title: Single cell sequencing reveals expanded cytotoxic CD4+ T cells and two states of peripheral helper T cells in synovial fluid of ACPA+ RA patients

abstract: Rheumatoid arthritis is an autoimmune disease affecting the synovial joints where different subsets of CD4+ T cells are suspected to play a pathogenic role. So far, our understanding of the contribution of cytotoxic CD4+ T cells is incomplete, particularly in the context of the recently described peripheral helper T-cell subset (TPH). Here, using single cell sequencing and multi-parameter flow cytometry, we show that cytotoxic CD4+ T cells are enriched in synovial fluid of anti-citrullinated peptides antibody (ACPA)-positive RA patients. We identify two distinct TPH states differentially characterized by the expression of CXCL13 and PRDM1, respectively. Our data reveal that the adhesion G-Protein Coupled Receptor 56 (GPR56), a marker of circulating cytotoxic cells, delineates the synovial TPH CD4+ T-cell subset. At the site of inflammation, GPR56+CD4+ T cells expressed the tissue-resident memory markers LAG-3, CXCR6 and CD69. Further, TCR clonality analysis revealed that most expanded clones in SF are contained within the cytotoxic and the CXCL13+ TPH CD4+ T-cell populations. Finally, the detection of common TCRs between the two TPH and cytotoxic CD4+ T-cell clusters suggest a shared differentiation. Our study provides comprehensive immunoprofiling of the heterogenous T-cell subsets at the site of inflammation in ACPA+ RA and suggests GPR56 as a therapeutic target to modulate TPH cells and cytotoxic CD4+ T cell function.

category: rheumatology


title: Functional Rating Scales in Spinal and Bulbar Muscular Atrophy: A Systematic Review, Meta-Analysis and Critical Appraisal of their Measurement Properties

abstract: Tracking disease progression and treatment effect of spinal bulbar muscular atrophy, or Kennedys disease, is challenging given its slowly progressive nature. To achieve success in SBMA clinical trials, a reliable, responsive, and validated patient-reported motor function scale must capture progression of SBMA-specific motor dysfunction. Here, we conducted a systematic review, meta-analysis, and appraisal of core measurement properties of the SBMA functional rating scale (SBMAFRS). We established that the SBMAFRS has satisfactory internal consistency, inter-rater reliability, and construct validity for measuring progressive motor dysfunction over similar neurodegenerative motor function scales but inadequate sensitivity to change over time. Further development to validate and improve the SBMAFRS ability to capture longitudinal responsiveness in larger cohorts is warranted.

category: neurology


title: Factors associated with home birth in Peru: An analysis of the Demographic and Health Survey, 2019

abstract:
ObjectiveTo determine the proportion and factors associated with home birth in Peru, 2019.

Material and methodsCross-sectional analytical design study where the 2019 Peruvian Demographic and Family Health Survey was analyzed. The association was evaluated using Poisson Regression, supplemented with the crude prevalence ratio (cPR) and adjusted (aPR).

ResultsThe records of 18,401 women were evaluated, where 5.39% (95%CI:4.83-6.03%) presented home birth. The probability of a home birth occurs increases when the pregnant woman is from the andean (aPR:1.24; 95%CI:1.02-1.48) and amazon region (aPR:1.38; 95%CI:1.16-1.64), resides in rural areas (aPR:3.34; 95%CI:2.61-4.29), presents less than 6 prenatal care (aPR:1.66; 95%CI:1.39 -1.96), it is very poor (aPR:9.62; 95%CI:5.13-18.1) or poor (aPR:2.39; 95%CI:1.26-4.52), it has not studied (aPR:2.66; 95%CI:2.02-3.50) or reached primary education (aPR:2.18: 95%CI:1.85-2.58) and has 2 children (aPR:1.64; 95%CI:1.46-1.85) or 3 or more children (aPR:2.18; 95%CI:1.67-2.87). On the other hand, having higher educational instruction (aPR:0.49; 95%CI:0.31-0.78) is associated with a lower probability of a home birth.

ConclusionsThere is a low proportion of home births; however, this indicator increases significantly according to various geographical, sociodemographic, and obstetric factors that have been identified.

HIGHLIGHTSO_LIThe proportion of home births in Peru is low, although it reaches high values in the amazon and rural areas.
C_LIO_LISociodemographic determinants such as poverty and low educational level are risk factors for home birth.
C_LIO_LIObstetric determinants such as having few prenatal controls or had having previously multiple deliveries are risk factors for home birth.
C_LI

category: obstetrics and gynecology


title: Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

abstract: Rapid progress of the discovery of genetic loci associated with common, complex diseases has outpaced the elucidation of mechanisms pertinent to disease pathogenesis. To address relevant barriers for coronary artery disease (CAD), we combined genetic discovery analyses with downstream characterization of likely causal variants, genes, and biological pathways. Specifically, we conducted a genome-wide association study (GWAS) comprising 181,522 cases of CAD among 1,165,690 participants. We detected 241 associations, including 54 associations and 30 loci not previously linked to CAD. Next, we prioritized likely causal variants using functionally-informed fine-mapping, yielding 42 associations with fewer than five variants in the 95% credible set. Combining eight complementary predictors, we prioritized 185 candidate causal genes, including 94 genes supported by three or more predictors. Similarity-based clustering underscored a role for early developmental processes, cell cycle signaling, and vascular proliferation in the pathogenesis of CAD. Our analysis identifies and systematically characterizes risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

category: genetic and genomic medicine


title: COVID Oximetry @home: evaluation of patient outcomes

abstract:
BackgroundCOVID-19 has placed unprecedented demands on hospitals. A clinical service, COVID Oximetry @home (CO@h) was launched in November 2020 to support remote monitoring of COVID-19 patients in the community. Remote monitoring through CO@h aims to identify early patient deterioration and provide timely escalation for cases of silent hypoxia, while reducing the burden on secondary care.

MethodsWe conducted a retrospective service evaluation of COVID-19 patients onboarded to CO@h from November 2020 to March 2021 in the North Hampshire (UK) community led service (a collaboration of 15 GP practices covering 230,000 people). We have compared outcomes for patients admitted to Basingstoke & North Hampshire Hospital who were CO@h patients (COVID-19 patients with home monitoring of SpO2 (n=115)), with non-CO@h patients (those directly admitted without being monitored by CO@h (n=633)). Crude and adjusted odds ratio analysis was performed to evaluate the effects of CO@h on patient outcomes of 30-day mortality, ICU admission and hospital length of stay greater than 3, 7, 14, and 28 days.

ResultsAdjusted odds ratios for CO@h show an association with a reduction for several adverse patient outcome: 30-day hospital mortality (p<0.001 OR 0.21 95% CI 0.08-0.47), hospital length of stay larger than 3 days (p<0.05, OR 0.62 95% CI 0.39-1.00), 7 days (p<0.001 OR 0.35 95% CI 0.22-0.54), 14 days (p<0.001 OR 0.22 95% CI 0.11-0.41), and 28 days (p<0.05 OR 0.21 95% CI 0.05-0.59). No significant reduction ICU admission was observed (p>0.05 OR 0.43 95% CI 0.15-1.04). Within 30 days of hospital admission, there were no hospital readmissions for those on the CO@h service as opposed to 8.7% readmissions for those not on the service.

ConclusionsWe have demonstrated a significant association between CO@h and better patient outcomes; most notably a reduction in the odds of hospital lengths of stays longer than 7, 14 and 28 days and 30-day hospital mortality.

category: health systems and quality improvement


title: Rapid, Near Point-of-Care Assay for HLA-B*57:01 Genotype Associated with Severe Hypersensitivity Reaction to Abacavir

abstract:
ObjectiveThe nucleoside reverse transcriptase inhibitor abacavir is commonly used to treat young children with HIV infection. Abacavir can trigger a severe hypersensitivity reaction in people who are homozygous or heterozygous for HLA-B*57:01. Testing for HLA-B*57:01 prior to abacavir initiation is standard-of-care in high-resource settings, but current tests are too costly for resource-limited settings. To address this gap, we developed an inexpensive, simple-to-use rapid assay to detect HLA-B*57:01.

MethodsWe designed and optimized a multiplexed PCR to amplify HLA-B*57 subtypes and the human beta-globin gene. Subsequently, probes annealed to the amplicon and were ligated when specific for the HLA-B*57:01 allele. Ligated products were detected by immunocapture in a lateral flow strip. Cell lines with known HLA genotypes were used to optimize the assay. The assay was then evaluated by comparing the genotype of clinical specimens (n=60) enriched for individuals with HLA-B*57:01 by the new assay to that from sequencing.

ResultsThe optimized multiplex PCR for B*57 and beta-globin resulted in a 40-minute, 35-cycle amplification, followed by a 20-minute ligation reaction and 15-minute detection step. Evaluation of the HLA-B*57:01 oligonucleotide ligation assay using clinical specimens had a sensitivity of 100% (n=27/27 typed as B*57:01) and specificity of 100% (n=33/33 typed as non-B*57:01) by visual interpretation of lateral flow strips.

ConclusionsThis rapid and economical assay can accurately detect the presence of HLA-B*57:01 in clinical specimens. Use of this assay could expand access to HLA-B*57:01 genotyping and facilitate safe same-day initiation of abacavir-based treatment.

category: hiv aids


title: Incidence of chikungunya virus infections among Kenyan children with neurological disease: a prospective cohort study

abstract:
BackgroundNeurological complications due to chikungunya virus (CHIKV) infection have been described in different parts of the world, with children being disproportionately affected. However, the burden of CHIKV-associated neurological disease in Africa is currently unknown.

MethodsWe estimated the incidence of CHIKV infection among children hospitalised with neurological disease in coastal Kenya. We used reverse-transcriptase polymerase chain reaction (RT-PCR) to systematically test for CHIKV in cerebrospinal fluid (CSF) samples from children aged <16 years hospitalised with symptoms of neurological disease at Kilifi County Hospital between January 2014 and December 2018. Clinical records were linked to the Kilifi Health and Demographic Surveillance System and population incidence rates of CHIKV infection estimated.

