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Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis.Significance:Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms.See related commentary by Itzstein et al., p. 3441.

Supplementary Methods, Figures and Tables.

Introduction/Objective. Epidemiological research shows that we have a dramatic increase in the number of people with hip fractures, especially those over 65 years of age. The objectives of this study are to assess the association between preoperative comorbidity and the risk of postoperative complications and mortality and postoperative worsening of comorbid conditions and their relationship to mortality within one year of hip fracture surgery. Methods. In this retrospective study, from January 2018 until January 2020, 64 patients with hip fractures were operated on at the Department of Orthopedic Surgery in Kosovska Mitrovica. We monitored the number of comorbidities and their significance on the preoperative risk and the course of concomitant diseases in the postoperative period and one-year mortality after surgery, in patients with hip fractures. Results. We collected data on patients from the moment of admission to discharge from the hospital accompanied by medical histories, and after discharge after follow-up examinations, six months and one year from discharge. Of the total number of subjects, 23 (35.9%) had one or two comorbidities, most often of cardiac and neurological nature, in 25 patients (39.1%) we had three concomitant diseases, and in 11 (17.2%) four and more comorbidities. The mean age of the patients was 72.51 years (69?92 years). Conclusion. Approximately 45?60% of men and women who suffer a hip fracture have three or more comorbid states. In older people with hip fractures, the presence of three or more comorbidities is the strongest preoperative risk factor.

Objective and Background: The watershed (WS) infarcts development mechanism still remains very controversial, although mainly a hemodynamic cause is usually presumed. Herein we report a very rare case of complex combined and concomitant cortical and internal watershed infarctions and discuss its patomechanism and clinic-radiological correlation. Clinical case presentation: A 45-year-old female subject was sent from an urgency ambulance to Urgent Medicine, Neuroradiology Department suspected with clinical signs of left-sided weakness, both left-sided hand and leg weakness, with difficult walking and communication, that occurred approximately few days before hospital administration. Neurological findings: conscious, communicative, left central facialis, deviation of the head to the right, partial deviation of the bulbus to the right, left hemiparesis of a severe degree on the left, hemineglect on the left; blood pressure 157/85 mmHg; glucose 28 mmol/l; treated for type 2 diabetes mellitus (insulin dependent) and Haschimoto thyreoiditis for several years. His endocranial magnetic resonance imaging (MRI) including diffusion weighted MRI imaging showed multi-infarct changes in the right parieto-occipital, right frontal and parietal, right capsulothalamic and in the corpus callosum (splenium and genu) as part of the so-called watershed cerebral infarcts (borderzone infarcts) with development of cortical (external) and deep (internal) border zone infarctions. Results and Conclusions: Hemodynamic instability due to chronic arterial hypertension and concomitant uncontrolled type 2 diabetes mellitus could lead to WS infarctions. The WS infarcts development mechanism is multifactorial (very often synergistic), and distinguishing WS infarcts (cortical and internal types) from other stroke types is extremely important, because different pathogenic mechanisms require different therapeutic options and treatment strategies and MRI plays a pivotal role therein.

Objective To investigate the relations between caffeine-derived metabolites (methylxanthines) and plasma lipids by use of population-based data from 2 European countries. Methods Families were randomly selected from the general population of northern Belgium (FLEMENGHO), from August 12, 1985, until November 22, 1990, and 3 Swiss cities (SKIPOGH), from November 25, 2009, through April 4, 2013. We measured plasma concentrations (FLEMENGHO, SKIPOGH) and 24-hour urinary excretions (SKIPOGH) of 4 methylxanthines—caffeine, paraxanthine, theobromine, and theophylline—using ultra-high-performance liquid chromatography–tandem mass spectrometry. We used enzymatic methods to estimate total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels and the Friedewald equation for low-density lipoprotein cholesterol levels in plasma. We applied sex-specific mixed models to investigate associations between methylxanthines and plasma lipids, adjusting for major confounders. Results In both FLEMENGHO (N=1987; 1055 [53%] female participants) and SKIPOGH (N=990; 523 [53%] female participants), total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels increased across quartiles of plasma caffeine, paraxanthine, and theophylline (total cholesterol levels by caffeine quartiles in FLEMENGHO, male participants: 5.01±0.06 mmol/L, 5.05±0.06 mmol/L, 5.27±0.06 mmol/L, 5.62±0.06 mmol/L; female participants: 5.24±0.06 mmol/L, 5.15±0.05 mmol/L, 5.25±0.05 mmol/L, 5.42±0.05 mmol/L). Similar results were observed using urinary methylxanthines in SKIPOGH (total cholesterol levels by caffeine quartiles, male participants: 4.54±0.08 mmol/L, 4.94±0.08 mmol/L, 4.87±0.08 mmol/L, 5.27±0.09 mmol/L; female participants: 5.12±0.07 mmol/L, 5.21±0.07 mmol/L, 5.28±0.05 mmol/L, 5.28±0.07 mmol/L). Furthermore, urinary caffeine and theophylline were positively associated with high-density lipoprotein cholesterol in SKIPOGH male participants. Conclusion Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids, whereas the associations involving theobromine were less clear. We postulate that the positive association between caffeine intake and plasma lipids may be related to the sympathomimetic function of methylxanthines, mitigating the overall health-beneficial effect of caffeine intake.

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes.

Background Smoking and alcohol consumption may compromise health by way of epigenetic modifications. Epigenetic signatures of alcohol and tobacco consumption could provide insights into the reversibility of phenotypic changes incurred with differing levels of lifestyle exposures. This study describes and validates two novel epigenetic signatures of tobacco (EpiTob) and alcohol (EpiAlc) consumption and investigates their association with disease outcomes. Methods The epigenetic signatures, EpiTob and EpiAlc, were developed using data from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) (N = 689). Epigenetic and phenotypic data available from the 1921 (N = 550) and 1936 (N = 1091) Lothian Birth Cohort (LBC) studies, and two publicly available datasets on GEO Accession (GSE50660, N = 464; and GSE110043, N = 94) were used to validate the signatures. A multivariable logistic regression model, adjusting for age and sex, was used to assess the association between self-reported tobacco or alcohol consumption and the respective epigenetic signature, as well as to estimate the association between CVD and epigenetic signatures. A Cox proportional hazard model was used to estimate the risk of mortality in association with the EpiTob and EpiAlc signatures. Results The EpiTob signature was positively associated with self-reported tobacco consumption for current or never smokers with explained variance ranging from 0.49 (LBC1921) to 0.72 (LBC1936) (pseudo-R2). In the SKIPOGH, LBC1921 and LBC1936 cohorts, the epigenetic signature for alcohol consumption explained limited variance in association with self-reported alcohol status [i.e., non-drinker, moderate drinker, and heavy drinker] (pseudo-R2 = 0.05, 0.03 and 0.03, respectively), although this improved considerably when measuring self-reported alcohol consumption with standardized units consumed per week (SKIPOGH R2 = 0.21; LBC1921 R2 = 0.31; LBC1936 R2 = 0.41). Both signatures were associated with history of CVD in SKIPOGH and LBC1936, but not in LBC1921. The EpiTob signature was associated with increased risk of all-cause and lung-cancer specific mortality in the 1936 and 1921 LBC cohorts. Conclusions This study found the EpiTob and EpiAlc signatures to be well-correlated with self-reported exposure status and associated with long-term health outcomes. Epigenetic signatures of lifestyle exposures may reduce measurement issues and biases and could aid in risk stratification for informing early-stage targeted interventions.

Understanding the risk of infection from household- and community-exposures and the transmissibility of asymptomatic infections is critical to SARS-CoV-2 control. Limited previous evidence is based primarily on virologic testing, which disproportionately misses mild and asymptomatic infections. Serologic measures are more likely to capture all previously infected individuals. We apply household transmission models to data from a cross-sectional, household-based population serosurvey of 4,534 people ≥5 years from 2,267 households enrolled April-June 2020 in Geneva, Switzerland. We found that the risk of infection from exposure to a single infected household member aged ≥5 years (17.3%,13.7-21.7) was more than three-times that of extra-household exposures over the first pandemic wave (5.1%,4.5-5.8). Young children had a lower risk of infection from household members. Working-age adults had the highest extra-household infection risk. Seropositive asymptomatic household members had 69.4% lower odds (95%CrI,31.8-88.8%) of infecting another household member compared to those reporting symptoms, accounting for 14.5% (95%CrI, 7.2-22.7%) of all household infections., Household-based studies can provide insights into SARS-CoV-2 transmission. Here, the authors fit transmission models to serological data from Geneva, Switzerland, and estimate that the risk of infection from single household exposure (17.3%) was higher than for extra-household exposure (5.1%).

