title: Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel

abstract:
Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis. Using PCa patient-derived xenografts (PDXs) we assessed the metabolic changes after castration of tumor-bearing mice. We found that relapsed tumors had a significant increase in fatty acids and ketone body content compared with baseline. We confirmed that critical ketogenic/ketolytic enzymes (ACAT1, OXCT1, BDH1) were significantly augmented after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT.

Increased ACAT1 and OXCT1 was also observed for a subset of PCa patients that relapsed with low AR and ERG expression. These factors were associated with decreased biochemical relapse and progression free survival. In summary, our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

category: oncology


title: U-shaped effect of blood pressure on structural OCT metrics and retinal blood flow autoregulation in ophthalmologically healthy subjects

abstract:
Objective1) To investigate the effect of low blood pressure (BP), treated arterial hypertension (AHT), and untreated AHT on the ganglion cell-inner plexiform layer (GCIPL) and the retinal nerve fiber layer (RNFL) thickness of non-glaucomatous eyes and 2) to elucidate whether this effect is related to crossing the lower limit of retinal blood flow (RBF) autoregulation.

DesignCross-sectional, case-control.

SubjectsWe included 96 eyes of 96 ophthalmologically healthy subjects (age 50-65). Participants were prospectively recruited from a large-scale cohort study in the northern Netherlands (n=167,000; Lifelines Biobank). They were allocated to four groups (low BP, normal BP [controls], treated AHT, untreated AHT), based on information from previous visits and strict distribution criteria.

MethodsInner retinal layer thicknesses were obtained with optical coherence tomography (OCT). Fractal dimension of the superficial microvasculature was quantified with OCT-angiography and customized software. Central retinal vessel diameters were obtained from fundus images. BP and intraocular pressure measurements were also acquired. Measurements were combined with a validated physiological model to estimate vascular outcome measures. Structural and vascular metrics were compared across groups and mediation analysis was performed.

Main outcome measuresStructural: macular GCIPL and RNFL (mRNFL), peripapillary RNFL (pRNFL) thickness. Vascular: RBF, retinal vascular resistance (RVR), autoregulatory reserve (AR).

ResultsCompared to controls, GCIPL was thinner in the low BP group (P=0.013), treated hypertensives (P=0.007), and untreated hypertensives (P=0.007). Treated hypertensives exhibited the thinnest mRNFL (P=0.001), temporal pRNFL (P=0.045), and inferior pRNFL (P=0.034). In multivariable analysis, RBF was mediating the association of GCIPL thickness with BP within the combined low BP group and controls (P=0.003), RVR together with AR were mediating the same association within the combined treated hypertensives and controls (P=0.001 and P=0.032), and RVR was mediating the association within the combined untreated antihypertensives and controls (P=0.022).

ConclusionsWe uncovered GCIPL and RNFL thinning related to both tails of the BP distribution. GCIPL thinning was associated with reduced RBF autoregulatory capacity. This predisposition to glaucomatous damage could explain the frequent epidemiological finding of increased glaucoma risk in certain subgroups, such as subjects with nocturnal BP dipping or aggressively treated AHT. Longitudinal studies could confirm this postulation.

category: ophthalmology


title: A global overview of genetically interpretable comorbidities among common diseases in UK Biobank

abstract:
BackgroundComorbidities greatly increase global health burdens, but the landscapes of their genetic factors have not been systematically investigated.

MethodsWe used the hospital inpatient data of 385,335 patients in UK Biobank to investigate the comorbid relations among 439 common diseases. Post-GWAS analyses were performed to identify comorbidity shared genetic risks at the genomic loci, network, as well as overall genetic architecture levels. We conducted network decomposition for interpretable comorbidity networks to detect the hub diseases and the involved molecules in comorbidity modules.

Results11,285 comorbidities among 439 common diseases were identified, and 46% of them were genetically interpretable at the loci, network, or overall genetic architecture level. The comorbidities affecting the same and different physiological systems showed different patterns at the shared genetic components, with the former more likely to share loci-level genetic components while the latter more likely to share network-level genetic components. Moreover, both the loci- and network-level genetic components shared by comorbidities mainly converged on cell immunity, protein metabolism, and gene silencing. Furthermore, we found that the genetically interpretable comorbidities tend to form network modules, mediated by hub diseases and featuring physiological categories. Finally, we showcased how hub diseases mediating the comorbidity modules could help provide useful insights into the genetic contributors for comorbiditities.

ConclusionsOur results provide a systematic resource for understanding the genetic predispositions of comorbidity, and indicate that hub diseases and converged molecules and functions may be the key for treating comorbidity. We have created an online database to facilitate researchers and physicians to browse, search or download these comorbidities (https://comorbidity.comp-sysbio.org).

category: genetic and genomic medicine


title: Combining symbolic regression with the Cox proportional hazards model improves prediction of heart failure deaths

abstract:
Heart failure is a clinical syndrome characterised by a reduced ability of the heart to pump blood. Patients with heart failure have a high mortality rate, and physicians need reliable prognostic predictions to make informed decisions about the appropriate application of devices, transplantation, medications, and palliative care. In this study, we demonstrate that combining symbolic regression with the Cox proportional hazards model improves the ability to predict death due to heart failure compared to using the Cox proportional hazards model alone.

We used a newly invented symbolic regression method called the QLat-tice to analyse a data set of medical records for 299 Pakistani patients diagnosed with heart failure. The QLattice identified a minimal set of mathematical transformations of the available covariates, which we then used in a Cox model to predict survival.

An exponential function of age, the inverse of ejection fraction, and the inverse of serum creatinine were identified as the best risk factors for predicting heart failure deaths. A Cox model fitted on these transformed covariates had improved predictive performance compared with a Cox model on the same covariates without mathematical transformations.

Symbolic regression is a way to find transformations of covariates from patients medical records which can improve the performance of survival regression models. At the same time, these simple functions are intuitive and easy to apply in clinical settings. The direct interpretability of the simple forms may help researchers gain new insights into the actual causal pathways leading to deaths.

category: health informatics


title: Inequalities and policy gaps in maternal health among Empowered Action Group (EAG) States in India: Evidence from Demographic Health Survey

abstract: Health inequality in maternal health is one of the serious challenges currently faced by public health experts. Maternal mortality in Empowered Action Group (EAG) states is highest and so are the health inequalities prevalent. We have made a comprehensive attempt to understand maternal health inequality and the risk factors concerning the EAG states in India, using recent data of Demography Health Survey of India (2015-16). Bi-variate, multivariate logistic regression, and concentration indices were used. The study has measured the four outcome variables of maternal health namely antenatal care of at least 4 visits, institutional delivery, contraceptive use, and unmet need. The study revealed that better maternal health is heavily concentrated among the richer households, while the negative concentration index of unmet need clearly reflected the greater demand for higher unmet need among the poor households in the EAG states of India. Challenges of inequalities still persist at large in maternal health, but to achieve better health these inequalities must be reduced. Since inequality mainly affects the poor households due to a lower level of income. Therefore, specific measures must be taken from a demand-side perspective in order to enhance their income and reduce the disparities in the EAG states of India.

category: health policy


title: How to best test suspected cases of COVID-19: an analysis of the diagnostic performance of RT-PCR and alternative molecular methods for the detection of SARS-CoV-2

abstract: As COVID-19 testing is rolled out increasingly widely, the use of a range of alternative testing methods will be beneficial in ensuring testing systems are resilient and adaptable to different clinical and public health scenarios. Here, we compare and discuss the diagnostic performance of a range of different molecular assays designed to detect the presence of SARS-CoV-2 infection in people with suspected COVID-19. Using findings from a systematic review of 103 studies, we categorised COVID-19 molecular assays into 12 different test classes, covering point-of-care tests, various alternative RT-PCR protocols, and alternative methods such as isothermal amplification. We carried out meta-analyses to estimate the diagnostic accuracy and clinical utility of each test class. We also estimated the positive and negative predictive values of all diagnostic test classes across a range of prevalence rates. Using previously validated RT-PCR assays as a reference standard, 11 out of 12 classes showed a summary sensitivity estimate of at least 92% and a specificity estimate of at least 99%. Several diagnostic test classes were estimated to have positive predictive values of 100% throughout the investigated prevalence spectrum, whilst estimated negative predictive values were more variable and sensitive to disease prevalence. We also report the results of clinical utility models that can be used to determine the information gained from a positive and negative test result in each class, and whether each test is more suitable for confirmation or exclusion of disease. Our analysis suggests that several tests exist that are suitable alternatives to standard RT-PCR and we discuss scenarios in which these could be most beneficial, such as where time to test result is critical or, where resources are constrained. However, we also highlight methodological concerns with the design and conduct of many included studies, and also the existence of likely publication bias for some test classes. Our results should be interpreted with these shortcomings in mind. Furthermore, our conclusions on test performance are limited to their use in symptomatic populations: we did not identify sufficient suitable data to allow analysis of testing in asymptomatic populations.


title: Antibiotic Prescribing Patterns at COVID-19 Dedicated Wards in Bangladesh: A Single Center Point-Prevalence Survey

abstract:
There is a clear deficiency in antimicrobial usage data and ongoing stewardship programs both in government and private health care facilities in Bangladesh. As evidences are mounting regarding irrational and often unnecessary use of antibiotics during COVID-19 pandemic, a point prevalence survey (PPS) was conducted across COVID-19 dedicated wards in Dhaka Medical College and Hospital (DMCH). Antibiotic usage data were collected from 193 patients at different COVID-19 dedicated wards at DMCH between 21 May, 2020 and 10 June, 2020. Comparisons in antibiotic usage were made between different groups using Pearson chi-square and Fisher exact test. Factors associated with multiple antibiotic prescription were evaluated using binary logistic regression model.

