title: Strategy and performance evaluation of low-frequency variant calling for SARS-CoV-2 in wastewater using targeted deep Illumina sequencing

abstract: The ongoing COVID-19 pandemic, caused by SARS-CoV-2, constitutes a tremendous global health issue. Continuous monitoring of the virus has become a cornerstone to make rational decisions on implementing societal and sanitary measures to curtail the virus spread. Additionally, emerging SARS-CoV-2 variants have increased the need for genomic surveillance to detect particular strains because of their potentially increased transmissibility, pathogenicity and immune escape. Targeted SARS-CoV-2 sequencing of wastewater has been explored as an epidemiological surveillance method for the competent authorities. Few quality criteria are however available when sequencing wastewater samples, and those available typically only pertain to constructing the consensus genome sequence. Multiple variants circulating in the population can however be simultaneously present in wastewater samples. The performance, including detection and quantification of low-abundant variants, of whole genome sequencing (WGS) of SARS-CoV-2 in wastewater samples remains largely unknown. Here, we evaluated the detection and quantification of mutations present at low abundances using the SARS-CoV-2 lineage B.1.1.7 (alpha variant) defining mutations as a case study. Real sequencing data were in silico modified by introducing mutations of interest into raw wild-type sequencing data, or by mixing wild-type and mutant raw sequencing data, to mimic wastewater samples subjected to WGS using a tiling amplicon-based targeted metagenomics approach and Illumina sequencing. As anticipated, higher variation, lower sensitivity and more false negatives, were observed at lower coverages and allelic frequencies. We found that detection of all low-frequency variants at an abundance of 10%, 5%, 3% and 1%, requires at least a sequencing coverage of 250X, 500X, 1500X and 10,000X, respectively. Although increasing variability of estimated allelic frequencies at decreasing coverages and lower allelic frequencies was observed, its impact on reliable quantification was limited. This study provides a highly sensitive low-frequency variant detection approach, which is publicly available at https://galaxy.sciensano.be, and specific recommendations for minimum sequencing coverages to detect clade-defining mutations at specific allelic frequencies.


title: Longitudinal variation in SARS-CoV-2 antibody levels and emergence of viral variants: implications for the ability of serological assays to predict immunity.

abstract:
BackgroundSerological assays are being deployed to monitor antibody responses in SARS-CoV-2 convalescents and vaccine recipients. There is a need to determine whether such assays can predict immunity, as antibody levels wane and viral variants emerge.

MethodsWe measured antibodies in a cohort of SARS-CoV-2 infected patients using several high-throughput serological tests and functional neutralization assays. The effects of time and spike protein sequence variation on the performance and predictive value of the various assays was assessed.

FindingsNeutralizing antibody titers decreased over the first few months post-infection but stabilized thereafter, at about 30% of the level observed shortly after infection. Serological assays commonly used to measure antibodies against SARS-CoV-2 displayed a range of sensitivities that declined to varying extents over time. Quantitative measurements generated by serological assays based on the spike protein were better at predicting neutralizing antibody titers than assays based on nucleocapsid, but performance was variable and manufacturer positivity thresholds were not able to predict the presence or absence of detectable neutralizing activity. Even though there was some deterioration in correlation between serological measurements and functional neutralization activity, some assays maintained an ability to predict neutralizing titers, even against variants of concern.

InterpretationThe ability of high throughput serological assays to predict neutralizing antibody titers is likely crucial for evaluation of immunity at the population scale. These data will facilitate the selection of the most suitable assays as surrogates of functional neutralizing activity and suggest that such measurements may have utility in clinical practice.

category: infectious diseases


title: Breakthrough COVID-19 infection rate with Indian strain in Single-center Healthcare Workers: A real world data.

abstract:
IntroductionIt is observed that many healthcare workers got COVID-19 infection despite of completing both doses of Covishield vaccine. This study aimed to find real incidence of vaccine breakthrough infection.

Material and methodsAll hospital employees, who were fully vaccinated were included in study. Details about their vaccine side effects, infection prior to vaccination, post vaccination infection, severity of infection, hospital and ICU admission were noted.

ResultsNone encountered any significant side effects of vaccine. Of the 461 participants - 86 (18.65%) got infection average 38 days (range 14-70days) after vaccination. As per the NIH classification, out of 86, disease was mild in 69(80.2%), moderate in 10(11.62%), severe in 6(6.97%) and critical in 1(1.16%). Of these, 10(11.62%) required hospital admission. Of these 10, 2 were shifted to ICU. Of the 2, One recovered while one died. Thus mortality was 1/86(1.6%).

ConclusionBreakthrough infection rate in health care workers was 18.65%. Moderate, severe or critical disease occurred in 19.7% participants even after two doses of vaccine. Mortality due to disease cannot be completely obviated due to vaccine. The vaccine was safe without any significant adverse events.


title: The rise and fall of an emerging SARS-CoV-2 variant with the spike protein mutation L452R

abstract: Emerging SARS-CoV-2 variants may threaten global vaccination efforts and awaited reduction in outbreak burden. In this study, we report a novel variant carrying the L452R mutation that emerged from a local B.1.362 lineage, B.1.362+L452R. The L452R mutation is associated with the Delta and Epsilon variants and was shown to cause increased infection and reduction in neutralization in pseudoviruses. Indeed, the B.1.362+L452R variant demonstrated a X4-fold reduction in neutralization capacity of sera from BNT162b2-vaccinated individuals compared to a wild-type strain. The variant infected 270 individuals in Israel between December 2020 and March 2021, until diminishing due to the gain in dominance of the Alpha variant in February 2021. This study demonstrates an independent, local emergence of a variant carrying a critical mutation, L452R, which may have the potential of becoming a variant of concern and emphasizes the importance of routine surveillance and detection of novel variants among efforts undertaken to prevent further disease spread.


title: IFIH1 rs1990760 variants, systemic inflammation and outcome in critically-ill COVID-19 patients

abstract:
RationaleOutcomes in patients with severe SARS-CoV-2 infection (COVID-19) are conditioned by virus clearance and regulation of inflammation. Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections.

ObjectiveTo characterize the impact of IFIH1 rs199076 variants on host response and outcomes after severe COVID-19.

MethodsPatients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modelled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials.

Measurements and Main Results227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to a MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids (N=14) survived their ICU stay (HR 2.49, 95% confidence interval 1.29-4.79). Patients with a TT variant treated with dexamethasone (N=50) showed an increased hospital mortality (HR 2.19, 95% confidence interval 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings.

ConclusionsCOVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype.

category: intensive care and critical care medicine


title: Phylogenomics, Epigenomics, Virulome, and Mobilome of Gram-negative Bacteria Co-resistant to Carbapenems and Polymyxins: A One-Health Systematic Review and Meta-analyses

abstract:
Gram-negative bacteria (GNB) continue to develop resistance against important antibiotics including last-resort ones such as carbapenems and polymyxins. An analysis of GNB with co-resistance to carbapenems and polymyxins from a One Health perspective is presented.

Data of species name, country, source of isolation, resistance genes (ARGs), plasmid type, clones, and mobile genetic elements (MGEs) were deduced from 129 articles from January 2016 to March 2021. Available genomes and plasmids were obtained from PATRIC and NCBI. Resistomes and methylomes were analysed using BAcWGSTdb and REBASE whilst Kaptive was used to predict capsule typing. Plasmids and other MEGs were identified using MGE Finder and ResFinder. Phylogenetic analyses were done using RAxML and annotated with MEGA 7.

A total of 877 isolates, 32 genomes and 44 plasmid sequences were analysed. Most of these isolates were reported in Asian countries and were isolated from clinical, animal, and environmental sources. Colistin resistance was mostly mediated by mgrB inactivation, while OXA-48/181 was the most reported carbapenemase. IncX and IncI were the most common plasmids hosting carbapenemases and mcr genes. The isolates were co-resistant to other antibiotics, with floR (chloramphenicol) and fosA3 (fosfomycin) being common; E. coli ST156 and K. pneumoniae ST258 strains were common globally. Virulence genes and capsular KL-types were also detected. Type I, II, III and IV restriction modification systems were detected, comprising various MTases and restriction enzymes. The escalation of highly resistant isolates drains the economy due to untreatable bacterial infections, which leads to increasing global mortality rates and healthcare costs.

Author summaryCarbapenem and polymyxin co-resistance in Gram-negative bacteria (GNB) is a growing public health concern globally. China presented a high number of highly resistant bacteria from humans, animals, and environmental samples. Escherichia coli isolates were the most dominant in China, while Klebsiella pneumoniae isolates dominated Greece, the second country with high numbers of carbapenem and colistin co-resistant strains. Mobile genetic elements including plasmids are responsible for disseminating such resistance genes. Worryingly, GNB with Carbapenem and polymyxin co-resistance also harbours genes that make them resistant to other antibiotics, making them multi-drug resistant.

category: epidemiology


title: Masks in a Post COVID-19 World: A Better Alternative to Curtailing Influenza?

abstract: Over the course of the coronavirus pandemic, it has become apparent that non-pharmaceutical interventions such as masks and social distancing are of great help in mitigating the transmission of airborne infectious diseases. Additionally, data from respiratory specimen analysis from the past year show that current mask mandates established for COVID-19 have inadvertently reduced the rates of other respiratory diseases, including influenza. Thus, the question arises as to whether comparatively mild measures should be kept in place after the pandemic to reduce the impact of influenza. In this study, we employed a series of differential equations to simulate past influenza seasons, assuming people wore face masks. This was achieved by introducing a variable to account for the efficacy and prevalence of masks and then analyzing its impact on influenza transmission rate in an SEIR model fit to the actual past seasons. We then compared influenza rates in this hypothetical scenario with the actual rates over the seasons. Our results show that several combinations of mask efficacy and prevalence can significantly reduce the burden of seasonal influenza. Particularly, our simulations suggest that a minority of individuals wearing masks greatly reduce the number of influenza infections. Considering the efficacy rates of masks and the relatively insignificant monetary cost, we highlight that it may be a viable alternative or complement to influenza vaccinations. We conclude with a brief discussion of our results and other practical aspects


title: Predictors of black fungus fear during the COVID-19 pandemic among the Bangladeshi health workers: a cross-sectional study

abstract:
BackgroundThe emergence of mucormycosis cases amid the COVID-19 pandemic; fear associated with mucormycosis may turn out to be a terrifying public health issue. This study aimed to assess the association between fear and insomnia status and other predictors of mucormycosis among Bangladeshi healthcare workers.