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting.We used data from a population-based study conducted in Switzerland (SKIPOGH) to assess the association between childhood, adulthood, and life-course socioeconomic indicators, and blood-derived markers of epigenetic aging (Levine’s, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA) and the mortality risk score (MS)). We used mixed regression to explore the associations between socioeconomic indicators and markers of epigenetic aging independently, and counterfactual mediation to investigate the mechanisms underlying the life-course socioeconomic gradient in epigenetic aging.Individuals reporting a low father’s occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.0-1.5 years for Levine’s epigenetic age when compared to chronological age, 1.1-1.5 additional years for GrimAge, 5%-8% higher DunedinPoAm38 EAA, and 2%-5% higher MS score. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA.Our study provides novel empirical evidence for a “sensitive-period” life-course model, whereby adverse socioeconomic circumstances in childhood and adulthood negatively affected epigenetic aging. Counterfactual mediation analyses further showed that the effect of socioeconomic factors in adulthood operated through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear.

Objective Early life adversity has been associated with increased risk of inflammation and inflammation-related diseases in adulthood. This study aimed to examine the association of childhood socioeconomic conditions with chronic low-grade inflammation over adolescence. Methods We used information on 2942 members (1507 girls and 1435 boys) of the EPITeen (Epidemiological Health Investigation of Teenagers in Porto) cohort that was established in 2003 in Porto, Portugal, and included 13-year-old adolescents were further evaluated at 17 and 21 years. Mother’ and father’s education and occupation were used as indicators of childhood socioeconomic conditions. High-sensitivity C reactive protein (hs-CRP) was measured at three points in time (13, 17 and 21 years). hs-CRP levels were categorised in tertiles separately for each wave; chronic low-grade inflammation in adolescence was defined as having hs-CRP levels in the highest tertile in at least two waves and never in the lowest tertile. Results Prevalence of chronic low-grade inflammation during adolescence was significantly higher among participants with low parental socioeconomic position. Low parental socioeconomic position was associated with chronic low-grade inflammation in adolescence, after adjustment for sex, perinatal and physical environment factors, health-related behaviours and health status in adolescence OR=1.6; 95% CI: 1.1 to 2.4 for lowest versus highest mother’s education and OR=1.6; 95% CI: 1.1 to 2.3 for lowest versus highest father’s occupation. Conclusion Low childhood socioeconomic conditions are associated with chronic low-grade inflammation during adolescence. Our results suggest that the early life socioeconomic environment has an impact on inflammatory processes over adolescence. The study was supported by FEDER through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology – FCT under the project 'BioAdversity: How childhood social adversity shapes health: The biology of social adversity' (Ref. FCT PTDC/DTP-EPI/1687/2014; POCI-01-0145-FEDER- 016838), and under the project 'When do health inequalities start? Understanding the impact of childhood social adversity on health trajectories from birth to early adolescence' (Ref. FCT PTDC/SAU-PUB/29567/2017; POCI-01-0145-FEDER-029567). Support was obtained from the Epidemiology Research Unit (Ref. UID/DTP/04750/2019; POCI-01-0145-FEDER-006862) and the FCT Investigator contract CEECIND/01516/2017/CP1406/FCT0001 (to SF), co-funded by the FCT and the Human Capital Operational Programme and European Social Fund - HCOP/ESF Programme. We also received support from the LIFEPATH project funded by the European Commission (Horizon 2020 grant n° 633666) and from the University of Lausanne (Pro-Femmes grant – to SiS).

Résumé. L’étude CoLaus nous a permis d’identifier de larges inégalités sociales en matière de santé au sein de la population de la ville de Lausanne. En effet, les participants avec un statut socio-économique faible avaient une prévalence plus élevée de facteurs de risque cardio-métaboliques, de comportements à risque, de troubles du sommeil, ainsi que des marqueurs inflammatoires plus élevées par rapport aux participants les plus favorisés du point de vue socio-économique. Dans la plupart des cas, ces inégalités sont similaires à celles retrouvées dans les cantons et pays voisins.

Background Nasopharyngeal antigen Rapid Diagnostic Tests (RDTs), saliva RT-PCR and nasopharyngeal (NP) RT-PCR have shown different performance characteristics to detect patients infected by SARS-CoV-2, according to the viral load (VL)—and thus transmissibility. Methods In October 2020, we conducted a prospective trial involving patients presenting at testing centres with symptoms of COVID-19. We compared detection rates and performance of RDT, saliva PCR and nasopharyngeal (NP) PCR, according to VL and symptoms duration. Results Out of 949 patients enrolled, 928 patients had all three tests performed. Detection rates were 35.2% (95%CI 32.2–38.4%) by RDT, 39.8% (36.6–43.0%) by saliva PCR, 40.1% (36.9–43.3%) by NP PCR, and 41.5% (38.3–44.7%) by any test. For those with viral loads (VL) ≥106 copies/ml, detection rates were 30.3% (27.3–33.3), 31.4% (28.4–34.5), 31.5% (28.5–34.6), and 31.6% (28.6–34.7%) respectively. Sensitivity of RDT compared to NP PCR was 87.4% (83.6–90.6%) for all positive patients, 94.5% (91.5–96.7%) for those with VL≥105 and 96.5% (93.6–98.3%) for those with VL≥106. Sensitivity of STANDARD-Q®, Panbio™ and COVID-VIRO® Ag tests were 92.9% (86.4–96.9%), 86.1% (78.6–91.7%) and 84.1% (76.9–89.7%), respectively. For those with VL≥106, sensitivity was 96.6% (90.5–99.3%), 97.8% (92.1–99.7%) and 95.3% (89.4–98.5%) respectively. No patient with VL4 was detected by RDT. Specificity of RDT was 100% (99.3–100%) compared to any PCR. RDT sensitivity was similar Conclusions RDT results allow rapid identification of COVID cases with immediate isolation of most contagious individuals. RDT can thus be a game changer both in ambulatory care and community testing aimed at stopping transmission chains, and even more so in resource-constrained settings thanks to its very low price. When PCR is performed, saliva could replace NP swabbing. Trial registration ClinicalTrial.gov Identifier: NCT04613310 (03/11/2020).

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting. We included 684 participants (52 % women, mean age 52.6 ± 15.5 years) from a population and family-based Swiss study. We used nine life-course socioeconomic indicators as the main exposure variables, and four blood-derived, second generation markers of epigenetic aging as the outcome variables (Levine's DNAmPhenoAge, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA), and the mortality risk score (MS)). First, we investigated the associations between socioeconomic indicators and markers of epigenetic aging via mixed-effect linear regression models, adjusting for age, sex, participant's recruitment center, familial structure (random-effect covariate), seasonality of blood sampling, and technical covariates. Second, we implemented counterfactual mediation analysis to investigate life-course and intermediate mechanisms underlying the socioeconomic gradient in epigenetic aging. Effect-size estimates were assessed using regression coefficients and counterfactual mediation parameters, along with their respective 95 % confidence intervals. Individuals reporting a low father's occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older and had a higher mortality risk score than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.1-1.5 years for Levine's epigenetic age (β and 95 %CI range, β (minimum and maximum): 1.1-1.5 95 %CI[0.0-0.2; 2.3-3.0]), 1.1-1.5 additional years for GrimAge (β: 1.1-1.5 95 %CI[0.2-0.6; 1.9-3.0]), a 1-3 % higher DunedinPoAm38 age acceleration (β: 0.01-0.03 95 %CI[0.00; 0.03-0.04]), and a 10-50 % higher MS score (β: 0.1-0.4 95 %CI[0.0-0.2; 0.3-0.4]) for the aforementioned socioeconomic indicators. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA (31-89 % mediated proportion). This study provides emerging evidence for an association between disadvantaged life-course socioeconomic circumstances and detrimental epigenetic aging patterns, supporting the "sensitive-period" life-course model. Counterfactual mediation analyses further indicated that the effect of socioeconomic factors in adulthood operates through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear.

