title: Analytical and Clinical Validation of an Amplicon-based Next Generation Sequencing Assay for Ultrasensitive Detection of Circulating Tumor DNA

abstract: Next-generation sequencing of circulating tumor DNA presents a promising approach to cancer diagnostics, complementing conventional tissue-based diagnostic testing by enabling minimally invasive serial testing and broad genomic coverage through a simple blood draw to maximize therapeutic benefit to patients. LiquidHALLMARK(R) is an amplicon-based next-generation sequencing assay developed for the genomic profiling of plasma-derived cell-free DNA. The comprehensive 80-gene panel profiles point mutations, insertions/deletions, copy number alterations, and gene fusions, and further detects oncogenic viruses (EBV and HBV) and microsatellite instability. Here, the analytical and clinical validation of the assay is reported. Analytical validation using reference genetic materials demonstrated a sensitivity of 99.38% for point mutations and 95.83% for insertions/deletions at 0.1% variant allele frequency (VAF), and a sensitivity of 91.67% for gene fusions at 0.5% VAF, with high specificity even at 0.1% VAF (99.11% per-base). The limit of detection for copy number alterations, EBV, HBV, and microsatellite instability were also empirically determined. Orthogonal comparison of EGFR variant calls made by LiquidHALLMARK and a reference allele-specific PCR method for 355 lung cancer specimens revealed an overall concordance of 93.80%, while external validation with cobas(R) EGFR Mutation Test v2 for 50 lung cancer specimens demonstrated an overall concordance of 84.00%, with a 100% concordance rate for EGFR variants above 0.4% VAF. Clinical application of LiquidHALLMARK in 1,592 consecutive patients demonstrated a high detection rate (74.8% alteration-positive in cancer samples) and broad actionability (50.0% of cancer samples harboring alterations with biological evidence for actionability). Among ctDNA-positive lung cancers, 72.5% harbored at least one biomarker with a guideline-approved drug indication. These results establish the high sensitivity, specificity, accuracy, and precision of the LiquidHALLMARK assay and supports its clinical application for blood-based genomic testing.


title: Deconvoluting complex correlates of COVID19 severity with local ancestry inference and viral phylodynamics: Results of a multiomic pandemic tracking strategy

abstract: The SARS-CoV-2 pandemic has differentially impacted populations of varied race, ethnicity and socioeconomic status. Admixture mapping and local ancestry inference represent powerful tools to examine genetic risk within multi-ancestry genomes independent of these confounding social constructs. Here, we leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from 1,327 nasopharyngeal swab residuals and integrate them with digital phenotypes from electronic health records. We demonstrate over-representation of individuals possessing Oceanian and Indigenous American ancestry in SARS-CoV-2 positive populations. Genome-wide-association disaggregated by admixture mapping reveals regions of chromosomes 5 and 14 associated with COVID19 severity within African and Oceanic local ancestries, respectively, independent of overall ancestry fraction. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. We further present summary data from a multi-omic investigation of human-leukocyte-antigen (HLA) typing, nasopharyngeal microbiome and human transcriptomics that reveal metagenomic and HLA associations with severe COVID19 infection. This work demonstrates the power of multi-omic pandemic tracking and genomic analyses to reveal distinct epidemiologic, genetic and biological associations for those at the highest risk.

category: genetic and genomic medicine


title: SARS-CoV-2 Suppression and Early Closure of Bars and Restaurants : A Longitudinal Natural Experiment

abstract: Despite severe economic damage, full-service restaurants and bars have been closed in hopes of suppressing the spread of SARS-CoV-2 worldwide. This paper explores whether the early closure of restaurants and bars in February 2021 reduced symptoms of SARS-CoV-2 in Japan. Using a large-scale nationally representative longitudinal survey, we found that the early closure of restaurants and bars decreased the utilization rate among young persons (OR 0.688; CI95 0.515-0.918) and those who visited these places before the pandemic (OR 0.754; CI95 0.594-0.957). However, symptoms of SARS-CoV-2 did not decrease in these active and high-risk subpopulations. Among the more inactive and low-risk subpopulations, such as elderly persons, no discernible impacts are observed in both the utilization of restaurants and bars and the symptoms of SARS-CoV-2. These results suggest that the early closure of restaurants and bars without any other concurrent measures does not contribute to the suppression of SARS-CoV-2.

category: health policy


title: Geographic barriers to establishing a successful hospital referral system in rural Madagascar

abstract:
BackgroundThe provision of emergency and hospital care has become an integral part of the global vision for universal health coverage. It is recommended that at least 80% of a countrys population should be within two hours of a facility with essential surgery and anesthetic services. In order to strengthen health systems to achieve this goal, there needs to be an understanding of the time necessary for populations to reach a hospital. The goal of this study was to develop methods that accurately estimate referral and pre-hospital time for rural health districts in LMICs. We used these estimates to assess how the local geography can limit the impact of a strengthened referral program in a rural district of Madagascar.

MethodsWe developed a database containing 1) travel speed in a subset of routes by foot and motorized vehicles in Ifanadiana District; 2) a full mapping of all roads, footpaths and households in the district; and 3) remotely sensed data on terrain, land cover and climatic characteristics. We used this information to calibrate estimates of referral and pre-hospital time based on shortest route algorithms and statistical models of local travel speed. We compared these estimates with those from other commonly used methods in geographic accessibility modeling. Finally, we studied the impact of referral time on the evolution of the number of referrals completed by each health center in the district in 2014-2020 via generalized linear mixed models, using model estimates to predict the impact on referral numbers of strategies aimed at reducing referral time for underserved populations.

ResultsAbout 10% of the population lived less than two hours from the hospital, and more than half lived over four hours away, with variable access depending on climatic conditions. Only the four health centers (out of 21) located near the paved road had referral times to the hospital within one hour, which contributed over 75% of all 8,464 hospital referrals. Referral time remained the main barrier limiting the number of referrals despite health system strengthening efforts. The addition of two new referral centers is estimated to triple the population living within two hours from a center with higher acute care capacity and nearly double the number of referrals expected.

ConclusionThis study demonstrates how adapting geographic accessibility modeling methods to local scales can occur through improving the precision of travel time estimates and pairing them with data on health facility data. Such information can substantially improve the design of a local health system to overcome existing barriers to care and achieve universal health coverage.

category: health systems and quality improvement


title: Optimized Flow Cytometric Detection of Transient Receptor Potential Vanilloid-1 (TRPV1) in Human Hematological Malignancies

abstract: The ectopic overexpression of transient receptor potential vanilloid-1 (TRPV1) has been detected in numerous solid cancers including breast, prostate, pancreatic, and tongue epithelium cancer. However, the expression of TRPV1 in hematological malignancies remains unknown. Here we show through in silico analysis that elevated TRPV1 mRNA expression occurs in a range of hematological malignancies and present an optimized flow cytometry method to rapidly assess TRPV1 protein expression for both cell lines and primary patient samples. Three anti-TRPV1 antibodies were evaluated for intracellular TRPV1 detection using flow cytometry resulting in an optimized protocol for the evaluation of TRPV1 in hematological malignant cell lines and patients peripheral blood mononuclear cells (PBMC). Overexpression of TRPV1 was observed in THP-1 (acute monocytic leukemia) and U266B1 (multiple myeloma, MM), but not U937 (histiocytic lymphoma) compared to healthy PBMC. TRPV1 was also detected in all 49 patients (including B-cell non-Hodgkins lymphoma (B-NHL), MM and others, and 20 healthy controls. TRPV1 expression was increased in 8% of patients (MM=2, B-NHL=2). In conclusion, we provide an optimized flow cytometry method for routine expression analysis of clinical samples and show that TRPV1 is increased in 8% of patients with hematological malignancies.

category: hematology


title: Multispectral Imaging for MicroChip Electrophoresis Enables Point-of-Care Newborn Hemoglobin Variant Screening

abstract: Hemoglobin (Hb) disorders affect nearly 7% of the worlds population. Globally, around 400,000 babies are born annually with sickle cell disease (SCD), primarily in sub-Saharan Africa where morbidity and mortality rates are high. Although treatments are available for Hb disorders, screening, early diagnosis, and monitoring are not widely accessible due to technical challenges and cost, especially in low-and-middle-income countries. We hypothesized that multispectral imaging will allow sensitive hemoglobin variant identification in existing affordable paper-based Hb electrophoresis, which is a clinical standard test for Hb variant screening. To test this hypothesis, we developed the first integrated point-of-care multispectral Hb variant test: Gazelle-Multispectral. Here, we evaluated the accuracy of Gazelle-Multispectral for Hb variant newborn screening in 321 completed tests in subjects younger than 6 months with known hemoglobin variants including hemoglobin A (Hb A), hemoglobin F (Hb F), hemoglobin S (Hb S) and hemoglobin C (Hb C). Gazelle-multispectral detected levels of Hb A, Hb F, Hb S, and Hb C, demonstrated high correlations with the results reported by laboratory gold standard high performance liquid chromatography (HPLC) at Pearson Correlation Coefficient = 0.97, 0.97, 0.89, and 0.94. Gazelle-multispectral demonstrated 100% sensitivity and 100% specificity in both disease vs normal and disease vs trait, 98.1% sensitivity and 97.0% specificity in trait vs normal in comparison to HPLC in newborns. The ability to obtain rapid and accurate results on newborn samples suggest that Gazelle-Multispectral is suitable for large-scale newborn screening and potentially for accurate diagnosis of SCD in low resource settings.


title: A Machine Learning Model Incorporating Laboratory Blood Tests Discriminates Between SARS-CoV-2 and Influenza Infections at Emergency Department Visit

abstract:
IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus are contagious respiratory pathogens with similar symptoms but require different treatment and management strategies. This study investigated whether laboratory blood tests can discriminate between SARS-CoV-2 and influenza infections at emergency department (ED) presentation.

Methods723 influenza A/B positive (2018/1/1 to 2020/3/15) and 1,281 SARS-CoV-2 positive (2020/3/11 to 2020/6/30) ED patients were retrospectively analyzed. Laboratory test results completed within 48 hours prior to reporting of virus RT-PCR results, as well as patient demographics were included to train and validate a random forest (RF) model. The dataset was randomly divided into training (2/3) and testing (1/3) sets with the same SARS-CoV-2/influenza ratio. The Shapley Additive Explanations technique was employed to visualize the impact of each laboratory test on the differentiation.

ResultsThe RF model incorporating results from 15 laboratory tests and demographic characteristics discriminated SARS-CoV-2 and influenza infections, with an area under the ROC curve value 0.90 in the independent testing set. The overall agreement with the RT-PCR results was 83% (95% CI: 80-86%). The test with the greatest impact on the differentiation was serum total calcium level. Further, the model achieved an AUC of 0.82 in a new dataset including 519 SARS-CoV-2 ED patients (2020/12/1 to 2021/2/28) and the previous 723 influenza positive patients. Serum calcium level remained the most impactful feature on the differentiation.

ConclusionWe identified characteristic laboratory test profiles differentiating SARS-CoV-2 and influenza infections, which may be useful for the preparedness of overlapping COVID-19 resurgence and future seasonal influenza.

category: infectious diseases


title: Machine learning detects SARS-CoV-2 and variants rapidly on DNA aptamer metasurfaces

abstract: COVID-19 is detected using reverse transcription polymerase chain reaction (RT-PCR) of nasal swabs. A very sensitive and rapid detection technique using easily-collected fluids like saliva must be developed for safe and precise mass testing. Here, we introduce a metasurface platform for direct sensing of COVID-19 from unprocessed saliva. We computationally screen gold metasurfaces out of a pattern space of 2100 combinations for strongly-enhanced light-virus interaction with machine learning and use it to investigate the presence and concentration of the SARS-CoV-2. We use machine learning to identify the virus from Raman spectra with 95.2% sensitivity and specificity on 36 PCR positive and 33 negative clinical samples and to distinguish wild-type, alpha, and beta variants. Our results could pave the way for effective, safe and quantitative preventive screening and identification of variants.


title: 'I can't cope with multiple inputs': Qualitative study of the lived experiences of 'brain fog' after Covid-19

abstract:
ObjectiveTo explore the lived experience of  brain fog--the wide variety of neurocognitive symptoms that can follow Covid-19.

Design and settingUK-wide longitudinal qualitative study comprising online interviews and focus groups with email follow-up.

Method50 participants were recruited from a previous qualitative study of the lived experience of long Covid (n = 23) and online support groups for people with persistent neurological problems following Covid-19 (n = 27). In remotely-held focus groups, participants were invited to describe their cognitive symptoms and comment on others accounts. Individuals were followed up by email 4-6 months later. Data were audiotaped, transcribed, anonymised and coded in NVIVO. They were analysed by an interdisciplinary team with expertise in general practice, clinical neuroscience, the sociology of chronic illness and service delivery, and checked by three people with lived experience of brain fog.

Results84% of participants were female and 60% were White British ethnicity. Most had never been hospitalised for Covid-19. Qualitative analysis revealed the following themes: mixed views on the appropriateness of the term  brain fog; rich descriptions of the experience of neurocognitive impairments (especially executive function, attention, memory and language), accounts of how the illness fluctuated--and in some but not all cases, resolved--over time; the profound psychosocial impact of the condition on relationships, personal and professional identity; self-perceptions of guilt, shame and stigma; strategies used for self-management; challenges accessing and navigating the healthcare system; and participants search for physical mechanisms to explain their symptoms.

ConclusionThese qualitative findings complement research into the epidemiology and underlying pathophysiological mechanisms for neurological symptoms after Covid-19. Services for such patients should include: an ongoing therapeutic relationship with a clinician who engages with the illness in its personal, social and occupational context as well as specialist services that are accessible, easily navigable, comprehensive, and interdisciplinary.

SummaryO_ST_ABSStrengths and Limitations of StudyC_ST_ABSO_LITo our knowledge, this is the largest and most in-depth qualitative study of the lived experience of brain fog in survivors of Covid-19.
C_LIO_LIThe research team was interdisciplinary and interprofessional, and included consultation with patient experts by experience, who helped with data interpretation and peer review.
C_LIO_LIOversampling from men and non-white ethnic groups allowed partial correction of an initially skewed sample.
C_LIO_LIThe sample was drawn entirely from the UK
C_LIO_LIResidual skews in the samples, particularly regarding minority ethnic groups and occupational classes, limited our ability to capture the full range of experiences
C_LI

Funding statementThis research is funded from the following sources: National Institute for Health Research (BRC-1215-20008), ESRC (ES/V010069/1), and Wellcome Trust (WT104830MA). Funders had no say in the planning and execution of the study or writing up of the paper. KTSP is supported by the National Institute for Health Research Biomedical Research Centre based at Oxford University Hospitals NHS Foundation Trust and the University of Oxford.

Competing Interests StatementEL and TG provided evidence on long Covid for House of Lords Select Committee TG was on the oversight group for the long Covid guideline at the National Institute for Health and Clinical Excellence, and at the time of writing is on the UKs National Long Covid Task Force.

KP and CC have no competing interests to declare.


title: Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2

abstract: While antibodies provide significant protection from SARS-CoV-2 infection and disease sequelae, the specific attributes of the humoral response that contribute to immunity are incompletely defined. In this study, we employ machine learning to relate characteristics of the polyclonal antibody response raised by natural infection to diverse antibody effector functions and neutralization potency with the goal of generating both accurate predictions of each activity based on antibody response profiles as well as insights into antibody mechanisms of action. To this end, antibody-mediated phagocytosis, cytotoxicity, complement deposition, and neutralization were accurately predicted from biophysical antibody profiles in both discovery and validation cohorts. These predictive models identified SARS-CoV-2-specific IgM as a key predictor of neutralization activity whose mechanistic relevance was supported experimentally by depletion. Validated models of how different aspects of the humoral response relate to antiviral antibody activities suggest desirable attributes to recapitulate by vaccination or other antibody-based interventions.

category: allergy and immunology


title: Immune and metabolic beneficial effects of Beta 1,3-1,6 glucans produced by two novel strains of Aureobasidium pullulans in healthy middle-aged Japanese men: An exploratory study

abstract:
BackgroundImbalances in glucose and lipid metabolism in the background of a declining immune system, along with aging, make one prone to glucolipotoxicity-related diseases such as hepatic steatosis and to high risk of infection-related mortality, as with COVID-19, warranting a safe prophylactic measure to help regulate both metabolism and the immune system. Based on the beneficial effects of the AFO-202 strain of black yeast Aureobasidium pullulans-produced beta 1,3-1,6 glucan in balancing of blood glucose and immune enhancement, and that of the N-163 strain of the same species in lipid metabolism and immune modulation, in this pilot study, we have evaluated their specific benefits in healthy human subjects.

MethodsSixteen healthy Japanese male volunteers (aged 40 to 60 years) took part in this clinical trial. They were divided into four groups (n = 4 each): Group I consumed AFO-202 beta glucan (2 sachets of 1 g each per day), IA for 35 days and IB for 21 days; Group II consumed a combination of AFO-202 beta glucan (2 sachets of 1 g each) and N-163 beta glucan (1 sachet of 15 g gel each per day), IIA for 35 days and IIB for 21 days. Investigations for immune stimulation, anti-glycaemic, and anti-cholesterolemia biomarkers were undertaken in all four groups.

ResultsIn terms of metabolic control of glucose, the decrease in HbA1C and glycated albumin (GA) was significantly better in Group I compared with the other groups. Immune enhancement in terms of a significant increase of eosinophils and monocytes and marginal decrease in D-dimer levels, decrease in neutrophil-to-lymphocyte ratio (NLR), with an increase in the lymphocyte-to-CRP ratio (LCR) and leukocyte-to-CRP ratio (LeCR) was observed in Group I. Regulation of lipids by decrease in total and LDL cholesterol was better in Group II, and immunomodulation of coagulation-associated and anti-inflammatory markers by a decrease of CD11b, serum ferritin, galectin-3, fibrinogen was profound in Group II.

ConclusionA. pullulans, a polythermotolerant black yeast - produced AFO-202 beta glucan has balanced blood glucose with marginal immune enhancement in healthy individuals, which when combined with N-163 beta glucan, balanced the lipid profile and immunomodulation. This outcome warrants larger clinical trials to understand the mechanisms and explore the potentials of these safe food supplements in prevention and prophylaxis of diseases due to dysregulated glucose and lipid metabolism, such as fatty liver disease, and infections such as COVID-19 in which a balanced immune activation and immunomodulation are of utmost importance, besides their administration as an adjunct to existing therapeutic approaches of both communicable and non-communicable diseases.

category: endocrinology


title: SARS-CoV-2 Breakthrough Infections among the Healthcare Workers Post-Vaccination with ChAdOx1 nCoV-19 Vaccine in the South Indian State of Kerala.

abstract:
ObjectiveThe national COVID-19 vaccination campaigns in India, prioritized healthcare workers to be vaccinated with ChAdOx1 nCoV-19 (AZD1222). So, we aimed to ascertain the effectiveness of ChAdOx1 nCoV-19 vaccine among the healthcare workers by characterizing the breakthrough infections which occurred 14 days after the second dose of the vaccine.

MethodsWe prospectively evaluated the  Institutional Covid Vaccination Database to categorize the SARS-CoV-2 positive healthcare workers into 2 cohorts: infected vaccinated and infected unvaccinated cohort. Along with comparing the descriptive statistics of the cohorts, the relative risk (RR), relative risk reduction (RRR), and the vaccine effectiveness were calculated. The study population was compared for the significant difference by using the parametric model (binary logistic regression) for the Odds ratio and the non-parametric model (cox proportionality model) for the Hazard ratio.

