title: Strategies to Estimate Prevalence of SARS-CoV-2 Antibodies in a Texas Vulnerable Population: Results from Phase I of the Texas Coronavirus Antibody REsponse Survey (TX CARES)

abstract:
IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and immunity remains uncertain in populations. The state of Texas ranks 2nd in infection with over 2.71 million cases and has seen a disproportionate rate of death across the state. The TX CARES project was funded by the state of Texas to estimate the prevalence of SARS-CoV-2 antibody status in children and adults.

Materials and MethodsThe TX CARES (Texas Coronavirus Antibody Response Survey) is an ongoing prospective population-based convenience sample from the Texas general population that commenced in October 2020. Volunteer participants are recruited across the state to participate in a 3-time point data collection TX CARES to assess antibody response over time. We use the Roche Elecsys(R) Anti-SARS-CoV-2 Immunoassay to determine SARS-CoV-2 antibody status.

ResultsThe crude antibody positivity prevalence in Phase I was 26.1% (80/307). The fully adjusted seroprevalence of the sample was 31.5%. Specifically, 41.1% of males and 21.9% of females were seropositive. For age categories, 33.5% of those 18-34; 24.4% of those 35-44; 33.2% of those 45-54; and 32.8% of those 55+ were seropositive. In this sample,42.2% (89/211) of those negative for the antibody test reported having had a COVID-19 test.

ConclusionsIn this survey we enrolled and analyzed data for 319 participants, demonstrating a high survey and antibody test completion rate, and ability to implement a questionnaire and SARS-CoV-2 antibody testing within FQHC clinical settings. We were also able to determine our capability to estimate the cross-sectional seroprevalence within Texass FQHC clinical settings. The crude positivity prevalence for SARS-CoV-2 antibodies in this sample was 26.1% indicating potentially high exposure to COVID-19 for FQHC clinic employees and patients. These methods are being used to guide the completion of a large longitudinal survey in the state of Texas with implications for practice and population health.

category: infectious diseases


title: SARS-CoV-2 antibody changes in patients receiving COVID-19 convalescent plasma from normal and vaccinated donors

abstract:
Background and ObjectivesVaccination has been shown to stimulate remarkably high antibody levels in donors who have recovered from COVID-19. Our objective was to examine patient antibody responses following COVID-19 Convalescent Plasma (CCP) transfusion and compare responses to CCP from vaccinated and nonvaccinated donors.

Materials and methodsPlasma samples were obtained from 25 recipients of CCP and COVID-19 antibody levels measured before and after CCP treatment. Factors that effect antibody levels were examined.

ResultsIn the 21 patients who received CCP from nonvaccinated donors, only modest increases in antibody levels were observed. Patients who received two units were more likely to seroconvert than those receiving just one unit. The strongest predictor of changes in patient antibody level was the CCP dose. Using patient plasma volume and donor antibody level, the post-transfusion antibody level could be predicted with remarkable accuracy. In contrast, the 4 patients who received CCP from vaccinated donors all had dramatic increases in antibody levels following transfusion of a single unit. In this subset of recipients, antibody levels observed after transfusion of CCP were comparable to those seen in donors who had fully recovered from COVID-19.

ConclusionIf available, CCP from vaccinated donors with very high antibody levels should be used. CCP from vaccinated donors increases patient antibody levels much more than 1 or 2 units of CCP from unvaccinated donors.


title: Increased circulating cell-free DNA in eosinophilic granulomatosis with polyangiitis: implications for eosinophil extracellular traps and immunothrombosis

abstract:
BackgroundEndogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV.

MethodsWe enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure, stability, and platelet adhesion of eosinophil extracellular traps (EETs) were also assessed in vitro.

ResultsSerum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. EETs showed greater stability against DNase than neutrophil extracellular traps and provided a scaffold for platelet adhesion in vitro.

ConclusioncfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs might contribute to the occurrence of immunothrombosis in EGPA.

category: allergy and immunology


title: DEVELOPMENT AND VALIDATION OF A MODEL FOR THE PREDICTION OF MORTALITY IN CHILDREN UNDER FIVE YEARS WITH CLINICAL PNEUMONIA IN RURAL GAMBIA

abstract:
BackgroundPneumonia is the leading cause of death in children aged 1-59 months. Prediction models for child pneumonia mortality have been developed using regression methods but their performance is insufficient for clinical use.

MethodsWe used a variety of machine learning methods to develop a predictive model for mortality in children with clinical pneumonia enrolled in population-based surveillance in the Basse Health and Demographic Surveillance System in rural Gambia (n=11,012). Four machine learning algorithms (support vector machine, random forest, artifical neural network, and regularized logistic regression) were implemented, fitting all possible combinations of two or more of 16 selected features. Models were shortlisted based on their training set performance, the number of included features, and the reliability of feature measurement. The final model was selected considering its clinical interpretability.

ResultsWhen we applied the final model to the test set (55 deaths), the area under the Receiver Operating Characteristic Curve was 0.88 (95% confidence interval: 0.84, 0.91), sensitivity was 0.78 and specificity was 0.77.

ConclusionsOur evaluation of multiple machine learning methods combined with minimal and pragmatic feature selection led to a predictive model with very good performance. We plan further validation of our model in different populations.

category: epidemiology


title: Association between anticholinergic burden and dementia in UK Biobank

abstract: Previous studies on the association between the long-term use of anticholinergic drugs and dementia report heterogenous results. This variability could be due to, among other factors, different anticholinergic scales used, and differential effects of distinct classes of anticholinergic drugs. Here, we use 171,775 participants of UK Biobank with linked GP prescription records to calculate the cumulative annual anticholinergic burden (ACB) and ascertain dementia diagnoses through GP- and inpatient records. We then compare 13 anticholinergic scales and anticholinergic burden (ACB) due to different classes of drugs in their association with dementia. We find dementia to be more strongly predicted by ACB than by polypharmacy across most anticholinergic scales (standardised ORs range: 1.027-1.125). Furthermore, not only the baseline ACB, but the slope of the longitudinal trajectory of ACB (HR=1.094; 95% CI: 1.068-1.119) is predictive of dementia. However, the association between ACB and dementia holds only for some classes of drugs - especially antidepressants, antiepileptics, and high-ceiling antidiuretics. Moreover, we do not find a clear relationship between reported anticholinergic potency and dementia risk. The heterogeneity in findings on the association between ACB and dementia may in part be due to different effects for different classes of drugs. Future studies should establish such differences in more detail and further examine the practicality of using a general measure of anticholinergic potency as it relates to the risk of dementia.

category: psychiatry and clinical psychology


title: Learning about COVID-19 across borders: Public health information and adherence among international travellers to the UK

abstract:
ObjectivePublic health control measures at borders have long been central to national strategies for the prevention and containment of infectious diseases. Travel was inevitably associated with the rapid global transmission of COVID-19. In the UK, public health authorities took action to reduce risks of travel-associated spread by providing public health information at ports of entry. This study aims to understand individual risk assessment processes, decision making, and adherence to official advice among international travellers; to provide evidence to inform future policy on the presentation of public health information to facilitate safer international travel.

Study designThis study is a qualitative study evaluation.

MethodSemi-structured interviews were conducted to investigate risk assessment processes, decision making, and adherence to official Public Health England (PHE) advice among travellers.

ResultsParticipants regarded official advice as adequate at the time, despite observing differences between the intervention measures implemented in the countries of departure. Participants however also described adopting precautionary measures including self-isolation and the use of face coverings that went beyond official advice, and variability in the extent to which they adhered to guidance on contacting health authorities. Adherence to official guidance was informed by the perceived salience of specific transmission possibilities and containment measures assessed in relation to participants social and institutional environments.

ConclusionAnalysis of travellers reported motivations demonstrates that responses to public health advice constitute a proactive process of risk assessment and rationalised decision-making that incorporates consideration of living situation, trust in information sources, correspondence with cultural logics, and willingness to accept potential risk to self and significant others in guiding preventive action. Our findings concerning international passengers understanding of, and compliance with, official advice and mitigation measures provide valuable evidence to inform future policy and we provide recommendations on the presentation of public health information to facilitate safer international travel. Access to a central source of regularly updated official information would help minimise confusion between different national guidelines. Greater attention to the differentiated information needs of diverse groups in creating future public-facing guidance would help to minimise the uncertainties generated by receipt of generic information.

category: public and global health


title: Accelerated partner therapy contact tracing for people with chlamydia: The LUSTRUM cluster cross-over randomised controlled trial

abstract:
ObjectiveTo assess accelerated partner therapy (APT) as a contact tracing intervention for people with chlamydia.

DesignCross-over cluster-randomised controlled trial.

Setting17 sexual health clinics (clusters) in the United Kingdom, 2018-2019.

ParticipantsHeterosexual people aged over 16 years with a positive Chlamydia trachomatis test result and/or clinical diagnosis of pelvic inflammatory disease, cervicitis, non-gonococcal urethritis or epididymo-orchitis, and reporting one or more contactable sexual partner in the past six months, and their sexual partners.

InterventionsClusters were assigned by random permutation to either (a) usual care: health care professional advises the index patient to tell their sex partner(s) to attend clinic for sexually transmitted infection (STI) screening and treatment, or (b) usual care plus the offer of APT: healthcare professional assesses sex partner(s) by telephone, then sends or gives the index patient antibiotics and STI self-sampling kits for their sex partner(s). After a two-week washout period, clinics crossed over to the opposite exposure. Each period lasted 6 months.

Main outcome measuresThe primary outcome was the proportion of index patients with a positive C. trachomatis test 12-24 weeks after treatment. Secondary outcomes included proportions and types of sex partners treated.

AnalysisIntention-to-treat, fitting random effects logistic regression models.

