title: Assessing and improving the validity of COVID-19 autopsy studies - a multi center approach to establish essential standards for immunohistochemical and ultrastructural analyses

abstract:
BackgroundAutopsy studies have provided valuable insights into the pathophysiology of COVID-19. Controversies remain whether the clinical presentation is due to direct organ damage by SARS-CoV-2 or secondary effects, e.g. by an overshooting immune response. SARS-CoV-2 detection in tissues by RT-qPCR and immunohistochemistry (IHC) or electron microscopy (EM) can help answer these questions, but a comprehensive evaluation of these applications is missing.

MethodsWe assessed publications using IHC and EM for SARS-CoV-2 detection in autopsy tissues. We systematically evaluated commercially available antibodies against the SARS-CoV-2 spike protein and nucleocapsid, dsRNA, and non-structural protein Nsp3 in cultured cell lines and COVID-19 autopsy tissues. In a multicenter study, we evaluated specificity, reproducibility, and inter-observer variability of SARS-CoV-2 nucleocapsid staining. We correlated RT-qPCR viral tissue loads with semiquantitative IHC scoring. We used qualitative and quantitative EM analyses to refine criteria for ultrastructural identification of SARS-CoV-2.

FindingsPublications show high variability in the detection and interpretation of SARS-CoV-2 abundance in autopsy tissues by IHC or EM. In our study, we show that IHC using antibodies against SARS-CoV-2 nucleocapsid yields the highest sensitivity and specificity. We found a positive correlation between presence of viral proteins by IHC and RT-qPCR-determined SARS-CoV-2 viral RNA load (r=-0.83, p-value <0.0001). For EM, we refined criteria for virus identification and also provide recommendations for optimized sampling and analysis. 116 of 122 publications misinterpret cellular structures as virus using EM or show only insufficient data. We provide publicly accessible digitized EM and IHC sections as a reference and for training purposes.

InterpretationSince detection of SARS-CoV-2 in human autopsy tissues by IHC and EM is difficult and frequently incorrect, we propose criteria for a re-evaluation of available data and guidance for further investigations of direct organ effects by SARS-CoV-2.

Key messagesO_LIDetection of SARS-CoV-2 proteins by IHC in autopsy tissues is less sensitive in comparison to SARS-CoV-2 RNA detection by RT-qPCR.
C_LIO_LIFor determination of SARS-CoV-2 protein positive cells by IHC in autopsy tissues, detection of spike protein is less sensitive than nucleocapsid protein.
C_LIO_LICorrect identification of SARS-CoV-2 particles in human samples by EM is limited to the respiratory system.
C_LIO_LIInterpretation of IHC and EM should follow substantiated consensus criteria to enhance accuracy.
C_LIO_LIExisting datasets describing SARS-CoV-2 presence in human autopsy tissues need to be critically re-evaluated.
C_LI

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title: Incidence and Risk Factors of Immediate Hypersensitivity Reactions and Immunisation Stress-related Responses with COVID-19 mRNA Vaccine

abstract:
BackgroundWith the implementation of mass vaccination campaigns against COVID-19, the safety of vaccine needs to be evaluated.

ObjectiveWe aimed to assess the incidence and risk factors for immediate hypersensitivity reactions (IHSR) and immunisation stress-related responses (ISRR) with the Moderna COVID-19 vaccine.

MethodsThis nested case-control study included recipients who received the Moderna vaccine at a mass vaccination centre, Japan. Recipients with IHSR and ISRR were designated as cases 1 and 2, respectively. Controls 1 and 2 were selected from recipients without IHSR or ISRR and matched (1:4) with cases 1 and cases 2, respectively. Conditional logistic regression analysis was used to identify risk factors associated with IHSR and ISRR.

ResultsOf the 614,151 vaccine recipients who received 1,201,688 vaccine doses, 306 recipients (cases 1) and 2,478 recipients (cases 2) showed 318 events of IHSR and 2,558 events of ISRR, respectively. The incidence rates per million doses were estimated as - IHSR: 266 cases, ISRR: 2,129 cases, anaphylaxis: 2 cases, and vasovagal syncope: 72 cases. Risk factors associated with IHSR included female, asthma, atopic dermatitis, thyroid diseases, and history of allergy; for ISRR, they were younger age, female, asthma, thyroid diseases, mental disorders, and a history of allergy and vasovagal reflex.

ConclusionIn the mass vaccination settings, the Moderna vaccine can be used safely owing to the low incidence rates of IHSR and anaphylaxis. However, providers should beware of the occurrence of ISRR. Risk factor identification may contribute to the stratification of high-risk recipients for IHSR and ISRR.

category: allergy and immunology


title: Socio-economic inequalities in adolescent mental health in the UK: multiple socio-economic indicators and reporter effects

abstract: There are socio-economic inequalities in the experience of mental ill-health. However, less is known about the extent of inequalities by different indicators of socio-economic position (SEP). This is relevant for insights into the mechanisms by which these inequalities arise. For young peoples mental health there is an additional layer of complexity provided by the widespread use of proxy reporters. Using data from the UK Millennium Cohort Study (N=10,969), we investigated the extent to which five objective SEP indicators (parent education, household income, household wealth, parent occupational status, and relative neighbourhood deprivation) predict adolescent internalising mental health and how this varies as a function of reporter. Both parent report and adolescent self-report were considered. Regression models demonstrated that whilst all five SEP indicators were associated with parent-reported adolescent mental health (regression coefficients for the most disadvantaged groups and adolescent mental health: parent education {beta}=0.53 [0.44;0.62], household income {beta}=0.56 [0.50;0.62], household wealth {beta}=0.18 [0.10;0.27], parent occupational status {beta}=0.40 [0.35;0.46], and relative neighbourhood deprivation {beta}=0.41 [0.33;0.49]), only income ({beta}=0.11 [0.04;0.17]), wealth ({beta}=0.12 [0.02;0.21]), and occupational status ({beta}=0.08 [0.03;0.13]) were associated with self-reported mental health. The magnitude of these effects was greater for parent-reported than self-reported adolescent internalising symptoms: SEP indicators jointly predicted 5.2% of the variance in parent-reported compared to 1.4% of the variance in self-reported internalising mental health. Income predicted the most variance in both parent (4.2% variance) and self-reported internalising symptoms (0.5% variance). Interestingly, the gradient of parent-reported adolescent mental health across SEP indicators mirrors that of parents own mental health (for example, income predicted 7.3% variance). Our findings highlight that the relevance of different SEP indicators to adolescent internalising mental health differs between parent and adolescent reports. Therefore, it is important to consider the various perspectives of mental health inequalities gained from different types of reporters.

category: epidemiology


title: Treatment Noncompliance Level Among Patients with Type 2 Diabetes Mellitus: A Hospital Based Cross-Sectional Study in Bangladesh.

abstract:
IntroductionThe consequence of good diabetic treatment depends on the patients commitment to a large degree. Noncompliance leads to inadequacy of metabolic control, which strengthens the advancement and speeds up diabetic complications.

MethodologyThis descriptive cross-sectional study was conducted at Medical Center Hospital, Chattogram, Bangladesh. The study included two hundred and fifty-nine patients with T2DM. Data regarding sociodemographic factors, patients characteristics, medication factors, physician-related factors, and noncompliance were collected using a pretested and structured questionnaire. Treatment adherence was assessed by Morisky Medication Adherence Scales (MMAS-8). Data analyses were conducted on SPSS v23.0 Software. The studys main goal was to assess the treatment noncompliance level among patients with type-2 diabetes mellitus (T2DM) in Bangladesh.

ResultThe majority of the participants (56%) were in the 40-45 years of age group, followed by 32% in the older age group ([≥]60 years), and 62.5% of them were male. One hundred and sixty-eight (64.86%) patients were considered low adherent as per the response of the MMAS-8 scale (score <6), followed by 57 (22.0%) patients were regarded as high adherent (score 8) and 34 (13.13%) patients were considered medium adherent (score 6-7) to treatment. Observing the frequency distribution for noncompliance, financial concerns (32.3 %), forgetfulness (27.7%), a busy daily schedule (17.7%), and fear of antihyperglycemic drug side effects were all identified as significant explanations. On multivariate analysis, participants aged 60 years or more, monthly family incomes of <30,000BDT or 30,000 - 50,000 BDT, smoking, and uncontrolled glycemic status showed higher chances of noncompliance than their counterparts.

ConclusionPatient counseling and awareness programs may enhance treatment adherence among people with T2DM. Our findings will help physicians and public health workers to develop targeted strategies to increase awareness of the same among their patients.

HighlightsO_LIOne of the most preventable causes of treatment failure is noncompliance with treatment.
C_LIO_LIAge group, educational level, and monthly family income had a significant association with the compliance to treatment in diabetic patients
C_LIO_LIMajority of the respondents (64.86%) were low adherent to the medications as per MMA-8 scale.
C_LIO_LIFinancial issues (32.3 percent), forgetfulness (27.7%), a hectic daily schedule (17.7%), and fear of antidiabetic medicine side effects were all cited as key causes for noncompliance with antidiabetic treatment.
C_LIO_LIAged participants ([≥] 60 years), monthly family income of (30,000-50,000) BDT, uncontrolled glycemic status and smokers portrayed higher frequency of noncompliance.
C_LI

category: public and global health


title: The mental health of staff working on Intensive Care Units over the COVID-19 winter surge of 2020 in England: a cross sectional survey.

abstract:
BackgroundThe COVID-19 pandemic generated a surge of critically ill patients greater than the NHS capacity. Additionally, there have been multiple well-documented impacts associated with the national COVID-19 pandemic surge on ICU workers, including an increased prevalence of mental health disorders on a scale potentially sufficient to impair high-quality care delivery.

AimTo identify prevalence of probable mental health disorders and functional impairment. As well as establish demographic and professional predictors of probable mental health disorders and functional impairment in ICU staff between November 2020 to April 2021.

MethodsEnglish ICU staff were surveyed before, during and after the winter 2020/2021 surge using a survey which comprised of validated measures of mental health.

