title: Inflight Transmission of COVID-19 Based on Aerosol Dispersion Data

abstract:
BackgroundAn issue of concern to the travelling public is the possibility of in-flight transmission of COVID-19 during long- and short-haul flights. The aviation industry maintain the probability of contracting the illness is small based on reported cases, modelling and data from aerosol dispersion experiments conducted on-board aircraft.

MethodsUsing experimentally derived aerosol dispersion data for a B777-200 aircraft and a modified version of the Wells-Riley equation we estimate inflight infection probability for a range of scenarios involving quanta generation rate and face mask efficiency. Quanta generation rates were selected based on COVID-19 events reported in the literature while mask efficiency was determined from the aerosol dispersion experiments.

ResultsThe MID-AFT cabin exhibits the highest infection probability. The calculated maximum individual infection probability (without masks) for a 2-hour flight in this section varies from 4.5% for the "Mild Scenario" to 60.2% for the "Severe Scenario" although the corresponding average infection probability varies from 0.1% to 2.5%. For a 12-hour flight, the corresponding maximum individual infection probability varies from 24.1% to 99.6% and the average infection probability varies from 0.8% to 10.8%. If all passengers wear face masks throughout the 12-hour flight, the average infection probability can be reduced by approximately 73%/32% for high/low efficiency masks. If face masks are worn by all passengers except during a one-hour meal service, the average infection probability is increased by 59%/8% compared to the situation where the mask is not removed.

ConclusionsThis analysis has demonstrated that while there is a significant reduction in aerosol concentration due to the nature of the cabin ventilation and filtration system, this does not necessarily mean that there is a low probability or risk of in-flight infection. However, mask wearing, particularly high-efficiency ones, significantly reduces this risk.


title: Pregnancy and neonatal outcomes of COVID-19, co-reporting of common outcomes from the PAN-COVID and AAP SONPM registry

abstract:
BackgroundFew large, cohort studies report data on individuals maternal, fetal, perinatal, and neonatal outcomes associated with SARS-CoV-2 infection in pregnancy. We report outcomes from a collaboration formed early during the pandemic between the investigators of two registries, the UK and global Pregnancy and Neonatal outcomes in COVID-19 (PAN-COVID) study and the US American Academy of Pediatrics Section on Neonatal Perinatal Medicine (AAP SONPM) National Perinatal COVID-19 Registry.

MethodsPAN-COVID (suspected or confirmed SARS-CoV-2 infection at any stage in pregnancy) and the AAP SONPM registry (positive maternal testing for SARS-CoV-2 from 14 days before delivery to 3 days after delivery) studies collected data on maternal, fetal, perinatal and neonatal outcomes. PAN-COVID results are presented as all inclusions and those with confirmed SARS-CoV-2 infection only.

ResultsWe report 4004 women in pregnancy affected by suspected or confirmed SARS-CoV-2 infection (1606 from PAN-COVID and 2398 from the AAP SONPM) from January 1st 2020 to July 25th 2020 (PAN-COVID) and August 8th (AAP SONPM). For obstetric outcomes in PAN-COVID and AAP SONPM, respectively, maternal death occurred in 0.5% and 0.17%, early neonatal death in 0.2% and 0.3%, and stillbirth in 0.50% and 0.65% of women. Delivery was pre-term (<37 weeks gestation) in 12% of all women in PAN-COVID, in 16.2% of those women with confirmed infection in PAN-COVID and 16.2% of women in AAP SONPM. Very preterm delivery (< 27 weeks gestation) occurred in 0.6% in PAN-COVID and 0.7% in AAP SONPM.

Neonatal SARS-CoV-2 infection was reported in 0.8% of PAN-COVID all inclusions, 2.0% in PAN-COVID confirmed infections and 1.8% in the AAP SONPM study; the proportions of babies tested were 9.5%, 20.7% and 87.2% respectively.

The proportion of SGA babies was 8.2% in PAN-COVID all inclusions, 9.7% in PAN-COVID confirmed infection and 9.6% in AAP SONPM. Gestational age adjusted mean z-scores were -0.03 for PAN-COVID and -0.18 for AAP SONPM.

ConclusionsThe findings from the UK and US SARS-CoV-2 in pregnancy registries were remarkably concordant. Pre-term delivery affected a higher proportion of women in pregnancy than expected from historical and contemporaneous national data. The proportions of women affected by stillbirth, small for gestational age infants and early neonatal death were comparable to historical and contemporaneous UK and US data. Although maternal death was uncommon, the proportion was higher than expected from UK and US population data, likely explained by under-ascertainment of women affected by milder and asymptomatic infection in pregnancy. The data presented support strong guidance for enhanced precautions to prevent SARS-COV-2 infection in pregnancy, particularly in the context of increased risks of preterm delivery and maternal mortality, and for priority vaccination of women planning pregnancy.

What is known about SARS-COV-2 infection in pregnancy and neonates?Cohort, population surveillance studies and living systematic reviews have included limited numbers of women in pregnancy affected by COVID-19 and report that most women and infants had good outcomes.

What this study addsPreterm deliveries occurred in a high proportion of women participating in these two registries in comparison to contemporaneous and historical national data in the UK and US. The majority of preterm deliveries occurred late preterm (between 32+0 and 36+6 weeks gestation).

SARS-COV-2 infection in pregnancy did not appear to be associated with a clinically significant effect on the rate of stillbirth, fetal growth, or neonatal outcomes.

Although maternal death was uncommon, the proportion was higher than expected from UK and US population data, likely explained by under-ascertainment of women affected by milder and asymptomatic infection in pregnancy.

category: obstetrics and gynecology


title: HeAlth System StrEngThening in four sub_Saharan African countries (ASSET) to achieve high-quality, evidence-informed surgical, maternal and newborn, and primary care: protocol for pre-implementation phase studies

abstract:
ObjectivesTo achieve universal health coverage, health systems need to be strengthened to support the consistent delivery of high-quality, evidence-informed care at scale. The aim of the National Institute for Health Research (NIHR) Global Research Unit on HeAlth System StrEngThening in Sub-Saharan Africa (ASSET) is to address this need in a four-year programme spanning three healthcare platforms (primary health care for the integrated treatment of chronic conditions in adults, maternal and newborn, surgical care) involving eight work packages. This paper describes the pre-implementation phase research protocols that assess: (1) barriers to accessing care; (2) health system bottlenecks in care process and pathways; (3) quality of care, and; (4) people centredness. Findings from this research are used to engage stakeholders and to inform the selection of a set of health system strengthening interventions (HSSIs) and subsequent methodology for evaluation.

SettingsPublicly funded health systems in rural and urban areas in Ethiopia, Sierra Leone, South Africa, and Zimbabwe.

PopulationStakeholders including patients and their caregivers, community representatives, clinicians, managers, administrators, and policymakers.

Study methodologies and deliveryIn each work package, we apply a mixed-methods approach, including: literature reviews; situation analyses; cohort studies; cross-sectional surveys; ethnographic observations; semi-structured interviews, and; focus group discussions. At the end of the pre-implementation phase, findings are fed back to stakeholders in participatory theory of change workshops that are used to select/adapt an initial set of contextually relevant HSSIs. To ensure a theory-informed approach across ASSET, implementation science determinant frameworks are also applied, to help identify any additional contextual barriers and enablers and complementary HSSIs. Outputs from these activities are used to finalise underlying assumptions, potential unintended consequences, process indicators and implementation and clinical outcomes.

ConclusionsASSET places a strong emphasis of the pre-implementation phase of the programme in order to provide an in-depth and systematic diagnosis of the existing heath system functioning, needs for strengthening and active stakeholder engagement. This approach will inform the design and evaluation of the HSSIs to increase effectiveness across work packages and contexts, to better understand what works, for whom, and how.

Strengths and limitations of this studyO_LIThe National Health Institute of Research (NIHR) Global Research Unit on Health System Strengthening in sub-Saharan Africa (ASSET) is a four-year programme (2017-2021) that is closely aligned with the SDG goal of UHC, and the recommendations of the Lancet Commission for High Quality Health Systems.
C_LIO_LIThe aim of ASSET is to develop and evaluate effective and sustainable HSSIs, promoting consistent delivery of high-quality, people-centred care.
C_LIO_LIThe ASSET programme is being conducted in two phases including the diagnostic pre-implementation and piloting/rolling implementation phase.
C_LIO_LIThe purpose of this paper is to describe the methodology for the pre-implementation phase, which has the core aim of mapping comprehensive care pathways of a patients journey though the health system including the community, different providers), and health facilities, documenting what care is provided at what level of the health system and the associated health system bottlenecks.
C_LIO_LIAt the end of the pre-implementation phase of ASSET, it is hoped the common approach taken across different countries, care platforms and health conditions will facilitate cross platform learning and understanding of how differences in health systems and broader contextual influences shaped the development of the interventions.
C_LIO_LIThe overarching expectation is that by using an in-depth participatory process to engage with the stakeholders and map care pathways to and through the health system, we develop a HSS programme that can be implemented at scale that meets the needs and priorities of the local community.
C_LI

category: health systems and quality improvement


title: Combining science and social engagement againstCovid-19 in a Brazilian Slum

abstract:
ObjectivesFor many underdeveloped countries, strategies implemented by social communities allied to scientific knowledge may be a rote to attenuate the rapid spread of Covid-19 cases and allow services to the population. This work presents a joint effort collaboration between scientists and underserved community groups from a Brazilian slum/Santa Marta in Rio de Janeiro City in the fight against Covid-19. Measurements of contamination in the air near the ground, georeferencing of data of infected people, were regressed with sanitization activities aiming at reducing the Covid-19 incidence.