ResultsAll clinics completed both periods. Overall, 1536 and 1724 recruited index patients provided data in intervention and control phases respectively. In total, 4807 sex partners were reported, of whom 1636 (34%) were committed/established partners. Overall, 293/1536 (19.1%) of index patients chose APT for a total of 305 partners, of whom 248 accepted. In intervention and control phases, 666 (43%) and 800 (46%) of index patients were tested for C. trachomatis at 12-24 weeks; 31 (4.7%) and 53 (6.6%) were positive, adjusted odds ratio (aOR) 0.66 (95% CI 0.41-1.04, p=0.07). Among index patients with treatment status recorded, the proportion with [≥]1 sex partner treated was 775 (88.0%) in the intervention and 760 (84.6%) in the control phase, aOR 1.27 (95% CI 0.96-1.68, p=0.10). Seven adverse events of low severity were recorded.

ConclusionsAPT can be safely offered as a contact tracing option for people with C. trachomatis and might reduce the risk of repeat infection. Future research should find ways to increase uptake and develop alternative interventions for one-off partners.

Trial registrationISRCTN15996256

Ethical approvalLondon - Chelsea Research Ethics Committee (18/LO/0773)

Protocoldoi: 10.1136/bmjopen-2019-034806

What is already known on this topicO_LIContact tracing (partner notification) for chlamydia is a key element of infection control in the population but achieving even modest outcomes can be challenging.
C_LIO_LIAccelerated partner therapy (APT) is a contact tracing intervention that provides testing and treatment for sex partners without the need for a face-to-face consultation.
C_LIO_LIPilot studies of APT found improvements in patient-reported outcomes of contact tracing but evidence about biological outcomes is required and the types of sexual partnerships benefitting most from APT are unknown.
C_LI

What this study addsO_LIThe offer of APT as an additional contact tracing method to usual care likely caused a small reduction in repeat chlamydia infection 12-24 weeks after treatment and an increase in proportion of sex partners treated, compared with usual care alone.
C_LIO_LIAPT can be safely offered as a cost-saving contact tracing option for heterosexual people with chlamydia and might reduce the risk of repeat infection, particularly for those in emotionally connected relationships, although uptake needs to be improved and novel approaches are needed for one-off partners.
C_LI

category: sexual and reproductive health


title: Perceived racial discrimination and eating habits: Systematic review and conceptual models

abstract:
Contextthere is no systematic organization of the available evidence about the relationship between racial discrimination and eating habits. Also, there is no consensus about its causal mechanism.

Objectivesa systematic review was conducted to synthesize evidence on the association between perceived racial discrimination and eating habits (eating behavior and food consumption). A conceptual model was developed to depict the most common mechanisms used to explain this association.

Data Sourcesarticles and dissertations were retrieved from the PubMed, EMBASE, Lilacs, and PsycINFO databases from inception to January 2021.

Data Analysis19 studies were included. The assessment of methodological quality was conducted using the Newcastle-Ottawa Scale. On average, the studies showed a methodological quality of 66%. Forty-six associations were evaluated. There were 38 associations between perceived racial discrimination and negative eating habits, 29 concerning eating behavior, and 17 regarding food consumption.

Conclusionsperceived racial discrimination negatively affects eating habits. A broader conceptual framework based on ecosocial theory is suggested to guide future research that would include different racial discrimination dimensions, such as internalized and structural.

category: nutrition


title: Increasing Numbers of Non-communicable Disease Co-morbidities: Major Risk Factors for Hospitalization among a Cohort of People with HIV and COVID-19 Coinfection

abstract: Data regarding coronavirus disease (COVID-19) infection complications among people with HIV (PWH) are expanding but sometimes conflicting. This report presents the results of a retrospective review of 103 patients at a single urban academic health center with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study showed that hospitalization is related to host factors such as age 65 years or older with an increasing number of specific non-communicable disease comorbidities, and not to HIV-attributable factors.

category: hiv aids


title: More rapid, robust and sustainable antibody responses to mRNA COVID-19 vaccine in convalescent COVID-19 individuals

abstract:
Longitudinal studies are needed to evaluate the SARS-CoV-2 mRNA vaccine antibody response under "real-world" conditions. This longitudinal study investigated the quantity and quality of SARS-CoV-2 antibody response in 846 specimens from 350 subjects: comparing BNT162b2-vaccinated individuals (19 previously diagnosed with COVID-19 [RecoVax]; 49 never been diagnosed [NaiveVax]) to 122 hospitalized unvaccinated (HospNoVax) and 160 outpatient unvaccinated (OutPtNoVax) COVID-19 patients.

NaiveVax experienced a delay in generating SARS-CoV-2 total antibody levels (TAb) and neutralizing antibodies (SNAb) after the 1st vaccine dose (D1), but a rapid increase in antibody levels was observed after the 2nd dose (D2). However, these never reached the robust levels observed in RecoVax. In fact, NaiveVax TAb and SNAb levels decreased 4-weeks post-D2 (p=0.003;p<0.001). For the most part, RecoVax TAb persisted throughout this study, after reaching maximal levels 2-weeks post-D2; but SNAb decreased significantly [~]6-months post-D1 (p=0.002). Although NaiveVax avidity lagged behind that of RecoVax for most of the follow-up periods, NaiveVax did reach similar avidity by [~]6-months post-D1. These data suggest that one vaccine dose elicits maximal antibody response in RecoVax and may be sufficient. Also, despite decreasing levels in TAb and SNAb overtime, long-term avidity maybe a measure worth evaluating and possibly correlating to vaccine efficacy.


title: The symptomatology of fever: a step towards qualitative definition of fever

abstract:
BackgroundThe old definitions of fever are based on cross-sectional surveys of the population without analyzing the associated symptomatology.

ObjectivesTo analyze associated symptoms with fever in a longitudinal follow-up study.

MethodsIn a longitudinal study over one year, 196 participants recorded three temperature readings daily, one after waking up, one between 12-3 PM, one before sleeping, and filled the symptomatology questionnaire in a thermometry diary.

ResultsPer protocol analysis was done for febrile participants (n=144). Fatigue (50.3%), warmth (47.3%), headache/head heaviness (47.0%), feeling malaise/general weakness (46.7%), loss of appetite (46.5%), muscle cramps/muscle aches (45.6%), chills/shivering (44.6%), increased sweating (43.0%), nausea (42.5%), irritability (38.9%), increased breathing rate (37.1%), and restlessness/anxiety/palpitations (36.5%) were the symptoms maximally seen during the febrile phase. A higher number of associated symptoms are associated with higher temperature readings. Dehydration suggested the numerically highest temperature values (100.86 {+/-} 1.70{degrees}F) but seen in few febrile patients.

ConclusionsIncorporation of symptom analysis in febrile patients is the need of the hour. Fatigue and warmth are found to be most prevelent symptoms during febrile phase. Associated symptoms can help in predicting the intensity of fever also.

category: intensive care and critical care medicine


title: Association of Systemic immune-inflammation index With Short-Term Mortality of Congestive Heart Failure: A Retrospective Cohort Study

abstract:
PurposeThe present study aimed to clarify the potential predictive significance of Systemic immune-inflammation index (SII) in assessing the poor prognosis of critically ill patients with congestive heart failure (CHF).

MethodsDetailed clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care III database after gaining access and building the local platform. The 30- and 90-day and hospital all-cause mortalities of the patient was the primary outcome, and the readmission rate and the occurrence of major cardiovascular adverse events (MACEs) were the secondary outcomes. the Cox proportional hazard model and Logistic regression analysis were selected to reveal the relationship between SII level and the research outcome. Further, the propensity score matching (PSM) analysis was performed to improve the reliability of results by reducing the imbalance across groups.

ResultsThere were a total of 4606 subjects who passed the screening process and entered the subsequent analysis. Multivariate regression analysis showed that after adjusting for possible confounders, including age, heart rate, and albumin, etc., the high level of SII was independently associated with 30- and 90-day and hospital mortalities (tertile 3 versus tertile 1: HR, 95% CIs: 1.23, 1.04-1.45; 1.21, 1.06-1.39; 1.26, 1.05-1.50) and the incidence of MACEs (tertile 3 versus tertile 1: OR, 95% CI: 1.39, 1.12-1.73) in critically ill patients with CHF, but no significant correlation was found between SII and the readmission rate. Consistently, patients with high SII level still presented a significantly higher short-term mortality than patients with low SII in the PSM subset.

ConclusionIn critically ill patients with CHF, high level of SII could effectively predict high 30- and 90-day and hospital mortalities, as well as the high risk of occurrence of MACEs.

category: cardiovascular medicine


title: Association between obesity and hospitalization in mild COVID-19 young adult outpatients in Brazil: a prospective cohort study

abstract:
Background/ObjectivesThe aim of this study was to evaluate the association between obesity and hospitalization in mild COVID-19 adult outpatients in Brazil.

Subjects/MethodsAdults with signs and symptoms suggestive of acute SARS-CoV-2 infection who sought two hospitals (one public and one private) emergency department (ED) were prospectively enrolled. Patients with confirmed COVID-19 at inclusion were followed by phone calls at day (D) D7, D14 and D28. Multivariable logistic regression models were employed to explore the association between obesity and other potential predictors for hospitalization.

ResultsA total of 1,050 participants were screened, 310 were diagnosed with COVID-19 by RT-PCR. Median age was 37.4 (IQR 29.8-45.0) years, and 186 (60.0%) were female. Duration of symptoms was 3.0 (IQR 2.0-5.0) days, and 10.0 (IQR 8.0-12.0) was the median number of symptoms at inclusion. A total of 98 (31.6%) were obese, and 243 (78.4%) had no previous medical conditions. Twenty three participants (23/310, 7.4%) required hospitalization during the period. After adjusting, obesity (BMI[≥]30.0 kg/m2) (OR=2.69, 95%CI 1.63-4.83, P<0.001) and older age (OR=1.05, 95%CI 1.01-1.09, P<0.001), were significantly associated with higher risks of hospitalization.