MethodsFrom 25 May 2021 to 05 June 2021, a cross-sectional study was carried out among healthcare workers. A total of 422 healthcare workers participated in this study. A semi-structured online questionnaire was used for data collection during the COVID-19 pandemic, followed by convenient and snowball sampling methods. A multivariable linear regression model was fitted to assess the association between fear and insomnia status and other predictors of mucormycosis.

ResultsThe results indicated that the respondents with insomnia status had a higher score of mucormycosis fear than not having insomnia ({beta} = 3.91, 95% CI: 2.49, 5.33, p <0.001), significantly. Alongside the increased knowledge score of mucormycosis, the average score of fear increased significantly({beta} = 0.35, 95% CI: 0.20, 0.50, p <0.001). The gender, profession, and death of friends and family members due to COVID-19 significantly affected mucormycosis fear score increment.

ConclusionsThis is the first study that focused on assessing the association between mucormycosis fear and insomnia status among the health care workers so far. These study findings recommend emphasizing the mental health aspects and ensuring support to the healthcare workers to better tackle the ongoing public health crisis.

category: public and global health


title: Prospective cohort study of workers diagnosed with COVID-19 and subsequent unemployment

abstract:
ObjectivesThe purpose of this study was to investigate the relationships of workers being diagnosed with coronavirus disease 2019 (COVID-19) and being identified as close contacts of infected persons with unemployment in Japan.

MethodsThis was a prospective cohort study using questionnaires about COVID-19 administered to Japanese workers. A baseline survey conducted on December 22-25, 2020, was used to determine history of being diagnosed with COVID-19 or being identified as a close contact of an infected person. Unemployment since the baseline survey was ascertained with a follow-up survey on February 18 and 19, 2021. The odds ratios of unemployment were estimated using a multilevel logistic model with adjusted covariates nested in prefecture of residence.

ResultsWomen (n = 8,771) accounted for 44% of the total sample (n = 19,941), and the mean age was 48.0 years. In terms of unemployment because of negative reasons, the multivariate analysis showed that the odds ratio of unemployment associated with being diagnosed with COVID-19 was 2.18 (95% CI: 1.05-4.55) and that the odds ratio associated with being identified as a close contact was 0.93 (95% CI: 0.29-2.95).

ConclusionsThere is an association between workers being diagnosed with COVID-19 and unemployment. Occupational health professionals should follow up closely with workers diagnosed with COVID-19 after they return to work to prevent them from becoming unemployed against their will.

category: occupational and environmental health


title: High mortality of COVID-19 associated mucormycosis in France: a nationwide retrospective study

abstract: We studied COVID-19 associated mucormycosis based on 17 cases reported nationwide and assessed the differences with India. They differed by frequencies of diabetes mellitus (47% in France versus 95% in India), hematological malignancies (35% versus 1%), anatomical sites (53% lung versus >80% rhino-orbito-cerebral) and prognosis (>80% mortality versus <50%).


title: Tocilizumab and sarilumab alone or in combination with corticosteroids for COVID-19: A systematic review and network meta-analysis

abstract:
ObjectiveTo compare the effects of interleukin-6 (IL-6) receptor blockers, with or without corticosteroids, on mortality in patients with COVID-19.

DesignSystematic review and network meta-analysis

Data sourcesWHO COVID-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses

Study selectionTrials in which people with suspected, probable, or confirmed COVID-19 were randomized to IL-6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care.

ResultsWe assessed the risk of bias of included trials using a modification of the Cochrane risk of bias tool. We performed a Bayesian fixed effect network meta-analysis and assessed the certainty of evidence using the GRADE approach.

We identified 45 eligible trials (20,650 patients), 36 (19,350 patients) of which could be included in the network meta-analysis. 27 of 36 trials were rated at high risk of bias, primarily due to lack of blinding. Tocilizumab (20 more per 1000, 15 fewer to 59 more; low certainty) and sarilumab (11 more per 1000, 38 fewer to 55 more; low certainty) alone may not reduce the risk of death. Tocilizumab, in combination with corticosteroids, probably reduces the risk of death compared to corticosteroids alone (35 fewer per 1000, 52 fewer to 18 more; moderate certainty) and sarilumab, in combination with corticosteroids, may reduce the risk of death compared to corticosteroids alone (43 fewer, 73 fewer to 12 more; low certainty). Tocilizumab and sarilumab, both in combination with corticosteroids, may have similar effects (8 more per 1000, 20 fewer to 35 more; low certainty).

ConclusionIL-6 receptor blockers, when added to standard care that includes corticosteroids, in patients with severe or critical COVID-19, probably reduce mortality. Tocilizumab and sarilumab may have similar effectiveness.

Systematic review registrationNA

What is already known on this topic?O_LIIL-6 receptor blockers have immunosuppressive effects that may be important in COVID-19 patients with immune system dysfunction and inflammation
C_LIO_LICorticosteroids reduce the risk of death in patients with severe or critical COVID-19
C_LI

What this study addsO_LIOur systematic review and network meta-analysis provides a comprehensive review of the evidence addressing the effects of IL-6 receptor blockers, alone or in combination with corticosteroids, in COVID-19
C_LIO_LIIL-6 receptor blockers when added to a standard care that includes corticosteroids, in patients with severe or critical COVID-19, probably reduce mortality.
C_LIO_LITocilizumab and sarilumab in combination with corticosteroids may have similar effectiveness for reducing mortality.
C_LI


title: Genomic surveillance reveals the spread patterns of SARS-CoV-2 in coastal Kenya during the first two waves

abstract:
BackgroundThe transmission networks of SARS-CoV-2 in sub-Saharan Africa remain poorly understood.

MethodsWe undertook phylogenetic analysis of 747 SARS-CoV-2 positive samples collected across six counties in coastal Kenya during the first two waves (March 2020 - February 2021). Viral imports and exports from the region were inferred using ancestral state reconstruction (ASR) approach.

ResultsThe genomes were classified into 35 Pango lineages, six of which accounted for 79% of the sequenced infections: B.1 (49%), B.1.535 (11%), B.1.530 (6%), B.1.549 (4%), B.1.333 (4%) and B.1.1 (4%). Four identified lineages were Kenya specific. In a contemporaneous global subsample, 990 lineages were documented, 261 for Africa and 97 for Eastern Africa. ASR analysis identified >300 virus location transition events during the period, these comprising: 69 viral imports into Coastal Kenya; 93 viral exports from coastal Kenya; and 191 inter-county import/export events. Most international viral imports (58%) and exports (92%) occurred through Mombasa City, a key touristic and commercial Coastal Kenya center; and many occurred prior to June 2020, when stringent local COVID-19 restriction measures were enforced. After this period, local virus transmission dominated, and distinct local phylogenies were seen.

ConclusionsOur analysis supports moving control strategies from a focus on international travel to local transmission.

FundingThis work was funded by Wellcome (grant#: 220985) and the National Institute for Health Research (NIHR), project references: 17/63/and 16/136/33 using UK aid from the UK Government to support global health research, The UK Foreign, Commonwealth and Development Office.


title: Transmission networks of SARS-CoV-2 in coastal Kenya during the first two waves: a retrospective genomic study


title: Efficacy of remdesivir-containing therapy in hospitalized COVID-19 patients: a prospective clinical experience

abstract:
Objectivesremdesivir is currently approved for the treatment of COVID-19. The recommendation for using remdesivir in COVID-19 was based on the in vitro and in vivo activity of this drug against SARS-CoV-2.

Methodsthis was a prospective, observational study conducted on a large population of patients hospitalized for COVID-19. The primary endpoint of the study was to evaluate the impact of remdesivir-containing therapy on 30-day mortality; secondary endpoint was the impact of remdesivir-containing therapy on the need of high flow oxygen therapy (HFNC) or non-invasive ventilation (NIV) or mechanical ventilation. Data were analyzed after propensity score matching.

Results407 patients with SARS-CoV-2 pneumonia were consecutively enrolled. Out of these, 294 (72.2%) and 113 (27.8%) were respectively treated or not with remdesivir. Overall, 61 (14.9%) patients were treated during hospitalization with non-invasive or mechanical ventilation, while a 30-day mortality was observed in 21 (5.2%) patients with a global in-hospital mortality of 11%. Cox regression analysis, after propensity score matching, showed that therapies, including remdesivir-containing therapy, were not statistically associated with 30-day survival or mortality, while need of HFNC/NIV (HR 17.921, CI95% 0.954-336.73, p=0.044) and mechanical ventilation (HR 3.9, CI95% 5.36-16.2, p=0.003) resulted independently associated with 30-day mortality. Finally, therapies including or not remdesivir were not independently associated with a lower or higher risk of HFNC/NIV or mechanical ventilation.

Conclusionsthis real-life experience about the remdesivir use in hospitalized patients with COVID-19 was not associated with significant increase in rates of survival or reduced use of HFNC/NIV or mechanical ventilation, compared to patients treated with other therapies not including remdesivir.


title: Preserved C-reactive protein responses to blood stream infections following tocilizumab treatment for COVID-19

abstract: C-reactive protein (CRP) levels are elevated following bacterial infections but may be attenuated by the IL-6-receptor antagonist tocilizumab. In hospitalised COVID-19 patients, tocilizumab induced a transient (<21 day) fall in CRP but retained CRP responses to nosocomial blood stream infections, and therefore its utility in guiding antibiotic prescribing.


title: High resolution linear epitope mapping of the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 mRNA vaccine recipients.

abstract:
The prompt rollout of the coronavirus disease (COVID-19) messenger RNA (mRNA) vaccine is facilitating population immunity, which shall become more dominant than natural infection-induced immunity. At the beginning of the vaccine era, understanding the epitope profiles of vaccine-elicited antibodies will be the first step in assessing functionality of vaccine-induced immunity. In this study, the high-resolution linear epitope profiles of Pfizer-BioNTech COVID-19 mRNA vaccine recipients and COVID-19 patients were delineated by using microarrays mapped with overlapping peptides of the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The vaccine-induced antibodies targeting RBD had broader distribution across the RBD than that induced by the natural infection. Thus, relatively lower neutralizability was observed when a half-maximal neutralization titer measured in vitro by live virus neutralization assays was normalized to a total anti-RBD IgG titer. However, mutation panel assays targeting the SARS-CoV-2 variants of concern have shown that the vaccine-induced epitope variety, rich in breadth, may grant resistance against future viral evolutionary escapes, serving as an advantage of vaccine-induced immunity.

