary for women with a singleton pregnancy with a prior preterm birth due to cervical insufficiency and in women with a prior preterm birth and short cervical length in current pregnancy. In addition, we will be able to compare the costs of both interventions. Since the placement of a pessary is less expensive compared to the surgical application of a cerclage, implementation of this therapy will potentially yield a major cost-reduction.
Aim, design and setting
We will perform an international randomised controlled trial under the acronym the PC Study (Pessary or Cerclage to prevent preterm delivery in women with short cervical length and a history of preterm birth; Netherlands Trial Registry NTR 4415, registered at the 29th of January 2014: website http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4415). The study will assess the effect of a cervical pessary on preterm birth rates and neonatal outcome compared to treatment with a cervical cerclage. The study is set in the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology - NVOG Consortium 2.0, a collaborative network of all major hospitals in The Netherlands and the Dutch Society of Obstetrics and Gynaecology (NVOG). In addition, international hospitals interested in the trial can participate in this study.
According to local protocols, asymptomatic women with a singleton pregnancy and a prior spontaneous preterm birth before 34 weeks of gestation are offered the use of progesterone and cervical length measurements before 24 weeks of gestation. Women with a cervix ≤25 mm before 24 weeks of gestation are eligible to participate in the trial as these women would be eligible for a secondary cerclage. Additionally, women who are considered for a placement of a cerclage before 16 weeks gestation based on their obstetric history of cervical insufficiency (primary cerclage) are eligible.
All women with an indication for a primary or secondary cerclage, as described above, are eligible to participate in this study. Women with placenta praevia, vasa praevia, PPROM, cervical length of less than 2 mm, cervical dilation of 3 cm or more, identified major congenital or chromosomal abnormalities and women with signs of intrauterine infection will be excluded from the study. In addition, maternal age less than 18 years and inability to give informed consent are exclusion criteria.
Procedures, recruitment, randomisation and collection of baseline data
All eligible women will be informed in brief about the clinical trial by the supervising gynaecologist or by the attending resident. Subsequently, the investigator or an authorised member of the investigational staff must explain to potential subjects the aims, methods, reasonably anticipated benefits, and potential hazards of the study. Women will be informed that their participation is voluntary and that they may withdraw consent to participate at any time. They will be informed that choosing not to participate will not affect the care they will receive.
Each woman must give written consent prior to randomisation. The woman will be given sufficient time to read the patient information and the informed consent form and have the opportunity to ask questions. An independent physician will be accessible for any questions the women may have. The consent form must be signed before any study-related activity can take place. A copy of the informed consent form must be given to the participating woman. Patient information is provided in Dutch and English. Women who meet all inclusion criteria but decline to participate are asked to be included in an observational cohort (see Figure 1).
Flow diagram PC Study
Randomisation will be centrally controlled using an on-line computerised randomisation service made specifically for randomization in clinical trials, ALEA (https://nl.tenalea.net/amc/ALEA/). Centres will be able to access the randomisation service 24 h/day. Eligible women will be randomized in a 1:1 ratio to cervical cerclage and pessary (see Figure 1). Randomisation will be stratified by indication for type of cerclage (primary or secondary) and centre (to prevent any imbalance between groups in aspects of maternal or neonatal care that may differ between centres). We will apply block randomisation with a variable block size of 4 and 6. Due to the type of interventions this study will not be blinded.
Baseline characteristics (e.g. patient demographics, obstetric and medical history), details of delivery, maternal and neonatal assessments during pregnancy or post-partum will be recorded into a web-based Case Report Form (CRF) that is accessible through a closed part of a web-secured database (see Figure 1). We included core outcomes for preterm birth in the CRF [21]. The CRF can be found in Additional file 1.
Confidentiality and data security
Initials of participants as well as year of birth are recorded in the electronic database. Linking personal data with randomisation number can only be done in the local clinics. Each participating clinic receives a login name and password to gain access to the web-secured database. The access is restricted to the database of the clinic to which the password and login name belongs. Full access to the entire database is possible to some members of the research staff, but has to be requested via the trial bureau and data manager of the NVOG Consortium 2.0.
Eligible women will be randomly allocated to receive either a cervical cerclage or a cervical pessary (Arabin® pessary). Both will be placed before 24 weeks, or before 16 weeks in case of a primary intervention. Women allocated to a cervical cerclage will be receiving the intervention according to local protocol. Women allocated to a cervical pessary will receive a simple vaginal examination to assess which size pessary fits best. It is important that the pessary is placed by a care giver with expertise to ensure careful placement of the pessary. In case of complaints, (vaginal) examination of the patient is advised to reposition the pessary or to replace the pessary with another size if necessary. Both interventions will stay in place until 36 weeks of gestation or until delivery, whatever comes first. If recurrent or persistent blood loss, premature rupture of the membranes or contractions occur during the use of a pessary, the pessary should be removed. Further management will be according to the national guideline on prevention of preterm birth and local protocols (see Figure 1).
