title: Increased risk of death in covid-19 hospital admissions during the second wave as compared to the first epidemic wave. A prospective dynamic cohort study in South London, UK.

abstract:
ObjectiveTo assess whether mortality of patients admitted for covid-19 treatment was different in the second UK epidemic wave of covid-19 compared to the first wave accounting for improvements in the standard of care available and differences in the distribution of risk factors between the two waves.

DesignSingle-centre, analytical, dynamic cohort study.

Participants2,701 adults ([≥]18 years) with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and/or clinico-radiological diagnosis of covid-19, who required hospital admission to covid-19 specific wards, between January 2020 and March 2021. There were 884 covid-19 admissions during the first wave (before 30 Jun 2020) and 1,817 during the second wave.

Outcome measuresin-hospital covid-19 associated mortality, ascertained from clinical records and Medical Certificate Cause of Death.

ResultsThe crude mortality rate was 25% lower during the second wave (2.23 and 1.66 deaths per 100 person-days in first and second wave respectively). However, after accounting for age, sex, dexamethasone, oxygen requirements, symptoms at admission and Charlson Comorbidity Index, mortality hazard ratio associated with covid-19 hospital admissions was 1.62 (95% confidence interval 1.26, 2.08) times higher in the second wave compared to the first.

ConclusionsAnalysis of covid-19 admissions recorded in St. Georges Hospital, shows a larger second epidemic wave, with a lower crude mortality in hospital admissions. Nevertheless, after accounting for other factors underlying risk of death for covid-19 admissions was higher in the second wave. These findings are temporally and ecologically correlated with an increased circulation of SARS-CoV-2 variant of concern 202012/1 (alpha).


title: Vaccination history for diphtheria and tetanus is associated with less severe COVID-19

abstract:
BackgroundCOVID-19 is characterized by strikingly large, mostly unexplained, interindividual variation in symptom severity. While some individuals remain nearly asymptomatic, others suffer from severe respiratory failure. It has been hypothesized that previous vaccinations for other pathogens, in particular tetanus, may provide protection against severe COVID-19.

MethodsWe made use of data on COVID-19 testing from 103,049 participants of the UK Biobank (mean age 71.5 years, 54.2% female), coupled to immunization records of the last ten years. Using logistic regression, covarying for age, sex, respiratory disease diagnosis, and socioeconomic status, we tested whether individuals vaccinated for tetanus, diphtheria or pertussis, differed from individuals that had only received other vaccinations on 1) undergoing a COVID-19 test, 2) the outcome of this test, and 3) whether they developed severe COVID-19.

ResultsWe found that individuals with registered diphtheria or tetanus vaccinations were less likely to develop severe COVID-19 than people who had only received other vaccinations (diphtheria OR=0.46, p=3.6x10-4; tetanus OR=0.50, p=5.8x10-4).

DiscussionThese results indicate that a history of diphtheria or tetanus vaccinations is associated with less severe manifestations of COVID-19. These vaccinations may protect against severe COVID-19 symptoms by stimulating the immune system. We note the correlational nature of these results, yet the possibility that these vaccinations may influence the severity of COVID-19 warrants follow-up investigations.

category: epidemiology


title: SARS-CoV-2 in wastewater from Mexico City used for irrigation in the Mezquital Valley: quantification and modelling of geographic dispersion

abstract: Quantification of SARS-CoV-2 in urban wastewaters has emerged as a cheap, efficient strategy to follow trends of active COVID-19 cases in populations. Moreover, mathematical models have been developed that allow prediction of active cases following the temporal patterns of viral loads in wastewaters. In Mexico, no systematic efforts have been reported in the use of this strategies. In this work, we quantified SARS-CoV-2 in rivers and irrigation canals in the Mezquital Valley, Hidalgo, an agricultural region where wastewater from Mexico City is distributed and used for irrigation. Using quantitative RT-PCR, we detected the virus in 6 out of 8 water samples from rivers, and 5 out of 8 water samples from irrigation canals. Notably, samples showed a general consistent trend of having the highest viral loads in the sites closer to Mexico City, indicating that this is the main source that contributes to detection. Using the data for SARS-CoV-2 concentration in the river samples, we generated a simplified transport model that describes the spatial patterns of dispersion of virus in the river. We suggest that this model can be extrapolated to other wastewater systems that require knowledge of spatial patterns of viral dispersion at a geographic scale. Our work highlights the need for improved practices and policies related to the use of wastewater for irrigation in Mexico and other countries.


title: Parental inflammatory bowel disease and autism in the offspring: Triangulating the evidence using four complementary study designs.

abstract:
ImportanceEvidence linking parental diagnoses of inflammatory bowel disease (IBD) with offspring autism is inconclusive.

ObjectiveTo investigate associations between parental diagnoses of IBD and offspring autism and elucidate their underlying aetiology by conducting four complementary studies.

Design, Setting and Participants(1) Nationwide population-based cohort study using Swedish registers to examine associations between parental IBD diagnoses and autism diagnoses in offspring, (2) Linkage disequilibrium (LD)-score regression to estimate the genetic correlation between the phenotypes. (3) Polygenic risk score (PRS) analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate associations between maternal genetic liability to IBD and autism factor mean score in offspring. (4) Two-sample Mendelian randomization (MR) to assess bidirectional causal links between genetic liability to IBD and autism.

ResultsObservational analyses provided evidence of an association between parental IBD diagnoses and offspring autism diagnosis in mutually adjusted models (maternal: OR= 1.32; 95% CI: 1.25 to 1.40; p<0.001; paternal: OR= 1.09; 95% CI: 1.02 to 1.17; p=0.012; n=2 324 227, 52.3% male). PRS analyses in ALSPAC indicated associations between maternal PRS for IBD subtypes and a measure of broad autism phenotype, autism factor mean score, in the offspring (UC: {beta}PRS= 0.02; 95%CI: 0.003 to 0.05; p= 0.02; R2=0.06; Crohns: {beta}PRS= 0.03; 95%CI: 0.01 to 0.05; p= 0.004; R2= 0.06; n= 7357, 50.3% male). MR analyses provided evidence of a potential causal effect of genetic liability for IBD, especially ulcerative colitis, on autism (ORMR= 1.03; 95%CI: 1.01 to 1.06). There was little evidence to suggest a causal effect of genetic liability to autism on risk of IBD, or a genetic correlation between the two conditions.

Conclusions and relevanceTriangulating evidence from a nationwide register-based cohort study, genetic correlation, polygenic risk score analyses and MR, we found evidence of a potentially causal link between parental, particularly maternal, diagnoses and genetic liability to IBD and offspring autism. Perinatal immune system dysregulation, micronutrient malabsorption and anaemia may be implicated.


title: Using real-time data to guide decision-making during an influenza pandemic: a modelling analysis

abstract: Influenza pandemics typically occur in multiple waves of infection, often associated with initial emergence of a novel virus, followed (in temperate regions) by a later resurgence accompanying the onset of the annual influenza season. Here, we examined whether data collected from an initial pandemic wave could be informative, for the need to implement non-pharmaceutical measures in any resurgent wave. Drawing from the 2009 H1N1 pandemic in 10 states in the USA, we calibrated simple mathematical models of influenza transmission dynamics to data for virologically confirmed hospitalisations during the initial  spring wave. We then projected pandemic outcomes (cumulative hospitalisations) during the fall wave, and compared these projections with data. Model results show reasonable agreement for all states that reported a substantial number of cases in the spring wave. Using this model we propose a probabilistic decision framework that can be used to determine the need for pre-emptive measures such as postponing school openings, in advance of a fall wave. This work illustrates how model-based evidence synthesis, in real-time during an early pandemic wave, could be used to inform timely decisions for pandemic response.


title: A Survey of Copy Number Variants Associated with Neurodevelopmental Disorders in a Large-Scale, Multi-Ancestry Biobank

abstract:
BACKGROUNDPast clinical genetic studies have identified rare, copy number variants (CNVs) as risk factors for multiple neurodevelopmental disorders (NDD), including autism spectrum disorder and schizophrenia. However, the broad, clinical characterization of these NDD-CNVs in large population cohorts, especially of diverse ancestry, is relatively understudied. We characterized the clinical presentation of NDD-CNVs in the BioMe biobank, comprising [~]25,000 individuals across diverse ancestry, medical and neuropsychiatric clinical presentation, with a mean age of 50.3 years.

METHODSIndividuals within the BioMe biobank harboring NDD-CNVs were identified using a consensus of two CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by a series of novel, in-silico clinical assessments.

RESULTSThe overall prevalence of a set of 64 NDD-CNVs was calculated at [~]2.5%, with prevalence varying by locus, corroborating the presence of some relatively, highly-prevalent NDD-CNVs (i.e., 15q11.2 deletion/duplication, 2q13(NPHP1) deletion/duplication). An aggregate set of rare, NDD-CNVs were enriched for congenital disorders (OR=1.8, p-value=0.02) and major depressive disorders (OR=1.3, p-value=0.04) in multi-ancestry analyses, and major depressive-disorder in an African ancestry-stratified group (OR=1.8, p-value=0.01). In a meta-analysis of medical diagnoses (n=195 hierarchically-clustered diagnostic codes), an aggregated set of rare, NDD-CNVs was significantly associated with obstructive sleep apnea (Z-score=3.6 p=3.2x10-4). Further, an aggregated set of rare, NDD-CNVs was associated with increased body mass index (BMI) in a multi-ancestry analysis (Beta=0.14, p-value=0,04), and in Hispanic-stratified analyses (Beta=0.30, p-value=4.2x10-3). For 38 common serum laboratory tests, there was no identified association with an aggregate set of NDD-CNVs.

