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Aims To describe dispensation patterns of glucose-lowering drugs in newly diagnosed type 2 diabetes in Germany. Materials and methods Based on claims data from four statutory health insurances (German Pharmacoepidemiological Research Database,>25 million insurants), all individuals with newly diagnosed type 2 diabetes were identified. Eligible patients had a first diagnosis for type 2 diabetes between January 2012 and December 2016. We analyzed the dispensation patterns of first-line glucose-lowering therapies initiated in the year after diabetes diagnosis and patterns of second-line therapies dispensed one year after first-line treatment. Results A total of 356,647 individuals with newly diagnosed type 2 diabetes were included (average age [SD]: 63.5 [13.4] years; 49.3% males). Of the 31.6% of individuals who were pharmacologically treated in the year after diagnosis, metformin monotherapy was most frequently dispensed (73.1%), followed by dual therapy of metformin and dipeptidyl peptidase-4 inhibitors (DPP-4is) (6.4%), and monotherapy with DPP-4is (2.9%). From 2012 through 2016, sulfonylurea dispensations were reduced by more than 50%. Dispensations for combination therapies with DPP-4is increased up to 10.6%. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors contributed to 2% of all treatments. After a median of 5 months, 20.0% of individuals on pharmacological therapy initiated second-line glucose-lowering treatment. Conclusions Data from German statutory health insurances (2012 to 2016) showed that most individuals with newly diagnosed type 2 diabetes were dispensed metformin monotherapy in line with diabetes care guidelines. A substantial decrease in the use of sulfonylureas was observed after the introduction of DPP-4i and GLP-1 receptor agonists.

Die korperliche Aktivitat stellt ein komplexes Verhalten dar, dessen valide und reliable Erfassung in gros angelegten populationsbasierten Studien mit besonderen Herausforderungen einhergeht. In der bundesweiten NAKO Gesundheitsstudie liegen zur Halbzeit der Basiserhebung die Daten zur korperlichen Aktivitat fur 100.000 Teilnehmende vor. Beschreibung der Erfassung der korperlichen Aktivitat und Prasentation erster deskriptiver Ergebnisse. Das multimodale Erhebungskonzept bestand aus zwei Fragebogen, dem Questionnaire on Annual Physical Activity Pattern (QUAP) und dem Global Physical Activity Questionnaire (GPAQ), einem computerbasierten Erinnerungsprotokoll der vergangenen 24 h (cpar24) und einer 7‑Tage-Akzelerometrie (Actigraph GT3X/+; Fa. ActiGraph, Pensacola, FL, USA). Fur die einzelnen Erhebungsmodule lagen auswertbare Datensatze in unterschiedlicher Zahl vor (QUAP: n = 16.372; GPAQ: n = 90.900; cpar24: n = 23.989; Akzelerometrie: n = 35.218). Die Analysen der einzelnen Module ergaben unterschiedliche Durchschnittswerte fur die moderate oder intensive korperliche Gesamtaktivitat der Teilnehmenden: Bei Frauen wurden 75–216 min/Tag gemessen, bei Mannern 73–224 min/Tag. Personen der Altersgruppe 20–39 Jahre verbrachten 66–200 min/Tag in moderater oder intensiver korperlicher Gesamtaktivitat, wahrend Personen der Altersgruppe 40–69 Jahre 78–244 min/Tag aufwendeten. Erste modulubergreifende Analysen der korperlichen Aktivitat in der NAKO zeigen den Nutzen komplementar eingesetzter Erhebungsmethoden. Die umfangreichen Daten stellen eine wertvolle Ressource fur die Charakterisierung der Zusammenhange zwischen korperlicher Aktivitat und Krankheitspravention dar, die in der Zukunft erfolgen soll.

The German National Cohort (NAKO) is an ongoing, prospective multicenter cohort study, which started recruitment in 2014 and includes more than 205,000 women and men aged 19–74 years. The study data will be available to the global research community for analyses. Although the ultimate decision about the analytic methods will be made by the respective investigator, in this paper we provide the basis for a harmonized approach to the statistical analyses in the NAKO. We discuss specific aspects of the study (e.g., data collection, weighting to account for the sampling design), but also give general recommendations which may apply to other large cohort studies as well.

Context/Objective Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D. Design/Patients Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging. Results T2D patients (known diabetes duration: 2.5 [0.1; 5.0] years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P Conclusions Impaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.