ImportanceEstablishing vaccine-based population immunity has been the key factor in attaining herd protection. Thanks to expedited worldwide research efforts, the potency of messenger RNA vaccines against the coronavirus disease 2019 (COVID-19) is now incontestable. The next debate is regarding the coverage of SARS-CoV-2 variants. At the beginning of this vaccine era, it is of importance to describe the similarities and differences between the immune responses of COVID-19 vaccine recipients and naturally infected individuals. In this study, we demonstrated that the antibody profiles of vaccine recipients are richer in variety, targeting a key protein of the invading virus, than those of naturally infected individuals. Yet vaccine-elicited antibodies included more non-neutralizing antibodies than infection-elicited, their breadth in antibody variations suggested possible resilience against future SARS-CoV-2 variants. The antibody profile achieved by vaccinations in naive individuals pose important insight into the first step towards vaccine-based population immunity.


title: Anticoagulants and Antiplatelets in COVID-19: Impact on Survival and Thromboembolism Development

abstract:
BackgroundHigher rates of venous and arterial thromboembolism have been noted in coronavirus disease-2019 (COVID-19). There has been limited research on the impact of anticoagulant and antiplatelet choice in COVID-19.

MethodsThis was a single-centre retrospective cohort study of 933 patients with COVID-19 infection presenting between 01/02/2020 and 31/05/2020. Survival time at 90 days post-diagnosis and thromboembolism development were the measured outcomes.

ResultsOf 933 total patients, mean age was 68 years and 54.4% were male. 297 (31.8%) did not survive at 90 days. A Cox proportional hazards model analysis found no statistically significant relationship between anticoagulant or antiplatelet choice and survival (p<0.05).

57 (6.3%) developed thromboembolism. Antiplatelet choice was not shown to have a statistically significant relationship with thromboembolism development. Warfarin and direct oral anticoagulant (DOAC) use did not have a statistically significant impact on thromboembolism development (p<0.05). Therapeutic low-molecular-weight heparin (LMWH) use was associated with increased thromboembolism risk (Odds ratio = 14.327, 95% CI 1.904 - 107.811, p = 0.010).

ConclusionsAntiplatelet choice was shown to have no impact on survival or thromboembolism development in COVID-19. Anticoagulant choice did not impact survival or thromboembolism development, aside from LMWH. Therapeutic LMWH use was associated with increased risk of thromboembolism. However, it should be noted that the sample size for patients using therapeutic LMWH was small (n=4), and there may be confounding variables affecting both LMWH use and thromboembolism development. These findings should be repeated with a larger sample of patients using therapeutic LMWH with additional adjustment for cofounding variables.

category: cardiovascular medicine


title: SARS-CoV-2 IgG detection in human oral fluids

abstract:
Seroepidemiological studies to monitor antibody kinetics are important for assessing the extent and spread of SARS-CoV-2 in a population. Non-invasive sampling methods are advantageous to reduce the need for venepuncture, which may be a barrier to investigations particularly in paediatric populations. Oral Fluids are obtained by gingiva-crevicular sampling from children and adults and are very well accepted. ELISA based on these samples have acceptable sensitivity and specificity compared to conventional serum-based antibody ELISAs and are suitable for population-based surveillance.

We describe the development and evaluation of SARS-COV-2 IgG ELISAs using SARS-CoV-2 viral nucleoprotein (NP) and spike (S) proteins in IgG isotype capture format and an indirect receptor-binding-domain (RBD) IgG ELISA, intended for use in children. All three assays were assessed using a panel of 1999 paired serum and oral fluids from children and adults participating in national primary school SARS-CoV-2 surveillance studies during and after the first and second pandemic wave in the UK. The anti NP IgG capture assay was the best candidate, with an overall sensitivity of 75% (95% CI: 71-79%) specificity of 99% (95% CI: 78-99%) when compared with paired serum antibodies measured using a commercial assay SARS-CoV-2 nucleoprotein IgG assay (Abbott, Chicago, IL, USA). Higher sensitivity was observed in children (80%, 95% CI: 71-88%) compared to adults (67%, CI: 60%-74%). Oral fluid assays using spike protein and RBD antigens were also 99% specific and achieved reasonable but lower sensitivity in the target population (78%, 95% CI (68%-86%) and 53%, 95% CI (43%-64%), respectively).

Conclusion statementOral Fluid assays based on the detection of SARS-CoV-2 antibodies are a suitable tool for population based seroepidemiology studies in children.


title: Navigating uncertain illness trajectories for young children with serious infectious illness: a mixed-methods modified grounded theory study.

abstract:
Infectious illness is the biggest cause of death in children due to a physical illness, particularly in children under five years. If mortality is to be reduced for this group of children, it is important to understand factors affecting their pathways to hospital.

The aim of this study was to retrospectively identify organisational and environmental factors, and individual child, family, and professional factors affecting timing of admission to hospital for children under five years of age with a serious infectious illness (SII).

MethodsAn explanatory modified grounded theory mixed methods design was used in collaboration with parents. Two stages of data collection were conducted: Stage 1, interviews with 22 parents whose child had recently been hospitalised with a SII and 14 health professionals (HPs) involved in their pre-admission trajectories; Stage 2, focus groups with 18 parents and 16 HPs with past experience of SII in young children. Constant comparative analysis generated the explanatory theory.

FindingsThe core category was  navigating uncertain illness trajectories for young children with serious infectious illness. Uncertainty was prevalent throughout the parents and HPs stories about their experiences of navigating social rules and overburdened health services for these children. The complexity of and lack of continuity within services, family lives, social expectations and hierarchies provided the context and conditions for childrens, often complex, illness trajectories. Parents reported powerlessness and perceived criticism leading to delayed help-seeking. Importantly, parents and professionals missed symptoms of serious illness. Risk averse services were found to refer more children to emergency departments.

ConclusionsParents and professionals have difficulties recognising signs of SII in young children and can feel socially constrained from seeking help. The increased burden on services has made it more difficult for professionals to spot the seriously ill child.

category: pediatrics


title: Diagnostic errors are common in acute pediatric respiratory disease: a prospective, single-blinded multicentre diagnostic accuracy study in Australian Emergency Departments

abstract:
BackgroundDiagnostic errors are a global health priority and a common cause of preventable harm. There is limited data available for the prevalence of misdiagnosis in pediatric acute-care settings. Respiratory illnesses, which are particularly challenging to diagnose, are the most frequent reason for presentation to pediatric emergency departments.

ObjectiveTo determine the diagnostic error rate of acute childhood respiratory diseases in emergency departments.

MethodsProspective, multicenter, single-blinded, diagnostic accuracy study in two well-resourced pediatric emergency departments in a large Australian city. Between September 2016 and August 2018, a convenience sample of children aged 29 days to 12 years who presented with respiratory symptoms was enrolled. The emergency department discharge diagnoses were reported by clinicians based upon standard clinical diagnostic definitions. These diagnoses were compared against consensus diagnoses given by an expert panel of pediatric specialists using standardized disease definitions after they reviewed all medical records.

ResultsFor 620 participants, the positive and negative percent agreement (%, [95% CI]) of the emergency department compared with the expert panel diagnoses were generally poor: isolated upper respiratory tract disease (61.4 [51.2, 70.9], 90.9 [88.1, 93.3]), croup (75.6 [64.9, 84.4], 97.9 [96.2, 98.9]), lower respiratory tract disease (86.4 [83.1, 89.6], 92.9 [87.7, 96.4]), bronchiolitis (66.9 [58.6, 74.5], 94.3 [80.8, 99.3]), asthma/reactive airway disease (91.0 [85.8, 94.8], 93.0 [90.1, 95.3]), clinical pneumonia (62{middle dot}9 [49{middle dot}7, 74{middle dot}8], 95{middle dot}0 [92{middle dot}8, 96{middle dot}7]), focal (consolidative) pneumonia (54{middle dot}8 [38{middle dot}7, 70{middle dot}2], 86.2 [79.3, 91.5]). Only 59% of chest x-rays with consolidation were correctly identified. Between 6.9% and 14.5% of children were inappropriately prescribed based on their eventual diagnosis.

ConclusionIn well-resourced emergency departments, we have identified a previously unrecognized high diagnostic error rate for acute childhood respiratory disorders, particularly in pneumonia and bronchiolitis. These errors lead to the potential of avoidable harm and the administration of inappropriate treatment.


title: Investigating the clinical utility of biomarkers and other novel tests in younger onset neurocognitive disorders: the BeYOND study, protocol for a longitudinal clinical study in a real-world setting.

abstract:
BackgroundYounger-onset dementia (YOD) can be challenging to diagnose due to its younger age of onset, heterogeneous aetiologies and broad range of presentations. Misdiagnosis is common with psychiatric conditions often diagnosed initially and diagnostic delay of five years is common. More information is needed to better understand and diagnose YOD, including the nature of symptom onset, progression of the disease, the relationship between cognition and functional outcomes for patients and carers, imaging changes and novel biomarkers. This paper reports on the background behind the "Investigating the clinical utility of biomarkers and other novel tests in younger-onset neurocognitive disorders", the BeYOND study, and its methodology.

MethodsBeYOND is a clinically-oriented "real-world" longitudinal study that follows younger people presenting with an onset of neuropsychiatric symptoms [≤] 65 years of age. We aim to collect information on participants cognition, neuroimaging, mental health, and blood and cerebrospinal fluid (CSF) biomarkers at 18-month time-points over 3 years. We also aim to collect information regarding the experience of carers and/or family of participants.