FindingsThere were 18,341 paediatric admissions during the 5-year study period, of which 4,332 (24%) had CSF collected. The most common clinical reasons for CSF collection were impaired consciousness, seizures and coma (47%, 22% and 21% of all collections, respectively). After acute investigations done for immediate clinical care, CSF samples were available for 3,980 admissions, of which 367 (9.2%) were CHIKV RT-PCR positive. The annual incidence of CHIKV-associated neurological disease varied between 13 to 58 episodes per 100,000 person-years among all children <16 years old. Among children aged <5 years, the incidence of CHIKV-associated neurological disease was 77 per 100,000 person-years, compared with 20 per 100,000 for cerebral malaria and 7 per 100,000 for bacterial meningitis during the study period.

InterpretationAlthough not previously recognized, CHIKV-associated neurological disease is common in coastal Kenya and a significant public health burden.

category: infectious diseases


title: Cross-reactive antibodies after SARS-CoV-2 infection and vaccination

abstract: Current SARS-CoV-2 vaccines are losing efficacy against emerging variants and may not protect against future novel coronavirus outbreaks, emphasizing the need for more broadly protective vaccines. To inform the development of a pan-coronavirus vaccine, we investigated the presence and specificity of cross-reactive antibodies against the spike (S) proteins of human coronaviruses (hCoV) after SARS-CoV-2 infection and vaccination. We found an 11 to 123-fold increase in antibodies binding to SARS-CoV and MERS-CoV as well as a 2 to 4-fold difference in antibodies binding to seasonal hCoVs in COVID-19 convalescent sera compared to pre-pandemic healthy donors, with the S2 subdomain of the S protein being the main target for cross-reactivity. In addition, we detected cross-reactive antibodies to all hCoV S proteins after SARS-CoV-2 S protein immunization in macaques, with higher responses for hCoV more closely related to SARS-CoV-2. These findings support the feasibility of and provide guidance for development of a pan-coronavirus vaccine.


title: Evaluation of the INDICAID COVID-19 Rapid Antigen Test in symptomatic populations and asymptomatic community testing

abstract:
BackgroundAs the COVID-19 pandemic continues to cause substantial morbidity and mortality, there is an increased need for rapid, accessible assays for SARS-CoV-2 detection.

MethodsHere we present a clinical evaluation and real-world implementation of the INDICAID COVID-19 Rapid Antigen Test (INDICAID Rapid Test). A multi-site clinical evaluation of the INDICAID Rapid Test using prospectively collected samples from symptomatic subjects was performed. The INDICAID Rapid Test was then implemented at COVID-19 outbreak screening centers in Hong Kong to screen individuals for COVID-19 to prioritize confirmatory RT-PCR testing among asymptomatic populations.

ResultsThe clinical evaluation in symptomatic patient populations demonstrated a positive percent agreement and negative percent agreement of 85.3% (95% confidence interval [95% CI]: 75.6% - 91.6%) and 94.9% (95% CI: 91.6% - 96.9%), respectively, when compared to laboratory-based RT-PCR testing. When used during outbreak testing of 22,994 asymptomatic patients, the INDICAID Rapid Test demonstrated a positive percent agreement of 84.2% (95% CI: 69.6% - 92.6%) and a negative percent agreement of 99.9% (95% CI: 99.9% - 100%) compared to laboratory-based RT-PCR testing. When incorporated in a testing algorithm, the INDICAID Rapid Test reduced time to confirmatory positive result from an average 10.85 hours (standard RT-PCR only) to 0.84 hours, depending on the algorithm.

ConclusionThe INDICAID Rapid Test has excellent performance when compared to laboratory-based RT-PCR testing, and when used in tandem with RT-PCR, reduces the time to confirmatory positive result.

SummaryIn clinical evaluations, the INDICAID COVID-19 Rapid Antigen Test demonstrated high sensitivity and specificity in symptomatic and asymptomatic patient populations. When used in tandem with RT-PCR testing, the INDICAID Rapid Test expedited confirmatory results and may help reduce SARS-CoV-2 outbreaks.


title: Regular testing of asymptomatic healthcare workers identifies cost-efficient SARS-CoV-2 preventive measures

abstract: Protecting healthcare professionals is crucial in maintaining a functioning health-care system. The risk of infection and optimal preventive strategies for health-care workers during the COVID-19 pandemic remain poorly understood. Here we report the results of a weekly testing regime that has been performed since the beginning of the COVID-19 pandemic to identify pre- and asymptomatic healthcare workers. Based on these observations we have developed a mathematical model of SARS-CoV-2 transmission that integrates the sources of infection from inside and outside the hospital. The data were used to study how regular testing and a desynchronisation protocol are effective in preventing transmission of COVID-19 infection at work, and compared both strategies in terms of workforce availability and cost-effectiveness. We showed that case incidence among healthcare workers is higher than would be explained solely by community infection. Furthermore, while testing and desynchronisation protocols are both effective in preventing nosocomial transmission, regular testing maintains work productivity with implementation costs.

category: epidemiology


title: Performance evaluation of virus concentration methods for implementing SARS-CoV-2 Wastewater-based epidemiology emphasizing quick data turnaround.

abstract: Wastewater based epidemiology (WBE) has drawn significant attention as an early warning tool to detect and predict the trajectory of COVID-19 cases in a community, in conjunction with public health data. This means of monitoring for outbreaks has been used at municipal wastewater treatment centers to analyze COVID-19 trends in entire communities, as well as by universities and other community living environments to monitor COVID-19 spread in buildings. Sample concentration is crucial, especially when viral abundance in raw wastewater is below the threshold of detection by RT-qPCR analysis. We evaluated the performance of a rapid ultrafiltration-based virus concentration method using InnovaPrep Concentrating Pipette (CP) Select and compared this to the established electronegative membrane filtration (EMF) method. We evaluated sensitivity of SARS-CoV-2 quantification, surrogate virus recovery rate, and sample processing time. Results suggest that the CP Select concentrator is more efficient at concentrating SARS-CoV-2 from wastewater compared to the EMF method. About 25% of samples that tested negative when concentrated with the EMF method produced a positive signal with the CP Select protocol. Increased recovery of the surrogate virus control using the CP Select confirms this observation. We optimized the CP Select protocol by adding AVL lysis buffer and sonication, to increase the recovery of virus. Sonication increased Bovine Coronavirus (BCoV) recovery by 19%, which seems to compensate for viral loss during centrifugation. Filtration time decreases by approximately 30% when using the CP Select protocol, making this an optimal choice for building surveillance applications where quick turnaround time is necessary.


title: Prevalence of persistent symptoms in children during the COVID-19 pandemic: evidence from a household cohort study in England and Wales

abstract: Using data from 4678 children participating in VirusWatch, a household cohort study, we estimated the prevalence of persistent symptoms lasting [≥]4 weeks as 1.7%, and 4.6% in children with a history of SARS-CoV-2 infection. Persistent symptom prevalence was higher in girls, teenagers and children with long-term conditions.

category: pediatrics


title: Tracing contacts to evaluate the transmission of COVID-19 from highly exposed individuals in public transportation

abstract: We investigate, through a data-driven contact tracing model, the transmission of COVID-19 inside buses during distinct phases of the pandemic in a large Brazilian city. From this microscopic approach, we recover the networks of close contacts within consecutive time windows. A longitudinal comparison is then performed by upscaling the traced contacts with the transmission computed from a mean-field compartmental model for the entire city. Our results show that the effective reproduction numbers inside the buses, Rebus, and in the city, Recity, followed a compatible behavior during the first wave of the local outbreak. Moreover, by distinguishing the close contacts of healthcare workers in the buses, we discovered that their transmission, Rehealth, during the same period, was systematically higher than Rebus. This result reinforces the need for special public transportation policies for highly exposed groups of people.


title: COVID-19 Sniffer Dog experimental training: which protocol and which implications for reliable identification?

abstract: The introduction of trained sniffer dogs for COVID-19 disease detection could be an opportunity, as previously described for other diseases. Dogs could be trained to detect volatile organic compounds (VOCs), the whiff of COVDI-19 disease. Dogs involved in the study were three one male and two females from different breeds, Black German Shepherd, German Shepherd and Dutch Shepherd. The training was performed using sweat samples from COVID-19 positive apteints and from covid-19 free patients admitted at the University Hospital Campus Bio-medico of Rome. Gauze with sweat were collected in glass jar with metal top and put in metal boxes used for dog training. The dog training protocol was performed in two phase: the olfactory conditioning and the olfactory discrimintaion research. The training palnning was focused on the switch moment for the sniffer dog, the moment when the dog was able to identify VOCs specific for COVID-19 disease. At this time the dog was able to identify VOCs specific for COVID-19 disease with significant reliability, in terms of number of correct versus uncorrect (p<0.0001) reporting. In conclusion, this protocol could provide a useful tool for sniffer dogs training and their introduction in mass screening context, cheaper and faster than a conventional testing method.


title: Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients

abstract:
Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.