Aims/hypothesis The aim of this work was to investigate diabetes incidence after infection with coronavirus disease-2019 (Covid-19). Individuals with acute upper respiratory tract infections (AURI), which are frequently caused by viruses, were selected as a non-exposed control group. Methods We performed a retrospective cohort analysis of the Disease Analyzer, which comprises a representative panel of 1171 physicians’ practices throughout Germany (March 2020 to January 2021: 8.8 million patients). Newly diagnosed diabetes was defined based on ICD-10 codes (type 2 diabetes: E11; other forms of diabetes: E12–E14) during follow-up until July 2021 (median for Covid-19, 119 days; median for AURI 161 days). Propensity score matching (1:1) for sex, age, health insurance, index month for Covid-19/AURI and comorbidity (obesity, hypertension, hyperlipidaemia, myocardial infarction, stroke) was performed. Individuals using corticosteroids within 30 days after the index dates were excluded. Poisson regression models were fitted to obtain incidence rate ratios (IRRs) for diabetes. Results There were 35,865 individuals with documented Covid-19 in the study period. After propensity score matching, demographic and clinical characteristics were similar in 35,865 AURI controls (mean age 43 years; 46% female). Individuals with Covid-19 showed an increased type 2 diabetes incidence compared with AURI (15.8 vs 12.3 per 1000 person-years). Using marginal models to account for correlation of observations within matched pairs, an IRR for type 2 diabetes of 1.28 (95% CI 1.05, 1.57) was estimated. The IRR was not increased for other forms of diabetes. Conclusions/interpretation Covid-19 confers an increased risk for type 2 diabetes. If confirmed, these results support the active monitoring of glucose dysregulation after recovery from mild forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Graphical abstract

IntroductionAs chronic systemic autoimmune disease, which can affect every organ, SLE is creating significant burden and increased mortality. Despite better outcomes over the past decades by optimising standard of care, new interventions are needed for further improvements. Changing strategy to ‘treat-to-target’ (T2T) may be a promising concept proven successful in other chronic diseases.Methods and analysisIn this cluster-randomised trial, SLE centres will be assigned 1:1:1 to standard of care (SoC), remission (no clinical disease activity+prednisolone ≤5 mg/day+Physician Global Assessment (PGA 0–3) ConclusionsThis is the first trial to assess if the implementation of a T2T concept in clinical care minimises damage accrual and improves HRQoL in patients with SLE. Comparison of remission and LLDAS will help to identify the target with the best benefit–risk ratio concerning attainability, adverse events and damage. The emphasis on SDM will strengthen patient autonomy and will improve both their satisfaction and medical condition.

Purpose The aims of this study were to analyze the prevalence and course of disordered eating behavior (DEB) in adolescents with intensively treated type I diabetes, describe differences in age-specific DEB symptoms, and identify predictors of current DEB. Methods Data were taken from 332/218 11- to 27-year-old participants (55.7% girls/women, mean age [SD] 17.8 [3.4] years, mean diabetes duration 14.9 [3.0] years) of two/three surveys of a Germany-wide longitudinal study on early-onset and long duration diabetes, respectively. A diabetes-adapted version of the SCOFF questionnaire was used to assess DEB. Both screening-based overall and age- and sex-specific prevalence of DEB and its symptoms were determined. To estimate transition probabilities between DEB states, first-order Markov transition models were implemented adjusting for previous sociodemographic, socioeconomic, and diabetes-specific covariates. Results The overall screening-based DEB prevalence among all 1,318 observations was 10.8% (95% confidence interval [CI]: 9.2%, 12.6%) with age-specific differences in symptom prevalence. Transition probabilities for developing/persistent DEB were twofold higher among female than male participants (risk ratio [RR] 2.3 [1.4, 3.9]/2.1 [1.3, 3.4]). In multiple adjusted regression, previous DEB (odds ratio [OR] 2.8 [95% CI 1.4, 5.6]), follow-up time (ORper 1-year increase 3.4 [1.4, 8.0]), and sex (ORgirls/women 2.1 [1.1, 3.9]) were the most important predictors of current DEB with further weaker associations for previous age and HbA1c. Conclusions Our results contribute to better understanding the course of DEB in patients with early-onset diabetes and emphasize the relevance of regular DEB screenings including the age group of young adults.

OBJECTIVE To evaluate whether the sodium–glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of −1.8% (95% CI −3.4, −0.2; P = 0.02) and relative change in LFC of −22% (−36, −7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change −2.5 kg [−3.7, −1.4]; P < 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (−74 mol/L [−108, −42]; P < 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P < 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D.