Results6080 surveys were completed, by nurses (57.5%), doctors (27.9%), and other healthcare staff (14.5%). Reporting probable mental health disorders increased from 51% (prior to), to 64% (during) and then dropped to 46% (after). Younger, less experienced and nursing staff were most likely to report probable mental health disorders. Additionally, during and after the winter, over 50% of participants met threshold criteria for functional impairment. Staff who reported probable post-traumatic stress disorder, anxiety or depression were more likely to meet threshold criteria for functional impairment.

ConclusionsThe winter of 2020/2021 was associated with an increase in poor mental health outcomes and functional impairment during a period of peak caseload. These effects are likely to impact on patient care outcomes and the longer-term resilience of the healthcare workforce.


title: Lower hypothalamus subunit volumes link with long-term growth failure after preterm birth: a longitudinal case-control study

abstract:
BackgroundPreterm birth is associated with an increased risk for impaired growth. While it is known that in prematurity several somatic to environmental factors such as endocrine factors or nutrition modulate short- and long-term growth failure, the contribution of potentially impaired growth control in the brain remains elusive. We hypothesized that the structure of hypothalamic nuclei involved in growth control is altered after preterm birth, with these alterations being associated with aberrant weight development into adulthood.

MethodsWe assessed 101 very preterm (i.e., <32 weeks of gestational age) and/or very low birth weight (i.e., <1500g; VP/VLBW) and 110 full-term born (FT) adults of the population-based Bavarian Longitudinal Study with T1-weighted MRI, deep learning-based hypothalamus subunit segmentation, and multiple body weight assessments from birth into adulthood.

ResultsVolumes of the whole hypothalamus and hypothalamus subunits relevant for growth control were reduced in VP/VLBW adults and associated with birth variables (i.e., gestational age and intensity of neonatal treatment), body weight (i.e., weight at birth and adulthood), and growth trajectories (i.e., trajectory slopes and trajectories of those small for gestational age and with long-term catch-up growth). Concerning VP/VLBW weight trajectories, relatively larger hypothalamic volumes comparable to those of FT adults, especially in subunits including the lateral hypothalamus, were associated with favorable long-term growth trajectories.

ConclusionsResults demonstrate lower volumes of growth control-related hypothalamus sub-units after preterm birth that link with long-term growth failure. Data suggest postnatal development of growth-related hypothalamic nuclei in VP/VLBW individuals that corresponds with distinct body growth trajectories into adulthood.

FundingThis study was supported by the Deutsche Forschungsgemeinschaft (BA 6370/2-1 to C.S.), the German Federal Ministry of Education and Science (BMBF 01ER0801 to P.B. and D.W., BMBF 01ER0803 to C.S.) and the Kommission fur Klinische Forschung, Technische Universitat Munchen (KKF 8700000474 to D.M.H.).

category: radiology and imaging


title: Deep Learning Based Long Term Mortality Prediction in the National Lung Screening Trial

abstract: In this study, the long-term mortality in the National Lung Screening Trial (NLST) was investigated using a deep learning-based method. Binary classification of the non-lung-cancer mortality (i.e. cardiovascular and respiratory mortality) was performed using neural network models centered around a 3D-ResNet. The models were trained on a participant age, gender, and smoking history matched cohort. Utilising both the 3D CT scan and clinical information, the models can achieve an AUC of 0.73 which outperforms humans at cardiovascular mortality prediction. By interpreting the trained models with 3D saliency maps, we examined the features on the CT scans that correspond to the mortality signal. The saliency maps can potentially assist the clinicians and radiologists to identify regions of concern on the image that may indicate the need to adopt preventative healthcare management strategies to prolong the patients life expectancy.

category: respiratory medicine


title: Data-driven analysis shows robust links between fatigue and depression in early multiple sclerosis

abstract:
Fatigue is common and disabling in multiple sclerosis, yet its mechanisms are poorly understood. In particular, overlap in measures of fatigue and depression complicates interpretation. A clearer understanding of relationships between fatigue and key clinical, neuropsychiatric and imaging variables including depression could yield clinically relevant mechanistic insight. We applied a data-driven multivariate network approach to quantify relationships between fatigue and other variables in early multiple sclerosis.

Data were collected from Scottish patients with newly diagnosed, immunotherapy-naive, relapsing-remitting multiple sclerosis at baseline and month 12 follow-up in FutureMS, a nationally representative multicentre cohort. Subjective fatigue was assessed using the validated Fatigue Severity Scale. Detailed phenotyping included measures assessing physical disability, affective disorders, objective cognitive performance, subjective sleep quality, and structural brain imaging. Bivariate correlations between fatigue and other variables were calculated. Network analysis was then conducted to estimate partial correlations between variables, after accounting for all other included variables. Secondary networks included individual depressive symptoms, to control for overlapping symptom items in measures of fatigue and depression.

Data from 322 participants at baseline, and 323 at month 12, were included. At baseline, 49.5% of the cohort reported clinically significant fatigue. Bivariate correlations confirmed that fatigue severity was significantly correlated with all included measures of physical disability, affective disturbance (anxiety and depression), cognitive performance (processing speed and memory/attention), and sleep quality, but not with structural brain imaging variables including normalized lesion and grey matter volumes. In the network analysis, fatigue showed strong correlations with depression, followed by Expanded Disability Status Scale. Weak connections with walking speed, subjective sleep quality and anxiety were identified. After separately controlling for measurement of "tiredness" in our measure of depression, some key depressive symptoms (anhedonia, subjective concentration deficits, subjectively altered speed of movement, and appetite) remained linked to fatigue. Conversely, fatigue was not linked to objective cognitive performance, white matter lesion volume, or grey matter volumes (cortical, subcortical or thalamic). Results were consistent at baseline and month 12. Depression was identified as the most central variable in the networks. Correlation stability coefficients and bootstrapped confidence intervals of the edge weights supported stability of the estimated networks.

Our findings support robust links between subjective fatigue and depression in early relapsing-remitting multiple sclerosis, despite absence of links between fatigue and either objective cognitive performance, or structural brain imaging variables. Depression, including specific depressive symptoms, could be a key target of treatment and research in multiple sclerosis-related fatigue.

category: neurology


title: Evidence from human placenta, ER-stressed trophoblasts and transgenic mice links transthyretin proteinopathy to preeclampsia

abstract: We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia (PE) and identified several aggregated proteins in the circulation of PE patients, most significantly the serum protein transthyretin (TTR). Here we show robust accumulation of TTR aggregates in the placentas of women with early-onset PE (e-PE). TTR aggregation was inducible in primary human trophoblasts (PHTs) and the TCL-1 trophoblast cell line by ER stress inducers or autophagy-lysosomal disruptors. Hypoxia/reoxygenation (H/R) of cultured PHTs increased intracellular BiP, phosphorylated IRE1, PDI and Ero-1, all markers of the UPR, and the apoptosis mediator caspase-3. Blockade of IRE1 inhibited H/R-induced upregulation of Ero-1 in PHTs. Excessive UPR was observed in the PE placenta. Further, pregnant mice, overexpressing transgene encoded wild type human TTR, displayed aggregated TTR in the junctional zone of the placenta and PE-like features including hypertension, proteinuria, intrauterine growth restriction, kidney injury, and elevated levels of the PE biomarkers serum sFlt-1 and endoglin. High Resolution Ultrasound analysis revealed low blood flow in uterine and umbilical arteries compared to that found in wild type pregnant mice. On the other hand, loss of mouse TTR function did not cause any pregnancy abnormalities in Ttr-/- mice. These observations in the PE placenta, cultured trophoblast cells and TTR transgenic mice indicate that TTR aggregation is an important causal contributor to PE pathophysiology.

category: obstetrics and gynecology


title: Development and validation of the MMCD score to predict kidney replacement therapy in COVID-19 patients

abstract:
BackgroundAcute kidney injury (AKI) is frequently associated with COVID-19 and the need for kidney replacement therapy (KRT) is considered an indicator of disease severity. This study aimed to develop a prognostic score for predicting the need for KRT in hospitalized COVID-19 patients.

MethodsThis study is part of the multicentre cohort, the Brazilian COVID-19 Registry. A total of 5,212 adult COVID-19 patients were included between March/2020 and September/2020. We evaluated four categories of predictor variables: (1) demographic data; (2) comorbidities and conditions at admission; (3) laboratory exams within 24 h; and (4) the need for mechanical ventilation at any time during hospitalization. Variable selection was performed using generalized additive models (GAM) and least absolute shrinkage and selection operator (LASSO) regression was used for score derivation. The accuracy was assessed using the area under the receiver operating characteristic curve (AUC-ROC). Risk groups were proposed based on predicted probabilities: non-high (up to 14.9%), high (15.0 - 49.9%), and very high risk ([≥] 50.0%).

ResultsThe median age of the model-derivation cohort was 59 (IQR 47-70) years, 54.5% were men, 34.3% required ICU admission, 20.9% evolved with AKI, 9.3% required KRT, and 15.1% died during hospitalization. The validation cohort had similar age, sex, ICU admission, AKI, required KRT distribution and in-hospital mortality. Thirty-two variables were tested and four important predictors of the need for KRT during hospitalization were identified using GAM: need for mechanical ventilation, male gender, higher creatinine at admission, and diabetes. The MMCD score had excellent discrimination in derivation (AUROC = 0.929; 95% CI 0.918-0.939) and validation (AUROC = 0.927; 95% CI 0.911-0.941) cohorts an good overall performance in both cohorts (Brier score: 0.057 and 0.056, respectively). The score is implemented in a freely available online risk calculator (https://www.mmcdscore.com/).