ResultsOut of the 324 healthcare workers employed in our institution 243 (75%) were vaccinated. When 6.58% (16) of the vaccinated healthcare workers were tested positive, 43.75% (35) were infected in the unvaccinated cohort and the median time of infection in the vaccinated cohort was 65 days (range 20 -91 days). While the cox proportionality model reveals that the age, sex, and the contact exposure status of the cohort are not significant factors for getting infected after being vaccinated, binary logistic regression proves that a significant relationship exists between the incidence of infection and the unvaccinated status (p = 0.001, OR = 4.278). Completing the two-dose of vaccination decreased the hazard of testing positive for the SARS-CoV-2 by 84.96 % when compared with the unvaccinated individuals, which is the effectiveness of the ChAdOx1 nCoV-19 vaccine.

ConclusionThere is an increased risk of the third wave of COVID-19 infection in the upcoming months. So, primary infection control measures should be followed even if vaccinated, to prevent the risk of breakthrough infections.

category: epidemiology


title: Associations of behavioral problems and white matter properties of the cerebellar peduncles in boys and girls born full term and preterm

abstract: Accumulating evidence suggests that the role of cerebellum includes regulation of behaviors; Cerebellar impairment may lead to behavioral problems. Behavioral problems differ by sex: internalizing problems are more common in girls, externalizing problems in boys. Behavioral problems are also elevated in children born preterm (PT) compared to children born full-term (FT). The current study examined internalizing and externalizing problems in 8-year-old children in relation to sex, birth-group, FA of the cerebellar peduncles, and interactions among these predictor variables. Participants (N=78) were 44 boys (28 PT) and 34 girls (15 PT). We assessed behavioral problems via standardized parent-reports and FA of the cerebellar peduncles using deterministic tractography. Internalizing problems were higher in children born PT compared to children born FT (p=.032); the interaction of sex and birth-group was significant (p=.044). When considering the contribution of the mean-tract FA of cerebellar peduncles to behavioral problems, there was a significant interaction of sex and mean-tract FA of the ICP with internalizing problems; the slope was negative in girls (p=.020) but not boys. In boys, internalizing problems were only associated with mean-tract FA ICP in those born preterm (p=.010). We found no other significant associations contributing to internalizing or externalizing problems. Thus, we found sexual dimorphism and birth-group differences in the association of white matter metrics of the ICP and internalizing problems in school-aged children. The findings inform theories of the origins of internalizing behavioral problems in middle childhood and may suggest approaches to treatment at school age.

category: pediatrics


title: Clinical pneumonia in the hospitalised child in Malawi in the post-pneumococcal conjugate vaccine era: a prospective hospital-based observational study

abstract:
ObjectiveAssess characteristics of clinical pneumonia after introduction of pneumococcal conjugate vaccine (PCV), by HIV exposure status, in children hospitalized in a governmental hospital in Malawi.

Methods and findingsWe evaluated 1,139 children [≤]5 years old hospitalised with clinical pneumonia: 101 HIV-exposed uninfected (HEU) and 1038 HIV-unexposed, uninfected (HUU). Median age was 11 months (IQR 6-20), 59% were male, median mid-upper arm circumference (MUAC) was 14 cm (IQR 13-15) and mean weight-for-height z score was -0.7 ({+/-}2.5). The highest Respiratory Index of Severity in Children (RISC) scores were allocated to 10.4% of the overall cohort, respectively. Only 45.7% had fever, and 37.2% had at least one danger sign at presentation. The most common clinical features were crackles (54.7%), nasal flaring (53.5%), and lower chest wall indrawing (53.2%). Compared to HUU, HEU children were significantly younger (9 months v. 11 months), with lower mean birth weight (2.8 kg v. 3.0 kg) and MUAC (13.6 cm v. 14.0 cm), had higher prevalence of vomiting (32.7% v. 22.0%), tachypnoea (68.4% v. 49.8%), and highest RISC scores (20.0% v. 9.4%). Five children died (0.4%). However, clinical outcomes were similar for both groups.

ConclusionsIn this post-PCV setting where prevalence of HIV and malnutrition is high, children hospitalised fulfilling the WHO Integrated Management of Childhood Illness criteria for clinical pneumonia present with heterogeneous features. These vary by HIV exposure status but this does not influence either the frequency of danger signs or mortality. The poor performance of available severity scores in this population and the absence of more specific diagnostics hinder appropriate antimicrobial stewardship and the rational application of other interventions.

Strengths and limitations of the studyO_LIWe evaluated over 1,100 children hospitalized with pneumonia in a low-income country setting after introduction of PCV.
C_LIO_LIThis observational cohort was nested within a prospective hospital-based study of PCV13 effectiveness
C_LIO_LIWe assessed the demographic and clinical characteristics of clinical pneumonia patients and compared HEU vs. HUU children, and computed RISC scores for severe pneumonia
C_LI


title: Genetic variants associated with cross-disorder and disorder-specific risk for psychiatric disorders are enriched at epigenetically active sites in peripheral lymphoid cells

abstract: Multiple psychiatric disorders have been associated with abnormalities in both the innate and adaptive immune systems. The role of these abnormalities in pathogenesis, and whether they are driven by psychiatric risk variants, remains unclear. We tested for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), or 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. We used three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) were enriched at epigenetically active sites in brain tissues and in lymphoid cells (T, B and NK cells), especially stimulated CD4+ T cells. There was no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a model where stimuli (e.g. infection) activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.

category: psychiatry and clinical psychology


title: Metabolomic and Inflammatory Signatures of Symptom Dimensions in Major Depression

abstract:
BackgroundMajor depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions.

MethodsUsing three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism.

ResultsThe IMD clinical dimension and the inflammatory index were positively correlated (r=0.19, p=.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids.

ConclusionThe IMD dimension of depression is reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.


title: Breastfeeding Practices Among Mothers During COVID-19 in India

abstract:
IntroductionThe Covid-19 pandemic is disrupting normal life globally. The COVID-19 pandemic is an emerging concern regarding the potential effects during breastfeeding. The aim of this study was to conduct a systemic review of mother-to -child transmission of COVID-19 during breastfeeding.

MethodThis study systematically searched electronic databases; google scholar, PubMed, Medline, up December 2020. The study was included studies relevant to transmission breast milk and respiratory droplets during breastfeeding of mothers with COVID-19 positive. To identify the quality of data, prism standard was used and Strobe checklist scale.

ResultA total of 3160 records were identified in this systemic review with eight relevant studies involving 159 mothers (63 mothers with COVID-19 positive, 55 of their breast milk samples tested negative for the-Covid-19. Twenty-one breast milk samples from 8 women tested positive for Covid-19. Of 73 infants were born to mothers with COVID-19 at the time of delivery. Two infants tested positive for Covid-19. The average mother-child separation time was 36*7 {+/-} 21*1 days among mothers confirmed with COVID-19. Out of 22 mothers, ((37.5%) chose to breastfeed their babies after confirm covid-19 positive.

ConclusionThis study shown that breastfeeding practices were extremely impacted during the COVID-19 epidemic among both confirmed positive cases and suspected mothers. However, the risk of mother-to-infant transmission of Covid-19 vertically or horizontally, in the perinatal period is very low.

category: public and global health


title: Green spaces, especially forest, linked to lower SARS-CoV-2 infection rates: A one-year nationwide study

abstract: This study examined the associations between green spaces and one-years worth of SARS-CoV- 2 infection rates across all 3,108 counties in the contiguous United States after controlling for multiple categories of confounding factors. We found green spaces at the county level have a significant negative association with infection rates. Among all types of green spaces, forest yields the most consistent and strongest negative association. Sensitivity analyses confirmed the negative association of forest across five urbanicity levels, and the strength of the association increases as disease incidence increases across five time periods. Although forest located in moderately urbanized counties yields the strongest association, the negative pattern of significant associations holds across all five urbanicity levels. A population-weighted analysis revealed that proximity to forest within a moderate walking distance ([≤] 1.0-1.4 km) may provide the greatest protection against the risk of infection.


title: Precision of Mammogram and USG based evaluation of NAST response in breast cancer and its impact on oncoplastic surgery decisions

abstract:
BackgroundPrecise prediction of residual tumour size following neoadjuvant systemic therapy for breast cancer is crucial in assessing response and surgical decision making. Our study is aimed at assessing the performance of conventional imaging modalities like ultrasound and mammography in predicting the residual tumour size after neoadjuvant systemic therapy and in evaluating the impact of imaging on the surgical outcomes.

MethodsWe retrospectively compared the tumour size measured by ultrasonography and mammography and the residual tumour size on final histopathology in 109 patients. Concordance was defined as a size difference within 25% of the histopathology size. We also looked at the distribution of concordance between different T status and molecular subtypes, accuracy of USG in predicting pathological complete response and axillary lymph nodal metastasis and also surgical outcomes in the discordant cases.

ResultsThe concordance rates of mammography and ultrasonography were 68.2% and 52.3% respectively without statistically significant difference between the two modalities (p = 0.081). Combination of both the modalities had a concordance rate of 57.8%. Ultrasonography had accuracy of 81.7% for predicting pathological complete response and 79.8% for predicting axillary nodal metastasis. We did not identify any influence of histologic subtype on the associations between preoperative measurements and pathology size or the accuracy for detecting pathological complete response (p values 0.43 and 0.46 respectively). In 12 cases, the radiology-pathology discordance could have led to large excision volume surgeries. In the overall cohort, recurrence free survival and overall survival rates at median follow up of 19.1 month were 87.2% and 95.4% respectively.

ConclusionsUltrasound and mammography showed moderate concordance with pathology for estimation of the residual tumour size without any significant difference in the performance between the two. Despite the moderate concordance, surgical outcomes were fairly well managed in the discordant cases with the oncoplastic surgical techniques. Our study highlights the usefulness of the cheaper and widely available conventional imaging modalities in the developing countries where the cost of treatment is to be contained.

category: radiology and imaging


title: Deep Learning-Based Magnetic Resonance Imaging Lung Segmentation and Volumetric Marker Extraction in Preterm Infants

abstract:
Objective and Impact StatementWe apply a deep learning (DL) segmentation method and automate the extraction of imaging markers for neonatal lung structure using magnetic resonance imaging (MRI) in order to inform clinical care with robust and quantifiable information about the neonatal lung.

IntroductionQuantification of lung structural information in a standardized fashion is crucial to inform diagnostic processes that enable personalized treatment and monitoring strategies. Increased efficiency and accuracy in image quantification is especially needed in prematurely born infants, for whom long-term survival is critically determined by acute and chronic pulmonary complications, currently diagnosed based on clinical criteria due to the lack of routinely applicable diagnostic tools.

MethodsWe prospectively enrolled 107 premature infants in two clinical centers with and without chronic lung disease, i.e., Bronchopulmonary Dysplasia (BPD) to perform quiet-breathing lung MRI. An ensemble of deep convolutional neural networks was developed to perform lung segmentation, with a subsequent reconstruction of the 3-dimensional lung and computation of MRI volumetric measurements and compared to the standard manual segmentation.

ResultsThe DL model successfully annotates lung segments with a volumetric dice score of 0.908 (Site 1) and 0.880 (Site 2), thereby reaching expert-level performance while demonstrating high transferability between study sites and robustness towards technical (low spatial resolution, movement artifacts) and disease conditions. Estimated lung volumes correlated with infant lung function testing measures and enabled the separation of neonates with and without BPD. Conclusion: Our work demonstrates the potential of AI-supported MRI measures to perform monitoring of neonatal lung development and characterization of respiratory diseases in this high-risk patient cohort.


title: Development of an online Langerian mindfulness program for stroke survivors and caregivers

abstract:
BackgroundMindfulness is promising for individuals with neurological disorders and their caregivers to improve psychological well-being. The potential application of a Langerian mindfulness intervention, focused on attention to variability, however, is still unknown.

ObjectiveTo determine the feasibility (usability, satisfaction, and potential effectiveness on psychological well-being) of an online mindfulness intervention for stroke survivors and caregivers.

MethodologyUsing mixed-methods, 11 stroke survivors and 3 caregivers participated in a 3-week, online, Langerian mindfulness intervention. A semi-structured interview assessed the interventions usability and gathered feedback. Self-reported measures about psychological well-being were documented remotely three times (pre, post, one-month follow-up).

ResultsQualitatively, participants were highly satisfied with the intervention, reported subjective benefits, but the usability of the online platform was poor. None of the self-reported measures changed over time.

ConclusionThis study provided evidence of feasibility of an online Langerian mindfulness intervention in a new population: stroke survivors and caregivers.

category: rehabilitation medicine and physical therapy


title: Feasibility of an online Langerian mindfulness program for stroke survivors and caregivers


title: Physiological pattern of cognitive aging

abstract: The effect of aging on cognition in cognitively healthy adult populations remains poorly investigated. Given that cognition evolves in time and thus, during aging, and becomes eroded in several disorders, some of which have recently acquired biological definitions, it is imperative to understand the process of cognitive aging. To determine the association of aging with cognitive performance in a cognitively healthy population, we studied cognitive performance in population-based cohort of 673 adults (aged 25-89). We found a gradual decline in cognitive performance across the lifespan, which requires two decades to demonstate significant change. This age-related decline was not significantly altered by either gender or education. These findings contribute to understand cognitive aging and provide essential data on physiological cognition for more precise diagnostics and timely intervention of early changes in cognition.

category: neurology


title: Distribution of rare LOXL1 missense alleles, haplotypes and diplotypes suggests association with reduced risk of glaucoma-related exfoliation syndrome.

abstract:
PurposeCommon LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele has been associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study was to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States.

MethodsLOXL1 rare (minor allele frequency less than 1%) variants were identified from Humanexome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls. Distribution of rare variants, haplotypes (defined using IMPUTE2) and diplotypes were examined using the Fishers exact test. Rare variant allele distribution was confirmed in an independent set of primary open angle glaucoma (POAG) controls and multi-ethnic datasets. Correlation of LOXL1 common allele homozygosity with disease risk used data from gnomAD (gnomad.broadinstitute.org/) and an existing multi-ethnic meta-analysis.

ResultsFour rare LOXL1 missense alleles were identified, and all were more common in controls (combined P= 7.6E-4), with two of these located in a LOXL1 intrinsic disordered region (IDR) known to be involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases (OR= 0.33, P=1.7E-8). Heterozygous diplotypes were significantly associated with reduced risk overall (OR= 0.45 P= 1.7 E-89) with the largest effects observed for diplotypes with more than one heterozygous genotype (OR= 0.05, P= 1.0E-39). A homozygous diplotype was associated with increased disease risk (OR= 6.8, P= 4.7E-157) and homozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (Pearson= 0.92, P<0.001).

ConclusionsUsing exome array data from XFS/XFG cases and controls from the United States, we identify 4 rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes are associated with reduced risk of XFS/XFG. The diplotype results also demonstrate that LOXL1 allelic heterozygosity is protective while homozygosity is associated with increased disease risk. These results suggest that LOXL1 minor allele frequency variation among populations, with corresponding variation in genotype heterozgyosity and homozygosity, determines the XFS/XFG association effects and that genotypic effects may also impact protein aggregation involving intrinsic disordered regions.


title: Injection Drug use Practices and HIV infection among People Who Inject Drugs in Kigali, Rwanda.

abstract:
BackgroundIn Rwanda, epidemiological data characterizing people who inject drugs (PWID) and their burden of HIV are limited. We examined injecting drug use (IDU) history, practices, and HIV infection in a sample of PWID in Kigali.

MethodsFrom October 2019-February 2020, 322 PWID aged [≥]18 were enrolled in a cross-sectional study using convenience sampling in Kigali. Participants underwent a structured interview and HIV testing. We used Poisson regression with robust variance estimation to assess IDU practices associated with HIV infection.

ResultsThe median age was 28 years(IQR:24-31) and 81%(248) were male. The median age at first injection was 23 years (IQR:20-27). HIV prevalence was 9.5%(95%CI:8.7-9.3).

In the six months preceding the study, heroin was the primary drug of choice for 99%(303); but cocaine and methamphetamine were also reported by 10%(31) and 4%(12) respectively. Furthermore, 31%(94) and 33%(103) of participants, shared or reused needles in the previous six months, respectively. Up to 43%(133) knew someone who died from a drug-related overdose. PWID reporting sharing needles at least half the time in the previous six months had increased likelihood of HIV-infection, compared to those who did not (aPR: 2.67; 95%CI:1.23-5.78).

ConclusionHIV infection was common in this sample of PWID in Kigali. The high prevalence of needle reuse and sharing practices highlight significant risk for onward transmission and acquisition of HIV and hepatitis B and C. PWID-focused harm reduction services, including needle and syringe programs, safer injection education, naloxone distribution, and substance use disorder treatment programs, are needed in Rwanda.

category: hiv aids


title: Aberrant stromal tissue factor and mycolactone-driven vascular permeability, exacerbated by IL-1β, orchestrate pathogenic fibrin formation in Buruli ulcer lesions

abstract:
The neglected tropical disease Buruli ulcer, caused by Mycobacterium ulcerans infection, displays coagulative necrosis in affected skin tissues. We previously demonstrated that exposure to the M. ulcerans exotoxin mycolactone depletes the expression of thrombomodulin and impacts anticoagulation at the endothelial cell surface. Moreover, while widespread fibrin deposition is a common feature of BU lesions, the cause of this phenotype is not clear. Here, we performed sequential staining of serial tissue sections of BU patient biopsies and unbiased analysis of up to 908 individual non-necrotic vessels of eight BU lesions to investigate its origins. Most vessels showed evidence of endothelial dysfunction being thrombomodulin-negative, von Willebrand factor-negative and/or had endothelium that stained positively for tissue factor (TF). Primary haemostasis was rarely evident by platelet glycoprotein CD61 staining. Localisation of TF in these lesions was complex and aberrant, including diffuse staining of the stroma some distance from the basement membrane and TF-positive infiltrating cells (likely eosinophils). This pattern of abnormal TF staining was the only phenotype that was significantly associated with fibrin deposition, and its extent correlated significantly with the distance that fibrin deposition extended into the tissue. Hence, fibrin deposition in Buruli ulcer lesions is likely driven by the extrinsic pathway of coagulation. To understand how this could occur, we investigated whether clotting factors necessary for fibrin formation might gain access to the extravascular compartment due to loss of the vascular barrier. In vitro assays using primary vascular and lymphatic endothelial cells showed that mycolactone increased the permeability of monolayers to dextran within 24 hours. Moreover, co-incubation of cells with interleukin-1{beta} exacerbated mycolactones effects, nearly doubling the permeability of the monolayer compared to each challenge alone. We propose that leaky vascular and lymphatic systems are important drivers of extravascular fibrin deposition, necrosis and oedema frequently seen in Buruli ulcer patients.