On survey date all (100%) patients were receiving at least one antibiotic with 133 patients (68.91%) receiving multiple antibiotics. Overall, patients presenting with severe disease received more antibiotics on average. Third generation cephalosporin ceftriaxone (53.8%), meropenem (40.9%), moxifloxacin (29.5%) and doxycycline (25.4%) were the four most prescribed antibiotics among survey patients. Among comorbidities diabetes mellitus (DM) was independently associated with increased antibiotic prescribing. Abnormal C-reactive protein (CRP) and serum d-dimer were linked with higher odds of antibiotic prescribing among survey patients. Overall, prevalence of antibiotic prescribing in COVID-19 patients at DMCH was very high. This could be attributed to a lack of clear treatment protocol against COVID-19 till date as well as lack of modern laboratory facilities to support judicial antibiotic prescribing in Bangladesh. A well-functioning antibiotic stewardship program in Bangladesh is required to prevent an impending health crisis.

category: infectious diseases


title: Factor V is an immune inhibitor that is expressed at increased levels in leukocytes of patients with severe Covid-19

abstract: Severe Covid-19 is associated with elevated plasma Factor V (FV) and increased risk of thromboembolism. We report that neutrophils, T regulatory cells (Tregs), and monocytes from patients with severe Covid-19 express FV, and expression correlates with T cell lymphopenia. In vitro full length FV, but not FV activated by thrombin cleavage, suppresses T cell proliferation. Increased and prolonged FV expression by cells of the innate and adaptive immune systems may contribute to lymphopenia in severe Covid-19. Activation by thrombin destroys the immunosuppressive properties of FV. Anticoagulation in Covid-19 patients may have the unintended consequence of suppressing the adaptive immune system.


title: Anticipating the curve: can online symptom-based data reflect COVID-19 case activity in Ontario, Canada?

abstract:
BackgroundLimitations in laboratory diagnostic capacity and reporting delays have hampered efforts to mitigate and control the ongoing COVID-19 pandemic globally. Syndromic surveillance of COVID-19 is an important public health tool that can help detect outbreaks, mobilize a rapid response, and thereby reduce morbidity and mortality. The primary objective of this study was to determine whether syndromic surveillance through self-reported COVID-19 symptoms could be a timely proxy for laboratory-confirmed case trends in the Canadian province of Ontario.

MethodsWe retrospectively analyzed self-reported symptoms data collected using an online tool - Outbreaks Near Me (ONM) - from April 20th to Oct 11th, 2020 in Ontario, Canada. We estimated the correlation coefficient between the weekly proportion of respondents reporting a COVID-like illness (CLI) to both the weekly number of PCR-confirmed COVID-19 cases and the percent positivity in the same period for the same week and with a one-week lag.

ResultsThere were 314,686 responses from 188,783 unique respondents to the ONM symptom survey. Respondents were more likely to be female and be in the 40-59 age demographic compared to the Ontario general population. There was a strong positive correlation between the weekly number of reported cases in Ontario and the percent of respondents reporting CLI each week (r = 0.89, p <0.01) and with a one-week lag (r = 0.89, p <0.01).

InterpretationWe demonstrate a strong positive and significant correlation (r = 0.89, p <0.01) between percent of self-reported COVID-like illness and the subsequent weeks COVID-19 cases reported, highlighting that a rise in CLI may precede official statistics by at least 1 week. This demonstrates the utility of syndromic surveillance in predicting near-future disease activity. Digital surveillance systems are low-cost tools that may help measure the burden of COVID-19 in a community if there is under-detection of cases through conventional laboratory diagnostic testing. This additional information can be used to guide a healthcare response and policy decisions.


title: A Vital Sign-based Prediction Algorithm for Differentiating COVID-19 Versus Seasonal Influenza in Hospitalized Patients

abstract: Patients with influenza and SARS-CoV2/Coronavirus disease 2019 (COVID-19) infections have different clinical course and outcomes. We developed and validated a supervised machine learning pipeline to distinguish the two viral infections using the available vital signs and demographic dataset from the first hospital/emergency room encounters of 3,883 patients who had confirmed diagnoses of influenza A/B, COVID-19 or negative laboratory test results. The models were able to achieve an area under the receiver operating characteristic curve (ROC AUC) of at least 97% using our multiclass classifier. The predictive models were externally validated on 15,697 encounters in 3,125 patients available on TrinetX database that contains patient-level data from different healthcare organizations. The influenza vs. COVID-19-positive model had an AUC of 98%, and 92% on the internal and external test sets, respectively. Our study illustrates the potentials of machine-learning models for accurately distinguishing the two viral infections. The code is made available at https://github.com/ynaveena/COVID-19-vs-Influenza and may be have utility as a frontline diagnostic tool to aid healthcare workers in triaging patients once the two viral infections start cocirculating in the communities.


title: Innate lymphoid cells and disease tolerance in SARS-CoV-2 infection

abstract: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. This study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan -- T cell subsets decrease less than 2-fold -- and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was higher in females than in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males.


title: High prevalence of Plasmodium malariae and Plasmodium ovale in co-infections with Plasmodium falciparum in asymptomatic malaria parasite carriers in Southwest Nigeria

abstract: Asymptomatic malaria parasite carriers do not seek anti-malarial treatment and may constitute a silent infectious reservoir. In order to assess the level of asymptomatic and symptomatic carriage amongst adolescents in a highly endemic area, and to identify the risk factors associated with such carriage, we conducted a cross sectional survey of 1032 adolescents (ages 10-19) from eight schools located in Ibadan, Southwest Nigeria in 2016. Blood films and blood spot filter paper samples were prepared for microscopy and DNA analysis. The prevalence of asymptomatic malaria was determined using microscopy, rapid diagnostic tests and PCR for 658 randomly selected samples. Of these, we found that 80% of asymptomatic schoolchildren were positive for malaria parasites by PCR, compared to 47% and 9% determined by RDT and microscopy, respectively. Malaria parasite species typing was performed using PCR targeting the mitochondrial CoxIII gene, and revealed high rates of carriage of Plasmodium malariae (53%) and Plasmodium ovale (24%). Most asymptomatic infections were co-infections of two or more species (62%), with P. falciparum + P. malariae the most common (35%), followed by P. falciparum + P. malariae + P. ovale (21%) and P. falciparum + P. ovale (6%). Single infections of P. falciparum, P. malariae and P. ovale accounted for 24%, 10% and 4% of all asymptomatic infections respectively. To compare the species composition of asymptomatic and symptomatic infections, further sample collection was carried out in 2017 at one of the previously sampled schools, and at a nearby hospital. Whilst the species composition of the asymptomatic infections was similar to that observed in 2016, the symptomatic infections were markedly different, with single infections of P. falciparum observed in 91% of patients, P. falciparum + P. malariae in 5% and P. falciparum + P. ovale in 4%.


title: Detection of SARS-Cov-2 RNA in serum is associated with increased mortality risk in hospitalized COVID-19 patients.

abstract:
BackgroundCOVID-19 has overloaded national health services worldwide. Thus, early identification of patients at risk of poor outcomes is critical. Our objective was to analyse SARS-CoV-2 RNA detection in serum as a severity biomarker in COVID-19.

Methods and FindingsRetrospective observational study including 193 patients admitted for COVID-19. Detection of SARS-CoV-2 RNA in serum (CoVemia) was performed with samples collected at 48-72 hours of admission by two techniques from Roche and Thermo Fischer Scientific (TFS). Main outcome variables were mortality and need for ICU admission during hospitalization for COVID-19.

CoVemia was detected in 50-60% of patients depending on technique. The correlation of Ct in serum between both techniques was good (intraclass correlation coefficient: 0.612; p < 0.001). Patients with CoVemia were older (p = 0.006), had poorer baseline oxygenation (PaO2/FiO2; p < 0.001), more severe lymphopenia (p < 0.001) and higher LDH (p < 0.001), IL-6 (p = 0.021), C-reactive protein (CRP; p = 0.022) and procalcitonin (p = 0.002) serum levels.

We defined "relevant CoVemia" when detection Ct was < 34 with Roche and < 31 for TFS. These thresholds had 95% sensitivity and 35 % specificity. Relevant CoVemia predicted death during hospitalization (OR 9.2 [3.8 - 22.6] for Roche, OR 10.3 [3.6 - 29.3] for TFS; p < 0.001). Cox regression models, adjusted by age, sex and Charlson index, identified increased LDH serum levels and relevant CoVemia (HR = 9.87 [4.13-23.57] for TFS viremia and HR = 7.09 [3.3-14.82] for Roche viremia) as the best markers to predict mortality.

ConclusionsCoVemia assessment at admission is the most useful biomarker for predicting mortality in COVID-19 patients. CoVemia is highly reproducible with two different techniques (TFS and Roche), has a good consistency with other severity biomarkers for COVID-19 and better predictive accuracy.

AUTHOR SUMMARYCOVID-19 shows a very heterogeneous clinical picture. In addition, it has overloaded national health services worldwide. Therefore, early identification of patients with poor prognosis is critical to improve the use of limited health resources. In this work, we evaluated whether baseline SARS-CoV2 RNA detection in blood (CoVemia) is associated with worse outcomes. We studied almost 200 patients admitted to our hospital and about 50-60% of them showed positive CoVemia. Patients with positive CoVemia were older and had more severe disease; CoVemia was also more frequent in patients requiring admission to the ICU. Moreover, we defined "relevant CoVemia", as the amount of viral load that better predicted mortality obtaining 95% sensitivity and 35% specificity. In addition, relevant CoVemia was a better predictor than other biomarkers such as LDH, lymphocyte count, interleukin-6, and indexes used in ICU such as qSOFA and CURB65.