In a non-interventional study of older persons, we assessed the impact of changes in BMI and waist circumference (WC) on reversion from glucose- and HbA1c-defined prediabetes to normoglycaemia (in short: reversion) and on persistence of normoglycaemia. Moreover, we studied whether reversion reduced cardiovascular risk.From the population-based KORA S4/F4/FF4 cohort study conducted in Southern Germany, we utilized data from the second and third visit to the study center (median follow-up 6.5 years). We used two overlapping data sets, one with 563 persons with HbA1c6.5% (mean age 69 years, 51.5% men), one with 510 persons with glucose-based prediabetes or normal glucose tolerance. We calculated proportions of reversion, and estimated adjusted relative risks for the association between initial BMI/WC and change of BMI/WC, respectively, and reversion (and persistence of normoglycaemia, respectively). We estimated 10-year cardiovascular risks using the Framingham 2008 score. Overall, 27.3% of persons with HbA1c-defined prediabetes and 9.2% of persons with glucose-based prediabetes returned to normoglycaemia during follow-up. Lower initial BMI/WC and reduction of BMI/WC were associated with larger probabilities of returning to normoglycaemia (e.g., for HbA1c 5.7-6.4%, RR = 1.24 (95% CI: 1.09-1.41) per 1 kg/mIn older adults, even moderate weight reduction contributes to reversion from prediabetes to normoglycaemia and to maintaining normoglycaemia.

Non-alcoholic fatty liver disease (NAFLD) is associated with abnormal mitochondrial capacity. While oxidative capacity can be increased in steatosis, hepatic ATP decreases in long-standing diabetes. However, longitudinal studies on diabetes-related NAFLD and its relationship to hepatic energy metabolism are lacking.This prospective study comprised volunteers with type 1 (T1DM, n = 30) and type 2 (T2DM, n = 37) diabetes. At diagnosis and 5 years later, we usedAt diagnosis, individuals with T2DM had higher HCL and adipose tissue volumes, but lower whole-body insulin sensitivity than those with T1DM, despite comparable glycemic control. NAFLD was present in 38% of individuals with T2DM and 7% with T1DM. After 5 years, visceral adipose tissue only increased in individuals with T2DM, while HCL almost doubled in this group (p0.001), resulting in a 70% prevalence of NAFLD (independent of diabetes treatment). Changes in HCL correlated with adipose tissue volume and insulin resistance (r = 0.50 and r = 0.44, both p0.05). Pi decreased by 17% and 10% in individuals with T2DM and T1DM (p0.05), respectively. In T1DM, HCL did not change, whereas γATP decreased by 10% and correlated negatively with glycated hemoglobin (r = -0.56, p0.05).The rapid increase in HCL during the early course of T2DM likely results from enlarging adipose tissue volume and insulin resistance in response to impaired hepatic mitochondrial adaptation. The decrease of phosphorus metabolites in T1DM may be due to pharmacological insulin supply.Previous studies suggested that the impaired function of mitochondria, the power plants of cells, can promote fatty liver and type 2 diabetes mellitus. This study now shows that during the first 5 years of type 2 diabetes the increase in body fat content rapidly leads to a doubling of liver fat content, whereas the energy metabolism of the patients' livers progressively declines. These data suggest that fat tissue mass and liver mitochondria have an important role in the development of fatty liver disease in humans with diabetes.NCT01055093.

Asthma is one of the most common chronic diseases in both children and adults. Asthma first occurring in adulthood (adult-onset asthma, AOA) is associated with poorer prognosis compared to childhood-onset asthma (COA), which urgently calls for more research in this area. The aim of this work was to analyze the data on asthma collected in the German National Cohort and compare it with the German Health Interview and Examination Survey for Adults (DEGS), in particular regarding AOA.Our analysis was based on the dataset of the main questionnaire at mid-term of the German National Cohort baseline examination, comprising 101,723 participants. Variables considered in the analyses were self-reported diagnosis of asthma, age at first diagnosis, asthma treatment in the past 12 months, age, and sex.In the midterm dataset, 8.7% of women and 7.0% of men in the German National Cohort reported that they had ever been diagnosed with asthma. Approximately one third of participants with asthma received their initial diagnosis before their 18th birthday. COA affected 2.2% of women and 2.8% of men, whereas AOA affected 6.5% of women and 4.2% of men. During the previous 12 months, 33% of COA cases and 60% of AOA cases were medically treated.The proportion of persons affected by asthma in the German National Cohort, as well as observed patterns regarding age and gender, corresponds to other data sources such as DEGS. However, in our analysis, the proportion of individuals with AOA was higher than described in the literature. The increase in cumulative asthma diagnoses with age is markedly steeper in younger participants, indicating a rising trend over time.HINTERGRUND: Asthma bronchiale stellt über alle Bildungsschichten hinweg eine der häufigsten chronischen Erkrankungen im Kindes- und Erwachsenenalter dar. Im Erwachsenenalter erstmals auftretendes Asthma (Adult-onset Asthma, AOA) ist im Vergleich zu Childhood-onset Asthma (COA) mit einer schlechteren Prognose assoziiert, was verstärkte Untersuchungen in diesem Bereich erfordert. Ziel der Arbeit war es, Häufigkeiten und das Alter bei Erstdiagnose aus Selbstangaben zu Asthma bei Erwachsenen in der NAKO Gesundheitsstudie darzustellen und mit Daten der Studie zur Gesundheit Erwachsener in Deutschland (DEGS) zu vergleichen.Unsere Analyse beruht auf einem Datensatz zur Halbzeit der NAKO-Basiserhebung mit 101.284 Personen. Verwendete Variablen waren die Selbstangabe zum jemals ärztlich diagnostizierten Asthma, Alter bei Erstdiagnose, Behandlung in den letzten 12 Monaten, Alter und Geschlecht.Laut Datenbasis zur Halbzeit berichteten in der NAKO 8,7 % der Frauen und 7,0 % der Männer, dass bei ihnen jemals Asthma diagnostiziert wurde. Etwa bei einem Drittel der Teilnehmenden mit Asthma wurde die Diagnose bereits im Kindes‑/Jugendalter (18 Jahre) gestellt. Dabei waren 2,2 % der Frauen und 2,8 % der Männer von COA betroffen und 6,5 % der Frauen und 4,2 % der Männer von AOA. In den vorangegangenen 12 Monaten gaben 33 % der COA-Fälle und 60 % der AOA-Fälle an, ärztlich behandelt worden zu sein.Die Häufigkeit von Asthma in der NAKO Gesundheitsstudie in Abhängigkeit von Alter und Geschlecht entspricht weitgehend den Daten aus anderen Studien wie DEGS. Allerdings ist der AOA-Anteil höher als in der Literatur beschrieben. Der Anstieg der kumulativen Asthmadiagnosen ist bei den jüngeren Geburtsjahrgängen deutlich steiler, was für eine Zunahme über die Zeit spricht.

