Association between circulating cytokine levels, diabetes and insulin resistance in a population-based sample (CoLaus study).

OBJECTIVE: The associations between inflammation, diabetes and insulin resistance remain controversial. Hence, we assessed the associations between diabetes, insulin resistance (using HOMA-IR) and metabolic syndrome with the inflammatory markers high-sensitive C-reactive protein (hs-CRP), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). DESIGN: Cross-sectional study. PARTICIPANTS: Two thousand eight hundred and eighty-four men and 3201 women, aged 35-75, participated in this study. METHODS: C-reactive protein was assessed by immunoassay and cytokines by multiplexed flow cytometric assay. In a subgroup of 532 participants, an oral glucose tolerance test (OGTT) was performed to screen for impaired glucose tolerance (IGT). RESULTS: IL-6, TNF-α and hs-CRP were significantly and positively correlated with fasting plasma glucose (FPG), insulin and HOMA-IR. Participants with diabetes had higher IL-6, TNF-α and hs-CRP levels than participants without diabetes; this difference persisted for hs-CRP after multivariate adjustment. Participants with metabolic syndrome had increased IL-6, TNF-α and hs-CRP levels; these differences persisted after multivariate adjustment. Participants in the highest quartile of HOMA-IR had increased IL-6, TNF-α and hs-CRP levels; these differences persisted for TNF-α and hs-CRP after multivariate adjustment. No association was found between IL-1β levels and all diabetes and insulin resistance markers studied. Finally, participants with IGT had higher hs-CRP levels than participants with a normal OGTT, but this difference disappeared after controlling for body mass index (BMI). CONCLUSION: We found that subjects with diabetes, metabolic syndrome and increased insulin resistance had increased levels of IL6, TNF-α and hs-CRP, while no association was found with IL-1β. The increased inflammatory state of subjects with IGT is partially explained by increased BMI.

Dosing regimen of gentamicin in neonates: evaluation of current guidelines based on a large population pharmacokinetic analysis

Objectives: Gentamicin is among the most commonly prescribed antibiotics in newborns, but large interindividual variability in exposure levels exists. Based on a population pharmacokinetic analysis of a cohort of unselected neonates, we aimed to validate current dosing recommendations from a recent reference guideline (Neofax®). Methods: From 3039 concentrations collected in 994 preterm (median gestational age 32.3 weeks, range 24.2-36.5) and 455 term newborns, treated at the University Hospital of Lausanne between 2006 and 2011, a population pharmacokinetic analysis was performed with NONMEM®. Model-based simulations were used to assess the ability of dosing regimens to bring concentrations into targets: trough ≤ 1mg/L and peak ~ 8mg/L. Results: A two-compartment model best characterized gentamicin pharmacokinetics. Model parameters are presented in the table. Body weight, gestational age and postnatal age positively influence clearance, which decreases under dopamine administration. Body weight and gestational age influence the distribution volume. Model based simulations confirm that preterm infants need doses superior to 4 mg/kg, and extended dosage intervals, up to 48 hours for very preterm newborns, whereas most term newborns would achieve adequate exposure under 4 mg/kg q. 24 h. More than 90% of neonates would achieve trough concentrations below 2 mg/L and peaks above 6 mg/L following most recent guidelines. Conclusions: Simulated gentamicin exposure demonstrates good accordance with recent dosing recommendations for target concentration achievement.

Population genetic structure and demography analysis in palinurus elephas populations from atlantic and mediterranean waters

Report for the scientific sojourn at the University of Reading, United Kingdom, from January until May 2008. The main objectives have been firstly to infer population structure and parameters in demographic models using a total of 13 microsatellite loci for genotyping approximately 30 individuals per population in 10 Palinurus elephas populations both from Mediterranean and Atlantic waters. Secondly, developing statistical methods to identify discrepant loci, possibly under selection and implement those methods using the R software environment. It is important to consider that the calculation of the probability distribution of the demographic and mutational parameters for a full genetic data set is numerically difficult for complex demographic history (Stephens 2003). The Approximate Bayesian Computation (ABC), based on summary statistics to infer posterior distributions of variable parameters without explicit likelihood calculations, can surmount this difficulty. This would allow to gather information on different demographic prior values (i.e. effective population sizes, migration rate, microsatellite mutation rate, mutational processes) and assay the sensitivity of inferences to demographic priors by assuming different priors.