Publisher Copyright: Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. BACKGROUND: Few studies have examined the interactions between individual socioeconomic position and neighbourhood deprivation and the findings so far are heterogeneous. Using a large sample of diverse cohorts, we investigated the interaction effect of neighbourhood socioeconomic deprivation and individual socioeconomic position, assessed using education, on mortality. METHODS: We did a longitudinal multicohort analysis that included six cohort studies participating in the European LIFEPATH consortium: the CoLaus (Lausanne, Switzerland), E3N (France), EPIC-Turin (Turin, Italy), EPIPorto (Porto, Portugal), Melbourne Collaborative Cohort Study (Melbourne, VIC, Australia), and Whitehall II (London, UK) cohorts. All participants with data on mortality, educational attainment, and neighbourhood deprivation were included in the present study. The data sources were the databases of each cohort study. Poisson regression was used to estimate the mortality rates and associations (relative risk, 95% CIs) with neighbourhood deprivation (Q1 being least deprived to Q5 being the most deprived). Baseline educational attainment was used as an indicator of individual socioeconomic position. Estimates were combined using pooled analysis and the relative excess risk due to the interaction was computed to identify additive interactions. FINDINGS: The cohorts comprised a total population of 168 801 individuals. The recruitment dates were 2003-06 for CoLaus, 1989-91 for E3N, 1992-98 for EPIC-Turin, 1999-2003 for EPIPorto, 1990-94 for MCCS, and 1991-94 for Whitehall II. We use baseline data only and mortality data obtained using record linkage. Age-adjusted mortality rates were higher among participants residing in more deprived neighbourhoods than those in the least deprived neighbourhoods (Q1 least deprived neighbourhoods, 369·7 per 100 000 person-years [95% CI 356·4-383·2] vs Q5-most deprived neighbourhoods 445·7 per 100 000 person-years [430·2-461·7]), but the magnitude of the association varied according to educational attainment (relative excess risk due to interaction=0·18, 95% CI 0·08-0·28). The relative risk for Q5 versus Q1 was 1·31 (1·23-1·40) among individuals with primary education or less, but less pronounced among those with secondary education (1·12; 1·04-1·21) and tertiary education (1·16; 1·07-1·27). Associations remained after adjustment for individual-level factors, such as smoking, physical activity, and alcohol intake, among others. INTERPRETATION: Our study suggests that the detrimental health effect of living in disadvantaged neighbourhoods is more pronounced among individuals with low education attainment, amplifying social inequalities in health. This finding is relevant to policies aimed at reducing health inequalities, suggesting that these issues should be addressed at both the individual level and the community level. FUNDING: The European Commission, European Regional Development Fund, the Portugese Foundation for Science and Technology.

BackgroundPopulation-based serological surveys provide a means for assessing the immunologic landscape of a community, without the biases related to health-seeking behaviors and testing practices typically associated with rt-PCR testing. This study assesses SARS-CoV-2 seroprevalence over the first epidemic wave in Canton Geneva, Switzerland, as well as biological and socio-economic risk factors for infection and symptoms associated with IgG seropositivity.Methods and findingsBetween April 6 and June 30, 2020, former participants of a yearly representative cross-sectional survey of the 20-75-year-old population of the canton of Geneva were invited to participate in a seroprevalence study, along with household members five years and older. We collected blood and tested it for anti-SARS-CoV-2 immunoglobulins G (IgG). Questionnaires were self-administered. We estimated seroprevalence with a Bayesian model accounting for test performance and sampling design. We included 8344 participants (53.5% women, mean age 46.9 years). The population-level seroprevalence over the 12-week study period was 7.8 % (95% Credible Interval (CrI) 6.8-8.9), accounting for sex, age and household random effects. Seroprevalence was highest among 18-49 year olds (9.5%, 95%CrI 8.1-10.9), with young children (5-9 years) and those >65 years having significantly lower seroprevalence (4.3% and 4.7-5.4% respectively). Men were more likely to be seropositive than women (relative risk 1.2, 95%CrI 1.1-1.4). Odds of seropositivity were reduced for female retirees (0.46, 95%CI 0.23-0.93) and unemployed men (0.35, 95%CI 0.13-1.0) compared to employed individuals, and for current smokers (0.36, 95%CI 0.23-0.55) compared to never-smokers. We found no significant association between occupation, level of education, neighborhood income and the risk of being seropositive. Symptoms most strongly associated with seropositivity were anosmia/dysgeusia, loss of appetite, fever, fatigue and myalgia and/or arthralgia. Thirteen percent of seropositive participants reported no symptoms.ConclusionsOur results confirm a low population seroprevalence of anti-SARS-CoV-2 antibodies after the first wave in Geneva, a region hard hit by the COVID-19 pandemic. Socioeconomic factors were not associated with seropositivity in this sample. The elderly and young children were less frequently seropositive, though it is not clear how biology and behaviors shape these differences. These specificities should be considered when assessing the need for targeted public health measures.

Context Urinary cadmium (Cd) excretion is associated with cancer and cardiovascular morbidity. A potential mechanism could be disturbance of steroidogenesis in gonads and adrenal glands. Objective We tested whether urinary excretion of Cd is correlated with that of cortico- and sex steroid metabolites in the general adult population. Setting The Swiss Kidney Project on Genes in Hypertension is a multicentric, family-based population study. Measures Urinary excretions of steroid hormone metabolites and Cd were measured with separate day and night collections. Associations were analyzed by mixed linear models. Results Urinary Cd and testosterone excretions in men were significantly correlated (respective day and night β values [standard error (SE)], 1.378 [0.242], P < 0.0005; and 1.440 [0.333], P < 0.0005), but not in women [0.333(0.257), P = 0.2; and 0.674 (0.361), P = 0.06]. Urinary Cd and cortisol excretions were positively associated in both sexes [day: β = 0.475 (SE, 0.157), P = 0.0025, and 0.877 (SE, 0.194), P < 0.0005, respectively; night: β = 0.875 (SE, 0.253), P < 0.0005 and 1.183 (SE, 0.277), P = 0.00002, respectively]. Cd excretion was correlated with mineralocorticoid metabolites excretion, except tetrahydroaldosterone, in both sexes (P < 0.01). There was an independent effect of Cd on sex hormone and corticosteroid synthesis and an interdependent effect on gluco- and mineralcorticoid production. Conclusion Our findings provide evidence for a global stimulating effect on steroid synthesis already at low-dose Cd exposure. These findings might explain the association of Cd with diseases such as steroid-sensitive cancers or metabolic disorders.

Forgoing healthcare for economic reasons has been previously associated with adverse health outcomes, including a higher risk of hospitalization, a lower quality of life, and worse self-reported health. However, the exact cause-to-effect relation between forgoing healthcare and health-related outcomes has been insufficiently described. Here, we investigate the prospective health consequences of forgoing healthcare for economic reasons using data from “ReBus” (N = 400), a prospective study examining the health consequences of forgoing healthcare (Baseline: 2008–2013, Follow-up: 2014–2016). Using regression models, we explored the baseline determinants of forgoing healthcare, including socioeconomic, demographic, and pre-existing health-risk factors, and examined the associations between forgoing healthcare at baseline and health deterioration at follow-up, using highly pertinent biomarkers (glucose, glycated hemoglobin, lipids, blood pressure) and SF-36 questionnaire data. Low income, low occupation, low education, and smoking were associated with higher odds of forgoing healthcare at baseline. Forgoing healthcare for economic reasons at baseline was subsequently related to detrimental changes in glucose, high-density lipoprotein cholesterol (HDL), and blood pressure (BP) at follow-up, independently of baseline socioeconomic factors (Glucose-β = 0.19, 95%CI[0.03;0.34], HDL-β = -0.07, 95%CI[-0.14;0.01], BP-β = 3.30, 95%CI[-0.01;6.60]). Moreover, we found strong associations between forgoing healthcare and adverse SF-36 health scores at follow-up, with individuals forgoing healthcare systematically displaying worse health scores (6%–11% lower scores). For the first time, we show that forgoing healthcare for economic reasons predicts adverse health-related consequences 2–8 years later. Our findings shall further encourage the implementation of public health measures aimed at identifying individuals who forgo healthcare and preventing the adverse health consequences of unmet medical needs.