Using data from DISCOVER (NCT02322762; NCT02226822), a 3-year, global, observational study programme of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we assessed socioeconomic factors associated with hypoglycaemic events and fear of hypoglycaemia.Data were collected at baseline (second-line therapy initiation) and 6, 12 and 24 months. Factors associated with experiencing a hypoglycaemic event at baseline or during follow-up were determined using a hierarchical logistic regression model and an interval-censored survival analysis, respectively. Fear of hypoglycaemia was assessed using the hypoglycaemia fear survey-II (HFS-II).The overall proportion of patients reporting hypoglycaemic events during follow-up was 7.3%; this was higher in middle-income countries than in high-income countries (8.4% vs 5.8%, p 0.001). Factors associated with an increased risk of hypoglycaemia during follow-up included living in a country with a low gross national income, use of glucose-monitoring equipment and second-line treatment with insulin, meglitinides or sulphonylureas (versus metformin). Experiencing hypoglycaemia was associated with increased HFS-II worry and overall scores.Our results highlight the global inequity in the treatment of type 2 diabetes. Increased risk of hypoglycaemia in middle-income countries may be explained by limited treatment options and may be underestimated because of limited access to glucose-monitoring equipment.

In epidemiologic studies, standardised measurement of socio-demographic and employment-related factors is becoming increasingly important, as variables such as gender, age, education or employment status are factors influencing health and disease risks.The article gives an overview of the scientific background and assessment of socio-demographic factors in the German National Cohort Study. In addition, the distribution of individual characteristics in the cohort as well as relationships with health-related measures are presented by way of example.The analysis is based on the data of the first half of the baseline survey (n = 101,724). On this basis, we present the distribution of key socio-demographic characteristics and analyse relationships with exemplary selected health indicators (body mass index, self-reported health) to assess the validity of socio-demographic data measurements.On average, study participants were 52.0 years old (SD = 12.4). Of the participants, 53.6% were women, 54.3% had high education, 60.1% were married and 72% were employed while 3.4% were unemployed. Well-established correlations between socio-demographic factors and health could be reproduced with the German National Cohort data. For example, low education, old age and unemployment were associated with an increased prevalence of obesity and poor self-reported health.The German National Cohort provides a comprehensive measurement of socio-demographic characteristics. Combined with a wide range of health data and the longitudinal measurements available in the future, this opens up new opportunities for health science and social epidemiological research in Germany.

High levels of adiposity in the population have a major impact on various diseases, but previous epidemiologic studies have largely been restricted to simple anthropometric measures such as the body mass index (BMI), an imperfect predictor of disease risk. There is a critical need for the use of improved measures of relative weight and body composition in large-scale, population-based research.The current article presents initial descriptive results of body composition and fat distribution based on the midterm baseline dataset of the German National Cohort, which included 101,817 participants who were examined in 18 study centers in Germany between March 2014 and March 2017. The anthropometric measures encompassed body weight, height, waist and hip circumference, bioelectrical impedance analysis (BIA), sonography of abdominal adipose tissue, 3D-body scanning, and magnetic resonance imaging.BMI analyses showed that 46.2% of men and 29.7% of women were overweight and 23.5% of men and 21.2% of women were obese. On average, women in almost all age groups demonstrated more subcutaneous adipose tissue layer thickness than men. The mean values of visceral adipose tissue layer thickness, on the other hand, were higher among men than among women in all age groups and increased continuously across age groups in both sexes.The comprehensive assessment of body composition and fat distribution provides novel future opportunities for detailed epidemiologic analyses of overweight and adiposity in relation to the development of chronic diseases.