The primary outcome will be delivery before 32 weeks of gestation.
Secondary outcome measures
Secondary outcomes will be time from intervention to delivery, gestational age at birth, preterm birth rate before 24, 28, 34 and 37 weeks of gestation (overall and stratified by spontaneous or indicated delivery), premature rupture of membranes, use of tocolysis and/or corticosteroids during pregnancy, mode of delivery, maternal infections, maternal side effects and both neonatal and maternal hospital admissions. Perinatal outcome will be assessed through a composite of adverse perinatal outcome. This composite outcome contains chronic lung disease, intraventricular haemorrhage (IVH) > grade II, periventricular leucomalacia (PVL) > grade I, necrotising enterocolitis (NEC) > stage I, retinopathy of prematurity (ROP), patent ductus arteriosus (PDA), treated seizures, early and late onset sepsis, neonatal meningitis, (intra-partum) stillbirth, death before discharge from the nursery. The definitions of these outcomes can be found in Table 1. All components of the composite outcome will also be assessed individually.
Definitions of secondary outcome measures
Defined as:
Maternal infections
Two measurements of maternal temperature above 37,8 degrees Celsius at a one hour interval and a maternal pulse >100 beats per minute requiring treatment with antibiotics
Maternal side effects
Vaginal discharge, bleeding, discomfort, dyspareunia, cervical laceration
Chronic lung disease
Babies born before 32 weeks: need for >30% oxygen, with or without positive pressure ventilation or continuous positive pressure at 36 weeks postmenstrual age, or discharge (whichever comes first).
Babies born after 32 weeks: need for >30% oxygen with or without positive pressure ventilation or continuous positive pressure at 56 days postnatal age, or discharge (whichever comes first).
IVH > grade II
Haemorrhage in the germinal matrix, ventricles, or cerebral parenchyma; observed on ultrasound examination or MRI
PVL > grade I
Periventricular lucency in the white matter
NEC > stage I
Defined as the presence of the characteristic clinical features of abdominal distension, with or without rectal bleeding, and abdominal radiographic finding associated with pneumatosis intestinalis
Early sepsis
If prior to or at 72 h of life the infant had an infection marked by positive blood, CSF, or urine (catheterised or suprapubic) cultures with or without suspicious clinical findings of infection on physical examination.
Late sepsis
If after 72 h of life the infant had an infection marked by positive blood, CSF, or urine (catheterised or suprapubic) cultures with or without suspicious clinical findings of infection on physical examination
if there is clinical evidence of cardiovascular collapse or an unequivocal X-ray confirming infection and often cardiovascular decomposition
Neonatal meningitis
Suspected or proven (caused by any pathogen)
In addition, a cost-effectiveness analysis will be performed that will be reported separately from the primary report on the randomised trial.
Follow up of women and infants
All details of delivery, maternal assessments and admittance during pregnancy will be recorded in an electronic case record form that will be accessible through the web-secured database. In case of admittance of a newborn, details of admittance will also be recorded. The outcome measures, when applicable, will be measured until 10 weeks after the expected term date of delivery.
The possibilities to perform long term follow-up will be assessed and planned, depending on the outcomes of the primary study and granted funding. Permission to approach women for follow-up research will be asked by the initial informed consent.
We plan to evaluate the non-inferiority of a cervical pessary as compared to cervical cerclage. We assume an event rate of 20% for the primary outcome, i.e. delivery before 32 weeks, for cerclage based on current literature. We will use a non-inferiority margin of 10%. If the event rate is 20% for the primary outcome in the cerclage arm, this is equivalent to saying that a pessary is non-inferior to cerclage when the upper limit of the 95% confidence interval of the event rate of the primary outcome in the pessary group is less than 30%. Using a one-sided alpha of 0.05 and power of 0.80 we need 2 groups of 200 women each.
Data will initially be analysed according to the intention to treat method. The primary outcome will be assessed investigating whether the prevalence of the primary outcome, birth before 32 weeks, is not more than 10% higher in the pessary group compared to the cerclage group. Non-inferiority will be concluded when the upper end of a one-sided 95% confidence interval for the risk difference between the prevalence of the primary outcome in the pessary group and the cerclage group is less than 10%.
