Des determinants genetiques peuvent influencer la sensibilite et la gravite de la COVID-19.

Contexte: Sous la supervision du Dr. J. Brent Richards, chercheur a l'Institut de recherche medicale Lady Davis de l'Hopital general juif, la plus grande biobanque d'echantillons biologiques et de donnees cliniques a ete coordonnee pour repondre a la mission provinciale de la BQC19. Une collaboration internationale en science ouverte a egalement ete initiee. Cette initiative permet aux chercheurs de pouvoir travailler avec des prelevements humains provenant de personnes atteintes par le virus SRAS-CoV-2 et des temoins non atteints pour tenter d'en elucider les causes et les mecanismes de severite. Entre autres, deux publications recentes sont issues des analyses realisees a partir de cette source de donnees. Methodes: Une etude a utilise des analyses de randomisation mendelienne (RM) a deux echantillons pour fournir de nouvelles informations biologiques sur la physiopathologie de la COVID-19 en balayant rapidement des centaines de proteines en circulation. Une autre etude a ete menee toujours avec la methode RM a deux echantillons afin d'estimer l'effet causal des niveaux du marquer biologique 25-hydroxyvitamin D (25OHD) sur la sensibilite et la gravite de la COVID-19. Resultats: La premiere etude a pu identifier que l'OAS-1 (2'-5'-Oligoadenylate Synthetase 1) est un gene protecteur qui permet de ne pas faire de forme grave de la maladie. La deuxieme etude a permis de montrer plus precisement que la supplementation en vitamine D en tant que mesure de sante publique pour ameliorer les resultats de la COVID-19 n'est pas soutenue, suggerant que l'investissement dans d'autres voies therapeutiques ou preventives devrait etre priorisees. Discussion/Conclusion: Cette BQC19 soutient les efforts visant a decouvrir et a developper de nouveaux biomarqueurs de sensibilite et de progression de la COVID-19, des therapies et des vaccins ainsi que tout effort de recherche en lien avec la prevention, le traitement et la gestion epidemiologique et populationnelle de la maladie. Declaration de liens d'interets: Les auteurs declarent ne pas avoir de liens d'interets.Copyright © 2022

Humoral immune responses to COVID-19 vaccines are reduced in patients with severe asthma

Background: Patients with severe asthma (SA) may be at higher risk of severe COVID-19 (C-19) illness. C-19 vaccines aim to reduce number and severity of infections. Patients with SA are often treated with maintenance oral corticosteroids (mOCS) and/or biologics (mAb)- it is unknown if vaccines will generate the same protective responses in patients with SA on such therapies. Aim(s): To compare magnitude and range of post-vaccination (PV) antibody responses (IgG) in patients with SA on mAb, mOCS or high-dose inhaled corticosteroids (ICS) with healthy controls (HC) without asthma. Method(s): The Virtus finger-prick quantitative C-19 antibody test was used to detect IgG levels 16-24 weeks post second-dose of the C-19 vaccine (123 AstraZeneca, 56 Pfizer, 5 Moderna). IgG>0.2AU was considered positive with range: very high >1.25AU, high 0.751-1.25AU, medium 0.401-0.75AU and low 0.201-0.4AU. SA was defined as per ATS/ERS criteria. Result(s): PV IgG results were obtained from 127 patients with SA (84 mAb, 13 mOCS and 46 ICS) and 57 HC. After adjusting for age, significantly fewer people with SA compared to HC had a positive PV IgG result (81% vs 95% p=0.016). Lower median IgG levels were seen in patients on mOCS (0.40AU) compared to HC (1.24AU) (p=0.051). Patients on mAb had high or very high IgG levels (omalizumab n=25, 0.80AU;mepolizumab n=25, 1.07AU;benralizumab n=34, 1.11AU). Conclusion(s): Overall, a higher proportion of patients with SA had a negative PV IgG level after receiving 2 doses of a C-19 vaccine. This was mainly seen in patients on mOCS while mAb use was associated with high levels of humoral antibody response. These results reinforce the need for booster vaccines in SA, especially in those on mOCS.