ConclusionSerial assessment of symptomatology, cognition, imaging, and blood and CSF biomarkers will be correlated with eventual diagnosis to determine the usefulness of these measures in determining a confident diagnosis. In addition, repeat measurements of the mental health and well-being of the participant and that of their carers/family while they traverse their diagnostic journey will provide important information about service provision and how they can be better supported.

category: psychiatry and clinical psychology


title: A Clinical Feasibility Study of an Artificial Intelligence-Powered Clinical Decision Support System

abstract:
ObjectiveWe examine the feasibility of an Artificial Intelligence (AI)-powered clinical decision support system (CDSS), which combines the operationalized 2016 Canadian Network for Mood and Anxiety Treatments guidelines with a neural-network based individualized treatment remission prediction.

MethodsDue to COVID-19, the study was adapted to be completed entirely at a distance. Seven physicians recruited outpatients diagnosed with major depressive disorder (MDD) as per DSM-V criteria. Patients completed a minimum of one visit without the CDSS (baseline) and two subsequent visits where the CDSS was used by the physician (visit 1 and 2). The primary outcome of interest was change in session length after CDSS introduction, as a proxy for feasibility. Feasibility and acceptability data were collected through self-report questionnaires and semi-structured interviews.

ResultsSeventeen patients enrolled in the study; 14 completed. There was no significant difference between appointment length between visits (introduction of the tool did not increase session length). 92.31% of patients and 71.43% of physicians felt that the tool was easy to use. 61.54% of the patients and 71.43% of the physicians rated that they trusted the CDSS. 46.15% of patients felt that the patient-clinician relationship significantly or somewhat improved, while the other 53.85% felt that it did not change.

ConclusionsOur results confirm the primary hypothesis that the integration of the tool does not increase appointment length. Findings suggest the CDSS is easy to use and may have some positive effects on the patient-physician relationship. The CDSS is feasible and ready for effectiveness studies.


title: Missense variants affecting the actin-binding domains of PLS3 cause X-linked congenital diaphragmatic hernia and body wall defects

abstract: Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with a novel X-linked condition characterized by diaphragm defects, variable anterior body wall anomalies, and/or facial dysmorphism. Using linkage analysis and whole exome or whole genome sequencing, we identified novel missense variants in the actin binding domains of plastin 3 (PLS3), a gene encoding an actin bundling protein, that co-segregate with disease in all families. Loss-of-function variants in PLS3 have been described previously in association with X-linked osteoporosis. To address these seemingly disparate clinical phenotypes, we performed in silico protein modeling and cellular overexpression experiments, which suggest that the affected residues in individuals with CDH are important for actin binding and result in disorganization of the actin cytoskeleton and a reduction in normal actin stress fiber formation. A mouse knock-in model of a variant identified in one of the families, p.W499C, shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal wall defects. Both the mouse model and one surviving adult patient with a PLS3 variant were observed to have increased, rather than decreased, bone mineral density. Together, these clinical and functional data in human and mouse reveal that specific missense variants affecting the actin binding domains of PLS3 may have a gain-of-function effect and cause a new Mendelian disorder.

category: genetic and genomic medicine


title: Anaesthetic Higher Specialty Training Recruitment in the United Kingdom During the COVID-19 Pandemic: A National Survey

abstract: The most recent ST3 Anaesthetic recruitment for posts commencing in August 2021 saw larger numbers of applicants (n = 1,056) compared to previous years, with approximately 700 applicants failing to secure an ST3 post. We surveyed 536 anaesthetic junior doctors who applied for ST3 posts during this application round with the aim of investigating their experience of the recruitment process this year (response rate 536/1,056 = 51%). Approximately 61% were not offered ST3 posts (n = 326), a similar proportion to that previously reported. We asked all respondents what their potential career plans were for the next 12 to 24 months. The majority expressed intentions to take up either CT3 top-up posts or non-training fellow posts from August 2021 (79%). Other options considered by respondents included: pursuing work abroad (17%), embarking on a career break (16%), taking up an ST3 post in intensive care medicine instead of anaesthetics (15%) and permanently leaving the medical profession (9%). A number of respondents expressed a desire to pursue training in a different medical specialty (9%). Some respondents expressed an intention to pursue further education or research (10%). A large proportion of respondents (42%) expressed a lack of confidence in being able to achieve the necessary training requirements to later apply for ST4 in August 2023. The majority of respondents reported not feeling confident in achieving GMC Specialty Registration in Anaesthesia in the future without a training number (75%), and that their wider life plans have been disrupted due to the impending time out of training (78%). We received a total of 384 free-text responses to a question asking about general concerns regarding the ST3 applications process. Sentiment analysis of these free-text responses indicated that respondents felt generally negatively about the ST3 recruitment process. Some themes that were elicited from the responses included: respondents feeling the recruitment process lacked fairness, respondents suffering burnout and negative impacts on their wellbeing, difficulties in making plans for their personal lives, and feeling undervalued and abandoned despite having made personal sacrifices to support the health service during the COVID-19 pandemic. These results suggest that junior anaesthetic doctors in the UK currently have a negative perception towards postgraduate training structures, which has been exacerbated by the COVID-19 pandemic, changes to the postgraduate training curriculum and difficulties in securing higher training posts.

category: anesthesia


title: The protocol for a scoping review analyzing the association between physical activity interventions after a genitourinary cancer diagnosis and incidences of depression and anxiety

abstract:
The following is a protocol for a planned scoping review of the effect of physical activity interventions on incidences of depression and anxiety incidences in men diagnosed with a genitourinary cancer. If exercise interventions are found to correlate with lower incidences of depression and anxiety, physical activity interventions offer a potentially modifiable, low-cost, accessible, and natural intervention to improve quality of life outcomes in men with genitourinary cancers. We plan to screen literature from publicly available databases, PubMed and Embase, for intervention studies in this area by implementing abstract/title and full-text screening by two independent reviewers followed by data extraction performed by two independent reviewers. Results will be synthesized in narrative format accompanied by relevant tabulated findings. We anticipate no ethical risks while completing this scoping review. Upon completion of this scoping review, results will be disseminated via publication.

Article Summary (Strengths and Limitations)O_LIThis scoping review will address a critical area of potentially-modifiable interventions to improve quality-of-life indicators in genitourinary cancer survivorship research.
C_LIO_LIThis scoping review could inform the use of readily available, low-cost, and low-barrier, treatment options to men suffering from depression and anxiety.
C_LIO_LIThis review is limited to information from interventional studies only as a preliminary review of available research.
C_LIO_LIThis review is limited to interventional studies in male cancer patients of specific genitourinary cancers (prostate, bladder, kidney, testicular).
C_LI


title: Critical Role of the Subways in the Initial Spread of SARS-CoV-2 in New York City

abstract: We studied the possible role of the subways in the spread of SARS-CoV-2 in New York City during late February and March 2020. Data on cases and hospitalizations, along with phylogenetic analyses of viral isolates, demonstrate rapid community transmission throughout all five boroughs within days. The near collapse of subway ridership during the second week of March was followed within 1-2 weeks by the flattening of COVID-19 incidence curve. We observed persistently high entry into stations located along the subway line serving a principal hotspot of infection in Queens. We used smartphone tracking data to estimate the volume of subway visits originating from each zip code tabulation area (ZCTA). Across ZCTAs, the estimated volume of subway visits on March 16 was strongly predictive of subsequent COVID-19 incidence during April 1-8. In a spatial analysis, we distinguished between the conventional notion of geographic contiguity and a novel notion of contiguity along subway lines. We found that the March 16 subway-visit volume in subway-contiguous ZCTAs had an increasing effect on COVID-19 incidence during April 1-8 as we enlarged the radius of influence up to 5 connected subway stops. By contrast, the March 31 cumulative incidence of COVID-19 in geographically-contiguous ZCTAs had an increasing effect on subsequent COVID-19 incidence as we expanded the radius up to 3 connected ZCTAs. The combined evidence points to the initial citywide dissemination of SARS-CoV-2 via a subway-based network, followed by percolation of new infections within local hotspots.


title: Stress-induced change in salience network coupling prospectively predicts trauma-related symptoms.

abstract:
Substantial individual differences exist in how acute stress affects large-scale neurocognitive networks, including Salience (SN), Default Mode (DMN) and Central Executive Networks (CEN). Changes in the connectivity strength of these network upon acute stress may predict vulnerability to long-term stress effects, which can only be tested in prospective longitudinal studies. Using such longitudinal design, we investigated whether the magnitude of acute-stress induced functional connectivity changes (delta-FC) predicts the development of posttraumatic stress disorder (PTSD) symptoms in a relatively resilient group of young police students that are known to be at high risk for trauma-exposure.

Using resting-state fMRI, we measured acute-stress induced delta-FC in 190 police recruits before (baseline) and after trauma exposure during repeated emergency aid services (16-month follow-up). Delta-FC was then linked to the changes in perceived stress levels (PSS) and post-traumatic stress symptoms (PCL and CAPS).

Weakened connectivity between the SN and DMN core regions upon acute stress induction at baseline predicted longitudinal increases in perceived stress level but not of post-traumatic stress symptoms, whereas increased coupling between the overall SN and anterior cerebellum was observed in participants with higher clinician-rated PTSD symptoms, particularly intrusion levels. All effects remained significant when controlling for trauma exposure-levels and cortisol stress-reactivity. Neither hormonal nor subjective measures exerted similar predictive or acquired effects.

The reconfiguration of large-scale neural networks upon acute stress induction is relevant for assessing and detecting risk and resilience factors for PTSD. This study highlights the SN connectivity-changes as a potential marker for trauma-related symptom-development, which is sensitive even in a relatively resilient sample.


title: Acute-stress induced change in salience network coupling prospectively predicts post-trauma symptom-development.


title: Durable Humoral and Cellular Immune Responses Following Ad26.COV2.S Vaccination for COVID-19

abstract: Interim immunogenicity and efficacy data for the Ad26.COV2.S vaccine for COVID-19 have recently been reported1-3. We describe here the 8-month durability of humoral and cellular immune responses in 20 individuals who received one or two doses of 5x1010 vp or 1011 vp Ad26.COV2.S and in 5 participants who received placebo2. We evaluated antibody and T cell responses on day 239, which was 8 months after the single-shot vaccine regimen (N=10) or 6 months after the two-shot vaccine regimen (N=10), although the present study was not powered to compare these regimens3. We also report neutralizing antibody responses against the parental SARS-CoV-2 WA1/2020 strain as well as against the SARS-CoV-2 variants D614G, B.1.1.7 (alpha), B.1.617.1 (kappa), B.1.617.2 (delta), P.1 (gamma), B.1.429 (epsilon), and B.1.351 (beta).


title: Incidence of Severe Acute Respiratory Syndrome Coronavirus-2 infection among previously infected or vaccinated employees

abstract:
IntroductionThe protective effect of previous infection versus vaccination is poorly studied. Among a clinical laboratory that has been conducting routine workforce screening since the beginning of the pandemic, we aimed to assess the relative risk of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection among individuals who were SARS-CoV-2 naive, previously infected, or vaccinated.

