Centre universitaire de médecine générale et santé publique, Lausanne

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

<ns3:p>This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into ten sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), extensions and additional analyses, data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 24 months.</ns3:p>

BACKGROUND AND AIM: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel. METHODOLOGY: Data references were identified through indexed journals and non-indexed sources. In this work, 13,000 articles were reviewed and 860 were selected based on their relevance. RESULTS: Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (≤ 0.5%) estimates were from northern European countries and the highest (≥ 3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel. CONCLUSION: Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region.

Valuing vaccination Using money as a motivation for the public to get vaccinated is controversial and has had mixed results in studies, few of which have been randomized trials. To test the effect of money as an incentive to obtain a vaccine, Campos-Mercade et al . set up a study in Sweden in 2021, when various age groups were first made eligible to receive the severe acute respiratory coronavirus 2 vaccine (see the Perspective by Jecker). The effect of a small cash reward, around US $24, was compared with the effect of several behavioral nudges. The outcome of this preregistered, randomized clinical trial was that money had the power to increase participation by about 4 percentage points. Nudging and reminding didn’t seem to be deleterious and even had a small positive effect. Of course, the question of whether it is ethical to pay people to be vaccinated like this needs to be addressed. —CA

Oxidative stress reflects a disturbance in the balance between the production and accumulation of reactive oxygen species (ROS). ROS are scavenged by the antioxidant system, but when in excess concentration, they can oxidize proteins, lipids, and DNA. DNA damage is usually repaired, and the oxidized products are excreted in urine. 8-hydroxy-2-deoxyguanosine is considered a biomarker for oxidative damage of DNA. It is needed to define background ranges for 8-OHdG, to use it as a measure of oxidative stress overproduction. We established a standardized protocol for a systematic review and meta-analysis to assess background ranges for urinary 8-OHdG concentrations in healthy populations. We computed geometric mean (GM) and geometric standard deviations (GSD) as the basis for the meta-analysis. We retrieved an initial 1246 articles, included 84 articles, and identified 128 study subgroups. We stratified the subgroups by body mass index, gender, and smoking status reported. The pooled GM value for urinary 8-OHdG concentrations in healthy adults with a mean body mass index (BMI) ≤ 25 measured using chemical methods was 3.9 ng/mg creatinine (interquartile range (IQR): 3 to 5.5 ng/mg creatinine). A significant positive association was observed between smoking and urinary 8-OHdG concentrations when measured by chemical analysis. No gender effect was observed.

INTRODUCTION: Interprofessional collaboration (IPC) is becoming more widespread in primary care due to the increasing complex needs of patients. However, its implementation can be challenging. We aimed to identify barriers and facilitators of IPC in primary care settings. METHODS: An overview of reviews was carried out. Nine databases were searched, and two independent reviewers took part in review selection, data extraction and quality assessment. A thematic synthesis was carried out to highlight the main barriers and facilitators, according to the type of IPC and their level of intervention (system, organizational, inter-individual and individual). RESULTS: Twenty-nine reviews were included, classified according to six types of IPC: IPC in primary care (large scope) (n = 11), primary care physician (PCP)-nurse in primary care (n = 2), PCP-specialty care provider (n = 3), PCP-pharmacist (n = 2), PCP-mental health care provider (n = 6), and intersectoral collaboration (n = 5). Most barriers and facilitators were reported at the organizational and inter-individual levels. Main barriers referred to lack of time and training, lack of clear roles, fears relating to professional identity and poor communication. Principal facilitators included tools to improve communication, co-location and recognition of other professionals' skills and contribution. CONCLUSIONS: The range of barriers and facilitators highlighted in this overview goes beyond specific local contexts and can prove useful for the development of tools or guidelines for successful implementation of IPC in primary care.

Background: European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods: Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings: Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation: At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration: ClinicalTrials.gov Identifier: NCT04271280. Funding: This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.

Qualitative research methods explore and provide deep contextual understanding of real world issues, including people’s beliefs, perspectives, and experiences. Whether through analysis of interviews, focus groups, structured observation, or multimedia data, qualitative methods offer unique insights in applied health services research that other approaches cannot deliver. However, many clinicians and researchers hesitate to use these methods, or might not use them effectively, which can leave relevant areas of inquiry inadequately explored. Thematic analysis is one of the most common and flexible methods to examine qualitative data collected in health services research. This article offers practical thematic analysis as a step-by-step approach to qualitative analysis for health services researchers, with a focus on accessibility for patients, care partners, clinicians, and others new to thematic analysis. Along with detailed instructions covering three steps of reading, coding, and theming, the article includes additional novel and practical guidance on how to draft effective codes, conduct a thematic analysis session, and develop meaningful themes. This approach aims to improve consistency and rigor in thematic analysis, while also making this method more accessible for multidisciplinary research teams.

Objective A consensual definition of occupational burnout is currently lacking. We aimed to harmonize the definition of occupational burnout as a health outcome in medical research and reach a consensus on this definition within the Network on the Coordination and Harmonisation of European Occupational Cohorts (OMEGA-NET). Methods First, we performed a systematic review in MEDLINE, PsycINFO and Embase (January 1990 to August 2018) and a semantic analysis of the available definitions. We used the definitions of burnout and burnout-related concepts from the Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) to formulate a consistent harmonized definition of the concept. Second, we sought to obtain the Delphi consensus on the proposed definition. Results We identified 88 unique definitions of burnout and assigned each of them to 1 of the 11 original definitions. The semantic analysis yielded a first proposal, further reformulated according to SNOMED-CT and the panelists` comments as follows: "In a worker, occupational burnout or occupational physical AND emotional exhaustion state is an exhaustion due to prolonged exposure to work-related problems". A panel of 50 experts (researchers and healthcare professionals with an interest for occupational burnout) reached consensus on this proposal at the second round of the Delphi, with 82% of experts agreeing on it. Conclusion This study resulted in a harmonized definition of occupational burnout approved by experts from 29 countries within OMEGA-NET. Future research should address the reproducibility of the Delphi consensus in a larger panel of experts, representing more countries, and examine the practicability of the definition.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Evidence on what people eat globally is limited in scope and rigour, especially as it relates to children and adolescents. This impairs target setting and investment in evidence-based actions to support healthy sustainable diets. Here we quantified global, regional and national dietary patterns among children and adults, by age group, sex, education and urbanicity, across 185 countries between 1990 and 2018, on the basis of data from the Global Dietary Database project. Our primary measure was the Alternative Healthy Eating Index, a validated score of diet quality; Dietary Approaches to Stop Hypertension and Mediterranean Diet Score patterns were secondarily assessed. Dietary quality is generally modest worldwide. In 2018, the mean global Alternative Healthy Eating Index score was 40.3, ranging from 0 (least healthy) to 100 (most healthy), with regional means ranging from 30.3 in Latin America and the Caribbean to 45.7 in South Asia. Scores among children versus adults were generally similar across regions, except in Central/Eastern Europe and Central Asia, high-income countries, and the Middle East and Northern Africa, where children had lower diet quality. Globally, diet quality scores were higher among women versus men, and more versus less educated individuals. Diet quality increased modestly between 1990 and 2018 globally and in all world regions except in South Asia and Sub-Saharan Africa, where it did not improve.