Author SummaryTo date, the debilitating skin disease Buruli ulcer remains a public health concern and financial burden in low or middle-income countries, especially in tropical regions. Late diagnosis is frequent in remote areas, perhaps due to the painlessness of the disease. Hence patients often present with large, destructive opened ulcers leading to delayed wound closure or even lifelong disability. The infectious agent produces a toxin called mycolactone that drives the disease. We previously found evidence that the blood clotting system is disrupted by mycolactone in these lesions, and now we have further explored potential explanations for these findings by looking at the expression of coagulation regulators in BU. In detailed analysis of patient skin punch biopsies, we identified distinct expression patterns of certain proteins and found that tissue factor, which initiates the so-called extrinsic pathway of blood clotting, is particularly important. Mycolactone is able to disrupt the barrier function of the endothelium, further aggravating the diseased phenotype, which explains how clotting factors access the tissue. Altogether, such localised hypercoagulation in Buruli ulcer skin lesions may contribute to the development of the lesion.


title: A booster dose is immunogenic and will be needed for older adults who have completed two doses vaccination with CoronaVac: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial

abstract:
ImportanceWhether herd immunity through mass vaccination is sufficient to curb SARS-CoV-2 transmission requires an understanding of the duration of vaccine-induced immunity, and the necessity and timing of booster doses. Objective: To evaluate immune persistence of two priming doses of CoronaVac, and immunogenicity and safety of a third dose in healthy adults [≥]60 years. Design, setting, and participants: We conducted a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of the two-dose schedule of CoronaVac among healthy adults[≥]60 years in Hebei, China. We examined neutralizing antibody titres six months or more after the second dose in all participants. We provided a third dose to 303 participants recruited in phase 2 trial to assess their immune responses.

InterventionsTwo formulations (3 g, and 6 g) were used in phase 1 trial, and an additional formulation of 1.5 g was used in phase 2 trial. All participants were given two doses 28 days apart and followed up 6 months after the second dose. Participants in phase 2 received a third dose 8 months after the second dose.

Main outcomes and measuresGeometric mean titres (GMT) of neutralizing antibodies to live SARS-CoV-2 and adverse events were assessed at multiple time points following vaccination.

ResultsNeutralizing antibody titres dropped below the seropositive cutoff of 8 at 6 months after the primary vaccination in all vaccine groups in the phase 1/2 trial. A third dose given 8 months or more after the second dose significantly increased neutralizing antibody levels. In the 3 g group (the licensed formulation), GMT increased to 305 [95%CI 215.3-432.0] on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose. All solicited adverse reactions reported within 28 days after a booster dose were of grade 1 or 2 severity.

Conclusion and relevanceNeutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. This evidence could help policymakers determine the necessity and the timing of a booster dose for older adults.

Trial registrationClinicalTrials.gov (NCT04383574).


title: Safety and Immunogenicity of CpG 1018 and Aluminium Hydroxide-Adjuvanted SARS-CoV-2 S-2P Protein Vaccine MVC-COV1901: A Large-Scale Double-Blinded, Randomised, Placebo-Controlled Phase 2 Trial

abstract:
BackgroundWe have assessed the safety and immunogenicity of the COVID-19 vaccine MVC-COV1901, a recombinant protein vaccine containing prefusion-stabilized spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide.

MethodsThis is a phase 2, prospective, randomised, double-blind, placebo-controlled, and multi-centre study to evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-2 vaccine candidate MVC-COV1901. The study comprised 3,844 participants of [≥] 20 years who were generally healthy or with stable pre-existing medical conditions. The study participants were randomly assigned in a 6:1 ratio to receive either MVC-COV1901 containing 15 g of S-2P protein or placebo containing saline. Participants received two doses of MVC-COV1901 or placebo, administered 28 days apart via intramuscular injection. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from Day 1 (the day of first vaccination) to Day 57 (28 days after the second dose). Immunogenicity of MVC-COV1901 was assessed through geometric mean titres (GMT) and seroconversion rates (SCR) of neutralising antibody and antigen-specific immunoglobulin. This clinical trial is registered at ClinicalTrials.gov: NCT04695652.

FindingsFrom the start of this phase 2 trial to the time of interim analysis, no vaccine-related Serious Adverse Events (SAEs) were recorded. The most common solicited adverse events across all study participants were pain at the injection site (64%), and malaise/fatigue (35%). Fever was rarely reported (<1%). For all participants in the MVC-COV1901 group, at 28 days after the second dose against wild type SARS-CoV-2 virus, the GMT was 662{middle dot}3 (408 IU/mL), the GMT ratio was 163{middle dot}2, and the seroconversion rate was 99{middle dot}8%.

InterpretationMVC-COV1901 shows good safety profiles and promising immunogenicity responses. The current data supports MVC-COV1901 to enter phase 3 efficacy trials and could enable regulatory considerations for Emergency Use Authorisation (EUA).

FundingMedigen Vaccine Biologics Corporation and Taiwan Centres for Disease Control.


title: Accessory Genomes Drive Independent Spread of Carbapenem-Resistant Klebsiella pneumoniae Clonal Groups 258 and 307

abstract:
BackgroundCarbapenem-resistant Klebsiella pneumoniae (CRKp) are urgent public health threats. Worldwide dissemination of CRKp has been largely attributed to the clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, Texas is the first large city in the US with co-circulation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307.

MethodsCRKp isolates were collected as part of the prospective, Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacterales 2 (CRACKLE-2) study. Hybrid short-read and long-read genome assemblies were generated from 119 CRKp isolates (95 originated from Houston hospitals). A comprehensive characterization of phylogenies, gene transfer, and plasmid content with pan-genome analysis were performed on all CRKp isolates. Plasmid mating experiments were performed with CG307 and CG258 isolates of interest. An inverse-probability weighted Desirability of Ordinal Outcome Ranking (DOOR) analysis was conducted to determine if patients infected/colonized with CG307 had differences in overall clinical outcomes from patients infected/colonized with CG258.

ResultsDissection of the accessory genomes suggested independent evolution and limited horizontal gene transfer between CG307 and CG258 lineages. CG307 contained a diverse repertoire of mobile genetic elements harboring carbapenemases, which were shared with other non-CG258 K. pneumoniae isolates. Three unique clades of Houston CG307 isolates contained a diverse repertoire of mobile genetic elements harboring carbapenemases and clustered distinctly from other global CG307 isolates. CG307 were often isolated from the urine of hospitalized patients, likely serving as important reservoirs for genes encoding carbapenemases and extended-spectrum beta-lactamases. The DOOR probability estimate (64%; 95% CI: 48, 79) of our Houston-based cohort suggested that there was a general trend for patients infected/colonized with CG307 to have more favorable outcomes than patients infected/colonized with CG258.

ConclusionsOur findings suggest parallel co-circulation of high-risk lineages with potentially divergent evolution. CG307 is widely circulating CRKp clone in the Houston region with the potential to transfer major resistance determinants to other non-CG258 CRKp lineages. Our findings provide major insights into the mechanism of epidemic spread of CRKp.


title: Automated ELISA on-chip for the detection of an-ti-SARS-CoV-2 antibodies

abstract: The COVID-19 pandemic has been the most critical public health issue in modern his-tory due to its highly infectious and deathly potential; and the limited access to massive, low-cost, and reliable testing has significantly worsened the crisis. The recovery and the vaccination of millions of people against COVID-19, have made serological tests highly relevant to identify the presence and levels of SARS-CoV-2 antibodies. Due to its advantages, microfluidic-based technologies represent an attractive alternative to the conventional testing methodologies used for these purposes. In this work, we describe the development of an automated ELISA on-chip capable of detecting anti-SARS-CoV-2 antibodies in serum samples from COVID-19 patients and vaccinated individuals. The colorimetric reactions were analyzed with a microplate reader. No statistically significant differences were observed when comparing the results of our automated ELISA on-chip against the ones obtained from a traditional ELISA on a microplate. Moreover, we demonstrated that it is possible to carry out the analysis of the colorimetric reaction by performing basic image analysis of photos taken with a smartphone, which constitutes a useful alternative when lacking specialized equipment or a laboratory setting. Our automated ELISA on-chip has the potential to be used in a clinical setting and mitigate some of the burden caused by testing deficiencies.


title: MAVS expression in alveolar macrophages is essential for host resistance against Aspergillus fumigatus

abstract: Our recent data demonstrates a critical role of the RIG-I-like receptor (RLR) family in regulating antifungal immunity against Aspergillus fumigatus in a murine model. However, the importance of this pathway in humans and the cell type(s) which utilize this innate immune receptor to detect A. fumigatus remains unresolved. Here using patients who underwent hematopoietic stem cell transplantation (HSCT), we demonstrate that a polymorphism in human MAVS present in the donor genome was associated with the incidence of invasive pulmonary aspergillosis (IPA). Moreover, in a separate cohort of confirmed IPA patients, polymorphisms in the IFIH1 gene alter the inflammatory response, including interferon-responsive chemokines. Returning to our murine model, we now demonstrate that CD11c+ SiglecF+ alveolar macrophages require Mavs expression to maintain host resistance against A. fumigatus. Our data support the role of MAVS signaling in mediating antifungal immunity in both mice and human at least in part through the role of MAVS-dependent signaling in alveolar macrophages.


title: Awake Prone Position in Hypoxemic Patients with Coronavirus Disease 19 (COVI-PRONE): A Study protocol and Statistical Analysis Plan for Randomized Clinical Trial

abstract:
BackgroundCoronavirus disease 2019 (COVID-19), may progress to respiratory failure requiring invasive mechanical ventilation. Due to ventilator shortage and healthcare systems strain, affordable interventions such as awake prone positioning has been used to improve oxygenation, however, the effect of this intervention on patient-important outcomes is uncertain. The COVI-PRONE trial aims to determine if awake prone positioning in hypoxemic COVID-19 patients reduces the need for invasive mechanical ventilation.

Study designA pragmatic, multicenter, international, parallel-group, and stratified randomized controlled trial, aiming to enrol 400 hospitalized adults with COVID-19.

ParticipantsThe target population is hospitalized adults with confirmed or suspected COVID-19, hypoxemia that requires [≥]40% oxygen or [≥] 5 L/min by nasal cannula, and abnormal chest x-ray. We will exclude patients with any of the following: immediate need for intubation; altered mental status; contraindication to prone positioning; hemodynamic instability; body mass index > 40 kg/m2; third trimester pregnancy; do not intubate status; previous enrolment or intubation within the same hospital admission; and prone positioning for more than one day prior to randomization.

Study intervention and controlFollowing informed a priori or deferred consent, eligible patients will be centrally randomized to either the intervention arm (prone positioning) or standard of care (no prone positioning). Patients randomized to the prone position will be required to either self-prone or assist-prone for a total of eight to ten hours per day until they meet pre-specified stopping criteria.