ConclusionsObesity, followed by aging, was the main factor associated with hospital admission for COVID-19 in a young population in a low-middle income country. Our findings highlighted the need for actions to promote additional protection for obese population, such as vaccination, and to encourage lifestyle changes.


title: Structural racism and COVID-19 response: Higher risk of exposure drives disparate COVID-19 deaths among Black and Hispanic/Latinx residents of Illinois, USA

abstract:
BACKGROUNDStructural racism has driven and continues to drive policies that create the social, economic, and community factors resulting in residential segregation, lack of access to adequate healthcare, and lack of employment opportunities that would allow economic mobility. This results in overall poorer population health for minoritized people. In 2020, Black and Hispanic/Latinx communities throughout the United States, including the state of Illinois, experienced disproportionately high rates of COVID-19 cases and deaths. Public health officials in Illinois implemented targeted programs at state and local levels to increase intervention access and reduce disparities.

METHODSTo quantify how disparities in COVID outcomes evolved through the epidemic, data on SARS-CoV-2 diagnostic tests, COVID-19 cases, and COVID-19 deaths were obtained from the Illinois National Electronic Disease Surveillance System for the period from March 1 to December 31, 2020. Relative risks of COVID-19 cases and deaths were calculated for Black and Hispanic/Latinx vs. White residents, stratified by age group and epidemic interval. Deaths attributable to racial/ethnic disparities in incidence and case fatality were estimated with counterfactual simulations.

RESULTSDisparities in case and death rates became less drastic after May 2020, but did not disappear, and were more pronounced at younger ages. From March to May of 2020, the risk of a COVID-19 case for Black and Hispanic/Latinx populations was more than twice that of Whites across all age groups. The relative risk of COVID-19 death reached above 10 for Black and Hispanic/Latinx individuals under 50 years of age compared to age-matched Whites in the early epidemic. In all Illinois counties, relative risk of a COVID-19 case was the same or significantly increased for minoritized populations compared to the White population. 79.3% and 86.7% of disparities in deaths among Black and Hispanic/Latinx populations, respectively, were attributable to differences in age-adjusted incidence compared to White populations rather than differences in case fatality ratios.

CONCLUSIONSRacial and ethnic disparities in the COVID-19 pandemic are products of society, not biology. Considering age and geography in addition to race/ethnicity can help to identify the structural factors driving poorer outcomes for certain groups. Studies and policies aimed at reducing inequalities in disease exposure will reduce disparities in mortality more than those focused on drivers of case fatality.


title: Exploring the Relationship of Rush Hour Period and Fatal and Non-Fatal Crash Injuries In The U.S.: A Systematic Review and Meta-Analysis

abstract: Road crashes are preventable causes of morbidity and mortality. In the U.S., substantial crashes occur during the rush hour period. The rush hour represents the period of the day during which the density of humans and vehicles in the road environment is highest. In the U.S., the rush hour period is bi-modal, occurring in the morning and the afternoon, at times that vary by state and urban-rural status. This systematic review and meta-analysis aimed to evaluate the association between the rush hour period and fatal and non-fatal crash injuries. Selected articles were limited to peer-reviewed full-text articles that measured crash injury as an outcome and rush hour as either a predictor, covariate, stratification, or a control variable. A total of 13 articles were identified for systematic review and seven articles were included in the meta-analysis. Across the selected studies, the rush-hour period signified the period of "peak traffic flow." During the rush hour period, aggressive driving behavior, truck driving, bicycle riding, and precipitation were associated with increased crash events or crash injuries. Across the seven studies included in the meta-analysis, the effective sample size was 220,471. The rush-hour period was associated with a 41% increased risk of fatal crash injury (Pooled RR: 1.41; 95% CI: 1.35 - 1.48). The morning and afternoon rush hour periods were associated with 40% (Pooled RR: 1.40; 95% CI: 1.13-1.67) and 27% (Pooled RR:1.27; 95% CI: 1.10-1.44) increased crash injury risk, respectively. The rush hour period, though less commonly studied as a predictor of fatal and non-fatal crash injuries, represents an important domain in need of crash injury prevention attention. The knowledge of the pattern of crash injuries, as it varies across countries, states, regions, and county can inform policy and intervention, in the presence of competing public health needs.


title: Mitigation of SARS-CoV-2 Transmission at a Large Public University

abstract: In the Fall of 2020, many universities saw extensive transmission of SARS-CoV-2 among their populations, threatening the health of students, faculty and staff, the viability of in-person instruction, and the health of surrounding communities.1, 2 Here we report that a multimodal "SHIELD: Target, Test, and Tell" program mitigated the spread of SARS-CoV-2 at a large public university, prevented community transmission, and allowed continuation of in-person classes amidst the pandemic. The program combines epidemiological modelling and surveillance (Target); fast and frequent testing using a novel and FDA Emergency Use Authorized low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD (Test); and digital tools that communicate test results, notify of potential exposures, and promote compliance with public health mandates (Tell). These elements were combined with masks, social distancing, and robust education efforts. In Fall 2020, we performed more than 1,000,000 covidSHIELD tests while keeping classrooms, laboratories, and many other university activities open. Generally, our case positivity rates remained less than 0.5%, we prevented transmission from our students to our faculty and staff, and data indicate that we had no spread in our classrooms or research laboratories. During this fall semester, we had zero COVID-19-related hospitalizations or deaths amongst our university community. We also prevented transmission from our university community to the surrounding Champaign County community. Our experience demonstrates that multimodal transmission mitigation programs can enable university communities to achieve such outcomes until widespread vaccination against COVID-19 is achieved, and provides a roadmap for how future pandemics can be addressed.


title: Returning Actionable Genomic Results in a Research Biobank: Analytic Validity, Clinical Implementation and Resource Utilization

abstract: Over 100 million research participants around the world have had research array-based genotyping (GT) or sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to patient recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.

category: genetic and genomic medicine


title: Multi-ancestry Multivariate Genome-Wide Analysis Highlights the Role of Common Genetic Variation in Cardiac Structure, Function, and Heart Failure-related Traits

abstract: Heart failure (HF) is a leading cause of cardiovascular morbidity and mortality, yet the contribution of common genetic variation to HF risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We conducted a multi-ancestry genome-wide association study (GWAS) meta-analysis of all-cause HF including up to 56,722 HF cases and 1,133,054 controls, identifying 4 novel loci. We then performed a multi-ancestry multivariate association study of HF and related cardiac imaging endophenotypes, identifying 71 conditionally-independent variants, including 16 novel loci. Secondary colocalization and transcriptome-wide association analyses identified known and novel candidate cardiomyopathy genes, which were validated in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provided convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization revealed 11 circulating proteins associated with HF or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate novel common genetic variation in the pathogenesis of HF, and identify circulating proteins that may represent novel cardiomyopathy treatment targets.


title: Deep Learning of Left Atrial Structure and Function Provides Link to Atrial Fibrillation Risk

abstract:
AimsIncreased left atrial (LA) volume is a known risk factor for atrial fibrillation (AF). There is also emerging evidence that alterations in LA function due to an atrial cardiomyopathy are associated with an increased risk of AF. The availability of large-scale cardiac MRI data paired with genetic data provides a unique opportunity to assess the joint genetic contributions of LA structure and function to AF risk.

Methods and resultsWe developed deep learning models to measure LA traits from cardiovascular magnetic resonance imaging (MRI) in 40,558 UK Biobank participants and integrated these data to estimate LA minimum (LAmin), maximum (LAmax), and stroke volume (LASV), as well as emptying fraction (LAEF). We conducted a genome-wide association study (GWAS) in 35,049 participants without pre-existing cardiovascular disease, identifying 20 common genetic loci associated with LA traits. Eight of the loci associated with LA traits were previously associated with AF: the AF risk alleles were associated with an increased LA minimum volume (LAmin) and a decreased LAEF. A Mendelian randomization analysis confirmed that AF causally affects LA volume (IVW P = 6.2E-06), and provided evidence that LAmin causally affects AF risk (IVW P = 4.7E-05). In UK Biobank participants, a polygenic prediction of LAmin was significantly associated with risk for AF (HR 1.09 per SD; P = 1.6E-36) and ischemic stroke (HR 1.04 per SD; P = 4.7E-03).

ConclusionsWe performed the largest and highest resolution assessment of LA structure and function to date. We then identified 20 common genetic variants associated with LA volumes or LAEF, 19 of which were novel. We found that a polygenic prediction of the minimal LA volume was associated with AF and stroke. Finally, we found an inverse relation between genetic variants associated with AF risk and LAEF. Our findings provide evidence of a causal relation between LA contractile function and AF.


abstract:
Identifying actual risk zones in a country where the overall test positive rate (TPR) is higher than 5% is crucial to contain the pandemic. However, TPR-based risk zoning methods are debatable since they do not consider the rate of infection in an area and thus, it has been observed to overestimate the risk. Similarly, the rate of infection in an area has been noticed to underestimate the risk of COVID-19 spreading for the zones with higher TPR. In this article, we discuss the shortcomings of currently available risk zoning methods that are followed in the lower-middle-income countries (LMIC), especially in Bangladesh. We then propose to determine a risk zone by combining the rate of infection with TPR and effective reproduction number, Rt in a distinct manner from existing methods. We evaluate the efficacy of the proposed method with respect to the mass-movement events and show its application to track the evolution of COVID-19 pandemic by identifying the risk zones over time. Demo website for the visualization of the analysis can be found at: http://erdos.dsm.fordham.edu:3000

CCS CONCEPTSO_LIApplied computing [->] Health informatics.
C_LI

ACM Reference FormatMd. Enamul Hoque, Md. Shariful Islam, Arnab Sen Sharma, Rashedul Islam, and Mohammad Ruhul Amin. 2021. Challenges in Tracking the Risk of COVID-19 in Bangladesh: Evaluation of A Novel Method. In Proceedings of August 15 (KDD Workshop on Data-driven Humanitarian Mapping, 27th ACM SIGKDD Conference). ACM, New York, NY, USA, 7 pages.


title: Impact of different diagnostic measures on drug class association with dementia progression risk: a longitudinal prospective cohort study

abstract:
BackgroundClinical Dementia Rating Sum of Boxes (CDRSOB) scale is known to be highly indicative of cognitive-functional status, but it is unclear whether it is consistent with clinical diagnosis in evaluating drug class associations with risk of progression to mild cognitive impairment (MCI) and dementia.