Campus travel health services

Travel and students are inextricably linked. The college years are a time when students want to explore the unfamiliar and learn more about the outside world. The benefits of travel are enormous and something any campus would want to encourage. At the same time, however, colleges have a responsibility to protect the health and safety of students as well as the broader community from any negative consequences of travel. It can be quite challenging to develop travel health programs as various models exist and planning requires addressing issues such as staffing levels and training, budget, coordination with various stakeholders, and community resources. Providing appropriate pre- and post-travel care mandates a comprehensive risk analysis and evidenced-based risk mitigation strategies performed by trained travel health staff. © Springer Nature Switzerland AG 2021.

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

Increasing serum iron levels and their role in the risk of infectious diseases: a Mendelian randomization approach.

OBJECTIVES: Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections. METHODS: As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI). RESULTS: Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P <0.05). CONCLUSION: Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them.

Repositioning sport as an innovation within national policy

Governments have historically assessed national well-being using metrics of economic productivity, such as Gross Domestic Product (GDP). Although sport and physical activity can contribute to the economy, it is widely recognized that its role in society is broader than its fiscal contribution. International consultation has identified key areas where sport and physical activity can contribute to the Sustainable Development Goals. This aligns with the Global Action Plan for Physical Activity, which is an initiative from the World Health Organization calling on national governments to work cross-sectorally in the promotion of physical activity at the population level. New Zealand has embraced these developments in international policy and provides an ideal case study in the positioning of sport within a national government agenda. Specifically, New Zealand has led the world in developing a well-being agenda and allocated its national budget accordingly in 2019. To support this approach, the 2020–2032 Sport New Zealand Outcomes Framework was developed to outline how sport and physical activity initiatives can contribute to current and future population well-being. Critically, the Framework is a key strategic platform for integrating sport and physical activity into policy across multiple government departments and has endured through the disruption caused by the COVID-19 pandemic. © 2023 selection and editorial matter, Mitchell McSweeney, Per G. Svensson, Lyndsay M.C. Hayhurst and Parissa Safai;individual chapters, the contributors.

Effects of Process Changes on Emergency Department Crowding in a Changing World: An Interrupted Time-Series Analysis

Objectives: Crowding at the emergency department (ED) is a problem in many countries. Crowding research often fails to consider external influences. In this study, we aimed to evaluate the effects of various process changes on ED crowding while taking into account changing external circumstances, such as the Covid-19 pandemic and centralization of acute care. Method(s): During a six-year period, we assessed the effects of several interventions to improve patient flow, using an interrupted time-series approach. Main outcome measures were crowding measured with the National ED Overcrowding Score, length of stay (LOS) and number of exit blocks. We determined time points of the various interventions and external circumstances and built an interrupted time-series model per outcome measure. We analysed changes in level and trend before and after the selected time points using linear regression, with baseline slope variables included to control for secular trend. Result(s): Crowding decreased when medical staffing increased during peak hours, and when next-day appointments at the ED were shifted to the policlinics. However, the closure of a neighbouring ED and further expansion of beds at the remaining ED coincided with increased crowding. During the Covid-19 surge, LOS increased but we observed no changes in crowding and number of exit blocks. Some of the interventions showed paradoxical effects, such as increased crowding after installing a psychiatric team during peak hours, but decreased LOS and number of exit blocks. Conclusion(s): Our findings reflect the importance of progressive interventions in response to changing external circumstances, in the ongoing battle against ED crowding. Timely feedback on new interventions is vital to increase the success and sustainability of projects, and long-term effects corrected for changing circumstances are pivotal to decide which interventions to prioritize. Our results show that it is possible to improve ED processes, even during changing conditions in challenging times. Copyright © 2022

Design, Delivery, and Evaluation of a Synchronous, Online Qualitative Methods Course: A Collaborative Response to COVID-19