ConclusionThe use of the MMCD score to predict the need for KRT may assist healthcare workers in identifying hospitalized COVID-19 patients who may require more intensive monitoring, and can be useful for resource allocation.

category: infectious diseases


title: Antigenic evolution of SARS-CoV-2 in immunocompromised hosts

abstract:
Prolonged infections of immunocompromised individuals have been proposed as a crucial source of new variants of SARS-CoV-2 during the COVID-19 pandemic. In principle, sustained within-host antigenic evolution in immunocompromised hosts could allow novel immune escape variants to emerge more rapidly, but little is known about how and when immunocompromised hosts play a critical role in pathogen evolution. Here, we use a simple mathematical model to understand the effects of immunocompromised hosts on the emergence of immune escape variants in the presence and absence of epistasis. We show that when the pathogen does not have to cross a fitness valley for immune escape to occur (no epistasis), immunocompromised individuals have no qualitative effect on antigenic evolution (although they may accelerate immune escape if within-host evolutionary dynamics are faster in immunocompromised individuals). But if a fitness valley exists between immune escape variants at the between-host level (epistasis), then persistent infections of immunocompromised individuals allow mutations to accumulate, therefore facilitating rather than simply speeding up antigenic evolution. Our results suggest that better genomic surveillance of infected immunocompromised individuals and better global health equality, including improving access to vaccines and treatments for individuals who are immunocompromised (especially in lower- and middle-income countries), may be crucial to preventing the emergence of future immune escape variants of SARS-CoV-2.

Lay SummaryWe study the role that immunocompromised individuals may play in the evolution of novel variants of the coronavirus responsible for the COVID-19 pandemic. We show that immunocompromised hosts can be crucial for the evolution of immune escape variants. Targeted treatment and surveillance may therefore prevent the emergence of new variants.


title: A unique dexamethasone-dependent gene expression profile in the lungs of COVID-19 patients

abstract:
Local immunopathogenesis of COVID-19 acute respiratory distress syndrome (CARDS) and the effects of systemic dexamethasone (DXM) treatment on pulmonary immunity in COVID-19 remain insufficiently understood. To provide further insight into insight into immune regulatory mechanisms in the lungs of CARDS (with and without DXM treatment) and critically ill non-COVID-19 patients (without DXM treatment), transcriptomic RNA-seq analysis of bronchoalveolar lavage fluid (BALF) was performed in these patients. Functional analysis was performed using gene ontology and a blood transcription module, and gene expression of select pro-inflammatory cytokines, interferon-stimulated genes (ISGs) and auto-IFN antibodies were assessed. We found 550 and 2173 differentially expressed genes in patients with non-DXM-CARDS and DXM-CARDS, respectively. DXM-CARDS was characterized by upregulation of genes related to pulmonary innate and adaptive immunity, notably B-cell and complement pathway activation, antigen presentation, phagocytosis and FC-gamma receptor signalling. Pro-inflammatory genes were not differentially expressed in CARDS vs. non-COVID-19, nor did they differ according to DXM. Most ISGs were specifically upregulated in CARDS, particularly in non-DXM-CARDS. Auto-IFN autoantibodies were detectable in BALF of some CARDS patients. In conclusion, DXM treatment was not associated with regulation of pro-inflammatory pathways in CARDS but with regulation of other specific local innate and adaptive immune responses.

summaryThis study identifies differentially expressed genes in bronchoalveolar fluid of COVID-19 acute respiratory distress patients with a distinct RNA expression profile of those treated with dexamethasone. These results challenge the concept of a COVID-19 specific cytokine storm.


title: Double-blind, Randomized, Placebo-Controlled study to evaluate the Efficacy of an early treatment with Herbal Supplement based in the Prevention of Post-Traumatic Stress Disorder in emergency department (PHYTeS Study)

abstract:
IntroductionThe prevention from Post-traumatic stress disorder (PTSD) is therefore of major public health interest and one of the concerns of any emergency physician. The purpose of our study was to evaluate the efficacy and safety of an herbal supplement to prevent the occurrence of PTSD in high-risk patients.

MethodsIt is a randomized, double-blind, prospective, interventional study including patients exposed to a potentially traumatic event that meets DSM-V Criterion A and has a Peri-traumatic Distress Inventory score or the Questionnary for traumatic dissociation experiments (PDEQ) and/or L.Crocq score higher than the thresholds between day 1 and day 3. Two hundred patients were included randomly assigned into two groups: Aleozen group and placebo group. Patients included in aleozen group received Aleozen(R) for 10 days while patients in placebo group received Placebo. A CAPS-5 assessment was performed for all patients at different moments. The main objective was to assess the efficacy of Aleozen(R) after 90 days of an exposition to traumatic events according to PTSD. Secondary objectives were to evaluate the safety of Aleozen(R) at 10 and 30 days after its administration and PTSD in the study population after one year of inclusion.

ResultsNo statistical differences were noted between the two groups in term of baseline characteristics including age, sex and the ISS score. After 90 days of follow-up, and according to the CAPS-5 scale, 85 patients (42.5%) of the population study showed PTSD. Concerning primary endpoint, less PTSD were seen in intervention group compared to placebo group (38.8% versus 61.2% respectively; p<0.001). During the study, no adverse events were noted.

ConclusionResults of this work suggest the potential preventive effects of an herbal supplement on PTSD for traumatic patient in emergency. Further confirmatory studies are needed.

Funding sourcesThis research is supported by << Aleonat >> Laboratories, who provided only the protocol treatments (active and placebo), without other financial support of the study. The sponsor and funder have no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities.

Ethical approvalThe study was approved by the local ethics committee (The Ethics Committee of the Faculty of Medicine of Sousse)

Ethical reviewA written informed consent was obtained from all participants.

Human and animal rights statementAll procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

category: emergency medicine


title: Estimating the relative proportions of SARS-CoV-2 strains from wastewater samples

abstract: Wastewater surveillance has become essential for monitoring the spread of SARS-CoV-2. The quantification of SARS-CoV-2 RNA in wastewater correlates with the Covid-19 caseload in a community. However, estimating the proportions of different SARS-CoV-2 strains has remained technically difficult. We present a method for estimating the relative proportions of SARS-CoV-2 strains from wastewater samples. The method uses an initial step to remove unlikely strains, imputation of missing nucleotides using the global SARS-CoV-2 phylogeny, and an Expectation-Maximization (EM) algorithm for obtaining maximum likelihood estimates of the proportions of different strains in a sample. Using simulations with a reference database of >3 million SARS-CoV-2 genomes, we show that the estimated proportions accurately reflect the true proportions given sufficiently high sequencing depth and that the phylogenetic imputation is highly accurate and substantially improves the reference database.


title: Exploring the effects of prescribed fire on ticks spread and propagation in a spatial setting

abstract: Lyme disease is one of the most prominent tick-borne diseases in the United States and prevalence of the disease has been steadily increasing over the past several decades due to a number of factors, including climate change. Methods for control of the disease have been considered, one of which is prescribed burning. In this paper the effects of prescribed burns on the abundance of ticks present in a spatial domain are assessed. A spatial stage-structured tick-host model with an impulsive differential equation system is developed to simulate the effect that controlled burning has on tick populations. Subsequently, a global sensitivity analysis is performed to evaluate the effect of various model parameters on the prevalence of infectious nymphs. Results indicate that while ticks can recover relatively quickly following a burn, yearly, high-intensity prescribed burns can reduce the prevalence of ticks in and around the area that is burned. The use of prescribed burns in preventing the establishment of ticks into new areas is also explored and it is observed that frequent burning can slow establishment considerably.


title: Estimation of age-stratified contact rates during the COVID-19 pandemic using a novel inference algorithm

abstract: Well parameterised epidemiological models including accurate representation of contacts, are fundamental to controlling epidemics. However, age-stratified contacts are typically estimated from pre-pandemic/peace-time surveys, even though interventions and public response likely alter contacts. Here we fit age-stratified models, including re-estimation of relative contact rates between age-classes, to public data describing the 2020-21 COVID-19 outbreak in England. This data includes age-stratified population size, cases, deaths, hospital admissions, and results from the Coronavirus Infection Survey (almost 9000 observations in all). Fitting stochastic compartmental models to such detailed data is extremely challenging, especially considering the large number of model parameters being estimated (over 150). An efficient new inference algorithm ABC-MBP combining existing Approximate Bayesian Computation (ABC) methodology with model-based proposals (MBP) is applied. Modified contact rates are inferred alongside time-varying reproduction numbers that quantify changes in overall transmission due to pandemic response, and age-stratified proportions of asymptomatic cases, hospitalisation rates and deaths. These inferences are robust to a range of assumptions including the values of parameters that cannot be estimated from available data. ABC-MBP is shown to enable reliable joint analysis of complex epidemiological data yielding consistent parametrisation of dynamic transmission models that can inform data-driven public health policy and interventions.


title: MuTILs: explainable, multiresolution computational scoring of Tumor-Infiltrating Lymphocytes in breast carcinomas using clinical guidelines

abstract: Tumor-Infiltrating Lymphocytes (TILs) have strong prognostic and predictive value in breast cancer, but their visual assessment is subjective. We present MuTILs, a convolutional neural network architecture specifically optimized for the assessment of TILs in whole-slide image scans in accordance with clinical scoring recommendations. MuTILs is a concept bottleneck model, designed to be explainable and to encourage sensible predictions at multiple resolutions. Our computational scores match visual scores and have independent prognostic value in invasive breast cancers from the TCGA dataset.

category: pathology


title: Maternal first trimester metabolic profile in TGA pregnancies - a case-control study

abstract:
ObjectiveTo evaluate the association between maternal first trimester metabolic profile and transposition of the great arteries (TGA) in the offspring.

DesignA matched case-control study using national register data and maternal first trimester blood samples.

SettingsFinland

PatientsA total of 100 mothers with TGA in their offspring and 200 controls matched by the year of birth and sex of the child, and the age and the body mass index (BMI) of the mother.

InterventionsNone.

Main outcome measuresTo identify the impact of 73 metabolic measure concentrations on the likelihood that a child would be born with TGA.

ResultsA higher concentration of four subtypes in extremely large very-low-density lipoprotein (VLDL) particles and one in large VLDL particles were observed in mothers with TGA in their offspring. This finding did not reach statistical significance after multiple testing correction. In the analysis of the subgroups of maternal BMI over 25 and 30 only, the odds ratios (OR) of the metabolic variables were higher compared to the original population. In the group with a BMI over 25 the mean OR was 1.3 (N= 111, total) and in the group with a BMI over 30 the mean OR was 2.1 (N= 42, total).

ConclusionsWe found no statistically significant difference between the metabolic profiles of mothers with TGA in their offspring, and their controls. However, the trend in our BMI-matched study potentially indicates that the likelihood of TGA development associates with maternal early-pregnancy metabolic profile, and the association is more pronounced in the subgroups of BMI over 25 and 30. Further studies are needed especially in the higher BMI groups.