CONCLUSIONThe current analyses elucidated clinical features of individuals harboring NDD-CNVs, in a large-scale, multi-ancestry biobank, identifying enrichments for congenital disorders and major depressive disorder, as well as identifying associations with obesity-related phenotypes, obstructive sleep apnea and increased BMI. Future recall of individuals harboring NDD-CNVs will allow for further clinical assessments beyond the electronic health records (EHR) presently analyzed, including neurocognitive and neuroimaging outcomes.

category: psychiatry and clinical psychology


title: Depression and Anxiety Symptoms among General Hospital Employees in need of Mental Health Treatment

abstract:
BackgroundDepression and anxiety are common and disabling mental disorders worldwide. It has been described a high prevalence of these disorders among health professionals.

AimThis study aimed to investigate the association between occupation and depressive/anxiety symptoms, education levels, among professionals from a Brazilian General Hospital in need of mental health treatment.

MethodsThis is a longitudinal twelve-years retrospective study, involving health professionals. Socio-demographic data were collected as well as two standardized scales for depression and anxiety symptoms.

ResultsData from 506 employees needing a mental health intervention have been described: mean age was 34.6 years, 46.2% of them worked in the administrative sector, 35.0% were nursing assistants, 7.5% were nursing technicians, 6.7% were nurses, and 4.5% reported other occupations. According to the ICD-10 criteria, the rates of diagnosis of depressive disorders and anxiety disorders were 60.9% and 37%, respectively.

ConclusionsThe rate of depression and anxiety is higher among health professionals than the general population. Thus, specific programs of prevention based on resilience, continuing education and health promotion are needed.

Highlights- Although 53,9% of studied individuals did not mention any kind of areas of difficulty in the workplace, 32.8% reported difficulties with coworkers or bosses.
- According to the ICD-10 criteria, diagnoses of depressive disorders (60.9%) and anxiety disorders (37%) were highly prevalent.
- Nursing technicians and nursing assistants reported higher somatic cluster BDI scores than other professionals of technical staff, but they were less inclined to receive a psychiatric diagnosis.


title: Personal space Increases during the COVID-19 Pandemic in Response to Real and Virtual Humans

abstract: Typically, people maintain a certain distance from others ("personal space") during daily life, in a largely automatic, unconscious manner. However during the COVID-19 pandemic, social distancing recommendations led to deliberate expansions of personal space outside of intimate social circles. In the laboratory, personal space preferences are quite stable over repeated measurements. Here, we collected such measurements both before and during the pandemic in the same individuals, using both conventional and virtual reality-based techniques. We found that the size of personal space, and discomfort ratings in response to personal space intrusions, increased significantly during the COVID-19 pandemic, in response to both real humans and virtual "others". Moreover, this increase in personal space requirements correlated with the perceived, not the actual, risk of being infected with COVID-19 - even in a virtual reality environment in which there was no possibility of infection. Thus, quantification of personal space may reveal some of the psychological effects of the pandemic, and subsequent progress towards recovery.

category: public and global health


title: What instructions are available to health researchers for writing lay summaries? A scoping review.

abstract:
STRUCTURED ABSTRACTO_ST_ABSObjectiveC_ST_ABSTo better understand the characteristics of, and requirements for, lay summaries by reviewing journals, global health organisations, professional medical associations and multi-disciplinary organisations, consumer advocacy groups and funding bodies.

DesignUsing a scoping review methodology, we searched the websites of each identified data source to determine if they require, suggest, or refer to lay summaries. Two reviewers extracted lay summary writing instructions from eligible data sources from Australia, USA, UK, Canada and New Zealand. Data sources were linked to the top 10 non-communicable diseases.

Main Outcome MeasuresUsing an inductive approach, we identified characteristics of lay summaries and lay summary writing instructions and extracted data on these characteristics. These characteristics are lay summary formats, audience, requirements, authorship and labels, and elements of lay summary writing instructions (e.g. word count/length). We also noted who was expected to write the lay summaries, whether they were mandatory or optional, and the terms used for to denote them.

ResultsThe websites of 526 data sources were searched. Of these, 124 published or mentioned lay summaries and 108 provided writing instructions. For lay summaries, most were in journals, written by the author of the published paper, and only half were mandatory. Thirty-three distinct labels for a lay summary were identified, the most common being "graphical abstract", "highlights" and "key points". From the lay summary writing instructions, the most common elements for written lay summaries referred to: structure (86%), content (80%) and word count/length (74%). The least common elements were readability (3%), use of jargon, acronyms and abbreviations (24%), and wording (29%). The target audience was unclear in 68 of 108 (63.0%) of lay summary instructions.

DiscussionAlthough we identified over 100 sources provided instructions for writing lay summaries, very few provided instructions related to readability, use of jargon, acronyms and abbreviations, and wording. Some instructions provided structured formats via subheadings or questions to guide content, but not all. Only half mandated the use of lay summaries.

ConclusionFor lay summaries to be effective, writing instructions should consider the intended audience, ideally incorporating consumer input into their development. Presently, lay summaries are likely to be inaccessible to many consumers, written at a high reading level, with jargon, acronyms and abbreviations. Ideally, all research articles will have an accompanying lay summary. Mandatory lay summaries, however, are of limited value without clear and thorough instructions to guide authors.

Public and patient involvement statementPatients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research study.

Protocol and registrationWe conducted a scoping review using methods outlined in the PRISMA extension for scoping reviews and information in the Joanna Briggs Institute Reviewers Manual for scoping reviews. A protocol for this study was completed prior to data analysis and is on Open Science Framework.


title: Relationship between the kinematics of wrist/finger joint movements and muscle loading during typing in people with different skill levels

abstract:
BackgroundMusculoskeletal disorders caused by computer use are associated with socio-economic problems. Reducing the biomechanical loading caused by hand movements could reduce the occurrence of such disorders. However, most participants recruited for past experimental studies had a certain level of typing skill, and differences in the biomechanical loading of those with different typing skills have not been examined. This study aimed to quantify the relationship between the movements of the wrist and finger joints and the loading on the forearm muscles and to clarify the differences between typists of different skill levels.

MethodsA 3D motion capture system measured wrist and index finger joint movements, and surface electromyography measured muscle activities for the right hand during a typing task. We compared wrist and finger joint movements and forearm muscle loading during typing, keystroke time, and key release time between skilled and unskilled typists.

FindingsSkilled typists move their wrists and fingers faster with less muscle activity during typing, the active tension of their finger flexor muscles during keystrokes are high, and they have higher mechanical stresses on the finger flexor tendons during keystrokes. Unskilled typists develop strategies to prevent excessive stiffness in their wrist joints when making keystrokes. They are expected to have a higher cumulative loading on the extensor muscles of the wrist during key release.

InterpretationBiomechanical loading in typing skill is different, which may make it possible to predict disability. This could provide information on the changes in physical parameters and environments to prevent disability.

category: rehabilitation medicine and physical therapy


title: Kinematic analysis of upper body movements in adolescent with mild idiopathic scoliosis: a preliminary study

abstract: Analysis of kinematic and postural data of adolescent idiopathic scoliosis (AIS) patients seems relevant for a better understanding of biomechanical aspects involved in AIS and its etiopathogenesis. The present project aimed at investigating kinematic differences and asymmetries in early AIS in a static task and in uniplanar trunk movements (rotations, lateral bending and forward bending). Trunk kinematics and posture were assessed using a 3D motion analysis system and a force plate. Fifteen healthy girls, fifteen AIS girls with left lumbar main curve and seventeen AIS girls with right thoracic main curve were compared. Statistical analyses were performed to investigate presumed differences between the three groups. This study showed kinematic and postural differences between mild AIS patients and controls such as static imbalance, a reduced range of motion in the frontal plane and a different kinematic strategy in lateral bending. These differences mainly occurred in the same direction whatever the type of scoliosis, and suggested that AIS patients behave similarly from a dynamic point of view.


title: The St. Gallen 2019 Guidelines understages the Axilla in Lobular Breast Cancer a Population-Based Study

abstract:
BackgroundThe St. Gallen 2019 guidelines recommend omission of completion axillary lymph node dissection (cALND) in breast cancer patients with 1-2 sentinel lymph node (SLN) metastases regardless of histopathology. Concurrently, adjuvant chemotherapy is endorsed for luminal A-like disease with [≥]4 axillary lymph node (ALN) metastases. We aimed to estimate the proportion of patients with invasive lobular cancer (ILC) and invasive ductal cancer of no special type (NST) and 1-2 SLN metastases for whom cALND would indicate need of adjuvant chemotherapy.

MethodsPatients with ILC and NST histopathology undergoing primary surgery 2014-2017 were identified in the Swedish National Quality Breast Cancer register. After exclusion of patients with incongruent or missing data, 1886 patients who fulfilled the St. Gallen 2019 criteria for cALND omission were included in the study cohort.

ResultsPatients with ILC (n = 329) had a higher metastatic nodal burden and more often a luminal A-like subtype compared with NST patients (n = 1507). The prevalence of [≥] 4 ALN metastases was higher in ILC (31%) than in NST (15%), corresponding to an adjusted odds of 2.26 (95% CI 1.59-3.21). Luminal A-like breast cancers with [≥]4 ALN metastases were overrepresented in ILC cases (52/281 (19%)) compared to NST cases (43/1299 (3%)), P<0.001.

ConclusionsPatients with ILC more often had a luminal A-like breast cancer with [≥]4 ALN metastases compared with NST patients. Abstaining cALND in patients with luminal A-like ILC with 1-2 SLN metastases warrants future attention as it risks nodal understaging and hence undertreatment in one-fifth of these patients.

Source of fundingThe authors declare no conflicts of interest. The Sk[a]ne County Councils Research and Developmental Foundation, the Governmental Funding of Clinical Research within the National Health Service (ALF), the Swedish Cancer Society, the Erling Persson Family Foundation, Kronoberg County Councils Research and Development Foundation, The Cancer Foundation Kronoberg, The Swedish Research Council and The Swedish Breast Cancer Association. The funding agencies had no role in study design or interpretation of data.