Study outcomesThe primary outcome is invasive mechanical ventilation at 30-days of randomization. Other outcomes include mortality at 60 days, invasive and non-invasive mechanical ventilation free days at 30 days, hospital length of stay at 60 days, days alive and outside of the hospital at 60 days, complications of proning, and serious adverse events.

category: intensive care and critical care medicine


title: Development and utilization of a surrogate SARS-CoV-2 viral neutralization assay to assess mRNA vaccine responses.

abstract:
BackgroundTests for SARS-CoV-2 immunity are needed to help assess responses to vaccination, which can be heterogeneous and may wane over time. The plaque reduction neutralization test (PRNT) is considered the gold standard for measuring serum neutralizing antibodies but requires high level biosafety, live viral cultures and days to complete. We hypothesized that competitive enzyme linked immunoassays (ELISAs) based on SARS-CoV-2 spike proteins receptor binding domain (RBD) attachment to its host receptor, the angiotensin converting enzyme 2 receptor (ACE2r), would correlate with PRNT, given the central role of RBD-ACE2r interactions in infection and published studies to date, and enable evaluation of vaccine responses.

Methods and FindingsConfiguration and development of a competitive ELISA with plate-bound RBD and soluble biotinylated ACE2r was accomplished using pairs of pre/post vaccine serum. When the competitive ELISA was used to evaluate N=32 samples from COVID-19 patients previously tested by PRNT, excellent correlation in IC50 results were observed (rs= .83, p < 0.0001). When the competitive ELISA was used to evaluate N=41 vaccinated individuals and an additional N=14 unvaccinated recovered COVID-19 patients, significant differences in RBD-ACE2r inhibitory activity were associated with prior history of COVID-19 and type of vaccine received. In longitudinal analyses pre and up to 200 days post vaccine, surrogate neutralizing activity increased markedly after primary and booster vaccine doses, but fell substantially, up to <12% maximal levels within 6 months.

ConclusionsA competitive ELISA based on inhibition of RBD-ACE2r attachment correlates well with PRNT, quantifies significantly higher activity among vaccine recipients with prior COVID (vs. those without), and highlights marked declines in surrogate neutralizing activity over a 6 month period post vaccination. The findings raise concern about the duration of vaccine responses and potential need for booster shots.


title: Prevalence and Factors Associated with Behavioural Problems in 5-year-old Children Born with Cleft Lip and/or Palate from the Cleft Collective

abstract:
ObjectivesWe determined the prevalence of behavioural problems in 5-year-old children born with Cleft Lip and/or Palate (CL/P) and compared it to the prevalence in general population samples. We also identified risk factors for behavioural problems in children with CL/P.

DesignObservational study using questionnaire data from the Cleft Collective (CC) 5-Year-Old cohort study and three general population samples.

Main Outcome MeasureThe Strengths and Difficulties Questionnaire (SDQ) was used to measure behavioural problems.

ParticipantsA total of 340 children born with CL/P whose mothers had completed the SDQ when their child was 5 years old. Published estimates from three large cohorts were used to approximate general population SDQ scores in the UK and these were used as comparison groups; Millennium Cohort Study (MCS) (n=12,511), Office of National Statistics (ONS) normative school-age SDQ data (n=5,855) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=9,386).

ResultsAn estimated 14.3% of 5-year-old children born with CL/P experienced behavioural problems. There was strong evidence to suggest children with CL/P were more likely to experience difficulties than children in the general population, as measured by SDQ total difficulties scores from all three population cohorts: MCS (OR = 2.07 [95% CI = 1.50-2.85]; P<.001), ONS Norms (OR = 1.53 [95% CI = 1.12-2.11]; P=.008), and ALSPAC (OR = 2.37 [95% CI = 1.72-3.27]; P<.001). The odds of hyperactivity, emotional, prosocial and peer problems were increased among children in the Cleft Collective compared with children in the Millennium Cohort Study. Odds ratios and 95% confidence intervals indicated that children in the Cleft Collective were nearly twice as likely as those in the MCS (OR = 1.91 [95% CI = 1.38-2.65]; P<.001) and three times those in ALSPAC (OR = 3.20 [95% CI = 2.29-4.47]; P<.001) to experience emotional difficulties. The odds of emotional difficulties were higher in boys than girls. Maternal smoking, marital status, younger maternal age at conception, lower maternal education, receiving income support, and measures of poor maternal and familial health showed some evidence of association with behavioural problems in 5-year-old children born with CL/P.

ConclusionsOur findings suggest elevated levels of behavioural problems in children born with CL/P, particularly emotional difficulties in boys, compared to the general population and indicate several factors associated observationally with these difficulties.

category: dentistry and oral medicine


title: Islet autoantibody level distributions in type 1 diabetes and their association with genetic and clinical characteristics

abstract:
Positivity for islet autoantibodies is used for diagnosis of type 1 diabetes. However, the importance of the autoantibody level at diagnosis of type 1 diabetes is not clear. Here, we assessed the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) autoantibody levels, measured using radiobinding assays, on genetic and clinical characteristics at diagnosis of 1536 participants with diabetes who were positive for these autoantibodies. We show that GADA and IA-2A levels had bimodal distributions, but ZnT8A level did not. The comparison of genetic and clinical characteristics between high and low level categories showed high GADA level was associated with older age at diagnosis, female sex and HLA-DR3-DQ2, whereas high IA-2A level was associated with younger age of diagnosis, ZnT8A positivity and HLA-DR4-DQ8. We replicated our findings in an independent cohort of 427 people with type 1 diabetes where autoantibodies were measured using enzyme-linked immunosorbent assays. In conclusion, Islet autoantibody levels provide additional information over positivity in type 1 diabetes at diagnosis. The bimodality of islet autoantibody levels highlights the novel aspect of heterogeneity of type 1 diabetes which may have implications on prediction, treatment and prognosis.

Islet autoantibodies are commonly used in the diagnosis and prediction of type 1 diabetes. They are well established as the biomarkers of the underlying autoimmune pathogenesis (1). Autoantibodies to islet cell antigen (ICA), glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), insulin (IAA) and zinc transporter 8 (ZnT8A) are the most commonly used islet autoantibodies at diagnosis (2). As detectable islet autoantibodies overlap between health and disease, a test is usually considered positive for a given islet autoantibody when the antibody level is higher than a 97.5-99th centile of a control population (3; 4). In routine clinical practice, quantitative islet autoantibody results are usually interpreted as positive or negative, and the level of the islet autoantibody, is not thought to be clinically meaningful.

Islet autoantibody levels may provide additional information over positivity in type 1 diabetes at diagnosis. Similar to type 1 diabetes, autoantibodies to a specific antigen are commonly used for diagnosis in many other autoimmune diseases (such as TSH receptor antibodies in Graves disease and Rheumatoid Factor and Citrullinated Protein in rheumatoid arthritis). For Graves disease and rheumatoid arthritis, along with autoantibody positivity for these antigens, autoantibody level at diagnosis is associated with disease severity, prognosis and treatment success (5; 6). Multiple studies have shown a role for islet autoantibody level in the prediction of onset of type 1 diabetes, those with a higher levels of IA-2A, IAA and ICA have an increased risk of developing type 1 diabetes in at-risk populations (1; 7-9). However, it is not clear if the islet autoantibody level at diagnosis of type 1 diabetes, in addition to its interpretation as  positive, is associated with the clinical phenotype similar to other autoimmune diseases.

In this study, we undertook an analysis of GADA, IA-2A and ZnT8A levels at diagnosis in a large cohort of participants with type 1 diabetes, assessing the association of islet autoantibody levels on genetic and clinical characteristics at diagnosis in people with type 1 diabetes.


title: Accelerometer-Derived and Genetically Inferred Physical Activity and Human Disease

abstract: Physical activity is favorable to health but the relations with human disease and causal effects are poorly quantified. Previous studies have largely relied on self-reported estimates1-3 which are subject to recall bias, confounding, and reverse causality. Using wrist-worn accelerometer measurements from the UK Biobank, we tested associations between moderate-to-vigorous physical activity (MVPA) - both total MVPA minutes and whether MVPA was above a guideline-based threshold of [≥]150 minutes/week4-6 - and incidence of over 1,200 diseases. In 96,466 adults who wore accelerometers for one week (mean age 62{+/-}8 years), MVPA was associated with 401 (33%) tested diseases at a false discovery rate of 1% during a median of 6.2 years follow-up. Greater MVPA was overwhelmingly associated with reduced disease risk (98% of associations) with hazard ratios (HRs) ranging from 0.10-0.95 per standard deviation (SD) and associations spanning all 18 disease categories tested. A similar pattern of associations was observed when assessing the guideline-based threshold of [≥]150 MVPA minutes/week. We examined a polygenic risk score for MVPA as an instrumental variable for activity within a separate UK Biobank sample (N=392,058, mean age 57{+/-}8 years). Greater genetically inferred MVPA was associated with reduced risk of 182 (14%) incident diseases (HR range 0.74-0.97 per 1 SD), and included strong associations conferring reduced risks of obstructive bronchitis, peripheral vascular disease, type 2 diabetes, and gastritis/duodenitis. Objective physical activity is broadly associated with lower disease incidence and many associations are consistent with a causal effect.


title: Classifying RSNA Abstracts with Deep Learning

abstract:
BackgroundThe Radiological Society of North America (RSNA) receives more than 8000 abstracts yearly for scientific presentations, scientific posters, and scientific papers. Each abstract is assigned manually one of 16 top-level categories (e.g. "Breast Imaging") for workflow purposes. Additionally, each abstract receives a grade from 1-10 based on a variety of subjective factors such as style and perceived writing quality. Using machine learning to automate, at least partially, the categorization of abstract submissions can result in saving many hours of manual labor.