What is already known on this topic?O_LIThe most important structures of the heart develop during early pregnancy, but studies on the association of maternal metabolomics during the first trimester with CHD development are scarce.
C_LIO_LIMaternal obesity and diabetes are known risk factors for CHD in the offspring but the precise developmental mechanisms underlying this risk remain unknown.
C_LI

What this study adds to this topic?O_LIThe maternal metabolomic profile in early pregnancy is potentially associated with the likelihood of TGA development in the offspring.
C_LIO_LIMetabolic markers in obese women may have a stronger association with the development of TGA but this connection requires further studies.
C_LI

category: pediatrics


title: Variation in US Drug Overdose Mortality Within and Between Hispanic/Latine Subgroups: A Disaggregation of National Data

abstract:
This study examined differences across Latine heritage groups (i.e., Mexican, Puerto Rican, Cuban, Dominican, Central American, South American) in rates of US drug overdose mortality. The study utilized 2015-2019 mortality data from the National Center for Health Statistics for 29,137 Hispanic individuals who died of drug overdose. Using population estimates from the American Community Survey, age-standardized drug overdose mortality rates were calculated by specific Latine heritage and sex, nativity, educational attainment, and geographic region. Standardized rate ratios (SRRs), incidence rate ratios (IRRs) from negative binomial regression models, and 95% Confidence Intervals (CIs) were calculated, and multiple imputation was used for missing Latine heritage group in select models.

Drug overdose mortality rates in the Puerto Rican heritage population were more than three times as high as in the Mexican heritage population (IRR 3.61 [95% CI 3.02-4.30] in unadjusted model; IRR 3.70 [95% CI 3.31-4.15] in model adjusting for age, sex, nativity, educational attainment, and region; SRR 3.23 [95% CI, 3.15-3.32] in age-standardized model with missing Hispanic heritage imputed). Higher age-standardized rates of drug overdose mortality were observed in males than females across all Latine groups, yet the magnitude of the sex differential varied by Latine heritage. The relationship between drug overdose mortality and nativity differed by Latine heritage; in all groups except Puerto Rican, overdose mortality rates were significantly higher in the US-born than those not US-born. In contrast, overdose mortality rates were significantly lower in US-born Puerto Ricans than in Puerto Ricans who were not US-born (e.g., born in Puerto Rico; SRR, 0.84 [95% CI 0.80-0.88]). The relationship between drug overdose mortality and educational attainment (for ages 25+) also varied between Latine groups.

The diverse subgroups comprising the US Latine population vary not only in rates of drug overdose mortality, but also in demographic risk factors for fatal drug overdose.


title: Livestock, pathogens, vectors, and their environment: a causal inference-based approach to estimating the pathway-specific effect of livestock on human African trypanosomiasis risk

abstract:
Livestock are important reservoirs for many diseases, and investigation of such zoonoses has long been the focus of One Health research. However, the effects of livestock on human and environmental health extend well beyond direct disease transmission.

In this retrospective ecological cohort study we use pre-existing data and methods derived from causal inference and spatial epidemiology to estimate three hypothesized mechanisms by which livestock can come to bear on human African trypanosomiasis (HAT) risk: the reservoir effect, by which infected cattle and pigs are a source of infection to humans; the zooprophylactic effect, by which preference for livestock hosts exhibited by the tsetse fly vector of HAT means that their presence protects humans from infection; and the environmental change effect, by which livestock keeping activities modify the environment in such a way that habitat suitability for tsetse flies, and in turn human infection risk, is reduced. We conducted this study in four high burden countries: at the point level in Uganda, Malawi, and Democratic Republic of Congo (DRC), and at the county-level in South Sudan.

Our results indicate cattle and pigs play an important reservoir role for the rhodesiense form (rHAT) in Uganda, however zooprophylaxis outweighs this effect for rHAT in Malawi. For the gambiense form (gHAT) we found evidence that pigs may be a competent reservoir, however dominance of the reservoir versus zooprophylactic pathway for cattle varied across countries. We did not find compelling evidence of an environmental change effect.

Author summaryOne Health research is most commonly interested in livestock as reservoirs of zoonotic diseases (i.e., infectious diseases transmissible from animals to humans), however livestock also exert environmental effects on a range of scales. At a local level, grazing and brush-clearing activities related to livestock keeping can reduce vegetation and increase temperature, in turn reducing habitat for and density of disease reservoirs and vectors. Furthermore, many arthropod vectors of human (zoonotic and non-zoonotic) diseases exhibit host species preference; when livestock hosts are preferred, the presence of these animals may reduce the risk of human infection. When all three of these effects act in concert, their relative strength governs whether the overall effect of livestock on human disease risk is positive (harmful) or negative (protective), a balance which is likely focus-specific.

Using pre-existing data and methods drawn from causal inference and spatial epidemiology, we estimate the contribution of these three pathways to the effect of cattle and pigs on human African trypanosomiasis (HAT) risk in Uganda, Malawi, Democratic Republic of Congo, and South Sudan. We find little evidence of an environmental change effect, however cattle and pigs appear to play both reservoir and zooprophylactic roles in the epidemiology of this disease.


title: XTRA Study Protocol: eXploring medical sTudents caReer reAdiness - A cross sectional study in the UK

abstract:
Background and objectivesProfessional and career enhancing opportunities are essential for developing skills required for a successful career in medicine. Research to date has mainly focused on the extent to which medical schools prepare students for clinical work as junior doctors. However, there remains a need to ascertain how students prepare for their career and what facilitates or hinders learning regarding careers in medicine. The purpose of the XTRA study is to examine career readiness of medical students at UK universities and the support they receive during their studies regarding career planning.

MethodsThe eXploring medical sTudents caReer reAdiness (XTRA) study is a national cross sectional study of all medical students enrolled at a UK medical school. Data collection will occur via a secure online survey designed as a training need analysis based on the principles of Supers theory (Super, 1953) of career development. A snowball sampling strategy will be used to recruit participants via social media and networks. Results will be analysed using quantitative analysis and thematic analysis to identify themes in qualitative responses. The primary outcome is to understand the perspective of current medical students on how well prepared they are about entering their careers in healthcare.

ConclusionsWe anticipate that findings from this study will help identify career readiness of medical students to facilitate the development of career development programmes and resources to ensure medical students are well equipped for their future careers.

category: medical education


title: Effectiveness of psychosocial interventions for hypertensive disorders in pregnancy: A systematic review and meta-analysis

abstract:
ObjectiveStudies on psychosocial interventions for perinatal mental health and wellbeing are mostly limited to the postpartum period. However, the physiological changes associated with hypertensive disorders in pregnancy predisposes women to severe psychological distress and adverse birth outcomes. This review investigated the effectiveness of psychosocial interventions for hypertensive disorders during pregnancy.

MethodsCochrane CENTRAL, Embase, MEDLINE, MIDIRS, CINAHL, PsycINFO, PsycArticles, and Web of Science were searched up to 22nd August 2021. Effect sizes on relevant health outcomes were pooled in a meta-analysis using STATA software.

ResultsEight randomised trials involving 460 participants met the inclusion criteria. Included studies adopted several interventions ranging from music, exercise, cognitive behavioural therapy (CBT), spiritual care education and psychoeducation. The pooled effect showed a significant reduction in anxiety (d= -0.35 [-0.58, -0.11], p=0.004) and depression (d= -0.37 [-0.57, -0.17], p=0.0003). Spiritual care education significantly reduced postpartum stress disorder (d= -62.00 [-93.10, -30.90], p= 0.0001). However, CBT showed no effect on gestational stress (d= -2.20 [-4.89, 0.48], p= 0.11).

ConclusionThis study provides satisfactory evidence that psychosocial interventions may likely reduce anxiety and depression associated with hypertensive disorders in pregnancy. However, the evidence is very uncertain about its effect on neonatal outcomes.

Summary of findings

O_TBL View this table:
org.highwire.dtl.DTLVardef@148f092org.highwire.dtl.DTLVardef@1aa3e6corg.highwire.dtl.DTLVardef@1e85064org.highwire.dtl.DTLVardef@f5e38corg.highwire.dtl.DTLVardef@12e1570_HPS_FORMAT_FIGEXP  M_TBL C_TBL


title: COVID-19 infection and vaccination rates in healthcare workers in British Columbia, Canada: A Longitudinal Urban versus Rural Analysis of the Impact of the Vaccine Mandate

abstract:
PurposeHealthcare workers (HCWs) play a critical role in responding to the COVID-19 pandemic. Early in the pandemic, urban centres were hit hardest globally; rural areas gradually became more impacted. We compared COVID-19 infection and vaccine uptake in HCWs living in urban versus rural locations within, and between, two health authorities in British Columbia (BC), Canada. We also analyzed the impact of a vaccine mandate for HCWs.

MethodsWe tracked laboratory-confirmed SARS-CoV-2 infections, positivity rates, and vaccine uptake in 29,021 HCWs in Interior Health (IH) and 24,634 HCWs in Vancouver Coastal Health (VCH), by occupation, age, and home location, comparing to the general population in that region. We then evaluated the impact of infection rates as well as the mandate on vaccination uptake.

ResultsBy October 27, 2021, the date that unvaccinated HCWs were prohibited from providing healthcare, only 1.6% in VCH yet 6.5% in IH remained unvaccinated. Rural workers in both areas had significantly higher unvaccinated rates compared with urban dwellers. Over 1,800 workers, comprising 6.4% of rural HCWs and 3.3% of urban HCWs, remained unvaccinated and set to be terminated from their employment. While the mandate prompted a significant increase in second doses, the impact on the unvaccinated was less clear.