Paper 3: EUROCAT data quality indicators for population-based registries of congenital anomalies.

The European Surveillance of Congenital Anomalies (EUROCAT) network of population-based congenital anomaly registries is an important source of epidemiologic information on congenital anomalies in Europe covering live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly. EUROCAT's policy is to strive for high-quality data, while ensuring consistency and transparency across all member registries. A set of 30 data quality indicators (DQIs) was developed to assess five key elements of data quality: completeness of case ascertainment, accuracy of diagnosis, completeness of information on EUROCAT variables, timeliness of data transmission, and availability of population denominator information. This article describes each of the individual DQIs and presents the output for each registry as well as the EUROCAT (unweighted) average, for 29 full member registries for 2004-2008. This information is also available on the EUROCAT website for previous years. The EUROCAT DQIs allow registries to evaluate their performance in relation to other registries and allows appropriate interpretations to be made of the data collected. The DQIs provide direction for improving data collection and ascertainment, and they allow annual assessment for monitoring continuous improvement. The DQI are constantly reviewed and refined to best document registry procedures and processes regarding data collection, to ensure appropriateness of DQI, and to ensure transparency so that the data collected can make a substantial and useful contribution to epidemiologic research on congenital anomalies.

Prospective evaluation of risk of vertebral fractures using quantitative ultrasound measurements and bone mineral density in a population-based sample of postmenopausal women: results of the Basel Osteoporosis Study.

OBJECTIVE: Prospective studies have shown that quantitative ultrasound (QUS) techniques predict the risk of fracture of the proximal femur with similar standardised risk ratios to dual-energy x-ray absorptiometry (DXA). Few studies have investigated these devices for the prediction of vertebral fractures. The Basel Osteoporosis Study (BOS) is a population-based prospective study to assess the performance of QUS devices and DXA in predicting incident vertebral fractures. METHODS: 432 women aged 60-80 years were followed-up for 3 years. Incident vertebral fractures were assessed radiologically. Bone measurements using DXA (spine and hip) and QUS measurements (calcaneus and proximal phalanges) were performed. Measurements were assessed for their value in predicting incident vertebral fractures using logistic regression. RESULTS: QUS measurements at the calcaneus and DXA measurements discriminated between women with and without incident vertebral fracture, (20% height reduction). The relative risks (RRs) for vertebral fracture, adjusted for age, were 2.3 for the Stiffness Index (SI) and 2.8 for the Quantitative Ultrasound Index (QUI) at the calcaneus and 2.0 for bone mineral density at the lumbar spine. The predictive value (AUC (95% CI)) of QUS measurements at the calcaneus remained highly significant (0.70 for SI, 0.72 for the QUI, and 0.67 for DXA at the lumbar spine) even after adjustment for other confounding variables. CONCLUSIONS: QUS of the calcaneus and bone mineral density measurements were shown to be significant predictors of incident vertebral fracture. The RRs for QUS measurements at the calcaneus are of similar magnitude as for DXA measurements.