MethodsA total of 45527 RSNA abstract submissions from 2014 through 2019 were ingested, tokenized, and pre-processed with a standard natural language programming protocol. A bag-of-words (BOW) model was used as a baseline to evaluate two more sophisticated models, convolutional neural networks and recurrent neural networks, and also evaluate an ensemble model featuring all three neural networks.

Resultsensemble model was able to achieve 73% testing accuracy for classifying the 16 top-level categories, outperforming all other models. The top model for classifying abstract grade was also an ensemble model, achieving a mean average error (MAE) of 1.01.

ConclusionWhile the baseline BOW model was the highest performing individual classifier, ensemble models that included state-of-the-art neural networks were able to outperform it. Our research shows that machine learning techniques can, to a reasonable degree of accuracy, predict both objective factors such as abstract category as well as subjective factors such as abstract grade. This work builds upon previous research involving using natural language processing on scientific abstracts to make useful inferences that address a meaningful problem.


title: Classifying Radiology Abstracts with Deep Learning


title: Occupational risk of SARS-CoV-2 infection and reinfection during the second pandemic surge: a cohort study.

abstract:
ObjectivesThis cohort study including essential workers, assessed the{square}risk and incidence of SARS-CoV-2{square}infection during the second surge of COVID-19 according to baseline serostatus and occupational sector.

MethodsEssential workers were selected from a seroprevalence survey cohort in Geneva, Switzerland and were linked to a state centralized registry compiling SARS-CoV-2 infections. Primary outcome was the number of virologically-confirmed infections from serological assessment (between May and September 2020) to January 25, 2021, according to baseline antibody status and stratified by three pre-defined occupational groups (occupations requiring sustained physical proximity, involving brief regular contact or others). Secondary outcomes included the incidence of infection.

Results10457 essential workers were included (occupations requiring sustained physical proximity accounted for 3057 individuals, those involving regular brief contact, 3645, and 3755 workers were classified under "Other essential occupations"). After a follow-up period of over 27 weeks, 5 (0.6%) seropositive and 830 (8.5%) seronegative individuals had a positive SARS-CoV-2 test, with an incidence rate of 0.2 (95% CI 0.1 to 0.6) and 3.2 (95% CI 2.9 to 3.4) cases per person-week, respectively. Incidences were similar across occupational groups. Seropositive essential workers had a 93% reduction in the hazard (HR of 0.07, 95% CI 0.03 to 0.17) of having a positive test during follow-up with no significant between-occupational group difference.

ConclusionsA ten-fold reduction in the hazard of being virologically tested positive was observed among anti-SARS-CoV-2 seropositive essential workers regardless of their sector of occupation, confirming the seroprotective effect of a previous SARS-CoV2 exposure at least six months after infection.

Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSRisk of SARS-CoV-2 reinfection is low in the general population and among healthcare workers.

What are the new findings?A ten-fold reduction of risk of being virologically tested positive reinfection is observed among anti-SARS-CoV-2 seropositive essential workers of different activity sectors, regardless of their occupation-related risk of exposure.

How might this impact on policy or clinical practice in the foreseeable future?Vaccination could be delayed in individuals with previous history of SARS-CoV-2 infection with serologic confirmation, regardless of their occupational exposure. These observations need to be confirmed for new SARS-CoV-2 variants.

category: occupational and environmental health


title: Association of VEGF and KDR polymorphisms with the development of schizophrenia

abstract:
AimSeveral approaches indicate different blood flow disturbances in schizophrenia (Scz). Vascular endothelial growth factor (VEGF) is widely recognized as one of the key molecules implicated in the angiogenesis process through mainly its receptor KDR. The current work was designed to investigate the potential association between three polymorphisms (rs699947; rs833061 and rs3025039) in VEGF gene and two SNPs (rs2305948 and rs1870377) within KDR gene and predisposition to Scz among the Tunisian population.

MethodsWe carried-out a case-control study composed of 200 schizophrenic patients and 200 healthy subjects using RFLP-PCR.

ResultsOf all analyzed polymorphisms, only rs3025039, rs833061 and rs1870377 showed a significant risk for Scz. Following the stratified analysis, rs833061 was more prevalent among undifferentiated form. Yet, rs1870377 was especially correlated with paranoid subtype. We found also that rs699947 and rs833061 had an impact on patients symptomatology. Haplotype analysis unveiled a strong LD between rs833061 and rs3025039 only for undifferentiated patients. Moreover, the -2578/-460/+936 CTT haplotype, with only one mutated allele +936T, conferred a high risk to Scz and, in particular, to undifferentiated and paranoid forms. Among the last-mentioned subgroup, we noticed another overrepresented haplotype (ATT). Furthermore, the +1192/+1719 GT haplotype carrying the minor allele +1719T displayed increased frequencies in schizophrenics as well as in paranoid patients.

ConclusionOur results show that all SNPs associated with the development or the severity of schizophrenia, were subsequently correlated with a decrease in the VEGF levels or influence VEGFR-2 binding affinity. Nevertheless, these data need to be strengthened by further independent analyses.

category: genetic and genomic medicine


title: Did Low Risk Perception Mediate the COVID-19 Second Wave in Bangladesh? A Cross-sectional Study on Risk Perception and Preventive Practice

abstract:
ObjectiveThis study assessed the risk perception and preventive behavioral practice towards COVID-19 just prior to the second wave of corona, as well as the impact of perceived risk on preventive practices.

Design, setting, participants, and outcome measuresA cross-sectional study was conducted between December 2020 and January 2021, involving 1382 respondents aged 18 years and above from all eight divisions in Bangladesh. We used multiple linear regression to identify sociodemographic predictors of risk perception and multiple logistic regression to determine the relationship between risk perception and preventive practice.

ResultsLow risk perception regarding COVID-19 was present among one-fifth of the respondents (19.8%). Younger age, being male, low education, single marital status, and rural residence were significantly associated with a low perceived risk of COVID-19. Hand washing and wearing mask were practiced by 80% and 67% of respondents, respectively. A low prevalence was noticed for social distancing (31%), avoiding social gathering (31%), and covering face while coughing/sneezing (18%). Furthermore, respondents with a high risk perception were found to be more likely than those with a low risk perception to practice all recommended COVID-19 preventive behaviors-hand washing (OR=2.4, 95% CI=1.5, 3.7), mask use (OR=3.4, 95% CI=2.3, 5), social distancing (OR=3.7, 95% CI=2.4, 5.6), sanitizer use (OR=2.7, 95% CI=1.8, 4.1), avoiding gathering (OR=2.3, 95% CI=1.6, 3.5), avoid touching face and mouth (OR=2.8, 95% CI=1.5, 5.3), and covering mouth while coughing/sneezing (OR=7, 95% CI=3.6, 13.4).

ConclusionConsiderable number of Bangladeshi adults had low risk perception and low practice of some vital COVID-19 preventive behaviors before the onset of second wave of corona. All preventive practices were also influenced by respondents risk perception. This highlights the importance of strengthening and optimizing risk communication strategy even when the number of corona cases are low.

STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIThe study explored the perceived risk and preventive practices for COVID-19 in Bangladesh right before the recent onset COVID-19 second wave in the South Asian region, and included a larger sample size than previous studies.
C_LIO_LIUnlike most other studies on COVID-19 risk perception that used online surveys, this study administered a face-to-face data collection from both urban and rural settings across all the eight divisions of Bangladesh.
C_LIO_LIThis is the first study in Bangladesh that investigated the effect of perceived risk of COVID-19 on the practice of a range of preventive behaviors, and used an analytical approach to quantify risk perception.
C_LIO_LIRespondents self-reported information on COVID-19 preventive behavior practice is subject to be influenced by recall and desirability bias.
C_LIO_LIThe study was unable to explore the respondents frequency and adherence to preventive practices, as well as the influence of psychological factors on preventive behaviors.
C_LI


title: The Impact of Climate Change on the Prevalence of Mental Illness Symptoms

abstract:
BackgroundThe repercussions of climate change threaten the population with an increased prevalence of extreme climate events. We explored the impact of climate change induced sea level rise (SLR) and tropical cyclone (TC) exposure on mental illness symptom prevalence.

MethodsUsing three datasets, TC exposure scores were calculated for each subject to determine how exposure affects posttraumatic stress disorder (PTSD), anxiety, and major depressive disorder (MDD) symptom prevalence. Inundation mapping of various SLR and storm surge (SS) scenarios were performed for the susceptible region of Miami-Dade and Broward counties to determine the population impact of flooding.

ResultsWe found an elevated risk of mental illness symptoms from exposure to more high-intensity TCs and identified demographic variables that may contribute to this risk. Furthermore, inundation mapping demonstrated severe and widespread impact of SLR and SS on the mental health of communities.

LimitationsThis study did not include data directly measuring comorbidity, resilience, preparedness, or ability to adapt to climate change. Also, multiple imputation using chained equations may have been imperfect. Finally, when conducting inundation mapping, static mapping may overestimate flooding severity.