ConclusionsAs rural areas often suffer from under-staffing, loss of HCWs could have serious impacts on healthcare provision as well as on the livelihoods of unvaccinated HCWs. Greater efforts are needed to understand how to better address the drivers of rural-related vaccine hesitancy as the pandemic continues.

category: occupational and environmental health


title: Extremely potent monoclonal antibodies neutralize Omicron and other SARS-CoV-2 variants

abstract: The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a devastating global health, social and economic crisis. The RNA nature and broad circulation of this virus facilitate the accumulation of mutations, leading to the continuous emergence of variants of concern with increased transmissibility or pathogenicity1. This poses a major challenge to the effectiveness of current vaccines and therapeutic antibodies1, 2. Thus, there is an urgent need for effective therapeutic and preventive measures with a broad spectrum of action, especially against variants with an unparalleled number of mutations such as the recently emerged Omicron variant, which is rapidly spreading across the globe3. Here, we used combinatorial antibody phage-display libraries from convalescent COVID-19 patients to generate monoclonal antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein with ultrapotent neutralizing activity. One such antibody, NE12, neutralizes an early isolate, the WA-1 strain, as well as the Alpha and Delta variants with half-maximal inhibitory concentrations at picomolar level. A second antibody, NA8, has an unusual breadth of neutralization, with picomolar activity against both the Beta and Omicron variants. The prophylactic and therapeutic efficacy of NE12 and NA8 was confirmed in preclinical studies in the golden Syrian hamster model. Analysis by cryo-EM illustrated the structural basis for the neutralization properties of NE12 and NA8. Potent and broadly neutralizing antibodies against conserved regions of the SARS-CoV-2 spike protein may play a key role against future variants of concern that evade immune control.


title: Immunity in Omicron SARS-CoV-2 breakthrough COVID-19 in vaccinated adults

abstract: The new SARS-CoV-2 variant of concern (VOC) Omicron has more than 30 mutations in the receptor binding domain (RBD) of the Spike protein enabling viral escape from antibodies in vaccinated individuals and increased transmissibility1-6. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a superspreader event had robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. We compared cases from a Christmas party where 81 of 110 (74%) developed Omicron breakthrough COVID-197, with Delta breakthrough cases and vaccinated non-infected controls. Omicron cases had significantly increased activated SARS-CoV-2 wild type Spike-specific (vaccine) cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, activated anti-Spike plasmablasts and anti-RBD memory B cells compared to controls. Omicron cases had significantly increased de novo memory T cell responses to non-Spike viral antigens compared to Delta breakthrough cases demonstrating development of broad immunity. The rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity.


title: An ensemble prediction model for COVID-19 mortality risk

abstract:
BackgroundIts critical to identify COVID-19 patients with a higher death risk at early stage to give them better hospitalization or intensive care. However, thus far, none of the machine learning models has been shown to be successful in an independent cohort. We aim to develop a machine learning model which could accurately predict death risk of COVID-19 patients at an early stage in other independent cohorts.

MethodsWe used a cohort containing 4711 patients whose clinical features associated with patient physiological conditions or lab test data associated with inflammation, hepatorenal function, cardiovascular function and so on to identify key features. To do so, we first developed a novel data preprocessing approach to clean up clinical features and then developed an ensemble machine learning method to identify key features.

ResultsFinally, we identified 14 key clinical features whose combination reached a good predictive performance of AUC 0.907. Most importantly, we successfully validated these key features in a large independent cohort containing 15,790 patients.

ConclusionsOur study shows that 14 key features are robust and useful in predicting the risk of death in patients confirmed SARS-CoV-2 infection at an early stage, and potentially useful in clinical settings to help in making clinical decisions.

category: intensive care and critical care medicine


title: Humoral and T-cell immune response after three doses of mRNA SARS-CoV-2 vaccines in fragile patients: the Italian VAX4FRAIL study

abstract:
BackgroundPatients with solid or hematological tumors, neurological and immune-inflammatory disorders represent potentially fragile subjects with increased risk to experience severe COVID-19 and inadequate response to SARS-CoV2 vaccination.

MethodsWe designed a prospective Italian multicentric study to assess humoral and T-cell response to SARS-CoV2 vaccination in patients (n=378) with solid tumors (ST), hematological malignancies (HM), neurological (ND) and immuno-rheumatological diseases (ID). The immunogenicity of primary vaccination schedule and of the booster dose were analyzed.

ResultsOverall, patient seroconversion rate after two doses was 62.1%. A significant lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%); a lower median level of antibodies was detected in HM and ID versus the others (p<0.0001). A similar rate of patients with a positive SARS-CoV2 T-cell response was observed in all disease groups, with a higher level observed in the ND group. The booster dose improved humoral responses in all disease groups, although with a lower response in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, the independent predictors for seroconversion were disease subgroups, type of therapies and age. Notably, the ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (p<0.0001), but had no effects on the T-cell responses.

ConclusionsImmunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination. The booster dose can improve both humoral and T-cell response.

Articles main point- Lower rate of seroconversion was observed in fragile patients as compared to healthy controls
- The booster dose improves humoral and T-cell response in all fragile patient groups
- Immunosuppressive treatment was associated with the worst humoral response to vaccination, but had no effects on T-cell responses.


title: Utility of estimated pulse wave velocity for assessing vascular stiffness: comparison of methods

abstract:
AimPulse wave velocity independently predicts cardiovascular risk. Easy to use single cuff oscillometric methods are utilized in clinical practice to estimate pulse wave velocity. We applied the approach in master athletes to assess possible beneficial effects of lifelong exercise on vascular health. Furthermore, we compared single cuff measurements with a two-cuff method in another cohort.

MethodsWe obtained single cuff upper arm oscillometric measurements thrice in 129 master athletes aged 35 to 86 years and estimated pulse wave velocity using the ArcSolver algorithm. We applied the same method in 24 healthy persons aged 24 to 55 years participating in a head down tilt bedrest study. In the latter group, we also obtained direct pulse wave velocity measurements using a thigh cuff.

ResultsEstimated pulse velocity very highly correlated with age (R{superscript 2}= 0.90) in master athletes. Estimated pulse wave velocity values were located on the same regression line like values obtained in participants of the head down tilt bed rest study. The modest correlation between estimated and measured PWV (r2 0.40; p<0.05) was attenuated after adjusting for age; the mean difference between pulse wave velocity measurements was 1 m/s.

ConclusionEstimated pulse wave velocity mainly reflects the entered age rather than true vascular properties and, therefore, failed detecting beneficial effects of life long exercise.

FundingThe AGBRESA-Study was funded by the German Aerospace Center (DLR), the European Space Agency (ESA, contract number 4000113871/15/NL/PG) and the National Aeronautics and Space Administration (NASA, contract number 80JSC018P0078). FH received funding by the DLR and the German Federal Ministry of Economy and Technology, BMWi (50WB1816). SM, JT and JJ were supported by the Austrian Federal Ministry for Climate Action, Environment, Energy, Mobility, Innovation and Technology, BMK (SPACE4ALL Project, FFG No. 866761).

category: cardiovascular medicine


title: Correlations in sleeping patterns and circadian preference between spouses

abstract: Spouses may affect each others sleeping behaviour. In 47,420 spouse-pairs from the UK Biobank, we found a weak positive phenotypic correlation between spouses for self-reported sleep duration (r=0.11; 95% CI=0.10, 0.12) and a weak inverse correlation for chronotype (diurnal preference) (r=-0.11; -0.12, -0.10), which replicated in up to 127,035 23andMe spouse-pairs. Using accelerometer data on 3,454 UK Biobank spouse-pairs, the correlation for derived sleep duration was similar to self-report (r=0.12; 0.09, 0.15). Timing of diurnal activity was positively correlated (r=0.24; 0.21, 0.27) in contrast to the inverse correlation for chronotype. In Mendelian randomization analysis, positive effects of sleep duration (mean difference=0.13; 0.04, 0.23 SD per SD) and diurnal activity (0.49; 0.03, 0.94) were observed, as were inverse effects of chronotype (-0.15; -0.26, -0.04) and snoring (-0.15; -0.27, -0.04). Findings support the notion that an individuals sleep may impact that of their partner, with implications for sleep health.


title: Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study

abstract:
Previous Mendelian randomization (MR) studies using population samples (population-MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. Mendelian randomization using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis.

Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72,932 siblings from UK Biobank and the Norwegian HUNT study and summary-level data from a within-sibship Genome-wide Association Study including over 140,000 individuals.

Both population and within-sibship MR estimates provided evidence that educational attainment influences BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independent of potential demographic and family-level confounders.


title: Post-traumatic stress symptoms in cancer patients during the COVID-19 pandemic: a one-year longitudinal study

abstract:
BackgroundCancer patients may be particularly vulnerable to psychological consequences of the COVID-19 pandemic and successive lockdowns. We studied the prevalence and evolution of post-traumatic stress disorder (PTSD) symptoms in cancer patients during the pandemic waves, and investigated factors associated with high symptoms.

MethodsCOVIPACT is a one-year longitudinal prospective study of French patients with solid/hematologic malignancy receiving treatment during the first nationwide lockdown. PTSD symptoms were measured every 3 months from April 2020 using the Impact of Event Scale-Revised. Patients also completed validated questionnaires on quality of life (QoL), cognitive complaints and insomnia, and a survey on their COVID-19 lockdown experience.

ResultsLongitudinal analyses involved 386 patients with at least one PTSD assessment after baseline (median age 63, 76% female). Among them, 21.5% had moderate/severe PTSD symptoms during the first lockdown. The rate of patients reporting PTSD symptoms decreased at lockdown release (13.6%), increased again at second lockdown (23.2%), and slightly declined from the second release period (22.7%) to the third lockdown (17.5%). Patients were grouped into three trajectories of evolution. Most patients had stable low symptoms throughout the period, 6% had high baseline symptoms slowly decreasing over time, and 17.6% had moderate symptoms worsening during second lockdown. Female sex, feeling socially isolated, worrying about COVID-19 infection, and using psychotropic drugs were associated with PTSD symptoms. PTSD symptoms were associated with impaired QoL, sleep and cognition.

ConclusionsAround a quarter of cancer patients presented high and persistent PTSD symptoms over the first year of the COVID-19 pandemic and may benefit from psychological support.


title: Genetic overlap between Parkinson disease and inflammatory bowel disease

abstract:
ImportanceParkinson disease (PD) and inflammatory bowel disease (IBD) have been associated, implying shared pathophysiology. Characterizing genetic pleiotropy between the two conditions aids the exploration of common etiology.