Previous communicationPreliminary findings were published as part of Ulrik Narbes doctoral thesis.

Trial registrationISRCTN registry: ISRCTN14341750

category: surgery


title: Timing of cholecystectomy after percutaneous cholecystectomy for acute cholecystitis- A systematic review and meta-analysis

abstract:
IntroductionThere is a controversy about the optimum timing of cholecystectomy after percutaneous cholecystostomy.

This systematic review and meta-analysis aimed to evaluate outcomes of early versus late cholecystectomy after percutaneous cholecystostomy.

MethodsThe study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and MOOSE guidelines. Heterogeneity was measured using Q tests and I2 statistics. The random-effects model was used. We evaluated cholecystectomy performed at different periods after percutaneous cholecystostomy within 72 hours or later, within or after one week or percutaneous cholecystostomy, within 10 days or after 10 days, less than 2 weeks or more than 2 weeks, less than 4 weeks or more than 4 weeks, less than 8 weeks or more than 8 weeks as per literature.

ResultsSix studies including 18640 patients were included in the final analysis. There was no difference in overall complications within or after 72 hours cholecystectomy group, but mortality and biliary complications were significantly high in the less than 72 hours group (p=0.05 and 0.0002 respectively). There was no difference in mortality, overall complication, biliary tract complications in less than 1 week versus more than 1 week and less than 10 days versus more than 10 days group. Overall complications were significantly less in the less than 2 weeks group compared to the more than 2 weeks group. There was no difference in mortality and biliary tract complications between less than 2 weeks and more than 2 weeks group. Overall complication rate (risk ratio 0.67, p <0.0001), postoperative mortality (risk ratio 0.46, p=0.003), bile duct injury (risk ratio 0.62, p=0.01) was significantly less in earlier than 4-week group. Hospital stay was not significantly different between less than 4 weeks versus more than 4 weeks group. (Mean difference= -2.74, p=0.12). Ove all complication rates were significantly more in less than 8 weeks group. (Risk ratio 1.07, p=0.01). Hospital stay was significantly less in less than 8 weeks group. (Mean difference 0.87, p=0.01).

ConclusionEarly cholecystectomy preferably within 4 weeks after percutaneous cholecystostomy is preferable over late cholecystectomy.


title: GWAS on Birth Year Infant Mortality Rates Provides New Evidence of Recent Natural Selection

abstract: Following more than a century of phenotypic measurement of natural selection processes, much recent work explores relationships between molecular genetic measurements and realized fitness in the next generation. We take a novel approach to the study of contemporary selective pressure by examining which genetic variants are "sustained" in populations as mortality exposure declines. Specifically, we deploy a so-called "regional GWAS" that links the infant mortality rate (IMR) by place and year in the UK with common genetic variants among cohorts in the UK Biobank. These cohorts (born 1936-1970) saw a decline in IMR from above 65 per 1,000 to under 20 per 1,000, with substantial subnational variation and spikes alongside wartime exposures. Our results show several genome-wide significant loci, including LCT and TLR10/1/6, related to area-level cohort IMR exposure during gestation and infancy. Genetic correlations are found across multiple domains, including fertility, cognition, health behaviors, and health outcomes, suggesting an important role for cohort selection in modern populations.

category: genetic and genomic medicine


title: Genetic and early environmental predictors of adulthood self-reports of trauma

abstract:
BackgroundEvidence suggests that retrospective self-reports of childhood trauma are associated with a greater risk of psychopathology in adulthood than are prospective measures. However, it remains unclear why retrospectively reported trauma confers a greater risk for poor outcomes. Investigating the heritable characteristics and environmental adversities associated with measures of self-reported trauma could increase understanding of this risk pathway to psychopathology.

MethodsOur sample included 3,963 unrelated individuals from the Twins Early Development Study. We tested whether polygenic scores for 21 psychiatric, cognitive, anthropometric and personality traits were associated with childhood emotional and physical abuse retrospectively self-reported in adulthood. To assess the presence of gene-environment correlation, we investigated whether these associations remained after controlling for composite scores of environmental adversity between birth and age 16.

ResultsRetrospectively self-reported childhood trauma was associated with polygenic scores for autism spectrum disorder (ASD), body mass index and risky behaviours. When composite scores of environmental adversity were included in one model, only associations with parent-reported environmental adversity in middle childhood, self-reported environmental adversity in early adolescence and the polygenic score for ASD remained significant.

ConclusionsRetrospective self-reports of childhood trauma are associated with heritable characteristics of the reporter. Genetic predisposition to ASD may increase liability to experiencing or interpreting events as traumatic. Associations between genetic predisposition for risky behaviour and high BMI with self-reported childhood trauma may be environmentally-mediated. Studies of the association between retrospectively self-reported childhood trauma and later life outcomes should consider that genetically-influenced reporter characteristics may confound associations, both directly and through gene-environment correlation.


title: Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer's disease-associated genes: DTNB and DLG2

abstract: Alzheimers disease (AD) is a genetically complex disease for which roughly 30 genes have been identified via genome-wide association studies. We attempted to identify rare variants (minor allele frequency <0.01) associated with AD in a region-based, whole genome sequencing (WGS) association study (GSAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved p-values < 10-6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden test and replicated in case/control samples from the ADSP study (pmeta = 4.74x10-8). SKAT analysis revealed region-based association around the discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta =1x10-6). Here, in a region-based GSAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.


title: COVID19, Consumption and Inequality: A Systematic Analysis of Rural Population of India

abstract:
BackgroundCOVID19 pandemic has had major impact on consumption levels and inequality within India. Government policy interventions have targeted poor households for cash and food transfers. It is important, however, to study the impact of the pandemic on consumption levels of non-poor in India, and in particular the middle class. In this paper, we aim to quantify the changes in consumption levels and inequality over time, across all groups of rural households in India.

MethodsWe analyze three rounds of COVID 19-related shock surveys between May and September 2020. These surveys cover rural households of six large states in India and are representative of more than 442 million (52% of Indias rural population).

FindingsIn the early phase of the pandemic, it was the bottom 40% of households that experienced the most severe decline in consumption. But as the pandemic deepened, consumption declined across all classes of households. Besides the poorest, it was particularly severe for the middle class (defined as 40%-80%). We also measure consumption inequality over time and find that the Gini coefficient of consumption distribution increased significantly.

InterpretationIn addition to focusing on poor households, policy responses to alleviate peoples sufferings would have to consider a more comprehensive boost to consumption and compensate for the reduced consumption among middle class families as well.

FundingNone.

category: health economics


title: From Tabulated Data to Knowledge Graph: A Novel Way of Improving the Performance of the Classification Models in the Healthcare Data

abstract:
In sectors like healthcare, having classification models that are both reliable and accurate is vital. Regrettably, contemporary classification techniques employing machine learning disregard the correlations between instances within data. This research, to rectify this, introduces a basic but effective technique for converting tabulated data into data graphs, incorporating structural correlations. Graphs have a unique capacity to capture structural correlations between data, allowing us to gain a deeper insight in comparison to carrying out isolated data analysis. The suggested technique underwent testing once the integration of graph data structure-related elements had been carried out and returned superior results to testing solely employing original features. The suggested technique achieved validity by returning significantly improved levels of accuracy.

DataThe extracted graph topological features datasets are available from:

category: health informatics


title: The impact of Covid-19 vaccination on the Italian healthcare system: a scenario analysis

abstract:
IntroductionThe objective of this study is to estimate the effects of the national immunisation strategy for Covid-19 in Italy on the national healthcare system.

MethodsAn epidemiological scenario analysis was developed in order to simulate the impact of the Covid-19 pandemic on the Italian national healthcare system in 2021. Hospitalisations, ICU admissions and death rates were modelled based on 2020 data. We forecast the impact of the introduction of a primary prevention strategy on the national healthcare system by considering vaccine efficacy, availability of doses and potential population coverage over time.

ResultsIn the absence of immunisation, between 57,000 and 63,000 additional deaths are forecast in 2021. Based on the assumptions underlying the two epidemiological scenarios from the 2020 data, our model predicts that cumulative hospital admissions in 2021 will range from 3.4 to 3.9 million. The deployment of vaccine immunisation has the potential to control the evolution of 2021 infections and avoid from 60 to 67 percent of deaths compared to not vaccinating.

ConclusionsIn order to inform Italian policymakers on delivering a mass vaccination programme, this study highlights and detects some key factors that must be controlled to ensure that immunisation targets will be met in reasonable time.

category: health policy


title: The Impact of Face-Masks on Total Mortality Heterogenous Effects by Gender and Age

abstract: Governments around the world have been implementing several non-pharmaceutical interventions (NPIs) to fight Covid-19 spread and its associated mortality. We estimate the causal impact of mandatory face-mask wearing policy in public places on (total) mortality in Switzerland. We exploit the staggered introduction of the policy across Swiss cantons using a Difference-in-Difference and an event study approach. We find that the extension of compulsory mask wearing to public places has an heterogeneous impact on mortality, with small positive effects on male mortality entirely driven by older age-cohorts (90+). Finally, we show that adding contact tracing and stricter distancing to compulsory face-mask policy does not lead to better results in terms of mortality.


title: Rising Through the Pandemic: A scoping review of quality improvement in public health during the COVID-19 pandemic

abstract:
BackgroundThe COVID-19 pandemic generated a growing interest in and need for evidence-based tools to facilitate the implementation of emergency management strategies within public health practice. Quality improvement (QI) has been identified as a key framework and philosophy to guide organizational emergency response efforts; however, the nature and extent to which it has been used in public health settings during the COVID-19 pandemic remains unclear.