There remains some uncertainty about the magnitude of the associations between elevated blood pressure (BP) in childhood or adolescence and cardiovascular morbidity and mortality in adulthood. We summarized evidence on the long-term impact of elevated BP in childhood or adolescence on cardiovascular morbidity and mortality in adulthood. PubMed and Embase databases were searched up to August 1, 2019, and retrieved studies were reviewed manually. Our systematic review included all eligible prospective cohort studies on the associations between BP status in childhood or adolescence and intermediate markers or hard outcomes of cardiovascular disease in adults, including high pulse wave velocity, high carotid intima-media thickness, left ventricular hypertrophy, and cardiovascular disease (fatal and nonfatal) and total mortality. A total of 19 articles were finally included, and 12 could be synthesized by meta-analysis. Elevated BP in childhood or adolescence was significantly associated, in adulthood, with high pulse wave velocity (3 articles, N=3725; pooled odds ratio [OR], 1.83 [95% CI, 1.39-2.40]); high carotid intima-media thickness (2 articles, N=4152; OR, 1.60 [95% CI, 1.29-2.00]); and left ventricular hypertrophy (2 articles, N=3019; OR, 1.40 [95% CI, 1.20-1.64]). Additionally, our systematic review also shows evidence of associations of elevated BP in youth with cardiovascular disease and mortality in adulthood. In conclusion, our systematic review and meta-analysis confirms that elevated BP in childhood or adolescence is associated with several intermediate markers and hard outcomes of cardiovascular disease in adulthood. These findings emphasize the importance for children and adolescents to have their BP within normal values.

Abstract In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients ( F ROH ) for &gt;1.4 million individuals, we show that F ROH is significantly associated ( p &lt; 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.

The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.8-14.4 million) incident T2D cases, representing 70.3% (68.8-71.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.0-27.1%)), excess refined rice and wheat intake (24.6% (22.3-27.2%)) and excess processed meat intake (20.3% (18.3-23.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.4-87.7%)) and Latin America and the Caribbean (81.8% (80.1-83.4%)); and lowest proportional burdens were in South Asia (55.4% (52.1-60.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally.

Abstract Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals ( P &lt; 5 × 10 −8 ) from the largest single-stage blood pressure (BP) genome-wide association study to date ( n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P = 2.22 × 10 −126 ) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P = 4.13 × 10 −44 ) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P = 1.98 × 10 −34 ). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

AIMS: Occupational Burnout (OB) is currently measured through several Patient-Reported Outcome Measures (PROMs) and some of them have become widely used in occupational health research and practice. We, therefore, aimed to review and grade the psychometric validity of the five OB PROMs considered as valid for OB measure in mental health professionals (the Maslach Burnout Inventory (MBI), the Pines' Burnout Measure (BM), the Psychologist Burnout Inventory (PBI), the OLdenburg Burnout Inventory (OLBI) and the Copenhagen Burnout Inventory (CBI)). METHODS: We conducted systematic literature searches in MEDLINE, PsycINFO and EMBASE databases. We reviewed studies published between January 1980 and September 2018 following a methodological framework, in which each step of PROM validation, the reference method, analytical technics and result interpretation criteria were assessed. Using the COnsensus-based Standards for the selection of health Measurement Instruments we evaluated the risk of bias in studies assessing content and criterion validity, structural validity, internal consistency, reliability, measurement error, hypotheses testing and responsiveness of each PROM. Finally, we assessed the level of evidence for the validity of each PROM using the GRADE approach. RESULTS: We identified 6541 studies, 19 of which were included for review. Fifteen studies dealt with MBI whereas BM, PBI, OLBI and CBI were each examined in only one study. OLBI had the most complete validation, followed by CBI, MBI, BM and PBI, respectively. When examining the result interpretation correctness, the strongest disagreement was observed for MBI (27% of results), BM (25%) and CBI (17%). There was no disagreement regarding PBI and OLBI. For OLBI and CBI, the quality of evidence for sufficient content validity, the crucial psychometric property, was moderate; for MBI, BM and PBI, it was very low. CONCLUSION: To be validly and reliably used in medical research and practice, PROM should exhibit robust psychometric properties. Among the five PROMs reviewed, CBI and, to a lesser extent, OLBI meet this prerequisite. The cross-cultural validity of these PROMs was beyond the scope of our work and should be addressed in the future. Moreover, the development of a diagnostic standard for OB would be helpful to assess the sensitivity and specificity of the PROMs and further reexamine their validity.The study protocol was registered in PROSPERO (CRD 42019124621).

The COVID-19 pandemic continues to pose a major public health threat,\nespecially in countries with low vaccination rates. To better understand\nthe biological underpinnings of SARS-CoV-2 infection and COVID-19\nseverity, we formed the COVID-19 Host Genetics Initiative1\n. Here we\npresent a genome-wide association study meta-analysis of up to 125,584\ncases and over 2.5 million control individuals across 60 studies from\n25 countries, adding 11 genome-wide significant loci compared with\nthose previously identified2\n. Genes at new loci, including SFTPD, MUC5B\nand ACE2, reveal compelling insights regarding disease susceptibility\nand severity

BACKGROUND: In many countries, lockdown measures were implemented to curb the COVID-19 pandemic. This situation may have an impact on mental health, tobacco smoking and alcohol consumption. The aim of this research report is therefore to describe changes in tobacco and alcohol consumption in the general French population during the first 2 weeks of lockdown and identify any associated factors. METHODS: Self-reported changes in smoking and alcohol consumption following the lockdown implemented in France on 17 March 2020 were collected from 2003 respondents aged 18 years and older in an online cross-sectional survey carried out from 30 March to 1 April 2020. Anxiety and depression levels were assessed using the Hospital Anxiety and Depression Scale. RESULTS: Among current smokers, 26.7% reported an increase in their tobacco consumption since lockdown and 18.6% reported a decrease, while it remained stable for 54.7%. The increase in tobacco consumption was associated with an age of 18-34 years, a high level of education, and anxiety. Among alcohol drinkers, 10.7% reported an increase in their alcohol consumption since lockdown and 24.4% reported a decrease, while it remained stable for 64.8%. The increase in alcohol consumption was associated with an age of 18-49 years, living in cities of more than 100 000 inhabitants, a high socio-professional category, and a depressive mood. CONCLUSIONS: The national lockdown implemented in France during the COVID-19 pandemic influenced tobacco and alcohol consumption in different ways according to sociodemographic group and mental health.

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.

CONTEXT: No universal waist circumference (WC) percentile cutoffs used have been proposed for screening central obesity in children and adolescents. OBJECTIVE: To develop international WC percentile cutoffs for children and adolescents with normal weight based on data from 8 countries in different global regions and to examine the relation with cardiovascular risk. DESIGN AND SETTING: We used pooled data on WC in 113,453 children and adolescents (males 50.2%) aged 4 to 20 years from 8 countries in different regions (Bulgaria, China, Iran, Korea, Malaysia, Poland, Seychelles, and Switzerland). We calculated WC percentile cutoffs in samples including or excluding children with obesity, overweight, or underweight. WC percentiles were generated using the general additive model for location, scale, and shape (GAMLSS). We also estimated the predictive power of the WC 90th percentile cutoffs to predict cardiovascular risk using receiver operator characteristics curve analysis based on data from 3 countries that had available data (China, Iran, and Korea). We also examined which WC percentiles linked with WC cutoffs for central obesity in adults (at age of 18 years). MAIN OUTCOME MEASURE: WC measured based on recommendation by the World Health Organization. RESULTS: We validated the performance of the age- and sex-specific 90th percentile WC cutoffs calculated in children and adolescents (6-18 years of age) with normal weight (excluding youth with obesity, overweight, or underweight) by linking the percentile with cardiovascular risk (area under the curve [AUC]: 0.69 for boys; 0.63 for girls). In addition, WC percentile among normal weight children linked relatively well with established WC cutoffs for central obesity in adults (eg, AUC in US adolescents: 0.71 for boys; 0.68 for girls). CONCLUSION: The international WC cutoffs developed in this study could be useful to screen central obesity in children and adolescents aged 6 to 18 years and allow direct comparison of WC distributions between populations and over time.