In summary, detection of CoVemia is the best biomarker to predict death in COVID-19 patients. Furthermore, it is easy to be implemented and is reproducible with two techniques (Roche and Thermo Fisher Scientific) that are currently used for diagnosis in nasopharyngeal swabs samples.


title: From "don, doff, and discard" to "don, doff, and decontaminate" - determination of filtering facepiece respirator and surgical mask integrity and inactivation of a SARS-CoV-2 surrogate and a small non-enveloped virus following multiple-cycles of vaporised hydrogen peroxide, ultraviolet germicidal irradiation, and dry heat decontamination

abstract:
BackgroundAs the SARS-CoV-2 pandemic accelerates, the supply of personal protective equipment remains under strain. To combat shortages, re-use of surgical masks and filtering facepiece respirators has been recommended. Prior decontamination is paramount to the re-use of these typically single-use only items and, without compromising their integrity, must guarantee inactivation of SARS-CoV-2 and other contaminating pathogens.

AimWe provide information on the effect of time-dependent passive decontamination at room temperature and evaluate inactivation of a SARS-CoV-2 surrogate and a non-enveloped model virus as well as mask and respirator integrity following active multiple-cycle vaporised hydrogen peroxide (VHP), ultraviolet germicidal irradiation (UVGI), and dry heat (DH) decontamination.

MethodsMasks and respirators, inoculated with infectious porcine respiratory coronavirus or murine norovirus, were submitted to passive decontamination or single or multiple active decontamination cycles; viruses were recovered from sample materials and viral titres were measured via TCID50 assay. In parallel, filtration efficiency tests and breathability tests were performed according to EN standard 14683 and NIOSH regulations.

Results and DiscussionInfectious porcine respiratory coronavirus and murine norovirus remained detectable on masks and respirators up to five and seven days of passive decontamination. Single and multiple cycles of VHP-, UVGI-, and DH were shown to not adversely affect bacterial filtration efficiency of masks. Single- and multiple UVGI did not adversely affect respirator filtration efficiency, while VHP and DH induced a decrease in filtration efficiency after one or three decontamination cycles. Multiple cycles of VHP-, UVGI-, and DH slightly decreased airflow resistance of masks but did not adversely affect respirator breathability. VHP and UVGI efficiently inactivated both viruses after five, DH after three, decontamination cycles, permitting demonstration of a loss of infectivity by more than three orders of magnitude. This multi-disciplinal approach provides important information on how often a given PPE item may be safely reused.


title: The impact of high dose oral cotrimoxazole in patients with COVID-19 with hypoxic respiratory failure requiring non-invasive ventilation: A Case Control Study

abstract:
BackgroundCOVID-19 can be fatal in a significant proportion of people who develop critical illness, resulting in hypoxic respiratory failure secondary to Acute Respiratory Distress Syndrome (ARDS) which is thought to be mediated by a cytokine storm syndrome. Steroids have been shown to be of some benefit, but the mainstay of treatment remains supportive.

MethodsThe data was collected retrospectively from consecutive, newly diagnosed patients presenting to the critical care facility of I Q City Medical College Hospital, Durgapur, India between June and November 2020 with critical COVID-19 on non-invasive ventilation treated with high dose oral cotrimoxazole (CTX) in addition to standard therapy (ST) and compared with patients with critical COVID-19 receiving standard therapy alone.

Results201 patients were identified. Of which 151 patients received CTX in addition to ST (mean age {+/-} SD 59 {+/-} 13 years, 81% male and mean BMI {+/-} SD 28 {+/-} 2) and 50 patients received ST alone (mean age {+/-} SD 63 {+/-} 12, 64% male and mean BMI {+/-} SD 27 {+/-} 2). We observed that the patients with critical COVID-19 receiving CTX in addition to ST had significantly better outcomes including reduced in-patient mortality (13% versus 40%, p <0.001), length of hospital and critical care unit stay (mean, 11 versus 15 days (p <0.001) and 6 versus 11 days (p <0.001) respectively), and the need for mechanical ventilation (16% versus 42%, p <0.001) with improved CRP at day 7 (mean, 38mg/L versus 62mg/L, p = 0.001).

ConclusionThese results may be due to the antibiotic and anti-cytokine effects of CTX. Clinical trials are currently underway to test our observations.


title: Unsupervised clustering reveals a unique Treg profile in slow progressors to type 1 diabetes

abstract:
ObjectiveTo profile CD4+ regulatory T cells (Tregs) in a well-characterised cohort of slow progressors to type 1 diabetes, individuals positive for multiple islet autoantibodies who remain diabetes-free for at least 10 years.

Research Design and MethodsPeripheral blood samples were obtained from extreme slow progressor individuals (n=8), with up to 32 years follow-up, and age and gender-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment, and was individually evaluated in the data analysis. PBMCs were isolated, from donors, and to assess frequency, phenotype and function of Tregs, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, FlowSOM and CITRUS, was used to evaluate Treg phenotypes.

ResultsTreg mediated suppression of CD4+ effector T cells, from slow progressors was significantly impaired, compared to healthy donors (P<0.05). Effector CD4 T cells, from slow progressors, were more responsive to Treg suppression, compared to healthy donors, demonstrated by increased suppression of CD25 expression on effector CD4 T cells (P<0.05). Unsupervised clustering on memory CD4 T cells, from slow progressors, showed an increased frequency of activated-memory CD4 Tregs associated with increased expression of GITR, compared to healthy donors (P<0.05). The participant with a raised HbA1c had a different Treg profile, compared to slow progressors and the matched controls.

ConclusionsCD4+ Tregs from slow progressor individuals have a unique Treg signature. This report highlights the need for further study of Treg heterogeneity in individuals at-risk of developing type 1 diabetes.

category: endocrinology


title: Puberty and sex-specific trajectories of systolic blood pressure: a prospective cohort study

abstract:
BackgroundSex differences in systolic blood pressure (SBP) emerge during adolescence but the role of puberty is not well understood. We examined sex-specific changes in SBP preceding and following puberty and examined the impact of puberty timing on SBP trajectories in females and males.

MethodsTrajectories of SBP before and after puberty and by timing of puberty in females and males in a contemporary English birth cohort study were analysed. Repeated measures of height from age 5 to 20 years were used to identify puberty timing (age at peak height velocity). SBP was measured on ten occasions from 3 to 24 years (N participants=4,062, repeated SBP measures=29,172). Analyses were preformed using linear spline multilevel models based on time before and after puberty and were adjusted for parental factors and early childhood factors including BMI gain from age one up to 9 years.

ResultsMean age at peak height velocity was 11.7 years (standard deviation (SD) =0.8) for females and 13.6 years (SD=0.9) for males. In adjusted models, females and males had similar SBP at age 3. Males had faster rates of increase in SBP before puberty leading to 10.19mmHg (95% CI: 6.80, 13.57) higher mean SBP at puberty which remained similar at 24 years [mean difference; 11.43mmHg (95% CI: 7.22, 15.63)]. Puberty timing was associated with small transient differences in SBP trajectories post-puberty in both sexes and small differences at 24 years in females only.

ConclusionA large proportion of the higher SBP observed in males compared to females in early adulthood is accrued before puberty. Prevention of high SBP in adult males may therefore benefit from a life course approach starting from before puberty. Interventions targeting puberty timing are unlikely to greatly influence SBP in females and males in early adulthood.

category: epidemiology


title: Optimising SARS-CoV-2 pooled testing strategies on social networks for low-resource settings

abstract: Controlling the COVID-19 pandemic is an urgent global challenge. The rapid geographic spread of SARS-CoV-2 directly reflects the social structure. Before effective vaccines and treatments are widely available, we have to rely on alternative, non-pharmaceutical interventions, including frequency testing, contact tracing, social distancing, mask wearing, and hand-washing, as public health practises to slow down the spread of the disease. However frequent testing is the key in the absence of any alternative. We propose a network approach to determine the optimal low resources setting oriented pool testing strategies that identifies infected individuals in a small number of tests and few rounds of testing, at low prevalence of the virus. We simulate stochastic infection curves on societies under quarantine. Allowing some social interaction is possible to keep the COVID-19 curve flat. However, similar results can be strategically obtained searching and isolating infected persons to preserve a healthier social structure. Here, we analyze which are the best strategies to contain the virus applying an algorithm that combine samples and testing them in groups [1]. A relevant parameter to keep infection curves flat using this algorithm is the dairy frequency of testing at zones where a high infection rate is reported. On the other hand, the algorithm efficiency is low for random search of infected people.


title: X-ray Dark-Field Chest Imaging can Detect and Quantify Emphysema in COPD Patients

abstract:
BackgroundDiseases of the respiratory system are leading global causes of chronic morbidity and mortality. While advanced medical imaging technologies of today deliver detailed diagnostic information, a low-dose, fast, and inexpensive option for early detection and/or follow-ups is still lacking. Here, we report on the first human application of a novel modality, namely X-ray dark-field chest imaging, which might fill this gap. Enabling the assessment of microstructural changes in lung parenchyma, this technique presents a more sensitive alternative to conventional chest X-rays, and yet requires only a fraction of the dose applied in computed tomography (CT).

MethodsFor this first clinical evaluation, we have built a novel dark-field chest X-ray system, which is also capable of simultaneously acquiring a conventional thorax radiograph (7 seconds, 0{middle dot}035 mSv effective dose). Representing a major medical condition, we selected chronic obstructive pulmonary disease as study subject to obtain a first impression of potential diagnostic benefits relevant to humans. For a collective of 77 patients with different disease stages, X-ray dark-field- and CT-images were acquired and visually assessed by 5 readers. In addition, pulmonary function tests were performed for every patient. The individual data sets were evaluated in a statistical work-up using correlation testing, rank-based analysis of variance, and pair-wise post-hoc comparison.