20 years of eosinophilic esophagitis in Olten county: population-based, prospective documentation of an increasing incidence

Background and Aims: Eosinophilic Esophagitis (EoE) is reported with increasing frequency over the last two decades. However, it is still unknown whether this reflects a true increase in incidence or just an increased awareness by gastroenterologists. Therefore, we evaluated the incidence and cumulative prevalence of EoE in Olten county over the last 20 years. Methods: Olten county is an area of approximately 91,000 inhabitants without pronounced demographic changes in the last two decades. EoE evaluation is based upon two gastroenterology centers and one pathology center. No public programs for increased EoE awareness were implemented in this region. All EoE patients diagnosed from 1989 to 2009 were entered prospectively into the Olten county database. Results: Fourty-six patients (76% males, mean age 41±16 yrs) were diagnosed with EoE from 1989 to 2009. Ninety-four percent presented with dysphagia. In 70% of the patients concomitant allergies were found. The number of upper endoscopies per year was stable during the entire observation period. An average annual incidence rate of 2/100,000 was found (range 0-8) with a marked increase in the period from 2001 to 2009. A current cumulative EoE prevalence of 43/100,000 inhabitants was calculated. The mean diagnostic delay (time from first symptoms to diagnosis) was 4.3 years from 1989 to 1998 and 4.8 years from 1999 to 2009. Conclusions: Over the last 20 years, a significant increase in EoE incidence was found in a stable indicator region of Switzerland. The constant rate of upper endoscopies, the constant diagnostic delay, as well as the lack of EoE awareness programs in Olten county indicate a true increase in EoE incidence.

Escalating epidemiology of eosinophilic esophagitis: 21 years of prospective population-based documentation in Olten county

Background and Aims: Eosinophilic Esophagitis (EoE) is detected with a dramatically increasingfrequency during the last decades. However, it is still unknown whether this reflects atrue increase in incidence or just an increased awareness by gastroenterologists. We therefore,prospectively assessed incidence and prevalence of EoE in an epidemiologically well definedindicator area over the last 21 years. Methods: Olten County is an area of approximately90,000 inhabitants without pronounced demographic changes during the last two decades.Two EoE-experienced gastroenterologists and one pathology centre are responsible forcovering the gastroenterological service of the area. No public programs for increasingawareness of EoE were implemented in this region. Since 1989 all individuals with confirmeddiagnosis of EoE living in Olten County were entered prospectively into the database. Results:Forty-six patients (76% males, mean age 41±16 yrs) were diagnosed with EoE between1989 and 2009. Ninety-four percent of patients presented with dysphagia. An average annualincidence rate of 1.88/100,000 was found (range 0-8) with a marked increase in the periodfrom 2004 to 2009. The cumulative EoE prevalence rose up to 35.1/100,000 inhabitantsin 2009. No significant change was observed for the median diagnostic delay, as it was 3years from 1989 to 1998 and 2 years from 1999 to 2009 with age < 40 years representinga risk factor for retarded diagnosis. The number of upper endoscopies per year increasedby 63% in the period from 1999 to 2009 compared to the years 1989 to 1998 which ismarkedly less then the increase in the incidence rate of 150% for the same periods. Conclusions:Over the last 21 years, a significant increase in EoE incidence and prevalence wasfound in an epidemiologically stable indicator region of Switzerland. The constant diagnosticdelay, the number of newly diagnosed EoE cases that was much more pronounced thanthe modest increase of performed upper endoscopies, as well as the lack of EoE awarenessprograms in Olten County indicates a true increase in EoE incidence.

Seroepidemiology of Herpes Simplex virus type 1 and 2 in Western and Southern Switzerland in adults aged 25-74 in 1992-93: a population-based study.