MethodsUsing an electronic laboratory information system, employees were divided into three groups: (1) SARS-CoV-2 naive and unvaccinated, (2) previous SARS-CoV-2 infection, and (3) vaccinated. Person-days were measured from the date of the employee first test and truncated at the end of the observation period. SARS-CoV-2 infection was defined as two positive SARS-CoV-2 PCR tests in a 30-day period. Individuals with fewer than 14 days of follow up were excluded. Incidence estimates and the 95% confidence intervals were calculated using the Poisson Exact equation. The incidence rate ratio (IRR) was used as a measure of association between groups. Analyses were performed on StataSE (StataCorp, College Station, TX).

ResultsWe identified 4313, 254 and 739 employee records for groups 1, 2, and 3, respectively. The median age of employees was 29.0 years (interquartile range: 23.6, 39.9). During the observation period, 254, 0, and 4 infections were identified among groups 1, 2, and 3, respectively. Group 1 had an incidence of 25.9 per 100 person-years (95% CI: 22.8-29.3). Group 2 had an incidence of 0 per 100 person-years (95% CI: 0-5.0). Group 3 had an incidence of 1.6 per 100 person-years (95% CI: 0.04-4.2). The IRR of reinfection among those with previous infection compared to SARS-CoV-2 naive was 0 (95% CI: 0-0.19). The IRR of those vaccinated compared to SARS-CoV-2 naive was 0.06 (95% CI: 0.02-0.16). The IRR of those vaccinated compared to prior SARS-CoV-2 was 0 (95% CI: 0-4.98).

ConclusionPrevious SARS-CoV-2 infection and vaccination for SARS-CoV-2 were associated with decreased risk for infection or re-infection with SARS-CoV-2 in a routinely screened workforce. The was no difference in the infection incidence between vaccinated individuals and individuals with previous infection. Further research is needed to determine whether our results are consistent with the emergence of new SARS-CoV-2 variants.


title: Mutation induced infection waves in diseases like COVID-19

abstract: After almost 4 million deaths worldwide, the ongoing vaccination to conquer the COVID-19 disease is now competing with the emergence of increasingly contagious mutations, repeatedly supplanting earlier strains. Following the near-absence of historical examples of the long-time evolution of infectious diseases under similar circumstances, models are crucial to exemplify possible scenarios. Accordingly, in the present work we systematically generalize the popular susceptible-infectedrecovered model to account for mutations leading to repeatedly occurring new strains, which we coarse grain based on tools from statistical mechanics to derive a model predicting the most likely outcomes. The model predicts that mutations can induce a super-exponential growth of infection numbers at early times, which can self-amplify to giant infection waves which are caused by a positive feedback loop between infection numbers and mutations and lead to a simultaneous infection of the majority of the population. At later stages - if vaccination progresses too slowly - mutations can interrupt an ongoing decrease of infection numbers and can cause infection revivals which can occur as single waves or even as whole wave trains featuring alternative periods of decreasing and increasing infection numbers. Our results might be useful for discussions regarding the importance of a release of vaccine-patents to reduce the risk of mutation-induced infection revivals but also to coordinate the release of measures following a downwards trend of infection numbers.


title: Excess years of life lost to COVID-19 and other causes of death by sex, neighbourhood deprivation and region in England & Wales during 2020

abstract:
BackgroundDeaths in the first year of the COVID-19 pandemic in England & Wales have been shown to be unevenly distributed socioeconomically and geographically. However, the full scale of inequalities may have been underestimated as most measures of excess mortality do not adequately account for varying age profiles of deaths between social groups. We measured years of life lost (YLL) attributable to the pandemic, directly or indirectly, comparing mortality across geographic and socioeconomic groups.

MethodsYLL for registered deaths in England & Wales, from 27th December 2014 until 25th December 2020, were calculated using 2019 single year sex-specific life tables for England & Wales. Panel time-series models were used to estimate expected YLL by sex, geographical region, and deprivation quintile between 7th March 2020 and 25th December 2020 by cause: direct deaths (COVID-19 and other respiratory diseases), cardiovascular disease & diabetes, cancer, and other indirect deaths - all other causes). Excess YLL during the pandemic period were calculated by subtracting observed from expected values. Additional analyses focused on excess deaths for region and deprivation strata, by age-group.

FindingsBetween 7th March 2020 and 25th December 2020 there were an estimated 763,550 (95% CI: 696,826 to 830,273) excess YLL in England & Wales, equivalent to a 15% (95% CI: 14 to 16) increase in YLL compared to the equivalent time period in 2019. There was a strong deprivation gradient in all-cause excess YLL, with rates per 100,000 population ranging from (916; 95% CI: 820 to 1,012) for the least deprived quintile to (1,645; 95% CI: 1,472 to 1,819) for the most deprived. The differences in excess YLL between deprivation quintiles were greatest in younger age groups; for all-cause deaths, an average of 9.1 years per death (95% CI: 8.2 to 10.0) were lost in the least deprived quintile, compared to 10.8 (95% CI: 10.0 to 11.6) in the most deprived; for COVID-19 and other respiratory deaths, an average of 8.9 years per death (95% CI: 8.7 to 9.1) were lost in the least deprived quintile, compared to 11.2 (95% CI: 11.0 to 11.5) in the most deprived. There was marked variability in both all-cause and direct excess YLL by region, with the highest rates in both in the North West.

InterpretationDuring 2020, the first calendar year of the COVID-19 pandemic, longstanding socioeconomic and geographical health inequalities in England & Wales were exacerbated, with the most deprived areas suffering the greatest losses in potential years of life lost.

FundingNone


title: Modelling, Simulations and Analysis of the First and Second COVID-19 Epidemics in Beijing

abstract: Modeling and simulation are important tools that can be used to control, prevent and understand an epidemic spread. This paper introduces a symptomatic-asymptomatic-recoverer-death differential equation model (SARDDE). It presents the conditions of the asymptotical stability on the disease-free equilibrium of the SARDDE. It proposes the necessary conditions of disease spreading for the SARDDE. Based on the reported data of the first and the second COVID-19 epidemics in Beijing and simulations, it determines the parameters of the SARDDE, respectively. Numerical simulations of the SARDDE describe well the outcomes of current symptomatic and asymptomatic individuals, recovered symptomatic and asymptomatic individuals, and died individuals, respectively. The numerical simulations suggest that both symptomatic and asymptomatic individuals cause lesser asymptomatic spread than symptomatic spread; the blocking rates of about 90% and 97% to the symptomatic individuals cannot prevent the spread of the first and second COVID19 epidemics in Beijing, respectively. Virtual simulations suggest that the strict prevention and control strategies implemented by Beijing government are effective and necessary. The numerical simulations suggest also that using the data from the beginning to the days after about two weeks from the turning points can estimate approximately the following outcomes of the two COVID-19 academics, respectively. A recommendation to avoid multiple epidemic outbreaks is proposed. It is expected that the research can provide better understanding, explaining, and dominating for epidemic spreads, prevention and control measures.


title: Peritraumatic Distress of COVID-19 on Physicians in Bangladesh: Implications and Policy Recommendations

abstract: COVID-19 pandemic has been an ultimate test of resource management for any governance, especially in the healthcare system. Bangladesh, being a developing country and with very limited resources, is fighting the COVID-19 pandemic. The frontline workers, especially the physicians and nurses are going through immense physical and psychological stress during the pandemic. Social unawareness, the absence of strict preventive policies, increasing workload, and the lack of resource management are making the frontline healthcare workers extremely vulnerable to COVID-19. In this paper, we present the outcome of our study on peritraumatic distress of COVID-19 among physicians in Bangladesh. Based on the user study, we have identified a number of key factors behind the peritraumatic distress and psychological stress caused by COVID-19. Our study shows, more than 78% respondents are suffering from peritraumatic psychological distress. We also recommended some very important and yet easy to implement policies to reduce the peritraumatic stress of the physicians of Bangladesh. These policy recommendations were a result of the survey analysis and the suggestions from the COVID-19 designated physicians.


title: What We Learned From COVID 19? Trying to find best approach from pathophysiology to treatment.

abstract:
ObjectiveCOVID-19 may yield a variety of clinical pictures, differing from pneumonitis to Acute Respiratory Distress Syndrome (ARDS) along with vascular damage in the lung tissue, named as endotheliitis. To date, no specific treatment strategy was approved by any authority for the prevention or treatment of COVID-19 in terms of endotheliitis-related comorbidities. Here, we present our experience of COVID-19 by evaluating 11,190 COVID-19 patients with the manifestations of endotheliitis in skin, lung, and brain tissues according to the different phases of COVID-19.

MethodsAfter a retrospective examination, patients were divided into three groups according to their repercussions of vascular distress, which were represented by radiological, histopathological, and clinical findings. (Group A: no or mild pulmonary involvement, Group B: moderate pulmonary involvement with clinical risk of deterioration, Group C: severe pulmonary involvement and respiratory failure). We presented the characteristics and disease course of seven representative and complicated cases which represents the different phases of the disease, and discussed the treatment strategies in each group. The current pathophysiological mechanisms responsible from SARS-CoV-2 infection, COVID-19 related respiratory failure and current treatment strategies were reviewed and discussed in detail.

ResultsAmong 11.190 patients, 9294 patients met the criteria for Group A, and 1376 patients were presented to our clinics with Group B characteristics. Among these patients, 1896 individuals(Group B and Group C) were hospitalized. While 1220 inpatients were hospitalized within the first 10 days after the diagnosis, 676 of them were worsened and hospitalized 10 days after their diagnosis. Among hospitalized patients, 520 of them did not respond to group A and B treatments and developed hypoxemic respiratory failure (Group C) and 146 individuals needed ventilator support and were followed in the intensive care unit, and 43 (2.2%) patients died.