FindingsCompared to CT-based parameters (quantitative emphysema: {rho}=-0{middle dot}27, p=0{middle dot}0893 and visual emphysema: {rho}=-0{middle dot}45, p=0{middle dot}0028), the dark-field signal ({rho}=0{middle dot}62, p<0{middle dot}0001) yields a stronger correlation with diffusion capacity in the evaluated collective. Emphysema assessment based on dark-field chest X-ray features yields consistent conclusions with findings from visual CT image interpretation and shows improved diagnostic performance in comparison to conventional clinical tests characterizing emphysema.

InterpretationX-ray dark-field chest imaging allows the diagnosis of pulmonary emphysema as it provides relevant information representing the structural condition of lung parenchyma. Significant diagnostic benefits are also expected for other lung disorders.

FundingEuropean Research Council, Royal Philips, Karlsruhe Nano Micro Facility.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWith a rising number of examinations in the last decades, X-rays play an indispensable role in clinical routine. Contrast formation in medical X-ray imaging such as radiography, fluoroscopy, and computed tomography is based on attenuation, which generally benefits from large differences in atomic number and/or mass density between involved materials. If these conditions are not prevalent, or the resolution of the imaging system is not sufficient, diagnostic capabilities are limited. However, attenuation is not the only physical effect X-rays are subjected to when penetrating matter. Variations in an objects electron density lead to refraction and coherent small-angle scattering of incident X-rays. Phase-sensitive imaging techniques can detect these wave-optical phenomena, yielding additional object information. The dark-field signal, being a function of small-angle scattering, can provide structural information on the micron scale, generally below the resolution limit of the imaging system. Due to their very stringent requirements to X-ray source coherence, these techniques were originally limited to large-scale synchrotron facilities. The proposal of a three-grating interferometer in 2006, however, enabled the use of low-brilliance sources for X-ray phase-contrast imaging and thereby paved the way into the clinics. Such an apparatus elegantly allows the simultaneous acquisition of the conventional attenuation, differential phase-contrast, and novel dark-field signals. In a compact table-top system suitable for investigating murine disease models, numerous studies on pulmonary disorders such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumothorax, ventilator-associated lung injury, lung cancer, and pneumonia have been conducted and demonstrated a broad diagnostic value of the dark-field modality in particular. Adapting the system to enable imaging of the human body is a technical challenge due to limitations of the micrometer-fine, high aspect ratio grating structures in terms of fabricable size and performance at clinically relevant X-ray energies. The first evidences that these limitations are manageable were delivered in 2017 and 2018 by in-vivo porcine and human cadaver studies with an experimental prototype system.

Added value of this studyWith this work we present the first X-ray dark-field chest images of human subjects in-vivo and demonstrate the methods feasibility in a clinical surrounding. To enable this study, we have conceived, constructed, and commissioned a custom-built first demonstrator system suitable for patient use. This includes satisfying clinical demands regarding safety, usability, acquisition time, radiation dose, field of view, and image quality. This study marks the transition from investigating artificially induced disease models to evaluating the modalitys actual diagnostic performance in patients.

Implications of all available evidenceOur findings indicate that X-ray dark-field radiography provides image-type information of the lungs underlying microstructure in humans. In view of the strong link between alveolar structure and the functional condition of the lung, this capability is highly relevant for respiratory medicine and might help to establish a better understanding of pulmonary disorders. With regard to early detection of COPD, which is generally accompanied by structural impairments of the lung, this novel technique might support resolving the prevalent under-diagnosis reported in literature. With an effective dose significantly lower (about a factor of hundred) compared to thorax computed tomography, dark-field radiography could be used as broadly deployed screening tool.

category: radiology and imaging


title: What delirium detection tools are used in routine clinical practice in the UK? A Freedom of Information investigation of UK hospitals.

abstract:
PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care.

category: geriatric medicine


title: What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations.


title: The Use of Procalcitonin as an Antimicrobial Stewardship Tool and a Predictor of Disease Severity in COVID-19

abstract: In our study, procalcitonin was associated with both antibiotic use and duration in patients with COVID-19, as well as established biochemical markers of COVID-19 disease severity and oxygen requirement, suggesting a potential role for procalcitonin in COVID-19 antimicrobial stewardship.


title: Persistently increased systemic ACE2 activity and Furin levels are associated with increased inflammatory response in smokers with SARS-CoV-2 COVID-19

abstract:
BackgroundTobacco smoking is known to be involved in the pathogenesis of several cardiopulmonary diseases, and smokers are susceptible to infectious agents. However, the progression of lung injury based on COVID-19 susceptibility and severity amongst smokers and those with pre-existing pulmonary diseases is not known. We determined the systemic expression and activity of COVID-19 related proteins, cytokine/chemokines, and lipid mediators (lipidomics) amongst COVID-19 patients with and without a history of smoking with a view to define biomarkers.

MethodsWe obtained serum from COVID-19 positive and COVID-19 recovered patients with and without a history of smoking. We conducted a Luminex multiplex assay (cytokine levels), LC/MS (eicosanoids or oxylipin panel) and enzymatic activity assays on the serum samples to study the systemic changes in COVID-19 patients.

ResultsOn comparing the cytokine profiles among COVID-19 positive and COVID-19 negative patients, we found a significant upregulation in the production of pro-inflammatory cytokines like IL-1, IL-8, IL-2, VEGF and IL-10 in COVID-19 positive patients as compared to the respective controls. Interestingly, smoking history resulted in further augmentation of the release of some hyper-inflammatory cytokines, like IFN-{gamma}, Eotaxin, MCP-1 and IL-9 amongst COVID-19 positive patients. The enzymatic activity for ACE2, the binding partner for SARS-CoV2 virus in the host cell, was found to be significantly increased in the serum of patients with a smoking history compared to the serum collected from the non-smoking controls. Similarly to our cytokine analysis, our measurement of serum Furin levels was also affected by the patients smoking history, in which we reported a substantial rise in serum Furin levels of COVID-19 patients. The analysis of lipid mediators revealed a distinct signature amongst the COVID-19 positive versus recovered subjects in PGF2, HETEs, LXA4 and LTB4 levels. However, we did not find any changes in the levels of any lipid mediators based on the smoking history of the patients. Overall, our results point towards distinct systemic signatures amongst COVID-19 positive patients. We also show that smoking adversely affects the systemic levels of inflammatory markers and COVID-19 related proteins, thus suggesting that COVID-19 infection may have severe outcomes amongst smokers which is reflected systemically.


title: Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study

abstract:
ObjectivesThe epidemiology of post-COVID syndrome (PCS) is currently undefined. We quantified rates of organ-specific impairment following recovery from COVID-19 hospitalisation compared with those in a matched control group, and how the rate ratio (RR) varies by age, sex, and ethnicity.

DesignObservational, retrospective, matched cohort study.

SettingNHS hospitals in England.

Participants47,780 individuals (mean age 65 years, 55% male) in hospital with COVID-19 and discharged alive by 31 August 2020, matched to controls on demographic and clinical characteristics.

Outcome measuresRates of hospital readmission, all-cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney and liver diseases until 30 September 2020.

ResultsMean follow-up time was 140 days for COVID-19 cases and 153 days for controls. 766 (95% confidence interval: 753 to 779) readmissions and 320 (312 to 328) deaths per 1,000 person-years were observed in COVID-19 cases, 3.5 (3.4 to 3.6) and 7.7 (7.2 to 8.3) times greater, respectively, than in controls. Rates of respiratory, diabetes and cardiovascular events were also significantly elevated in COVID-19 cases, at 770 (758 to 783), 127 (122 to 132) and 126 (121 to 131) events per 1,000 person-years, respectively. RRs were greater for individuals aged <70 than [≥] 70 years, and in ethnic minority groups than the White population, with the biggest differences observed for respiratory disease: 10.5 [9.7 to 11.4] for <70 years versus 4.6 [4.3 to 4.8] for [≥] 70 years, and 11.4 (9.8 to 13.3) for Non-White versus 5.2 (5.0 to 5.5) for White.

ConclusionsIndividuals discharged from hospital following COVID-19 face elevated rates of multi-organ dysfunction compared with background levels, and the increase in risk is neither confined to the elderly nor uniform across ethnicities. The diagnosis, treatment and prevention of PCS require integrated rather than organ- or disease-specific approaches. Urgent research is required to establish risk factors for PCS.


title: Posttraumatic Stress Disorder and the Nature of Trauma in Patients with Cardiovascular Diseases: A Case-Control study

abstract:
IntroductionA large body of evidence indicates a significant and morbid association between posttraumatic stress disorder (PTSD) and cardiovascular disease (CVD). Few studies, however, have addressed the range of trauma in this medical population, from massive heart attack, to defibrillator shock to previous interpersonal aggression.

ObjectiveThe main objective of this study was to examine the nature of trauma associated with the development of PTSD in CVD patients. More precisely, we were interested in knowing if trauma was medical in nature and whether cumulative trauma resulted in PTSD.

MethodsWe performed a 1:3 case-control study. The authors compared CVD patients diagnosed with PTSD (n=37) to those with adjustment disorder (n=111) in terms of trauma/stressor types and medical and demographic characteristics.

ResultsHalf (51%) of CVD patients suffering from PTSD had endured a medical trauma, 35% an external (non-medical) trauma, and 14% both. There were no significant differences with CVD patients diagnosed with adjustment disorder, 40% of them having experienced a medical stressor, 40% an external (non-medical) stressor and 20% both. Cumulative trauma was seen in only 19% of CVD patients suffering from PTSD. Traditional risk factors (female sex, younger age) were not prominent in CVD patients with PTSD as compared to those with adjustment disorder. Cases were, however, significantly more likely to have psychiatric antecedents and recent surgical interventions.