MethodsWe monitored aerosol containing SARS-Cov-2 virus in outdoor ambient air using various virus collection mediums (solid, liquid, and gelatinous substrates) at different aerodynamic sizes. We implemented a local statistics survey for the Covid-19 database correlated with varying sanitization levels between April 2020 and June 2021 developed in the Santa Marta slum.

FindingsWe detected the SARS-CoV-2 virus in the air near the ground in diameters ranging from 0.25 to 0.5 {micro}m, demonstrating that there is a circulation of the virus in the slum atmosphere. We demonstrate that Covid-19 cases for the Santa Marta slum were significatively lowered with improved sanitization levels (r = -0.74).

ConclusionsDespite previous publications that discarded the use of sanitization as a relevant tool in the fight against Covid-19, our results suggest that profits can be achieved in mitigating Covid-19 in underserved community sites. Furthermore, a permanent sanitization activity may induce positive social behavior for the sake of combating Covid-19.

category: public and global health


title: How social engagement against Covid-19 in a Brazilian Slum helped mitigate rising statistics


title: The Conundrum of Giglio Island: unraveling the dynamics of an apparent resistance to COVID-19. A descriptive study

abstract:
ObjectivesDespite an extensive risk of exposure to COVID-19, the residents of Giglio Island, Italy, did not develop any symptom of SARS-CoV-2. The present study aims to characterize the nature of exposure and to describe the local population dynamics underlying its apparent resistance to COVID-19.

MethodsWe conducted seroprevalence screening from April 29 to May 3, 2020 across the three main settlements on the island. We invited the adult resident population, present on the island to undergo testing by rapid serologic assay and to provide a sample of saliva for molecular validation. We monitored the participation through the official municipality residents list. Serologic testing was performed using a COVID-19 IgG/IgM rapid test while molecular analyses were carried out by Allplex 2019-nCoV Assay (Seegene).

ResultsA total of 634 residents out of 748 (84.8%) present at the time, and 89 non-residents underwent serological testing. 364 males and 359 females with a median age of 58.5 years. The serological screening identified one positive, asymptomatic subject. The Nucleic Acid Amplification Tests did not yield any positive result.

ConclusionDespite extensive exposure to SARS-CoV-2, only one new asymptomatic infection occurred in this population. This may be due to unknown protective factors or chance. On the basis of this first descriptive study, using its population as a reference model, further investigations will be conducted to characterize the summer period exposure and to test the advanced hypotheses, focusing on the evaluation of a possible cross-reactivity to SARS-CoV-2 from exposure to endemic viruses.

category: epidemiology


title: Association of Inflammation with Depression and Anxiety: Evidence for Symptom-Specificity and Potential Causality from UK Biobank and NESDA Cohorts

abstract: We examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, circulating CRP was associated with depressive symptoms of depressed mood (OR=1.06, 95%CI=1.05-1.08), altered appetite (OR=1.25, 95%CI=1.23-1.28), sleep problems (OR=1.05, 95%CI=1.04-1.06), and fatigue (OR=1.12, 95%CI=1.11-1.14), and with anxiety symptoms of irritability (OR=1.06, 95%CI=1.05-1.08) and worrying control (OR=1.03, 95%CI=1.02-1.04). Further analyses in NESDA using IL-6 as exposure confirmed associations with depressive symptoms, including anhedonia (OR=1.30, 95%CI=1.12-1.52). Both CRP (OR=1.27, 95%CI=1.13-1.43) and IL-6 (OR=1.26, 95%CI=1.07-1.49) were associated with increased sleep. CRP was associated with increased appetite (OR=1.21, 95%CI=1.08-1.35) while IL-6 with decreased appetite (OR=1.45, 95%CI=1.18-1.79). In Mendelian Randomization analyses, increased risk of fatigue (estimate=0.25, SE=0.08) and sleep problems (estimate=0.19, SE=0.07) were associated with genetically-predicted higher IL-6 activity. Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms.

category: psychiatry and clinical psychology


title: Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

abstract: Cytokine storms and hyperinflammation, potentially controlled by glucocorticoids, occur in COVID-19; the roles of lipid mediators and acetylcholine (ACh) and how glucocorticoid therapy affects their release in Covid-19 remain unclear. Blood and bronchoalveolar lavage (BAL) samples from SARS-CoV-2- and non-SARS-CoV-2-infected subjects were collected for metabolomic/lipidomic, cytokines, soluble CD14 (sCD14), and ACh, and CD14 and CD36-expressing monocyte/macrophage subpopulation analyses. Transcriptome reanalysis of pulmonary biopsies was performed by assessing coexpression, differential expression, and biological networks. Correlations of lipid mediators, sCD14, and ACh with glucocorticoid treatment were evaluated. This study enrolled 190 participants with Covid-19 at different disease stages, 13 hospitalized non-Covid-19 patients, and 39 healthy-participants. SARS-CoV-2 infection increased blood levels of arachidonic acid (AA), 5-HETE, 11-HETE, sCD14, and ACh but decreased monocyte CD14 and CD36 expression. 5-HETE, 11-HETE, cytokines, ACh, and neutrophils were higher in BAL than in circulation (fold-change for 5-HETE 389.0; 11-HETE 13.6; ACh 18.7, neutrophil 177.5, respectively). Only AA was higher in circulation than in BAL samples (fold-change 7.7). Results were considered significant at P<0.05, 95%CI. Transcriptome data revealed a unique gene expression profile associated with AA, 5-HETE, 11-HETE, ACh, and their receptors in Covid-19. Glucocorticoid treatment in severe/critical cases lowered ACh without impacting disease outcome. We first report that pulmonary inflammation and the worst outcomes in Covid-19 are associated with high levels of ACh and lipid mediators. Glucocorticoid therapy only reduced ACh, and we suggest that treatment may be started early, in combination with AA metabolism inhibitors, to better benefit severe/critical patients.


title: The incremental value of computed tomography of COVID-19 pneumonia in predicting ICU admission

abstract:
RationaleTriage is crucial for patients management and estimation of the required Intensive Care Unit (ICU) beds is fundamental for Health Systems during the COVID-19 pandemic.

ObjectiveTo assess whether chest Computed Tomography (CT) of COVID-19 pneumonia has an incremental role in predicting patients admission to ICU.

MethodsWe performed volumetric and texture analysis of the areas of the affected lung in CT of 115 outpatients with COVID-19 infection presenting to the Emergency Room with dyspnea and unresponsive hypoxyemia. Admission blood laboratory including lymphocyte count, serum lactate dehydrogenase, D-dimer and C-Reactive Protein and the ratio between the arterial partial pressure of oxygen and inspired oxygen were collected. By calculating the areas under the receiver-operating characteristic curves (AUC), we compared the performance of blood laboratory-arterial gas analyses features alone and combined with the CT features in two hybrid models (Hybrid radiological and Hybrid radiomics)for predicting ICU admission. Following a machine learning approach, 63 patients were allocated to the training and 52 to the validation set.

Measurements and Main ResultsTwenty-nine (25%) of patients were admitted to ICU. The Hybrid radiological model comprising the lung %consolidation performed significantly (p=0.04) better in predicting ICU admission in the validation (AUC=0.82; 95%Confidence Interval 0.68-0.95) set than the blood laboratory-arterial gas analyses features alone (AUC=0.71; 95%Confidence Interval 0.56-0.86). A risk calculator for ICU admission was derived and is available at:https://github.com/cgplab/covidapp

ConclusionsThe volume of the consolidated lung in CT of patients with COVID-19 pneumonia has a mild but significant incremental value in predicting ICU admission.

category: radiology and imaging


title: Pregnancy Loss and Cardiovascular Disease: A Nationwide Cohort Study

abstract:
ObjectivesTo examine how pregnancy loss influences the risk of cardiovascular disease later in life.

DesignProspective historical cohort study.

SettingDanish nationwide health registries.

ParticipantsAll Danish women with a recorded pregnancy from 1977 to 2017.

Main outcome measuresVenous thromboembolism, myocardial infarction, or ischemic stroke.

ResultsIn this two-part study, part one evaluated the 20-year absolute risk of cardiovascular disease from age 40 among 596,699 women with a full registered reproductive history. Adjusting for calendar year, diabetes, autoimmune disease, live births, and education, the absolute risk of an outcome after 0 and [≥]4 pregnancy losses, respectably was: venous thromboembolism 3.0% (95% CI 2.8 to 3.2%) and 5.0% (3.4 to 6.8%); myocardial infarction 1.5% (1.4 to 1.6%) and 2.4% (1.4 to 3.6%); ischemic stroke 2.0% (1.9 to 2.1%) and 2.6% (1.5 to 3.6%). Prior stillbirth increased the absolute risk of later venous thromboembolism by 1.1% (0.2 to 2.3%); myocardial infarction by 1.1% (0.3 to 2.0%).

In study part two, we included 966,490 women from first pregnancy in a time-dependent Cox regression model. Adjusted for confounders, each additional pregnancy loss increased the hazard ratio of venous thromboembolism 1.10 (95% CI 1.07 to 1.13); myocardial infarction 1.12 (1.07 to 1.18); and ischemic stroke 1.10 (1.06 to 1.14). Stillbirth was strongly associated with myocardial infarction before age 40, adjusted hazard ratio of 4.60 (2.65 to 8.00).