MethodsWe employed multivariable logistic regression on longitudinal NACC data, to identify drug classes associated with disease progression risk, using clinical diagnosis and CDRSOB as the outcome.

ResultsAnticoagulants, non-steroidal anti-inflammatory drugs, antihypertensives, antidepressants, and Parkinsons medications were significantly associated with decreased progression to mild cognitive impairment (MCI)/dementia, and antipsychotics, antidiabetics, hypolipidemic drugs, and Alzheimers disease (AD) medications were significantly associated with increased progression risk. Associations were however dependant on the diagnostic measure used, e.g., levodopa was associated with reduced MCI-to-AD risk using CDRSOB as the outcome (OR:0.28, FDR p<0.002), but not with clinical diagnosis. Additionally, some associations appear to be gender specific; for instance, antiadrenergic agents had lower MCI-to-Dementia risk only for men (OR:0.67, FDR p<0.001) using CDRSOB.

ConclusionsOverall, we demonstrate that choice of diagnostic measure can influence the magnitude and significance of risk or protection attributed to drug classes. A consensus must be reached within the research community with respect to the most accurate diagnostic outcome to identify risk and improve reproducibility.


title: Temporal Geospatial Analysis of COVID-19 Pre-infection Determinants of Risk in South Carolina

abstract:
IntroductionDisparities and their geospatial patterns exist in coronavirus disease 2019 (COVID-19) morbidity and mortality for people who are engaged with clinical care. However, studies centered on viral infection cases are scarce. It remains unclear with respect to the disparity structure, its geospatial characteristics, and the pre-infection determinants of risk (PIDRs) for people with the infection. This work aimed to assess the geospatial associations between PIDRs and COVID-19 infection at the county level in South Carolina by different timepoints during the pandemic.

MethodWe used global models including spatial error model (SEM), spatial lag model (SLM), and conditional autoregressive model (CAR), as well as geographically weighted regression model (GWR) as a local model to examine the associations between COVID-19 infection rate and PIDRs. The data were retrieved from multiple sources including USAFacts, US Census Bureau, and Population Estimates Program.

ResultsThe percentage of males and the percentage of the unemployed population were statistically significant (p values < 0.05) with positive coefficients in the three global models (SEM, SLM, CAR) throughout the time. The percentage of white population and obesity rate showed divergent spatial correlations at different times of the pandemic. GWR models consistently have a better model fit than global models, suggesting non-stationary correlations between a region and its neighbors.

ConclusionCharacterized by temporal-geospatial patterns, disparities and their PIDRs exist in COVID-19 incidence at the county level in South Carolina. The temporal-geospatial structure of disparities and their PIDRs found in COVID-19 incidence are different from mortality and morbidity for patients who are connected with clinical care. Our findings provided important evidence for prioritizing different populations and developing tailored interventions at different times of the pandemic. These findings provided implications on containing early viral transmission and mitigating consequences of infectious disease outbreaks for possible future pandemics.


title: Cytogenetic & Molecular analysis in Premature Ovarian Failure

abstract:
IntroductionPremature Ovarian Failure (POF) being a heterogeneous genetic disease involves the interaction of multiple genetic defects and environmental factors and has been associated with several chromosomal abnormalities, single gene mutations, and genetic polymorphisms. BMP15 is a member of the transforming growth factor {beta} (TGF-{beta}) family. BMP15 gene product (protein) have 3 domians, mature domain (c-terminal region) of BMP15 binds to receptors located on granulosa cell surface to participate in key steps regarding ovarian function, such as granulosa cell proliferation and follicle maturation, ovulation rate modulation, oocyte competence determination and regulating granulosa cell sensitivity to FSH. Single nucleotide polymorphisms (SNPs) of the BMP-15 gene are associated with POF.

Materials & Methods30 POF patients and 30 healthy age matched controls were recruited for cytogenetic and molecular analysis. 10 ml whole blood was collected for karyotyping and PCR and PCR was performed for known SNPs of BMP-15 gene (-9C>G, 538G>A, 788insTCT and 852C>T) respectively. Amplified PCR products were sequenced commercially.

Observation/ResultThirty cases (mean age 30 years) and thirty healthy controls (mean age 23 years) were recruited for the study. On cytogenetic analysis 2 cases had a 45, XO chromosomal complement. One case was heterozygous for the SNP (-9C>G) and one control was homozygous for the same SNP.

DiscussionThe prevalence of this SNP was about 10.7% in cases & 3.3% in healthy controls. This polymorphism in promoter region may cause altered expression of the gene and results in POF.


title: COVID-19 impact on stroke admissions during France's first epidemic peak: an exhaustive, nationwide, observational study

abstract:
Background and PurposeThe COVID-19 pandemic continues to have great impacts on the care of non-COVID-19 patients. This was especially true during the first epidemic peak in France, which coincided with the national lockdown (17 March 2020 to 10 May 2020). Patients with serious and urgent disease like stroke may have experienced a degradation of care, or may have been hesitant to seek healthcare during this period. The aim of this study was to identify, on a national level, whether a decrease in stroke admissions occurred in spring 2020, by analyzing the evolution of all stroke admissions in France from January 2019 to June 2020.

MethodsWe conducted a nationwide cohort study using the French national database of hospital admissions (PMSI) to extract exhaustive data on all hospitalizations in France with at least one stroke diagnosis between 1 January 2019 and 30 June 2020. The primary endpoint was the difference in the slope gradients of stroke hospitalizations between pre-epidemic, epidemic peak and post-epidemic periods. Modeling was carried out using Bayesian techniques.

ResultsStroke hospitalizations dropped from 10 March 2020 (slope gradient: -11.70), and began to rise again from 22 March (slope gradient: 2.090) to 7 May. In total, there were 23 873 stroke admissions during the period March-April 2020, compared to 29 263 at the same period in 2019, representing a decrease of 18.42%. The percentage change was -15.63%, - 25.19%, -18.62% for ischemic strokes, transient ischemic attacks, and hemorrhagic strokes, respectively. In spatial models of French departments, the incidence of COVID-19 explained the ratio of stroke hospitalizations.

ConclusionsStroke hospitalizations in France experienced a decline during the first lockdown period, which cannot be explained by a sudden change in stroke incidence. This decline is therefore likely to be a direct, or indirect, result of the COVID-19 pandemic.

category: neurology


title: Spatiotemporal changes in along-tract profilometry of cerebellar peduncles in cerebellar mutism syndrome

abstract:
Cerebellar mutism syndrome, characterised by mutism, emotional lability and cerebellar motor signs, occurs in up to 39% of children following resection of medulloblastoma, the most common malignant posterior fossa tumour of childhood. Its pathophysiology remains unclear, but prior studies have implicated damage to the superior cerebellar peduncles. In this study, the objective was to conduct high-resolution spatial profilometry of the cerebellar peduncles and identify anatomic biomarkers of cerebellar mutism syndrome.

In this retrospective case-control study, twenty-eight children with medulloblastoma (mean age 8.8 {+/-} 3.8 years) underwent diffusion MRI at four timepoints over one year. Forty-nine healthy children (9.0 {+/-} 4.2 years), scanned at a single timepoint, served as age- and sex-matched controls. Automated Fibre Quantification was used to segment cerebellar peduncles and compute fractional anisotropy at 30 nodes along each tract.

Thirteen patients developed cerebellar mutism syndrome. Fractional anisotropy was significantly lower in the distal segments of the superior cerebellar peduncle pre-operatively in all patients (p=0.01). Pre-operative changes in fractional anisotropy did not predict cerebellar mutism syndrome. However, post-operative reductions in fractional anisotropy were highly specific to the distal left superior cerebellar peduncle, and were most pronounced at follow-up timepoints (p=0.042,0.038), in those that developed cerebellar mutism syndrome compared to patients that did not.

High spatial resolution cerebellar profilometry identifies a site-specific alteration of the distal segment of the superior cerebellar peduncle unique to cerebellar mutism syndrome with important surgical implications in the treatment of these devastating tumours of childhood.


title: Expression of Exosome Biogenesis Genes is Pervasively Altered by Aging in the Mouse and in the Human Brain During Alzheimer's Disease

abstract: Extracellular vesicles (EVs) like exosomes are secreted by numerous cell types in a variety of tissues. EVs have been implicated in both aging and age-related disorders like Alzheimers disease (AD). However, how aging and AD affect EV biogenesis within and across cell types is poorly understood. Moreover, cells acquire characteristics based on tissue niche, but the impact of tissue residence on cell type EV biogenesis is unknown.We explored the Tabula Muris Senis, Mayo RNA-seq and ROSMAP data sets to characterize the cell and tissue-specific effects of aging and AD on genes involved in EV biogenesis. Specifically, we examined the age-dependent expression (age coefficient) of genes involved in EV biogenesis (22 genes), EV cargo (3 genes) and senescence (5 genes). Of the 131 cell populations (cell type x tissue) studied, 95 have at least one EV biogenesis gene impacted by age. The most common gene increased by age was charged multivesicular body protein 2A (CHMP2A) (54 cell populations). The most common gene decreased by age was syndecan binding protein (SDCBP) (58 cell populations). The senescence-associated genes cyclin-dependent kinase 1A (CDKN1A) and CDKN2A were not related to changes in CHMP2A and SDCBP and were altered by age in fewer cell populations. Finally, individuals with AD had decreased CHMP2A and increased SDCBP expression, opposite of what is observed with aging in the absence of diagnosed neurological disease. These findings indicate that age modifies exosome biogenesis gene expression in many cell populations mostly independent of senescence, and may be further altered in AD.


title: EndoTime: Non-categorical timing estimates for luteal endometrium

abstract:
STUDY QUESTIONCan the accuracy of timing of luteal phase endometrial biopsies based on urinary ovulation testing be improved by measuring the expression of a small number of genes and a continuous, non-categorical modelling approach?