MethodsWe conducted a scoping review of literature published January 2020 - February 2021 and focused on the topic of QI at public health agencies during the COVID-19 pandemic. The search was conducted on four bibliographic databases, in addition to a supplementary grey literature search using custom Google search engines and targeted website search methods. Of the 1,878 peer-reviewed articles assessed, 15 records met the inclusion criteria. An additional 11 relevant records were identified during the grey literature search, for a total of 26 records included in the scoping review.

ResultsRecords were organized into five topics: 1) collaborative problem solving and analysis with stakeholders; 2) supporting learning and capacity building in QI; 3) learning from past emergencies; 4) implementing QI methods during COVID-19; and 5) evaluating performance using frameworks/indicators.

ConclusionsThe literature indicates that QI-oriented activities are occurring at the organizational and program levels to enhance COVID-19 response. To optimize the benefits that QI approaches and methodologies may offer, it is important for public health agencies to focus on both widespread integration of QI as part of an organizations management philosophy and culture, as well as project level activities at all stages of the emergency management cycle.

category: health systems and quality improvement


title: Antibody Responses after SARS-CoV-2 Vaccination in Lymphoma

abstract:
Individuals with lymphoid malignancies have an increased mortality risk from COVID-19. Paradoxically, this population is least likely to be protected by SARS-CoV-2 vaccination as a result of disease- or treatment-related immunosuppression. Current data on vaccine responses in persons with lymphoid malignancies is limited.

PROSECO is a UK multi-centre prospective observational study evaluating COVID-19 vaccine immune responses in individuals with lymphoma. This early interim analysis details the antibody responses to first- and second-SARS-CoV-2 vaccination with either BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca), in 129 participants. Responses are compared to those obtained in healthy volunteers.

The key findings of this interim analysis are first, 61% of participants who are vaccinated during or within 6 months of receiving systemic anti-lymphoma treatment, do not have detectable antibodies despite two doses of vaccine. Second, individuals with curable disease such has Hodgkin (6/6) and aggressive B-cell non-Hodgkin lymphoma (13/16) develop robust antibody levels to either first or second doses, when vaccinated > 6 months after treatment completion. Third, participants incurable, indolent lymphomas have reduced antibody levels to first and second vaccine doses, irrespective of treatment history. Finally, whilst there was no difference in antibody responses between BNT162b2 and ChAdOx1 in lymphoma participants, BNT162b2 induces 11-fold higher antibody responses than ChAdOx1 after the second dose in healthy donors.

These findings serve to reassure the community that individuals with treated Hodgkin and aggressive B-NHL can develop antibody responses to SARS-CoV-2 vaccine. Simultaneously it also highlights the critical need to identify an alternative strategy against COVID-19 for those undergoing systemic anti-lymphoma treatment, and for individuals with indolent lymphomas.

category: hematology


title: CD56brightCD16- NATURAL KILLER CELLS ARE IN HIGHER COUNTS IN THE UMBILICAL CORD BLOOD THAN IN THE PERIPHERAL BLOOD

abstract:
Umbilical cord blood (UCB) is an alternative source for hematopoietic stem cells allogeneic hematopoietic stem cell transplantation in the absence of compatible donor. UCB transplantation has a lower incidence of chronic graft versus host disease (GvHD) but is associated with slower engraftment and slower immune reconstitution as compared to other sources. Dendritic cells (DC) and Natural Killer cells (NK) play a central role in the development of GVHD, the graft versus leukemia (GvL) effect, and in the control of infectious complications. We quantified by multiparametric flow cytometry monocytes, lymphocytes, NK cells, and DC, including their subsets, in UCB samples from 54 healthy newborns and peripheral blood (PB) from 25 healthy adult volunteers. In the UCB samples, there were higher counts of CD56brightCD16-NK cells (median 0.024x109/L), as compared to the PB samples (0.012x109/L, P<0.0001), CD56dimCD16bright NK cells (median 0.446x109/L vs. 0.259x109/L for PB samples, P= 0.001), and plasmacytoid dendritic cells (pDC, median 0.008x109/L for UCB samples vs. 0.006x109/L for PB samples, P= 0.03). Moreover, non-classical monocytes counts were lower in UCB than in PB (median 0.024x109/L vs. 0.051 x109/L, respectively, P< 0.0001). In conclusion, there were higher counts of NK cells and pDC, and lower counts of non-classical monocytes in UCB than in PB from healthy individuals. These findings might explain the lower incidence and severity of chronic GVHD although maintaining the GVL effect in UCB transplants recipients as compared to other stem cell sources.

HighlightsO_LICD56brightCD16- NK cells are more frequent in UCB than in PB.
C_LIO_LIPlasmacytoid dendritic cells are more frequent in UCB than in PB.
C_LIO_LINon-classical monocytes are more frequent in PB than in UCB.
C_LI


title: Second wave of COVID-19 in India could be predicted with genomic surveillance of SARS-CoV-2 variants coupled with epidemiological data: A tool for future

abstract: India recently witnessed a devastating second wave of COVID-19, which peaked by the end of the first week of May 2021. We aimed to understand formation and spread of the second wave in the country. We analyzed time series distribution of the genomic sequence data for SARS-CoV-2 and correlated that with the epidemiological data for new cases and deaths, for the corresponding period of the second wave. Further we analyzed the phylodynamics of the circulating SARS-CoV-2 variants in the Indian population in the period of study. Our analysis shows that the first indications of arrival of the second wave were observable by the end of January 2021, and by the end of March, 2021 it was clearly indicated. B.1.617 lineage variants drove the wave, particularly B.1.617.2 (a.k.a. delta variant). Based on the observations of this study, we propose that genomic surveillance of the SARS-CoV-2 variants augmented with epidemiological data can be a promising tool for forecasting imminent COVID-19 waves.

category: infectious diseases


title: REGEN-COV Antibody Cocktail in Outpatients with Covid-19

abstract:
BackgroundContinued SARS-CoV-2 infections and COVID-19-related hospitalizations highlight the need for effective anti-viral treatments in the outpatient setting. In a descriptive interim analysis of the phase 1/2 portion of a double-blind phase 1/2/3 trial in COVID-19 outpatients conducted between June 16, 2020 and September 4, 2020, REGEN-COV(R) (casirivimab plus imdevimab) antibody combination reduced SARS-CoV-2 viral load versus placebo.

MethodsThis final phase 1/2 analysis comprises 799 outpatients, including 275 from the previous descriptive analysis (group-1) and 524 from phase 2 (group-2). Patients were randomized (1:1:1) to placebo, REGEN-COV 2400mg, or REGEN-COV 8000mg. Prespecified hierarchical analyses of virologic endpoints were performed in group-2. The proportion of patients with [≥]1 COVID-19-related medically attended visit (MAV) through day 29 was assessed in group-1+2. Efficacy was assessed in patients confirmed SARS-CoV-2-positive by baseline nasopharyngeal RT-qPCR. Safety was assessed in all treated patients.

ResultsData from 799 outpatients enrolled from June 16, 2020 to September 23, 2020 are reported. Time-weighted average daily reduction in viral load through day 7 was significantly greater in the REGEN-COV combined 2400mg+8000mg group versus placebo in patients with baseline viral load >107 copies/mL (prespecified primary endpoint): -0.68 log10 copies/ml (95% CI, -0.94 to -0.41; P<.0001). This reduction was - 0.73 (P<.0001) and -0.36 (P=.0003) log10 copies/mL in serum antibody-negative patients and in the overall population, respectively. REGEN-COV reduced the proportion of patients with [≥]1 COVID-19-related MAV versus placebo (2.8% [12/434] REGEN-COV combined dose group versus 6.5% [15/231] placebo; P=.024; relative risk reduction [RRR]=57%); in patients with [≥]1 risk factor for hospitalization, the treatment effect was more pronounced (RRR=71%). Adverse events were similar across groups.

ConclusionsIn COVID-19 outpatients enrolled prior to the widespread circulation of delta and omicron variants, treatment with REGEN-COV significantly reduced viral load and COVID-19-related MAVs.


title: REGEN-COV Antibody Combination in Outpatients With COVID-19 - Phase 1/2 Results


title: Plasma zinc status and hyperinflammatory syndrome in hospitalized COVID-19 patients

abstract:
Deficiency of the element zinc is associated with cytokine releasing syndrome (CRS) and the related acute respiratory distress syndrome as well as impaired antiviral response. Similar complications associate with severe SARS-CoV-2.

We conducted a prospective, single-center, observational study in a tertiary university hospital (CUB-Hopital Erasme, Brussels) to address the zinc status, the association between the plasma zinc concentration, development of CRS, and the clinical outcomes in PCR-confirmed and hospitalized COVID-19 patients. One hundred and thirty-nine eligible patients were included between May 2020 and November 2020 (median age of 65 years [IQR, 54 to 77]).

Our cohorts mean plasma zinc concentration was 56.2 {micro}g/dL (standard deviation [SD], 14.8) compared to 75.7 {micro}g/dL (SD = 18.9 {micro}g/dL) in the retrospective non-COVID-19 control group (N = 1513; P <.001). Markedly, the absolute majority of patients (96%) were zinc deficient (<80 {micro}g/dL).

The mean zinc concentration was lower in patients with CRS compared to those without CRS (-5 {micro}g/dL; 95% CI, -10.5 to 0.051; P = 0.048).