ConclusionPregnancy loss was associated with later venous thromboembolism, myocardial infarction, and ischemic stroke. The absolute and relative risk of outcomes increased in a dose-response manner with increasing numbers of prior pregnancy losses. Stillbirth was strongly associated with myocardial infarction before age 40.


title: Polygenic Risk Scores for Alzheimer's Disease and Mild Cognitive Impairment in Hispanics/Latinos in the U.S: The Study of Latinos - Investigation ofNeurocognitive Aging

abstract:
IntroductionPolygenic Risk Score (PRS) are powerful summaries of genetic risk alleles that can potentially be used to predict disease outcomes and guide treatment decisions. Hispanics/Latinos suffer from higher rates of Alzheimers Disease (AD) and Mild Cognitive Impairment (MCI) compared to non-Hispanic Whites, yet the strongest known genetic risk factor for AD, APOE-{epsilon}4 allele, has weak association with AD in Hispanics/Latinos. We evaluated PRS constructed based on Genome-Wide Association Studies (GWAS) of AD in predicting MCI in Hispanics/Latinos when accounting for APOE alleles and variants.

MethodsWe used summary statistics from four GWAS of AD to construct PRS that predict MCI in 4,189 diverse Hispanics/Latinos (mean age 63 years, 47% males) from the Study of Latinos-Investigation of Neurocognitive Aging. We assessed the PRS associations with MCI in the combined set of people and in groups defined by genetic ancestry and Hispanic/Latino background, and when including and excluding single nucleotide polymorphisms (SNPs) from the APOE gene region.

ResultsA PRS constructed based on GWAS of AD in the FINNGEN Biobank was associated with MCI (OR = 1.34, 95% CI [1.15, 1.55]), and its association was mostly driven by 158 APOE region SNPs. A PRS constructed based on a multi-ethnic AD GWAS was associated with MCI (OR=1.22, 95% CI [1.08, 1.37]) without including any APOE region SNPs. APOE-{epsilon}4 and APOE-{epsilon}2 alleles were not associated with MCI.

DiscussionA combination of APOE region SNPs is associated with MCI in Hispanics/Latinos despite APOE-{epsilon}4 and APOE-{epsilon}2 alleles not being associated with MCI.

category: genetic and genomic medicine


title: BinomiRare: A carriers-only test for association of rare genetic variants with a binary outcome for mixed models and any case-control proportion

abstract: Whole genome and exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g. family or household) when testing genetic associations. However, no existing tests of the association of a rare variant association with a binary outcome in the presence of correlated data controls the Type 1 error where there are (1) few carriers of the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing the carriers-only test framework for testing rare variant association with a binary trait. In this framework, we estimate outcome probabilities under the null hypothesis, and then use them, within the carriers, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test, and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small vessel disease stroke, short sleep, and venous thromboembolism, in whole-genome sequence data from the Trans-Omics for Precision Medicine program.


title: The Effect of Temperature on Covid-19 Confirmed Cases: Evidence from US Counties

abstract:
This paper studies the effect of air temperature on the transmission of COVID-19 in the U.S. using daily observations across counties. This study uses various ordinary least squares (OLS) models with a comprehensive set of fixed effects to overcome unobserved heterogeneity issues across counties as well as the generalized method of moments (GMM) estimators as dynamic models to address endogeneity issue. Our main results indicate that an increase of one degree in temperature is associated with a reduction of 0.041 cases per 100,000 population at the county-level. We run several robustness tests and all the models confirm the impact of temperature on COVID-19 confirmed new cases. These results help policymakers and economists in optimizing decisions and investments to reduce COVID- 19 new cases.

JEL CodesI10; Q51; Q54; H12

category: health economics


title: How can the public health impact of vaccination be estimated?

abstract: Deaths due to vaccine preventable diseases cause a notable proportion of mortality worldwide. To quantify the importance of vaccination, it is necessary to estimate the burden averted through vaccination. The Vaccine Impact Modelling Consortium (VIMC) was established to estimate the health impact of vaccination. We describe the methods implemented by the VIMC to estimate impact by calendar year, birth year and year of vaccination (YoV). The calendar and birth year methods estimate impact in a particular year and over the lifetime of a particular birth cohort, respectively. The YoV method estimates the impact of a particular years vaccination activities through the use of impact ratios which have no stratification and stratification by activity type and/or birth cohort. Furthermore, we detail an impact extrapolation (IE) method for use between coverage scenarios. We compare the methods, focusing on YoV for hepatitis B, measles and yellow fever. We find that the YoV methods estimate similar impact with routine vaccinations but have greater yearly variation when campaigns occur with the birth cohort stratification. The IE performs well for the YoV methods, providing a time-efficient mechanism for updates to impact estimates. These methods provide a robust set of approaches to quantify vaccination impact.

category: infectious diseases


title: Tuberculosis biomarkers discovered using Diversity Outbred mice.

abstract:
BackgroundBiomarker discovery for pulmonary tuberculosis (TB) may be accelerated by modeling human genotypic diversity and phenotypic responses to Mycobacterium tuberculosis (Mtb). To meet these objectives, we use the Diversity Outbred (DO) mouse population and apply novel classifiers to identify informative biomarkers from multidimensional data sets.

MethodTo identify biomarkers, we infected DO mice with aerosolized Mtb confirmed a human-like spectrum of phenotypes, examined gene expression, and inflammatory and immune mediators in the lungs. We measured 11 proteins in 453 Mtb-infected and 29 non-infected mice. We have searched all combinations of six classification algorithms and 239 biomarker subsets and independently validated the selected classifiers. Finally, we selected two mouse lung biomarkers to test as candidate biomarkers of active TB, measuring their diagnostic performance in human sera acquired from the Foundation for Innovative New Diagnostics.

FindingsDO mice discovered two translationally relevant biomarkers, CXCL1 and MMP8 that accurately diagnosed active TB in humans with > 90% sensitivity and specificity compared to controls. We identified them through the two classifiers that accurately diagnosed supersusceptible DO mice with early-onset TB: Logistic Regression using MMP8 as a single biomarker, and Gradient Tree Boosting using a panel of 4 biomarkers (CXCL1, CXCL2, TNF, IL-10).

InterpretationThis work confirms that the DO population models human responses and can accelerate discovery of translationally relevant TB biomarkers.

FundingSupport was provided by NIH R21 AI115038; NIH R01 HL145411; NIH UL1-TR001430; and the American Lung Association Biomedical Research Grant RG-349504.


title: Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

abstract:
BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-{beta}-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking.

ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-{beta}-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients.

DesignOpen-label, randomized, adaptive, controlled trial.

SettingMulti-center trial with patients from France.

Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory support

InterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-{beta}-1a (44 g of subcutaneous IFN-{beta}-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days).

MeasurementsThe primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses.

ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-{beta}-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE.

LimitationsNot a placebo-controlled, no anti-inflammatory agents tested.

ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings.

RegistrationNCT04315948.

FundingPHRC 2020, Dim OneHealth, REACTing


title: Ivermectin as a potential treatment for mild to moderate COVID-19: A double blind randomized placebo-controlled trial

abstract:
ObjectiveIvermectin has been suggested as a treatment for COVID-19.This randomised control trial was conducted to test the efficacy of Ivermectin in the treatment of mild and moderate COVID-19.

DesignParallel, double blind, randomised, placebo controlled trial Setting: A tertiary care dedicated COVID-19 hospital in Bihar, India

ParticipantsAdult patients (> 18 years) admitted with mild to moderate COVID 19 disease (saturation > 90% on room air, respiratory rate < 30 and no features of shock) with no contraindications to ivermectin and willing to participate in the study

InterventionPatients in the intervention arm were given ivermectin 12 mg on day 1 and day 2 of admission. Patients in the placebo arm were given identical looking placebo tablets. Rest of the treatment was continued as per the existing protocol and the clinical judgment of the treating teams.

Outcome MeasuresThe primary outcome measure was a negative RT-PCR test for SARS-CoV-2 on day 6 of admission. The secondary outcome measures were symptom status on day 6, discharge status on day 10, admission to ICU, need for invasive mechanical ventilation and in-hospital mortality.

ResultsA total of 115 patients were enrolled for the study of which 112 were included in the final analysis. Of them, 55 were randomised to the intervention arm while 57 were randomised to the placebo arm. There was no significant difference in the baseline characteristics of the two arms. There was no significant difference in the primary outcome, i.e. negative RT-PCR status on day 6 between the two groups. Similarly, there was no significant difference between the two groups in most of the secondary outcome measures, viz. symptom status on day 6, discharge status on day 10, admission to ICU, and need for invasive mechanical ventilation. However, while there was no in-hospital mortality in the intervention arm, there were 4 deaths in the placebo arm. As a result, all patients in the intervention arm (n=56) were successfully discharged as compared to 93.1% (n=54/58) in the placebo arm (RR 1.1, 95% CI 1.0 to 1.2, p=0.019).

ConclusionThere was no difference in the primary outcome i.e. negative RT-PCR status on day 6 of admission with the use of ivermectin. However, a significantly higher proportion of patients were discharged alive from the hospital when they received ivermectin.