BACKGROUND: Genital herpes is one of the most prevalent sexually-transmitted diseases, and accounts for a substantial morbidity. Genital herpes puts newborns at risk for very severe disease and also increases the risk of horizontal HIV transmission. It thus stands as an important public health problem. The recent availability of type-specific gG-based assays detecting IgG against HSV-1 and HSV-2 allows to establish the prevalence of each subtype. Worldwide, few data have been published regarding the seroprevalence in general populations of HSV-2, the major causative agent for genital herpes, while no data exist regarding the Swiss population. METHODS: To evaluate the prevalence of IgG antibodies against HSV-1 and HSV-2 in Switzerland, we used a population-based serum repository from a health examination survey conducted in the Western and Southern area of Switzerland in 1992-93. A total of 3,120 sera were analysed by type-specific gG-based ELISA and seroprevalence was correlated with available volunteers characteristics by logistic regression. RESULTS: Overall, seroprevalence rates were 80.0 +/- 0.9% (SE, 95% CI: 78.1-81.8) for HSV-1 and 19.3 +/- 0.9% (SE, 95% CI: 17.6-21.1) for HSV-2 in adults 35-64 year old. HSV-1 and HSV-2 seroprevalence increased with age, with a peak HSV-2 seroprevalence in elderly gentlemen, possibly a seroarcheological evidence of sexually transmitted disease epidemics during World War II. Risk factors for HSV-2 infection included female sex, marital status other than married, and size of town of residence larger than 1500 inhabitants. Unexpectedly and conversely to HSV-1, HSV-2 seroprevalence increased with educational level. HSV-2 infection was less prevalent among HSV-1 infected individuals when compared to HSV-1 uninfected individuals. This effect was most apparent among women at high risk for HSV-2 infection. CONCLUSIONS: Our data demonstrate that by the early nineties, HSV-2 had spread quite largely in the Swiss population. However, the epidemiology of HSV-2 in Switzerland presents paradoxical characteristics, e.g. positive correlation with education level, that have not been observed elsewhere.

Association between social relationships and survival of Swiss octogenarians. A five-year prospective, population-based study.

BACKGROUND AND AIMS: Data from the literature reveal the contrasting influences of family members and friends on the survival of old adults. On one hand, numerous studies have reported a positive association between social relationships and survival. On the other, ties with children may be associated with an increased risk of disability, whereas ties with friends or other relatives tend to improve survival. A five-year prospective, population-based study of 295 Swiss octogenarians tested the hypothesis that having a spouse, siblings or close friends, and regular contacts with relatives or friends are associated with longer survival, even at a very old age. METHODS: Data were collected through individual interviews, and a Cox regression model was applied to assess the effects of kinship and friendship networks on survival, after adjusting for socio-demographic and health-related variables. RESULTS: Our analyses indicate that the presence of a spouse in the household is not significantly related to survival, whereas the presence of siblings at baseline improves the oldest old's chances of surviving five years later. Moreover, the existence of close friends is a central component in the patterns of social relationships of oldest adults, and one which is significantly associated with survival. Overall, the protective effect of social relationships on survival is more related to the quality of those relationships (close friends) than to the frequency of relationships (regular contacts). CONCLUSIONS: We hypothesize that the existence of siblings or close friends may beneficially affect survival, due to the potential influence on the attitudes of octogenarians regarding health practices and adaptive strategies.

Determinants and burden of chronic kidney disease in the population-based CoLaus study: a cross-sectional analysis.

BACKGROUND: Chronic kidney disease (CKD) represents an increasing health burden. We present the population-based prevalence of CKD and compare the CKD Epidemiology collaboration (CKD-EPI) and modification of diet in renal disease (MDRD) equations to estimate the glomerular filtration rate, using the revised CKD classification with three albuminuria classes. We also explore factors associated with CKD. METHODS: The Swiss population-based, cross-sectional CoLaus study conducted in Lausanne (2003-2006) included 2810 men and 3111 women aged 35-75. CKD prevalence was assessed using CKD-EPI and MDRD equations and albuminuria estimated by the albumin-to-creatinine ratio in spot morning urine. Multivariate logistic regression was used to analyse determinants of CKD. RESULTS: Prevalence [95% confidence interval (CI)] of all stages CKD was 10.0% (9.2-10.8%) with CKD-EPI and 13.8% (12.9-14.6%) with MDRD. Using the revised CKD classification, the prevalence of low-, medium-, high- and very high-risk groups was 90.0, 8.46, 1.18 and 0.35% with CKD-EPI, respectively. With MDRD, the corresponding values were 86.24, 11.86, 1.55 and 0.35%. Using the revised classification, CKD-EPI systematically reclassified people in a lower risk category than MDRD. Age and obesity were more strongly associated with CKD in men [odds ratio (95% CI): 2.23(1.95; 2.56) per 10 years and 3.05(2.08;4.47), respectively] than in women [1.46 (1.29; 1.65) and 1.78 (1.30;2.44), respectively]. Hypertension, type 2 diabetes, serum homocysteine and uric acid were positively independently associated with CKD in men and women. CONCLUSIONS: One in 10 adults suffers from CKD in the population of Lausanne. CKD-EPI systematically reclassifies people in a lower CKD risk category than MDRD. Serum homocysteine and uric acid levels are associated with CKD independently of classical risk factors such as age, hypertension and diabetes.