Statement of Translational RelevanceNon Hodgkin lymphoma (NHL) and Chronic Lymphocytic leukemia (CLL) patients who are treated with anti-CD20 antibody therapy, BTK inhibitor therapy, or who are monitored with active disease, have decreased antibody response to SARS-CoV-2 vaccination and decreased antibody titers compared to healthy controls. Antibody titers do not boost following second vaccination, and very few patients generate neutralizing antibodies against SARS-CoV-2. This data is of particular importance, given the recent guidance from the CDC that vaccinated patients no longer need to be masked indoors as well as outdoors. Patients with NHL or CLL who fall into these categories should not consider their immunity from vaccination to be assured. If infected with SARS-CoV-2, they should be a high priority for monoclonal antibody directed therapy. Unless immune response to vaccination is confirmed with laboratory testing, they should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.

category: hematology


title: Interim estimates of increased transmissibility, growth rate, and reproduction number of the Covid-19 B.1.617.2 variant of concern in the United Kingdom

abstract: This paper relates to data from the Wellcome Sanger Institute, UK, regarding Covid-19 genomic surveillance. We use a simple model to give point estimates of the effective reproduction numbers of the B.1.617.2 and B.1.1.7 lineages in England, from sequenced data as at 15 May 2021. Comparison with the estimated reproduction number of B.1.1.7 enables an estimate of the increased transmissibility of B.1.617.2. We conclude that it is almost certain that there is increased transmissibility that will rapidly lead to B.1.617.2 becoming the prevailing variant in the UK. The derived estimates of increased transmissibility have uncertainty relating to the actual distribution of the generation interval, but they do point, under present conditions of vaccination coverage and NPIs, to exponential growth of positive cases.


title: Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection

abstract: A proportion of patients surviving acute COVID-19 infection develop post-COVID syndrome (long COVID) encompassing physical and neuropsychiatric symptoms lasting longer than 12 weeks. Here we studied a prospective cohort of individuals with long COVID compared to age/gender matched subjects without long COVID (from the ADAPT study), healthy donors and individuals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found highly activated innate immune cells and an absence of subsets of un-activated naive T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. These activated myeloid cells may contribute to the elevated levels of type I (IFN-{beta}) and III interferon (IFN-{lambda}1) that remained persistently high in long COVID subjects at 8 months post-infection. We found positive inter-analyte correlations that consisted of 18 inflammatory cytokines in symptomatic long COVID subjects that was not observed in asymptomatic COVID-19 survivors. A linear classification model was used to exhaustively search through all 20475 combinations of the 29 analytes measured, that had the strongest association with long COVID and found that the best 4 analytes were: IL-6, IFN-{gamma}, MCP-1 (CCL2) and VCAM-1. These four inflammatory biomarkers gave an accuracy of 75.9%, and an F1 score of 0.759, and have also previously been associated with acute severe disease. In contrast, plasma ACE2 levels, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.


title: Function is more reliable than quantity to follow up the humoral response to the Receptor Binding Domain of SARS- CoV-2 Spike Protein after Natural Infection or COVID-19 vaccination

abstract: Both the SARS-CoV-2 pandemic and emergence of variants of concern have highlighted the need for functional antibody assays to monitor the humoral response over time. Antibodies directed against the spike (S) protein of SARS-CoV-2 are an important component of the neutralizing antibody response. In this work, we report that in a subset of patients--despite a decline in total S-specific antibodies--neutralizing antibody titers remain at a similar level for an average of 98 days in longitudinal sampling of a cohort of 59 Hispanic/Latino patients exposed to SARS-CoV-2. We also report that serum neutralization capacity correlates with IgG titers, wherein IgG1 was the predominant isotype (62.71%), followed by IgG4 (15.25%), IgG3 (13.56%), and IgG2 (8.47%) at the earliest tested timepoint. IgA titers were detectable in just 28.81% of subjects, and only 62.71% of subjects had detectable IgM in the first sample despite confirmation of infection by a molecular diagnostic assay. Our data suggests that 100% of seroconverting patients make detectable neutralizing antibody responses which can be quantified by a surrogate viral neutralization test. Examination of sera from 10 out of the 59 subjects which had received an initial first dose of mRNA-based vaccination revealed that both IgG titers and neutralizing activity of sera were higher after vaccination compared to a cohort of 21 SARS-CoV-2 naive subjects. One dose was sufficient for induction of neutralizing antibody, but two doses were necessary to reach 100% surrogate virus neutralization in subjects irrespective of previous SARS-CoV-2 natural infection status. Like the pattern seen after natural infection, after the second vaccine dose, the total anti-S antibodies titers declined, however, neutralizing activity remained relatively constant for more than 80 days after the first vaccine dose. The decline in anti-S antibody titer, however, was significantly less in pre-exposed individuals, highlighting the potential for natural infection to prime a more robust immune response to the vaccine. Furthermore, our data indicates that--compared with mRNA vaccination--natural infection induces a more robust humoral immune response in unexposed subjects. However, this difference was significant only when neutralizing antibody titers were compared among the two groups. No differences were observed between naturally infected and vaccinated individuals when total anti-S antibodies and IgG titers were measured. This work is an important contribution to understanding the natural immune response to the novel coronavirus in a population severely impacted by SARS-CoV-2. Furthermore, by comparing the dynamics of the immune response after the natural infection vs. the vaccination, these findings suggest that a functional neutralizing antibody tests are more relevant indicators than the presence or absence of binding antibodies. In this context, our results also support standardizing methods of assessing the humoral response to SARS-CoV-2 when determining vaccine efficacy and describing the immune correlates of protection for SARS-CoV-2.


title: Analytical comparison of nine SARS-CoV-2 antigen-detecting rapid diagnostic tests for emerging SARS-CoV-2 variants

abstract: Several SARS-CoV-2 variants of concern/interest (VOC/VOI) emerged recently, with VOCs outcompeting earlier lineages on a global scale. To date, few data on routine diagnostic performance for VOC/VOIs are available. Here, we investigate the analytical performance of nine commercially available antigen-detecting rapid diagnostic tests (Ag-RDTs) for VOC B.1.1.7, B.1.351, P.1 and VOI P.2 with cultured SARS-CoV-2. Comparable or higher sensitivity was observed for VOC/VOI compared to a non-VOC/VOI early-pandemic virus for all Ag-RDTs.


title: Dominant role of abdominal adiposity in circulating lipoprotein, lipid, and metabolite levels in UK Biobank: Mendelian randomization study

abstract:
BackgroundThe causal impact of excess adiposity on systemic metabolism is unclear. We used multivariable Mendelian randomization to compare the direct effects of total adiposity (using body mass index (BMI)) and abdominal adiposity (using waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites with a five-fold increase in sample size over previous studies.

MethodsWe used new metabolic data on 109,532 UK Biobank participants. BMI and WHR were measured in 2006-2010, during which EDTA plasma was collected. Plasma samples were used in 2019-2020 to quantify 249 metabolic traits with high-throughput nuclear magnetic resonance spectroscopy including subclass-specific lipoprotein concentrations, apolipoprotein B, cholesterol and triglycerides, plus pre-glycemic and inflammatory metabolites. We used two-stage least squares regression models with genetic risk scores for BMI and WHR as instruments to estimate the total (unadjusted) and direct (mutually adjusted) effects of BMI and WHR on metabolic traits. We also estimated the effects of BMI and WHR on statin use, and examined interaction of main effects by sex, statin use, and age as a proxy for medication use.

ResultsHigher BMI (per standard deviation (SD) or 4.8 kg/m2) was estimated to moderately decrease apolipoprotein B and low-density lipoprotein (LDL) cholesterol before and after adjustment for WHR, whilst higher BMI increased triglycerides before but not after WHR adjustment. Estimated effects of higher WHR (per SD, or 0.090 ratio-unit) on lipoproteins, lipids, and metabolites were often larger than those of BMI, but null for LDL cholesterol, and attenuations were minimal upon adjustment for BMI. Patterns of effect estimates differed by sex, e.g., only BMI independently increased triglycerides among men, whereas only WHR independently increased triglycerides among women. Higher BMI and WHR (per SD) were each estimated to directly increase the relative odds of using statins (by 3.49 (95% CI = 3.42, 3.57) times higher for WHR). These patterns were most pronounced among women, and there was strong evidence that the effects of BMI and WHR on metabolic traits differed by statin use and age. Among the youngest adults (38-53 years, statin use 5%), higher BMI and WHR (per SD) each modestly increased LDL cholesterol (0.04 SD, 95% CI = -0.01, 0.08 for total effect of BMI and 0.10 SD, 95% CI = 0.02, 0.17 for total effect of WHR). This estimate for BMI fully attenuated, and the estimate for WHR remained unchanged, upon mutual adjustment. These direct effects on LDL cholesterol were more inverse for BMI and less positive for WHR at intermediate ages (54-62 years, statins 17%) and older ages (63-73 years, statins 29%) where the mutually adjusted effects of BMI and WHR on LDL cholesterol had reversed to -0.19 SD (95% CI = -0.27, -0.11) and -0.05 SD (95% CI = -0.16, 0.06), respectively.

ConclusionsOur results suggest that abdominal adiposity has a dominant role in driving the metabolic harms of excess adiposity, particularly among women. Our findings also suggest that apparent effects of adiposity on lowering LDL cholesterol are explained by an effect of adiposity on statin use.


title: Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

abstract:
Delhi, the national capital of India, has experienced multiple SARS-CoV-2 outbreaks in 2020 and reached a population seropositivity of over 50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant B.1.617.2 (Delta) replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and partial reduction of immunity elicited by prior infection (median estimates; x1.5-fold, 20% reduction). Seropositivity of an employee and family cohort increased from 42% to 86% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.

One-Sentence SummaryDelhi experienced an overwhelming surge of COVID-19 cases and fatalities peaking in May 2021 as the highly transmissible and immune evasive Delta variant replaced the Alpha variant.


title: Neural asymmetry during memory encoding and its association with markers of preclinical Alzheimers Disease

abstract:
BackgroundAlzheimers Disease (AD) is the most common form of dementia and is characterized by cognitive dysfunction that impacts daily functioning. Beta-amyloid (A{beta}) is a cytotoxic protein that deposits in the brain many years prior to the onset of cognitive dysfunction. The preclinical period is a stage of AD in which significant pathology is present without clinical symptoms. A{beta} has been shown to deposit asymmetrically early in the AD trajectory, which has shown to have functional consequences (e.g., asymmetric hypometabolism). We aimed to investigate whether markers of AD and cognitive function were correlated with neural activation asymmetry during memory encoding tasks.