The secondary outcome time from intervention to delivery will be evaluated by Cox proportional hazard analysis and Kaplan-Meier estimates and plots, with account for different durations of gestation at entry and stratification by indication for intervention (and centre when data allows), and will be tested with the log rank test. Secondary dichotomous outcome measures will be assessed by calculating absolute and relative risks, along with 95% confidence intervals. Differences in continuous outcomes between both strategies will be assessed using a linear mixed model.
In all analyses, stratification by centre will be accounted for with a random intercept for each centre, and by adding the cerclage indication as a covariate to the log-binomial or linear mixed models. If these models fail, A Cochran–Mantel–Haenszel (CMH) approach will be used to take into account that randomisation was stratified on indication for cerclage (and centre, if the data allows). Such a stratified analysis of the estimates the risk differences from each covariate subgroup and uses CMH weights to estimate treatment difference and its standard error. When appropriate, numbers needed to treat will be calculated.
Subgroup analysis
We pre-specify three subgroup analyses based on: (1) the indication of the type of cerclage to investigate the effectiveness of the pessary compared to a primary and secondary cerclage separately, (2) the number of previous preterm births (overall and separately for indication for primary or secondary intervention) in which we distinguish those with one previous preterm birth from those with two or more previous preterm births and (3) cervical length ≤15 mm and >15 mm in women with an indication for secondary intervention. Subgroup effects will be investigated for the primary outcome, preterm delivery before 32 weeks of gestation, and for the composite of perinatal outcome. Subgroup effects will be assessed by including an interaction term between the subgrouping variable and treatment allocation as covariate to the regression model. Afterwards, a stratified subgroup analysis will be performed to study the effect of treatment in different strata of the subgroups.
To evaluate the potential of each of the strategies, we will also perform a per protocol analysis, taking into account only those cases that were treated according to protocol.
(Serious) Adverse Event ([S]AE)
All AEs reported spontaneously by the subject or observed by the investigator or his staff will be recorded. All SAEs will be reported through the web portal ToetsingOnline to the accredited medical ethics committee (MEC) that approved the protocol.
Interim safety review
Safety reviews will be performed after all outcomes of 110 inclusions are available for analysis, and thereafter as determined necessary by the independent data and safety monitoring board (DSMB). The DSMB will be unblinded before making recommendations, but the researchers are to remain blinded. An extra meeting will be planned if indicated by the safety review. The data and safety monitoring committee can advise to stop the study for safety reasons.
To our knowledge there are no other registered on-going trials comparing the effect of a cervical pessary and a cervical cerclage in women at high risk for preterm birth.
When the pessary was first described in 1959, it was used in women with recurrent late miscarriages and possible cervical insufficiency [13]. The largest randomised controlled trial so far shows no difference between cervical cerclage and pessary in women with previous spontaneous preterm birth and an indication for a cerclage [20]. In addition, the recent PECEP study, a study which compared treatment with a pessary in women with a short cervix with expectative management, included 11% women with at least one prior preterm birth. This study showed an overall significant decrease in preterm birth in the intervention (pessary) group (spontaneous delivery before 34 weeks 12 (6%) in the pessary group vs. 51 (27%) in de control group; OR 0.18; 95% CI 0.08–0.37; p < 0·0001), however, no subgroup analysis was performed for women with a previous preterm birth [15]. There are clues that a cervical pessary might be as effective as a cerclage in the prevention of preterm birth, however, large recent randomized controlled trials with information on the effectiveness of a pessary in women with a previous preterm birth are lacking.
A cervical cerclage is considered to be effective in the prevention of preterm birth in women with cervical insufficiency and/or short cervix during pregnancy with a previous preterm birth. However, it is associated with serious risks such as premature rupture of membranes, premature contractions, cervical and/or uterine infections, vaginal bleeding and cervical laceration [11, 12]. Although the chance of these complications occurring is indeed low, the impact on the course of the pregnancy is major. Additionally, cervical cerclage is a surgical intervention which is usually performed under general anaesthesia, and as such is at risk of surgical complications. A cervical pessary is a non-invasive intervention and can be placed in an outpatient setting. In addition, severe complications related to cerclage are considered to occur more often compared to complications related to the use of pessary. This makes a pessary more attractive as intervention, however, the effect on preterm birth and neonatal outcome should be addressed first.
The outcome of this study will determine whether treatment with a cervical pessary can replace a cerclage to prevent preterm birth in women at high-risk for preterm delivery.