Aims/hypothesis Diabetes has been identified as a risk factor for poor prognosis of coronavirus disease-2019 (COVID-19). The aim of this study is to identify high-risk phenotypes of diabetes associated with COVID-19 severity and death. Methods This is the first edition of a living systematic review and meta-analysis on observational studies investigating phenotypes in individuals with diabetes and COVID-19-related death and severity. Four different databases were searched up to 10 October 2020. We used a random effects meta-analysis to calculate summary relative risks (SRR) with 95% CI. The certainty of evidence was evaluated by the GRADE tool. Results A total of 22 articles, including 17,687 individuals, met our inclusion criteria. For COVID-19-related death among individuals with diabetes and COVID-19, there was high to moderate certainty of evidence for associations (SRR [95% CI]) between male sex (1.28 [1.02, 1.61], n = 10 studies), older age (>65 years: 3.49 [1.82, 6.69], n = 6 studies), pre-existing comorbidities (cardiovascular disease: 1.56 [1.09, 2.24], n = 8 studies; chronic kidney disease: 1.93 [1.28, 2.90], n = 6 studies; chronic obstructive pulmonary disease: 1.40 [1.21, 1.62], n = 5 studies), diabetes treatment (insulin use: 1.75 [1.01, 3.03], n = 5 studies; metformin use: 0.50 [0.28, 0.90], n = 4 studies) and blood glucose at admission (≥11 mmol/l: 8.60 [2.25, 32.83], n = 2 studies). Similar, but generally weaker and less precise associations were observed between risk phenotypes of diabetes and severity of COVID-19. Conclusions/interpretation Individuals with a more severe course of diabetes have a poorer prognosis of COVID-19 compared with individuals with a milder course of disease. To further strengthen the evidence, more studies on this topic that account for potential confounders are warranted. Registration PROSPERO registration ID CRD42020193692. Graphical abstract

Objective To analyze the interrelationship of metabolic control, age- and sex-adjusted body mass index, and daily insulin dose and to identify heterogeneous multivariate developmental curves from childhood to young adulthood in a large cohort of children with type 1 diabetes (T1D) Study design Data were extracted from the diabetes follow-up registry DPV. Longitudinal data from 9239 participants with T1D age 8-18 years with diabetes duration ≥2 years and ≥5 years of follow-up were analyzed. We applied group-based multitrajectory modeling to identify latent groups of subjects following similar developmental curves across outcomes (hemoglobin A1c [HbA1c], age/sex-standardized body mass index [BMI-SDS], daily insulin dose per kg). Group number was based on Bayes information criterion and group size (≥5%). Results The group-based multitrajectory approach revealed 5 heterogeneous 3-variate trajectories during puberty. Individuals with stable good metabolic control, high-normal increasing BMI-SDS, and rising insulin dose patterns were classified as group 1 (33%). Group 2 (20%) comprised youths with intermediate-increasing HbA1c, low BMI-SDS, and steeply increasing insulin dose trajectories. Group 3 (11%) followed intermediate-rising HbA1c and high-normal increasing BMI-SDS developmental curves, while insulin dose increased steeply. In group 4 (14%), both high-increasing HbA1c and insulin dose trajectories were observed, while BMI-SDS was stable-normal. Group 5 (22%) included subjects with intermediate-rising HbA1c patterns, high-increasing BMI-SDS, and increasing insulin dose patterns. Conclusions This study identified 5 distinct 3-variate curves of HbA1c, BMI-SDS, and insulin dose during puberty among youths with T1D. This approach demonstrates a considerable heterogeneity highlighting the importance of personalized medical care.

In systematic reviews, meta-analyses are routinely applied to summarize the results of the relevant studies for a specific research question. If one can assume that in all studies the same true effect is estimated, the application of a meta-analysis with common effect (commonly referred to as fixed-effect meta-analysis) is adequate. If between-study heterogeneity is expected to be present, the method of choice is a meta-analysis with random effects. The widely used DerSimonian and Laird method for meta-analyses with random effects has been criticized due to its unfavorable statistical properties, especially in the case of very few studies. A working group of the Cochrane Collaboration recommended the use of the Knapp-Hartung method for meta-analyses with random effects. However, as heterogeneity cannot be reliably estimated if only very few studies are available, the Knapp-Hartung method, while correctly accounting for the corresponding uncertainty, has very low power. Our aim is to summarize possible methods to perform meaningful evidence syntheses in the situation with only very few (ie, 2-4) studies. Some general recommendations are provided on which method should be used when. Our recommendations are based on the existing literature on methods for meta-analysis with very few studies and consensus of the authors. The recommendations are illustrated by 2 examples coming from dossier assessments of the Institute for Quality and Efficiency in Health Care.