ConclusionThe impacts of climate change have been frequently studied in terms of physical health, natural disaster prevalence, and economic impacts, but rarely on mental health burden. However, it is vital that national, state, and local governments develop and deploy plans to address mental health needs along with expenditures for protecting infrastructure, the economy, and physical health from the combined effects of SLR and climate change-induced natural disasters.


title: Evaluating Semantic Similarity Methods for Comparison of Text-derived Phenotype Profiles

abstract: Semantic similarity is a valuable tool for analysis in biomedicine. When applied to phenotype profiles derived from clinical text, they have the capacity to enable and enhance  patient-like me analyses, automated coding, differential diagnosis, and outcome prediction, by leveraging the wealth of background knowledge provided by biomedical ontologies. While a large body of work exists exploring the use of semantic similarity for multiple tasks, including protein interaction prediction, and rare disease differential diagnosis, there is less work exploring comparison of patient phenotype profiles for clinical tasks. Moreover, there are no experimental explorations of optimal parameters or methods in the area. In this work, we develop a reproducible platform for benchmarking experimental conditions for patient phentoype similarity. Using the platform, we evaluate the task of ranking shared primary diagnosis from uncurated phenotype profiles derived from text narrative associated with admissions in MIMIC-III. In doing this, we identify and interpret the performance of a large number of semantic similarity measures for this task, and provide a basis for further research on related tasks in the area.

category: health informatics


title: Ongoing mitigation strategies and further needs of the United States food industry to control COVID-19 in the work environment

abstract: The COVID-19 pandemic has had dire effects on the United States (US) food industry through impacts on workers health and wellbeing and supply chain disruptions. The objectives of this study were to determine what the food industry needs to be able to control COVID-19 impacts in the work environment and what mitigation strategies are being implemented. A web-based needs assessment survey was distributed from January to April 2021, via 13 food professional/trade organizations and 2 social networks, targeting management professionals at food (produce, dairy, poultry, and beef/pork) processing facilities and produce farm operations in the US. Statistical analyses evaluated patterns in self-reported adoption of mitigation strategies against COVID-19 in the participants facilities/operations and perceived needs of the industry regarding COVID-Responses to open-ended questions were analyzed using thematic analysis. In total 145 responses were received, of which 79 were usable, including 38 (48%) from the dairy, 17 (22%) from the fresh produce, and 24 (30%) from a mixture of other food industry sectors. Only two usable responses were from the beef/pork sector and none from the poultry sector. Findings revealed that several social distancing, biosecurity, and surveillance mitigation strategies against COVID-19 are commonly implemented in the participants facilities/operations, but their implementation frequency differs by the facility/operation size and industry sector. Also, findings indicated that collaboration between the food industry and government agencies, contingency plans and appropriate training, and new technologies are needed to control COVID- 19 in the food industry. Subject to limitations associated with the relatively low response rate (possible selection bias), the findings suggest that the US food industry is prepared to safeguard workers health and businesses in the event of a new COVID-19 variant or similar future disaster, provided that appropriate structures are put in place to ensure coordination and compliance, both before and during such an outbreak.


title: The effect of eye protection on SARS-CoV-2 transmission: a systematic review

abstract:
BackgroundThe effect of eye protection to prevent SARS-CoV-2 infection in the real-world remains uncertain. We aimed to synthesize all available research on the potential impact of eye protection on transmission of SARS-CoV-2.

MethodsWe searched PROSPERO, PubMed, Embase, The Cochrane Library for clinical trials and comparative observational studies in CENTRAL, and Europe PMC for pre-prints. We included studies that reported sufficient data to estimate the effect of any form of eye protection including face shields and variants, goggles, and glasses, on subsequent confirmed infection with SARS-CoV-2.

FindingsWe screened 898 articles and included 6 reports of 5 observational studies from 4 countries (USA, India, Columbia, and United Kingdom) that tested face shields, googles and wraparound eyewear on 7567 healthcare workers. The three before-and-after and one retrospective cohort studies showed statistically significant and substantial reductions in SARS-CoV-2 infections favouring eye protection with odds ratios ranging from 0.04 to 0.6, corresponding to relative risk reductions of 96% to 40%. These reductions were not explained by changes in the community rates. However, the one case-control study reported odds ratio favouring no eye protection (OR 1.7, 95% CI 0.99, 3.0). The high heterogeneity between studies precluded any meaningful meta-analysis. None of the studies adjusted for potential confounders such as other protective behaviours, thus increasing the risk of bias, and decreasing the certainty of evidence to very low.

InterpretationCurrent studies suggest that eye protection may play a role in prevention of SARS-CoV-2 infection in healthcare workers. However, robust comparative trials are needed to clearly determine effectiveness of eye protections and wearability issues in both healthcare and general populations.

FundingThere was no funding source for this study. All authors had full access to all data and agreed to final manuscript to be submitted for publication.


title: Follow the Money: A Closer Look at US Tobacco Industry Marketing Expenditures

abstract:
IntroductionWhile much of the concern with tobacco industry marketing has focused on direct media advertising, a less explored form of marketing strategy is to discount prices. Price discounting is important because it keeps the purchase price low and can undermine the impact of tax increases.

MethodsWe examine annual marketing expenditures from 1975 to 2019 by the largest cigarette and smokeless tobacco companies. We consider three categories: direct advertising, promotional allowances, and price discounting. In addition to considering trends in these expenditures, we examine how price discounting expenditures relate to changes in product prices and excise taxes.

ResultsUS direct advertising expenditures for cigarettes fell from 80% of total industry marketing expenditures in 1975 to less than 3% in 2019, while falling from 39% in 1985 to 6% in 2019 for smokeless tobacco. Price-discounting expenditures for cigarettes became prominent after the Master Settlement Agreement and related tax increases in 2002. By 2019, 87% of cigarette marketing expenditures were for price discounts and 7% for promotional allowances. Smokeless marketing expenditures were similar: 72% for price promotions and 13% for promotional allowances. Price discounting increased with prices and taxes until reaching their currently high levels.

ConclusionsWhile much attention focuses on direct advertising, other marketing practices, especially price discounting, has received less attention. Local, state and federal policies that use non-tax mechanisms to increase tobacco prices and restrict industry contracts with retailers are needed to offset/disrupt industry marketing expenditures. Further study is needed to better understand industry decisions about marketing expenditures.

Key pointsO_LIWhile much of the concern with tobacco industry marketing has focused on direct media advertising, a less explored form of marketing strategy is to discount prices. Price discounting is important because it keeps the purchase price low and can undermine the impact of tax increases, contributing to tobacco initiation and exacerbating socio-economic health disparities.
C_LIO_LIWhile cigarette and smokeless tobacco industry direct marketing expenditures have drastically fallen over time, price-discounting expenditures have dramatically increased in line with increases in prices and taxes.
C_LIO_LILocal, state and federal policies that restrict non-tax mechanisms to increase tobacco prices and restrict industry contracts with retailers are needed to offset/disrupt industry marketing expenditures.
C_LI


title: COVID-19 in Brazilian children and adolescents: findings from 21 hospitals

abstract:
IntroductionChildren and adolescents with Covid-19 have been shown lower mortality less intense symptoms when compared to adults, but studies in Brazil have been based on the compulsory notifying system only.

ObjectiveTo analyse clinical, laboratory, radiological characteristics and outcomes of hospitalized patients under 20 years with Covid-19.

MethodsCases series of hospitalized patients with confirmed Covid-19 under 20 years, obtained from a cohort study in 37 hospitals from five states of Brazil.

ResultsFrom 36 patients, 20 (55.5%) were adolescentes, 20 (55.5%) were male, 18 (50.0%) had comorbidities, 2 were pregnant and in 7 (19.4%), initial symptoms occurred during hospitalization for other causes, of whom 3 were possibly infected in the hospital. Fever (61.1%), dyspnea (33.3%) and neurological symptoms (33.0%) were the most common complaints. C-reactive protein was higher than 50mg/L in 16.7% and D-dimer was above the reference limit in 22.2%. Chest X-rays were performed in 20 (55.5%) patients, 9 had abnormalities, and chest tomography in 5. Hospital length of stay ranged from 1-40 days (median 5 [interquartile range 3-10]), 16 (44.4%) needed intensive therapy, 6 (16.7%) required mechanical ventilation and one patient (2.8%) died.

ConclusionIn case series patients under 20 years from hospitals from 5 states of Brazil, comorbidities were frequent, and most common symptoms were fever, dyspnea and neurological symptoms. Forty-four percent required intensive therapy, showing that the disease was not as mild as it was expected, and one patient died.


title: Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination

abstract: The high prevalence of post-acute sequelae of SARS-CoV-2 infection (PASC) is a significant health concern. In particular, virus-specific immunity in patients who suffer from chronic neurologic symptoms after acute SARS-CoV-2 infection remain poorly understood. Here, we report that Neuro-PASC patients have a specific immunological signature composed of humoral and cellular responses that are biased towards different SARS-CoV-2 structural proteins compared to healthy COVID convalescents, including a significant elevation in Nucleocapsid-specific antibody and T cell responses. Interestingly, the severity of cognitive deficits or quality of life markers in Neuro-PASC patients are associated with reduced effector molecule expression in memory T cells. Furthermore, we demonstrate a sustained elevation in T cell responses to SARS-CoV-2 mRNA vaccines in Neuro-PASC patients compared with healthy COVID convalescents. These data provide a framework for the rational design of predictive biomarkers and therapeutics for long COVID syndrome.


title: SARS-CoV-2 vaccine effectiveness in immunosuppressed kidney transplant recipients

abstract: COVID-19 vaccine protection against infection in immunosuppressed solid organ transplant recipients is unknown but possibly weak with the low proportion of these patients mounting a robust humoral and cellular immune response after vaccination. Using a retrospective cohort study design with cross-over, we assessed vaccine effectiveness among 782 kidney transplant recipients registered at Hamad Medical Corporation, the national public healthcare provider in Qatar, where the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines have been used in the national immunization campaign. Vaccine effectiveness against any SARS-CoV-2 infection was estimated at 46.6% (95% CI: 0.0-73.7%) [≥]14 days after the second dose, 66.0% (95% CI: 21.3-85.3%) [≥]42 days after the second dose, and 73.9% (95% CI: 33.0-89.9%) [≥]56 days after the second dose. Vaccine effectiveness against any severe, critical, or fatal COVID-19 disease was estimated at 72.3% (95% CI: 0.0-90.9%) [≥]14 days after the second dose, 85.0% (95% CI: 35.7-96.5%) [≥]42 days after the second dose, and 83.8% (95% CI: 31.3-96.2%) [≥]56 days after the second dose. Most vaccine breakthrough infections occurred in the first few weeks after receiving the first and/or second dose. Vaccine effectiveness reached considerable levels in kidney transplant recipients, but vaccine protection mounted slowly and did not reach a high level until several weeks after the second dose.