Among the tested outcomes, zinc concentration is significantly correlated with only the length of hospital stay (rho = -0.19; P = 0.022), but not with mortality or morbidity. As such, our findings do not support the role of zinc as a robust prognostic marker among hospitalized COVID-19 patients who in our cohort presented high prevalence of zinc deficiency. It might be more beneficial to explore the role of zinc as a biomarker for assessing the risk of developing a tissue-damaging CRS and predicting outcomes in patients diagnosed with COVID-19 at the early stage of the disease.


title: Plasma zinc status and hyperinflammatory syndrome in hospitalized COVID-19 patients: an observational study


title: Spatial Accessibility Modeling of Vaccine Deserts as Barriers to Controlling SARS-CoV-2 Transmission

abstract: SARS-CoV-2 vaccine distribution is at risk of further propagating the inequities of COVID-19, which in the United States (US) has disproportionately impacted the elderly, people of color, and the medically vulnerable. We identify vaccine deserts - US Census tracts with localized, geographic barriers to vaccine-associated herd immunity - using a comprehensive supply database (VaccineFinder) and an empirically parameterized model of spatial access to essential resources. Incorporating high-resolution COVID-19 burden and time-willing-to-travel for vaccination, we show that early (February - March 2021) vaccine allocation disadvantaged rural and medically vulnerable populations. Data-driven vaccine distribution to vaccine deserts may improve immunization in the hesitant and control SARS-CoV-2.


title: Development and usability testing of two arts-based knowledge translation tools for parents about pediatric fever

abstract:
Fever is defined as an elevated body temperature greater or equal to 38 degrees celsius when measured via the ear canal. It is a common bodily response in children and is typically a benign process that is self-limiting. However, fever can be an anxiety provoking event for some parents because their child can look unwell and become irritable as a result. Past attempts at translating medical knowledge about fever and its management strategies into parent-friendly formats exist; however, parent misperceptions about definition and management persist despite these educational tools.

Our research team employs patient engagement techniques to develop resources for parents to enhance the uptake of complex medical knowledge. First, our research group conducts qualitative interviews and knowledge synthesis of the literature. Following analysis, salient themes are used to develop a script and skeleton for our videos and infographics, respectively. Employing this same process, this paper discusses the development and usability testing of two digital tools for fever. Prototypes for the video and infographic were tested by parents in urban and remote emergency department (ED) waiting rooms. A total of 58 surveys were completed by parents. Overall, parents rated both the fever video and infographic favourably, suggesting that patient engaged research methods and digital formats are mediums that can facilitate knowledge transfer.

category: pediatrics


title: Preterm birth, stillbirth, and early neonatal mortality during the Danish COVID-19 lockdown

abstract:
ImportanceUsing provisional or opportunistic data, three nationwide studies (The Netherlands, USA, and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, these findings have been challenged as none of the studies accounted for perinatal deaths.

ObjectiveTo determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be a result of an increase in number of perinatal deaths; and to assess the impact of extended COVID-19 restrictions on the prevalence of preterm birth and perinatal death.

DesignThe study is a nationwide Danish register-based prevalence proportion study using detailed data to capture all births (induced abortions were excluded) throughout Denmark. We assessed the prevalence of stillbirth, preterm birth, and early neonatal death.

SettingPopulation-based study

ParticipantsAll singleton pregnancies delivered in Denmark, between February 27, and September 30, 2015-2020. COVID-19 lockdown was studied in 31,164 births and the extended period of COVID-19 restrictions in 214,862 births.

ExposureCOVID-19 restrictions broadly (February 27, - September 30, 2020) or COVID-19 lockdown specifically (March 12, - April 14, 2020).

Main OutcomePrevalence of preterm births, stillbirths and early neonatal deaths across the periods under study.

ResultsThe extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period, while perinatal mortality was not significantly different. During the extended period of restrictions, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found.

Conclusion and RelevanceStillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes.

FundingNone

Key pointsO_ST_ABSQuestionC_ST_ABSCan changes in stillbirth and early neonatal mortality rates during the COVID-19 lockdown explain the reduction in extremely preterm birth seen in Denmark?

FindingsIn this nationwide register-based study that included data pertaining to 245,999 pregnancies, the statistically significant reduction in extremely preterm birth during the COVID-19 lockdown was confirmed. The stillbirth and early neonatal mortality rates were unchanged during lockdown, while the stillbirth rate was reduced over the extended period of COVID-19 restrictions.

MeaningThe reduction in extremely preterm births seen during the COVID-19 lockdown in Denmark is not a result of increased stillbirth or early neonatal death.


title: The effect of obesity-related traits on COVID-19 severe respiratory symptoms is mediated by socioeconomic status: a multivariable Mendelian randomization study

abstract:
BackgroundObesity has been associated with more severe clinical manifestations of coronavirus disease 2019 (COVID-19). However, this association can be affected by many correlates of these traits. Due to its large impact on human health, socioeconomic status (SES) could at least partially influence the association between obesity and COVID-19 severity. To estimate the independent effect of traits related to body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (MR) study analyzing the effect of obesity-related anthropometric traits on COVID-19 outcomes.

MethodsApplying two-sample MR approaches, we evaluated the effects of body mass index (BMI), waist circumference (WC), hip circumference, (HIP) and waist-hip ratio (WHR) studied in up to 234,069 participants from the Genetic Investigation of ANthropometric Traits (GIANT) consortium with respect to three COVID-19 outcomes: severe respiratory COVID-19 (5,101 cases vs. 1,383,241 controls), hospitalized COVID-19 (9,986 cases vs. 1,877,672 controls), and COVID-19 infection (38,984 cases vs. 1,644,784 controls) obtained from the COVID-19 Host Genetics Initiative (HGI). Finally, to test the effect of SES using multivariable MR methods, we analyzed genetic data related to self-reported household income (HI) information from 286,301 UK Biobank (UKB) participants.

ResultsBMI and WC were associated with severe respiratory COVID-19 (BMI: OR=1.68 p=0.0004; WC: OR=1.72, p=0.007) and COVID-19 hospitalization (BMI: OR=1.62, p=1.35e-06; WC: OR=1.62, p=0.0001). Also, HIP influenced hospitalized COVID-19 (OR=1.31, p=0.012) and COVID-19 infection (OR=1.18, p=0.002). Conversely, HI was associated with lower odds of severe respiratory COVID-19 (OR=0.57, p=0.011) and hospitalized COVID-19 (OR=0.71, p=0.045). Testing these effects in multivariable MR models, we observed that the effect of these obesity-related anthropometric traits on COVID-19 outcomes is not independent of SES effect assessed as HI.

ConclusionsOur findings indicate that low SES is a contributor to the observed association between body size and COVID-19 outcomes.


title: Cigarette Smoking-Associated Isoform Switching and 3-prime UTR Lengthening Via Alternative Polyadenylation

abstract:
BackgroundCigarette smoking accounts for approximately one in five deaths in the United States. Previous genomic studies have primarily focused on gene level differential expression to identify related molecular signatures and pathways, but the genome-wide effects of smoking on alternative isoform regulation and posttranscriptional modulation have not yet been described.

ResultsWe conducted RNA sequencing (RNA-seq) in whole-blood samples of 454 current and 767 former smokers in COPDGene Study. We assessed the association of current smoking with differential expression of genes and isoforms and differential usage of isoforms and exons. At 10% FDR, we detected 3,167 differentially expressed genes, 2,014 differentially expressed isoforms, 945 differentially used isoforms and 160 differentially used exons. Genes containing differentially used isoforms were enriched in biological pathways involving GTPase activity and innate immunity. The majority of these genes were not differentially expressed, thus not identifiable from conventional differential gene expression analysis. Isoform switch analysis revealed for the first time widespread 3' UTR lengthening associated with cigarette smoking, where current smokers were found to have higher expression and usage of isoforms with markedly longer 3' UTRs. The lengthening of 3' UTRs appears to be mediated through alternative usage of distal polyadenylation sites, and these extended 3' UTR regions are significantly enriched with functional sequence elements including adenylate-uridylate (AU)-rich elements, microRNA and RNA-protein binding sites. Expression quantitative trait locus analyses on differentially used 3' UTRs identified 79 known GWAS variants associated with multiple smoking-related human diseases and traits.

ConclusionsSmoking elicits widespread transcriptional and posttranscriptional alterations with disease implications. It induces alternative polyadenylation (APA) events resulting in a switch towards the usage of isoforms with strikingly longer 3' UTRs in genes related to multiple biological pathways including GTPase activity and innate immunity. The extended 3' UTR regions are enriched with functional sequence elements facilitating post-transcriptional regulation of protein expression and mRNA stability. These findings warrant further studies on APA events as potential biomarkers and novel therapeutic targets for smoking-related diseases.

category: respiratory medicine


title: Pretransplant BK virus-specific T-cell-mediated immunity and serotype specific antibodies may have utility in identifying patients at risk for BK virus associated haemorrhagic cystitis after allogeneic HSCT

abstract: BK polyomavirus (BKV) persists lifelong in the urinary tract with asymptomatic urinary shedding in healthy individuals. In immunocompromised persons after transplantation of hematopoietic stem cells (HSCT) the BKV high-rate replication is associated with haemorrhagic cystitis (HC) with a reported incidence of 17 %. Numerous studies of reconstitution of the immune system after HSCT have established the principal role of T cell effectors in the control of viral replication and reactivation. The value of pretransplant BKV-specific antibodies in transplanted patients for the protection from viral disease was long considered insignificant. We hypothesized that the status of BKV immunity prior to HSCT could provide evidence for the BKV tendency to reactivate and that examining the level of subtype-specific antibodies and T-cell response in individual patients could help to predict the risk of BKV reactivation and HC. Evaluation of the risk of HC in relation to pretransplant anti-BKV1,2,4 IgG levels together with clinical factors known before transplantation revealed that patients with "medium" anti-BKV IgG and significant clinical risk (SR) have a very significantly increased HC risk in comparison with the reference group of "low" anti-BKV IgG level and low clinical risk (LR) (P=0.0009). Predictive value of pretransplant BKV specific IgG was confirmed on the level of virus genotypes. Analysis of pretransplant T cell immunity to BKV antigens VP1 and LTag has shown that magnitude of IFN-gamma T cell response inversely corelated with posttransplant DNAuria. We hypothesize that the control of BKV latency by BKV specific T cells before HSCT would be one of the factors that influence BKV reactivation after HSCT. Our study has shown that prediction using a combination of clinical and immunological pretransplant risk factors can help early identification of patients who are at risk of developing BKV disease after HSCT.