ObjectiveTo estimate the genetic correlation between PD and IBD and to identify specific loci influencing both conditions.

DesignGenetic study with applications of high definition likelihood and conditional false discovery rate (FDR) framework.

SettingThe study was based on summary statistics of genome-wide association studies (GWAS).

ParticipantsThe PD GWAS comprised 37,688 cases and 981,372 controls, and the IBD GWAS included 25,042 cases and 34,915 controls. Participants were of mixed ethnicity.

ExposuresNone.

Main Outcomes and MeasuresThe main outcomes were a set of single nucleotide polymorphisms (SNPs) identified by conditional FDR analysis as jointly associated with PD and IBD.

ResultsWeak but statistically significant genetic correlations were detected for PD with both Crohns disease (CD) and ulcerative colitis (UC), the two main subtypes of IBD. A total of 1333 SNPs in 28 genomic loci and 1915 SNPs in 22 loci were jointly associated with PD-CD and PD-UC, respectively, at conjunctional FDR under 0.01. The pleiotropic loci appeared distinctive for PD-CD and PD-UC, are mostly novel and comprise loci with either same or opposing genetic effects on the two phenotypes. Positional and eQTL mapping prioritized 316 PD-CD and 303 PD-UC genes, among which only <10% are differentially expressed in both colon and substantia nigra. The KEGG pathways enriched by all prioritized genes were highly concordant between PD-CD and PD-UC, with the majority being related to immune and/or autoimmune dysfunction.

Conclusions and RelevanceOverall, we found robust evidence for a genetic link between PD and each subtype of IBD. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both common etiology and antagonistic pleiotropy. At the functional level, our results highlighted a central role of host immunity and/or autoimmunity in the PD-IBD relationship.

category: genetic and genomic medicine


title: Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users

abstract: There is evidence that stress and craving contribute to the development, maintenance, and relapse in cocaine use disorder. Previous research has shown altered physiological responses to psychosocial stress as well as increased vegetative responding to substance-related cues in chronic cocaine users (CU). However, how psychosocial stress and cue-induced craving interact in relation to the physiological response of CU is largely unknown. Therefore, we investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. Participants were randomly exposed first to a video-based cocaine-cue paradigm and second to the Trier Social Stress Test (TSST) or vice versa in a crossed and balanced design to investigate possible mutually augmenting effects of both stressors on the physiological stress response. Plasma cortisol, ACTH, and noradrenaline as well as subjective stress and craving were assessed repeatedly over the course of the experimental procedure. Growth models and discontinuous growth models were used to estimate the responses during the cocaine-cue paradigm and TSST. Overall, both groups did not differ in their endocrinological responses to the TSST but CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU. However, if the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. Cocaine-cues robustly evoked craving in CU but no stress response, while cue-induced craving was intensified after the TSST. Taken together, CU did not show an altered acute stress response during the TSST but stress and craving together seem to have mutually augmenting effects on their stress response.

category: addiction medicine


title: The impact of depression diagnosis on diabetes and lifetime hyperglycaemia

abstract:
AimsThe aim of this study was to evaluate longitudinal associations between the mean and variability of HbA1c levels in individuals with type 2 diabetes (T2D) and major depressive disorder (MDD).

MethodsIndividuals with T2D from the UK Biobank with linked primary care records were analysed. An HbA1c measurement within +/- 6-months of T2D diagnosis was taken as baseline, with subsequent HbA1c measurements used as the outcome in generalised least squares regression to evaluate longitudinal associations with a three-level MDD diagnosis variable (MDD controls, pre-T2D MDD cases and post-T2D MDD cases).

ResultsUsing 7,968 T2D individuals, we show that MDD has utility in explaining mean HbA1c levels (p=6.53E-08). This is attributable to MDD diagnosis interacting with baseline T2D medication (p=3.36E-04) and baseline HbA1c (p=2.66E-05), but not with time-when all else is equal, the temporal trend in expected HbA1c did not differ by MDD diagnosis. However, joint consideration with baseline T2D medication showed that each additional medication prescribed was associated with a +4 mmol/mol (2.5%) increase in expected HbA1c across follow up for post-T2D MDD cases, relative to pre-T2D MDD cases and MDD controls. Furthermore, variability in HbA1c increased across time for post-T2D MDD cases but decreased for MDD controls and pre-T2D MDD cases.

ConclusionsThese findings suggest closer monitoring of individuals with both T2D and MDD is essential to improve their diabetic control, particularly for those who develop MDD after T2D diagnosis.

Novelty statementO_ST_ABSWhat is already known?C_ST_ABSComorbid T2D and MDD is associated with poorer diabetic control and worse prognosis.

What this study has found?We demonstrate a strong complex relationship between MDD and diabetic control, influenced by diabetic medication and baseline HbA1c levels. We showed that individuals who develop MDD after their T2D diagnosis have greater variability in HbA1c levels over time.

What are the implications of the study?This study shows the importance of closer monitoring of HbA1c in individuals with both T2D and MDD, particularly those who develop MDD after diabetes, to improve diabetic control and reduce complications associated comorbid T2D and MDD.

category: endocrinology


title: People with HIV Have Higher Risk of COVID-19 Diagnosis but Similar Outcomes than the General Population

abstract:
BackgroundWe investigated the effect of HIV on COVID-19 outcomes with attention to selection bias due to differential testing and to comorbidity burden.

MethodsRetrospective cohort analysis using four hierarchical outcomes: positive SARS-CoV-2 test, COVID-19 hospitalization, intensive care unit (ICU) admission, and hospital mortality. The effect of HIV status was assessed using traditional covariate-adjusted, inverse probability weighted (IPW) analysis based on covariate distributions for testing bias (testing IPWs), HIV infection status (HIV IPWs), and combined models. Among PWH, we evaluated whether CD4 count and HIV plasma viral load (pVL) discriminated between those who did or did not develop study outcomes using receiver operating characteristic analysis.

ResultsBetween March and November 2020, 63,319 people were receiving primary care services at UCSD, of whom 4,017 were people living with HIV (PWH). PWH had 2.1 times the odds of a positive SARS-CoV-2 test compared to those without HIV after weighting for potential testing bias, comorbidity burden, and HIV-IPW (95% CI 1.6-2.8). Relative to persons without HIV, PWH did not have an increased rate of COVID-19 hospitalization after controlling for comorbidities and testing bias [adjusted incidence rate ratio (aIRR): 0.5, 95% CI: 0.1 - 1.4]. PWH had neither a different rate of ICU admission (aIRR:1.08, 95% CI; 0.31 - 3.80) nor in-hospital death (aIRR:0.92, 95% CI; 0.08 - 10.94) in any examined model. Neither CD4 count nor pVL predicted any of the hierarchical outcomes among PWH.

ConclusionsPWH have a higher risk of COVID-19 diagnosis but similar outcomes compared to those without HIV.

Summary pointAfter considering the effects of potential bias due to differential testing, comorbidities, and other patient characteristics, people with HIV had an increased rate of SARS-CoV-2 positivity and similar rates of hospitalization, ICU admission, and death.

category: hiv aids


title: Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

abstract:
BackgroundType 2 diabetes (T2D) has a heterogeneous etiology which is increasingly recognized to influence the risk of complications and choice of treatment. A data driven cluster analysis in four separate European populations of patients with type 2 diabetes identified four subtypes of severe insulin dependent (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) (Ahlqvist et al., Lancet Diabetes Endocrinology, 2018). Our aim was to extend this classification to the Arab population of Qatar and characterize the biological processes that differentiate these subtypes in relation to metabolomic and proteomic signatures.

MethodsThe Ahlqvist et al. subtype clustering approach was applied to 631 individuals with T2D from the Qatar Biobank (QBB) and validated in an independent set of 420 participants from the same population. The association between blood metabolites (n=1,159) and protein levels (n=1,305) with each cluster were established.

FindingsThe four subtypes of T2D were reproduced and validated in the population of Qatar. Cluster-specific metabolomic and proteomic associations revealed subtype-specific molecular processes. Activation of the complement system with many features of autoimmune diabetes and reduced 1,5-anhydroglucitol (1,5-AG) characterized SIDD, with evidence of impaired insulin signaling in SIRD, elevated leptin and fatty acid binding protein in MOD, whilst MARD appeared to be the healthiest subgroup.

InterpretationWe have replicated the four T2D clusters in an Arab population and identified distinct metabolic and proteomic signatures, providing insights into underlying etiology with the potential to deploy subtype-specific treatment options.


title: Viral dynamics and duration of PCR positivity of the SARS-CoV-2 Omicron variant

abstract:
BackgroundThe Omicron SARS-CoV-2 variant is responsible for a major wave of COVID-19, with record case counts reflecting high transmissibility and escape from prior immunity. Defining the time course of Omicron viral proliferation and clearance is crucial to inform isolation protocols aiming to minimize disease spread.

MethodsWe obtained longitudinal, quantitative RT-qPCR test results using combined anterior nares and oropharyngeal samples (n = 10,324) collected between July 5th, 2021 and January 10th, 2022 from the National Basketball Associations (NBA) occupational health program. We quantified the fraction of tests with PCR cycle threshold (Ct) values <30, chosen as a proxy for potential infectivity and antigen test positivity, on each day after first detection of suspected and confirmed Omicron infections, stratified by individuals detected under frequent testing protocols and those detected due to symptom onset or concern for contact with an infected individual. We quantified the duration of viral proliferation, clearance rate, and peak viral concentration for individuals with acute Omicron and Delta variant SARS-CoV-2 infections.