OBJECTIVE In Germany, as in many other countries, nationwide data on mortality attributable to diagnosed diabetes are not available. This study estimated the absolute number of excess deaths associated with diabetes (all types) and type 2 diabetes in Germany. RESEARCH DESIGN AND METHODS A prevalence approach that included nationwide routine data from 64.9 million people insured in the German statutory health insurance system in 2010 was used for the calculation. Because nationwide data on diabetes mortality are lacking in Germany, the mortality rate ratio from the Danish National Diabetes Register was used. The absolute number of excess deaths associated with diabetes was calculated as the number of deaths due to diabetes minus the number of deaths due to diabetes with a mortality that was as high as in the population without diabetes. Furthermore, the mortality population-attributable fraction was calculated. RESULTS A total of 174,627 excess deaths were due to diabetes in 2010, including 137,950 due to type 2 diabetes. Overall, 21% of all deaths in Germany were attributable to diabetes and 16% were attributable to type 2 diabetes. Most of the excess deaths (34% each) occurred in the 70- to 89-year-old age-group. CONCLUSIONS In this first nationwide calculation of excess deaths related to diabetes in Germany, the results suggest that the official German estimates that rely on information from death certificates are grossly underestimated. Countries without national cohorts or diabetes registries could easily use this method to estimate the number of excess deaths due to diabetes.

Aim The diet of people with type 1 diabetes may differ from that of healthy peers due to disease-related factors that may affect the course of diabetes. This cross-sectional study sought to compare meal and snacking frequency and corresponding carbohydrate intake among adolescents with intensively-treated type 1 diabetes and healthy peers and to analyze their association with glycemic control among diabetes patients. Methods Nutritional data of 712 11- to Results After comprehensive adjustment, diabetes patients had, on average, 4.6 [95% confidence interval 3.6, 5.5] more meals or snacks/week but consumed 75.9 [64.5, 87.3] fewer grams of carbohydrates/day than the comparison group. Diabetes subjects also consumed breakfast, lunch, dinner, and snacks more frequently but ate fewer carbohydrates at all eating occasions. Total carbohydrate intake and carbohydrate intake at breakfast were associated with higher HbA1c levels, while increased breakfast frequency was associated with lower HbA1c levels. Conclusion Eating frequency and carbohydrate intake differed between adolescents with early-onset type 1 diabetes and non-diabetic peers. The observed associations with glycemic control challenge the concept of a completely unregulated eating frequency and carbohydrate intake for people on intensified insulin therapy.

OBJECTIVE Worsening of glycemic control in type 1 diabetes during puberty is a common observation. However, HbA1c remains stable or even improves for some youths. The aim is to identify distinct patterns of glycemic control in type 1 diabetes from childhood to young adulthood. RESEARCH DESIGN AND METHODS A total of 6,433 patients with type 1 diabetes were selected from the prospective, multicenter diabetes patient registry Diabetes-Patienten-Verlaufsdokumentation (DPV) (follow-up from age 8 to 19 years, baseline diabetes duration ≥2 years, HbA1c aggregated per year of life). We used latent class growth modeling as the trajectory approach to determine distinct subgroups following a similar trajectory for HbA1c over time. RESULTS Five distinct longitudinal trajectories of HbA1c were determined, comprising group 1 = 40%, group 2 = 27%, group 3 = 15%, group 4 = 13%, and group 5 = 5% of patients. Groups 1–3 indicated stable glycemic control at different HbA1c levels. At baseline, similar HbA1c was observed in group 1 and group 4, but HbA1c deteriorated in group 4 from age 8 to 19 years. Similar patterns were present in group 3 and group 5. We observed differences in self-monitoring of blood glucose, insulin therapy, daily insulin dose, physical activity, BMI SD score, body-height SD score, and migration background across all HbA1c trajectories (all P ≤ 0.001). No sex differences were present. Comparing groups with similar initial HbA1c but different patterns, groups with higher HbA1c increase were characterized by lower frequency of self-monitoring of blood glucose and physical activity and reduced height (all P < 0.01). CONCLUSIONS Using a trajectory approach, we determined five distinct longitudinal patterns of glycemic control from childhood to early adulthood. Diabetes self-care, treatment differences, and demographics were related to different HbA1c courses.