In this chapter, I (Janet) describe how university mandates related to the COVID pandemic required me to teach a qualitative methods #1 class online - a learning platform with which I, an advocate of social constructivist pedagogy, was unfamiliar. The extant literature did not offer much help, but collaboration with my former student and volunteer technical expert, research assistant, Christy, proved highly successful. With Christy as a technical advisor, I was able to follow my usual course curriculum and design and support my students as they learned how to create a priori research questions as a first step to structuring an inquiry;devise simulated inquiries through problem-solving teamwork;engage in all group collaborative projects;and write weekly critiques of published inquiries that employed case studies, phenomenology, arts-based research, narrative, oral history, autoethnography and grounded theory, followed by small group discussions about each method of inquiry. As a final individual assignment, my students devised and presented a simulated inquiry followed by class members asking questions and offering their suggestions for improvement. Scholars note that traditional course evaluation surveys are not adequate for online courses (Roulston et al., 2018). Therefore, Christy and I provide students’ responses to an informal pilot end-of-semester survey we designed to ascertain their perceptions of the class. We based the survey questions on tenets of three constructs identified in the Community of Inquiry (CoI) framework, which presents critical prerequisite factors for student understanding and satisfaction in online learning environments (Garrison, et al., 2000, 2001;Garrison and Vaughn, 2008;also see Ol pak et al., 2016). We close the chapter with an overview of our concerns and accomplishments about the course. © 2022 by Janet C. Richards, Audra Skukauskaitė and Ron Chenail.

Humoral immune responses to COVID-19 vaccines are reduced in patients with severe asthma

BackgroundPatients with severe asthma (SA) may be at higher risk of severe COVID-19 (C-19) illness. C-19 vaccines aim to reduce number and severity of infections. Patients with SA are often treated with maintenance oral corticosteroids (mOCS) and/or biologics- it is unknown if vaccines will generate the same protective responses in patients with SA on such therapies.AimsTo compare magnitude and range of post-vaccination (PV) antibody responses (IgG) in patients with SA on biologics, mOCS or high-dose inhaled corticosteroids (ICS) with healthy controls (HC) without asthma.To review temporal trends in PV IgG in patients with SAMethodsThe Virtus finger-prick quantitative C-19 antibody test was used to detect IgG levels 16–24 weeks post second-dose of the C-19 vaccine (123 AstraZeneca, 56 Pfizer, 5 Moderna). PV IgG levels were also measured in a subset of patients 6 weeks PV. IgG>0.2 AU was considered positive with range: very high >1.25 AU, high 0.751–1.25 AU, medium 0.401–0.75 AU and low 0.201–0.4 AU. SA was defined as per ATS/ERS criteria.ResultsPV IgG results were obtained from 127 patients with SA (84 on biologics, 13 mOCS and 46 ICS) and 57 HC. After adjusting for age, significantly fewer people with SA compared to HC had a positive PV IgG result (81% vs 95% p=0.016). Compared to HC (1.24 AU), lower median IgG levels were seen in patients on high dose ICS (1.02 AU, p=0.033) and mOCS (0.40 AU, p=0.017).Patients on biologics had high or very high IgG levels (omalizumab n=25, 0.80 AU;mepolizumab n=25, 1.07 AU;benralizumab n=34, 1.11 AU).Paired temporal measurements in 37 SA patients showed regression coefficient -0.005 (95%CI -0.006,-0.003) and can be interpreted as IgG decreases, on average, by 0.15 AU per month.ConclusionOverall, a higher proportion of patients with SA had a negative PV IgG level after receiving 2 doses of a C-19 vaccine. This was mainly seen in patients on mOCS while biologic use was not associated with reduced humoral antibody response. These results reinforce the need for booster vaccines in SA, especially in those on mOCS.

Dehydration is associated with production of organic osmolytes and predicts physical long-term symptoms after COVID-19: a multicenter cohort study.

BACKGROUND: We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19. METHODS: The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental. RESULTS: Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern. CONCLUSIONS: Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID. TRIAL REGISTRATION: The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).

Sex-biased expression of the TLR7 gene in severe COVID-19 patients: Insights from transcriptomics and epigenomics.