ConclusionsBy uncovering characteristics of PTSD patients/trauma in CVD patients, this work will serve future research and clinical initiatives to better screen at-risk patients or at-risk medical situations.

category: psychiatry and clinical psychology


title: An Estimation of Reproduction Number of SARS-CoV-2 by Age Class for Age Classes in Japan

abstract:
BackgroundInfectiousness of COVID-19 by age class inferred from the infection source and by infected people might be different. However, studies of such infectiousness have not been reported.

ObjectThe object of this study was estimation of reproduction numbers by age class of the source of infection and the infected persons. To do so, after examining a new procedure for reproduction number estimation, we checked infected places by age class of the source of infection and the infected persons.

MethodWe ignore patients who infected no one because their reliability might be lower than that of patients who infected more than one person. We estimated the reproduction number from the histogram of the number of the infected people by the same patient, assuming that the histogram follows an exponential distribution.

Discussion and ConclusionThe obtained results demonstrated that the effective reproduction numbers for infection from children were very low. They were higher among adult and elderly people than among the same age class. Moreover, although the highest and second-highest infected places were  other and  at home with some exceptions, the data for infection at hospitals were remarkable among adults and elderly people. Among elderly people, infection at facilities for elderly was also high. Infections at nursing schools, schools, restaurants, and entertainment venues at night were negligible.

category: public and global health


title: Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2

abstract:
To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India), conducted a sero-survey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS CoV2 anti-nucleocapsid (anti-NC) antibodies; 95% with surrogate neutralization activity. Three-fourth recalled no symptoms. Repeat serology tests at 3 (n=346) and 6 (n=35) months confirmed stability of antibody response and neutralization potential. Local sero-positivity was higher in densely populated cities and was inversely correlated with a 30 day change in regional test positivity rates (TPR). Regional seropositivity above 10% was associated with declining TPR. Personal factors associated with higher odds of sero-positivity were high-exposure work (Odds Ratio, 95% CI, p value; 2{middle dot}23, 1{middle dot}92-2{middle dot}59, 6{middle dot}5E-26), use of public transport (1{middle dot}79, 1{middle dot}43-2{middle dot}24, 2{middle dot}8E-06), not smoking (1{middle dot}52, 1{middle dot}16-1{middle dot}99, 0{middle dot}02), non-vegetarian diet (1{middle dot}67, 1{middle dot}41-1{middle dot}99, 3{middle dot}0E-08), and B blood group (1{middle dot}36,1{middle dot}15-1{middle dot}61, 0{middle dot}001).

Impact StatementWidespread asymptomatic and undetected SARS-CoV2 infection affected more than a 100 million Indians by September 2020. Declining new cases thereafter may be due to persisting humoral immunity amongst sub-communities with high exposure.

FundingCouncil of Scientific and Industrial Research, India (CSIR)


title: Development of Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD)

abstract:
IntroductionAssessment of cognition and everyday function is essential in clinical trials for Alzheimers disease (AD). Two novel measures of cognition (No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment Scale (CFAS)) were designed to have robust psychometric properties and reduced practice and ceiling effects. This study aims to evaluate if the NPE and CFAS demonstrate stronger psychometric properties and reduced practice effects compared with established measures, including the Preclinical Alzheimer Cognitive Composite (PACC), Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Functional Activities Questionnaire (FAQ).

MethodsThis parallel group, four-site study will randomize 320 cognitively intact adults aged 60 to 85 years to novel or well-established measures of cognition and function. All participants will receive assessments at baseline (week 0), week 12, and week 52, as well as a brain MRI scan and Apolipoprotein E genetic test at study entry. Analyses will determine psychometric properties of the NPE and CFAS, compare the sensitivity of measures to AD risk markers, and identify cognitive domains within the NPE.

DiscussionPractice effects have been a major limitation of Alzheimers disease clinical trials that typically assess cognitive changes over serial assessments. Detection of functional impairment in cognitively normal individuals with biomarkers for Alzheimers disease requires instruments sensitive to very subtle functional changes. This study is intended to support the validation of two new composite measures, the NPE battery and the CFAS, which may advance clinical testing of interventions for individuals across the spectrum of early stage Alzheimers disease.

Trial RegistrationNCT03900273


title: Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci.

abstract:
Kleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6x10-9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3 region of TRANK1 gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reduced TRANK1 rs71947865 association. While theTRANK1 rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p<2.0x10-22 at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Significance StatementGenetic markers in TRANK1 gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in the TRANK1 gene region may predispose to KLS when patients have had a difficult birth, suggesting that TRANK1 gene region modulate newborns response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.


title: A Serology Strategy for Epidemiological Studies Based on the Comparison of the Performance of Seven Different Test Systems - The Representative COVID-19 Cohort Munich

abstract:
BackgroundSerosurveys are essential to understand SARS-CoV-2 exposure and enable population-level surveillance, but currently available tests need further in-depth evaluation. We aimed to identify testing-strategies by comparing seven seroassays in a population-based cohort.

MethodsWe analysed 6,658 samples consisting of true-positives (n=193), true-negatives (n=1,091), and specimens of unknown status (n=5,374). For primary testing, we used Euroimmun-Anti-SARS-CoV-2-ELISA-IgA/IgG and Roche-Elecsys-Anti-SARS-CoV-2; and virus-neutralisation, GeneScript(R)cPass, VIRAMED-SARS-CoV-2-ViraChip(R), and Mikrogen-recomLine-SARS-CoV-2-IgG, including common-cold CoVs, for confirmatory testing. Statistical modelling generated optimised assay cut-off-thresholds.

FindingsSensitivity of Euroimmun-anti-S1-IgA was 64.8%, specificity 93.3%; for Euroimmun-anti-S1-IgG, sensitivity was 77.2/79.8% (manufacturers/optimised cut-offs), specificity 98.0/97.8%; Roche-anti-N sensitivity was 85.5/88.6%, specificity 99.8/99.7%. In true-positives, mean and median titres remained stable for at least 90-120 days after RT-PCR-positivity. Of true-positives with positive RT-PCR (<30 days), 6.7% did not mount detectable seroresponses. Virus-neutralisation was 73.8% sensitive, 100.0% specific (1:10 dilution). Neutralisation surrogate tests (GeneScript(R)cPass, Mikrogen-recomLine-RBD) were >94.9% sensitive, >98.1% specific. Seasonality had limited effects; cross-reactivity with common-cold CoVs 229E and NL63 in SARS-CoV-2 true-positives was significant.

ConclusionOptimised cut-offs improved test performances of several tests. Non-reactive serology in true-positives was uncommon. For epidemiological purposes, confirmatory testing with virus-neutralisation may be replaced with GeneScript(R)cPass or recomLine-RBD. Head-to-head comparisons given here aim to contribute to the refinement of testing-strategies for individual and public health use.


title: Metabolic markers distinguish COVID-19 from other intensive care patients and show potential to stratify for disease risk

abstract:
Coronavirus disease 2019 (COVID-19) is a viral infection affecting multiple organ systems of great significance for metabolic processes. Thus. there is increasing interest in metabolic and lipoprotein signatures of the disease and early analyses have demonstrated metabolic pattern typical for atherosclerotic and hepatic damage in COVID-19 patients. However, it remains unclear whether these are specific for COVID-19 or a general marker of critical illness. To answer this question, we have analyzed 276 serum samples from 92 individuals using NMR metabolomics, including longitudinally collected samples from 5 COVID-19 and 11 cardiogenic shock intensive care patients, 18 SARS-CoV-2 antibody-positive individuals, and 58 healthy controls.

COVID-19 patients showed a distinct metabolic serum profile, including changes typical for severe dyslipidemia and a deeply altered metabolic status compared to healthy controls. Specifically, VLDL parameters, IDL particles, large-sized LDL particles, and the ApoB100/ApoA1 ratio were significantly increased, whereas HDL fractions were decreased. Moreover, a similarly perturbed profile was apparent, even when compared to other ICU patients suffering from cardiogenic shock, highlighting the impact of COVID-19 especially on lipid metabolism and energy status. COVID-19 patients were separated with an AUROC of 1.0 when compared to both healthy controls and cardiogenic shock patients. Anti-SARS-CoV-2 antibody-positive individuals without acute COVID-19 did not show a significantly perturbed metabolic profile compared to age- and sex-matched healthy controls, but SARS-CoV-2 antibody-titers correlated significantly with metabolic parameters, including levels of glycine, ApoA2, and small-sized LDL and HDL subfractions. Our data suggest that NMR metabolic profiles are suitable for COVID-19 patient stratification and post-treatment monitoring.

category: intensive care and critical care medicine


title: Reduction in transfer of micro-organisms between patients and staff using short-sleeved gowns and hand/arm hygiene in Intensive Care during the Covid pandemic: a simulation-based randomised trial.

abstract:
BackgroundCurrent PPE practices in UK intensive care units involve "sessional" gown use. This protects staff, but puts patients at risk of nosocomial infection via PPE gowns. Anecdotal reports of such infections in ITUs during Covid are frequent. We therefore explored the use of short-sleeved gowns with hand and arm hygiene as an alternative to sessional gowns.

MethodsITU Staff were invited for simulation suite training in Covid intubation and proning. They were trained in a specific hand and arm washing technique before performing simulated tasks using both standard and modified (short sleeved) PPE. Fluorescent powder was used to simulate micro-organisms, and detected using standardised photos under U/V light. Teams of staff were randomised to use standard or modified PPE first. Individuals were questioned about their feeling of personal safety, comfort and the patients safety at 4 intervals.