ResultsA total of 97 infections were confirmed or suspected to be from the Omicron variant and 107 from the Delta variant. Of 27 Omicron-infected individuals testing positive [≤] 1 day after a previous negative or inconclusive test, 52.0% (13/25) were PCR positive with Ct values <30 at day 5, 25.0% (6/24) at day 6, and 13.0% (3/23) on day 7 post detection. Of 70 Omicron-infected individuals detected [≥] 2 days after a previous negative or inconclusive test, 39.1% (25/64) were PCR positive with Ct values <30 at day 5, 33.3% (21/63) at day 6, and 22.2% (14/63) on day 7 post detection. Overall, Omicron infections featured a mean duration of 9.87 days (95% CI 8.83-10.9) relative to 10.9 days (95% CI 9.41-12.4) for Delta infections. The peak viral RNA based on Ct values was lower for Omicron infections than for Delta infections (Ct 23.3, 95% CI 22.4-24.3 for Omicron; Ct 20.5, 95% CI 19.2-21.8 for Delta) and the clearance phase was shorter for Omicron infections (5.35 days, 95% CI 4.78-6.00 for Omicron; 6.23 days, 95% CI 5.43-7.17 for Delta), though the rate of clearance was similar (3.13 Ct/day, 95% CI 2.75-3.54 for Omicron; 3.15 Ct/day, 95% CI 2.69-3.64 for Delta).

ConclusionsWhile Omicron infections feature lower peak viral RNA and a shorter clearance phase than Delta infections on average, it is unclear to what extent these differences are attributable to more immunity in this largely vaccinated population or intrinsic characteristics of the Omicron variant. Further, these results suggest that Omicrons infectiousness may not be explained by higher viral load measured in the nose and mouth by RT-PCR. The substantial fraction of individuals with Ct values <30 at days 5 of infection, particularly in those detected due to symptom onset or concern for contact with an infected individual, underscores the heterogeneity of the infectious period, with implications for isolation policies.

category: epidemiology


title: Hydroxychloroquine/Chloroquine in COVID-19 With Focus on Hospitalized Patients - A Systematic Review

abstract:
BackgroundIn the beginning of the COVID-19 pandemic, many hospitalized patients received empiric hydroxychloroquine/chloroquine (HC/CQ). Although some retrospective-observational trials suggested potential benefit, all subsequent randomized clinical trials (RCTs) failed to show benefit and use generally ceased. Herein, we summarize key studies that clinicians advising patients on HC/CQs efficacy:safety calculus in hospitalized COVID-19 patients would want to know about in a practical one-stop-shopping source.

MethodsPubmed and Google were searched on November 4, 2021. Search words included: COVID-19, hydroxychloroquine, chloroquine, in vitro, animal studies, clinical trials, and meta-analyses. Studies were assessed for import and included if considered impactful for benefit:risk assessment.

ResultsThese searches led to inclusion of 12 in vitro and animal reports; 12 retrospective-observational trials, 19 interventional clinical trials (17 RCTs, 1 single-arm, 1 controlled but unblinded), and 51 meta-analyses in hospitalized patients.

Inconsistent efficacy was seen in vitro and in animal studies for coronaviruses and nil in SARS-CoV-2 animal models specifically. Most retrospective-observational studies in hospitalized COVID-19 patients found no efficacy; QT prolongation and increased adverse events and mortality were reported in some. All RCTs and almost all meta-analyses provided robust data showing no benefit in overall populations and subgroups, yet concerning safety issues in many.

ConclusionsHC/CQ have inconsistent anti-coronavirus efficacy in vitro and in animal models, and no convincing efficacy yet substantial safety issues in the overwhelming majority of retrospective-observational trials, RCTs, and meta-analyses in hospitalized COVID-19 patients. HC/CQ should not be prescribed for hospitalized COVID-19 patients outside of clinical trials.

Key Summary PointsPreclinical hydroxychloroquine/chloroquine in vitro studies found inconsistent activity against coronaviruses including SARS-CoV-2.

Preclinical hydroxychloroquine/chloroquine animals studies found inconsistent efficacy for coronaviruses in general and none for SARS-CoV-2.

The overhwelming majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in hospitalized COVID-19 patients, and many found concerning safety signals.

The majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in COVID-19 outpatients or for pre- or post-exposure prophylaxis, and some found concerning safety signals.

The overwhelming majority of meta-analyses found no benefit for hydroxychloroquine/chloroquine in COVID-19 inpatients, outpatients, or for prophylaxis, and many found concerning safety signals.


title: Empirical Approach to Developing an Optimal Socioeconomic Status Index for Health Surveillance

abstract: The association between multi-dimensional deprivation and public health is well established, and many area-based indices have been developed to measure or account for socioeconomic status in health surveillance. The Yost Index, developed in 2001, has been adopted in the US for cancer surveillance and is based on the combination of two heavily weighted (household income, poverty) and five lightly weighted (rent, home value, employment, education and working class) indicator variables. Our objectives were to 1) update indicators and find a more parsimonious version of the Yost Index by examining potential models that included indicators with more balanced weights/influence and reduced redundancy and 2) test the statistical consistency of the factor upon which the Yost Index is based. Despite the usefulness of the Yost Index, a one-factor structure including all seven Yost indicator variables is not statistically reliable and should be replaced with a three-factor model to include the true variability of all seven indicator variables. To find a one-dimensional alternative, we conducted maximum likelihood exploratory factor analysis on a subset of all possible combinations of fourteen indicator variables to find well-fitted one-dimensional factor models and completed confirmatory factor analysis on the resulting models. One indicator combination (poverty, education, employment, public assistance) emerged as the most stable unidimensional model. This model is more robust to extremes in local cost of living conditions, is comprised of ACS variables that rarely require imputation by the end-user and is a more parsimonious solution than the Yost index with a true one-factor structure.


title: Rapid detection of single nucleotide polymorphisms using the MinION nanopore sequencer: a feasibility study for perioperative precision medicine

abstract:
IntroductionPrecision medicine is a phrase used to describe personalized medical care tailored to specific patients based on their clinical presentation and genetic makeup. However, despite the fact that several single nucleotide polymorphisms (SNPs) have been reported to be associated with increased susceptibility to particular anesthetic agents and the occurrence of perioperative complications, genomic profiling and thus precision medicine has not been widely applied in perioperative management.

MethodsWe validated six SNP loci known to affect perioperative outcomes in Japanese patients using genomic DNA from saliva specimens and nanopore sequencing of each SNP loci to facilitate allele frequency calculations and then compared the nanopore results to those produced using the conventional dideoxy sequencing method.

ResultsNanopore sequencing reads clustered into the expected genotypes in both homozygous and heterozygous cases. In addition, the nanopore sequencing results were consistent with those obtained using conventional dideoxy sequencing and the workflow provided reliable allele frequency estimation, with a total analysis time of less than 4 h.

ConclusionThus, our results suggest that nanopore sequencing may be a promising and versatile tool for SNP genotyping, allowing for rapid and feasible risk prediction of perioperative outcomes.

category: anesthesia


title: Association of Retinal Age Gap with Arterial Stiffness and Incident Cardiovascular Disease

abstract:
BackgroundRetinal parameters could reflect systemic vascular changes. With the advances of deep learning technology, we have recently developed an algorithm to predict retinal age based on fundus images, which could be a novel biomarker for ageing and mortality.

ObjectiveTo investigate associations of retinal age gap with arterial stiffness index (ASI) and incident cardiovascular disease (CVD).

MethodsA deep learning (DL) model was trained based on 19,200 fundus images of 11,052 participants without any past medical history at baseline to predict the retinal age. Retinal age gap (retinal age predicted minus chronological age) was generated for the remaining 35,917 participants. Regression models were used to assess the association between retinal age gap and ASI. Cox proportional hazards regression models and restricted cubic splines were used to explore the association between retinal age gap and incident CVD.

ResultsWe found each one-year increase in retinal age gap was associated with increased ASI ({beta}=0.002, 95% confidence interval [CI]: 0.001-0.003, P<0.001). After a median follow-up of 5.83 years (interquartile range [IQR]: 5.73-5.97), 675 (2.00%) developed CVD. In the fully adjusted model, each one-year increase in retinal age gap was associated with a 3% increase in the risk of incident CVD (hazard ratio [HR]=1.03, 95% CI: 1.01-1.06, P=0.012). In the restricted cubic splines analysis, the risk of incident CVD increased significantly when retinal age gap reached 1.21 (HR=1.05; 95% CI, 1.00-1.10; P-overall <0.0001; P-nonlinear=0.0681).

ConclusionWe found that retinal age gap was significantly associated with ASI and incident CVD events, supporting the potential of this novel biomarker in identifying individuals at high risk of future CVD events.


title: Quality of Care for Children Under Five with Malaria Using IMCI Approach at Public Health Centre: Literature Review

abstract: Integrated Management of Childhood Illness is one of the strategies in health care services for infants and children under five at primary health care facilities. Children with fever in high malaria endemic areas must have a blood test done to check whether the children have malaria or not. IMCI is one of the interventions recommended by WHO to screen and also ensure that children receive proper initial treatment at first-level health facilities. This article aims to discuss the quality of care for children under five with malaria using IMCI approach. This is a systematic review by searching 4 databases including Scopus, Web of Science, SAGE and Proquest. Health care services for children under five with an integrated management of childhood illness are intended to provide immediate and appropriate treatment. The guideline for treating children under five with malaria using IMCI approach is very helpful for nurses both in assessing, classifying, treating/curing and making decisions for pre-referral measures for severe cases. Several factors to support quality of care are trained officers, supervision and procurement of essential medicines, RDT and malaria microscopy. Enforcement of the right diagnosis will improve the quality of life of children and prevent death in children under five.


title: Pramipexole Enhances Reward Learning by Preserving Value Estimates

abstract:
BackgroundDopamine D2-like receptor agonists show promise as treatments for depression. They are thought to act by altering how individuals learn from rewarding experiences. However, the nature of these reward learning alterations, and the mechanisms by which they are produced is not clear. Reinforcement learning accounts describe three distinct processes that may produce similar changes in reward learning behaviour; increased reward sensitivity, increased inverse decision temperature and decreased value decay. As these processes produce equivalent effects on behaviour, arbitrating between them requires measurement of how expectations and prediction errors are altered. In the present study, we characterised the behavioural effects of a sustained 2-week course of the D2/3/4 receptor agonist pramipexole on reward learning and used fMRI measures of expectation and prediction error to assess which of these three mechanistic processes were responsible for the behavioural effects.

Methods40 healthy volunteers (Age: 18-43, 50% female) were randomly allocated to receive either two weeks of pramipexole (titrated to 1mg/day) or placebo in a double-blind, between subject design. Participants completed a probabilistic instrumental learning task, in which stimuli were associated with either rewards or losses, before the pharmacological intervention and twice between days 12-15 of the intervention (once with and once without fMRI). Both asymptotic choice accuracy, and a reinforcement learning model, were used to assess reward learning.