AIM For many European countries, including Germany, no valid estimates are available on age at diagnosis of Type 2 diabetes. Thus, we aimed to estimate the age at diagnosis in Germany. METHODS Age at diagnosis of Type 2 diabetes in Germany was estimated based on Type 2 diabetes prevalence and incidence and the age distribution of the German population. Age- and sex-specific incidence and prevalence in 2014/2015, based on claims data from statutory health insurance (n= 69 000 000, ~85% of the German population), and the age pyramid for Germany in 2015 were used for the calculation. Age at Type 2 diabetes diagnosis was stratified by sex. CIs were estimated using bootstrap methods. In addition, the age range in which 50% of the population received a diagnosis of Type 2 diabetes was calculated (the interquartile range). RESULTS The mean ± sd age at Type 2 diabetes diagnosis in 2015 was 61.0 ± 13.4 years (95% CI 60.9-61.0) in men. Women were diagnosed ~2 years later than men (mean age 63.4 ± 14.9 years; 95% CI 63.4-63.5). The age range in which 50% of the population was diagnosed with diabetes was 53-72 years for men and 54-76 years for women. CONCLUSIONS The sex differences are mainly attributable to a higher incidence of Type 2 diabetes in men than women during middle age and the higher absolute number of women in the older ages. The early age at diabetes diagnosis compared to average life expectancy means that the risk of diabetes-related complications is increased.

We used data from the GUIDANCE Study to determine the care of people with type 2 diabetes according to age and accompanying cardiovascular diseases and to assess indicators of overtreatment of glycaemia. The GUIDANCE study was a retrospective, cross-sectional study from 2009–2010 based on the records of 7597 people in France, Belgium, Italy, the Netherlands, Sweden, UK, Ireland and Germany. We analysed the level of metabolic control achieved and blood glucose-lowering medication used in different age groups and in relation to accompanying diseases. 4.459 patients (59.1%) were 65 years or older. Their HbA1c levels were similar to those with

Purpose Recent studies highlighted that early diabetic neurodegeneration is present before microvascular changes are visible. Retinal neurodegeneration can decrease retinal layer thickness. We aimed to determine whether decreased retinal layer thickness is present already in the early time course of disease. Methods A cross-sectional analysis of patients and healthy adults from the German Diabetes Study (GDS, ClinicalTrials.gov Identifier number: CT01055093, https://clinicaltrials.gov/ct2/show/NCT01055093). Inclusion criteria were a diagnosis of diabetes mellitus (DM) within the last 12 months. Retinal layers thickness in the nasal pericentral segment was measured by spectral domain ocular coherence tomography (SD-OCT). For statistical analysis proc mixed (sas-version 9.4) was used. Results One hundred and seventy-eight eyes of 89 patients with type 1 DM (58 males, age 36 ± 11 years, BMI 25.5 ± 4.2 kg/m²) and 242 eyes of 121 patients with type 2 DM (84 males, age 53 ± 10 years, BMI 31.9 ± 6.3 kg/m²) with a disease duration of less than 1 year were compared to 76 eyes of 38 controls (27 males, age 41 ± 16 years, BMI 27.3 ± 6.4 kg/m²). Analysis of retinal layer thickness and visual function did not reveal a significant difference between patients and controls. Conclusion In the early course of DM potential, neurodegeneration does not relate to measureable changes of retinal layer thickness.

The aim of this study was to investigate the modifying effect of the glucose transporter (GLUT2) gene SLC2A2 (rs8192675) variant on the glycaemic response to metformin in individuals recently diagnosed with type 2 diabetes. Individuals with type 2 diabetes (n = 508) from the prospective German Diabetes Study (age [mean ± SD] 53 ± 10 years; 65% male; BMI 32 ± 6 kg/m2, metformin use 57%) underwent detailed metabolic characterisation (hyperinsulinaemic–euglycaemic clamp, IVGTT) during the first year after diagnosis. Participants provided self-reported data from the time of diagnosis. The change in fasting glucose was assessed in relation to SLC2A2 genotype and glucose-lowering treatment using two-way ANCOVA with gene×treatment interactions adjusted for age, sex, BMI and diabetes duration. The C variant allele of rs8192675 was associated with a higher prevalence of diabetes symptoms at diabetes diagnosis. In the metformin monotherapy group only, patients with a C allele showed a larger adjusted blood glucose reduction during the first year after diabetes diagnosis than patients with the TT genotype (6.3 mmol/l vs 3.9 mmol/l; genotype difference 2.4 mmol/l, p = 0.02; p value for genotype interaction [metformin monotherapy vs non-pharmacological therapy]