category: transplantation


title: Multi-omic landscaping of human midbrains identifies neuroinflammation as major disease mechanism in advanced-stage Parkinson's disease

abstract: Parkinsons disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The disease mechanisms of sporadic PD are not yet completely understood. Therefore, causative therapies are still lacking. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains. Tissue from 13 PD patients and 10 controls was subjected to small RNA sequencing, transcriptomics, and proteomics analysis. Differential expression analyses were performed reveal multiple deregulated molecular targets linked to known pathomechanisms of PD as well as novel processes. We found significant differential expression of miR-539-3p, miR-376a-5p, miR-218-5p, and miR-369-3p, the valid miRNA-mRNA interacting pairs of miR-218-5p/RAB6C, and miR-369-3p/GTF2H3, as well as multiple proteins relevant in the pathology of PD, including CHI3L1, SELENBP1, PRDX1, HSPA1B, and TH. Vertical integration of multiple omics analyses allowed to validate disease-mediated molecular alterations across different molecular layers and functional annotation of differentially expressed targets identified a strong enrichment of pathways related to inflammation and activation of the immune response. This suggests that neuroinflammation may significantly contribute to disease progression in PD and may be a promising therapeutic target in advanced stages of PD.

category: neurology


title: You're too young to have an eye problem: Reasons for nonadherence to referrals for follow-up eye care for schoolchildren in Nigeria -- a descriptive qualitative study

abstract:
Study objectivesto identify reasons for non-adherence to referrals for follow-up eye care after children fail a school vision screening test.

MethodsTen focus groups were held with parents or guardians ( parents) of children who had not adhered to the referral for further care in Cross River State, Nigeria, in 2019. Data from verbatim transcripts were analysed deductively using topics from the interview guide plus  Other to capture unanticipated results. Analysts followed procedures for Qualitative Content Analysis plus a modified Framework Method to identify overarching themes and barriers that are both highly salient (most frequently mentioned) and relevant (discussed in at least half of all groups).

ResultsThree themes identified in the data are 1) modifiable barriers (key among them being parental beliefs and problems with the referral letter), 2) contextual factors (parents situation, attitudes towards children and beliefs about care) and 3) participants recommendations to improve the child eye care program (educate the general public and correct parents misconceptions). Many of the findings echoed those from previous studies conducted in both low-and-middle income countries (LMICs) and high-income countries (HICs).

ConclusionThis study went beyond identifying modifiable barriers to also identify contextual factors and what parents recommend be done to improve vision care for children in Cross River State, Nigeria. If acted on, these findings may increase acceptance and uptake of eye care services that can promote sustainability and spread of the program to other parts of Nigeria and/or Africa.

category: ophthalmology


title: Inequalities in healthcare disruptions during the Covid-19 pandemic: Evidence from 12 UK population-based longitudinal studies

abstract:
BackgroundHealth systems worldwide have faced major disruptions due to COVID-19 which could exacerbate health inequalities. The UK National Health Service (NHS) provides free healthcare and prioritises equity of delivery, but the pandemic may be hindering the achievement of these goals. We investigated associations between multiple social characteristics (sex, age, occupational social class, education and ethnicity) and self-reported healthcare disruptions in over 65,000 participants across twelve UK longitudinal studies.

MethodsParticipants reported disruptions from March 2020 up to late January 2021. Associations between social characteristics and three types of self-reported healthcare disruption (medication access, procedures, appointments) and a composite of any of these were assessed in logistic regression models, adjusting for age, sex and ethnicity where relevant. Random-effects meta-analysis was conducted to obtain pooled estimates.

ResultsPrevalence of disruption varied across studies; between 6.4% (TwinsUK) and 31.8 % (Understanding Society) of study participants reported any disruption. Females (Odd Ratio (OR): 1.27 [95%CI: 1.15,1.40]; I2=53%), older persons (e.g. OR: 1.39 [1.13,1.72]; I2=77% for 65-75y vs 45-54y), and Ethnic minorities (excluding White minorities) (OR: 1.19 [1.05,1.35]; I2=0% vs White) were more likely to report healthcare disruptions. Those in a more disadvantaged social class (e.g. OR: 1.17 [1.08, 1.27]; I2=0% for manual/routine vs managerial/professional) were also more likely to report healthcare disruptions, but no clear differences were observed by education levels.

ConclusionThe COVID-19 pandemic has led to unequal healthcare disruptions, which, if unaddressed, could contribute to the maintenance or widening of existing health inequalities.


title: Polymorphism of NAT2, PXR, ABCB1, and GSTT1 genes among tuberculosis patients of North Eastern States of India

abstract:
BackgroundAnti-tuberculosis drug-induced liver injury (AT-DILI) in tuberculosis (TB) patients has been linked to polymorphisms in genes encoding drug metabolism enzymes and proteins.

ObjectiveThis study aimed to monitor polymorphisms of NAT2, PXR, ABCB1, and GSTT1 genes in TB patients from three states (Manipur, Tripura, and Nagaland) in the North Eastern Region of India.

MethodsGenomic DNA was isolated from the whole blood samples of TB patients (n=219; Manipur:139; Tripura: 60; Nagaland: 20). The TaqMan allelic discrimination assay and statistical tools were used to investigate single nucleotide polymorphisms (SNP) patterns in NAT2, PXR, ABCB1, and GSTT1 genes.

ResultsIn the study population, ten distinct genotypes of the NAT2 gene and single variation in the PXR, ABCB1, and GSTT1 genes were identified. A strong linkage disequilibrium (LD) was observed between rs1801280 and rs1799931 of the NAT2 gene. Majority of the study populations were intermediate (~46.1%), rest were either slow acetylators (~35.6%) or fast acetylators. Interestingly, ~55% of the TB patients in Tripura were slow acetylators and majority in Manipur and Nagaland were of intermediate acetylator genotypes. For all of the markers investigated, the population had a greater prevalence of ancestral alleles and genotypes. According to a combinational study of the genotypes linked to AT-DILI, ~26.1% of the population possessed the risk genotypes.

ConclusionThese TB patients from north eastern states of India were found as carriers of the ancestral alleles and genotypes. And the risk for AT-DILI during TB treatment is low. Expanding such studies with additional markers and larger sample sizes will be useful to generate precise population-specific pharmacogenomics details for efficient TB management.


title: MicroRNA-based regulation of genomics and transcriptomics of inflammatory cytokines in COVID-19

abstract:
BackgroundCoronavirus disease 2019 is characterized by the elevation of a wide spectrum of inflammatory mediators, which are associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future.

MethodsThe cytokine regulating immune-expressed genes (CRIEG) was sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape.

ResultsSixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the MiRNA database yielded 10 (ten) miRNAs that are significantly involved in regulating these genes and their transcription factors.

ConclusionAn in-silico representation of a network involving miRNAs, CRIEGs, and TF which take part in the inflammatory response in COVID-19 has been elucidated. These regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.

category: allergy and immunology


title: Data-driven methodology for discovery and response to pulmonary symptomology in hypertension through AI and machine learning: Application to COVID-19 related pharmacovigilance

abstract:
BackgroundPotential therapy and confounding factors including typical co-administered medications, patients disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials.

MethodsIn this study, we implemented adaptive signal detection approaches to correct spurious association, hidden factors, and confounder misclassification when the covariates are unknown or unmeasured on medications affecting the renin-angiotensin system (RAS), potentially creating an increased risk of life-threatening outcomes in high-risk patients.

ResultsFollowing multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pADEs. Macitentan and bosentan were associates with 64% and 56% of pADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by our signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy.

ConclusionsWe consider pulmonary ADE (pADE) profiles in a long-standing group of therapeutics, RAS-acting agents, in patients with hypertension associated with high-risk for COVID-19. Using these techniques, we confirmed our hypothesis that drugs from the same drug class could have very different pADE profiles affecting outcomes in acute respiratory illness. We found that several indidvual drugs have significant differences between their drug classes and compared to other drug classes.

FundingGJW and MJD accepted funding from BioNexus KC for funding on this project but BioNexus KC had no direct role in this article.