SUMMARY ANSWERMeasuring the expression levels of six genes (IL2RB, IGFBP1, CXCL14, DPP4, GPX3, and SLC15A2) is sufficient to obtain substantially more accurate timing estimates and assess the reliability of timing estimates for each sample.

WHAT IS KNOWN ALREADYCommercially available endometrial timing approaches based on gene expression require much larger gene sets and use a categorical approach that classifies samples as pre-receptive, receptive, or post-receptive.

STUDY DESIGN, SIZE, DURATIONGene expression was measured by RT-qPCR in 260 endometrial biopsies obtained 4 to 12 days after a self-reported positive home ovulation test. A further 36 endometrial samples were profiled by RT-qPCR as well as RNA-sequencing.

PARTICIPANTS/MATERIALS, SETTING, METHODSA computational procedure, named  EndoTime, was established that models the temporal profile of each gene and estimates the timing of each sample. Iterating these steps, temporal profiles are gradually refined as sample timings are being updated, and confidence in timing estimates is increased. After convergence, the method reports updated timing estimates for each sample while preserving the overall distribution of time points.

MAIN RESULTS AND THE ROLE OF CHANCEThe Wilcoxon Rank Sum Test was used to confirm that ordering samples by EndoTime estimates yields sharper temporal expression profiles for held-out genes (not used when determining sample timings) than ordering the same expression values by patient-reported times (GPX3: p < 0.005; CXCL14: p < 2.7e-6; DPP4: p < 3.7e-13). Pearson correlation between EndoTime estimates for the same sample set but based on RT-qPCR or RNA-sequencing data showed high degree of congruency between the two (p = 8.6e-10, R2 = 0.687).

LIMITATIONS, REASONS FOR CAUTIONTiming estimates are predominantly informed by glandular gene expression and will only represent the temporal state of other endometrial cell types if in synchrony with the epithelium. Methods that estimate the day of ovulation are still required as these data are essential inputs in our method. Our approach - in its current iteration - performs batch correction such that larger sample batches impart greater accuracy to timing estimations. In theory, our method requires endometrial samples obtained at different days in the luteal phase. In practice, however, this is not a concern as timings based on urinary ovulation testing are associated with a sufficient level of noise to ensure that a variety of time points will be sampled.

WIDER IMPLICATIONS OF THE FINDINGSOur method is the first to assay the temporal state of luteal-phase endometrial samples on a continuous domain. It is freely available with fully shared data and open source software. EndoTime enables accurate temporal profiling of any gene in luteal endometrial samples for a wide range of research applications and, potentially, clinical use.

STUDY FUNDING/COMPETING INTEREST(S)This study was supported by a Wellcome Trust Investigator Award (Grant/Award Number: 212233/Z/18/Z) and the Tommys National Miscarriage Research Centre. None of the authors have any competing interests. JL was funded by the Biotechnology and Biological Sciences Research Council (UK) through the Midlands Integrative Biology Training Partnership (MIBTP).

TRIAL REGISTRATION NUMBERN/A.

category: obstetrics and gynecology


title: The clinical feature of triple-negative breast cancer in Beijing, China

abstract:
ObjectiveTo collect and analyze the clinical feature of triple-negative breast cancer (TNBC) in Beijing, to provide the information for the local oncologist to make sound treatment plans.

MethodThe clinical data of 280 breast cancer patients with TNBC admitted to the oncology hospital of China Academy of Medical Sciences were collected and divided into (recurrence and metastasis) group and non-(recurrence and metastasis) group. Breast cancer patients with TNBC were classified according to age distribution, family history of breast cancer, pathological type, histological grade, clinical stage, tumor thrombus, tumor size and lymph node metastasis. and 15 BRCA1 gene SNP loci were also measured by a high throughput Mass ARRAY time-of-flight mass spectrometry biochip system and compared the expression of 15 BRCA1 gene SNP loci between (recurrence and metastasis) group and non-(recurrence and metastasis) group. {chi}2 test was used to analyze the difference between two groups, and P<0.05 considered statistically significant.

ResultsA total of 280 breast cancer patients with TNBC were enrolled in this study, median age 45 years old. There were 117 cases breast cancer patients with TNBC in (recurrence and metastasis) group, accounting for 41.79% in total breast cancer patients with TNBC and 163 cases breast cancer patients with TNBC in non-(recurrence and metastasis) group, accounting for 58.21% in total breast cancer patients with TNBC; There was no significant difference in age distribution, family history of breast cancer, pathological type and histological grade between non-(recurrence and metastasis) group and (recurrence and metastasis) group (P>0.05); but there were significant differences in clinical stage, vascular tumor thrombus, tumor size and lymph node metastasis between two groups (P<0.05); and then we compared the expression of 15 BRCA1 gene SNP loci in (recurrence and metastasis) group and non-(recurrence and metastasis) group, found that BRCA1gene rs 12516 CC loci (38.8% VS 44.4%), BRCA1gene rs 12516 TT loci (15.6% VS 10.4%), BRCA1 gene rs 16940 CC loci (15.1% VS 10.4%), BRCA1 gene rs 16940 TT loci (39.0% VS 44.8%), BRCA1 gene rs 16941 AA loci (38.1% VS 44%), BRCA1 gene rs 16941 GG loci (15.0% VS 10.3%), BRCA1 gene rs16942 AA loci (39.0% VS 44.8%), BRCA1 gene rs16942 GG loci (15.1% VS 10.4%), BRCA1gene rs799906 CC loci (15.9% VS 10.4%), BRCA1gene rs799906 TT loci (38.7% VS 44.8%), BRCA1gene rs799917 CC loci (38.7% VS 44.4%), BRCA1gene rs799917 TT loci (15.7% VS 10.4%), BRCA1gene rs1060915 CC loci (15.5% VS 10.4%), BRCA1gene rs1060915 TT loci (39.1%VS 44.8%), BRCA1gene rs1799966 AA loci (37.7% VS 44.4%), BRCA1gene rs1799966 GG loci (15.1% VS 10.4%), BRCA1 Gene rs2070833 AA loci (3.1% VS 7.0%), BRCA1 Gene rs2070833 CC loci (56.3% VS 51.3%), BRCA1gene rs3737559 GG loci(78.5% VS 84.5%), BRCA1gene rs3737559 GA loci(19.0% VS 14.6%), BRCA1gene rs8176199 AA loci (60.5% VS 64.6%), BRCA1gene rs8176318 GG loci (38.4% VS 43.4%), BRCA1gene rs8176318 TT loci (15.1% VS 10.6%), BRCA1gene rs8176323 CC loci (38.6% VS 43.9%), BRCA1gene rs8176323 GG loci (15.2% VS10.5%), BRCA1gene rs11655505 AA loci (14.9% VS 10.4%), BRCA1gene rs11655505 GG loci (39.1% VS 44.8%) had a difference at the accident rate between recurrence and metastasis group and non-(recurrence and metastasis) group, but the frequencies of genotypes in the (recurrence and metastasis) group and non-(recurrence and metastasis) group were similar, there was no statistical significant correlation between the SNP genotype of the BRCA1 gene and the recurrence and metastasis risk of TNBC (P>0.05).

ConclusionsThere were higher recurrence and metastasis (41.79%) in total 280 cases breast cancer patients with TNBC in Beijing area; breast cancer patients with TNBC in Beijing area had a unique clinical feature no matter at clinical stage, vascular tumor thrombus, tumor size and lymph node metastasis or the expression of 15 BRCA1 gene SNP loci, those data may provide some information for clinical staff for TBNC treatment.

category: oncology


title: Pre-diagnostic plasma metabolomics and the risk of exfoliation glaucoma

abstract:
ObjectiveTo identify pre-diagnostic plasma metabolomic biomarkers associated with risk of exfoliation glaucoma (XFG).

MethodsWe conducted a metabolomic study using a 1:1 matched nested case-control study design within the Nurses Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Participants provided blood samples in 1989-90 (NHS) and 1993-95 (HPFS); we identified 205 participants who newly developed XFG during follow-up to 2018 (average time to diagnosis from blood draw =11.8 years); XFG was confirmed with medical record review. We profiled plasma metabolites using liquid chromatography- mass spectrometry and identified 379 known metabolites that passed quality control checks. Metabolites were transformed using probit scores for normality. We used multivariable-adjusted logistic regression adjusting for matching factors (such as age, residential latitude, season and time of blood draw), glaucoma family history and other covariates. Metabolite Set Enrichment Analysis was used to identify metabolite classes associated with risk of XFG. Number of effective tests (NEF) and False Discovery Rate (FDR) were used to adjust for multiple comparisons.

ResultsMean age of cases (n=205) at diagnosis was 71 years; 84% were women and >99% were Caucasian; matched controls (n=205) all reported eye exams as of the matched cases index date. A total of 33 metabolites were nominally significantly associated with XFG risk (p<0.05) and 4 metabolite classes were significantly associated (FDR<0.05). Overall, adverse associations were observed for the classes of lysophosphatidylcholines (FDR=0.02) and phosphatidylethanolamine plasmalogens (FDR=0.004). Inverse associations were observed for triglycerides (FDR<0.001) and steroid and steroid derivatives (FDR=0.03); in particular, the multivariable-adjusted odds ratio for XFG risk associated with each 1 standard deviation increase in plasma cortisone levels was 0.49 (95% CI=0.32-0.74; NEF=0.05). Results did not differ materially by time between blood draw and diagnosis, latitude of residence (< or [≥]41{degrees}N latitude), age (< or [≥]60 years), sex or glaucoma family history.