ConclusionDistinctive manifestations in each COVID-19 patient, including non-respiratory conditions in the acute phase and the emerging risk of long-lasting complications, suggest that COVID-19 has an endotheliitis-centred thrombo-inflammatory pathophysiology. Endotheliitis can also explain the mechanism behind the respiratory failure in COVID-19, and the difference of COVID-19 related ARDS from ARDS seen in other critical conditions. In addition, use of early corticosteroid in patients with early symptoms and early tocilizumab in ICU helps to reduce mortality and progression of the disease. Endotheliitis-based pathophysiological mechanisms are known to be momentarily changing and difficut to manage due to their risk of sudden aggrevation. Hence, daily evaluation of clinical, laboratory and radiological findings of patients and deciding appropriate pathophysiological treatment would help to reduce the mortality rate of COVID-19.

category: respiratory medicine


title: What We Learned from COVID-19: From endotheliitis to treatment


title: Using the behaviour change wheel approach to optimise self-sampling packs for sexually transmitted infections and blood borne viruses

abstract:
PurposeThis paper describes the process of optimising a widely offered intervention - the self-sampling pack for sexually transmitted infections (STIs) and blood born viruses (BBVs). We drew upon the BCW approach, incorporating the theoretical domains framework (TDF) and the behaviour change technique taxonomy (BCTT) to systematically specify potential intervention components that may optimise the packs.

MethodsA behaviour change wheel analysis built upon prior thematic analyses of qualitative data collected through focus groups and interviews with members of the public and people recruited from sexual health clinics in Glasgow and London (n=56). Salient barriers and facilitators to specific sequential behavioural domains associated with wider behavioural system of pack-use were subjected to further analyses, coding them in relation to the TDF, the BCWs intervention functions, and finally specifying potential optimisation in relation to behaviour change techniques (BCTs).

ResultsOur TDF analysis suggested that across the overall behavioural system of pack use the most important theoretical domains were  beliefs about consequences and  memory, attention and decision-making. BCW analysis on the overall pack suggested useful intervention functions should focus on  environmental restructuring,  persuasion,  enablement,  education and  modelling. Ways of optimising the intervention were also specified in relation to potentially useful behaviour change techniques (BCTs).

ConclusionsA detailed behavioural analysis building on earlier qualitative work using the TDF and the BCW provided a systematic approach to optimising an existing intervention. The approach enabled the specification of highly specific, evidence-based, and theoretically informed recommendations for intervention optimisation.

What is already known on this subject?O_LIThe use of self-sampling packs for sexually transmitted infections (STIs) and blood borne viruses (BBVs) has been widely implemented without in-depth assessment of user perspectives, adequate theorisation in relation to behaviour change, or optimisation
C_LIO_LIIn a previous qualitative study we reported on our use of thematic analyses (inductive and deductive) to understand the behavioural system of using self-sampling packs. We identified multiple modifiable barriers, and several important facilitators to using these packs, and their content, correctly
C_LIO_LIOur thematic analyses showed that self-sampling packs offered a largely acceptable approach to STI and BBV testing and that with some modification it may be possible to increase both the range of people who can benefit from them and increase the return of samples
C_LI

What does this study add?O_LIThis study theorises key barriers and facilitators to each sequential step within the behavioural system of using the self-sampling pack. Across the whole behavioural system of pack use we identified  beliefs about consequences and  memory, attention and decision-making as being particularly important theoretical domains
C_LIO_LITo optimise self-sampling packs for STIs, our use of the behaviour change wheel suggested that to modify the pack we should use intervention functions that detail environmental restructuring and assist the user using pack contents through persuasion and enablement with some education and modelling
C_LIO_LIThe study provides an exemplar of how to use the behaviour change wheel within the process of intervention optimisation when building upon prior qualitative analyses. The results informed the redesign of the pack and the development of on-line support materials to be used within a large multi-site trial
C_LI

category: sexual and reproductive health


title: Does prior healthcare experience predict success on clinical courses and add value to admissions processes?

abstract:
ObjectivesThis work sought to assess whether prior clinical experience provided any guide to likely course achievement from three completed cohorts of Physician Associates at the University of Sheffield.

MethodsSixty students who entered the PA course at TUoS since it began in 2016 were included in the study. Each students original course application was reviewed for healthcare experience and mapped against first sit examination scores. Statistical analysis was undertaken with a two-tailed t-test.

ResultsNo correlation was found between previous healthcare experience and performance in examinations. Students with previous healthcare experience performed slightly worse than those without in the OSCE examination but not at a level of statistical significance.

ConclusionsThe use of clinical experience as part of the criteria of entry does not predict success on a Physician Associate course. We support the position of the 2010 Ottawa conference that quality assured methodologies along with objective cut offs for previous academic attainment are the most appropriate way to select students for clinical courses.

category: medical education


title: Examining Medical Student Volunteering During The COVID-19 Pandemic As A Prosocial Behavior During An Emergency

abstract:
IntroductionCOVID-19 has caused major disruptions to healthcare, with voluntary opportunities offered to medical students to provide clinical support. We used the conceptual framework of prosocial behavior during an emergency - behaviors whose primary focus is benefiting others - to examine volunteering during COVID-19.

MethodsWe conducted an in-depth, mixed-methods cross-sectional survey, from 2nd May to 15th June 2020, of medical students studying at UK medical schools. Data analysis was informed by Latane and Darleys theory of prosocial behavior during an emergency and aimed to understand students decision-making processes.

ResultsA total of 1145 medical students from 36 medical schools completed the survey. While 947 (82.7%) of students were willing to volunteer, only 391 (34.3%) had volunteered. The majority (92.7%) of students understood that they may be asked to volunteer; however, we found that deciding ones responsibility to volunteer was mitigated by a complex interaction between the interests of others and self-interest. Further, concerns revolving around professional role boundaries influenced students decisions over whether they had the required skills and knowledge to volunteer. Deciding to volunteer depended not only on possession of necessary skills, but also seniority and identification with the nature of volunteering roles offered.

ConclusionsWe propose two additional domains to Latane and Darleys theory of prosocial behavior during an emergency that students consider before making their final decision to volunteer. These are  logistics - whether it is logistically feasible to volunteer - and  safety - whether it is safe to volunteer. This study highlights a number of modifiable barriers to prosocial behavior that medical students encounter and provides suggestions regarding how Latane and Darleys theory of prosocial behavior can be operationalized within educational strategies to address these barriers. Optimizing the process of volunteering can aid healthcare provision and may facilitate a safer volunteering process for all.


title: Fear of COVID-19 among nurses in mobile COVID-19 testing units in Greece

abstract:
BackgroundMobile COVID-19 testing units are used worldwide to test quickly and easily individuals for COVID-19.

AimTo assess the level of fear of COVID-19 among nurses in mobile COVID-19 testing units and compare it with demographic characteristics.

MethodsA cross-sectional study was conducted during November and December 2020. Study population included 57 nurses working in mobile COVID-19 testing units in Attica, Greece. We collected demographic data from the nurses, i.e. gender, age, marital status, children, living status (alone or with others), clinical experience, and chronic disease. We used the fear of COVID-19 scale to measure fear of the COVID-19 pandemic.

ResultsThe mean score on the fear of COVID-19 scale was 14.3. Among nurses, 31.6% experienced elevated fear indicative of presence of anxiety symptoms, while the respective percentages for health anxiety and post-traumatic stress symptomatology were 22.8% and 17.5%. Fear of COVID-19 was not affected by demographic variables. However, fear was higher in females, nurses who had children and nurses who lived with others. Increased clinical experience was related with decreased fear.

ConclusionsCreating a secure work environment for nurses in these units could decrease fear of COVID-19 and increase work performance.

category: nursing


title: Migraine Disability, Pain Catastrophizing, And Headache Severity Are Associated With Evoked Pain And Targeted By Mind-Body Therapy

abstract:
Meta-analysis suggests migraine patients are no more sensitive to experimentally evoked pain than healthy controls. At the same time, studies have linked some migraine symptoms to Quantitative Sensory Testing (QST) profiles. Unfortunately, previous studies associating migraine symptoms and QST have important methodological shortcomings, stemming from inappropriate statistics, small sample sizes, and frequent use of univariate statistics for multivariate research questions. In the current study we seek to address these limitations by using a large sample of episodic migraine patients (n=103) and a multivariate analysis that associates pain ratings from many thermal intensities simultaneously with 12 clinical measures ranging from headache frequency to sleep abnormalities. We identified a single dimension of association between QST and migraine symptoms that relates to pain ratings for all stimulus intensities and a subset of migraine symptoms relating to disability (Headache Impact Trauma 6 and Brief Pain Inventory interference), catastrophizing (Pain Catastrophizing Scale), and pain severity (average headache pain, Brief Pain Inventory severity, and Short Form McGill Pain Questionnaire 2). Headache frequency, allodynia, affect, and sleep disturbances were unrelated to this dimension. Consistent with previous research, we did not observe any difference in QST ratings between migraine patients and healthy controls. Additionally, we found that the linear combination of symptoms that related to QST were modified by mind-body therapy. These results suggest that QST has a selective relationship with pain symptoms even in the absence of between-subjects differences between chronic pain patients and healthy controls.

HighlightsO_LIExperimentally evoked pain ratings have been linked to migraine symptoms, though there are methodological shortcomings
C_LIO_LIWe find evoked pain ratings are related to disability, pain catastrophizing, and pain severity, but not to headache frequency, affect, nor sleep disturbances
C_LIO_LIEvoked pain and symptoms relate even in the absence of pain sensitivity differences between patients and healthy controls
C_LIO_LIMind-body therapy altered symptoms that related to evoked pain
C_LIO_LIExperimentally evoked pain should be used to study specific ensembles of symptoms, even when pain ratings do not differ between patients and healthy controls
C_LI

category: pain medicine


title: Analysis of the association between TLR2 rs111200466 variants and cervical Cancer susceptibility in Sudanese women

abstract:
Worldwide there are more than 273,000 deaths from cervical cancer each year and it accounts for 9% of female cancer deaths. The high-risk variants of human papillomavirus such as HPV 16 and 18 are major etiological agents of cervical cancer. The persistency of infection with HPV may due to inappropriate immune response due to SNPs interfering with the function of particular part of the immune system. Toll-like receptors (TLRs) play an important role in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. The -196 to -174del polymorphism affects the TLR2 gene and alters its promoter activity.