Clinical trial numberN/A

Author SummaryUnderlying comorbidities continue to negatively affect COVID-19 patients. A recent focus has been on medications affecting RAS. Therefore, with the advent of COVID-19 acute respiratory distress syndrome (ARDS) in high-risk patients with hypertension, identifying specific RAS medications with the lowest incidence of pADEs would be beneficial. For this purpose, we curated the FDA ADE database to search for information related to human pADEs. As part of post-marketing drug safety surveillance, state/federal regulatory agencies and other institutions provide massive collections of ADE reports, these large data-sets present an opportunity to investigate ADEs to provide patient management based on comparative population data analysis. The abundance and prevalence of ADEs are not always detectable during randomized clinical trials and before a drug receives FDA approval for use in the clinic, which may appear with more widespread use. This is especially true for specific agents or diseases since there are simply too few events to be assessed, even in a large clinical trial for side effect profiles of specific disease states. For this purpose, we employed a novel method identifying extraneous causes of differential reporting including sampling variance and selection biases by reducing the effect of covariates.

category: cardiovascular medicine


title: Modelling the impact of fexinidazole use on human African trypanosomiasis (HAT) transmission in the Democratic Republic of the Congo

abstract: Gambiense human African trypanosomiasis is a deadly disease that has been declining in incidence since the start of the Century, primarily due to increased screening, diagnosis and treatment of infected people. The main treatment regimen currently in use requires a lumbar puncture as part of the diagnostic process to determine disease stage and hospital admission for drug administration. Fexinidazole is a new oral treatment for stage 1 and non-severe stage 2 human African trypanosomiasis. The World Health Organization has recently incorporated fexinidazole into its treatment guidelines for human African trypanosomiasis. The treatment does not require hospital admission or a lumbar puncture for all patients, which is likely to ease access for patients; however, it does require concomitant food intake, which is likely to reduce adherence. Here, we use a mathematical model calibrated to case and screening data from Mushie territory, in the Democratic Republic of the Congo, to explore the potential negative impact of poor compliance to an oral treatment, and potential gains to be made from increases in the rate at which patients seek treatment. We find that reductions in compliance in treatment of stage 1 cases are projected to result in the largest increase in further transmission of the disease, with failing to cure stage 2 cases also posing a smaller concern. Reductions in compliance may be offset by increases in the rate at which cases are passively detected. Efforts should therefore be made to ensure good adherence for stage 1 patients to treatment with fexinidazole and to improve access to passive care.

category: epidemiology


title: Early evidence for the safety of certain COVID-19 vaccines using empirical Bayesian modeling from VAERS

abstract: The advent of vaccines against SARS-CoV-2 ushered in an unprecedented global response to COVID-19, with the largest and most ambitious mass vaccination campaign in human history. The scale of this effort means that safety signals suggesting adverse effects may only be detectable using passive reporting. This paper examines reports to the CDC/FDAs VAERS system in the first six months of 2021, using an empirical Bayesian model with a gamma Poisson shrinker to identify potential safety signals from COVID-19 vaccines currently on the U.S. market. Based on this preliminary data, it is concluded that the COVID-19 vaccines safety significantly exceeds that of previously marketed vaccines, and other than a known risk of thrombotic events, no safety signals of concern emerge.


title: Data-driven identification of health conditions associated with incident Alzheimer's disease dementia risk: a 15 years follow-up cohort from electronic health records in France and the United Kingdom

abstract:
ImportanceThe identification of modifiable risk factors for Alzheimers disease (AD) is paramount for early prevention and the targeting of new interventions.

ObjectiveTo assess the associations between health conditions diagnosed in primary care and the risk of incident AD over time.

Design, Setting, and ParticipantsData for 20,214 AD patients from the United Kingdom and 19,458 AD patients from France were extracted from The Health Improvement Network (THIN) database. For each AD case, a control was randomly assigned after matching for sex and age at dementia diagnosis. We agnostically tested the associations between 123 different ICD10 diagnoses extracted from health records and AD dementia, by conditional logistic regression. We focused on two time periods: 2 to 10 years vs. 0 to 2 years before the diagnosis of AD, to separate risk factors from early symptoms/comorbidities.

ExposuresWe considered all health conditions that had been recorded in more than 0.1% of visits per 1000 person-years in both cohorts, corresponding to 123 potential types of exposure.

Main Outcomes and MeasuresOdds ratios (ORs) for the association of AD with the various health conditions were calculated after Bonferroni correction for multiple comparisons.

ResultsTen health conditions were significantly associated with high odds ratios for AD when diagnosed 2 to 10 years before AD, in the British and French samples: major depressive disorder (OR 95% confidence interval (UK):1.23-1.46)), anxiety (1.25-1.47), reaction to severe stress (1.24-1.59), hearing loss (1.11-1.28), constipation (1.22-1.41), spondylosis (1.14-1.39), abnormal weight loss (1.33-1.63), malaise and fatigue (1.14-1.32), memory loss (6.65-8.76) and syncope and collapse (1.1-1.37). Depression was the first comorbid condition associated with AD, appearing at least nine years before the first clinical diagnosis of AD, followed by, anxiety, constipation and abnormal weight loss.

Conclusions and RelevanceThese results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimers disease. These results could guide new dementia prevention strategies.


title: Modeling and reviewing analysis of the COVID-19 epidemic in Algeria with diagnostic shadow

abstract: In this paper, we formulate a special epidemic dynamic model to describe the transmission of COVID-19 in Algeria. We derive the threshold parameter control reproduction number [Formula], and present the effective control reproduction number (Rc(t)) as a real-time index for evaluating the epidemic under different control strategies. Due to the limitation of the reported data, we redefine the number of accumulative confirmed cases with diagnostic shadow and then use the processed data to do the optimal numerical simulations. According to the control measures, we divide the whole research period into six stages. And then the corresponding medical resource estimations and the average effective control reproduction numbers for each stage are given. Meanwhile, we use the parameter values which are obtained from the optimal numerical simulations to forecast the whole epidemic tendency under different control strategies.


title: SARS-CoV-2-antibody response in health care workers after vaccination or natural infection in a longitudinal observational study

abstract:
BackgroundFollowing a year of development, several vaccines have been approved to contain the global COVID-19 pandemic. Real world comparative data on immune response following vaccination or natural infection are rare.

MethodsWe conducted a longitudinal observational study in employees at a secondary care hospital affected by the COVID-19 pandemic. Comparisons were made about the presence of anti-SARS-CoV-2 immunglobulin G (IgG) antibody ratio after natural infection, or vaccination with one or two doses of BioNTech/Pfizer (BNT162b2), or one dose of AstraZenca (Vaxzevria) vaccine.

ResultsWe found a 100% humoral response rate in participants after 2 doses of BNT162b2 vaccine. The antibody ratio in participants with one dose BNT162b2 and Vaxzevria did not differ significantly to those with previous PCR-confirmed infection, whereas this was significantly lower in comparison to two doses of BioNTech/Pfizer. We could not identify a correlation with previous comorbidities, obesity or age within this study. Smoking showed a negative effect on the antibody response (p=0.006)

ConclusionOur data provide an overview about humoral immune response after natural SARS-CoV-2 infection or following vaccination, and supports the usage of booster vaccinations, especially in patients after a natural SARS-CoV-2 infection.


title: SARS-COV-2 VIRUS INFECTED PATIENT IDENTIFICATION THROUGH CANINE OLFACTIVE DETECTION ON AXILLARY SWEAT SAMPLES

abstract:
Facing the COVID-19 pandemic, testing individuals in order to promptly isolate positive people is one of the key actions. One approach to rapid testing might be to consider the olfactory capacities of trained detection dogs in order to develop a non-invasive, rapid and cheap mass detection approach, through the Volatile Organic Compounds (VOCs) signature of SARS-CoV-2 infection.

The goal of this study was to determine the individual values of sensitivity and specificity of trained dogs when performing olfactory detection of COVID-19 on axillary sweat samples. Seven dogs were used to sniff a total of 218 samples (62 COVID-19 positive and 156 COVID-19 negative samples), based on a randomised and double-blinded protocol carried out on olfaction cone line-ups. To ensure a wide olfactory range as close as possible to operational conditions, the samples were retrieved from 13 different sites.

Sensitivities varied from 87% to 94% for 6 dogs, and were above 90% for 3 of them. Only one dog, whose sensitivity was 60%, was not selected to subsequently enter the operational stage. Specificities varied from 78% to 92%, with 6 dogs over 85% and 4 dogs over 90%.

Based on the calculated sensitivity and specificity for each dog, positive and negative predictive values (PPV and NPV) were calculated according to several prevalence rates of SARS-CoV-2 scenarii, and were compared to PPV and NPV of an "almost perfect" diagnostic tool. For 6 out of the 7 dogs, and for a prevalence rate of SARS-CoV-2 lower or equal than 40%, the NPV of the dogs were virtually the same as the one of the "almost perfect" tool. Along with other studies on olfactory detection of COVID-19 by dogs these positive and encouraging results suggest that olfactory dogs may play an important part in mass COVID-19 pre-testing situations.


title: Comprehensive characterization of COVID-19 patients with repeatedly positive SARS-CoV-2 tests using a large US electronic health record database

abstract:
BackgroundIn the absence of genome sequencing, two positive molecular SARS-CoV-2 tests separated by negative tests, prolonged time, and symptom resolution remain the best surrogate measure of possible re-infection.

MethodsUsing a large electronic health record database, we characterized clinical and testing data for 23 patients with repeatedly positive SARS-CoV-2 PCR test results [≥]60 days apart, separated by [≥]2 consecutive negative test results. Prevalence of chronic medical conditions, symptoms and severe outcomes related to COVID-19 illness were ascertained.

ResultsMedian age was 64.5 years, 40% were Black, and 39% were female. 83% smoked within the prior year, 61% were overweight/obese, 83% had immune compromising conditions, and 96% had [≥]2 comorbidities. Median interval between the two positive tests was 77 days. Among the 19 patients with 60-89 days between positive tests, 17 (89%) exhibited symptoms or clinical manifestations indicative of COVID-19 at the time of the second positive test and 14 (74%) were hospitalized at the second positive test. Of the four patients with [≥]90 days between two positive tests, two had mild or no symptoms at the second positive test and one, an immune compromised patient, had a brief hospitalization at the first diagnosis, followed by ICU admission at the second diagnosis three months later.

ConclusionsOur study demonstrated a high prevalence of immune compromise, comorbidities, obesity and smoking among patients with repeatedly positive SARS-CoV-2 tests. Despite limitations, including lack of semi-quantitative estimates of viral load, these data may help prioritize suspected cases of reinfection for investigation and continued surveillance.