ConclusionsFour broad classes of metabolites (including steroids such as cortisone and 3 lipid classes) in pre-diagnostic plasma collected almost a decade before diagnosis were associated with XFG risk; these results should be confirmed in future studies.

category: ophthalmology


title: Combining SNP-to-gene linking strategies to pinpoint disease genes and assess disease omnigenicity

abstract: Although genome-wide association studies (GWAS) have identified thousands of disease-associated common SNPs, these SNPs generally do not implicate the underlying target genes, as most disease SNPs are regulatory. Many SNP-to-gene (S2G) linking strategies have been developed to link regulatory SNPs to the genes that they regulate in cis, but it is unclear how these strategies should be applied in the context of interpreting common disease risk variants. We developed a framework for evaluating and combining different S2G strategies to optimize their informativeness for common disease risk, leveraging polygenic analyses of disease heritability to define and estimate their precision and recall. We applied our framework to GWAS summary statistics for 63 diseases and complex traits (average N=314K), evaluating 50 S2G strategies. Our optimal combined S2G strategy (cS2G) included 7 constituent S2G strategies (Exon, Promoter, 2 fine-mapped cis-eQTL strategies, EpiMap enhancer-gene linking, Activity-By-Contact (ABC), and Cicero), and achieved a precision of 0.75 and a recall of 0.33, more than doubling the precision and/or recall of any individual strategy; this implies that 33% of SNP-heritability can be linked to causal genes with 75% confidence. We applied cS2G to fine-mapping results for 49 UK Biobank diseases/traits to predict 7,111 causal SNP-gene-disease triplets (with S2G-derived functional interpretation) with high confidence. Finally, we applied cS2G to genome-wide fine-mapping results for these traits (not restricted to GWAS loci) to rank genes by the heritability linked to each gene, providing an empirical assessment of disease omnigenicity; averaging across traits, we determined that the top 200 (1%) of ranked genes explained roughly half of the heritability linked to all genes. Our results highlight the benefits of our cS2G strategy in providing functional interpretation of GWAS findings; we anticipate that precision and recall will increase further under our framework as improved functional assays lead to improved S2G strategies.


title: CuNA: Cumulant-based Network Analysis of genotype-phenotype associations in Parkinson's Disease

abstract: Parkinsons Disease (PD) is a progressive neurodegenerative movement disorder characterized by loss of striatal dopaminergic neurons. Progression of PD is usually captured by a host of clinical features represented in different rating scales. PD diagnosis is associated with a broad spectrum of non-motor symptoms such as depression, sleep disorder as well as motor symptoms such as movement impairment, etc. The variability within the clinical phenotype of PD makes detection of the genes associated with early onset PD a difficult task. To address this issue, we developed CuNA, a cumulant-based network analysis algorithm that creates a network from higher-order relationships between eQTLs and phenotypes as captured by cumulants. We also designed a multi-omics simulator, CuNAsim to test CuNAs qualitative accuracy. CuNA accurately detects communities of clinical phenotypes and finds genes associated with them. When applied on PD data, we find previously unreported genes INPP5J, SAMD1 and OR4K13 associated with symptoms of PD affecting the kidney, muscles and olfaction. CuNA provides a framework to integrate and analyze RNA-seq, genotype and clinical phenotype data from complex diseases for more targeted diagnostic and therapeutic solutions in personalized medicine. CuNA and CuNAsim binaries are available upon request.


title: Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and disease.

abstract: We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohns Disease as well as 2 novel therapeutic targets: IL-27 (Crohns disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.


title: Genomic Basis of Multiple Myeloma Subtypes from the MMRF CoMMpass Study

abstract: Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The MMRF CoMMpass study is a longitudinal, observational clinical study of newly diagnosed multiple myeloma patients where tumor samples are characterized using whole genome, exome, and RNA sequencing at diagnosis and progression, and clinical data is collected every three months. Analyses of the baseline cohort identified genes that are the target of recurrent gain- and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high- risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.


title: CAREGIVERS' PERSPECTIVE- SATISFACTION WITH HEALTHCARE SERVICES AT THE PAEDIATRIC SPECIALIST CLINIC OF THE NATIONAL REFERRAL CENTRE IN MALAYSIA

abstract:
BackgroundThe idea of consumer satisfaction is gaining momentum across all business sectors around the world and a satisfaction survey is utilized as an instrument to recognize deficiencies with various facets of services and offers a valuable opportunity for customers to evaluate their experience with healthcare services. A first research performed at a public hospitals paediatric clinic, which is also the first hospital to adopt the Public-Private-Partnership (PPP) model under the Ministry of Health Malaysia (MoH), with the aim of discovering prevalence and factors affecting the satisfaction of caregivers at the national referral centre.

Materials and MethodsCross-sectional research using the standard self-administered SERVQUAL questionnaire was conducted amongst caregivers accompanying their child to the clinic. It consists of 16 paired statements to evaluate their expectations and experiences with the clinic services. 459 caregivers were involved with a majority being satisfied with the clinic services.

ResultThe most significant dimensions were "tangibles", "assurance" and "outcome". Caregivers from the Indian community, lower household income, and lower educational background demonstrated a higher level of satisfaction.

ConclusionThis article suggests that although most caregivers are very satisfied with the services, greater emphasis must be placed on delivering reliable service in response to MoHs mission to provide quality and integrated people-centred health services in Malaysia.

category: health systems and quality improvement


title: Sensitive and multiplexed RNA detection with Cas13 droplets and kinetic barcoding

abstract: Rapid and sensitive quantification of RNA is critical for detecting infectious diseases and identifying disease biomarkers. Recent direct detection assays based on CRISPR-Cas13a1-4 avoid reverse transcription and DNA amplification required of gold-standard PCR assays5, but these assays have not yet achieved the sensitivity of PCR and are not easily multiplexed to detect multiple viruses or variants. Here we show that Cas13a acting on single target RNAs loaded into droplets exhibits stochastic nuclease activity that can be used to enable sensitive, rapid, and multiplexed virus quantification. Using SARS-CoV-2 RNA as the target and combinations of CRISPR RNA (crRNA) that recognize different parts of the viral genome, we demonstrate that reactions confined to small volumes can rapidly achieve PCR-level sensitivity. By tracking nuclease activity within individual droplets over time, we find that Cas13a exhibits rich kinetic behavior that depends on both the target RNA and crRNA. We demonstrate that these kinetic signatures can be harnessed to differentiate between different human coronavirus species as well as SARS-CoV-2 variants within a single droplet. The combination of high sensitivity, short reaction times, and multiplexing makes this droplet-based Cas13a assay with kinetic barcoding a promising strategy for direct RNA identification and quantification.


title: Effects of repeated vaccination and vaccine formulation on the induction of broadly neutralizing antibody responses against influenza A virus in children

abstract: The induction of broadly neutralizing antibodies (bNAbs) that target the hemagglutinin stalk domain is a promising strategy for the development of "universal" influenza virus vaccines. bNAbs can be boosted in adults by sequential exposure to heterosubtypic viruses through natural infection or vaccination. However, little is known about if/how bNAbs are induced by vaccination in more immunologically naive children. Here, we describe the impact of repeated seasonal influenza vaccination and vaccine type on induction of bNAbs in a well-characterized paediatric cohort enrolled in a series of randomized control trials of seasonal influenza vaccination. Repeated seasonal vaccination resulted in significant boosting of a durable bNAb response. Boosting of serological bNAbs titers was comparable within inactivated and live attenuated (LAIV) vaccinees and declined with age. These data provide new insights into vaccine-elicited bNAb induction in children, which has important implications for the design of "universal" influenza vaccine modalities in this critical population.


title: Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection in a large cohort

abstract:
ImportanceIsrael was among the first countries to launch a large-scale COVID-19 vaccination campaign, and quickly vaccinated its population, achieving early control over the spread of the virus. However, the number of COVID-19 cases is now rapidly increasing, which may indicate that vaccine protection decreases over time.

ObjectiveTo determine whether time elapsed since the second BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) injection is significantly associated with the risk of post-vaccination COVID-19 infection.

DesignThis is a retrospective cohort study performed in a large state-mandated health care organization in Israel.

ParticipantsAll fully vaccinated adults who have received a RT-PCR test between May 15, 2021 and July 26, 2021, at least two weeks after their second vaccine injection were included. Patients with a history of past COVID-19 infection were excluded.

Main Outcome and MeasurePositive result for the RT-PCR test.

ResultsThe cohort included 33,993 fully vaccinated adults, 49% women, with a mean age of 47 years (SD, 17 years), who received an RT-PCR test for SARS-CoV-2 during the study period. The median time between the second dose of the vaccine and the RT-PCR test was 146 days, interquartile range [121-167] days. 608 (1.8%) patients had positive test results. There was a significantly higher rate of positive results among patients who received their second vaccine dose at least 146 days before the RT-PCR test compared to patients who have received their vaccine less than 146 days before: odds ratio for infection was 3.00 for patients aged over 60 (95% CI 1.86-5.11); 2.29 for patients aged between 40 and 59 (95% CI 1.67-3.17); and 1.74 for patients aged between 18 and 39 (95% CI 1.27-2.37); P<0.001 in each age group.

Conclusions and RelevanceIn this large population study of patients tested for SARS-CoV-2 by RT-PCR following two doses of mRNA BNT162b2 vaccine, we observe a significant increase of the risk of infection in individuals who received their last vaccine dose since at least 146 days ago, particularly among patients older than 60.


title: Effect of laser assisted local anesthesia in single-visit root canal treatment for mandibular molar teeth with acute irreversible pulpitis

abstract:
Present study evaluated the efficacy of laser activation to control intra- and post-operative pain in single-visit root treatment for mandibular molar teeth with acute irreversible pulpitis following 2% lignocaine inferior alveolar nerve block. Ninety-eight patients presenting with pain were randomly divided into two anesthetic groups. Group-I inferior alveolar nerve block plus buccal infiltration and intra-ligamentary injections, Group-II inferior alveolar nerve block followed by laser irradiation focused directly on the pulp tissue. Intra- and post-operative pain intensities were assessed on a 10-point scale.The mean intra-operative pain scores in group-I was 6.62 {+/-} 1.6 and in group-II before and after laser irradiation pain scores was 6.94 {+/-} 2.1 and 1.3 {+/-} 2.04, respectively. Post-operative pain scores at 24-hrs in the laser group were significantly higher. Laser irradiation applied directly on pulp tissue for control of intra-operative pain was effective, thereby negating the need for additional local anesthesia.

