Effect of acute iron infusion on insulin secretion: A randomized, double-blind, placebo-controlled trial.

Background: Chronic exposure to high iron levels increases diabetes risk partly by inducing oxidative stress, but the consequences of acute iron administration on beta cells are unknown. We tested whether the acute administration of iron for the correction of iron deficiency influenced insulin secretion and the production of reactive oxygen species. Methods: Single-center, double-blinded, randomized controlled trial conducted between June 2017 and March 2020. 32 women aged 18 to 47 years, displaying symptomatic iron deficiency without anaemia, were recruited from a community setting and randomly allocated (1:1) to a single infusion of 1000 mg intravenous ferric carboxymaltose (iron) or saline (placebo). The primary outcome was the between group mean difference from baseline to day 28 in first and second phase insulin secretion, assessed by a two-step hyperglycaemic clamp. All analyses were performed by intention to treat. This trial was registered in ClinicalTrials.gov NCT03191201. Findings: Iron infusion did not affect first and second phase insulin release. For first phase, the between group mean difference from baseline to day 28 was 0 µU × 10 min/mL [95% CI, -22 to 22, P = 0.99]. For second phase, it was -5 µUx10min/mL [95% CI, -161 to 151; P = 0.95] at the first plateau of the clamp and -249 µUx10min/mL [95% CI, -635 to 137; P = 0.20] at the second plateau. Iron infusion increased serum ascorbyl/ascorbate ratio, a marker of plasma oxidative stress, at day 14, with restoration of normal ratio at day 28 relative to placebo. Finally, high-sensitive C-reactive protein levels remained similar among groups. Interpretation: In iron deficient women without anaemia, intravenous administration of 1000 mg of iron in a single sitting did not impair glucose-induced insulin secretion despite a transient increase in the levels of circulating reactive oxygen species. Funding: The Swiss National Science Foundation, University of Lausanne and Leenaards, Raymond-Berger and Placide Nicod Foundations.

Polypill eligibility and equivalent intake in a Swiss population-based study.

The polypill has been advocated for cardiovascular disease (CVD) management. The fraction of the population who could benefit from the polypill in Switzerland is unknown. Assess (1) the prevalence of subjects (a) eligible for the polypill and (b) already taking a polypill equivalent; and (2) the determinants of polypill intake in the first (2009-2012) and second follow-ups (2014-2017) of a population-based prospective study conducted in Lausanne, Switzerland. The first and the second follow-ups included 5038 and 4596 participants aged 40-80 years, respectively. Polypill eligibility was defined as having a high CVD risk as assessed by an absolute CVD risk ≥ 5% with the SCORE equation for Switzerland and/or presenting with CVD. Four polypill equivalents were defined: statin + any antihypertensive with (A) or without (B) aspirin; statin + calcium channel blocker (CCB) (C); and statin + CCB + angiotensin-converting enzyme inhibitor (D). The prevalence of polypill eligibility was 20.6% (95% CI 19.5-21.8) and 27.7% (26.5-29.1) in the first and second follow-up, respectively. However, only around one-third of the eligible 29.5% (95% CI 26.7-32.3) and 30.4% (27.9-33.0) respectively, already took the polypill equivalents. All polypill equivalents were more prevalent among men, elderly and in presence of CVD. After multivariable adjustment, in both periods, male gender was associated with taking polypill equivalent A (OR: 1.93; 95% CI 1.45-2.55 and OR: 1.67; 95% CI 1.27-2.19, respectively) and polypill equivalent B (OR: 1.52; 95% CI 1.17-1.96 and OR: 1.41; 95% CI 1.07-1.85, respectively). Similarly, in both periods, age over 70 years, compared to middle-age, was associated with taking polypill equivalent A (OR: 11.71; CI 6.74-20.33 and OR: 9.56; CI 4.13-22.13, respectively) and equivalent B (OR: 13.22; CI 7.27-24.07 and OR: 20.63; CI 6.51-56.36, respectively). Former or current smoking was also associated with a higher likelihood of taking polypill equivalent A in both periods. A large fraction of the population is eligible for the polypill, but only one-third of them actually benefits from an equivalent, and this proportion did not change over time.

Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes.

The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.

Trends and Determinants of Polypharmacy and Potential Drug-Drug Interactions at Discharge From Hospital Between 2009-2015.