Results68 staff and 17 proning volunteers were studied in 17 sessions. Modified PPE completely prevented staff contamination during Covid intubation, which occurred in 30/67 staff wearing standard PPE (p = 0.0029, McNemar). Conversely, proning volunteers were contaminated by staff in 15/17 sessions with standard PPE and in 1/17 with modified PPE (P = 0.0227 McNemar). Impressions of staff comfort were superior with modified PPE (p< 0.001, t-test); personal safety scored higher with standard PPE, but the difference decreased during the session (p<0.001 start, 0.068 end). Impressions of patient safety were initially similar (p=0.87) but finished strongly in favour of modified PPE (p<0.001).

ConclusionsModified PPE using short sleeves and hand/arm cleansing appears superior to standard PPE with sessional gowns in preventing transfer of contamination between staff and patients. A clinical trial of this strategy is merited.


title: A Paradoxical Screening Serological Assay for the Diagnosis of Whipple's Disease (infection with Tropheryma whipplei)

abstract: Whipples disease (WD) is a rare infection due to Tropheryma whipplei. Following in-vitro cultivation of T. whipplei, an indirect-immunofluorescence serological assay (IFA) was developed. We tested the hypothesis that this assay could be used to either identify WD patients, or rule out WD, in patients in whom the diagnosis is being considered, based on the antibody titers of their IgM and IgG antibody responses. In this small study fourteen WD patients and 22 healthy volunteers sera were obtained from across Australia. All specimens were coded and de-identified before testing. A patient with an IgG antibody titer of [≤]1:16 may have WD [sensitivity 57% (8/14) and specificity close to 100% (22/22)]. High IgM antibody titers ([≥]1:256) were more common in WD patients [sensitivity 50% (7/14) and specificity 86% (19/22)] than in controls. The area under Receiver-Operator-Characteristic curve for IgG in the IFA assay was 0.84 (95% CI 0.69-1.00). At an IgG antibody titer of [≤]1:16 the Youdens index was 0.57. WD patients under-produce IgG antibody to T.whipplei but are more likely to over-produce IgM antibodies. This screening IFA serological assay may be clinically useful in detecting those with a possible diagnosis of WD. Patients with an IgG antibody titer of [≤]1:16 and an IgM antibody titer of [≥]1:256 may have WD and should proceed to a tissue biopsy and PCR for confirmation. Further validation of this assay, by increasing the sample size, by testing it in patients with non-WD disease and trialing in other countries should be undertaken.


title: Non-invasive brain stimulation effectiveness in anxiety disorder treatment: a meta-analysis on sham/behavior-controlled studies

abstract:
BackgroundRecently, the possibility of using non-invasive brain stimulation (NIBS) to treat mental disorders received considerable attention. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are considered effective treatments for depressive symptoms. However, no recommendation is available for anxiety disorders, suggesting that evidence is still limited.

ObjectiveWe systematically revised the existing literature, and quantitatively analyzed the effectiveness of rTMS and tDCS in anxiety disorders treatment.

MethodFollowing PRISMA guidelines, 3 electronic databases were screened to the end of February 2020 to select English-written peer-reviewed articles including (i) a clinical sample of patients with anxiety disorders, (ii) the use of a NIBS technique, (iii) the inclusion of a control condition, and (iv) pre-post scores at a validated questionnaire measuring anxious symptoms.

ResultsEleven papers met the inclusion criteria, comprising 154 participants assigned to the real stimulation condition and 164 to the sham or control group. The Hedge g for scores at disorder specific and general anxiety questionnaires before and after the treatment was computed as effect size and analyzed in two independent random-effects meta-analyses. Considering the well-known comorbidity between anxiety and depression, a third meta-analysis was run, analyzing depression scores outcomes. Results showed a significant effect of NIBS in reducing questionnaires scores in the real vs. control condition at specific and general anxiety measures, and depressive symptoms.

ConclusionAlbeit preliminary, our findings highlighted that real stimulation reduced anxiety and depression scores compared to the control condition, suggesting that NIBS can alleviate clinical symptoms in patients with anxiety diseases.


title: SARS-CoV-2 seropositivity and seroconversion in patients undergoing active cancer-directed therapy

abstract: Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. To gauge the effectiveness of these measures at the University of Pennsylvania, we conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between 5/21/2020 and 10/8/2020. Participants completed questionnaires and had up to five serial blood collections. Of 124 enrolled patients, only two (1.6%) had detectable SARS-CoV-2 antibodies on initial blood draw, and no initially seronegative patients developed newly detectable antibodies on subsequent blood draw(s), corresponding to a seroconversion rate of 0% (95%CI 0.0-4.1%) over 14.8 person-years of follow up, with a median of 13 healthcare visits per patient. These results suggest that cancer patients receiving in-person care at a facility with aggressive mitigation efforts have an extremely low likelihood of COVID-19 infection.


title: SARS-CoV-2 viral load distribution in different patient populations and age groups reveals that viral loads increase with age.

abstract:
ObjectiveTo describe the SARS-CoV-2 viral load distribution in different patient groups and age categories.

MethodsAll SARS-CoV-2 RT-PCR results from nasopharyngeal (NP) and oropharyngeal (OP) swabs (first PCR from unique patients only) that were collected between January 1 and December 1, 2020, predominantly in the Public Health Services regions Kennemerland and Hollands Noorden, province of North Holland, the Netherlands were included in this study. Swabs were derived from patients with respiratory symptoms who were presented at the general practitioner (GP), hospital, or hospital health care workers (HCWs) of four regional hospitals, nursing home residents and HCWs of multiple nursing homes, and in majority (>75%) from Public Health testing facilities of the two Public Health Services. SARS-CoV-2 PCR crossing point (Cp) values were used to estimate viral loads (higher Cp-values indicate lower viral loads).

ResultsIn total, 278.455 unique patients were tested of whom 9{middle dot}1% (n=25.374) were SARS-CoV-2 positive. As there were differences in viral load distribution between tested populations, further analyses focused on PCRs performed by public health services (n=211.914) where sampling and inclusion were uniform. These data reveal a clear relation between age and SARS-CoV-2 viral load, with especially children aged<12 years showing lower viral loads than shown in adults ({beta}: -0{middle dot}03, 95CI% -0{middle dot}03 to -0{middle dot}02, p<0{middle dot}001), independent of sex and/or symptom duration. Interestingly, the median Cp-values between the oldest (>79 years) and youngest (<12 years) population differed by over 4 PCR cycles, suggesting approximately a 16-fold difference in viral load. In addition, the proportion of children aged <12 years with a low load (Cp-value >30) was significantly higher compared to the other patients (31{middle dot}1% vs. 17{middle dot}2%, p-value<0.001).

ConclusionWe observed that in patients tested by Public Health Services, SARS-CoV2 viral load increases significantly with age. Previous studies suggest that young children (<12 years) play a limited role in SARS-CoV-2 transmission. Currently, the relation between viral load and infectivity is not yet well understood, and further studies should elucidate whether the lower viral load in children is indeed related to their suggested limited role in SARS-CoV-2 transmission. Moreover, as rapid antigen tests are less sensitive than PCR, these results suggest that SARS-CoV-2 antigen tests could have lower sensitivity in children than in adults.


title: SARS-CoV-2 viral load distribution reveals that viral loads increase with age: a retrospective cross-sectional cohort study


title: Acute Endotheliitis (Type 3 Hypersensitivity Vasculitis) in Ten COVID-19 Autopsy Brains

abstract: Central nervous system (CNS) involvement in COVID-19 may occur through direct SARS-CoV-2 invasion through peripheral or cranial nerves or through vascular endothelial cell infection. The renin-angiotensin system may play a major part in CNS morbidity. Effects of hypoxia have also been implicated in CNS lesions in COVID-19. This communication reports on ten consecutive autopsies of individuals with death due to COVID-19 with decedent survival ranging from 30 minutes to 84 days after admission. All ten brains examined had neutrophilic microvascular endotheliitis present in variable amounts and variably distributed. Importantly, this acute stage of type 3 hypersensitivity vasculitis can be followed by fibrinoid necrosis and inner vascular wall sclerosis, but these later stages were not found. These results suggest that a vasculitis with autoimmune features occurred in all ten patients. It is possible that viral antigen in or on microvascular walls or other antigen-antibody complexes occurred in all ten patients proximate to death as a form of autoimmune vasculitis.

category: pathology


title: Correlates of and changes in aerobic physical activity and strength training before and after the onset of COVID-19 pandemic in the UK. Findings from the HEBECO study.

abstract:
ObjectivesUnderstanding changes in moderate to vigorous aerobic physical activity (MVPA) and strength training (MSA) from before to after (pre-/post-) the onset of the Covid-19 pandemic in the UK (first lockdown) and their correlates can inform interventions.

MethodsCross-sectional analysis of retrospective and concurrent data on MVPA/MSA pre- and post-Covid-19 (until 14th June 2020) among 2,657 UK adults. The associations between socio-demographic and health characteristics, MVPA/MSA pre-Covid-19, living and exercise conditions and meeting WHO recommended levels for MVPA/MSA/both (vs meeting neither), and changes in MVPA/MSA from pre-to post-Covid-19 following stratification for pre-Covid-19 MVPA/MSA levels were evaluated.

ResultsA third of adults maintained (30.4%), decreased (36.2%) or increased (33.4%) their MVPA levels post-Covid-19. For MSA, the percentages were 61.6%, 18.2%, and 20.2%, respectively. MVPA increased or decreased by an average of 150min/week, and MSA by 2 days/week. Meeting both MSA+MVPA recommendations during lockdown (vs. meeting neither) was positively associated with meeting MVPA+MSA pre-lockdown (aOR=16.11,95%CI=11.24-23.07), and post-16-years of age education (aOR=1.57,1.14-2.17), and negatively associated with being obese (aOR=0.49,0.33-0.73), older age (65+ vs [≤]34; aOR=.53.32-.87), and annual household income <50.000GBP (vs [≥]50.000GBP; aOR=0.65,0.46-0.91). The odds for decreasing MVPA were significantly lower for white ethnicity, post-16-years of age education, access to garden/balcony, and higher for those who were in total isolation. The odds for decreasing MSA were significantly higher for those who were overweight or obese.