Clinical relevanceLaser activation was effective method to control intra-operative pain in irreversibly inflamed pulp.

Laser irradiation did not cause adverse post-operative pain.

category: dentistry and oral medicine


title: Dynamics of COVID-19 pandemic in India and Pakistan: A metapopulation modelling approach

abstract: India has been the latest global epicenter for COVID-19, a novel coronavirus disease that emerged in China in late 2019. We present a base mathematical model for the transmission dynamics of COVID-19 in India and its neighbour, Pakistan. The base model, which takes the form of a deterministic system of nonlinear differential equations, is parameterized using cumulative COVID-19 mortality data from each of the two countries. The model was used to assess the population-level impact of the control and mitigation strategies implemented in the two countries (notably community lockdowns, use of face masks, and social-distancing). Numerical simulations of the basic model indicate that, based on the current baseline levels of the control and mitigation strategies implemented, the pandemic trajectory in India is on a downward trend (as characterized by the reproduction number of the disease dynamics in India below, but close to, unity). This downward trend will be reversed, and India will be recording mild outbreaks (i.e., pandemic waves), if the control and mitigation strategies are relaxed from their current levels (e.g., relaxed to the extent that the associated community transmission parameters are increased by 20% or 40% from their current baseline values). Our simulations suggest that India could record up to 460,000 cumulative deaths by early September 2021 under the baseline levels of the control strategies implemented (up to 25,000 of the projected deaths could be averted if the control and mitigation measures are strengthened to the extent that the associated community transmission parameters are reduced by 20% from their baseline values). Our simulations show that the pandemic in Pakistan is much milder, with an estimated projected cumulative mortality of about 24,000 by early September 2021 under the baseline scenario. The basic model was extended to assess the impact of back-and-forth mobility between the two countries. Simulations of the resulting metapopulation model show that the burden of the COVID-19 pandemic in Pakistan increases with increasing values of the average time residents of India spend in Pakistan. In particular, it is shown that the India- to-Pakistan mobility pattern may trigger a fourth wave of the pandemic in Pakistan (under certain mobility scenarios), with daily mortality peaking in mid-August to mid-September of 2021. Under the respective baseline control scenarios, our simulations show that the back-and-forth mobility between India and Pakistan could delay the time-to-elimination of the COVID-19 pandemic in the two countries by three to five months (specifically, under the respective baseline scenarios, elimination could be delayed in India and Pakistan to November 2022 and July 2022, respectively).


title: Quantifying bias from dependent left truncation in survival analyses of real world data

abstract: In real world data (RWD) studies, observed datasets are often subject to left truncation, which can bias estimates of survival parameters. Standard methods can only suitably account for left truncation when survival and entry time are independent. Therefore, in the dependent left truncation setting, it is important to quantify the magnitude and direction of estimator bias to determine whether an analysis provides valid results. We conduct simulation studies of common RWD analytic settings in order to determine when standard analysis provides reliable estimates, and to identify factors that contribute most to estimator bias. We also outline a procedure for conducting a simulation-based sensitivity analysis for an arbitrary dataset subject to dependent left truncation. Our simulation results show that when comparing a truncated real-world arm to a non-truncated arm, we observe the estimated hazard ratio biased upwards, providing conservative inference. The most important data-generating parameter contributing to bias is the proportion of left truncated patients, given any level of dependence between survival and entry time. For specific datasets and analyses that may differ from our example, we recommend applying our sensitivity analysis approach to determine how results would change given varying proportions of truncation.


title: Quantitative SARS-CoV-2 tracking of variants Delta, Delta plus, Kappa and Beta in wastewater by allele-specific RT-qPCR

abstract: The Delta (B.1.617.2) variant has caused major devastation in India and other countries around the world. First detected in October 2020, it has now spread to more than 100 countries, prompting WHO to declare it as a global variant of concern (VOC). The Delta (B.1.617.2), Delta plus (B.1.617.2.1) and Kappa (B.1.617.1) variants are all sub-lineages of the original B.1.617 variant. Prior to the inception of B.1.617, vaccine rollout, safe-distancing and timely lockdowns greatly reduced COVID-19 hospitalizations and deaths. However, the Delta variant, allegedly more infectious and for which existing vaccines seemed less effective, has catalyzed the resurgence of cases. Therefore, there is an imperative need for increased surveillance of the B.1.617 variants. While the Beta variant is increasingly outpaced by the Delta variant, the spread of the Beta variant remains of concern due to its vaccine resistance. Efforts have been made to utilize wastewater-based surveillance for community-based tracking of SARS-CoV-2 variants, however wastewater with its low SARS-CoV-2 viral titers and mixtures of viral variants, requires assays to be variant-specific yet accurately quantitative for meaningful interpretation. Following on the design principles of our previous assays for the Alpha variant, here we report allele-specific and multiplex-compatible RT-qPCR assays targeting mutations T19R, D80A, K417N, T478K and E484Q, for quantitative detection and discrimination of the Delta, Delta plus, Kappa and Beta variants in wastewater. This method is open-sourced and can be implemented using commercially available RT-qPCR protocols, and would be an important tool for tracking the spread of B.1.617 and the Beta variants in communities.

category: infectious diseases


title: Helmet noninvasive ventilation for COVID-19 patients (Helmet-COVID): study protocol for a multicenter randomized controlled trial

abstract:
IntroductionNoninvasive ventilation delivered by helmet is has been used for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. The aim of this study is to compare helmet noninvasive ventilation with usual care versus usual care alone to reduce the mortality.

Methods and analysisThis is a multicenter, pragmatic, parallel, randomized controlled trial that compares helmet noninvasive ventilation with usual care to usual care alone in 1:1 ratio. A total of 320 patients will be enrolled in this study. The primary outcome is 28-day all-cause mortality. The primary outcome will be compared between the two study groups in the intention-to-treat and per-protocol cohorts. An interim analysis will be conducted for both safety and effectiveness.

Ethics and disseminationApprovals are obtained from the Institutional Review Boards (IRBs) of each participating institution. Our findings will be published in peer-review journals and presented at relevant conferences and meetings.

Trial registration numberNCT04477668 registered on July 20, 2020

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis trial compares helmet NIV to usual care for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia.
C_LIO_LIThe trial is a multi-center, pragmatic, parallel randomized controlled trial.
C_LIO_LIThe main limitation is the unblinded design due to the nature of the intervention.
C_LI


title: Efficacy and safety of a drug-free, barrier-forming nasal spray for allergic rhinitis: randomized, open-label, crossover noninferiority trial

abstract:
BackgroundSymptoms of allergic rhinitis can be reduced by nonpharmacological nasal sprays that create a barrier between allergens and the nasal mucosa. A new nasal spray (AM-301) containing the clay mineral bentonite was tested for its ability to reduce symptoms to grass pollen.

MethodsThis open label, crossover, noninferiority trial compared the efficacy and safety of AM-301 to that of hydroxypropyl methylcellulose (HPMC; Nasaleze Allergy Blocker), an established barrier method. Adults with seasonal allergic rhinitis were exposed to Dactylis glomerata pollen, in the Fraunhofer Allergen Challenge Chamber, first without protection and then protected by HPMC or AM-301 (7 days apart). Efficacy was assessed from total nasal symptom score (TNSS), nasal secretion weight, and subjective rating. The primary endpoint was the difference, between AM-301 and HPMC, in least square mean change in TNSS over a 4-hour exposure to allergen.

ResultsThe study enrolled 36 persons, and 35 completed all study visits. The mean TNSS was 5.91 during unprotected exposure, 5.20 during protection with HPMC, and 4.82 during protection with AM-301. The difference in least square means between the two treatments was -0.39 (95% CI, -0.89 to 0.10), establishing the noninferiority of AM-301. No difference in mean weight of nasal secretions was observed between the treatments. Efficacy was rated as good or very good for AM-301 by 31% and for HPMC by 14% of subjects. 16 subjects reported adverse events with a relationship to AM-301 or HPMC; most adverse events were mild and none was serious.

ConclusionsAM-301 demonstrated noninferiority towards HPMC in the primary endpoint and was perceived better in subjective secondary endpoints. Both barrier-forming products had a persisting protective effect over 4 hours and were safe.

Trial registrationGerman Clinical Trial Register (DRKS00024356). EUDAMED (CIV-20-10-034870).

category: allergy and immunology


title: Inequality in access to dental services in a market-based dental care system. A population study from Norway 1975-2018

abstract:
ObjectiveTo examine income-related inequalities in access to dental services from 1975 to 2018. In Norway, dental care services for adults are privately financed. This might lead to income-related inequalities in access to dental services. However, over the last decades Norwegians have experienced a rapid growth in income, including people with lower income. This may have led to improved access to dental services for these people. Therefore, inequalities in access to dental services may have become less over the last decades.

Research designThis was a prospective study. Statistics Norway collected samples of cross-sectional health survey data for the following years: 1975, 1985, 1995, 2002, 2008, 2012 and 2018. For each sample, individuals 20 years and older were drawn randomly from the non-institutionalized adult population using a two-stage stratified cluster sample technique. Inequalities were measured using the concentration index. The dependent variable was use of dental services during the last year and the key independent variable was equalized household income.

ResultsThe concentration index for inequalities in use of dental services according to income decreased from 0.10 (95% confidence interval = 0.09, 0.11) in 1975 to 0.04 (95% confidence interval = 0.03, 0.05) in 2018. The decrease was particularly large from 2002 to 2012. This was a period with a large growth in gross national income.