ResultsBehaviourally, pramipexole specifically increased choice accuracy in the reward condition, with no effect in the loss condition. Pramipexole increased the BOLD response in the orbital frontal cortex during the expectation of win trials but decreased the BOLD response to reward prediction errors in the ventromedial prefrontal cortex. This pattern of results indicates that pramipexole enhances choice accuracy by reducing the decay of estimated values during reward learning.

ConclusionsThe D2-like receptor agonist pramipexole enhances reward learning by preserving learned values. This is a plausible candidate mechanism for pramipexoles observed anti-depressant effect.

category: psychiatry and clinical psychology


title: The effectiveness of psychological interventions for anxiety in the perinatal period: A systematic review and meta-analysis

abstract:
BackgroundAnxiety disorders are a relatively common occurring mental health issue during pregnancy and the perinatal period. There is evidence that untreated perinatal anxiety is a risk factor for adverse outcomes for mother and infant. Despite their potential acceptability to users, psychological interventions research for this population is still in its infancy. This systematic review and meta-analysis aimed to comprehensively evaluate the evidence of the effectiveness of psychological interventions for reducing perinatal anxiety.

MethodThis review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases searched included EMBASE, MEDLINE, PsychINFO, MIDIRS, CINAHL and the Cochrane Library. Search terms included: Psychological Therapy, Perinatal Period, Antenatal, Postnatal, Anxiety, Obsessive Compulsive Disorder and Phobia.

ResultsThe search strategy identified 2,025 studies. A total of 21 studies published between 2004 and 2021 fulfilled inclusion criteria. Of those, 17 were included in the meta-analysis. Overall results indicated that psychological interventions were more effective than control conditions in reducing symptoms of perinatal anxiety with a medium post treatment effect size. Significant effect sizes were also identified for online, face-to-face, group and guided self-help treatment modalities.

LimitationsA small sample of studies are represented and limited to articles published in English. The review was unable to draw specific conclusions about what works (i.e. therapeutic modality/delivery) for whom (i.e. specific diagnoses) due to purposefully broad inclusion criteria. The longer-term effects of psychological interventions for perinatal anxiety and infant outcomes could not be established.

ConclusionsThis review demonstrates that psychological interventions are effective in reducing symptoms of both anxiety and comorbid anxiety and depression in the antenatal and postnatal periods. The results also demonstrate the efficacy of delivering such interventions in multiple settings, including online, and in group format. Further research is required to optimise treatment delivery to individual needs.


title: Addressing selection bias in the UK Biobank neurological imaging cohort

abstract: The UK Biobank is a national prospective study of half a million participants between the ages of 40 and 69 at the time of recruitment between 2006 and 2010, established to facilitate research on diseases of aging. The imaging cohort is a subset of UK Biobank participants who have agreed to undergo extensive additional imaging assessments. However, Fry et al. (2017) finds evidence of "healthy volunteer bias" in the UK Biobank - participants are less likely to smoke, be obese, consume alcohol daily than the target population of UK adults. Here we examine selection bias in the UK Biobank imaging cohort. We address two common misconceptions: first, that study size can compensate for bias in data collection, and second that selection bias does not affect estimates of associations, which are the primary interest of the UK Biobank. We introduce inverse probability weighting (IPW) as an approach commonly used in survey research that can be used to address selection bias in volunteer health studies like the UK Biobank. We discuss 6 such methods - five existing and one novel -, assess relative performance in simulation studies, and apply them to the UK Biobank imaging cohort. We find that our novel method, BART for predicting the probability of selection combined with raking, performs well relative to existing methods, and helps alleviate selection bias in the UK Biobank imaging cohort.

category: public and global health


title: Efficacy, Practicality, Intimal Health, and Sustainability of Menstrual Cups use among Undergraduate Medical Students: a cross-sectional study.

abstract:
IntroductionWomen need effective, safe, and affordable menstrual hygiene products. The menstrual cup is an alternative method.

ObjectiveTo identify the prevalence of menstrual cups among the medical students and the independent variables associated with their use adherence.

Methodsa cross-sectional study with an online survey applied to regularly matriculate women from FEMA Medical School in January 2021.

ResultsOf 277 women, 164 participated. The mean age was 22.26 (SD 3.21). 136 preferred external pads, 60 internal pads, 28 menstrual cups, and 11 did not use. Using a 1-10 scale, price, efficacy, sustain, practice, intimal health status, hygiene, and importance of internal genitalia integrity were questioned. 37 (22,56%) women related the use of menstrual cups in the last year. Using any method to reduce menstruation had an odds ratio adjusted of 0.310 (95%CI 0.122-0.787). Concern about the environmental biodegradation had ORadj of 6.369 (95%CI 1.372-29.562); Intimal Health, ORadj of 1.996 (95%CI 1.183-3.368); internal genital integrity, ORadj of 0.824 (95%CI 0.682-0.995), for menstrual cups use.

Conclusionwomen using a method to reduce their menstrual flow, concerning about biodegradation, concerning with intimal health, and with no concerns about manipulating their genitalia were significant independent factors for the adherence of menstrual cups.

category: obstetrics and gynecology


title: Cost of tuberculosis-related aeromedical retrievals in the Torres Strait, Australia

abstract: Tuberculosis (TB) remains a disease of public health significance at the Australia / Papua New Guinea (PNG) international border. In the remote Torres Strait Islands, aeromedical evacuation is a necessary but costly component of TB management and patients with critical care needs require support to prevent onward TB transmission. A detailed costing of an exemplar TB patient from PNG who presented to a Queensland Health facility in the Torres Strait and required urgent aeromedical evacuation was performed. Data were drawn from patient charts, financial and clinical information systems used within Queensland Health and the Torres and Cape Hospital and Health Service. The total cost of aeromedical evacuation was AUD 124,280; 54% of the cost was attributed to travel. Between 2016 and 2019, 19 patients diagnosed with TB were medically evacuated from an outer Torres Strait Island with a median length of hospital stay of 57 days. Aeromedical evacuation and medical management costs require adequate budget allocation.

category: infectious diseases


title: Characterizing features of outbreak duration for novel SARS-CoV-2 variants of concern

abstract: Characterizing the dynamics of epidemic trajectories is critical to understanding the potential impacts of emerging outbreaks and to designing appropriate mitigation strategies. As the COVID-19 pandemic evolves, however, the emergence of SARS-CoV-2 variants of concern has complicated our ability to assess in real-time the potential effects of imminent outbreaks, such as those presently caused by the Omicron variant. Here, we report that SARS-CoV-2 outbreaks across regions exhibit strain-specific times from onset to peak, specifically for Delta and Omicron variants. Our findings may facilitate real-time identification of peak medical demand and may help fine-tune ongoing and future outbreak mitigation deployment efforts.


title: Evaluating the association between hybrid magnetic resonance positron emission tomography and cardiac-related outcomes in cardiac sarcoidosis

abstract:
ObjectivesTo evaluate an extended hybrid MR/PET imaging strategy in cardiac sarcoidosis (CS) employing qualitative and quantitative assessment of PET tracer uptake, and to evaluate its association with cardiac-related outcomes.

BackgroundInvasive endomyocardial biopsy is the gold standard to diagnose CS, but it has poor sensitivity due to the patchy distribution of disease. Imaging with hybrid late gadolinium enhancement (LGE) MR and 18F-fluorodexyglucose (18F-FDG) PET allows simultaneous assessment of myocardial injury and disease activity and has shown promise for improved diagnosis of active CS based on the combined positive imaging outcome, MR(+)PET(+).

Methods148 patients with suspected CS were enrolled for hybrid MR/PET imaging. Patients were classified based on presence/absence of LGE (MR+/MR-), presence/absence of 18F-FDG (PET+/PET-), and pattern of 18F-FDG uptake (focal/diffuse) into the following categories: MR(+)PET(+)FOCAL, MR(+)PET(+)DIFFUSE, MR(+)PET(-), MR(-)PET(+)FOCAL, MR(-)PET(+)DIFFUSE, MR(-)PET(-). Patients classified as MR(+)PET(+)FOCAL were designated as having active CS [aCS(+)], while all others were considered as having inactive or absent CS and designated aCS(-). Quantitative values of standard uptake value (SUVmax), target-to-background ratio (TBRmax), target-to-normal-myocardium ratio (TNMRmax) and T2 were measured. Occurrence of a cardiac-related clinical outcome was defined as any of the following during the 6-month period after imaging: cardiac arrest, ventricular arrhythmia, complete heart block, need for cardiac resynchronization/defibrillator/pacemaker/monitoring device (CRT-D, ICD/WCD, or ILR). MR/PET imaging results were compared to the presence of the composite clinical outcome.

ResultsPatients designated aCS(+) had more than 4-fold increased odds of meeting the clinical endpoint compared to aCS(-) (unadjusted odds ratio 4.8; 95% CI 2.0-11.4; p<0.001). TNMRmax achieved an area under the receiver operating characteristic curve of 0.90 for separating aCS(+) from aCS(-).

ConclusionsHybrid MR/PET imaging with an extended image-based classification of CS was statistically associated with clinical outcomes in CS. TNMRmax had high sensitivity and excellent specificity for quantifying the imaging-based classification of active CS.

Condensed AbstractImaging with hybrid late gadolinium enhancement (LGE) MR and 18F-fluorodexyglucose (18F-FDG) PET allows simultaneous assessment of myocardial injury and disease activity and has shown promise for improved diagnosis of active cardiac sarcoidosis (CS). In this study, 148 patients with suspected CS were enrolled for hybrid MR/PET imaging. Patients were classified based on presence/absence of LGE (MR+/MR-), presence/absence of 18F-FDG (PET+/PET-), and pattern of 18F-FDG uptake (focal/diffuse). Patients classified as MR(+)PET(+)FOCAL were designated as having active CS and, compared to patients with any other imaging pattern, they had more than 4-fold increased odds of cardiac-related outcome at 6 months from imaging.

category: radiology and imaging