AimIn this study we investigated the presence and the influence of TLR2 -196 to - 174del polymorphism on the risk of cervical cancer development in Sudanese. The study was performed on 42 patients with cervical cancer and 27 healthy controls. Genotyping of -196 to -174del polymorphism of TLR2 was investigated using allele-specific polymerase chain reaction method in all subjects. We documented the presence of-196 to -174del polymorphism of TLR2 in Sudanese women with allele frequency 37% of control and 34% of patient sample although there was no observed association between this SNP and the risk of cervical cancer (p value. 394).Further studies are needed in a large and ethnically diverse population to determine the impact of the TLR2 polymorphism in the susceptibility of cervical cancer.


title: Sensitivity of SARS-CoV-2 antibody tests with late convalescent sera

abstract:
SARS-CoV-2-specific IgM antibodies wane during the first three months after infection and IgG antibody levels decline. This may limit the ability of antibody tests to identify previous SARS CoV-2 infection at later time points. To examine if the sensitivity of antibody tests falls off, we compared the sensitivity of two nucleoprotein-based antibody tests, the Roche Elecsis II Anti-SARS-CoV-2 and the Abbott SARS-CoV-2 IgG assay and three glycoprotein-based tests, the Abbott SARS-CoV-2 IgG II Quant, Siemens Atellica IM COV2T and Euroimmun SARS-CoV-2 assay with 56 sera obtained 6-8 months after SARS-CoV-2 infection. The sensitivity of the Roche, Abbott SARS-CoV-2 IgG II Quant and Siemens antibody assays was 94.6 % (95% confidence interval (CI) 85.1-98.9 %), 98.2 % (95% CI: 90.4-99.9 %) and 100 % (95% CI: 93.6-100 %). The sensitivity of the N-based Abbott SARS-CoV-2 IgG and the glycoprotein-based Euroimmun ELISA was 48.2 % (95% CI: 34.7-62.0 %) and 83.9 % (95% CI: 71.7-92.4 %). The nucleoprotein-based Roche and the glycoprotein-based Abbott RBD and Siemens tests were more sensitive than the N-based Abbott and the Euroimmun antibody tests (p=0.0001 to p=0.039). The N-based Abbott antibody test was less sensitive 6-8 months than 4-10 weeks after SARS-CoV-2 infection (p = 0.0002). The findings show that most SARS CoV-2 antibody assays correctly identified previous infection 6-8 months after infection. The sensitivity of pan-Ig antibody tests was not reduced at 6-8 months when IgM antibodies have usually disappeared. However, one of the nucleoprotein-based antibody tests significantly lost sensitivity over time.

HighlightsO_LIMost antibody tests correctly identified SARS CoV-2 infection 6-8 months after infection
C_LIO_LIThe sensitivity of the antibody tests was 48.2-100 %
C_LIO_LIThe three tests with the highest sensitivity (94.6-100 %) were the N-based Roche and the RBD-based Abbott and Siemens assays
C_LIO_LIThe N-based Abbott IgG CMIA was significantly less sensitive 6-8 months than 4-10 weeks after infection (p = 0.0002)
C_LI


title: Characteristics of children and antigen test performance at a SARS-CoV-2 community testing site

abstract:
BackgroundPerformance characteristics of SARS-CoV-2 antigen tests among children are limited despite the need for point-of-care testing in school and childcare settings. We describe children seeking SARS-CoV-2 testing at a community site and compare antigen test performance to real-time reverse transcription-polymerase chain reaction (RT-PCR) and viral culture.

MethodsTwo anterior nasal specimens were self-collected for BinaxNOW antigen and RT-PCR testing, along with demographics, symptoms, and exposure information from individuals [≥]5 years at a community testing site. Viral culture was attempted on residual antigen or RT-PCR positive specimens. Demographic and clinical characteristics, and the performance of SARS-CoV-2 antigen tests, were compared among children (<18 years) and adults.

ResultsAbout one in ten included specimens were from children (225/2110); 16.4% (37/225) were RT-PCR positive. Cycle threshold values were similar among RT-PCR positive specimens from children and adults (22.5 vs 21.3, p=0.46) and among specimens from symptomatic and asymptomatic children (22.5 vs 23.2, p=0.39). Sensitivity of antigen test compared to RT-PCR was 73.0% (27/37) among specimens from children and 80.8% (240/297) among specimens from adults; among specimens from children, specificity was 100% (188/188), positive and negative predictive value were 100% (27/27) and 94.9% (188/198) respectively. Virus was isolated from 51.4% (19/37) of RT-PCR positive pediatric specimens; all 19 had positive antigen test results.

ConclusionsWith lower sensitivity relative to RT-PCR, antigen tests may not diagnose all positive COVID-19 cases; however, antigen testing identified children with live SARS-CoV-2 virus.


title: Pre-vaccination and early B cell signatures predict antibody response to SARS-CoV-2 mRNA vaccine

abstract: SARS-CoV-2 mRNA vaccines are highly effective, although weak antibody responses are seen in some individuals with correlates of immunity that remain poorly understood. Here we longitudinally dissected antibody, plasmablast, and memory B cell (MBC) responses to the two-dose Moderna mRNA vaccine in SARS-CoV-2-uninfected adults. Robust, coordinated IgA and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses, but earlier and more intensely after dose two. Distinct antigen-specific MBC populations also emerged post-vaccination with varying kinetics. We identified antigen non-specific pre-vaccination MBC and post-vaccination plasmablasts after dose one and their spike-specific counterparts early after dose two that correlated with subsequent antibody levels. These baseline and response signatures can thus provide early indicators of serological efficacy and explain response variability in the population.


title: A case-control study of autoimmune AEFIs following COVID-19 vaccination reported to VAERS

abstract: Autoimmune adverse effects following immunisation (AEFIs) are widely regarded as a chief concern driving vaccine hesitancy. This case-control study seeks to shed light on the true risk of autoimmune AEFIs associated with the COVID-19 vaccine through a case-control analysis of VAERS reports. Reports of autoimmune aetiology were matched with reports of non-autoimmune controls. Statistical analysis reveals that the safety profile of COVID-19 vaccines with regard to autoimmune AEFIs is highly favourable. In particular, neuroautoimmune AEFIs have statistically significant reporting odds ratios below unity (Guillain-Barre syndrome: 0.35, multiple sclerosis: 0.70, transverse myelitis: 0.79), indicating a reduced association of reports of these conditions with the COVID-19 vaccine versus other vaccines. Only three autoimmune aetiologies exceed a ROR of 2.0 and thus present a potential signal. Of these, myasthenia gravis (ROR = 3.90, p < 0.001, 95% CI: 2.63-5.80) may be the result of epidemiological confounding factors not sufficiently controlled by matching, as the population most likely to develop myasthenia gravis was strongly prioritised in the COVID-19 vaccines initial rollout. Immune thrombocytopaenia (ROR = 26.83, p < 0.001, 95% CI: 16.93-42.54) is a clear safety signal, confirming a large number of case reports and studies that indicate a risk of immune thrombocytopaenic events following the COVID-19 vaccine. The lone strong safety signal of immune thrombocytopaenia notwithstanding, this study attests to the safety of the COVID-19 vaccine where autoimmune conditions are concerned. Through quantifying the risk of autoimmune disorders associated with COVID-19 vaccination, this study contributes to a growing body of evidence supporting the safety of such vaccines.


title: Model-based Evaluation of Continued COVID-19 Risk at Long Term Care Facilities

abstract:
The COVID-19 pandemic severely impacted long-term care facilities resulting in the death of approximately 8% of residents nationwide. As COVID-19 case rates decline and state and county restrictions are lifted, facility managers, local and state health agencies are challenged with defining their own policies moving forward to appropriately mitigate disease transmission. The continued emergence of variants of concern has highlighted the need for a readily available tool that can be employed at the facility-level to determine best practices for mitigation and ensure resident and staff safety. To assist leadership in determining the impact of various infection surveillance and response strategies, we developed an agent-based model and an online dashboard interface that simulates COVID-19 infection within congregate care settings under various mitigation measures. In this paper, we demonstrate how this dashboard can be used to quantify the continued risk for COVID-19 infections within a facility given a designated testing schedule and vaccine requirements. Our results highlight the critical nature of testing cadence, test sensitivity and specificity, and the impact of removing asymptomatic infected individuals from the workplace. We also show that monthly surveillance testing at long-term care facilities is unlikely to successfully mitigate SARS-CoV-2 outbreaks in congregate care settings.