Strengths and Limitations of the StudyO_LIThis study was randomised and double blind, thereby minimizing the chance of bias.
C_LIO_LIAll outcome measures except symptom status on day 6 were objective and placebo control was used for comparison.
C_LIO_LIOnly single repeat RT-PCR was done. So median time to viral clearance in the two groups could not be calculated.
C_LIO_LISevere cases were not included in the study.
C_LI


title: MassMark: A Highly Scalable Multiplex NGS-based Method for High-Throughput, Accurate and Sensitive Detection of SARS-CoV-2 for Mass Testing

abstract: Mass testing has been proposed as a strategy to address and contain the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic1,2. We have developed MassMark, a novel and highly scalable multiplex method that employs next generation sequencing for high-throughput, accurate and sensitive detection of SARS-CoV-2, while minimizing handling complexity and resources by utilizing a serial pooling strategy to accommodate over 9,000 samples per workflow. Analytical validation showed that MassMark was able to detect SARS-CoV-2 RNA down to a level of 100 copies per reaction. We evaluated the clinical performance of MassMark in a simulated screening testing with 22 characterized samples from three different sources (nasopharyngeal swabs, nasal swabs and saliva), comprising of 12 SARS-CoV-2 positive samples with mid to late Ct values (range: 22.98-32.72) and 10 negative samples. There was one false negative and no false positives, giving an overall sensitivity and specificity of 91.67% and 100% respectively, when compared against an optimized RT-PCR test with a target size within 70 bp (CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel3).


title: COVID-19 seroprevalence among healthcare workers of a large COVID Hospital in Rome reveals strengths and limits of two different serological tests

abstract:
In several hospitals worldwide, healthcare workers are currently at the forefront against coronavirus disease 2019 (COVID-19). Since Fondazione Policlinico Universitario A. Gemelli (FPG) IRCCS has been enlisted as a COVID hospital, healthcare workers deployed to COVID wards were separated from those with limited or no exposure, whereas administrative staff was destined to work-from-home.

Between June 4 and July 3 2020, an investigation was carried out to evaluate seroprevalence of SARS-CoV-2 IgG antibodies among employees of the FPG using point-of-care (POC) and venous blood tests. Sensitivity, specificity and predictive values were determined with reverse-transcription polymerase chain reaction (RT-PCR) on nasal/oropharyngeal swabs as gold standard.

Four thousand, seven hundred seventy-seven participants were enrolled. Seroprevalence was 3.66% using the POC test and 1.19% using venous blood test, with a significant difference between the two (p < 0.05).

POC sensitivity and specificity were, respectively, 63.64% (95% confidence interval (CI): 62.20% to 65.04%) and 96.64% (95% CI: 96.05% to 97.13%), while those of the venous blood test were, respectively, 78.79% (95% CI: 77.58% to 79.94%) and 99.36% (95% CI: 99.07% to 99.55%). Among low-risk population, point-of-cares predictive values were 58.33% (positive) and 98.23% (negative) whereas venous blood tests were 92.86% (positive) and 98.53% (negative). In conclusion, point-of-care tests have low diagnostic accuracy, while venous blood tests seem to show an overall poor reliability.


title: Levels of SARS-CoV-2 population exposure are considerably higher than suggested by seroprevalence surveys

abstract: Accurate knowledge of accurate levels of prior population exposure has critical ramifications for preparedness plans of subsequent SARS-CoV-2 epidemic waves and vaccine prioritization strategies. Serological studies can be used to estimate levels of past exposure and thus position populations in their epidemic timeline. To circumvent biases introduced by decaying antibody titers over time, population exposure estimation methods should account for seroreversion, to reflect that changes in seroprevalence measures over time are the net effect of increases due to recent transmission and decreases due to antibody waning. Here, we present a new method that combines multiple datasets (serology, mortality, and virus positivity ratios) to estimate seroreversion time and infection fatality ratios and simultaneously infer population exposure levels. The results indicate that the average time to seroreversion is six months, and that true exposure may be more than double the current seroprevalence levels reported for several regions of England.


title: Whole-Cell Dissociated Suspension Analysis in Human Brain Neurodegenerative Disease: A Pilot Study

abstract: Biochemical analysis of human brain tissue is typically done by homogenizing whole pieces of brain and separately characterizing the proteins, RNA, DNA, and other macromolecules within. While this has been sufficient to identify substantial changes, there is little ability to identify small changes or alterations that may occur in subsets of cells. To effectively investigate the biochemistry of disease in the brain, with its different cell types, we must first separate the cells and study them as phenotypically defined populations or even as individuals. In this project, we developed a new method for the generation of whole-cell-dissociated-suspensions (WCDS) in fresh human brain tissue that could be shared as a resource with scientists to study single human cells or populations. Characterization of WCDS was done in paraffin-embedded sections stained with H&E, and by phenotyping with antibodies using immunohistochemistry and fluorescence-activated cell sorting (FACS). Additionally, we compared extracted RNA from WCDS with RNA from adjacent intact cortical tissue, using RT-qPCR for cell-type-specific RNA for the same markers as well as whole transcriptome sequencing. More than 11,626 gene transcripts were successfully sequenced and classified using an external database either as being mainly expressed in neurons, astrocytes, microglia, oligodendrocytes, endothelial cells, or mixed (in two or more cell types). This demonstrates that we are currently capable of producing WCDS with a full representation of different brain cell types combined with RNA quality suitable for use in biochemical analysis.

category: pathology


title: Mathematical Model of a Personalized Neoantigen Cancer Vaccine and the Human Immune System: Evaluation of Efficacy

abstract:
Cancer vaccines are an important component of the cancer immunotherapy toolkit enhancing immune response to malignant cells by activating CD4+ and CD8+ T cells. Multiple successful clinical applications of cancer vaccines have shown good safety and efficacy. Despite the notable progress, significant challenges remain in obtaining consistent immune responses across heterogeneous patient populations, as well as various cancers. We present as a proof of concept a mechanistic mathematical model describing key interactions of a personalized neoantigen cancer vaccine with an individual patients immune system. Specifically, the model considers the vaccine concentration of tumor-specific antigen peptides and adjuvant, the patients major histocompatibility complexes I and II copy numbers, tumor size, T cells, and antigen presenting cells. We parametrized the model using patient-specific data from a recent clinical study in which individualized cancer vaccines were used to treat six melanoma patients. Model simulations predicted both immune responses, represented by T cell counts, to the vaccine as well as clinical outcome (determined as change of tumor size). These kinds of models have the potential to lay the foundation for generating in silico clinical trial data and aid the development and efficacy assessment of personalized cancer vaccines.

Author summaryPersonalized cancer vaccines have gained attention in recent years due to the advances in sequencing techniques that have facilitated the identification of multiple tumor-specific mutations. This type of individualized immunotherapy has the potential to be specific, efficacious, and safe since it induces an immune response to protein targets not found on normal cells. This work focuses on understanding and analyzing important mechanisms involved in the activity of personalized cancer vaccines using a mechanistic mathematical model. This model describes the interactions of a personalized neoantigen peptide cancer vaccine, the human immune system and tumor cells operating at the molecular and cellular level. The molecular level captures the processing and presentation of neoantigens by dendritic cells to the T cells using cell surface proteins. The cellular level describes the differentiation of dendritic cells due to peptides and adjuvant concentrations in the vaccine, activation, and proliferation of T cells in response to treatment, and tumor growth. The model captures immune response behavior to a vaccine associated with patient specific factors (e.g., different initial tumor burdens). Our model serves as a proof of concept displaying its utility in clinical outcomes prediction, lays foundation for developing in silico clinical trials, and aids in the efficacy assessment of personalized vaccines.

category: pharmacology and therapeutics


title: Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on risk of type 2 diabetes

abstract: Type 2 diabetes (T2D) is a disease for which both common genetic variants and environmental factors influence risk. A few genes have been identified in which very rare variants have large effects on risk and here we carry out a weighted burden analysis of rare variants in a sample of over 200,000 exome-sequenced participants in the UK Biobank project, of whom over 13,000 have T2D. Variant weights were allocated based on allele frequency and predicted effect, as informed by a previous analysis of hyperlipidaemia. There was an exome-wide significant increased burden of rare, functional variants in three genes, GCK, HNF4A and GIGYF1. GIGYF1 has not previously been identified as a diabetes risk gene but its product is plausibly involved in the modification of insulin signalling. A number of other genes did not attain exome-wide significance but were highly ranked and potentially of interest, including ALAD, PPARG, GYG1 and GHRL. Loss of function (LOF) variants were associated with T2D in GCK and GIGYF1 whereas nonsynonymous variants annotated as probably damaging were associated in GCK and HNF4A. Overall, fewer than 1% of T2D cases carried one of these variants. In two genes previously implicated in diabetes aetiology, HNF1A and HNF1B, there was an excess of LOF variants among cases but the small numbers of these fell well short of statistical significance, suggesting that even larger datasets will be helpful for more fully elucidating the contribution of rare genetic variants to T2D risk. This research has been conducted using the UK Biobank Resource.


title: DAGM: a novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations

abstract:
BackgroundBreast cancers can be divided into HER2-negative and HER2-positive subtypes according to the status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to accurately assess its potential risk and to understand the potential mechanisms.

MethodsWe developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs).

FindingsWe characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed the HER2 signalling pathway was up-regulated in the germline of HER2-negative patients, and those with high APSP risk scores had suppressed immunity. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk of developing HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations.

InterpretationThe DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer.

FundingThis work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW)

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe majority of hereditary breast cancers are caused by BRCA1/2 mutations, and the presence of these mutations is strongly associated with an increased risk of breast cancer. Meanwhile, BRCA1/2 gene mutations are rarely found in sporadic breast cancers and only account for a modest percentage of all breast cancer patients. Polygenic risk score (PRS), a widely-used approach for stratifying individuals according to their risk of a certain kind of complex disease, has been used to predict subjects at high risk for breast cancer. However, relying on SNPs from genome-wide association studies (GWAS) without including gene expressions or pathway activities, PRS is not very suitable for cross-population prediction and describes disease risk in terms of genomic mutations without alluding to the underlying pathogenic mechanism(s). Therefore, there is still an urgent need for a population-independent comprehensive method to accurately assess the risk of breast cancer and to gain insights on potential mechanism(s).