ConclusionPeople with a low income had a marked increase in their purchasing power from 1975 to 2018. This coincided with an increase in demand for dental care for this low-income group.


title: Development and performance evaluation of a low-cost in-house rRT-PCR assay in Ecuador for the detection of SARS-CoV-2

abstract: AntecedentsEcuador has had the greatest fatality rate from Coronavirus (COVID-19) in South America during the SARS-CoV-2 pandemic. To control the pandemic, it is necessary to test as much population as possible to prevent the spread of the SARS-CoV-2 infection. For the Ecuadorian population, accessing a PCR test is challenging, since commercial screening kits tend to be expensive. Objective: the objective of this study was to develop an in-house duplex rRT-PCR protocol for the detection of SARS-CoV-2 that contributes to the screening while keeping quality and low testing costs. Results: An in-house duplex rRT-PCR protocol based on the viral envelope (E) gene target of SARS-CoV-2 and a human ribonuclease P gene (RP) as an internal control is reported. The protocol was optimized to obtain primers E with an efficiency of up to 94.45% and detection of 100% of SARS-CoV-2 up to 15 copies per uL. The clinical performance was determined by a sensibility of 93.8% and specificity of 98.3%. Conclusion: we developed, standardized, and validated a low-cost, sensitive in-house duplex rRT-PCR assay that may be utilized in low-income countries.

category: epidemiology


title: Diagnostic Efficacy of Rapid Antigen Testing for SARS-CoV-2: The COVid-19 AntiGen (COVAG) study

abstract:
BackgroundWidely available rapid testing is pivotal to the fight against COVID-19. Real-time reverse transcription-polymerase chain reaction (rRT-PCR) remains the gold standard. We compared two frequently used commercial rapid diagnostic tests (RDTs) for SARS-CoV-2-antigens, the SD Biosensor SARS-CoV-2 Rapid Antigen Test (Roche Diagnostics) and the Panbio COVID-19 Ag Rapid Test (Abbott Diagnostics), against rRT-PCR for SARS-CoV-2 detection.

MethodsWe compared the tests in 2215 all-comers at a diagnostic centre between February 1 and March 31, 2021. rRT-PCR-positive samples were examined for SARS-CoV-2 variants.

Findings338 participants (15%) were rRT-PCR-positive for SARS-CoV-2. The sensitivities of Roche-RDT and Abbott-RDT were 60.4% and 56.8% (P<0{middle dot}0001) and specificities 99.7% and 99.8% (P=0{middle dot}076), respectively. Sensitivity inversely correlated with rRT-PCR-derived Ct values. Unadjusted, the RDTs had higher sensitivities in individuals referred by treating physicians and health departments than those tested for other reasons, in persons without comorbidities compared to those with comorbidities, in individuals with symptoms suggesting COVID-19, and in the absence of SARS-CoV-2 variants compared to Alpha variant carriers. The associations of sensitivity with clinical symptoms and the SARS-CoV-2 genotype were robust against adjustment for Ct values. Assuming that 10 000 symptomatic individuals are tested, 500 of which are truly positive, the RDTs would generate 38 false-positive and 124 false-negative results. Assuming that 10 000 asymptomatic individuals are tested, including 50 true positives, 18 false-positives and 34 false-negatives would be generated.

InterpretationThe sensitivities of the two RDTs are unsatisfactory. This calls into question whether their widespread use is effective in the ongoing SARS-CoV-2 pandemic.

FundingSYNLAB Holding Deutschland GmbH

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSmall studies and a meta-analysis from the Cochrance collaboration indicate vastly different diagnostic efficacies of commercial rapid diagnostic tests (RDTs) for SARS-CoV-2 antigen. The impact of SARS-CoV-2 variants has not been known.

Added value of this studyThis is one of the largest real-world studies of the diagnostic efficacy of two widely recommended RDTs SARS-CoV-2 antigen in comparison to rRT-PCR. The sensitivities of the two RDTs are unsatisfactory, mainly in asymptomatic persons. Presence of the SARS-CoV-2 Alpha Variant decreased both tests sensitivities significantly.

Implications of all the available evidencePolicy and health care providers should account for substantial limitations of RDTs for SARS-CoV-2 particular in asymptomatic persons. Research into alternative approaches to the screening for SARS-CoV-2 should be intensified.


title: Systematic review protocol exploring the impact of the COVID-19 pandemic on the wellbeing of general practitioners

abstract:
BackgroundOver recent years chronic stress and burnout have been reported by doctors working in general practice in the UK NHS and internationally. The COVID-19 pandemic has changed general practitioners working lives - adding potential pressures from avoiding infection and addressing pent-up demand for care, but also changing processes such as rapidly taking up remote consultations. To date, there has been a focus on exploring the impact of the pandemic on the wellbeing of hospital clinicians. No registered systematic reviews currently focus on exploring the impact of the pandemic on the mental health and wellbeing of general practitioners.

Aims and objectivesTo synthesise the current international evidence base exploring the impact of COVID-19 on the mental health and wellbeing of general practitioners, and which factors are associated with their reported mental health and wellbeing during the pandemic.

MethodsIn this paper we report a systematic review protocol, following PRISMA guidance. In our search strategy we will identify primary research studies or systematic reviews exploring the mental health and wellbeing of general practitioners during the COVID-19 pandemic in four databases (MEDLINE, Embase, PsychInfo and Medrxiv) and Google Scholar. We will hand-search reference lists and grey literature.

Two reviewers will undertake all stages including study selection, data extraction and quality assessment, with arbitration by a third reviewer where necessary. We will use standardised quality assessment tools to ensure transparency and reduce bias in quality assessment. Depending on the quality of included studies, we may undertake a sensitivity analysis by excluding studies from narrative synthesis that are rated as low quality using the checklists.

We will describe the findings across studies using narrative thematic data synthesis, and if sufficiently homogenous data are identified, we will pool quantitative findings through meta-analysis.

category: health policy


title: When do elementary students need masks in school? Model-estimated risk of in-school SARS-CoV-2 transmission and related infections among household members before and after student vaccination

abstract:
BackgroundWhile CDC guidance for K-12 schools recommends indoor masking regardless of vaccination status, final decisions about masking in schools will be made at the local and state level. The impact of the removal of mask restrictions, however, on COVID-19 outcomes for elementary students, educators/staff, and their households is not well known.

MethodsWe used a previously published agent-based dynamic transmission model of SARS-CoV-2 in K-12 schools to simulate an elementary school with 638 students across 12 scenarios: combinations of three viral infectiousness levels (reflecting wild-type virus, alpha variant, and delta variant) and four student vaccination levels (0%, 25%, 50% and 70% coverage). For each scenario, we varied observed community COVID-19 incidence (0 to 50 cases/100,000 people/day) and mitigation effectiveness (0-100% reduction to in-school secondary attack rate), and evaluated two outcomes over a 30 day period: (1) the probability of at least one in-school transmission, and (2) average increase in total infections among students, educators/staff, and their household members associated with moving from more to less intensive mitigation measures.

ResultsOver 30 days in the simulated elementary school, the probability of at least one in-school SARS-CoV-2 transmission and the number of estimated additional infections in the immediate school community associated with changes in mitigation measures varied widely. In one scenario with the delta variant and no student vaccination, assuming that baseline mitigation measures of simple ventilation and handwashing reduce the secondary attack rate by 40%, if decision-makers seek to keep the monthly probability of an in-school transmission below 50%, additional mitigation (e.g., masking) would need to be added at a community incidence of approximately 2/100,000/day. Once students are vaccinated, thresholds shift substantially higher.

LimitationsThe interpretation of model results should be limited by the uncertainty in many of the parameters, including the effectiveness of individual mitigation interventions and vaccine efficacy against the delta variant, and the limited scope of the model beyond the school community. Additionally, the assumed case detection rate (33% of cases detected) may be too high in areas with decreased testing capacity.

ConclusionDespite the assumption of high adult vaccination, the risks of both in-school SARS-CoV-2 transmission and resulting infections among students, educators/staff, and their household members remain high when the delta variant predominates and students are unvaccinated. Mitigation measures or vaccinations for students can substantially reduce these risks. These findings underscore the potential role for responsive plans, where mitigation is deployed based on local COVID-19 incidence and vaccine uptake.


title: Model-estimated relationship between elementary school-related SARS-CoV-2 transmission, mitigation interventions, and vaccination coverage across community incidence levels


title: Low SARS-CoV-2 infection rate and high vaccine-induced immunity among German healthcare workers at the end of the third wave of the COVID-19 pandemic

abstract: In this longitudinal cohort study, we assessed the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) seroconversion rates and analyzed the coronavirus disease 2019 (COVID-19) vaccine-induced immunity of 872 hospital workers at the University Medical Center Hamburg-Eppendorf between May 11 and May 31, 2021. The overall seroprevalence of anti-NC-SARS-CoV-2 antibodies was 4.7% (n=41), indicating low SARS-CoV-2 infection rates and persistent effectiveness of hospital-wide infection control interventions during the second and third wave of the pandemic. In total, 92.7% (n=808) out of the entire study cohort, 98.2% (n=325) of those who had been vaccinated once and all 393 individuals who had been vaccinated twice had detectable anti-S1-RBD-SARS-CoV-2 antibody titers and no significant differences in vaccine-induced immune response were detected between male and female individuals and between different age groups. Vaccinated study participants with detectable anti-NC-SARS-CoV-2 antibody titers (n=30) developed generally higher anti-S1-RBD-SARS-CoV-2 antibody titers compared to anti-NC-SARS-CoV-2 negative individuals (n=694) (median titer: 7812 vs. 345 BAU/ml, p<0.0001). Furthermore, study participants who received heterologous vaccination with AZD1222 followed by an mRNA vaccine showed markedly higher anti-S1-RBD-SARS-CoV-2 antibody titers than individuals who received two doses of an mRNA vaccine or two doses of AZD1222 (median titer: AZD1222 / AZD1222: 1069 BAU/ml, mRNA / mRNA: 1388 BAU/ml, AZD1222/mRNA: 9450 BAU/ml; p<0.0001). Our results demonstrate that infection control interventions were generally effective in preventing nosocomial transmission of SARS-CoV-2 and that COVID-19 vaccines can elicit strong humoral responses in the majority of a real-world cohort of hospital workers.