Pragmatic approach for interpreting antiretroviral drug concentrations based on a systematic review of population pharmacokinetic studies

Objectives: The study objective was to derive reference pharmacokinetic curves of antiretroviral drugs (ART) based on available population pharmacokinetic (Pop-PK) studies that can be used to optimize therapeutic drug monitoring guided dosage adjustment.¦Methods: A systematic search of Pop-PK studies of 8 ART in adults was performed in PubMed. To simulate reference PK curves, a summary of the PK parameters was obtained for each drug based on meta-analysis approach. Most models used one-compartment model, thus chosen as reference model. Models using bi-exponential disposition were simplified to one-compartment, since the first distribution phase was rapid and not determinant for the description of the terminal elimination phase, mostly relevant for this project. Different absorption were standardized for first-order absorption processes.¦Apparent clearance (CL), apparent volume of distribution of the terminal phase (Vz) and absorption rate constant (ka) and inter-individual variability were pooled into summary mean value, weighted by number of plasma levels; intra-individual variability was weighted by number of individuals in each study.¦Simulations based on summary PK parameters served to construct concentration PK percentiles (NONMEM®).¦Concordance between individual and summary parameters was assessed graphically using Forest-plots. To test robustness, difference in simulated curves based on published and summary parameters was calculated using efavirenz as probe drug.¦Results: CL was readily accessible from all studies. For studies with one-compartment, Vz was central volume of distribution; for two-compartment, Vz was CL/λz. ka was directly used or derived based on the mean absorption time (MAT) for more complicated absorption models, assuming MAT=1/ka.¦The value of CL for each drug was in excellent agreement throughout all Pop-PK models, suggesting that minimal concentration derived from summary models was adequately characterized. The comparison of the concentration vs. time profile for efavirenz between published and summary PK parameters revealed not more than 20% difference. Although our approach appears adequate for estimation of elimination phase, the simplification of absorption phase might lead to small bias shortly after drug intake.¦Conclusions: Simulated reference percentile curves based on such an approach represent a useful tool for interpretating drug concentrations. This Pop-PK meta-analysis approach should be further validated and could be extended to elaborate more sophisticated computerized tool for the Bayesian TDM of ART.

Evaluation of Health-Related Quality of Life according to Carbohydrate Metabolism Status: A Spanish Population-Based Study (Di@bet.es Study)

Objective. To evaluate the association between diabetes mellitus and health-related quality of life (HRQOL) controlled for several sociodemographic and anthropometric variables, in a representative sample of the Spanish population. Methods. A population-based, cross-sectional, and cluster sampling study, with the entire Spanish population as the target population. Five thousand and forty-seven participants (2162/2885 men/women) answered the HRQOL short form 12 questionnaire (SF-12). The physical (PCS-12) and the mental component summary (MCS-12) scores were assessed. Subjects were divided into four groups according to carbohydrate metabolism status: normal, prediabetes, unknown diabetes (UNKDM), and known diabetes (KDM). Logistic regression analyses were conducted. Results. Mean PCS-12/MCS-12 values were 50.9 ± 8.5/47.6 ± 10.2, respectively. Men had higher scores than women in both PCS-12 (51.8 ± 7.2 versus 50.3 ± 9.2; P < 0.001) and MCS-12 (50.2 ± 8.5 versus 45.5 ± 10.8; P < 0.001). Increasing age and obesity were associated with a poorer PCS-12 score. In women lower PCS-12 and MCS-12 scores were associated with a higher level of glucose metabolism abnormality (prediabetes and diabetes), (P < 0.0001 for trend), but only the PCS-12 score was associated with altered glucose levels in men (P < 0.001 for trend). The Odds Ratio adjusted for age, body mass index (BMI) and educational level, for a PCS-12 score below the median was 1.62 (CI 95%: 1.2–2.19; P < 0.002) for men with KDM and 1.75 for women with KDM (CI 95%: 1.26–2.43; P < 0.001), respectively. Conclusion. Current study indicates that increasing levels of altered carbohydrate metabolism are accompanied by a trend towards decreasing quality of life, mainly in women, in a representative sample of Spanish population.