Added value of this studyWhen subjecting germline rare coding mutations (gRCMs) to DAGM framework, which results in the corresponding APSP and APSP risk score. Both APSP and APSP risk score can identify HER2-negative from HER2-positive breast cancers. These findings suggest HER2-negative breast cancer does not develop accidentally, but rather is defined by a genomic evolutionary strategy. Furthermore, this study also revealed the up-regulation of HER2 signalling pathway in germlines of HER2-negative breast cancers and the immune suppression in subjects with high APSP risk score, shedding new light on the potential mechanisms of developing HER2-negative breast cancer. Moreover, our APSP risk score was able to relatively accurately evaluate the risk of developing HER2-negative breast cancer for each female, including not only BRCA1/2 carriers, but also non-carriers.

Implications of all the available evidenceThe present study suggests that HER2 signalling pathway activity, as an aggressive factor, contribute to the development of different types of breast cancers, either via the combined effects of multiple germline mutations in HER2-negative germlines or via amplifying the gene itself in HER2-positive tumour cells. This provides a theoretical basis for the prevention, diagnosis, and treatment of breast cancers. At the same time, the study provides preliminary methods for assessing the relative risk of HER2-negative breast cancer for females with or without BRCA1/2 mutations. Finally, our findings provide a new perspective and theoretical basis for identifying high-risk female subjects, based on the high APSP risk score, for early screening and prevention of HER2-negative breast cancer.

category: oncology


title: Quality of life and health-related utility after head&neck cancer surgery

abstract:
PurposeThis work describes the methodology adopted and the results obtained in a utility elicitation task. The purpose was to elicit utility coefficients (UCs) needed to calculate quality-adjusted life years for a cost/utility analysis of TORS (Trans-Oral robotic Surgery) versus TLM (Trans-oral Laser Microsurgery), which are two minimally-invasive trans-oral surgery techniques for head & neck cancers.

MethodsSince the economic evaluation would be conducted from the point of view of the Swiss healthcare system, Swiss people (healthy volunteers) have been interviewed in order to tailor the model to that specific country. The utility elicitation was performed using a computerized tool (UceWeb). Standard gamble and rating scale methods were used.

ResultsUCs have been elicited from 47 individuals, each one providing values for 18 health states, for a total of 1692 expected values. Health states, described using graphical factsheets, ranged from remission to palliative care. Elicited UCs were different among states, ranging from 0.980 to 0.213. Those values were comparable to previously published results from a Canadian population, except for states related to recurrent disease (local, regional, and distant), and palliation, where the Swiss population showed lower utility values.

ConclusionFrom a methodological point of view, our study shows that the UceWeb tool can be profitably used for utility elicitation from healthy volunteers. From an application point of view, the study provides utility values that can be used not only for a specific cost-utility analysis, but for future studies involving health states following trans-oral head & neck surgery. Moreover, the study confirms that some UCs vary among countries, demanding for tailored elicitation tasks.

category: otolaryngology


title: HIV - infected patients on cART had similar level of arterial stiffness to the patients with ST - segment elevation myocardial infarction.

abstract:
PurposeThe cardiovascular disease has become very common among HIV-infected patients. The aim was to compare the arterial stiffness and the endothelial dysfunction in HIV-infected patients to non-HIV-infected patients in week 4 after ST-segment elevation myocardial infarction (STEMI).

MethodsThe arterial stiffness was calculated by Endo-PAT 2000(ITAMAR(R)) and the endothelial function by Peripheral Arterial Tonometry(PAT(R)). The correct endothelial function was defined for natural logarithm of reactive hyperaemia index (lnRHI)>0.51. Arterial stiffness was assessed as the AI and corrected for heart rate of 75 bpm (AI@75).

ResultsSixty-three patients were recruited to this study, n=34 patients with HIV infection (n=18 on cART) and n=29 HIV-negative patients after recent STEMI. No statistically significant differences for AI and AI@75 were found in STEMI and in HIV on cART group. We observed p<0.05 for AI and AI@75 for patients without cART compared to STEMI and on cART patients. The observed lnRHI results were significantly different p<0.05 in STEMI and on cART patients. We get similar endothelial dysfunction p>0.05 for patients without cART compared to STEMI and on cART patients.

ConclusionsAssessing cardiovascular risk also with non-invasive methods among HIV-infected patients is very important especially in HIV-patients on cART. Endothelial dysfunction is connected with HIV infection and can be similar for STEMI and HIV-infected without cART.

category: hiv aids


title: HIV-infected patients on combined antiretroviral treatment had similar level of arterial stiffness to the patients with ST-segment elevation myocardial infarction.


title: An Augmented SEIR Model with Protective and Hospital Quarantine Dynamics for the Control of COVID-19 Spread

abstract: In this work, an attempt is made to analyse the dynamics of COVID-19 outbreak mathematically using a modified SEIR model with additional compartments and a nonlinear incidence rate with the help of bifurcation theory. Existence of a forward bifurcation point is presented by deriving conditions in terms of parameters for the existence of disease free and endemic equilibrium points. The significance of having two additional compartments, viz., protective and hospital quarantine compartments, is then illustrated via numerical simulations. From the analysis and results, it is observed that, by properly selecting transfer functions to place exposed and infected individuals in protective and hospital quarantine compartments, respectively, and with apt governmental action, it is possible to contain the COVID-19 spread effectively. Finally, the capability of the proposed model in predicting/representing the COVID-19 dynamics is presented by comparing with real-time data.


title: Detection of SARS-CoV-2 variants in Switzerland by genomic analysis of wastewater samples

abstract: The emergence of SARS-CoV-2 mutants with altered transmissibility, virulence, or immunogenicity emphasizes the need for early detection and epidemiological surveillance of genomic variants. Wastewater samples provide an opportunity to assess circulating viral lineages in the community. We performed genomic sequencing of 122 wastewater samples from three locations in Switzerland to analyze the B.1.1.7, B.1.351, and P.1 variants of SARS-CoV-2 on a population level. We called variant-specific signature mutations and monitored variant prevalence in the local population over time. To enable early detection of emerging variants, we developed a bioinformatics tool that uses read pairs carrying multiple signature mutations as a robust indicator of low-frequency variants. We further devised a statistical approach to estimate the transmission fitness advantage, a key epidemiological parameter indicating the speed at which a variant spreads through the population, and compared the wastewater-based findings to those derived from clinical samples. We found that the local outbreak of the B.1.1.7 variant in two Swiss cities was observable in wastewater up to 8 days before its first detection in clinical samples. We detected a high prevalence of the B.1.1.7 variant in an alpine ski resort popular among British tourists in December 2020, a time when the variant was still very rare in Switzerland. We found no evidence of local spread of the B.1.351 and P.1 variants at the monitored locations until the end of the study (mid February) which is consistent with clinical samples. Estimation of local variant prevalence performs equally well or better for wastewater samples as for a much larger number of clinical samples. We found that the transmission fitness advantage of B.1.1.7, i.e. the relative change of its reproductive number, can be estimated earlier and based on substantially fewer wastewater samples as compared to using clinical samples. Our results show that genomic sequencing of wastewater samples can detect, monitor, and evaluate genetic variants of SARS-CoV-2 on a population level. Our methodology provides a blueprint for rapid, unbiased, and cost-efficient genomic surveillance of SARS-CoV-2 variants.


title: Polymorphisms affecting expression of the vaccine antigen factor H binding protein influence invasiveness of Neisseria meningitidis

abstract: Many bacterial diseases are caused by organisms that ordinarily are harmless components of the human microbiome. Effective interventions against these conditions requires an understanding of the processes whereby symbiosis or commensalism breaks down. Here, we performed bacterial genome-wide association studies (GWAS) of Neisseria meningitidis, a common commensal of the human respiratory tract despite being a leading cause of meningitis and sepsis. GWAS discovered single nucleotide polymorphisms (SNPs) and other bacterial genetic variants associated with invasive meningococcal disease (IMD) versus carriage in several loci across the genome, revealing the polygenic nature of this phenotype. Of note, we detected a significant peak around fHbp, which encodes factor H binding protein (fHbp); fHbp promotes bacterial immune evasion of human complement by recruiting complement factor H (CFH) to the meningococcal surface. We confirmed the association around fHbp with IMD in a validation GWAS, and found that SNPs identified in the validation affecting the 5 region of fHbp mRNA alter secondary RNA structures, increase fHbp expression, and enhance bacterial escape from complement-mediated killing. This finding mirrors the known link between complement deficiencies and CFH variation with human susceptibility to IMD, highlighting the central importance of human and bacterial genetic variation across the fHbp:CFH interface in IMD susceptibility, virulence, and the transition from carriage to disease.


title: Efficacy of propolis as an adjunct treatment for hospitalized COVID-19 patients: a randomized, controlled clinical trial

abstract: Among candidate treatment options for COVID-19, propolis, produced by honey bees from bioactive plant exudates, has shown potential against viral targets and has demonstrated immunoregulatory properties. We conducted a randomized, controlled, open-label, single center trial, with a standardized propolis product (EPP-AF) on hospitalized adult COVID-19 patients. Patients received standard care plus propolis at an oral dose of 400mg/day (n=40) or 800mg/day (n=42) for seven days, or standard care alone (n=42). Standard care included all necessary interventions, as determined by the attending physician. The primary end point was the time to clinical improvement defined as the length of hospital stay or oxygen therapy dependency. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs. Time in the hospital after intervention was significantly shortened in both propolis groups compared to the controls; median 7 days with 400mg/day and 6 days with 800mg/day, versus 12 days for standard care alone. Propolis did not significantly affect the need for oxygen supplementation. With the higher dose, significantly fewer patients developed acute kidney injury than in the controls (2 versus 10 of 42 patients). Propolis as an adjunct treatment was safe and reduced hospitalization time. The registration number for this clinical trial is: NCT04480593 (20/07/2020).