ConclusionAerobic and strength training were differently impacted during the first UK lockdown, with poorer outcomes associated with older age, lower education, and higher body mass index.

O_TEXTBOXWhat are the new findingsO_LIAt the start of the Covid-19 pandemic, a third of UK adults decreased and a third increased moderate-to-vigorous physical activity; the corresponding proportions for muscle strength training were 18% and 20%.
C_LIO_LIOlder adults were more likely to maintain inactivity from before to start of the pandemic.
C_LIO_LIAdults with higher body mass index were at risk of not meeting WHO recommendations for weekly levels of strength and aerobic training, and at decreasing muscle strength training in this period.
C_LIO_LIThose with lower incomes, no post-16-years of age education, ethnic minority background and living in total isolation had poorer physical activity outcomes.
C_LI

C_TEXTBOX


title: High prevalence of mixed and non-vaccine HPV oncogenic types and their association with higher mortality in Black women with cervical cancer

abstract: We studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were <55 years of age. Of the 40 patients with typeable HPV genotypes, 10 (25%) had 16/18 HPV genotypes, 30 (75%) had one of the non-16/18 HPV genotypes, and 20 (50%) had one of the 7 genotypes (35, 39, 51, 53, 56, 59 and 68) that are not included in the nonavalent vaccine. Mixed HPV infections ([≥]2 types) were found in 11/40 (27.5%) patients. Patients infected with non-16/18 genotypes, including the most common genotype, HPV 35, had significantly shorter DFS and OS. PD-L1 (p=0.003), MMR expression (p=0.01), clinical stage (p=0.048), histologic grade (p=0.015) and mixed HPV infection (p=0.026) were independent predictors of DFS. A remarkably high proportion of cervical cancer cells in our patients expressed PD-L1 which opens the possibility of the use of immune checkpoint inhibitors to treat these cancers. Exclusion of the common HPV genotypes from the vaccine exacerbates mortality from cervical cancer in underserved Black patients.

category: sexual and reproductive health


title: Impact of socio-economic traditions on current tobacco and tea addictions (Siberia 17th to 20th century).

abstract:
ObjectiveTo investigate how tobacco and tea spread among virgin populations and how the first addictions have subsequently influenced the behavior of present-day populations.

DesignRetrospective observational study using data from frozen burials and levels of theobromine, theophylline, caffeine, nicotine, and cotinine measured in hair samples from frozen bodies of autochthonous people. Confrontation of the results with new ethnobotanical, historical and cultural data from the past and with present day epidemiological data from the same region.

SettingEastern Siberia (Yakutia) from the contact with Europeans (17th century) to the assimilation of people into Russian society (19th century).

Participants47 frozen bodies of autochthonous people from eastern Siberia and a review of present-day populations from Yakutia

InterventionLevels of theobromine, theophylline, caffeine, nicotine, and cotinine were measured in hair samples. Along with the collection of cultural data associated with the bodies, potential comorbidities were investigated.

Main outcome measureWe combined LC-HRMS and LC-MS/MS tools for toxicological investigations in hair and we assessed the association between xenobiotic concentrations and geography using several permutation-based methods to infer the economic circuits of tobacco and tea. Comparison of the results obtained with ethno-botanical analyses allowed to identify the products from which the metabolites were derived.

ResultsHair levels of theobromine, theophylline and caffeine vary with the type of beverage consumed: green, black or local herbal teas. At the beginning of our study period, a few heavy consumers of tobacco were found among light or passive consumers. Tobacco-related co-morbidities began to be recorded one century after contact with Europeans. Heavy tea users were only found from the 19th century and the heaviest users of the two substances date from this century. After the first contact, teas were widely consumed as beverages and medicines but also for shamanic reasons. Economic factors, fashion and social and family contacts seem to have played a decisive role in tobacco consumption very early on.

ConclusionEpidemiological characteristics of present-day Yakutia suggest that the high prevalence of smokers and tea consumers, the prevalence of female smokers and tobacco use in the north, find their origins in the diffusion phenomena of the 18th and 19th century. Behavioral evolution governed the process of substance integration and was determinant for the continuity of use of these substances over a long period of time.


title: Radiomics-based patient inclusion model improves clinical trial performance

abstract:
PurposeSuccess of new cancer therapies relies strongly on effective selection of the target patient populations. We hypothesize that computational analysis of imaging data can be used for patient enrichment in clinical trials and hence aimed to establish the appropriate framework for this analysis.

MethodsThis was tested among soft-tissue sarcoma (STS) patients accrued into a randomized clinical trial (SARC021) that evaluated the efficacy of evofosfamide (Evo), a hypoxia activated prodrug, in combination with doxorubicin (Dox). Notably, SARC021 failed to meet its overall survival (OS) objective. We tested whether a radiomic biomarker-driven inclusion/exclusion criterion could have been used to result in a significant treatment benefit of the Evo+Dox combination compared to Dox monotherapy. 164 radiomics features were extracted from 303 SARC021 patients with lung metastases, divided into training and test sets.

ResultsA single radiomics feature, Short Run Emphasis, was identified as the most informative. Combined into a model along with histological classification and smoking history, an enriched subset (42%) of patients had longer OS in Evo+Dox vs. Dox groups [p=0.01, Hazard Ratio (HR) =0.57 (0.36-0.90)]. Applying the same model and threshold value in an independent test set confirmed the significant survival difference [p=0.002, HR=0.29 (0.13-0.63)], identifying patients most likely to benefit from doxorubicin alone.

ConclusionThe study presents a first of its kind clinical-radiomic approach for patient enrichment in clinical trials. We show that, had an appropriate model been used for selective patient inclusion, SARC021 trial could have met its primary survival objective for patients with metastatic STS.


title: Psychological Legacies of Intergenerational Trauma under South African Apartheid: Prenatal Stress Predicts Increased Psychiatric Morbidity during Late Adolescence in Soweto, South Africa

abstract:
BackgroundSouth Africas rates of psychiatric morbidity are among the highest in sub-Saharan Africa and are foregrounded by the countrys long history of political violence during apartheid. Recent evidence suggests that maternal trauma during gestation may intergenerationally impact the developing fetus and elevate the future childs risk for psychiatric disease. We aim to evaluate the intergenerational effects of prenatal stress experienced during apartheid on late adolescent psychiatric morbidity and also assess the potential ameliorative effects of prenatal social support.

MethodParticipants (n = 1051) come from Birth-to-Twenty, a longitudinal birth cohort study in Soweto-Johannesburg, South Africas largest peri-urban township which was the epicenter of violent repression and resistance during the final years of the apartheid regime. Pregnant women were prospectively enrolled in 1990 and completed questionnaires assessing social experiences, and their childrens psychiatric morbidity were assessed at age 17-18.

ResultsFull data were available from 304 mother-child pairs in 2007-8. Pregnant women who experienced worse traumatic stress in 1990 had children who exhibited greater psychiatric morbidity during late adolescence. This relationship was only significant, however, among children born to younger mothers and adolescents who experienced greater concurrent stress. Social support did not buffer the long-term impacts of prenatal stress on future psychiatric morbidity.

ConclusionGreater prenatal stress predicted adverse psychiatric outcomes among children born to younger mothers and adolescents who experienced greater concurrent stress. Our findings suggest that prenatal stress may affect adolescent mental health, have stress-sensitizing effects, and represent possible intergenerational effects of trauma experienced under apartheid in this sample.


title: GCH1 mutations in hereditary spastic paraplegia

abstract: GCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinsons disease (PD) and tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have been reported in five patients with hereditary spastic paraplegia (HSP). Here, we analyzed a total of 400 HSP patients (291 families) from different centers across Canada by whole exome sequencing (WES). Three patients with heterozygous GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. The former variant is predicted to be likely pathogenic and the latter is pathogenic. The three patients presented with childhood-onset lower limb spasticity, hyperreflexia and abnormal plantar responses. One of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, who responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares processes and pathways with other HSP-associated genes, and structural analysis of the variants indicated a disruptive effect. In conclusion, GCH1 mutations may cause HSP; therefore, we suggest a levodopa trial in HSP patients and including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors, epigenetics, and stochasticity could play a role in the clinical presentation.

category: neurology


title: Regression Tree Modelling to Predict Total Average Extra Costs in Household Spending During COVID-19 Pandemic

abstract:
BackgroundPrevention of coronavirus (COVID-19) regarding households has many aspects, such as buying masks, hand sanitizer, face shield, and many others. As a result of buying the previous items, the household spending per month will be increase during the COVID-19 pandemic period.

AimsTo calculate the average costs of each extra item involved in households spending during COVID-19 pandemic and to predict the total average extra costs spending by households.

MethodsA cross-sectional study was conducted at High Institute of Public Health (HIPH), University Alexandria. Exponential snowball sampling was used to recruit students at HIPH and their friends. Trimming costs was done to remove extreme low and high values. A regression tree modelling was implemented to predict the total extra costs spending during COVID-19 pandemic.

ResultsMost of the respondents were female (81%) and aged between 30 and 40 (56.3%). About 63.1% of families had the same monthly income while 35.4% had a decrease in monthly income. A significant reduction in days of leaving home before and after COVID-19 pandemic was observed (before; mean= 5.86, after; mean = 4.66, P=0.000). The extra spending in grocery was the dominated item compared to other items (mean = 707.2, SD = 530.7). Regarding regression tree, the maximum average extra costs due to COVID-19 pandemic was 1386 L.E/month (around 88.23$/month) while the minimum average extra costs was 217 L.E/month (around 13.81$/month).