MethodsWe recruited participants who were cognitively normal to undergo functional magnetic resonance imaging (fMRI), positron emission tomography (PET) imaging, and cognitive testing. We conducted analyses to identify regions of significant activation during a well-established face-name pair memory encoding task, and to identify regions of significant asymmetry. We then computed hemispheric asymmetry (negative/positive values indicate left/right asymmetry, respectively) and absolute asymmetry (greater values indicate greater asymmetry in either hemisphere) and investigated their associations with age, sex, education, global cerebral amyloid, global cerebral metabolism, memory encoding task performance, white matter hyperintensities, and multiple domains of cognitive function.

ResultsWe identified expected regions of significant activation, including the hippocampus, and identified four regions with significant left-hemisphere asymmetry: superior medial frontal gyrus, middle frontal gyrus, supplemental motor area, and medial orbitofrontal gyrus, and two regions with significant right hemisphere asymmetry: putamen and ventral posterolateral nucleus of the thalamus. We found that greater left-hemisphere asymmetry in the middle frontal gyrus was correlated with greater global cerebral glucose metabolism. We also found that better performance in memory, learning, and executive attention was associated with greater absolute symmetry in the thalamus, while better visuospatial performance was associated with greater putamen absolute symmetry.

DiscussionFunctional asymmetry is correlated with functional markers (e.g., glucose metabolism) in older cognitively normal adults and may reflect metabolic and cognitive changes. Longitudinal studies may help us better understand these associations and the causal impact of neural activation asymmetry.

category: psychiatry and clinical psychology


title: Vitamin D receptor polymorphisms in overweight/obese chronic kidney disease patients undergoing hemodialysis

abstract:
BackgroundMany studies were carried out to investigate the relationship between single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene with obesity. However, little is known about the role of VDR gene polymorphism with obesity in hemodialysis (HD) patients. Therefore, we aimed to investigate VDR gene TaqI, ApaI and FokI SNPs in overweight/obese HD patients.

MethodsSeventy one normal weight and 68 overweight/obese HD patients were included in study. PCR-RFLP method was used for genotyping. Demographic and laboratory data obtained from medical records of patients.

ResultsFor all three SNPs, no significant association was found between normal and overweight/obese patients (P>0.05). Lower HDL concentrations and higher levels of triglyceride (TG) and glucose were detected in the obese/overweight patients compared to normal weight (p<0.001 for HDL, and TG and p=0.023 for glucose). In obese/overweight patients, subjects with CC genotype of TaqI showed higher PTH level (717.1{+/-}616.4 pg/ml) than those TC genotype (342.7{+/-}360.8 pg/ml) and TT genotype (310.2{+/-}323.4 pg/ml) (p=0.028); higher TG level was found in patients with CC genotype of ApaI (627.3{+/-}653.0 mg/dl) compared to AA (223.3{+/-}156.6) and AC genotypes (193.1{+/-}85.4) (p<0.001). Obese/overweight patients carrying FokI TT genotype had higher glucose concentration compared to those carrying CC and CT genotypes (CC=183.4{+/-}128.4 mg/dl; TT=151.9{+/-}66.1 mg/dl; CT=107.6{+/-}41.9 mg/dl, p=0.008).

ConclusionsOur study suggest that VDR TaqI, ApaI and FokI polymorphisms are not associated with obesity in HD patients. However, they might be increase the risk of secondary hyperparathyroidism, dyslipidemia, and hyperglycemia, which are among the most common obesity related comorbidities of chronic kidney disease.

category: nephrology


title: The Immunogenetic Basis of Idiopathic Bone Marrow Failure Syndromes: A Paradox of Similarity and Self-Presentation

abstract:
Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms potentially involved in autoimmunity.

Key pointsO_LIClass II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) syndromes are characterized by low functional divergence and decreased peptide binding capabilities, only partially explained by enrichment in risk alleles.
C_LIO_LIA superstructure at the interface with the peptide binding site of DRB1 locus, potentially involved in the presentation of self-antigenic specificities, can be identified in BMF patients.
C_LIO_LIThis immunogenetic pattern may contribute to decrease T-cell receptor repertoire diversity, expand autoreactive T-cell clones and increase autoimmune propensity in BMF.
C_LI


title: Changes in amygdalar functional connectivity following the water load symptom provocation task (WL-SPT) in youth with functional abdominal pain disorders

abstract: Pediatric functional abdominal pain disorders (FAPD) are highly prevalent, difficult to diagnose and challenging to treat. The brain mechanisms supporting FAPD remain poorly understood. This investigation examined the neuromechanisms of FAPD during a well-tolerated visceral pain induction task, the water load symptom provocation task (WL-SPT). Youth between the ages of 11 and 17 years participated. Functional connectivity (FC) was examined via the Blood Oxygenation Level Dependent (BOLD) effect using the left and right amygdala (AMY) as seed regions. Relationships of the time courses within these seeds with voxels across the whole brain were evaluated. Arterial spin labeling (ASL) was used to assess regional brain activation by examining cerebral blood flow. Increased FC between the left AMY with regions associated with nociceptive processing (e.g., thalamus), and right AMY FC changes with areas associated with cognitive functioning (dorsolateral prefrontal cortex) and the default mode network (DMN; parietal lobe) were observed in youth with FAPD following the WL-SPT. These changes were related to changes in pain unpleasantness. AMY FC changes post WL-SPT were also related to changes in pain intensity. AMY FC with the DMN in youth with FAPD also differed from healthy controls. Global CBF changes were also noted between FAPD and controls, but no significant differences in grey matter were detected either between groups or during the WL-SPT in youth with FAPD. Findings confirm youth with FAPD have changes in brain connectivity that could support the development of biomarkers to enhance understanding of the mechanisms of pain and treatment response.

category: pain medicine


title: A Comparison of Four Commercially Available RNA Extraction Kits for Wastewater Surveillance of SARS-CoV-2 in a College Population

abstract:
Localized wastewater surveillance has allowed for public health officials to gain a broader understanding of SARS-CoV-2 viral prevalence in the community allowing public health officials time to prepare for impending outbreaks. Given variable levels of virus in the population through public health interventions, proper concentration and extraction of viral RNA is a key step in ensuring accurate detections. With many commercial RNA extraction kits and methodologies available, the performance of 4 different kits were evaluated for SARS-CoV-2 RNA detection in wastewater, specifically focusing on their applicability to lower population densities such as those at university campus dorms. Raw wastewater samples were collected at 4 sites on a college campus over a 24 hour period as a composite sample. Included in these sites was an isolation site that housed students that tested positive for Covid-19 via nasopharyngeal swabs. These samples were analyzed using the following kits: Qiagen All Prep PowerViral DNA/RNA kit, New England BioLabs Monarch RNA MiniPrep Kit, and Zymo Quick RNA-Viral Kit, and the Zymo Quick-RNA Fecal/Soil Microbe MicroPrep Kit. All four sites were processed according to the manufacturers guidelines. Extractions were then quantified with RT-qPCR one-step reactions using an N2 primer and a linearized plasmid standard. While the Zymo Quick-RNA Fecal/Soil Microbe MicroPrep Kit (also known as the Zymo Environ Water RNA Kit) only recovered approximately 73% (+/- 38%) SARS-CoV-2 RNA compared to the Zymo Quick-RNA Viral kit, it was the most time efficient kit to yield comparable results. This extraction kit had a cumulative processing time of approximately five hours compared, while the other three kits had processing times between approximately 9 and 9.5 hours. Based on the current research, the most effective kits for smaller population densities are pellet based and include a homogenization, inhibitor removal, and RNA preservation step.

Highlights- Samples from smaller population densities make concentrating RNA vital for detection
- Pelleting may provide for more timely concentration and extraction of SARS-CoV-2 RNA
- RNA shields and PCR inhibitor removal may increase detection of RNA during RT-qPCR

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title: A comparison of four commercially available RNA extraction kits for wastewater surveillance of SARS-CoV-2 in a college population


title: Prevention and Attenuation of COVID-19 by BNT162b2 and mRNA-1273 Vaccines

abstract:
BACKGROUNDInformation is limited on messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection or attenuating disease when administered in real-world conditions.

METHODSProspective cohorts of 3,975 healthcare personnel, first responders, and other essential and frontline workers completed weekly SARS-CoV-2 testing during December 14 2020--April 10 2021. Self-collected mid-turbinate nasal swabs were tested by qualitative and quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR). VE was calculated as 100%x(1-hazard ratio); adjusted VE was calculated using vaccination propensity weights and adjustments for site, occupation, and local virus circulation.

RESULTSSARS-CoV-2 was detected in 204 (5.1%) participants; 16 were partially ([≥]14 days post-dose-1 to 13 days after dose-2) or fully ([≥]14 days post-dose-2) vaccinated, and 156 were unvaccinated; 32 with indeterminate status (<14 days after dose-1) were excluded. Adjusted mRNA VE of full vaccination was 91% (95% confidence interval [CI]=76%-97%) against symptomatic or asymptomatic SARS-CoV-2 infection; VE of partial vaccination was 81% (95% CI=64%-90%). Among partially or fully vaccinated participants with SARS-CoV-2 infection, mean viral RNA load (Log10 copies/mL) was 40% lower (95% CI=16%-57%), the risk of self-reported febrile COVID-19 was 58% lower (Risk Ratio=0.42, 95% CI=0.18-0.98), and 2.3 fewer days (95% CI=0.8-3.7) were spent sick in bed compared to unvaccinated infected participants.

CONCLUSIONSAuthorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infections when administered in real-world conditions and attenuated viral RNA load, febrile symptoms, and illness duration among those with breakthrough infection despite vaccination.


title: Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

abstract: The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids  not as prescribed. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N=132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed a positive genetic correlation with the largest available GWAS of opioid dependence and OUD (rg=0.64-0.80). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg=0.74), smoking initiation (rg=0.63), pain relief medication intake (rg=0.49), major depressive disorder (rg=0.44), chronic pain (rg=0.42), insomnia (rg=0.39), and loneliness (rg=0.28). Although POU was positively genetically correlated with risk-taking (rg=0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.


title: Projections of human papillomavirus (HPV) vaccination impact in Ethiopia, India, Nigeria, and Pakistan: a comparative modelling study

abstract:
BackgroundCervical cancer is the second most common cancer among women in Ethiopia, India, Nigeria, and Pakistan. However, of these four countries, only Ethiopia has introduced human papillomavirus (HPV) vaccination at the national level in 2018 and India in a few states in 2016. Our study objective was to estimate the potential health impact of HPV vaccination among ten cohorts of 9-year-old girls from 2021-2030 in Ethiopia, India, Nigeria, and Pakistan using two independent mathematical models, and assess similarities and differences in vaccine impact projections through comparative modelling analysis.

MethodsUsing two widely published models (Harvard and PRIME) to estimate HPV vaccination impact, we simulated a vaccination scenario of 90% annual coverage among 9-year-old girls from 2021-2030 in Ethiopia, India, Nigeria, and Pakistan. We estimated the potential health impact in terms of cervical cancer cases, deaths, and disability-adjusted life years (DALYs) averted among vaccinated cohorts from the time of vaccination until 2100. We also conducted a comparative modelling analysis to understand the differences in vaccine impact estimates generated by the two models.

ResultsPrior to harmonising model assumptions, the range between the PRIME model and the Harvard model for the potential health impact of HPV vaccination in terms of the number of cervical cancer cases averted among girls vaccinated 2021-2030 between the year of vaccination and 2100 was: 262,000 to 270,000 in Ethiopia; 1,640,000 to 1,970,000 in India; 330,000 to 336,000 in Nigeria; and 111,000 to 133,000 in Pakistan. When harmonising model assumptions, alignment on HPV type distribution significantly narrowed the differences in vaccine impact estimates.

ConclusionsThe main difference in estimates for cases, deaths, and DALYs averted by vaccination between the models are due to variation in interpretation around data on cervical cancer attribution to HPV-16/18; differences in estimates for DALYs averted are additionally due to differences in age-specific remaining life expectancy over time between the two models. As countries make progress towards the World Health Organization targets for cervical cancer elimination, continued explorations of underlying differences in model inputs, assumptions, and results when examining cervical cancer prevention policy will be critical.

category: public and global health


title: Head, facial and neck cooling as per-cooling modalities to improve exercise performance in the heat: A narrative review and practical applications

abstract:
It has been well established that athletic performance is greatly affected by environmental heat. Numerous studies have attempted to find reliable cooling strategies to improve athletic performance while exercising in the heat. Whole-body pre-cooling has been found to enhance endurance performance in both dry and humid heat. Nevertheless, positive physiological alternations induced by pre-cooling gradually disappear during exercise. Hence, there is a great need to find effective per-cooling strategies to improve athletic performance in the heat. Unfortunately, its impractical to adopt pre-cooling approaches as a per-cooling modality to improve athletic performance due to inherent issues of practicality. Thus, a narrative review was conducted to examine the impact of head, neck and facial cooling on athletic performance in the heat. Based on current evidences, head, neck and facial cooling could greatly decrease local skin temperature at those areas where cooling was applied and thereby, local perceptual sensations were greatly enhanced. Neck cooling during exercise is found effective to improve athletic performance for both endurance and team sports athletes in the heat. Besides, neck cooling is preferred over the head, facial & combined head/facial & neck cooling for both endurance and team sport athletes in the heat from a practical application viewpoint. Research is lacking on the systematically selection of per-cooling modalities to improve athletic performance based on environmental conditions and nature of the sports activity. In addition, powerful but portable head, neck and facial cooling systems are urgently required to help athletes improving performance in the heat.

Key pointsO_LINeck cooling during exercise is effective to enhance endurance performance for endurance athletes in the heat.
C_LIO_LINeck cooling during exercise could improve repeated sprint performance for team sport athletes in the heat.
C_LIO_LIHead, neck & facial cooling could largely reduce local skin temperature and thereby improving local perceptual responses.
C_LIO_LINeck cooling is preferred over the head, facial & combined head/facial & neck cooling for both endurance and team sport athletes.
C_LIO_LIIts challenging to adopt facial or head cooling to cool athletes during exercise due to inherent issues of practicality.
C_LI

category: sports medicine


title: Effects of Acute Normovolemic Hemodilution on Post-Cardiopulmonary Bypass Coagulation Tests and Allogeneic Blood Transfusion in Thoracic Aortic Repair Surgery: An Observational Cohort Study

abstract:
Background and AimPerioperative blood transfusion is associated with increased morbidity and mortality. Acute normovolemic hemodilution (ANH) is a blood conservation strategy associated with variable success, and rarely studied in more complex cardiac procedures. The study aim was to evaluate whether acute ANH improves coagulopathy and reduces blood transfusions in thoracic aortic surgeries.

MethodsSingle-center observational cohort study comparing ANH and standard institutional practice in patients who underwent thoracic aortic repair from 2019 to 2021.

Results89 patients underwent ANH and 116 standard practice. There were no significant differences between the groups in terms of demographic or major perioperative characteristics. In the ANH group coagulation tests before and after transfusion of autologous blood showed decreased INR and increased platelets, fibrinogen, all with p<0.0005. Coagulation results in the ANH and control groups were not statistically different. The average number of transfused allogeneic products per patient was lower in the ANH vs control group: FFP 1.1 {+/-}1.6 vs 1.9 {+/-}2.3 (p=0.003), platelets 0.6 {+/-}0.8 vs 1.2 {+/-}1.3 (p=0.0008), and cryoprecipitate 0.3 {+/-}0.7 vs 0.7 {+/-}1.1 (p=0.008). Reduction in RBC transfusion was not statistically significant. The percentage of patients who received any transfusion was 53.9% in ANH and 59.5% in the control group (p=0.42). There was no significant difference in major adverse outcomes.

ConclusionsANH is a safe blood conservation strategy for surgical repairs of the thoracic aorta. Laboratory data suggests that ANH can improve coagulopathy after separation from CPB, and significantly reduce the number of transfused FFP, platelets and cryoprecipitate.

category: surgery


title: Choosing questions before methods in dementia research with competing events and causal goals

abstract: Several of the hypothesized or studied exposures that may affect dementia risk are known to increase the risk of death. This may explain counterintuitive results, where exposures that are known to be harmful for mortality risk sometimes seem protective for the risk of dementia. Authors have attempted to explain these counterintuitive results as biased, but the bias associated with a particular analytic method cannot be defined or assessed if the causal question is not explicitly specified. Indeed, we can consider several causal questions when competing events like death, which cannot be prevented by design, are present. Current dementia research guidelines have not explicitly considered what constitutes a meaningful causal question in this setting or, more generally, how this choice justifies and should drive particular analytic decisions. To contextualize current practices, we first perform a systematic review of the conduct and interpretation of longitudinal studies focused on dementia outcomes where death is a competing event. We then describe and demonstrate how to address different causal questions (referred here as "the total effect" and "the controlled direct effect") with traditional analytic approaches under explicit assumptions. Our application focuses on smoking cessation in late-midlife. To illustrate core concepts, we discuss this example both in terms of a hypothetical randomized trial and with an emulation of such a trial using observational data from the Rotterdam Study.


title: Job stress and loneliness among remote workers

abstract:
BackgroundTo prevent the spread of coronavirus disease 2019 (COVID-19), physical distancing and isolation are crucial strategies in society. However, this response to the pandemic promotes loneliness. Previous studies have reported an increase in loneliness since the outbreak of COVID-19, but there is little evidence on the relationship between job stress and loneliness among remote workers.

AimsTo assess the relationship between job stress and loneliness among remote workers.

MethodsThis study is a part of nation-wide cross-sectional online survey evaluating the impact of the COVID-19 pandemic in Japan. A total of 27,036 full-time workers completed the self-administrated questionnaire in December 2020. We extracted data on 4,052 desk workers who indicated that they were doing remote work. Loneliness was assessed using a single question and job stress was measured using the Job Content Questionnaire. Multiple logistic regression was performed.

ResultsFrequency of remote work was moderately associated with loneliness (adjusted odds ratio [AOR] = 1.60, 95% confidence interval [CI]: 1.04-2.46, P = 0.033). Participants who reported of having a low level of co-worker or supervisor support had greater odds of feeling lonely than those who were highly supported (co-worker support: AOR = 4.06, 95% CI: 2.82-5.84, P <0.001; supervisor support: AOR = 2.49, 95% CI: 1.79-3.47, P <0.001).

ConclusionsCo-worker support and supervisor support were strongly associated with loneliness, whereas frequency of remote work was moderately associated with feeling lonely. Support from co-workers and supervisors may be crucial factors to prevent loneliness caused by remote work.

category: occupational and environmental health


title: Relationship between obstructive sleep apnea and human leukocyte antigen variants

abstract:
Background and aimThe obstructive sleep apnea (OSA) is a common, complex and polygenic disease and it has high risk of serious complications. The human leukocyte antigen (HLA) system plays a crucial role in the regulation of immune function by discriminating self from non-self. In recent years there has been rapid advancement in "Next Generation Sequencing" technology. It enables the detection of HLA alleles in four or even six digits, providing a high level of precision. The aim of the present study was to investigate the genetic variants at HLA-A,-B,-C,-DQB1 and -DRB1 loci in OSA patients and unrelated healthy individuals by targeted NGS in the Turkish population.