Population pharmacokinetic study of gentamicin in a large cohort of premature and term neonates.

AIM: This study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population. METHODS: All gentamicin concentration data, along with clinical and demographic characteristics, were retrieved from medical charts in a Neonatal Intensive Care Unit over 5 years within the frame of a routine therapeutic drug monitoring programme. Data were described using non-linear mixed-effects regression analysis ( nonmem®). RESULTS: A total of 3039 gentamicin concentrations collected in 994 preterm and 455 term newborns were included in the analysis. A two compartment model best characterized gentamicin disposition. The average parameter estimates, for a median body weight of 2170 g, were clearance (CL) 0.089 l h(-1) (CV 28%), central volume of distribution (Vc ) 0.908 l (CV 18%), intercompartmental clearance (Q) 0.157 l h(-1) and peripheral volume of distribution (Vp ) 0.560 l. Body weight, gestational age and post-natal age positively influenced CL. Dopamine co-administration had a significant negative effect on CL, whereas the influence of indomethacin and furosemide was not significant. Both body weight and gestational age significantly influenced Vc . Model-based simulations confirmed that, compared with term neonates, preterm infants need higher doses, superior to 4 mg kg(-1) , at extended intervals to achieve adequate concentrations. CONCLUSIONS: This observational study conducted in a large cohort of newborns confirms the importance of body weight and gestational age for dosage adjustment. The model will serve to set up dosing recommendations and elaborate a Bayesian tool for dosage individualization based on concentration monitoring.

Correlations between major risk factors and closely related Mycobacterium tuberculosis isolates grouped by three current enotyping procedures: a population-based study in northeast Mexico

The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman’s rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB.

Clustering of risk behaviors with cigarette consumption: a population-based survey.

OBJECTIVE: This study assessed clustering of multiple risk behaviors (i.e., low leisure-time physical activity, low fruits/vegetables intake, and high alcohol consumption) with level of cigarette consumption. METHODS: Data from the 2002 Swiss Health Survey, a population-based cross-sectional telephone survey assessing health and self-reported risk behaviors, were used. 18,005 subjects (8052 men and 9953 women) aged 25 years old or more participated. RESULTS: Smokers more frequently had low leisure time physical activity, low fruits/vegetables intake, and high alcohol consumption than non- and ex-smokers. Frequency of each risk behavior increased steadily with cigarette consumption. Clustering of risk behaviors increased with cigarette consumption in both men and women. For men, the odds ratios of multiple (> or =2) risk behaviors other than smoking, adjusted for age, nationality, and educational level, were 1.14 (95% confidence interval: 0.97, 1.33) for ex-smokers, 1.24 (0.93, 1.64) for light smokers (1-9 cigarettes/day), 1.72 (1.36, 2.17) for moderate smokers (10-19 cigarettes/day), and 3.07 (2.59, 3.64) for heavy smokers (> or =20 cigarettes/day) versus non-smokers. Similar odds ratios were found for women for corresponding groups, i.e., 1.01 (0.86, 1.19), 1.26 (1.00, 1.58), 1.62 (1.33, 1.98), and 2.75 (2.30, 3.29). CONCLUSIONS: Counseling and intervention with smokers should take into account the strong clustering of risk behaviors with level of cigarette consumption.