title: The importance of non-pharmaceutical interventions during the COVID-19 vaccine rollout

abstract: The promise of efficacious vaccines against SARS-CoV-2 is fulfilled and vaccination campaigns have started worldwide. However, the fight against the pandemic is far from over. Here, we propose an age-structured compartmental model to study the interplay of disease transmission, vaccines rollout, and behavioural dynamics. We investigate, via in-silico simulations, individual and societal behavioural changes, possibly induced by the start of the vaccination campaigns, and manifested as a relaxation in the adoption of non-pharmaceutical interventions. We explore different vaccine efficacy, vaccination rollout speeds, prioritization strategies, as well as multiple behavioural responses. We apply our model to six countries worldwide (Egypt, Peru, Serbia, Ukraine, Canada, and Italy) selected to sample diverse socio-demographic and socio-economic contexts. To isolate the effects of age-structures and contacts patterns from the particular pandemic history of each location, we first study the model considering the same hypothetical initial epidemic scenario in all countries. We then calibrate the model using real epidemiological and mobility data for the different countries. Our findings suggest that early relaxation of safe behaviours can jeopardize the benefits brought by the vaccine in the short term: a fast vaccine distribution and policies aimed at keeping high compliance of individual safe behaviours are key to mitigate disease resurgence.


title: Migration and Outbreaks of Vaccine-Preventable Disease in Europe: A Systematic Review

abstract:
BackgroundMigrant populations (defined as foreign-born) are one of several under-immunised groups in the EU/EEA, yet little is known about how they are affected by outbreaks of vaccine-preventable diseases (VPDs). This information is vital to develop targeted strategies to improve the health of diverse migrant communities and to assess risk factors and correlations with major European peaks in incidence of key VPDs over time.

MethodsWe did a systematic review (PROSPERO CRD42019157473; Medline, EMBASE, and Global Health January 2000 to October 2019) adhering to PRISMA guidelines, to identify studies on VPD outbreaks (measles, mumps, rubella, diphtheria, pertussis, polio, hepatitis A, N meningitidis, and H influenzae) in migrants residing in the EU/EEA and Switzerland.

Results45 studies were included, reporting on 47 distinct VPD outbreaks across 13 countries (26 [55%] were reported between 2010 and 2020, including 16 [34%] since 2015). Most reported outbreaks involving migrants were of measles (n=24; 6578 total cases), followed by varicella (n=11; 596 cases), hepatitis A (n=7; 1510 cases), rubella (n=3; 487 cases) and mumps (n=2; 295 cases). 19 (40%) of outbreaks, predominantly varicella and measles, were reported in temporary camps or shelters for asylum seekers and refugees. Of 11 varicella outbreaks, 82% were associated with adult migrants. Half of measles outbreaks (n=12) were associated with migrants from Eastern European countries, often involving migrants of Roma ethnicity.

ConclusionsMigrants represent one of several under-immunised groups involved in VPD outbreaks in Europe, with adult and child refugees and asylum seekers residing in shelters or temporary camps at particular risk, alongside specific nationality groups. Vulnerability varies by disease, setting, and individual demographics, highlighting the importance of tailoring strategies for implementing catch-up vaccination to specific groups, alongside the strengthening of routine data collection, in order to meet regional and global vaccination targets. Better understanding vaccine uptake and demand issues in migrant groups, and reducing the barriers they face to accessing vaccination services, is urgently needed, with direct implications for COVID-19 vaccine delivery at the current time. Strengthening vaccine delivery to migrant populations will require a greater focus on co-designing vaccine uptake strategies in close collaboration with affected communities.

FunderNIHR


title: Women in Health Care Experiencing Occupational Stress and Burnout during COVID-19: A Review

abstract:
ContextCOVID-19 has had an unprecedent impact on physicians, nurses, and other health professionals around the world, and a serious health care burnout crisis is emerging as a result of this pandemic.

ObjectivesWe aim to identify the causes of occupational stress and burnout in women in medicine, nursing, and other health professions during the COVID-19 pandemic and interventions that can support female health professionals deal with this crisis through a rapid review.

MethodsWe searched MEDLINE, Embase, CINAHL, PsycINFO, and ERIC from December 2019 through September 30, 2020. The review protocol was registered in PROSPERO and is available online. We selected all empirical studies that discussed stress and burnout in women health care workers during the COVID-19 pandemic.

ResultsThe literature search identified 6148 citations. A review of abstracts led to the retrieval of 721 full-text articles for assessment, of which 47 articles were included for review. Our findings show that concerns of safety (65%), staff and resource adequacy (43%), workload and compensation (37%), job roles and security (41%) appeared as common triggers of stress in the literature.

Conclusions and RelevanceThe current literature primarily focuses on self-focused initiatives such as wellness activities, coping strategies, reliance of family, friends and work colleagues to organizational led initiatives such as access to psychological support and training. Very limited evidence exists about the organizational interventions such as work modification, financial security, and systems improvement.


title: Deep learning-based detection of COVID-19 using wearables data

abstract:
BackgroundCOVID-19 is an infectious disease caused by SARS-CoV-2 that is primarily diagnosed using laboratory tests, which are frequently not administered until after symptom onset. However, SARS-CoV-2 is contagious multiple days before symptom onset and diagnosis, thus enhancing its transmission through the population.

MethodsIn this retrospective study, we collected 15 seconds to one-minute heart rate and steps interval data from Fitbit devices during the COVID-19 period (February 2020 until June 2020). Resting heart rate was computed by selecting the heart rate intervals where steps were zero for 12 minutes ahead of an interrogated time point. Data for each participant was divided into train or baseline by taking the days before the non-infectious period and test data by taking the days during the COVID-19 infectious period. Data augmentation was used to increase the size of the training days. Here, we developed a deep learning approach based on a Long Short-Term Memory Networks-based autoencoder, called LAAD, to predict COVID-19 infection by detecting abnormal resting heart rate in test data relative to the users baseline.

FindingsWe detected an abnormal resting heart rate during the period of viral infection (7 days before the symptom onset and 21 days after) in 92% (23 out of 25 cases) of patients with laboratory-confirmed COVID-19. In 56% (14) of cases, LAAD detection identified cases in their pre-symptomatic phase whereas 36% (9 cases) were detected after the onset of symptoms with an average precision score of 0{middle dot}91 (SD 0{middle dot}13, 95% CI 0{middle dot}854-0{middle dot}967), a recall score of 0{middle dot}36 (0{middle dot}295, 0{middle dot}232-0{middle dot}487), and a F-beta score of 0{middle dot}79 (0{middle dot}226, 0{middle dot}693-0{middle dot}888). In COVID-19 positive patients, abnormal RHR patterns start 5 days before symptom onset (6{middle dot}9 days in pre-symptomatic cases and 1{middle dot}9 days later in post-symptomatic cases). COVID-19+ patients have longer abnormal resting heart rate periods (89 hours or 3{middle dot}7 days) as compared to healthy individuals (25 hours or 1{middle dot}1 days).

InterpretationThese findings show that deep learning neural networks and wearables data are an effective method for the early detection of COVID-19 infection. Additional validation data will help guide the use of this and similar techniques in real-world infection surveillance and isolation policies to reduce transmission and end the pandemic.

FundingThis work was supported by NIH grants and gifts from the Flu Lab, as well as departmental funding from the Stanford Genetics department. The Google Cloud Platform costs were covered by Google for Education academic research and COVID-19 grant awards.

Research in contextO_ST_ABSEvidence before the studyC_ST_ABSCOVID-19 resulted in up to 1{middle dot}7 million deaths worldwide in 2020. COVID-19 detection using laboratory tests is usually performed after symptom onset. This delay can allow the spread of viral infection and can cause outbreaks. We searched PubMed, Google, and Google Scholar for research articles published in English up to Dec 1, 2020, using common search terms including "COVID-19 and wearables", "Resting heart rate and viral infection", "Resting heart rate and COVID-19", "machine learning and COVID-19" and "deep-learning and COVID-19". Previous studies have attempted to use an elevated resting heart rate as an indicator of viral infection. Although these studies have investigated the early prediction of COVID-19 using resting heart rate and other wearables data, studies to investigate a deep learning-based prediction model with performance evaluation metrics at the user level has not been reported.

Added value of this studyIn this study, we created a deep-learning system that used wearables data such as abnormal resting heart rate to predict COVID-19 before the symptom onset. The deep-learning system was created using retrospective time-series datasets collected from 25 COVID-19+ patients, 11 non-COVID-19, and 70 healthy individuals. To our knowledge, this is the first deep-learning model to identify an early viral infection using wearables data at the user level. This study also greatly extends our previous phase-1 study and factors unpredictable behavior and time-series nature of the data, limited data size, and lack of data labels to evaluate performance metrics. The use of a real-time version of this model using more data along with user feedback may help to scale early detection as the number of patients with COVID-19 continues to grow.

Implications of all the available evidenceIn the future, wearable devices may provide high-resolution sleep, temperature, saturated oxygen, respiration rate, and electrocardiogram, which could be used to further characterize an individuals baseline and improve the deep-learning model performance for infectious disease detection. Using multi-sensor data with a real-time deep-learning model has the potential to alert individuals of illness prior to symptom onset and may greatly reduce the viral spread.


title: Visual Impairment and Risk of Dementia: the UK Biobank Study

abstract:
INTRODUCTIONThe association between visual impairment (VI) and the risk of dementia has been poorly understood. We sought to investigate the VI-dementia relationship in the UK Biobank Study.

METHODSA total of 117,187 volunteers (aged 40-69 years) deemed free of dementia at baseline were included. Habitual distance visual acuity worse than 0.3 logMAR units in the better-seeing eye was used to define VI. The incident dementia was based on electronically linked hospital inpatient and death records.