Materials methodsFifty newly diagnosed patients with OSA and 50 control subjects were enrolled in the study. OSA diagnosis was made by utilizing the apnea-hypopnea index (AHI)[≥]5 in overnight polysomnography (PSG). Blood samples were obtained in the morning, after PSG. Controls were randomly selected from healthy volunteers who had a low risk for OSA. Genotyping of HLA-A, B, C, DRB1 and DQB1 genes were performed by using next generation sequencing.

ResultsHLA-A*02:01, HLA-C*03:03:01, HLA-C*14:03, HLA DRB1*04:05 alleles were found more frequently in OSA patients, but not in the controls (p=0.036, p=0.007, p=0.043 and 0.013, respectively). The allele frequencies of HLA-A*03:01 and HLA-B*35:02 were significantly higher in controls compared to OSA patients (p=0.024 and p=0.043).

ConclusionThese results suggest that HLA-A*02:01, HLA-C*03:03:01, HLA-C*14:03, HLA DRB1*04:05 alleles may play a predisposing role in the Turkish population with OSA. In addition, HLA-A*03:01 and HLA-B*35:02 alleles may be protective in this population.


title: BrainXcan identifies brain features associated with behavioral and psychiatric traits using large scale genetic and imaging data

abstract: Advances in brain MRI have enabled many discoveries in neuroscience. Comparison of brain MRI features between cases and controls have highlighted potential causes of psychiatric and behavioral disorders (complex traits). However, due to the cost of collecting MRI data and the difficulty in recruiting particular patient groups, most studies have small sample sizes, limiting their reliability. Furthermore, reverse causality complicates interpretation because many observed brain differences are the result rather than the cause of the disease. Here we propose a method (BrainXcan) that leverages the power of large-scale genome-wide association studies (GWAS) and reference brain MRI data to discover new mechanisms of disease etiology and validate existing ones. BrainXcan tests the association with genetic predictors of brain MRI-derived features and complex traits to pinpoint relevant region-specific and cross-brain features. As this approach requires only genetic data, BrainXcan allows us to test a host of hypotheses on mental illness, across many disorders and MRI modalities, using existing public data resources. For example, our method shows that reduced axonal density across the brain is associated with the risk of schizophrenia, consistent with the disconnectivity hypothesis. We also find structural features in the hippocampus, amygdala, and anterior cingulate cortex, among others associated with schizophrenia risk highlighting the potential of our approach, which uses orthogonal lines of evidence to inform the biology of complex traits.


title: Eating disorder symptoms and their associations with anthropometric and psychiatric polygenic scores

abstract:
BackgroundEating disorder (ED) symptoms are prevalent in the general population, but their shared genetic underpinnings with psychiatric, metabolic, and anthropometric traits are not known. Here, we examined if polygenic scores (PGS) of traits associated with anorexia nervosa are also associated with adolescent ED symptoms in the Avon Longitudinal Study of Parents and Children (ALSPAC).

MethodsWe calculated PGS for 25 traits (16 psychiatric, 4 metabolic, and 5 anthropometric) and investigated their associations with eight ED symptoms, including behaviors such as fasting for weight loss and cognitions such as body dissatisfaction (n range=2,991-6,013).

ResultsHigher attention deficit hyperactivity disorder PGS and lower educational attainment PGS were associated with fasting for weight loss. Higher insomnia PGS was associated with increased body dissatisfaction. We found no evidence of an association between metabolic trait PGS and any ED symptom. Regarding anthropometrics, fat-free mass, fat mass, and body fat percentage PGSs, were positively associated with binge eating, excessive exercise, fasting for weight loss, body dissatisfaction, and weight and shape concern.

ConclusionsED symptoms are genetically associated with psychiatric and anthropometric, but not with metabolic traits. Our findings provide insights for future genetic research investigating why some individuals with ED symptoms progress to develop threshold EDs while others do not.


title: Humoral and cellular immune response against SARS-CoV-2 variants following heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination.

abstract: Cerebral venous thrombosis was reported as a rare but serious adverse event in young and middle-aged vaccinees following immunization with AstraZenecas ChAdOx1-nCov-19 vaccine. As a consequence, several European governments recommended using this vaccine only in individuals older than 60 years leaving millions of ChAd primed individuals with the decision to either receive a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical Schools COVID-19 Contact (CoCo) Study cohort of health care professionals (HCP) to monitor ChAd primed immune responses before and three weeks after booster with ChAd or BioNTech/Pfizers BNT162b2. Whilst both vaccines boosted prime-induced immunity, BNT induced significantly higher frequencies of Spike-specific CD4 and CD8 T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and the P.1 variants of concern of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2).


title: Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: an observational cohort

abstract:
BackgroundThere is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an ongoing infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high density unit (HDU), while novel treatment modalities may reduce the time course of illness. On the other hand, limited resources at times of high demand may lead to rationing of resources, with less beneficial consequences. Despite little evidence on how the values of such variables change over the course of a crisis (such as the current COVID-19 pandemic), they may nevertheless be used as proxies for disease severity, outcome measures for clinical trials, and to inform planning and logistics. We hypothesise that variation of this kind has been present over the first year of the pandemic.

Methods and FindingsWe investigate such time trends in an extremely large international cohort of 142,540 patients with symptom onset of, or hospital admission for, COVID-19 during 2020. The variables investigated are time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, case fatality ratio (CFR) and total length of hospital stay. Time from hospital symptom onset to hospital admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December. ICU/HDU admission was more frequent from June to August, while there were only modest time trends in time from hospital admission to ICU/HDU. The CFR was lowest from June to August, a trend mostly driven by patients with no ICU/HDU admission. Raw numbers for overall hospital stay showed little overall variation over the time period, but further examination reveals a clear decline in time to discharge for ICU/HDU survivors. The main limitations are that these are predominantly severe COVID-19 cases, and that there are temporal, spatial and demographic biases present in an observational study of this kind.

ConclusionsOur results establish that variables of these kinds have limitations when used as outcome measures in a rapidly-evolving situation.


title: Whole blood-based measurement of SARS-CoV-2-specific T cell responses reveals asymptomatic infection and vaccine efficacy in healthy subjects and patients with solid organ cancers

abstract: Accurate assessment of SARS-CoV-2 immunity in the population is critical to evaluating vaccine efficacy and devising public health policies. Whilst the exact nature of effective immunity remains incompletely defined, SARS-CoV-2-specific T cell responses are a critical feature of the immune response that will likely form a key correlate of protection against COVID-19. Here, we developed and optimised a high-throughput whole blood-based assay to determine the T cell response associated with prior SARS-CoV-2 infection and/or vaccination amongst 156 healthy donors and 67 cancer patients. Following overnight in vitro stimulation with SARS-CoV-2-specific peptides, blood plasma samples were harvested and analysed for TH1-type effector cytokines (IFN-{gamma} and IL-2). Amongst healthy donors, highly significant differential IFN-{gamma}+/IL-2+ SARS-CoV-2-specific T cell responses were seen amongst vaccinated or previously infected COVID-19-positive individuals in comparison to unknown/naive individuals (P < 0.0001). IL-2 production from T cells in response to SARS-CoV-2 derived antigens was a highly predictive diagnostic assay (P < 0.0001; 96.0% sensitivity, 93.9% specificity); measurement of IFN-{gamma}+ SARS-CoV-2 specific T cell responses was equally effective at identifying asymptomatic (antibody and T cell positive) participants. A single dose of COVID-19 vaccine induced IFN-{gamma} and/or IL-2 SARS-CoV-2-specific T cell responses in 28/29 (96.6%) of healthy donors, reducing significantly to 27/56 (48.2%) when measured in cancer patients (P = 0.0003). Overall, this cost-effective standardisable test ensures accurate and comparable assessments of SARS-CoV-2-specific T cell responses amenable to widespread population immunity testing.


title: Variant-of-concern-attributable health and health system-related outcomes: a population-level propensity-score matched cohort study

abstract:
BackgroundAs the transmission of SARS-CoV-2 variants intensifies globally, the burden of COVID-19 on the already strained health systems is becoming increasingly concerning. While there is growing literature on the effects of various variants-of-concern (VOC) on increased transmission, the extent to which VOCs may lead to more severe disease remains debated.

MethodsIn the current analysis, we use a population-based propensity-score matched cohort study of all incident laboratory-confirmed COVID-19 cases with VOC testing in Ontario, Canada to estimate healthcare resource use and health outcomes attributable to VOCs introduced to Ontario between January 1 and April 9, 2021, relative to the previously circulating wild-type strain.

ResultsWe find that VOCs are associated with a higher odds of hospitalisation (odds ratio [OR], 2.25; 95% confidence interval [CI], 2.10-2.40) and ICU admission (OR, 3.31; 95%CI, 2.84-3.86); as well as with a higher odds of mortality for both the general COVID-19 population (OR 1.75; 1.47-2.09) and hospitalised cases (OR, 1.62; 95%CI, 1.23-2.15).