AE:
Adverse event
CMH:
Cochran–Mantel–Haenszel
CRF:
Case report form
DSMB:
Data and safety monitoring board
IVH:
Intraventricular haemorrhage
MEC:
Medical ethics committee
NEC:
Necrotising enterocolitis
NVOG:
Dutch society of obstetrics and gynaecology
PDA:
Patent ductus arteriosus
PECEP:
Pesario cervical para evitar prematuridad
PPROM:
Preterm pre-labour rupture of membranes
PVL:
Periventricular leukomalacia
ROP:
Retinopathy of prematurity
SAE:
Serious adverse event
This study is funded by ZonMw grant 837,002,406.
EP, MAO, BWJM, DJB, CAN, ES and BK represent the PC study group and were involved in conception and design of the study. LEMK and MDZ are involved in the logistics of the study. MTMF, SWAN, MS, MB, MAB, ABH, BBJH, AAMT, JJZ, DPH, FWM, FP, BMT, DNMP, AJMH, HCIS, MEH, THMH, NWES, KCV, MAM, IME, MSP, KB, HV, NAMC, JL, NYCS are local investigators at the participating centres. EP, MAO, BWJM, CAN, ES and BK drafted the manuscript, which follows the SPIRIT checklist for reporting randomised trials (see Additional file 2). All authors read and approved the final draft of the manuscript.
The trial has been approved by the medical ethics committee of the Academic Medical Centre Amsterdam, reference number MEC AMC 2013_365, and by the boards of management of all participating hospitals. The trial is registered in the Netherlands Trial Registry, reference number NTR 4415: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4415. The full study protocol can be downloaded from the study website (http://www.studies-obsgyn.nl/pc). All participants are asked for written consent before randomisation.
Additional file 1: Case Report Form (CRF) PC Study. (DOCX 155 kb)
Additional file 2: SPIRIT checklist for reporting randomised trials for the PC Study. (DOC 120 kb)
Department of Obstetrics and Gynaecology, Academic Medical Center (AMC), Amsterdam, The Netherlands
Julius Center for General Practice and Health Sciences, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis (OLVG) Oost, Amsterdam, The Netherlands
Department of Obstetrics and Gynaecology, University Medical Center Groningen (UMCG), Groningen, The Netherlands
Department of Obstetrics and Gynaecology, Isala Hospital, Zwolle, The Netherlands
Department of Obstetrics and Gynaecology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
Department of Obstetrics and Gynaecology, Flevoziekenhuis, Almere, The Netherlands
Department of Obstetrics and Gynaecology, VU Medical Center (VUmc), Amsterdam, The Netherlands
Department of Obstetrics and Gynaecology, Zaans Medical Center (ZMC), Zaandam, The Netherlands
Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis (OLVG) West, Amsterdam, The Netherlands
Department of Obstetrics and Gynaecology, Albert Schweitzer Hospital, Dordrecht, The Netherlands
Department of Obstetrics and Gynaecology, Deventer Hospital, Deventer, The Netherlands
Department of Obstetrics and Gynaecology, Martini Hospital, Groningen, The Netherlands
Department of Obstetrics and Gynaecology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands
Department of Obstetrics and Gynaecology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy
Department of Obstetrics and Gynaecology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
Department of Obstetrics and Gynaecology, Amphia Hospital, Breda, The Netherlands
Department of Obstetrics and Gynaecology, Gelre Hospital, Apeldoorn, The Netherlands
Department of Obstetrics and Gynaecology, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
Department of Obstetrics and Gynaecology, HagaZiekenhuis, Den Haag, The Netherlands
Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, The Netherlands
Department of Obstetrics and Gynaecology, Diakonessenhuis, Utrecht, The Netherlands
Department of Obstetrics and Gynaecology, Spaarne Gasthuis, Haarlem, The Netherlands
Department of Obstetrics and Gynaecology, Spaarne Gasthuis, Hoofddorp, The Netherlands
Department of Obstetrics and Gynaecology, Meander Medical Center, Amersfoort, The Netherlands
Department of Obstetrics and Gynaecology, Medical Center Leeuwarden, Leeuwarden, The Netherlands
Department of Obstetrics and Gynaecology, Rijnstate Hospital, Arnhem, The Netherlands
Department of Obstetrics and Gynaecology, Tergooi Hospital, Hilversum, The Netherlands
Department of Obstetrics and Gynaecology, Westfries Gasthuis, Hoorn, The Netherlands
Department of Obstetrics and Gynaecology, Zuyderland Hospital, Heerlen, The Netherlands
Department of Obstetrics and Gynaecology, Elizabeth TweeSteden Hospital, Tilburg, The Netherlands
Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
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