RESULTSDuring a median follow up of 5.96 years, the presence of VI was significantly associated with incident dementia (HR=1.78, 95% CI: 1.18-2.68, P=0.006). There was a clear trend between the severity of VI and the risk of dementia (P for trend=0.002).

DISCUSSIONVisually impaired individuals were more likely to develop incident dementia, with a progressively greater risk among those with worse visual acuity. Our findings highlight the value of regular vision screening and elimination of VI.

HIGHLIGHTSO_LIThe association between VI and dementia has been poorly understood;
C_LIO_LIVI is associated with incident dementia in non-demented adults;
C_LIO_LIThere is a clear trend between the severity of VI and the risk of dementia;
C_LIO_LIVI may be a marker of increased dementia risk.
C_LI

RESEARCH IN CONTEXTO_ST_ABSSYSTEMATIC REVIEWC_ST_ABSWe searched and reviewed the literature using traditional sources (e.g., PubMed and GoogleScholar). While the association between VI and cognitive function/decline are increasingly studies, investigation of the association between VI and the risk of dementia has been largely overlooked.

INTERPRETATIONWe found that visually impaired individuals were more likely to develop incident dementia, with a progressively greater risk among those with worse visual acuity. Our findings imply that VI may be an important marker of dementia.

FUTURE DIRECTIONSThese findings call for more studies to investigate (a) the role of visual acuity changes on the risk of dementia; (b) the relationship between other components of visual function and incident dementia; (c) the relationship between eye diseases and incident dementia; and (d) the potential benefits of vision rehabilitation on dementia prevention.

category: ophthalmology


title: Factors indicating intention to vaccinate with a COVID-19 vaccine among older U.S. Adults

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBACKGROUNDC_ST_ABSThe success of vaccination efforts to curb the COVID-19 pandemic will require broad public uptake of immunization and highlights the importance of understanding factors associated with willingness to receive a vaccine.

METHODSAdults enrolled in the Heartline clinical study were invited to complete a COVID-19 vaccine assessment through the Heartline mobile application between November 6-20, 2020. Factors associated with willingness to receive a COVID-19 vaccine were evaluated using an ordered logistic regression as well as a Random Forest classification algorithm.

RESULTSAmong 9,106 study participants, 81.3% (n=7402) responded and had available demographic data. The majority (91.3%) reported a willingness to be vaccinated. Factors most strongly associated with vaccine willingness were beliefs about the safety and efficacy of COVID-19 vaccines and vaccines in general. Women and Black or African American respondents reported lower willingness to vaccinate. Among those less willing to get vaccinated, 66.2% said that they would talk with their health provider before making a decision. During the study, positive results from the first COVID-19 vaccine outcome study were released; vaccine willingness increased after this report.

CONCLUSIONSEven among older adults at high-risk for COVID-19 complications who are participating in a longitudinal clinical study, 1 in 11 reported lack of willingness to receive COVID-19 vaccine in November 2020. Variability in vaccine willingness by gender, race, education, and income suggests the potential for uneven vaccine uptake. Education by health providers directed toward assuaging concerns about vaccine safety and efficacy can help improve vaccine acceptance among those less willing.

Clinicaltrials.gov NCT04276441


title: Indoor dust as a matrix for surveillance of COVID-19 outbreaks

abstract:
Ongoing disease surveillance is a critical tool to mitigate viral outbreaks, especially during a pandemic. Environmental monitoring has significant promise even following widespread vaccination among high-risk populations. The goal of this work is to demonstrate molecular SARS-CoV-2 monitoring in bulk floor dust and related samples as a proof-of-concept of a non-invasive environmental surveillance methodology for COVID-19 and potentially other viral diseases. Surface swab, passive sampler, and bulk floor dust samples were collected from rooms of individuals infected with COVID-19, and SARS-CoV-2 was measured with quantitative reverse transcription polymerase chain reaction (RT-qPCR) and two digital PCR (dPCR) methods. Bulk dust samples had geometric mean concentration of 159 copies/mg-dust and ranged from non-detects to 23,049 copies/mg-dust detected using ddPCR. An average of 88% of bulk dust samples were positive for the virus among detection methods compared to 55% of surface swabs and fewer on the passive sampler (19% carpet, 29% polystyrene). In bulk dust, SARS-CoV-2 was detected in 76%, 93%, and 97% of samples measured by qPCR, chip-based dPCR, and droplet dPCR respectively. Detectable viral RNA in the bulk vacuum bags did not measurably decay over 4 weeks, despite the application of a disinfectant before room cleaning. Future monitoring efforts should further evaluate RNA persistence and heterogeneity in dust. This study did not measure virus viability in dust or potential transmission associated with dust. Overall, this work demonstrates that bulk floor dust is a potentially useful matrix for long-term monitoring of viral disease outbreaks in high-risk populations and buildings.

ImportanceEnvironmental surveillance to assess pathogen presence within a community is proving to be a critical tool to protect public health, and it is especially relevant during the ongoing COVID-19 pandemic. Importantly, environmental surveillance tools also allow for the detection of asymptomatic disease carriers and for routine monitoring of a large number of people as has been shown for SARS-CoV-2 wastewater monitoring. However, additional monitoring techniques are needed to screen for outbreaks in high-risk settings such as congregate care facilities. Here, we demonstrate that SARS-CoV-2 can be detected in bulk floor dust collected from rooms housing infected individuals. This analysis suggests that dust may be a useful and efficient matrix for routine surveillance of viral disease outbreaks.


title: Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

abstract:
Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex chronic condition affecting multiple body systems, with unknown cause, unclear pathogenesis mechanisms, and fluctuating symptoms which may lead to severe debilitation. It is frequently reported to have been triggered by an infection, particularly with herpes virus family members; however, there are no clear differences in exposure to, or seroprevalence of, any herpes virus in people with ME/CFS and healthy individuals. Herpes viruses exist in lytic and latent forms, and it is possible that ME/CFS is associated with viral reactivation, which has not been detectable previously due to insensitive testing methods.

Saliva samples were collected from 30 people living with ME/CFS at monthly intervals for six months and at times when they experienced symptom exacerbation, as well as from 14 healthy control individuals. The viral DNA load of the nine human herpes viruses was determined by digital droplet PCR. Symptoms were assessed by questionnaire at each time point.

Human herpes virus (HHV) 6B, HHV-7, herpes simplex virus 1 and Epstein Barr virus were detectable within the saliva samples, with higher HHV-6B and HHV-7 viral loads detected in people with ME/CFS than in healthy controls. Participants with ME/CFS could be broadly separated into two groups: one group displayed fluctuating patterns of herpes viruses detectable across the six months while the second group displayed more stable viral presentation. In the first group, there was positive correlation between HHV-6B and HHV-7 viral load and severity of symptom scores, including pain, neurocognition and autonomic dysfunction.

The results indicate that fluctuating viral load, related to herpesvirus reactivation state, may play a role in ME/CFS pathogenesis, or might be a consequence of dysregulated immune function. The sampling strategy and molecular tools developed permit large-scale epidemiological investigations.

Contribution to the FieldThe cause of ME/CFS and the mechanisms underlying disease pathogenesis are not known, although symptoms are often triggered by infection. Human herpes virus (HHV) family members have been implicated, although there is no difference in the seroprevalence of any HHV in people with ME/CFS and healthy controls, showing there is similar prior infection rate. HHVs exist in either latent or active, lytic, phases in the human host, and it is possible that ME/CFS symptoms and their severity is related to HHV reactivation from a latent state. We have used droplet digital PCR, a sensitive and specific method, to measure the prevalence and DNA concentration of HHVs in the saliva of people with ME/CFS and controls, and analysed the correlation with disease over a six-month timecourse. We found that two HHVs, HHV-7 and HHV-6B, were elevated in saliva from people with ME/CFS, and that in people who were severely affected by ME/CFS, the concentration HHV DNA correlated with symptom severity over time in a subgroup of patients with fluctuating salivary HHV repertoire. Our study demonstrates the feasibility of measuring HHV concentration in readily acquired samples, enabling future large-scale studies aimed at testing the causal role of HHV reactivation in ME/CFS disease.


title: Cohort Profile: a Prospective Household cohort study of Influenza, Respiratory Syncytial virus, and other respiratory pathogens community burden and Transmission dynamics in South Africa (PHIRST), 2016-2018

abstract:
PurposeThe PHIRST study (Prospective Household cohort study of Influenza, Respiratory Syncytial virus, and other respiratory pathogens community burden and Transmission dynamics in South Africa) aimed to estimate the community burden of influenza and respiratory syncytial virus (RSV) including the incidence of infection, symptomatic fraction, and disease severity, and to assess household transmission. We further aimed to estimate the impact of HIV infection and age on disease burden and transmission, and to assess the burden of Bordetella pertussis and Streptococcus pneumoniae.

ParticipantsWe enrolled 1684 individuals in 327 randomly selected households in two sites (rural Agincourt subdistrict, Mpumalanga Province and urban Jouberton Township, North West Province) over 3 consecutive influenza and RSV seasons. A new cohort of households was enrolled each year. Eligible households included those with >2 household members where [≥]80% of household members provided consent (and assent for children aged 7-17 years). Enrolled household members were sampled with nasopharyngeal swabs twice weekly during the RSV and influenza seasons of the year of enrolment. Serology samples were collected at enrolment and before and after the influenza season annually.

Findings to dateThere were 122,113 potential individual follow-up visits over the 3 years, and participants were interviewed for 105,783 (87%) of these. Out of 105,683 nasopharyngeal swabs from follow-up visits, 1,258 (1%), 1,026 (1%), 273 (<1%), 38,829 (37%) tested positive on PCR for influenza viruses, respiratory syncytial virus, pertussis and pneumococcus respectively.