ConclusionTaken together, these findings suggest that health systems may face increased demand for healthcare resources as VOCs predominate worldwide in view of low global vaccination coverage.


title: Affinity tag coating enables reliable detection of antigen-specific B cells in ImmunoSpot assays

abstract: Assessment of humoral immunity to SARS-CoV-2 and other infectious agents is typically restricted to detecting antigen-specific antibody in the serum. Rarely does immune monitoring entail assessment of the memory B cell compartment itself, although it is these cells that engage in secondary antibody responses capable of mediating immune protection when pre-existing antibodies fail to prevent re-infection. There are few techniques that are capable of detecting rare antigen-specific B cells while also providing information regarding their precursory frequency, class/subclass usage and functional affinity. In theory, the ELISPOT/FluoroSpot (collectively ImmunoSpot) assay platform is ideally-suited for antigen-specific B cell assessments since it provides this information at single-cell resolution for individual antibody-secreting cells (ASC). Here, we tested the hypothesis that antigen coating efficiency could be universally improved across a diverse set of viral antigens if the standard direct (non-specific, low affinity) antigen absorption to the membrane was substituted by high affinity capture. Specifically, we report an enhancement in assay sensitivity and a reduction in required protein concentrations through the capture of recombinant proteins via their encoded hexahistidine (6XHis) affinity tag. Affinity tag antigen coating enabled detection of SARS-CoV-2 Spike receptor binding domain (RBD)-reactive ASC, and also significantly improved assay performance using additional control antigens. Collectively, establishment of a universal antigen coating approach streamlines characterization of the memory B cell compartment after SARS-CoV-2 infection or COVID-19 vaccinations, and facilitates high-throughput immune monitoring efforts of large donor cohorts in general.

category: allergy and immunology


title: The COVID-19 pandemic storm in India subsides, but the calm is still far away

abstract: In May 2021, the number of new COVID-19 patients in India began to decline, as predicted by the generalized SIR-model (susceptible-infected-removed). The calculations of the final size of this pandemic wave and its duration probably were too pessimistic. New SIR simulations with the use of fresher datasets are necessary in order to update the predictions and to calculate the difference between the registered (laboratory-confirmed) and real number of cases.


title: What most influences severity and death of COVID-19 patients in Brazil? Is it clinical, social, or demographic factors? An observational study.

abstract:
ObjectiveThis study aimed to assess the space distribution and factors associated with the risk of severe acute respiratory syndrome (SARS) and death in COVID-19 patients, based on routine register data; and to develop and validate a predictive model of the risk of death from COVID-19.

MethodsA cross-sectional, epidemiological study of positive SARS-CoV-2 cases, reported in the south region of the city of Sao Paulo, SP, Brazil, from March 2020 to February 2021. Data were obtained from the official reporting databases of the Brazilian Ministry of Health for influenza-like illness (ILI) (esus-VE, in Portuguese) and for patients hospitalized for SARS (SIVEP-Gripe). The space distribution of cases is described by 2D kernel density. To assess potential factors associated with the outcomes of interest, generalized linear and additive logistic models were adjusted. To evaluate the discriminatory power of each variable studied as well as the final model, C-statistic was used (area under the receiver operating characteristics curve). Moreover, a predictive model for risk of death was developed and validated with accuracy measurements in the development, internal and temporal (March and April 2021) validation samples.

ResultsA total of 16,061 patients with confirmed COVID-19 were enrolled. Morbidities associated with a higher risk of SARS were obesity (OR=25.32) and immunodepression (OR=12.15). Morbidities associated with a higher risk of death were renal disease (OR=11.8) and obesity (OR=8.49), and clinical and demographic data were more important than the territory per se. Based on the data, a calculator was developed to predict the risk of death from COVID-19, with 92.2% accuracy in the development sample, 92.3% in the internal validation sample, and 80.0% in the temporal validation sample.

ConclusionsThe risk factors for SARS and death in COVID-19 patients seeking health care, in order of relevance, were age, comorbidities, and socioeconomic factors, considering each discriminatory power.


title: The INDSCI-SIM model for COVID-19 in India

abstract: Estimating the burden of COVID-19 in India is difficult because the extent to which cases and deaths have been undercounted is hard to assess. The INDSCI-SIM model is a 9-component, age-stratified, contact-structured compartmental model for COVID-19 spread in India. We use INDSCI-SIM, together with Bayesian methods, to obtain optimal fits to reported cases and deaths across the span of the first wave of the Indian pandemic, over the period Jan 30, 2020 to Feb 15, 2021. We account for lock-downs and other non-pharmaceutical interventions, an overall increase in testing as a function of time, the under-counting of cases and deaths, and a range of age-specific infection-fatality ratios. We first use our model to describe data from all individual districts of the state of Karnataka, benchmarking our calculations using data from serological surveys. We then extend this approach to aggregated data for Karnataka state. We model the progress of the pandemic across the cities of Delhi, Mumbai, Pune, Bengaluru and Chennai, and then for India as a whole. We estimate that deaths were undercounted by a factor between 2 and 5 across the span of the first wave, converging on 2.2 as a representative multiplier that accounts for the urban-rural gradient across the country. We also estimate an overall under-counting of cases by a factor of between 20 and 25 towards the end of the first wave. Our estimates of the infection fatality ratio (IFR) are in the range 0.05 - 0.15, broadly consistent with previous estimates but substantially lower than values that have been estimated for other LMIC countries. We find that approximately 40% of India had been infected overall by the end of the first wave, results broadly consistent with those from serosurveys. These results contribute to the understanding of the long-term trajectory of COVID-19 in India.


title: CHST6-related macular corneal dystrophy: a matter of endothelium

abstract:
Macular corneal dystrophy (MCD) is classified as corneal stromal dystrophy. In this study, we retrospectively reviewed the surgical outcomes of 118 MCD patients receiving surgical treatment in the past 30 years and found patients receiving penetrating keratoplasty had the lowest recurrence rate 13.75%, compared with 40.91% patients receiving deep anterior lamellar keratoplasty and 25% receiving phototherapeutic keratectomy. Transcriptomic analysis in human corneal single-cell sequencing atlas found the MCD pathogenic gene CHST6 was abundant in corneal endothelium rather than other cell types. CHST6 protein showed a similar expression pattern to its mRNA. The mouse homologous gene Chst5 was 120-fold higher in corneal endothelium than in the epithelial and stromal layers. Mice with specifically Chst5 knockdown in the endothelial layer by microinjection of the adeno-associated virus serotype 9 - shRNA plasmids into the anterior chamber, rather than Chst5 knockdown into the stroma, showed MCD-like phenotypes. Corneal opacification and abnormally larger collagen fibrils were observed in the endothelial Chst5 knockdown mice. The same corneal characteristics were observed after overexpressing human CHST6 mutant R50H in the mouse endothelium. These observations indicating the pathogenesis of MCD is more related to the corneal endothelium rather than the stroma.

Significance StatementOur study gave evidence that corneal endothelium contributing more to the macular corneal dystrophy (MCD) development, rather than other cell types in the cornea. We proposed penetrating keratoplasty might serve as a more proper surgical treatment for MCD according to the recurrence rate analysis. We also provided a novel method to construct MCD mouse model.

category: ophthalmology


title: SARS-CoV-2 specific memory B-cells from individuals with diverse disease severities recognize SARS-CoV-2 variants of concern.

abstract: In this investigation we examined the magnitude, breadth, and durability of SARS-CoV-2 specific antibodies in two distinct B-cell compartments: long-lived plasma cell-derived antibodies in the plasma, and peripheral memory B-cells along with their associated antibody profiles elicited after in vitro stimulation. We found that magnitude varied amongst individuals, but was the highest in hospitalized subjects. Variants of concern (VoC) -RBD-reactive antibodies were found in the plasma of 72% of samples in this investigation, and VoC-RBD-reactive memory B-cells were found in all but 1 subject at a single time-point. This finding, that VoC-RBD-reactive MBCs are present in the peripheral blood of all subjects including those that experienced asymptomatic or mild disease, provides a reason for optimism regarding the capacity of vaccination, prior infection, and/or both, to limit disease severity and transmission of variants of concern as they continue to arise and circulate.


title: Wastewater Based Epidemiology Enabled Surveillance of Antibiotic Resistance

abstract: Wastewater-based epidemiology (WBE) for disease monitoring is highly promising, but requires consistent methodologies that incorporate predetermined objectives, targets, and metrics. We demonstrate a comprehensive metagenomics-based approach for global surveillance of antibiotic resistance in sewage, enabling assessment of: 1) which antibiotic resistance genes (ARGs) are shared across regions/communities; 2) which ARGs are discriminatory; and 3) factors associated with overall trends including antibiotic concentrations in sewage. Across an internationally-sourced transect of sewage samples collected using a centralized, standardized protocol, ARG relative abundances (16S rRNA gene-normalized) were highest in Hong Kong and India and lowest in Sweden and Switzerland, reflecting national policy, measured antibiotic concentrations, and metal resistance genes. Asian versus European/US resistomes were distinct, with macrolide-lincosamide-streptogramin, phenicol, quinolone, and tetracycline versus multidrug resistance ARGs being discriminatory, respectively. Sales data were not predictive of antibiotics measured in sewage, emphasizing need for direct measurements. The WBE approach defined herein demonstrates multi-site comparability and sensitivity to local/regional factors.


title: Why is non-suicidal self-injury more prevalent among women? Mediation and moderation analyses of psychological distress, emotion dysregulation, and impulsivity

abstract:
ObjectiveNon-suicidal self-injury (NSSI) appears to be more common among women than men, though the underlying reasons for this remain unclear. In a community sample of young adults (n=996, aged 18-30) assessed during the COVID-19 pandemic, we investigated gendered patterns in NSSI etiology.

MethodsMediation and moderation analyses considered associations between past-year NSSI prevalence, gender, and putative mechanistic variables: self-reported psychological distress (K10), emotion dysregulation (DERS), and impulsivity (UPPS-P).

ResultsNearly twice as many women as men reported past-year NSSI (14.47% versus 7.78%). Women reported significantly higher psychological distress and significantly lower sensation seeking and positive urgency than men. Psychological distress partially statistically mediated the relationship between gender and past-year NSSI. Gender did not significantly moderate associations between self-reported distress, emotion dysregulation, or impulsivity and past-year NSSI. Past-year NSSI prevalence did not significantly decrease with age and we found no significant age by gender interaction.

ConclusionsGreater levels of NSSI in young women are explained by their greater levels of emotional distress. Women do not appear to be more likely than men to report NSSI due to differences in how they manage emotional distress: gender did not moderate the association between psychological distress and past-year NSSI, and there were no gender differences in emotion dysregulation or negative urgency. Furthermore, we show that NSSI remains prevalent beyond adolescence. Early interventions which reduce distress or improve distress tolerance, strengthen emotion regulation skills, and provide alternative coping strategies merit investigation for NSSI.