ImportanceComprehensive characterization of clinical and SARS-CoV-2 testing data for patients with repeatedly positive SARS-CoV-2 tests can help prioritize suspected cases of reinfection for investigation in the absence of sequencing data and for continued surveillance for potential long-term health consequences of SARS-CoV-2 infection.


title: Seasonal variation in SARS-CoV-2 transmission in temperate climates

abstract: While seasonal variation has a known influence on the transmission of several respiratory viral infections, its role in SARS-CoV-2 transmission remains unclear. As previous analyses have not accounted for the implementation of non-pharmaceutical interventions (NPIs) in the first year of the pandemic, they may yield biased estimates of seasonal effects. Building on two state-of-the-art observational models and datasets, we adapt a fully Bayesian method for estimating the association between seasonality and transmission in 143 temperate European regions. We find strong seasonal patterns, consistent with a reduction in the time-variable Rt of 42.1% (95% CI: 24.7% - 53.4%) from the peak of winter to the peak of summer. These results imply that the seasonality of SARS-CoV-2 transmission is comparable in magnitude to the most effective individual NPIs but less than the combined effect of multiple interventions.


title: A Survey of the Smokefree Status of Pedestrian-Only Spaces in 10 New Zealand Local Government Areas

abstract:
AimTo describe the smokefree status and signage of outdoor pedestrian-only plazas/malls/boulevards in 10 New Zealand local government (council) areas.

MethodsThe 10 council areas were a convenience sample. Council websites were examined for smokefree policies and a systematic attempt was made to identify the five largest pedestrian-only sites with permanent seating in each council area (10 sites each for two larger cities). Field visits were conducted to all selected sites.

ResultsSmokefree policies with components covering smokefree outdoor plazas/malls/boulevards were common (80%; 8/10 councils), albeit with some gaps (eg, around signage and vaping policy). A total of 60 relevant pedestrianised sites with permanent seating were identified and surveyed. Of these 63% were officially designated smokefree. Smokefree signage was only present in 15% (9/60) of all the sites and in 24% (9/38) of the designated smokefree sites. In these designated sites the average number of smokefree signs was only 1.4 (range: 0 to 14). Issues identified with the signs included small size, being only a small part of a larger other sign, limited use of te reo M[a]ori wording, and not covering vaping. At sites where tables were present, 12% had ash trays on the tables (none where smokefree).

ConclusionsSmokefree plazas/malls/boulevards in this survey had multiple policy and signage deficiencies that are inconsistent with achieving the national smokefree goal for 2025. There is scope to address these issues with an upgrade to the national smokefree law.

category: public and global health


title: Moving from development to implementation of digital innovations within the NHS: myHealthE, a remote monitoring system for tracking patient outcomes in child and adolescent mental health services.

abstract: This paper reports our experience of developing, implementing, and evaluating myHealthE (MHE); a digital innovation for Child and Adolescents Mental Health Services (CAMHS) which automates the remote collection and reporting of Patient Reported Outcome Measures (PROMs) into National Health Services (NHS) electronic health care records. We describe the logistical and governance issues encountered in developing the MHE interface with patient identifiable information, and the steps taken to overcome these development barriers. We describe the applications architecture and hosting environment to enable it to be operable within the NHS, as well the as the capabilities needed within the technical team to bridge the gap between academic developers and NHS operational teams. We present evidence on the feasibility and acceptability for this system within clinical services and describe the process of iterative development, highlighting additional functions which were incorporated to increase system utility. This article provides a framework with which to plan, develop and implement automated PROM collection from remote devices back to NHS infrastructure. The challenges and solutions described in this paper will be pertinent to other digital health innovation researchers aspiring to deploy interoperable systems within NHS clinical systems.


title: Evaluation and clinical implications of the time to a positive results of antigen testing for SARS-CoV-2

abstract:
Antigen tests for severe acute respiratory coronavirus 2 sometimes show positive lines earlier than their specified read time, although the implication of getting the results at earlier time is not well understood. This study aimed to evaluate the clinical utility of an antigen test by evaluating the time period to get positive results and by comparing the test sensitivity with that of a digital immunoassay (DIA) test.

We prospectively collected additional nasopharyngeal samples from patients who had already tested positive for SARS-CoV-2 by reverse transcription PCR. The additional swab was used for an antigen test, QuickNavi-COVID19 Ag, and the time periods to get positive results were measured. The sensitivity of QuickNavi-COVID19 Ag was also compared with that of a DIA.

In 84 of 96 (87.5%) analyzed cases, the results of QuickNavi-COVID19 Ag were positive. The time to obtain positive results was 15.0 seconds in median (inter quartile range: 12.0-33.3, range 11-736), and was extended in samples with higher cycle thresholds (Ct) (p<0.001). Positive lines appeared within a minute in 85.7% of cases and within 5 minutes in 96.4%. The sensitivities of QuickNavi-COVID19 Ag and the DIA were 87.5% (95% confident interval [CI]: 79.2%-93.4%) and 88.6% (95%CI: 75.4%- 96.2%), respectively. Their results were concordant in 90.9% of cases, with discrepancies present only in cases with Ct values >32.

QuickNavi-COVID19 Ag immediately showed positive results in most cases, and the time to a positive reaction may have indicated the viral load. In addition, the sensitivity of the test was comparable to the DIA.


title: A systematic review assessing the potential for release of vector species from competition following insecticide-based population suppression of Anopheles species in Africa

abstract:
BackgroundWhile insecticide-based vector control can effectively target vector species in areas of high malaria endemicity, such as Anopheles gambiae in Africa, residual disease transmission can occur. Understanding the potential role of competitive displacement between vector species could inform both current insecticide-based vector control programmes and the development of future complementary interventions.

MethodsA systematic review was conducted to identify studies of insecticide-based vector control of Anopheles species in Africa that reported indices for absolute densities of vector species. After screening against inclusion, exclusion and risk of bias criteria, studies were assigned to three categories based on whether they showed population density changes involving decreases in two or more vector species (D), increases in two or more vector species (I), or increases in one vector species concomitant with decreases in another vector species (ID). Category ID studies could thus provide evidence consistent with the release of vector species from competition following the insecticide-based population suppression of Anopheles species.

ResultsOf 5,569 papers identified in searches, 30 were selected for quantitative and qualitative analysis. Nineteen studies were assigned to category D and 1 study to category I. Ten studies categorised as ID provided evidence ranging from weak to persuasive that release from competition could have contributed to changes in species composition. Category ID showed no statistical differences from category D for reductions in malaria transmission and levels of insecticide resistance, but did so for insecticide type, pyrethroids being associated with category ID. A qualitative assessment identified 5 studies that provided the most convincing evidence that release from competition could have contributed to changes in species composition.

ConclusionThis review identified evidence that insecticide-based reductions in the density of Anopheles species in Africa could facilitate the release of other vector species from competition. While it remains uncertain whether this evidence is representative of most entomological sequelae from the use insecticide-based vector control in the field, 5 studies provided persuasive evidence that insecticide use could lead, at least under some circumstances, to competitive release of non-targeted vector species. These results should inform current and future integrated vector management approaches to malaria control.


title: Determinants of adherence to COVID-19 preventive behaviours in Canada: Results from the iCARE Study

abstract:
ObjectiveKey to slowing the spread of SARS-Cov-2 is adherence to preventive behaviours promoted through government policies, which may be influenced by policy awareness, attitudes and concerns about the virus and its impacts. This study assessed determinants of adherence to major coronavirus preventive behaviours, including demographics, attitudes and concerns, among Canadians during the first pandemic wave.

MethodsAs part of the iCARE study (www.iCAREstudy.com), we weighted data from two population-based, online surveys (April and June, 2020) of Canadian adults. Questions tapped into behaviour change constructs. Multivariate regression models identified determinants of adherence.

ResultsData from 6,008 respondents (51% female) were weighted for age, sex, and province. Awareness of government policies was high at both time points (80-99%), and adherence to prevention behaviours was high in April (87.5%-93.5%) but decreased over time, particularly for avoiding social gatherings (68.1%). Adherence was worse among men, those aged 25 and under, and those currently working. Aligned with the Health Beliefs Model, perceptions of the importance of prevention behaviours and the nature of peoples COVID-19-related concerns were highly predictive of adherence. Interestingly, health and social/economic concerns predicted better adherence, but having greater personal financial concerns predicted worse adherence at both time points.

ConclusionAdherence to COVID-19 prevention behaviours was worse among men, younger adults, and workers, and deteriorated over time. Perceived importance of prevention behaviours measures and health and social/economic concerns predicted better adherence, but personal financial concerns predicted worse adherence. Results have implications for tailoring policy and communication strategies during subsequent pandemic waves.


title: Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM Collaborative Project

abstract: Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to assure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Preventions Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease associated genes, including common pathogenic and difficult to detect variants. Variant types nominated included 346 SNVs, 104 deletions, 37 CNVs, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 in difficult to sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation.


title: Heterozygous deleterious MUTYH variants as a driver for tumorigenesis

abstract: MUTYH is a glycosylase involved in the base excision repair of the DNA. Biallelic mutations in the MUTYH gene cause the autosomal recessive condition known as MUTYH-associated adenomatous polyposis and increase colorectal cancer risk. However, the cancer risk associated with germline variants in individuals carrying only one MUTYH defective allele is controversial and based on studies involving few samples. Here, we described a comprehensive investigation of monoallelic deleterious MUTYH carriers among approximately 10,400 patients across 33 different tumor types and more than 117 thousand samples of normal individuals. Our results indicate MUTYH deficiency in heterozygosity can lead to tumorigenesis through a mechanism of Loss Of Heterozygosity (LOH) of the functional MUTYH allele. We confirmed that the frequency of damaging MUTYH monoallelic variant carriers is higher in individuals with cancer than in the general population, though its frequency is not homogeneous among tumor types. We also demonstrate that MUTYH related mutational signature is elevated only in those patients with loss of the functional allele. We also find that MUTYH characteristic base substitution (C>A) increases stop codon generation and we identify key genes affected during tumorigenesis. In conclusion, we propose that deleterious germline monoallelic MUTYH variant carriers are at a higher risk of developing tumors, especially those types with frequent LOH events, such as adrenal adenocarcinoma.

category: oncology