Future plansFuture planned analyses include analysis of influenza serology results and RSV burden and transmission. Households enrolled in the PHIRST study during 2016-2018 were eligible for inclusion in a study of SARS-CoV-2 transmission initiated in July 2020. This study uses similar testing frequency and household selection methods to assess the community burden of SARS-CoV-2 infection and the role of asymptomatic infection in virus transmission.

RegistrationClinical trials.gov NCT02519803

Article summaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIPHIRST was conducted in urban and rural African settings with high HIV prevalence, allowing assessment of the effect of HIV on community burden and transmission dynamics of respiratory pathogens.
C_LIO_LIHouseholds were selected randomly to provide a representative sample of the community. Twice weekly sampling from each cohort of individuals for 6-10 months irrespective of symptoms allows estimation of community burden, household secondary infection risk, and serial interval including asymptomatic or paucisymptomatic episodes.
C_LIO_LIPolymerase chain reaction testing of >100,000 nasopharyngeal swab samples for multiple pathogens (influenza, respiratory syncytial virus, pertussis and Streptoccocus pneumonia) allows detailed examination of disease burden and transmission and pathogen interactions
C_LIO_LIPHIRST was not powered to assess severe outcomes (i.e. hospitalisation and death).
C_LIO_LIWe only examined four pathogens, but other micro-organisms may be important. Samples have been stored which could allow us to implement broader multi-pathogen testing in the future.
C_LI


title: Viral mutation, contact rates and testing: a DCM study of fluctuations

abstract: This report considers three mechanisms that might underlie the course of the secondary peak of coronavirus infections in the United Kingdom. It considers: (i) fluctuations in transmission strength; (ii) seasonal fluctuations in contact rates and (iii) fluctuations in testing. Using dynamic causal modelling, we evaluated the contribution of all combinations of these three mechanisms using Bayesian model comparison. We found overwhelming evidence for the combination of all mechanisms, when explaining 16 types of data. Quantitatively, there was clear evidence for an increase in transmission strength of 57% over the past months (e.g., due to viral mutation), in the context of increased contact rates (e.g., rebound from national lockdowns) and increased test rates (e.g., due to the inclusion of lateral flow tests). Models with fluctuating transmission strength outperformed models with fluctuating contact rates. However, the best model included all three mechanisms suggesting that the resurgence during the second peak can be explained by an increase in effective contact rate that is the product of a rebound of contact rates following a national lockdown and increased transmission risk due to viral mutation.


title: Acute Metabolic Emergencies in Diabetes and COVID-19: a systematic review and meta-analysis of case reports

abstract:
IntroductionCOVID-19 is associated with DKA (Diabetic Ketoacidosis), HHS (Hyperglycaemic Hyperosmolar State) and EDKA (Euglycaemic DKA). High mortality has been observed in COVID-19-related diabetic ketoacidosis; however, evidence is scarce.

Patients and MethodsA systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January to December 2020 to identify all case reports describing DKA, HHS, and EDKA, in COVID-19 patients. The Joanna Briggs Institute critical appraisal checklist for case reports was used for quality assessment. Univariate and multivariate analysis assessed correlations of study origin, combined DKA/HHS, age, BMI, HbA1c, administered antidiabetics, comorbidities, symptoms onset, disease status, CRP, ferritin, d-dimers, glucose, osmolarity, pH, bicarbonates, ketones, lactates, {beta}-hydroxybutyric acid, anion gap, and acute kidney injury (AKI) with outcome.

ResultsFrom 312 identified publications, 41 including 71 cases analyzed qualitatively and quantitatively. Multivariate analysis demonstrated that COVID-19 disease status 4 (P<0.001), AKI (P<0.001), pH [≤]7.12 (P=0.032), and osmolarity [≥]324 (P=0.034), are all independently correlated with death. COVID-19 Disease Status 4 (P=3*10-8), combined DKA/HHS (P=0.021), and AKI (P=0.037) are independently correlated with death.

ConclusionCOVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality; key determinants are critical COVID-19 illness, co-presence of ketoacidosis and hyperosmosis and AKI.

category: endocrinology


title: Trends in lipid-modifying agent use in 83 countries

abstract:
AimsLipid-modifying agents (LMAs) are increasingly used to reduce lipid levels and prevent cardiovascular events, but the magnitude of their consumption in different world regions is unknown. We aimed to describe recent global trends in LMA consumption and to explore the relationship between country-level LMA consumption and cholesterol concentrations.

Methods and resultsThis cross-sectional and ecological study used monthly pharmaceutical sales data from January 2008 to December 2018, for 83 countries from the IQVIA Multinational Integrated Data Analysis System, and total and non-high-density lipoprotein (non- HDL) cholesterol concentrations from the NCD Risk Factor Collaboration. The compound annual growth rate (CAGR) was used to assess changes in LMA consumption over time. From 2008 to 2018, the use of LMAs increased from 7,468 to 11,197 standard units per 1000 inhabitants per year (CAGR 4.13%). Statins were the most used class of LMA and their market share increased in 75% of countries between 2008 and 2018. Fibrates were the most consumed nonstatin drugs. From 2013 to 2018, consumption of low-density lipoprotein lowering therapies increased (statins 3.99%; ezetimibe 4.01%; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors 104.47%). Limited evidence supports a clear relationship between country-level changes in LMA consumption and total and non-HDL cholesterol concentrations in 2008 versus 2018.

ConclusionSince 2008, global access to LMAs, especially statins, has improved. In line with international lipid guideline recommendations, recent trends indicate growth in the use of statins, ezetimibe, and PCSK9 inhibitors. Country-level patterns of LMA use and total and non-HDL cholesterol varied considerably.


title: Excess mortality during the 1918-20 influenza pandemic in Czechia

abstract: This research letter provides a replicable estimate of the mortality that the 1918-20 influenza pandemic caused in Czechia. A monthly all-cause excess mortality model identified clear periods of pandemic mortality in September 1918 through May 1919 and January 1920 through May 1920. The total excess mortality in those months implies a pandemic death toll of 71,967 and a national death rate of 0.75%.


title: Association of Visual Impairment with Risk for Future Parkinson's Disease

abstract:
BackgroundAlthough visual dysfunction is one of the most common non-motor symptoms among patients with Parkinsons disease (PD), it is not known whether such dysfunction predates the onset of clinical PD.

ObjectivesTo examine the association of visual impairment (VI) with the future development of PD in the UK Biobank Study.

MethodsThe UK Biobank Study is one of the largest prospective cohort studies of health, enrolling over 500,000 participants aged 40-69 years between 2006 and 2010 across the UK. VI was defined as a habitual distance visual acuity (VA) worse than 0.3 LogMAR in the better-seeing eye. Incident cases of PD were determined by self report data, hospital admission records or death records, whichever came first. Multivariable Cox proportional hazard regression models were used to investigate the association between VI and the risk of incident PD.

ResultsA total of 117,050 participants were free of PD at the baseline assessment. During the median observation period of 5.96 (interquantile range [IQR]: 5.77-6.23) years, PD occurred in 222 (0.19%) participants. Visually impaired participants were at a higher risk of developing PD than non-VI participants (p<0.001). Compared with the non-VI group, the adjusted hazard ratio was 2.28 (95% CI 1.29-4.04, p=0.005) in the VI group. These results were consistent in the sensitivity analysis, where incident PD cases diagnosed within one year after the baseline assessment were excluded.

ConclusionsThis prospective cohort study found that VI was associated with an increased risk of incident PD, suggesting that VI may represent a prodromal feature of PD.


title: A Fractional Order Dengue Fever Model in theContext of Protected Travellers

abstract: Climate changes are affecting the control of many vector-borne diseases, particularly in Africa. In this work, a dengue fever model with protected travellers is formulated. Caputo-Fabrizio operator is utilized to obtain some qualitative information about the disease. The basic properties and the reproduction number is studied. The two steady states are determined and the local stability of the states are found to be asymptotically stable. The fixed pointed theory is made use to obtain the existence and uniqueness of solutions of the model. The numerical simulation suggests that the fractional-order affects the dynamics of dengue fever.


title: Plasma β-amyloid in mild behavioural impairment - neuropsychiatric symptoms on the Alzheimer's continuum

abstract:
IntroductionSimple markers are required to recognize older adults at higher risk for neurodegenerative disease. Mild behavioural impairment (MBI) and plasma {beta}-amyloid (A{beta}) have been independently implicated in the development of incident cognitive decline and dementia. Here we studied the associations between MBI and plasma A{beta}42/A{beta}40.

MethodsParticipants with normal cognition (n = 86) or mild cognitive impairment (n = 53) were selected from the Alzheimers Disease Neuroimaging Initiative. MBI scores were derived from Neuropsychiatric Inventory items. Plasma A{beta}42/A{beta}40 ratios were assayed using mass spectrometry. Linear regressions were fitted to assess the association between MBI total score as well as MBI domain scores with plasma A{beta}42/A{beta}40.

ResultsLower plasma A{beta}42/A{beta}40 was associated with higher MBI total score (p = 0.04) and greater affective dysregulation (p = 0.04), but not with impaired drive/motivation (p = 0.095) or impulse dyscontrol (p = 0.29) MBI domains.

ConclusionIn persons with normal cognition or mild cognitive impairment, MBI was associated with low plasma A{beta}42/A{beta}40. Incorporating MBI into case detection can help capture preclinical and prodromal Alzheimers disease.


title: Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study

abstract:
BackgroundAbout every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis.

MethodsThis study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n=110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n=1,058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n=1,143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples.

ResultsNetwork analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria.

Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF- PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods.

ConclusionsGenetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.