HighlightsO_LIYoung women were significantly more likely to report past-year NSSI than young men
C_LIO_LIPsychological distress partially mediated the relationship between gender and NSSI
C_LIO_LIGender did not moderate associations between putative mechanistic variables and NSSI
C_LI


title: Physical integrity of medical exam gloves with repeated applications of disinfecting agents: evidence for extended use

abstract:
BackgroundThe COVID-19 pandemic has created global shortages of personal protective equipment (PPE) such as medical exam gloves, forcing healthcare workers to either forgo or reuse PPE to keep themselves and patients safe from infection. In severely resource-constrained situations, limited cycles of disinfection and extended use of gloves is recommended by the U.S. Centers for Disease Control and Prevention (CDC) to conserve supplies. However, these guidelines are based on limited evidence.

MethodsSerial cycles of hand hygiene were performed on gloved hands using alcohol-based hand rub (ABHR) (six and ten cycles), 0.1% sodium hypochlorite (bleach) solution (ten cycles), or soap and water (ten cycles) on three types of latex and three types of nitrile medical exam gloves, purchased in the United States and India. A modified FDA-approved water-leak test was performed to evaluate glove integrity after repeated applications of these disinfecting agents. 80 gloves per disinfectant-glove type combination were tested. Within each glove type the proportion of gloves that failed the water-leak test for each disinfectant was compared to that of the control using a non-inferiority design with a non-inferiority margin of five percentage points. Results were also aggregated by glove material, and combined for overall results.

FindingsWhen aggregated by glove material, the dilute bleach exposure demonstrated the lowest difference in proportion failed between treatment and control arms: -2.5 percentage points (95% CI: -5.3 to 0.3) for nitrile, 0.6 percentage points (95% CI: -2.6 to 3.8) for non-powdered latex. For US-purchased gloves tested with six and ten applications of ABHR, the mean difference in failure risk between treatment and control gloves was within the prespecified non-inferiority margin of five percentage points or less, though some findings were inconclusive because confidence intervals extended beyond the non-inferiority margin. The aggregated difference in failure risk between treatment and control gloves was 3.5 percentage points (0.6 to 6.4) for soap and water, and 2.3 percentage points (-0.5 to 5.0) and 5.0 percentage points (1.8 to 8.2) for 10 and 6 applications of ABHR, respectively. The majority of leaks occurred in the interdigital webs (35%) and on the fingers (34%).

ConclusionCurrent guidelines do not recommend extended use of a single-use PPE under normal supply conditions. However, our findings indicate that some combinations of glove types and disinfection methods may allow for extended use under crisis conditions. We found that ten applications of dilute bleach solution have the least impact on glove integrity, compared to repeated applications of ABHR and soap and water. However, the majority of glove and exposure combinations were inconclusive with respect to non-inferiority with a 5 percentage point non-inferiority margin. Testing specific glove and disinfectant combinations may be worthwhile for settings facing glove shortages during which extended use is necessary. The modified water-leak testing method used here is a low-resource method that could easily be reproduced in different contexts.


title: Association between motor task acquisition and hippocampal atrophy across cognitively unimpaired, amnestic Mild Cognitive Impairment, and Alzheimer's disease individuals

abstract: Hippocampal atrophy is a widely used biomarker for Alzheimers disease (AD), but the cost, time, and contraindications associated with magnetic resonance imaging (MRI) limit its use. Recent work has shown that a low-cost upper extremity motor task has potential in identifying AD risk. Fifty-four older adults (15 cognitively unimpaired, 24 amnestic Mild Cognitive Impairment, and 15 AD) completed six motor task trials and a structural MRI. Motor task acquisition significantly predicted bilateral hippocampal volume, controlling for age, sex, education, and memory. Thus, this motor task may be an affordable, non-invasive screen for AD risk and progression.

category: neurology


title: ctDNA detection by personalised assays in early-stage NSCLC

abstract: Blood-based assays have shown increasing ability to detect circulating tumour DNA (ctDNA) in patients with early-stage cancer. However, detection of ctDNA in patients with non-small cell lung cancer (NSCLC) has continued to prove challenging. We performed retrospective analysis to quantify ctDNA levels in a cohort of 100 patients with early-stage NSCLC prior to treatment with curative intent enrolled in the LUCID study (NCT04153526). Where tumour tissue was available for whole exome sequencing, mutations identified were used to define patient-specific sequencing assays. For those 90 patients, plasma cell-free DNA was sequenced to high depth across capture panels targeting a median of 328 mutations specific to each patient. Data was analysed using Integration of Variant Reads (INVAR), detecting ctDNA in 66.7% of patients, including 52.7% (29 of 55) patients with stage I disease and >88% detection for patients with stage II and III disease (16/18 and 15/17). ctDNA was detected in plasma at fractional concentrations as low as 9.1x10-6, and in patients with tumour volumes as low as 0.23 cm3. A 36-gene sequencing panel (InVisionFirst-Lung) was used to analyse plasma DNA in 27 samples including the 10 cases without tumour exome data, and detected ctDNA in 59% of samples tested (16 of 27). Across the entire cohort, detection rates were higher in squamous cell carcinoma patients compared to adenocarcinoma patients (81% vs. 59%). Detection of ctDNA prior to treatment was associated with significantly shorter time free from relapse, across all patients and in patient subgroups, with Hazard Ratios >11 for selected patient subsets. Our analysis indicates that for patients with stage I NSCLC, the median ctDNA fraction in plasma is approx. 12 parts per million (0.0012%). This indicates the limits of detection that would be required for ctDNA-based liquid biopsies to detect ctDNA in the majority of patients with early-stage NSCLC.

category: oncology


title: Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19.

abstract:
BackgroundCurrently, only dexamethasone, tocilizumab and sarilumab have conclusively been shown to reduce mortality of COVID-19. Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programmes. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices.

MethodsWe searched for repurposed drugs that have been approved by at least one of the WHO, FDA or NICE, or at least given emergency use authorisation or recommended for off-label prescription. Drug prices were searched for, for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab and imdevimab, and sarilumab using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from a range of low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug.

ResultsRepurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from $2.58 for IV dexamethasone (or $0.19 orally) and $4.34 for inhaled budesonide. No export price data was available for baricitinib, tocilizumab, casirivimab and imdevimab or sarilumab, but courses of these treatments are priced highly, ranging from $6.67 for baricitinib to $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries.

ConclusionsSuccessful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whilst monoclonal antibodies and IV treatment courses are more expensive.

Key PointsO_LIRe-purposed drugs must be affordable worldwide to compliment COVID-19 vaccine programmes.
C_LIO_LIEstimated costs/course were: dexamethasone (Oral $0.22, IV $2.58), budesonide ($4.34), baricitnib ($6.67), tocilizumab ($410.59), sarilumab ($875.70). Casirivimab and imdevimab = no data available.
C_LIO_LIHigh drug prices will limit access.
C_LI

category: health economics


title: Virologic features of SARS-CoV-2 infection in children

abstract:
BackgroundData on pediatric COVID-19 has lagged behind adults throughout the pandemic. An understanding of SARS-CoV-2 viral dynamics in children would enable data-driven public health guidance.

MethodsRespiratory swabs were collected from children with COVID-19. Viral load was quantified by RT-PCR; viral culture was assessed by direct observation of cytopathic effects and semiquantitative viral titers. Correlations with age, symptom duration, and disease severity were analyzed. SARS-CoV-2 whole genome sequences were compared with contemporaneous sequences.

Results110 children with COVID-19 (median age 10 years, range 2 weeks-21 years) were included in this study. Age did not impact SARS-CoV-2 viral load. Children were most infectious within the first five days of illness, and severe disease did not correlate with increased viral loads. Pediatric SARS-CoV-2 sequences were representative of those in the community and novel variants were identified.

ConclusionsSymptomatic and asymptomatic children can carry high quantities of live, replicating SARS-CoV-2, creating a potential reservoir for transmission and evolution of genetic variants. As guidance around social distancing and masking evolves following vaccine uptake in older populations, a clear understanding of SARS-CoV-2 infection dynamics in children is critical for rational development of public health policies and vaccination strategies to mitigate the impact of COVID-19.


title: Insecticide resistance outpaces behavioural adaptation, as a response to Long-Lasting Insecticidal Net distribution, in malaria vectors in Burkina Faso

abstract: The decline in malaria across Africa has been largely attributed to vector control using Long-Lasting Insecticidal Nets (LLINs). However, this intervention has prompted widespread insecticide resistance (IR) and been associated with changes in mosquito behaviour that reduce their contact with LLINs. The relative importance and rate at which IR and behavioural adaptations emerge are poorly understood. We conducted surveillance of mosquito behaviour and IR at 12 sites in Burkina Faso to assess the magnitude and temporal dynamics of insecticide and behavioural resistance in vectors in the 2-year following mass LLIN distribution. Insecticide resistance was present in all vector populations and increased rapidly over the study. In contrast, no longitudinal shifts in LLIN-avoidance behaviours (earlier or outdoor biting and resting) were detected. There was a moderate shift in vector species composition from Anopheles coluzzii to Anopheles gambiae which coincided with a reduction in the proportion of bites preventable by LLINs; possibly driven by between-species variation in behaviour. These findings indicate that adaptations based on insecticide resistance arise and intensify more rapidly than behavioural shifts within mosquito vectors. However, longitudinal shifts in mosquito vector species composition were evident within 2 years following a mass LLIN distribution. This ecological shift was characterized by a relative increase in the moderately more exophagic species (An. gambiae) and coincided with a predicted decline in the degree of protection expected from LLINs. Although human exposure fell through the study period due to reducing vector densities and infection rates, such ecological shifts in vector species along with insecticide resistance were likely to have eroded the efficacy of LLINs. While both adaptations impact malaria control, the rapid increase of the former indicates it is the most rapid strategy but interventions targeting both will be needed.