Introduction. Anomalies of the middle cerebral artery (MCA) are very rare. ?Rete MCA,? ?twig-like MCA? (T-MCA), ?aplastic MCA,? ?unfused MCA,? and others are all synonyms for unilateral embryological anomaly of the M1 segment of the MCA, where, due to an unknown cause, fusion of primordial arteries of the M1 segment did not happen. As a result, the M1 segment of the affected side consists of a mesh of small arteries from which arise normal perforators and cortical branches. Moyamoya disease, moyamoya-like syndrome, atherosclerotic steno-occlusive disease, vasculitis, and dissection of the MCA should be considered in differential diagnosis. Case outline. We present a 60-year-old female patient with twig-like left MCA, incidentally diagnosed due to persistent headaches six days prior to admission. Non-contrast computed tomography head examination was without peculiarities. Computed tomography angiography showed a network of small vessels in place of the left M1 segment, bridging internal carotid artery terminus with branches of the MCA bifurcation and giving rise to lenticulostriate arteries. Fourteen months later, on physical examination, the patient was in good general condition, without a neurological deficit, with occasional episodes of headache no stronger than 3?4/10 on the visual analogue scale. Conclusion. We report a patient with extremely rare variation of the M1 segment of the left MCA, incidentally diagnosed due to headaches.

This cross-sectional study examines the association between insurance plan deductibles and forgoing of health care, with consideration of socioeconomic factors, in a consumer-driven health care system with universal coverage in Switzerland., Key Points Question Are health insurance deductibles associated with forgoing of health care in a consumer-driven health care system with universal coverage? Findings In this cross-sectional study of 11 872 participants in Geneva, Switzerland, between 2007 and 2019, confounder-adjusted analysis revealed that those with higher-deductible plans were significantly more likely to forgo health care than those with low-deductible plans independent of socioeconomic status, known comorbidities, and cardiovascular risk factors. Meaning The findings suggest that despite a fixed range of health insurance deductibles established by the government, deductibles may be associated with forgoing of health care in a high-performing universal health care system., Importance Characteristics of a health care system can facilitate forgoing of health care owing to economic reasons and can influence population health. Whether health insurance deductibles are associated with forgoing of health care in a consumer-driven health care system with universal coverage, such as the Swiss health system, remains to be determined. Objective To assess the association between insurance plan deductibles and forgoing of health care with consideration of socioeconomic factors. Design, Setting, and Participants This cross-sectional study was conducted in Geneva, Switzerland, using data collected from January 1, 2007, to December 31, 2019. Population-based samples were obtained yearly through random stratified sampling by age and sex of the general population aged 20 to 74 years. Participants were invited to an appointment at 1 of the 3 study sites in Geneva, where they completed a sociodemographic and health questionnaire. Exposures Insurance plan deductible level. Main Outcomes and Measures The main outcome was forgoing of health care owing to economic reasons. Unadjusted and multivariable Poisson models were used to assess the association between deductible level and forgoing of health care. Differences in forgoing health care across the range of health insurance deductibles or household income levels were quantified using the relative index of inequality (RII). Results The study group included 11 872 participants (5974 [50.3%] male; median age, 48.1 years [interquartile range, 38.7-59.1 years]); 1146 (9.7%) reported forgoing health care. Participants with high-deductible plans reported forgoing health care more frequently than those with low-deductible plans (331 [13.5%] vs 591 [8.7%]). In adjusted analysis, higher-deductible plans were associated with a greater likelihood of forgoing health care (RII, 2.2; 95% CI, 1.7-3.0; P

Aims: Sleep disturbances exhibit a strong social patterning, and inadequate sleep has been associated with adverse health outcomes, including cardiovascular disorders (CVD). However, the contribution of sleep to socioeconomic inequalities in CVD is unclear. This study pools data from eight European cohorts to investigate the role of sleep duration in the association between life-course socioeconomic status (SES) and CVD. Methods and results: We used cross-sectional data from eight European cohorts, totalling 111 205 participants. Life-course SES was assessed using father’s and adult occupational position. Self-reported sleep duration was categorized into recommended (6–8.5 h/night), long (>8.5 h/night), and short (

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis. Significance: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms. See related commentary by Itzstein et al., p. 3441.

Background: Socioeconomic position as measured by education may be embodied and affect the functioning of key physiological systems. Links between social disadvantage, its biological imprint, and cause-specific mortality and morbidity have not been investigated in large populations, and yet may point towards areas for public health interventions beyond targeting individual behaviours. Methods: Using data from 366,748 UK Biobank participants with 13 biomarker measurements, we calculated a Biological Health Score (BHS, ranging from 0 to 1) capturing the level of functioning of five physiological systems. Associations between BHS and incidence of cardiovascular disease (CVD) and cancer, and mortality from all, CVD, cancer, and external causes were examined. We explored the role of education in these associations. Mendelian randomisation using genetic evidence was used to triangulate these findings. Findings: An increase in BHS of 0.1 was associated with all-cause (HR = 1.14 [1.12–1.16] and 1.09 [1.07–1.12] in men and women respectively), cancer (HR = 1.11 [1.09–1.14] and 1.07 [1.04–1.10]) and CVD (HR = 1.25 [1.20–1.31] and 1.21 [1.11–1.31]) mortality, CVD incidence (HR = 1.15 [1.13–1.16] and 1.17 [1.15–1.19]). These associations survived adjustment for education, lifestyle-behaviours, body mass index (BMI), co-morbidities and medical treatments. Mendelian randomisation further supported the link between the BHS and CVD incidence (HR = 1.31 [1.21–1.42]). The BHS contributed to CVD incidence prediction (age-adjusted C-statistic = 0.58), other than through education and health behaviours. Interpretation: The BHS captures features of the embodiment of education, health behaviours, and more proximal unknown factors which all complementarily contribute to all-cause, cancer and CVD morbidity and premature death. © 2020 The Author(s)

BackgroundKnowing the transmissibility of asymptomatic infections and risk of infection from household- and community-exposures is critical to SARS-CoV-2 control. Limited previous evidence is based primarily on virologic testing, which disproportionately misses mild and asymptomatic infections. Serologic measures are more likely to capture all previously infected individuals.ObjectiveEstimate the risk of SARS-CoV-2 infection from household and community exposures, and identify key risk factors for transmission and infection.DesignCross-sectional household serosurvey and transmission model.SettingGeneva, SwitzerlandParticipants4,524 household members ≥5 years from 2,267 households enrolled April-June 2020.MeasurementsPast SARS-CoV-2 infection confirmed through IgG ELISA. Chain-binomial models based on the number of infections within households used to estimate the cumulative extra-household infection risk and infection risk from exposure to an infected household member by demographics and infector’s symptoms.ResultsThe chance of being infected by a SARS-CoV-2 infected household member was 17.3% (95%CrI,13.7-21.7%) compared to a cumulative extra-household infection risk of 5.1% (95%CrI,4.5-5.8%). Infection risk from an infected household member increased with age, with 5-9 year olds having 0.4 times (95%CrI, 0.07-1.4) the odds of infection, and ≥65 years olds having 2.7 (95%CrI,0.88-7.4) times the odds of infection of 20-49 year olds. Working-age adults had the highest extra-household infection risk. Seropositive asymptomatic household members had 69.6% lower odds (95%CrI,33.7-88.1%) of infecting another household member compared to those reporting symptoms, accounting for 14.7% (95%CrI,6.3-23.2%) of all household infections.LimitationsSelf-reported symptoms, small number of seropositive kids and imperfect serologic tests.ConclusionThe risk of infection from exposure to a single infected household member was more than three-times that of extra-household exposures over the first pandemic wave. Young children had a lower risk of infection from household members. Asymptomatic infections are far less likely to transmit than symptomatic ones but do cause infections.Funding SourceSwiss Federal Office of Public Health, Swiss School of Public Health (Corona Immunitas research program), Fondation de Bienfaisance du Groupe Pictet, Fondation Ancrage, Fondation Privée des Hôpitaux Universitaires de Genève, and Center for Emerging Viral Diseases.

Background Previous investigations have reported that adverse socioeconomic circumstances across the life-course lead to the alteration of major biological processes, eventually resulting in a higher disease risk and premature death. In particular, a low life-course socioeconomic position (SEP) has been associated with a modified epigenetic signature of loci involved in inflammation, the physiological response to stress, and other regulatory processes. Methods In this study, we investigated the association between nine indicators of SEP across the life-course and the differential methylation of 451'000 genome-wide CpG markers, using data from 690 adults included in a Swiss population-based study. We further examined the interrelations between the SEP-related CpGs, and the biological pathways in which the identified markers are involved. Results Three SEP indicators in adulthood were associated the differential methylation of 161 genome-wide CpG markers, whereby 156 CpGs were less methylated in people with low versus high SEP. Among the identified CpGs, a substantial proportion of markers were no longer associated with SEP upon accounting for health behaviors and cardiometabolic disorders. In addition, the identified CpGs were found to be involved in immune, inflammatory, and cancer-related processes. Conclusions Our results support the hypothesis that adverse socioeconomic circumstances may lead to the dysregulation of inflammatory processes, eventually resulting in the occurrence of serious chronic conditions such as atherosclerosis, diabetes, or cancer. Key messages Socioeconomic position is a major determinant of health-related outcomes. Epigenetic modifications may constitute a biological mechanism through which socioeconomic circumstances affect health.

Background The Swiss health care system is consumer-driven with universal coverage and good population outcomes. Deductibles of mandatory insurance plans are self-selected, regulated, and unrelated to pre-existing conditions. In a Swiss population, we aimed to determine if forgoing health care was associated with insurance plan deductibles and if the association was dependent on socioeconomic status. Methods We used data from the Bus Santé Study; a cross-sectional survey study ongoing in Geneva (Switzerland) since 1993. We included adult participants in the study between 2007 and 2016. We divided participants according to insurance plan deductibles (low, medium, or high). Forgoing health care information was obtained from the study questionnaire. Forgoing dental health care was considered separately as mandatory insurance plans do not cover dental care. Inequalities were quantified using the regression-based relative index of inequality (RII) adjusted for potential confounders (age, gender, income, educational attainment, known comorbidities, cardiovascular risk factors, additional health insurance plans or subsidized premiums) Results We included 9081 participants, with 8.9% reporting forgoing non-dental healthcare. Those with a high-deductible insurance plan were younger, more often Swiss and male, with higher income and educational attainment, less known cardiovascular risk factors and comorbidities. Participants with high-deductible plans had a higher probability of forgoing non-dental health care (RII=2.2, p Conclusions In a population with universal coverage and good health outcomes, insurance plan deductibles are associated with inequities in forgoing health care independently of socioeconomic status and pre-existing conditions. Key messages In a highly performant health system, high insurance plan deductibles are associated with inequities in care independent of individual sociodemographic characteristics, risk factors and comorbidities. Uncovering associations between health system design features and inequities in care could inform decision-makers that seek to curtail inequities through improving their current health system design.

Background Chronic intake of caffeinated beverages might be associated with plasma lipids via disturbed lipid metabolism. Previous investigations have been limited by the use of self-reported caffeine intake instead of measured caffeine, whereas the associations between plasma lipids and other methylxanthines (paraxanthine, theobromine, theophylline) are unknown. Here, we investigated the associations of plasma lipids with caffeine and its metabolites in plasma and urine in two European populations. Methods Individuals were selected from the general population of North Belgium (FLEMENGHO) and Switzerland (SKIPOGH). Total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were measured in plasma using standard enzymatic methods. Plasma and 24h urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured using ultra-high performance liquid chromatography tandem mass spectrometry. We used mixed models to explore the associations of methylxanthines with plasma lipids while adjusting for major confounders. Results Overall, 1946 FLEMENGHO participants (911 men, age 45.9±15.2 years) and 990 SKIPOGH participants (467 men, age 47.1±17.3 years) were included. Mean plasma total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides in FLEMENGHO/SKIPOGH were 5.37/5.06, 3.12/3.12, 1.43/1.50, and 2.4/1.02 mmol/L. In both cohorts, adjusted mean total cholesterol, LDL cholesterol, and HDL cholesterol, increased with quartile of plasma caffeine, with stronger associations in men. Similar positive associations were observed for paraxanthine and theophylline. Similar associations were observed using 24h urine excretions in SKIPOGH. Conclusions Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids in men, whereas there were fewer meaningful associations in women. The increase in plasma lipids might mitigate the overall beneficial impact of caffeinated beverages on health. Key messages Caffeine constitutes one of the most widely consumed biological active substances. Plasma concentration and urinary excretion of caffeine and its derived metabolites is positively associated with plasma lipids.

BackgroundAssessing the burden of COVID-19 based on medically-attended case counts is suboptimal given its reliance on testing strategy, changing case definitions and the wide spectrum of disease presentation. Population-based serosurveys provide one avenue for estimating infection rates and monitoring the progression of the epidemic, overcoming many of these limitations.MethodsTaking advantage of a pool of adult participants from population-representative surveys conducted in Geneva, Switzerland, we implemented a study consisting of 8 weekly serosurveys among these participants and their household members older than 5 years. We tested each participant for anti-SARS-CoV-2-IgG antibodies using a commercially available enzyme-linked immunosorbent assay (Euroimmun AG, Lübeck, Germany). We estimated seroprevalence using a Bayesian regression model taking into account test performance and adjusting for the age and sex of Geneva’s population.ResultsIn the first three weeks, we enrolled 1335 participants coming from 633 households, with 16% InterpretationAssuming that the presence of IgG antibodies is at least in the short-term associated with immunity, these results highlight that the epidemic is far from burning out simply due to herd immunity. Further, no differences in seroprevalence between children and middle age adults are observed. These results must be considered as Switzerland and the world look towards easing restrictions aimed at curbing transmission.

Sodium and water handling by the kidney and the sympathetic nervous system have been implicated in the development of obesity-related hypertension and kidney disease. They have seldom been studied together during stress conditions. The objective of this study was to compare the systemic, renal and hormonal responses to lower body negative pressure (LBNP) in adult healthy participants (H), obese normotensive (OBN) and obese hypertensive patients (OBH). This was a prospective case-control study. Participants from the three groups were exposed to one hour of LBNP. Systemic and renal haemodynamics, sodium and water excretion and hormones were measured before and after LBNP. Intergroup LBNP responses were tested using a Student t-test or a Wilcoxon rank-sum test. An extension of the Wilcoxon rank-sum test was used to test for a trend across the three groups. The study included 54 participants (H: 25, OBN: 16, OBH: 13). LBNP induced a stepwise increase in systolic blood pressure (+2.7 ± 4.7 mmHg (H) vs. +4.7 ± 8.8 mmHg (OBN) vs. +8.0 ± 8.6 mmHg (OBH, p = .028)) and heart rate (−1.3 ± 4.9 bpm (H) vs. 2.2 ± 6.1 bpm (OBN) vs. 1.9 ± 4.1 bpm (OBH, p = .041). Urinary output (−2.8 ± 2.1 ml/min vs. −1.4 ± 1.7 ml/min, p = .028) and free water clearance (−1.9 ± 1.7 mOsm/kg vs. −0.7 ± 1.3 mOsm/kg, p = .016) responses were more marked in OBN compared to H. These results show that the systemic and the renal response to LBNP differ according to weight and to BP categories. Systolic BP and heart show a progressive increased response form healthy volunteers to OBN and then to obese hypertensive participants while urinary output and free water clearance responses are increased in OBN only, suggesting that the occurrence of hypertension in obese individuals modifies the early kidney responses to stress. NCT01734096

Summary Background Assessing the burden of COVID-19 on the basis of medically attended case numbers is suboptimal given its reliance on testing strategy, changing case definitions, and disease presentation. Population-based serosurveys measuring anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies provide one method for estimating infection rates and monitoring the progression of the epidemic. Here, we estimate weekly seroprevalence of anti-SARS-CoV-2 antibodies in the population of Geneva, Switzerland, during the epidemic. Methods The SEROCoV-POP study is a population-based study of former participants of the Bus Santé study and their household members. We planned a series of 12 consecutive weekly serosurveys among randomly selected participants from a previous population-representative survey, and their household members aged 5 years and older. We tested each participant for anti-SARS-CoV-2-IgG antibodies using a commercially available ELISA. We estimated seroprevalence using a Bayesian logistic regression model taking into account test performance and adjusting for the age and sex of Geneva's population. Here we present results from the first 5 weeks of the study. Findings Between April 6 and May 9, 2020, we enrolled 2766 participants from 1339 households, with a demographic distribution similar to that of the canton of Geneva. In the first week, we estimated a seroprevalence of 4·8% (95% CI 2·4–8·0, n=341). The estimate increased to 8·5% (5·9–11·4, n=469) in the second week, to 10·9% (7·9–14·4, n=577) in the third week, 6·6% (4·3–9·4, n=604) in the fourth week, and 10·8% (8·2–13·9, n=775) in the fifth week. Individuals aged 5–9 years (relative risk [RR] 0·32 [95% CI 0·11–0·63]) and those older than 65 years (RR 0·50 [0·28–0·78]) had a significantly lower risk of being seropositive than those aged 20–49 years. After accounting for the time to seroconversion, we estimated that for every reported confirmed case, there were 11·6 infections in the community. Interpretation These results suggest that most of the population of Geneva remained uninfected during this wave of the pandemic, despite the high prevalence of COVID-19 in the region (5000 reported clinical cases over

Funded by the European Commission Horizon 2020 programme, the Lifepath research consortium aimed to investigate the effects of socioeconomic inequalities on the biology of healthy aging. The main research questions included the impact of inequalities on health, the role of behavioral and other risk factors, the underlying biological mechanisms, the efficacy of selected policies, and the general implications of our findings for theories and policies. The project adopted a life-course and comparative approach, considering lifetime effects from childhood and adulthood, and pooled data on up to 1.7 million participants of longitudinal cohort studies from Europe, USA, and Australia. These data showed that socioeconomic circumstances predicted mortality and functional decline as strongly as established risk factors currently targeted by global prevention programmes. Analyses also looked at socioeconomically patterned biological markers, allostatic load, and DNA methylation using richly phenotyped cohorts, unraveling their association with aging processes across the life-course. Lifepath studies suggest that socioeconomic circumstances are embedded in our biology from the outset—i.e., disadvantage influences biological systems from molecules to organs. Our findings have important implications for policy, suggesting that (a) intervening on unfavorable socioeconomic conditions is complementary and as important as targeting well-known risk factors, such as tobacco and alcohol consumption, low fruit and vegetable intake, obesity and a sedentary lifestyle, and that (b) effects of preventive interventions in early life integrate interventions in adulthood. The report has an executive summary that refers to the different sections of the main paper. This study was supported by the European Commission (Horizon 2020 grant number 633666) and the Swiss State Secretariat for Education, Research and Innovation SERI.

The infection fatality risk (IFR) is the average number of deaths per infection by a pathogen and is key to characterizing the severity of infection across the population and for specific demographic groups. To date, there are few empirical estimates of IFR published due to challenges in measuring infection rates.1,2 Outside of closed, closely surveilled populations where infection rates can be monitored through viral surveillance, we must rely on indirect measures of infection, like specific antibodies. Representative seroprevalence studies provide an important avenue for estimating the number of infections in a community, and when combined with death counts can lead to robust estimates of the IFR. We estimated overall and age-specific IFR for the canton of Geneva, Switzerland using age-stratified daily case and death incidence reports combined with five weekly population-based seroprevalence estimates.3 From February 24th to June 2nd there were 5’039 confirmed cases and 286 reported deaths within Geneva (population of 506’765). We inferred age-stratified (5-9, 10-19, 20-49, 50-65 and 65+) IFRs by linking the observed number of deaths to the estimated number of infected individuals from each serosurvey. We account for the delays between infection and seroconversion as well as between infection and death.4 Inference is drawn in a Bayesian framework that incorporates uncertainty in seroprevalence estimates (supplement).Of the 286 reported deaths caused by SARS-CoV-2, the youngest person to die was 31 years old. Infected individuals younger than 50 years experienced statistically similar IFRs (range 0.00032-0.0016%), which increases to 0.14% (95% CrI 0.096-0.19) for those 50-64 years old to 5.6% (95% CrI 4.3-7.4) for those 65 years and older (supplement). After accounting for demography and age-specific seroprevalence, we estimate a population-wide IFR of 0.64% (95% CrI 0.38-0.98).Our results are subject to two notable limitations. Among the 65+ age group that died of COVID-19 within Geneva, 50% were reported among residents of assisted care facilities, where around 0.8% of the Geneva population resides. While the serosurvey protocol did not explicitly exclude these individuals, they are likely to have been under-represented. This would lead to an overestimation of the IFR in the 65+ age group if seroprevalence in this institutionalized population was higher than in the general population (supplement). Further, our IFR estimates are based on current evidence regarding post-infection antibody kinetics, which may differ between severe and mild infections. If mild infections have significantly lower and short-lived antibody responses, our estimates of IFR may be biased upwards.5Estimates of IFR are key for understanding the true pandemic burden and for weighing different risk reduction strategies. The IFR is not solely determined by host and pathogen biology, but also by the capacity of health systems to treat severe cases. Despite having among the highest per capita incidence in Switzerland, Geneva’s health system accommodated the influx of cases needing intensive care (peak of 80/110 ICU-beds including surge capacity) while maintaining care quality standards. As such, our IFR estimates can be seen as a best-case scenario with respect to health system capacity. Our results reveal that population-wide estimates of IFR mask great heterogeneity by age and point towards the importance of age-targeted interventions to reduce exposures among those at highest risk of death.

Background/Aim. Data about effects of antidepressant on calcium, phosphorous and magnesium metabolisms are very scorce. The aim of this study was to investigate effects of antidepressants on serum concentration of bone metabolism markers and main electrolytes in patients from routine psychiatric practice. Methods. A prospective, before-and-after, time-series research included 9 males and 24 females, with average 53.3 ? 11.5 years-of-age, suffering from depression (n = 26) and neurotic disorders (n = 7), mostly taking selective serotonin reuptake inhibitors. We measured analytes at baseline, and 4th, 6th and 12th weeks during the treatment and tested the parameter changes from baseline and the trends with appropriate statistics at p ? 0.05 significance level. Results. The age above 60 years was a significant factor for appearance of negative cumulative changes (in percent) of 25-hydroxyvitamin D ? 25(OH)D concentrations from the base-line (OR = 11.4, 95% CI 1.2?113.1, p = 0.037). Serum concentrations of calcium significantly correlated with sodium (rs = 0.531, p < 0.001), with chloride (r = 0.496, p < 0.001), with magnesium (rs = 0.402, p < 0.001) and with osteocalcin (r = 0.240, p = 0.019). Significant correlations were among phosphorous with chloride (r = -0.218, p = 0.035); magnesium with sodium (r = 0.295, p = 0.004) and with potassium, (r = 0.273, p = 0.009); osteocalcin with C-telopeptide (r = 0.760, p < 0.001) with sodium (r = 0.215, p = 0.039) and with chloride (r = 0.209, p = 0.041); sodium with chloride (r = 0.722, p < 0.001). There were no statistically significant changes between antidepressant treatment and changes of absolute serum concentration of calcium, magnesium, phosphorous, 25(OH)D, osteocalcin, C-telopeptide, sodium, potassium and chloride. There were no statistically significant changes in frequency of disturbances in values of laboratory analytes (below/above lower/upper normal limits), too. Conclusion. Antidepressant treatment was not significantly associated with the changes in study analytes but some of them positively correlated with each other, suggesting the need for individual patient approach and further research in the field of bone metabolism in patients with mental disorders.

Introduction/Objective. Tibial shaft fractures (TSF) are one of the most common fractures. External fixation (EF) may be used to treat TSF. The aim of this study was to analyze the treatment of TSF with Mitkovic EF. Methods. The study included 100 patients with TSF treated with Mitkovic EF as the primary and definite method of treatment. The results are compared to those in the literature. Results. The patient group comprised 67% male and 33% female patients aged 10?71years. TSF is common in adult males in the fourth and fifth decades of life. The most common cause is falling with the twisting of the leg (59%). Closed fractures were observed in 76 patients (57.4% of type A AO, 25.4% of type B AO, and 17.1% of type C AO), and open fractures in 34 patients (50% of type I GA, 32.35% of type II GA, and 17.64% of type III GA). The average time period from injury to surgery was 2.5 days (the range being 4 hours to 9 days). Bone healing was achieved in 93% of patients. The average healing time was 18.4 weeks (the range being 11?32 weeks). The distribution of complications is as follows: 10% for minor pin site infections; 4% for major pin site infections; 6% for nonunion; 1% for acute respiratory distress syndrome; 2% for osteitis. There was no deep vein thrombosis nor neurovascular damage. EuroQol score was excellent in 82% of the patients. Conclusion. Mitkovic EF can be used for treating all types of TSF. Functional results of treatment by this method are excellent. The data analysis of the series does not differ from the data in the literature.

Disadvantaged socioeconomic conditions in childhood heighten systemic inflammatory levels in adulthood; however, life-course mechanisms underlying this association are largely unknown. In the present observational study, we investigated the roles of adulthood socioeconomic and lifestyle factors in mediating this association. Participants were from two prospective Swiss population-based cohorts (N = 5,152, mean age 60 years). We estimated the total effect of paternal occupational position on adult heightened systemic inflammatory levels (C-reactive protein>3 mg/L), and the indirect effects via adulthood socioeconomic positions (SEPs: education and occupational position), financial hardship, and lifestyle factors (body mass index, smoking status, physical inactivity, and alcohol consumption). We estimated odds ratio (OR) and proportion mediated using counterfactual-based mediation models. Individuals whose father had a low occupational position had an OR of 1.51 [95% confidence interval (CI): 1.25, 1.84] for heightened inflammation compared to their more advantaged counterparts. This was jointly mediated (33 [95% CI: 14, 69]%) by adulthood SEPs, whereby the pathway through education followed by occupational position mediated 30 [95% CI: 11, 64]%, while the pathway via occupational position only mediated 3 [95% CI: 4, 13]%. Individuals with the lowest life-course SEPs had an OR of 2.27 [95% CI: 1.71, 2.98] for heightened inflammation compared to having the highest life-course SEPs. This was jointly mediated (63 [95% CI: 44, 97]%) by financial hardship and lifestyle factors. Our study supports a cumulative effect of life-course SEPs on adult heightened systemic inflammation along the pathway paternal occupational position -> education -> adult occupational position. Financial hardship and lifestyle factors in adulthood mediate half of that effect.

Background Early life adversity has been associated with increased risk of inflammation and inflammation-related diseases in adulthood. This study aimed to examine the association of parental socioeconomic position with chronic inflammation over adolescence. Methods We used information on 2942 members (1507 girls and 1435 boys) of the EPITeen cohort that was established in 2003 in Porto, Portugal, and included 13 years old adolescents that were further evaluated at 17 and 21 years. Mother’ and father’s education and occupation were used as indicators of parental socioeconomic position. High-sensitivity C-reactive protein (CRP) was measured at three points in time (13, 17 and 21 years). CRP levels were categorized in tertiles separately for each wave; chronic inflammation in adolescence was defined as having CRP levels in the highest tertile in at least 2 waves and never in the lowest tertile. Results Over adolescence, the prevalence of chronic inflammation was significantly higher among participants with low parental socioeconomic position. Low parental socioeconomic position was associated with chronic inflammation in adolescence, after adjustment for sex, perinatal and physical environment factors, health-related behaviours and health status in adolescence OR = 1.63; 95%CI: 1.11, 2.40 for lowest vs. highest mother’s education and OR = 1.61; 95%CI: 1.12, 2.30 for lowest vs. highest father’s education. Conclusions Low parental socioeconomic position is associated with chronic inflammation during adolescence. Our results suggest that the early life socioeconomic environment has an impact on inflammatory processes over adolescence.

Sleep-disordered breathing is a common condition, related to a higher cardiometabolic and neurocognitive risk. The main risk factors for sleep-disordered breathing include obesity, craniofacial characteristics, male sex and age. However, some studies have suggested that adverse socioeconomic circumstances and lifestyle-related behaviours such as smoking and alcohol use, may also be risk factors for sleep-disordered breathing. Here, we investigate the associations between socioeconomic status and sleep-disordered breathing, as measured by sleep apnea-hypopnea and oxygen desaturation indexes. Furthermore, we assess whether these associations are explained by lifestyle-related factors (smoking, sedentary behaviour, alcohol use and body mass index [BMI]). We used data from the CoLaus|HypnoLaus study, a population-based study including 2162 participants from Lausanne (Switzerland). Socioeconomic status was measured through occupation and education. Sleep-disordered breathing was assessed through polysomnography and measured using the apnea-hypopnea index (AHI: number of apnea/hypopnea events/hr: ≥15/≥30 events), and the ≥3% oxygen desaturation index (ODI: number of oxygen desaturation events/hr: ≥15/≥30 events). Lower occupation and education were associated with higher AHI and ODI (occupation: AHI30, odds ratio (OR) = 1.88, 95% confidence interval (CI) [1.07; 3.31]; ODI30, OR = 2.29, 95% CI [1.19; 4.39]; education: AHI30, OR = 1.21, 95% CI [0.85; 1.72]; ODI30, OR = 1.26, 95% CI [0.83; 1.91]). BMI was associated with socioeconomic status and AHI/ODI, and contributed to the socioeconomic gradient in SDB, with mediation estimates ranging between 43% and 78%. In this Swiss population-based study, we found that low socioeconomic status is a risk factor for sleep-disordered breathing, and that these associations are partly explained by BMI. These findings provide a better understanding of the mechanisms underlying social differences in sleep-disordered breathing and may help implement policies for identifying high-risk profiles for this disorder.

The association of blood pressure (BP) with manganese—an essential trace element required for human health—remains poorly studied. In 734 randomly recruited Swiss participants (mean age, 47.5 years; 51.4% women), we related ambulatory BP to 2 biomarkers, plasma manganese (pMn) and the urinary manganese (uMn) excretion. To allow for diurnal variation, we assessed BP and uMn over 24 hours and during wakefulness and sleep, using split urine samples. Twenty-four-hour, daytime, and nighttime systolic/diastolic BPs averaged 119.8/78.1, 123.8/81.2, and 107.0/68.3 mm Hg; the corresponding median uMn were 199.5, 83.0, and 51.5 μmol and median pMn, 0.52 μg/L. In analyses dichotomized by the median of the biomarkers, greater pMn was associated with higher 24-hour systolic/diastolic BP (+4.1/+2.3 mm Hg; P ≤0.0003), greater daytime uMn with lower daytime BP (−3.5/−1.9 mm Hg; P ≤0.0067), and greater nighttime uMn with higher nighttime BP (+2.9/+1.2 mm Hg; P ≤0.046). In multivariable-adjusted analyses, significance ( P ≤0.030) was retained for the positive association of 24-hour and daytime diastolic BP with pMn and for systolic BP in relation to uMn at night. The association sizes for a 2-fold increment in the biomarkers amounting to 0.77 mm Hg (95% CI, 0.08–1.47 mm Hg), 0.97 (CI, 0.20–1.76) and 1.33 (CI, 0.20–2.50 mm Hg), respectively. In conclusion, there were positive associations between diastolic BP and pMn over 24 hours and during daytime and between systolic BP and uMn at night.

Unhealthy behaviors and their social patterning have been frequently proposed as factors mediating socioeconomic differences in health. However, a clear quantification of the contribution of health behaviors to the socioeconomic gradient in health is lacking. This study systematically reviews the role of health behaviors in explaining socioeconomic inequalities in health. Published studies were identified by a systematic review of PubMed, Embase and Web-of-Science. Four health behaviors were considered: smoking, alcohol consumption, physical activity and diet. We restricted health outcomes to cardiometabolic disorders and mortality. To allow comparison between studies, the contribution of health behaviors, or the part of the socioeconomic gradient in health that is explained by health behaviors, was recalculated in all studies according to the absolute scale difference method. We identified 114 articles on socioeconomic position, health behaviors and cardiometabolic disorders or mortality from electronic databases and articles reference lists. Lower socioeconomic position was associated with an increased risk of all-cause mortality and cardiometabolic disorders, this gradient was explained by health behaviors to varying degrees (minimum contribution -43%; maximum contribution 261%). Health behaviors explained a larger proportion of the SEP-health gradient in studies conducted in North America and Northern Europe, in studies examining all-cause mortality and cardiovascular disease, among men, in younger individuals, and in longitudinal studies, when compared to other settings. Of the four behaviors examined, smoking contributed the most to social inequalities in health, with a median contribution of 19%. Health behaviors contribute to the socioeconomic gradient in cardiometabolic disease and mortality, but this contribution varies according to population and study characteristics. Nevertheless, our results should encourage the implementation of interventions targeting health behaviors, as they may reduce socioeconomic inequalities in health and increase population health.

Background: Sleep disorders are frequent symptoms described in psychiatric patients with major depression or schizophrenia. These patients also exhibit changes in the sleep architecture measured by polysomnography (PSG) during sleep. The aim of the present study was to identify potential biomarkers that would facilitate the diagnosis based on polysomnography (PSG) measurements.Subjects and Methods: 30 patients with schizophrenia, 30 patients with major depression and 30 healthy control subjects were investigated in the present study. The mean age in the group with schizophrenia was 36.73 (SD 6.43), in the group of patients with depression 40.77 (SD 7.66), in the healthy controls group 34.40 (SD 5.70). The gender distribution was as follows: 18 male, 12 female in the group with schizophrenia; in the group of patients with depression 11 male, 19 female; in the control group 16 male and 14 female. All subjects underwent polysomnography (PSG) for a minimum time of 8 hours according to the criteria of Rechtschaffen & Kales (1968). The following polysomnographic (PSG) parameters were analyzed: sleep latency (SL), total sleep time (TST), waking time after sleep onset (WTASO), number of awakenings (NAW), slow wave sleep (SWS), rapid eye movement sleep (REM), rapid eye movement sleep latency (REML), first REM period (REM 1), and first NREM period (NREM 1). We tested the potential of multiple sleep variables to predict diagnosis in different groups by using linear discriminate analysis (LDA).Results: There were significant differences in polysomnography (PSG) variables between healthy control subjects and psychiatric patients (total sleep time, sleep latency, number of awakenings, time of awakening after sleep onset, REM 1 latency, REM 1 and index of endogenous periodicity). Importantly, LDA was able to predict the correct diagnosis in 88% of all cases.Conclusions: The presented analysis showed commonalities and differences in polysomnography (PSG) changes in patients with major depressive disorder and in patients with schizophrenia. Our results underline the potential of polysomnography (PSG) measurements to facilitate diagnostic processes.

Background Caffeine intake is generally estimated by self-reported consumption, but it remains unclear how well self-report associates with metabolite urinary excretion. We investigated the associations of self-reported consumption of caffeinated drinks with urinary excretion of caffeine and its major metabolites in an adult population. Methods We used data from the population-based Swiss Kidney Project on Genes in Hypertension (SKIPOGH) study. Consumption of caffeinated coffee, decaffeinated coffee and other caffeinated beverages was assessed by self-administered questionnaire. Quantification of caffeine, paraxanthine, theobromine and theophylline was performed by ultra-high performance liquid chromatography tandem mass spectrometry in 24-h urine. Association of reported consumption of caffeinated drinks with urinary caffeine derived metabolites was determined by quantile regression. We then explored the association between urinary metabolite excretion and dichotomized weekly consumption frequency of caffeinated coffee, with Receiver Operator Characteristic (ROC) analysis. Results In the present analysis, we included 598 individuals (52% women, mean age =46 ± 17 years). Self-reported caffeinated coffee intake was positively associated with 24-h urinary excretions of paraxanthine, theophylline and caffeine (p

Hierarchical structure of the system, river terminals for bulk cargo unloading, connected with queuing and servicing and stochastic character of the input/output values are underlined. The approach using the queuing theory is developed for engineering use as simpler, faster and more convenient than the approach using simulation. Results obtained using the queuing theory and previously obtained results using simulation modelling are shown alongside. The obtained results can be used at the beginning of the design process when rough estimations of the system behaviour are needed. Some of the obtained results are applied and verified on the existing system.

Introduction. Suicide attempts are a significant public health problem. They are associated with significant morbidity and result in significant use of health care resources. Objective. The aim of our study was to analyze epidemiological characteristics attempts of suicide for persons in the period 2001-2010 who were hospitalized at the Psychiatric Clinic in Kragujevac after the attempt of suicide. Methods. We analysed 286 clinical records of patients who had attempted suicide (133 males, 153 females). We used the illness history of patients, who were treated at the Psychiatric Clinic in Kragujevac after their suicide attempts. We made the analysis of socio-demographic characteristics of the sample and characteristics of the suicide act itself. Results. Our results showed a higher rate of female population, except for the period 2003-2005: 2003 - 14 males (58.3%), 2004 - 15 (62.5%) and 2005 - 60%. The largest number of attempts was in the population aged between 25 and 34 years (23.8%). The percentage of persons from urban areas was higher (66.4%). Depressive disorder was a common pre-existing disorder before a suicide attempt (42.3%). Most attempts of suicide were performed by overdosing on medications (57.7%). Conclusion. In the last three years we observed a decrease of suicide attempts. We noticed that middle aged persons are the most frequent ones to attempt suicide. Depressive disorder is the most frequent pre-existing condition of suicide attempt. In order to prevent suicide attempts we must improve early detection of depressive disorder, as well as initial treatment.

Introduction. Consequences of heroin abuse include organic damage of cerebral structures. The level of impairments is in a direct and positive relation with the length of heroin abuse. Objective. The aim of this research was the evaluation of the reaction time with heroin addicts with different length of substance abuse. Methods. Research method: 90 examinees were divided into three groups with relation to the length of heroin abuse. Data collection included a questionnaire referring to socio-demographic and addictive characteristics. A specially designed programme was used for the evaluation of reaction time to audio/ visual signal. Results. In relation to the reaction time as overall model, the difference between examinees with different length of heroin abuse can be found on the marginal level of significance (F=1.69; df=12; p=0.07). In visual modality, with the increase of length of heroin abuse leads to a significant prolongation of simple (the first visual sign: F=3.29; df=2; p=0.04) and choice reaction time (the second visual sign: F=4.97; df=2; p=0.00; the third visual sign: F=3.08; df=2; p=0.05). Longer heroin consumption also leads to the prolongation of the simple (the first auditory task: F=3.41; df=2; p=0.04) and the complex auditory reaction time (the second auditory task: F=5.67; df=2; p=0.01; the third auditory task: F=6.42; df=2; p=0.00). Conclusion. Heroin abuse leads to the prolongation of both simple and choice reaction time in visual as well as auditory modality. The average daily dose of opiates was the most important predictor of the abovementioned cognitive dysfunction.

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.

Slovenia has a hilly character, and a high percentage of the population participates in mountaineering as an outdoor sport. Mountaineering enthusiasts produced the first mountain maps. It wasn't until 1969, however, that official mountain maps were published under the auspices of the National Mountaineering Association of Slovenia. The official mountain maps were initially in high demand because topographic maps produced by the military were generally unavailable throughout Slovenia – a situation that has completely changed since then. Today, the use of mountain maps is in decline because of competition from other high-quality topographic maps that are more readily available. The future viability of Slovenian mountain mapping as a separate program depends on the implementation of new technology and the development of new products that are relevant to mountaineers. Slovenie a un caractere vallonne et une bonne proportion de la population fait de l'alpinisme comme sport exterieur. Les passionnes de l'alpini...

The Fifth Workshop of the International Cartographic Association’s Commission on Mountain Cartography took place in Slovenia this spring. Previous mountain cartography workshops have been held in the Austrian Alps (Silvretta 1988, Rudolfshutte 2000), North America’s Cascade Range (Mount Hood 2002), and the Catalan Pyrenees (Val de Nuria 2004). This year the mountain cartographers returned again to the Alps, but this time to the southern limestone region. The workshop venue was the Gozdna sola (forest school), the National Training Centre of the Scout Association of Slovenia. The centre is located near Lake Bohinj, 533 m above sea level, in Triglav National Park, a protected area of forests and mountains, including Triglav (2864 m), the highest peak in Slovenia and the Slovenian national symbol.

Objective Serum parameters of calcium homeostasis were measured based on previously published evidence linking osteoporotic fractures and/or bone/mineral loss with antipsychotics. Methods Prospective, four-week, time-series trial was conducted and study population consisted of patients of both genders, aged 35-85 years, admitted within the routine practice, with acute psychotic symptoms, to whom an antipsychotic drug was either introduced or substituted. Serial measurements of serum calcium, phosphorous, magnesium, 25(OH)D, parathyroid hormone, calcitonin, osteocalcin and C-telopeptide were made from patient venous blood samples. Results Calcium serum concentrations significantly decreased from baseline to the fourth week (2.42±0.12 vs. 2.33±0.16 mmol/L, p=0.022, n=25). The mean of all calcemia changes from the baseline was -2.6±5.7% (-24.1 to 7.7) with more decreases than increases (78 vs. 49, p=0.010) and more patents having negative sum of calcemia changes from baseline (n=28) than positive ones (n=10) (p=0.004). There were simultaneous falls of calcium and magnesium from baseline (63/15 vs. 23/26, p