BACKGROUND: Polypharmacy (PP) and excessive polypharmacy (EPP) are increasingly common and associated with risk of drug-drug interactions (DDIs). We aimed to measure the trends and determinants of PP and DDIs among patients discharged from the Department of Internal Medicine of the Lausanne University Hospital. METHODS: The retrospective study included 17,742 adult patients discharged between 2009 and 2015. Polypharmacy and EPP were defined as the concomitant prescription of five or more and ten or more drugs, respectively. Drug-drug interactions were defined as any combination of a drug metabolized by a cytochrome P450 or P-glycoprotein, and a drug considered as strong inductor or inhibitor of the corresponding enzyme was defined as a potential interaction. RESULTS: Three most commonly classes of drugs prescribed were "alimentary tract and metabolism (including insulins)," "nervous system," and "blood and blood forming organs." Polypharmacy decreased from 45% in 2009 to 41% in 2015, whereas EPP increased from 40% to 46%. In 2015, 13% of patients received 15 or more drugs. Age, coming from other health care settings, higher Charlson Index, number of comorbidities, and quartiles of length of stay were significantly and independently associated with PP and EPP. The risk of having at least one DDI decreased from 67.0% (95% confidence interval = 64.8-69.0) in 2009 to 59.3% (57.6-62.0) in 2015 (P < 0.001). Multivariate analysis showed number of drugs (odds ratio and 95% confidence interval = 3.68 [3.3-4.1], 9.39 [8.3-10.6], and 20.5 [17.3-28.4] for [5-9], [10-14], and 15+ drugs, respectively), gastrointestinal disease (3.13 [2.73-3.58]), and cancer (1.37 [1.18-1.58]) to be positively associated, and lung (0.82 [0.74-0.90]) and endocrinological (0.62 [0.52-0.74]) diseases to be negatively associated with risk of DDI. CONCLUSIONS: The pattern of drug prescription has changed and most prescribed groups increased during the study period. Excessive polypharmacy is increasing among hospital patients. The decrease in the overall risk of DDI could be due to an improved management of multidrug therapy.

Ten-Year Trend in Polypharmacy in the Lausanne Population.

BACKGROUND: Aging and associated morbidities place individuals at higher risk of polypharmacy and drug-drug interactions (DDIs). How polypharmacy and DDIs change with aging is important for public health management. OBJECTIVES: The aim of the study was to assess the 10-year trends in prevalence of polypharmacy and potential DDIs in a population-based sample. METHODS: Baseline (2003-2006) and follow-up (2014-2016) data were obtained from a sample of 4512 participants (baseline age range = 35-75 y, 55.1% women) from the population of Lausanne, Switzerland. Polypharmacy and polyactive drug use were defined by the regular use of five or more medications and five or more pharmacologically active substances, respectively. Drug-drug interactions were defined according to the criteria of the Geneva University Hospital. RESULTS: The percentage of participants taking at least one drug increased from 56.1% to 79.5% (P < 0.001). Among participants taking drugs, number of medications increased from 2.6 ± 1.9 (mean ± standard deviation) to 3.8 ± 2.9 after 10.9-year follow-up (P < 0.001); the corresponding values for active substances were 2.7 ± 2.0 and 4.0 ± 3.0 (P < 0.001). The prevalence of polypharmacy and polyactive substance use increased from 7.7% to 25.0% and from 8.8% to 27.1%, respectively (P < 0.001). The presence of at least one potential DDI increased from less than 1% to almost one sixth of all participants. CONCLUSIONS: In a community-dwelling sample, the prevalence of polypharmacy and polyactive substance use tripled during a 10.9-year follow-up, with an even greater increase in the prevalence of potential DDIs. Increasing rates of polypharmacy and DDIS warns the importance of preventing potential DDIs throughout healthcare system through various interventions.

Syphilis and parvovirus B19 co-infection imitating a lupus nephropathy: A case report.

RATIONALE: Syphilis can share clinical features with autoimmune diseases, such as cutaneous Lupus or rheumatoid arthritis. Moreover, secondary syphilis can have visceral involvement, thus affecting the kidney. Syphilitic nephropathy causes nephrotic syndrome with a classic membranous pattern. We present a unique presentation of a co-infection by syphilis and parvovirus B19 sharing all the biological and histological features of proliferative lupus nephritis (LN). PATIENT CONCERNS: We present a case of a 71-year-old Caucasian male returning from a trip to Asia presenting with nephrotic syndrome with antinuclear antibodies (ANA) positivity. DIAGNOSES: Because of nephrotic syndrome a kidney biopsy was performed. It demonstrated a membranous nephropathy with extracapillary proliferation and a full house pattern (presence of IgA, IgG, IgM and C1Q deposits) on immunofluorescence (IF), highly suggestive of LN class III and V. However, several atypical clinical features notably the age, sex of the patient and the history of travel prompt us to search for another cause of nephropathy. INTERVENTIONS: A serology was positive for syphilis and a PCR in the renal biopsy was also positive for parvovirus B19. Thus, a co-infection by syphilis and parvovirus B19 was funded to be the cause of the renal lesions. OUTCOMES: The proteinuria improved; a course of antibiotic was administrated because of neurologic syphilitic involvement (presence of headache with positive syphilis serology in the CSF). LESSONS: A co-infection by syphilis and parvovirus B19 can share all the biological and histological features of proliferative LN and must be recognized as a cause of pseudo-lupus nephritis.

Salivary cortisol is not associated with incident insulin resistance or type 2 diabetes mellitus.

BACKGROUND: Excessive glucocorticoid secretion has been associated with type 2 diabetes mellitus (T2DM) and other features of the metabolic syndrome. We aimed to evaluate whether basal or evening salivary cortisol may predict the occurrence of incident insulin resistance (IR) or T2DM. METHOD: This was a prospective, population-based study derived from the CoLaus/PsyCoLaus study including 1525 participants (aged 57.7 ± 10.3 years; 725 women). A total of 1149 individuals were free from T2DM at baseline. Fasting plasma glucose and insulin were measured after a follow-up of 5.3 years. Basal and evening salivary cortisol were measured at baseline. The association between basal or evening salivary cortisol level and incidence of IR or T2DM were analyzed by logistic regression, and the results were expressed for each independent variable as ORs and 95% CI. RESULTS: After a median follow-up of 5.3 years, a total of 376 subjects (24.7%) developed IR and 32 subjects (2.1%) developed T2DM. Basal and evening salivary cortisol divided in quartiles were not associated with incidence of IR or T2DM. Multivariable analysis for age, gender, body mass index, physical activity and smoking status showed no association between basal or evening salivary cortisol and incidence of IR or T2DM. CONCLUSION: In the CoLaus/PsyCoLaus study of healthy adults, neither basal nor evening salivary cortisol was associated with incident IR or T2DM.

Effects of short- and long-term exposures to particulate matter on inflammatory marker levels in the general population.

The effect of particulate matter (PM) on health increases with exposure duration but the change from short to longer term is not well studied. We examined the exposure to PM smaller 10 µm (PM10) from short to longer duration and their associations with levels of inflammatory markers in the population-based CoLaus cohort in Lausanne, Switzerland. Baseline and follow-up CoLaus data were used to study the associations between PM10 exposure and inflammatory markers, including the high-sensitivity C-reactive protein (CRP), as well as interleukin 1-beta (IL-1ß), interleukin 6 (IL-6), and tumor-necrosis-factor alpha (TNF-α) using mixed models. Exposure was determined for each participant's home address from hourly air quality simulations at a 5-m resolution. Short-term exposure intervals were 1 day, 1 week, and 1 month prior to the hospital visit (blood withdrawal); long-term exposure intervals were 3 and 6 months prior to the visit. In most time windows, IL-6, IL-1ß, and TNF-α were positively associated with PM10. No significant associations were identified for CRP. Adjusted associations with long-term exposures were stronger and more significant than those for short-term exposures. In stratified models, gender, age, smoking status, and hypertension only led to small modifications in effect estimates, though a few of the estimates for IL-6 and TNF-α became non-significant. In this general adult cohort exposed to relatively low average PM10 levels, clear associations with markers of systemic inflammation were observed. Longer duration of elevated exposure was associated with an exacerbated inflammatory response. This may partially explain the elevated disease risk observed with chronic PM10 exposure. It also suggests that reducing prolonged episodes of high PM exposure may be a strategy to reduce inflammatory risk.

Menopausal Hormone Therapy Is Associated With Reduced Total and Visceral Adiposity: The OsteoLaus Cohort.

Context: After menopause, fat mass (FM) and visceral adipose tissue (VAT) increase and nonbone lean body mass (LBM) decreases. Whether menopausal hormone therapy (MHT) reverses these changes remains controversial. Objective: To assess the effect of MHT on FM, VAT, and LBM before and after its withdrawal and evaluate potential confounders. Design: Cross-sectional study. Setting: General community. Patients or Other Participants: Women of the OsteoLaus cohort (50 to 80 years old) who underwent dual-energy X-ray absorptiometry (DXA) with body composition assessment. After we excluded women with estrogen-modifying medications, the 1053 participants were categorized into current users (CUs), past users (PUs), and never users (NUs) of MHT. Intervention: None. Main Outcome Measures: VAT measured by DXA was the primary outcome. We assessed subtotal and android FM, LBM, muscle strength (hand grip), and confounding factors (caloric intake, physical activity, biomarkers). Results: The groups significantly differed in age, NU < CU < PU. Age-adjusted VAT was lower in CUs than NUs (P = 0.03). CUs exhibited lower age-adjusted body mass index (BMI) (-0.9 kg/m2) and a trend for lower FM (-1.3 kg). The 10-year gain of VAT (P < 0.01) and subtotal and android FM (P < 0.05) was prevented in CUs. No difference in LBM or hand grip was detected. No residual effect was detected for PUs, including for early MHT discontinuers. The confounding factors did not significantly differ between groups except for higher caloric intake in PUs compared with NUs. Conclusions: MHT is associated with significantly decreased VAT, BMI, and android FM. No benefit is detected for LBM. The benefits are not preserved in PUs, suggesting caution when MHT is discontinued.

Socio-demographic and lifestyle determinants of dietary patterns in French-speaking Switzerland, 2009-2012.

BACKGROUND: Food intake is a complex behaviour which can be assessed using dietary patterns. Our aim was to characterize dietary patterns and associated factors in French-speaking Switzerland. METHODS: Cross-sectional study conducted between 2009 and 2012 in the city of Lausanne, Switzerland, including 4372 participants (54% women, 57.3 ± 10.3 years). Food consumption was assessed using a validated food frequency questionnaire. Dietary patterns were assessed by principal components analysis. RESULTS: Three patterns were identified: "Meat & fries"; "Fruits & Vegetables" and "Fatty & sugary". The "Meat & fries" pattern showed the strongest correlations with total and animal protein and cholesterol carbohydrates, dietary fibre and calcium. The "Fruits & Vegetables" pattern showed the strongest correlations with dietary fibre, carotene and vitamin D. The "Fatty & sugary" pattern showed the strongest correlations with total energy and saturated fat. On multivariate analysis, male gender, low educational level and sedentary status were positively associated with the "Meat & fries" and the "Fatty & sugary" patterns, and negatively associated with the "Fruits & Vegetables" pattern. Increasing age was inversely associated with the "Meat & fries" pattern; smoking status was inversely associated with the "Fruits & Vegetables" pattern. Being born in Portugal or Spain was positively associated with the "Meat & fries" and the "Fruits & Vegetables" patterns. Increasing body mass index was positively associated with the "Meat & fries" pattern and inversely associated with the "Fatty & sugary" pattern. CONCLUSIONS: Three dietary patterns, one healthy and two unhealthy, were identified in the Swiss population. Several associated modifiable behaviours were identified; the information on socio- demographic determinants allows targeting of the most vulnerable groups in the context of public health interventions.

The bidirectional relationship between anxiety disorders and circulating levels of inflammatory markers: Results from a large longitudinal population-based study.

BACKGROUND: Although there has been abundant research on chronic low-grade inflammation as a potential mechanism underlying the link between mood disorders and cardiovascular risk, less is known about the role of inflammatory factors and anxiety disorders. The aim of this paper is to evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and high sensitivity C-reactive protein (hsCRP) with anxiety disorders and its subgroups. METHODS: The sample consisted of 3,113 participants (53.7% women; mean age: 51.0, S.D. 8.8 years), randomly selected from the general population, who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up (mean follow-up duration = 5.5 years, S.D. 0.6). Anxiety disorders were assessed with semistructured diagnostic interviews. Inflammatory biomarkers were analyzed in fasting blood samples. RESULTS: After adjustment for potential confounders, current anxiety disorders (ß = 0.09, 95% CI 0.00-0.17) and agoraphobia (ß = 0.25, 95% CI: 0.07-0.43) at baseline were associated with a steeper increase of hsCRP levels over the follow-up period. Current posttraumatic stress disorder (PTSD) was associated with a lower increase of IL-6 levels over the follow-up period (ß = -0.52, 95% CI: -1.00/-0.04). There was no evidence for an association between inflammation markers at baseline and anxiety disorders at follow-up. CONCLUSIONS: The prospective association between agoraphobia at baseline and hsCRP levels over the follow-up period suggests that chronic low-grade inflammation may be a consequence of this condition. The decrease in IL-6 in PTSD also requires further investigation. No evidence was found for chronic low-grade inflammation as a predictor of future anxiety disorders.

Prevalence and determinants of polypharmacy in Switzerland: data from the CoLaus study.

BACKGROUND: Polypharmacy is a frequent condition, but its prevalence and determinants in the Swiss mid-aged population are unknown. We aimed to evaluate the prevalence and determinants of polypharmacy in a large Swiss mid-aged population-based sample. METHODS: Data from 4938 participants of the CoLaus study (53% women, age range 40-81 years) were collected between 2009 and 2012. Polypharmacy was defined by the regular use of five or more drugs. RESULTS: Polypharmacy was reported by 580 participants [11.8%, 95% confidence interval (10.9; 12.6)]. Participants on polypharmacy were significantly older (mean ± standard deviation: 66.0 ± 9.1 vs. 56.6 ± 10.1 years), more frequently obese (35.9% vs. 14.7%), of lower education (66.6% vs. 50.7%) and former smokers (46.7% vs. 36.4%) than participants not on polypharmacy. These findings were confirmed by multivariate analysis: odds ratio and (95% confidence interval) for age groups 50-64 and 65-81 relative to 40-49 years: 2.90 (2.04; 4.12) and 10.3 (7.26; 14.5), respectively, p for trend < 0.001; for low relative to high education: 1.56 (1.17; 2.07); for overweight and obese relative to normal weight participants: 2.09 (1.65; 2.66) and 4.38 (3.39; 5.66), respectively, p for trend < 0.001; for former and current relative to never smokers: 1.42 (1.14, 1.75) and 1.63 (1.25, 2.12), respectively, p for trend < 0.001. CONCLUSION: One out of nine participants of our sample is on polypharmacy. Increasing age, body mass index, smoking and lower education independently increase the likelihood of being on polypharmacy.

A genetic variant in the catechol-O-methyl transferase (COMT) gene is related to age-dependent differences in the therapeutic effect of calcium-channel blockers.

Hypertension is the leading risk factor for cardiovascular disease and one of the major health concerns worldwide. Genetic factors impact both the risk for hypertension and the therapeutic effect of antihypertensive drugs. Sex- and age-specific variances in the prevalence of hypertension are partly induced by estrogen. We investigated 6 single nucleotide polymorphisms in genes encoding enzymes involved in estrogen metabolism in relation to sex- and age-specific differences in the systolic and diastolic blood pressure (SBP and DBP) outcome under the treatment of diuretics, calcium-channel blockers (CCBs), angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers (ARBs).We included 5064 subjects (age: 40-82) from the population-based CoLaus cohort. Participants were genotyped for the catechol-O-methyltransferase gene (COMT) variants rs4680, rs737865, and rs165599; the uridine-diphospho-glucuronosyltransferase 1A gene family (UGT1A) variants rs2070959 and rs887829; and the aromatase gene (CYP19A1) variant rs10046. Binomial and linear regression analyses were performed correcting for age, sex, body mass index, smoking, diabetes, and antihypertensive therapy to test whether the variants in focus are significantly associated with BP.All investigated COMT variants were strongly associated with the effect of diuretics, CCBs, and ARBs on SBP or DBP (P < .05), showing an additive effect when occurring in combination. After Bonferroni correction the polymorphism rs4680 (ValMet) in COMT was significantly associated with lower SBP in participants treated with CCBs (P = .009) with an especially strong impact in elderly individuals (age ≥ 70) alone (Δ = -14.08 mm Hg, P = .0005).These results underline the important role of estrogens and catecholamines in hypertension and the importance of genotype dependent, age-related adjustments of calcium-channel blocker treatment.

Partially distinct combinations of psychological, metabolic and inflammatory risk factors are prospectively associated with the onset of the subtypes of Major Depressive Disorder in midlife.

BACKGROUND: Given the well known heterogeneity of Major Depressive Disorder (MDD), dividing this complex disorder into subtypes is likely to be a more promising approach to identify its determinants than to study it as a whole. METHODS: In a prospective population-based cohort study (CoLaus|PsyCoLaus) with 5.5 years of follow-up, 1524 participants without MDD at baseline, aged 35-66 years (mean age 51.4 years, 43.4% females), participated in the physical and psychiatric baseline and the psychiatric follow-up evaluations. RESULTS: The incidence of both atypical and melancholic MDD during the follow-up period were predicted by female sex, a lifetime history of minor depressive disorders and higher neuroticism scores. Higher baseline body mass index was associated with the onset of atypical MDD, whereas the absence of hypertension and younger age were associated with the development of melancholic MDD. Unspecified MDD was predicted by younger age, low concentrations of tumor necrosis factor-α and elevated life-event impact scores. LIMITATIONS: The age range of our cohort restricts the identification of risk factors to MDD with onset in midlife and the recruitment in an urban area limits the generalizability of the findings. CONCLUSIONS: Our data suggest that MDD subtypes are predicted by partially distinct combinations of baseline characteristics suggesting that these subtypes not only differ in their clinical manifestations but also in factors that contribute to their development. Subjects with minor depressive episodes, especially in combination with particular personality features, deserve close clinical attention to prevent the subsequent onset of atypical and melancholic major depression.

[Precision medicine : a required approach for the general internist]. / Médecine de précision : un rendez-vous à ne pas manquer pour l'interniste généraliste.

The general internist cannot be a passive bystander of the anticipated medical revolution induced by precision medicine. This latter aims to improve the predictive and/or clinical course of an individual by integrating all biological, genetic, environmental, phenotypic and psychosocial knowledge of a person. In this article, national and international initiatives in the field of precision medicine are discussed as well as the potential financial, ethical and limitations of personalized medicine. The question is not to know if precision medicine will be part of everyday life but rather to integrate early the general internist in multidisciplinary teams to ensure optimal information and shared-decision process with patients and individuals.

L'interniste généraliste ne peut pas être un spectateur passif du bouleversement induit par la médecine de précision. Cette dernière vise à améliorer les aspects prédictifs ou l'évolution clinique d'une personne en intégrant toutes les connaissances biologiques et génétiques, environnementales, phénotypiques et psychosociales qui lui sont propres. Dans cet article, les initiatives nationales et internationales dans ce domaine sont abordées, ainsi que les potentiels enjeux financiers, éthiques et d'équité sociale. Cette médecine de précision fera partie de notre quotidien et il s'agit d'intégrer très tôt l'interniste généraliste dans des plateformes multidisciplinaires pour assurer les restitutions d'informations, les partages de décision, les incertitudes et ultimement contribuer au maintien de la santé de la population et améliorer la qualité des soins pour nos patients.

Determinants of change in polypharmacy status in Switzerland: the population-based CoLaus study.

OBJECTIVES: This study aimed to assess the prevalence, the change, and the determinants of change in polypharmacy in a population-based sample. METHODS: Baseline (2003-2006) and follow-up (2009-2012) data are from 4679 participants aged between 35 and 75 years (53.5% women, mean age 52.6 ± 10.6 years) from the population of Lausanne, Switzerland. Polypharmacy was defined by the regular use of ≥5 drugs. Four categories of change were defined: never (no polypharmacy at baseline and follow-up), initiating (no polypharmacy at baseline but at follow-up), maintaining, or quitting. RESULTS: Polypharmacy increased from 7.7% at baseline to 15.3% at follow-up. Cardiovascular drugs were the most prescribed medicines at baseline and follow-up. Gender, age, obesity, smoking, previously diagnosed hypertension, or diabetes or dyslipidemia were significantly and independently associated with initiating and maintaining polypharmacy. CONCLUSION: In a population-based sample, prevalence of polypharmacy doubled over a 5.6-year period. The main determinants of initiating polypharmacy were age, overweight and obesity, smoking status, and previously diagnosed cardiovascular risk factors.

Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness.

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10-8, METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options. The data provide molecular evidence that rather than being an isolated trait, MPB shares a substantial biological basis with numerous other human phenotypes and may deserve evaluation as an early prognostic marker, for example, for prostate cancer, sudden cardiac arrest and neurodegenerative disorders.

Impact of smoking on fertility and age of menopause: a population-based assessment.

BACKGROUND AND AIMS: Studies in patients seeking medically assisted reproduction have shown that smoking reduces fertility, but little information is available in the general population. We assessed the associations between smoking and the number of children, childbearing planning and age at menopause in a representative sample of the population of Lausanne, Switzerland. METHODS: Data from 6711 participants (3530 women, age range 35-75 years) collected between 2003 and 2006 and again in 2009 and 2012. Smoking status, number of offsprings and age of menopause were assessed. RESULTS: Women who currently smoke had significantly less children than former or never smokers: the number of children per women (average±SD) was 1.38±1.05, 1.45±1.07 and 1.576±1.16, respectively (p<0.001). Women who currently smoke had their first child at an earlier age than the others: 26.7±5.2, 27.4±5.4 and 26.9±5.2 years old for current, former and never smokers, respectively, (p=0.01). Similar findings were found for men: number of children per men 1.475±1.16, 1.67±1.13 and 1.55±1.22 for current, former and never smokers, respectively (p<0.001); no difference was found regarding age at the first child. The difference persisted after multivariate adjustment (adjusted for age, body mass index, Caucasian origins, alcohol consumption, caffeinated drinks consumption, educational level, receiving social help and women taking contraceptives) for the age at first child among women. No association was found between Heaviness of Smoking Index and the number of children among current smokers in both genders. Women who smoke had their menopause more than 1 year prior than never-smoking women (48.9±0.2 years compared with 47.8±0.3 years, respectively, p=0.002). CONCLUSIONS: Smoking is associated with an earlier age of having the first child and of menopause among women.

Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL.

Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells. Silencing of Chop and inhibition of ER stress markers by the chemical chaperone phenyl butyric acid (PBA) prevented cell death caused by oxidized LDL. Finally, we found that oxidative stress accounts for activation of ER stress markers induced by oxidized LDL. Induction of Chop/CHOP and p58IPK/P58IPK by oxidized LDL was mimicked by hydrogen peroxide and was blocked by co-treatment with the N-acetylcystein antioxidant. As a conclusion, the harmful effects of oxidized LDL in beta-cells requires ER stress activation in a manner that involves oxidative stress. This mechanism may account for impaired beta-cell function in diabetes and can be reversed by antioxidant treatment.

Association between anti-apolipoprotein A-1 antibodies and cardiovascular disease in the general population. Results from the CoLaus study.

We aimed to determine the association between autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG) and prevalent cardiovascular (CV) disease (CVD) as well as markers of CV risk in the general population. Cross-sectional data were obtained from 6649 subjects (age 52.6 ± 10.7 years, 47.4 % male) of the population-based CoLaus study. CVD was defined as myocardial infarction, angina pectoris, percutaneous revascularisation or bypass grafting for ischaemic heart disease stroke or transient ischaemic attack, and was assessed according to standardised medical records. Anti-apoA-1 IgG and biological markers were measured by ELISA and conventional automated techniques, respectively. Prevalence of high anti-apoA-1 IgG levels in the general population was 19.9 %. Presence of anti-apoA-1 IgG was significantly associated with CVD [odds ratio 1.34, 95 % confidence interval (1.05-1.70), p=0.018], independently of established CV risk factors (CVRFs) including age, sex, hypertension, smoking, diabetes, low and high-density lipoprotein cholesterol levels. The n=455 (6.8 %) study participants with a history of CVD (secondary prevention subgroup) presented higher median anti-ApoA-1 IgG values compared with subjects without CVD (p=0.029). Among patients in the secondary prevention subgroup, those with positive anti-apoA-1 IgG levels had lower HDL (p=0.002) and magnesium (p=0.001) levels, but increased uric acid and high-sensitivity C-reactive protein levels (p=0.022, and p<0.001, respectively) compared to patients with negative anti-apoA-1 IgG levels. In conclusion, anti-apoA-1 IgG levels are independently associated with CVD in the general population and also related to CV biomarkers in secondary prevention. These findings indicate that anti-apoA-1 IgG may represent a novel CVRF and need further study in prospective cohorts.