ConclusionsThe effect of COVID-19 pandemic in households spending varies largely between households, it depends on what they do to prevent COVID-19.

*Hint: Convert form L.E to dollar performed according to price of dollar at 18-12-2020

category: health economics


title: Estimating the effects of non-pharmaceutical interventions on the number of new infections with COVID-19 during the first epidemic wave

abstract: The novel coronavirus (SARS-CoV-2) has rapidly developed into a global epidemic. To control its spread, countries have implemented non-pharmaceutical interventions (NPIs), such as school closures, gathering bans, or even stay-at-home orders. Here we study the effectiveness of seven NPIs in reducing the number of new infections, which was inferred from the reported cases of COVID-19 using a semi-mechanistic Bayesian hierarchical model. Based on data from the first epidemic wave of n = 20 countries (i.e., the United States, Canada, Australia, the EU-15 countries, Norway, and Switzerland), we estimate the relative reduction in the number of new infections attributed to each NPI. Among the NPIs considered, event bans were most effective, followed by venue and school closures, whereas stay-at-home orders and work bans were least effective. With this retrospective cross-country analysis, we provide estimates regarding the effectiveness of different NPIs during the first epidemic wave.


title: Origin of HIV/AIDS and Vaccine Failure: Simulation of the Role of the Adjuvant Activation Hypothesis

abstract: Human Immunodeficiency Virus (HIV) is the etiological agent for Acquired Immunodeficiency Syndrome (AIDS). It is possible that vaccine failure could be related to the events involved at the origin of HIV/AIDS. In this work the role of the adjuvant activation hypothesis on the origin and on the failure of vaccines, as well as other effects is evaluated by means of a simulation using a mathematical analysis, differential equations and an Excel spreadsheet. The results show that the adjuvant activation alters the viral load and the cellular and humoral Immune Response. Under certain conditions it was possible to show how the adjuvant activation could have promoted the origin of the HIV/AIDS pandemic and also, as a consequence of the SIV adaptation to human beings at the origin, the failure of present day vaccine trials. Other effects such as Immunotolerance and Antibody Dependent Enhancement (ADE) were shown. This study provides a means to examine other effectors in order to suggest therapeutic alternatives. In this case passive immunization in combination with anti-retroviral therapy showed an acceptable adaptation to the conditions tested. It is concluded that the methodological strategy of this work may be useful for the analysis of the adjuvant activation hypothesis as well as other effects, interactions and new proposals, such as thermodynamics of HIV infections.

category: hiv aids


title: COVID-19 propagation by diffusion - a two-dimensional approach for Germany

abstract:
Diffusion comes anytime and everywhere. If there is a gradient or a potential difference of a quantity a diffusion process happens and this ends if an equilibrium is reached only. The concentration of a species maybe such quantity, or the voltage. An electric currant will be driven by a voltage difference for example.

In this COVID-19 pandemic one observes both regions with low incidence and other ones with high incidence. The local different people density could be a reason for that. In populous areas like big cities or congested urban areas higher COVID-19 incidences could be observed than in rural regions.

The aim of this paper consists in the application of a diffusion concept to describe one possible issue of the the COVID-19 propagation.

This will be discussed for the German situation based on the quite different incidence data for the different federal states of Germany.

With this ansatz some phenomenoms of the actual development of the pandemic could be confirmed. The model gives a possibility to investigate certain scenarios like border-crossings or local spreading events and their influence on the COVID-19 propagation as well.


title: Physician Perceptions of Catching COVID-19

abstract:
BackgroundRisk perception, influenced and biased by multiple factors, can affect behavior.

ObjectiveTo assess the variability of physician perceptions of catching COVID-19.

DesignCross sectional, random stratified sample of physicians registered with Sermo, a global networking platform open to verified and licensed physicians.

Main outcome measuresThe survey asked: "What is your likelihood of catching COVID-19 in the next three months?" The physicians were asked to give their best estimate as an exact percentage.

ResultsThe survey was completed by 1004 physicians (40 countries, 67 specialties, 49% frontline [e.g. ER, infectious disease, internal medicine]) with a mean (SD) age of 49.14 (12) years. Mean (SD) self-risk estimate was 32.3% {+/-} 26% with a range from 0% to 100% (Figure 1a). Risk estimates were higher in younger (<50 years) doctors and in non-US doctors versus their older and US counterparts (p<0.05 for all) (Figure 1b). Risk estimates were higher among front line versus non-frontline doctors (p<0.05). Risk estimates were higher for women than men (p<0.05) among respondents (60%) reporting gender.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/20249089v2_fig1A.gif" ALT="Figure 1A">
View larger version (17K):
org.highwire.dtl.DTLVardef@7dd844org.highwire.dtl.DTLVardef@17241org.highwire.dtl.DTLVardef@f43cb2org.highwire.dtl.DTLVardef@bcd7f1_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 1A.C_FLOATNO Distribution of risk prediction for overall sample (N=1004). Upper panel is a line box whisker and bottom panel shows the frequency distribution.

C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/20249089v2_fig1B.gif" ALT="Figure 1B">
View larger version (21K):
org.highwire.dtl.DTLVardef@51be7org.highwire.dtl.DTLVardef@16ae5fcorg.highwire.dtl.DTLVardef@12118a2org.highwire.dtl.DTLVardef@1d848c6_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure1B.C_FLOATNO Mean (SD) risk estimates by age, frontline status, and geographic region.

C_FIG ConclusionsTo our knowledge, this is the first global study to document physician risk perceptions for catching COVID-19 and how it is impacted by age, gender, practice specialty and geography. Accurate calibration of risk perception is vital since both over- and underestimation of risk could impact physician behavior and have implications for public health.


title: Invasive Mould Disease in Fatal COVID-1 19: A Systematic Review of Autopsies

abstract:
BackgroundInvasive mould disease (IMD) - most commonly pulmonary aspergillosis - is reported to affect up to a third of critically ill COVID-19 patients. Most reported cases are diagnosed with probable/putative COVID-19 associated pulmonary aspergillosis (CAPA) based on a combination of non-specific clinical, radiographic, and mycological findings, but the clinical significance - and whether these cases represent true invasive disease - is unresolved.

MethodsWe performed a systematic review of autopsy series of decedents with COVID-19 for evidence of IMD. We searched PubMed, Web of Science, OVID (Embase) and MedRxiv for English- or French-language case series published between January 1, 2019 to September 26, 2020. We included series describing lung histology of [≥]3 decedents, and authors were contacted for missing information as necessary.

FindingsWe identified 51 case series describing autopsies of 702 decedents. Individual-level data was available for 430 decedents. The median age was 72 (IQR 61 to 80) years. Diabetes mellitus, pre-existing lung disease, and immunocompromising conditions were reported for 129 (32%), 95 (22%), and 25 (6%) decedents, respectively. The median hospitalization length was 10 (IQR 5-22) days. 51.6% of decedents had received mechanical ventilation for a median of nine (IQR 5-20) days. Treatment included immunomodulation in 60 (most often steroids or tocilizumab) and antifungals in 41 decedents. Eleven decedents (1{middle dot}6%) had autopsy-confirmed IMD (6 with CAPA, 4 with invasive pulmonary mycosis not specified and 1 with disseminated mucormycosis). Among 173 decedents who received mechanical ventilation, 5 had IMD (2{middle dot}9%).

InterpretationAutopsy-proven IMD, including CAPA, is uncommon in fatal COVID-19.

FundingThis study is unfunded

CategoryReview


title: Electronic Computer-Based Model of Combined Ventilation Using a New Medical Device

abstract:
IntroductionThe increased demand for mechanical ventilation caused by the SARS-CoV-2 pandemic could generate a critical situation where patients may lose access to mechanical ventilators. Combined ventilation, in which two patients are ventilated simultaneously but independently with a single ventilator has been proposed as a life-saving bridge while waiting for new ventilators availability. New devices have emerged to facilitate this task and allow individualization of ventilatory parameters in combined ventilation. In this work we run computer-based electrical simulations of combined ventilation. We introduce an electrical model of a proposed mechanical device which is designed to individualize ventilatory parameters, and tested it under different circumstances.

Materials and MethodsWith an electronic circuit simulator applet, an electrical model of combined ventilation is created using resistor-capacitor circuits. A device is added to the electrical model which is capable of individualizing the ventilatory parameters of two patients connected to the same ventilator. Through computational simulation, the model is tested in different scenarios with the aim of achieving adequate ventilation of two subjects under different circumstances: 1) two identical subjects; 2) two subjects wiIth the same size but different lung compliance; and 3) two subjects with different sizes and compliances. The goal is to achieve the established charge per unit of size on each capacitor under different levels of end-expiratory voltage (as an end-expiratory pressure analog). Data collected included capacitor charge, voltage, and charge normalized to the weight of the simulated patient.

ResultsSimulations show that it is possible to provide the proper charge to each capacitor under different circumstances using an array of electrical components as equivalents to a proposed mechanical device for combined ventilation. If the pair of connected capacitors have different capacitances, adjustments must be made to the source voltage and/or the resistance of the device to provide the appropriate charge for each capacitor under initial conditions. In pressure control simulation, increasing the end-expiratory voltage on one capacitor requires increasing the source voltage and the device resistance associated with the other simulated patient. On the other hand, in the volume control simulation, it is only required to intervene in the device resistance.

ConclusionsUnder simulated conditions, this electrical model allows individualization of combined mechanical ventilation.

category: anesthesia