There is abundant epidemiological data indicating that the incidence of severe cases of coronavirus disease (COVID-19) is significantly higher in males than females worldwide. Moreover, genetic variation at the X-chromosome linked TLR7 gene has been associated with COVID-19 severity. It has been suggested that the sex-biased incidence of COVID-19 might be related to the fact that TLR7 escapes X-chromosome inactivation during early embryogenesis in females, thus encoding a doble dose of its gene product compared to males. We analyzed TLR7 expression in two acute phase cohorts of COVID-19 patients that used two different technological platforms, one of them in a multi-tissue context including saliva, nasal, and blood samples, and a third cohort that included different post-infection timepoints of long-COVID-19 patients. We additionally explored methylation patterns of TLR7 using epigenomic data from an independent cohort of COVID-19 patients stratified by severity and sex. In line with genome-wide association studies, we provide supportive evidence indicating that TLR7 has altered CpG methylation patterns and it is consistently downregulated in males compared to females in the most severe cases of COVID-19.

ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19.

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10-6) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.

Causal associations between body fat accumulation and COVID-19 severity: A Mendelian randomization study

Previous studies reported associations between obesity measured by body mass index (BMI) and coronavirus disease 2019 (COVID-19). However, BMI is calculated only with height and weight and cannot distinguish between body fat mass and fat-free mass. Thus, it is not clear if one or both of these measures are mediating the relationship between obesity and COVID-19. Here, we used Mendelian randomization (MR) to compare the independent causal relationships of body fat mass and fat-free mass with COVID-19 severity. We identified single nucleotide polymorphisms associated with body fat mass and fat-free mass in 454,137 and 454,850 individuals of European ancestry from the UK Biobank, respectively. We then performed two-sample MR to ascertain their effects on severe COVID-19 (cases: 4,792;controls: 1,054,664) from the COVID-19 Host Genetics Initiative. We found that an increase in body fat mass by one standard deviation was associated with severe COVID-19 (odds ratio (OR)body fat mass = 1.61, 95% confidence interval [CI]: 1.28–2.04, P = 5.51 × 10-5;ORbody fat-free mass = 1.31, 95% CI: 0.99–1.74, P = 5.77 × 10-2). Considering that body fat mass and fat-free mass were genetically correlated with each other (r = 0.64), we further evaluated independent causal effects of body fat mass and fat-free mass using multivariable MR and revealed that only body fat mass was independently associated with severe COVID-19 (ORbody fat mass = 2.91, 95% CI: 1.71–4.96, P = 8.85 × 10-5 and ORbody fat-free mass = 1.02, 95%CI: 0.61–1.67, P = 0.945). In summary, this study demonstrates the causal effects of body fat accumulation on COVID-19 severity and indicates that the biological pathways influencing the relationship between COVID-19 and obesity are likely mediated through body fat mass.

Developing the concept of leaveism: From presenteeism/absence to an emergent and expanding domain of employment?

The changing nature of employment has led to increased awareness of leaveism, a practice involving employees using allocated time off when unwell, taking work home, and picking up work when on annual leave. However, there are theoretical, methodological, and policy/practice-related weaknesses, apparent in current understandings. The main article aim is to develop, theoretically, the emergent notion of leaveism, drawing on concepts related to work intensification (WI) and ideal worker norms (IWNs), concepts underpinned by reference to information communication technologies (ICTs), then exploring such ideas via an electronic questionnaire (n = 959), aimed at UK-based employees performing leaveism. The main argument is leaveism is more than a lacuna between presenteeism and sickness absence;it is an unsustainable employer-driven social phenomenon sitting at the intersection of WI, IWNs and ICTs. The findings have policy/practice implications for human resource management (HRM) professionals, trade unions and governments. Recommendations for future research including exploring leaveism in an international context, and in a Covid-19 pandemic-defined era.

Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19.

The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

BackgroundThere is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.MethodsWe combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.ResultsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.ConclusionsThe major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

Despite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain­specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA's predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies.