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.