DisclosuresThis work was supported by Colorado State Universitys Center for Healthy Aging, the Center for Vector-Bourne Infectious Disease, the Office of the Vice President for Research, the College of Health and Human Sciences, the Collage of Natural Sciences, the College of Veterinary Medicine and Biomedical Sciences, and the Walter Scott Jr College of Engineering.


title: A Pilot Study of High-Intensity Interval Training in Older Adults with Treatment Naive Chronic Lymphocytic Leukemia.

abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the USA, affecting predominantly older adults. CLL is characterized by low physical fitness, reduced immunity, and increased risk of secondary malignancies and infections. One approach to improving physical fitness and immune functions is participation in a structured exercise program. The aims of this pilot study were to determine the feasibility and outcomes of 12-weeks of high-intensity interval training (HIIT) combined with muscle endurance-based resistance training on older adults with treatment naive CLL. We enrolled eighteen participants with CLL aged 64.9 (9.1) years and assigned them to groups depending on distance lived from our fitness center. Ten participants (4M/6F) completed HIIT and six participants (4M/2F) completed a non-exercising control group (Controls). HIIT consisted of three 30-minute treadmill sessions/week plus two concurrent 30-minute strength training sessions/week. We confirmed feasibility if >70% of HIIT participants completed >75% of prescribed sessions and prescribed minutes, and if >80% of high-intensity intervals were at a heart rate corresponding to 80% of aerobic capacity [139 (19) bpm]. Other outcomes included aerobic capacity, muscle strength and endurance, and natural killer (NK) cell recognition and killing of tumor cells. Results are presented as Hedges G effect sizes (g), with 0.2, 0.5 and 0.8 representing small, medium and large effects, respectively. Feasibility was achieved, with HIIT completing 5.0 (0.2) sessions/week and 99 (3.6)% of prescribed minutes/week at 142 (19)bpm. Following HIIT, leg strength (g=2.52), chest strength (g=1.15) and seated row strength (g=3.07) were 35.4%, 56.1% and 39.5% higher, respectively, while aerobic capacity was 3.8% lower (g=0.49) than changes for Controls. Similarly, following HIIT, in vitro NK-cell cytolytic activity against the K562 cell line (g=1.43), OSU-CLL cell line (g=0.95), and autologous B-cells (g=1.30) were 20.3%, 3.0% and 14.6% higher, respectively, than changes for Controls. We demonstrate that 12-weeks of HIIT combined with muscle endurance-based resistance training is feasible in older adults with untreated CLL and that HIIT has a large effect on muscle strength and important components of immune function.

category: oncology


title: Genome-wide pleiotropy analysis of coronary artery disease and pneumonia identifies shared immune pathways

abstract: Coronary artery disease (CAD) remains the leading cause of death despite scientific advances. Elucidating shared CAD/pneumonia pathways may reveal novel insights regarding CAD pathways. We performed genome-wide pleiotropy analyses of CAD and pneumonia, examined the causal effects of the expression of genes near independently replicated SNPs and interacting genes with CAD and pneumonia, and tested interactions between disruptive coding mutations of each pleiotropic gene and smoking status on CAD and pneumonia risks. Identified pleiotropic SNPs were annotated to ADAMTS7 and IL6R. Increased ADAMTS7 expression across tissues consistently showed decreased risk for CAD and increased risk for pneumonia; increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. We similarly observed opposing CAD/pneumonia effects for NLRP3. Reduced ADAMTS7 expression conferred a reduced CAD risk without increased pneumonia risk only among never-smokers. Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R, and related genes.


title: Comparing the genetic and environmental architecture of blood count, blood biochemistry and urine biochemistry biological ages with machine learning

abstract: While a large number of biological age predictors have been built from blood samples, a blood count-based biological age predictor is lacking, and the genetic and environmental factors associated with blood-measured accelerated aging remain elusive. In the following, we leveraged 31 blood count biomarkers measured from 489,079 blood samples, 28 blood biochemistry biomarkers measured from 245,147 blood samples, and four urine biochemistry biomarkers measured from 158,381 samples to build three distinct biological age predictors by training machine learning models to predict age. Blood biochemistry significantly outperformed blood count and urine biochemistry in terms of age prediction (RMSE: 5.92+-0.02 vs. 7.60+-0.02 years and 7.72+-0.04 years). We performed genome wide association studies [GWASs], and found accelerated blood biochemistry, blood count and urine biochemistry aging to be respectively 26.2+-0.3%, 18.1+-0.2% and 10.5{+/-}0.5% GWAS-heritable. We identified 1,081 single nucleotide polymorphisms [SNPs] associated with accelerated blood biochemistry aging, 2,636 SNPs associated with accelerated blood cells aging and 24 SNPs associated with accelerated urine biochemistry aging. Similarly, we identified biomarkers, clinical phenotypes, diseases, environmental and socioeconomic factors associated with accelerated blood biochemistry, blood cells and urine biochemistry aging.

category: health informatics


title: Epidemic preparedness - Leishmania tarentolae as an easy-to-handle tool to produce antigens for viral diagnosis: application to COVID-19

abstract: To control future epidemics, discovery platforms are urgently needed, for the rapid development of diagnostic assays. Molecular diagnostic tests for COVID-19 emerged shortly after the isolation of SARS-CoV-2, however, serological tests based on antiviral antibody detection, revealing previous exposure to the virus, required longer developmental phases, due to the need for correctly folded and glycosylated antigens. The delay between the identification of a new virus and the development of reliable serodiagnostic tools limits our readiness for the control of a future epidemic. In this context, we propose the protozoan Leishmania tarentolae as an easy-to-handle micro-factory for the rapid production of viral antigens, to be used at the forefront of emerging epidemics. As a study model, we engineered L. tarentolae to express the SARS-CoV-2 Receptor Binding Domain (RBD) and report the ability of the purified RBD antigen to detect SARS-CoV-2 infection, with a sensitivity and reproducibility comparable to that of a reference antigen produced in human cells. This is the first application of an antigen produced in L. tarentolae for the serodiagnosis of a Coronaviridae infection. Based on our results, we propose L. tarentolae as an effective system for viral antigen production, even in countries that lack high-tech cell factories.

category: infectious diseases


title: Sustaining effective COVID-19 control in Malaysia through large-scale vaccination

abstract:
IntroductionAs of 3rd June 2021, Malaysia is experiencing a resurgence of COVID-19 cases. In response, the federal government has implemented various non-pharmaceutical interventions (NPIs) under a series of Movement Control Orders and, more recently, a vaccination campaign to regain epidemic control. In this study, we assessed the potential for the vaccination campaign to control the epidemic in Malaysia and four high-burden regions of interest, under various public health response scenarios.

MethodsA modified susceptible-exposed-infectious-recovered compartmental model was developed that included two sequential incubation and infectious periods, with stratification by clinical state. The model was further stratified by age and incorporated population mobility to capture NPIs and micro-distancing (behaviour changes not captured through population mobility). Emerging variants of concern (VoC) were included as an additional strain competing with the existing wild-type strain. Several scenarios that included different vaccination strategies (i.e. vaccines that reduce disease severity and/or prevent infection, vaccination coverage) and mobility restrictions were implemented.

ResultsThe national model and the regional models all fit well to notification data but underestimated ICU occupancy and deaths in recent weeks, which may be attributable to increased severity of VoC or saturation of case detection. However, the true case detection proportion showed wide credible intervals, highlighting incomplete understanding of the true epidemic size. The scenario projections suggested that under current vaccination rates complete relaxation of all NPIs would trigger a major epidemic. The results emphasise the importance of micro-distancing, maintaining mobility restrictions during vaccination roll-out and accelerating the pace of vaccination for future control. Malaysia is particularly susceptible to a major COVID-19 resurgence resulting from its limited population immunity due to the countrys historical success in maintaining control throughout much of 2020.


title: Initial SARS-CoV-2 vaccination response can predict booster response for BNT162b2 but not for AZD1222

abstract:
ObjectivesOur objective was to determine whether SARS-CoV-2 antibody levels after the first dose can predict the final antibody response and whether this is dependent on the vaccine type.

Methods69 BNT162b2 (Pfizer/BioNTech) and 55 AZD1222 (AstraZeneca) vaccinees without previous infection or immunosuppressive medication were included. Anti-body levels were quantified 3 weeks after dose 1, in case of AZD1222 directly before boostering (11 weeks after dose 1) and 3 weeks after dose 2, with the Roche SARS-CoV-2 S total antibody assay.

ResultsPre-booster (BNT162b2: 80.6 [25.5-167.0] BAU/mL, AZD1222: 56.4 [36.4-104.8] BAU/mL, not significant) and post-booster levels (BNT162b2: 2,092.0 [1,216.3-4,431.8] BAU/mL, AZD1222: 957.0 [684.5-1,684.8] BAU/mL, p<0.0001) correlated well in BNT162b2 ({rho}=0.53) but not in AZD1222 recipients. Moreover, antibody levels after the first dose of BNT162b2 correlated inversely with age ({rho}=-0.33, P=0.013), whereas a positive correlation with age was observed after the second dose in AZD1222 recipients ({rho}=0.26, P=0.030).

ConclusionsIn conclusion, our data suggest that antibody levels quantified by the Roche Elecsys SARS-CoV-2 S assay before the booster shot could infer post-booster responses to BNT162b2, but not to AZ1222. In addition, we found a vaccine-dependent effect on antibody responses, suggesting a possible link between vaccine response and vector immunity.


title: Development and Content Validation of the Symptoms Evolution of COVID-19: A Patient-Reported Electronic Daily Diary in Clinical and Real-World Studies

abstract:
ImportanceAt the onset of the COVID-19 pandemic, there was limited understanding of symptom experience and disease progression.

ObjectiveWe developed and validated a fit-for-purpose, disease-specific instrument to assess symptoms in patients with COVID-19 to inform endpoints in an interventional trial for non-hospitalized patients.

DesignThe initial drafting of the 23-item Symptoms Evolution of COVID-19 (SE-C19) Instrument was developed based on the Centers for Disease Control and Prevention symptom list and available published literature specific to patients with COVID-19 as of Spring 2020. The measurement principles in the Food and Drug Administration patient-reported outcomes guidance and the four methodological Patient-Focused Drug Development Guidances were also considered.

SettingInterviews were conducted virtually with patients recruited through a healthcare research firm.

ParticipantsSemi-structured qualitative interviews were conducted with a purposive sample of 30 non-hospitalized patients with COVID-19

InterventionInterviews involved two stages: (1) concept elicitation, to obtain information about the symptoms experienced as a result of COVID-19 in patients own words, and (2) cognitive debriefing, for patients to describe their understanding of the SE-C19 instructions, specific symptoms, response options, and recall period to ensure the content of the SE-C19 is relevant and comprehensive. Five clinicians treating COVID-19 outpatients were interviewed to obtain their insights on symptoms experienced by patients and provide input on the SE-C19.

Main Outcome and MeasurePatients reported no issues regarding the relevance or appropriateness of the SE-C19 instructions, including the recall period. The comprehensiveness of the SE-C19 was confirmed against the conceptual model developed in the qualitative research. Minor conceptual gaps were revealed to capture nuances in the experience of nasal and gustatory symptoms, and systemic manifestations of sickness.

Almost all items were endorsed by patients as being appropriate and well understood. The clinicians largely approved all items, response options, and recall period.

Conclusions and RelevanceThe qualitative research provided supportive evidence of the content validity of the SE-C19 instrument to assess the symptoms of outpatients with COVID-19 and its use in clinical trials to evaluate the benefit of treatment. Minor changes may be considered to improve conceptual clarity and ease of responding.

Trial RegistrationR10933-10987-COV-2067 (https://clinicaltrials.gov/ct2/show/NCT04425629)