PurposeTo analyse the association of area-level deprivation (German Index of Multiple Deprivation, GIMD 2010) with health- and disease-related quality of life (QoL) and glycaemic control (HbA1c) jointly with individual-level socioeconomic status (SES) in young patients with preschool-onset type 1 diabetes.MethodsA total of 425 male and 414 female patients aged 11-21years from a Germany-wide population-based survey completed the generic KINDL-R, the DISABKIDS chronic-generic module (DCGM-12), and the DISABKIDS diabetes-specific module with impact and treatment scales (QoL indicators; range 0-100 with higher scores representing better QoL). To analyse the association of area-level deprivation and SES with QoL and HbA1c, multiple linear regression models were applied adjusting for sociodemographic and health-related variables.ResultsMean QoL scores (SD) were 73.2 (12.2) for the KINDL-R, 76.1 (16.1) for the DCGM-12, 66.2 (19.9) for diabetes impact, and 56.4 (27.3) for diabetes treatment (DISABKIDS). Mean HbA1c was 8.3 (1.4)%. While both QoL outcomes and HbA1c level improved with increasing individual SES, no association was observed between area-level deprivation (GIMD 2010) and either outcome.ConclusionsCompared with individual SES, area-level deprivation seems to be of minor importance for QoL and glycaemic control in young people with early-onset type 1 diabetes.

Background/objectives: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose–response relationship across number of cigarettes and whether this differs by sex remains unclear. Subject/methods: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. Results: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother–child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02–1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. Conclusions: A linear dose–response relationship of maternal smoking was observed in the range of 1–15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

Little evidence exists on the impact of diabetes risk scores, e.g. on physicians and patient’s behavior, perceived risk of persons, shared-decision making and particularly on patient’s health. The aim of this study is to investigate the impact of a non-invasive type 2 diabetes risk prediction model in the primary health care setting as component of routine health checks on change in physical activity. Parallel group cluster randomized controlled trial including 30 primary care physicians (PCPs) and 300 participants in the region of Dusseldorf and surrounding urban and rural municipalities, West Germany. On cluster level, PCPs will be randomized into intervention or control group using a biased coin minimization technique. Participants in the control group are going to have a routine health check “Check-up 35” which is recommended biannually for all people ≥35 years of age in Germany. In the intervention group, the routine health check is expanded by usage of a non-invasive diabetes risk prediction model (German Diabetes Risk Score). Primary outcome is change in physical activity after 1 year. Secondary outcomes include aspects of targeted counseling, motivation of participant’s to change lifestyle, perceived and objectively measured diabetes risk, acceptance of diabetes risk scores, quality of life, depression and anxiety. Patients will be followed over 12 months. Hierarchical or mixed models will be conducted, including a random intercept to adjust for cluster, the respective baseline value, and covariates to compare the groups. This pragmatic cluster randomized controlled trial will enhance our knowledge on the clinical impact of diabetes risk scores for the first time in the real-life primary health care setting. ClinicalTrials.gov NCT03234322 , registered on July 28, 2017.

Aim To describe for the first time the direct costs of Type 2 diabetes treatment by analysing nationwide routine data from statutory health insurance in Germany. Methods This cost-of-illness-study was based on a 6.8% random sample of all German people with statutory health insurance (4.3 out of 70 million people). The healthcare expenses show direct per capita costs from the payer perspective. Healthcare expenses for physicians, dentists, pharmacies, hospitals, sick benefits and other healthcare costs were considered. Per capita costs, cost ratios for people with Type 2 diabetes and without diabetes as well as diabetes-attributable costs were calculated. Results Per capita costs for people with Type 2 diabetes amounted to €4,957 in 2009 and €5,146 in 2010. People with Type 2 diabetes had 1.7-fold higher health expenses than people without diabetes. The largest differences in health expenses were found for prescribed medication from pharmacies (cost ratio diabetes/no diabetes: 2.2) and inpatient treatment (1.8). Ten percent of the total statutory health insurance expense, in total €16.1 billion, was attributable to the medical care of people with Type 2 diabetes. Conclusions This nationwide study indicates that one in 10 Euros of healthcare expenses is spent on people with Type 2 diabetes in Germany. In the future, national statutory health insurance data can be used to quantify time trends of costs in the healthcare system.

Background Precise blood pressure (BP) measurements are central for the diagnosis of hypertension in clinical and epidemiological studies. The purpose of this study was to quantify the variability in BP associated with arm side, body position, and successive measurements in the setting of a population-based observational study. Additionally, we aimed to evaluate the influence of different measurement conditions on prevalence of hypertension. Methods The sample included 967 men and 812 women aged 45 to 83 years at baseline. BP was measured according to a standardized protocol with oscillometric devices including three sitting measurements at left arm, one simultaneous supine measurement at both arms, and four supine measurements at the arm with the higher BP. Hypertension was defined as systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg. Variability in SBP and DBP were analysed with sex-stratified linear covariance pattern models. Results We found that overall, no mean BP differences were measured according to arm-side, but substantial higher DBP and for men also higher SBP was observed in sitting than in supine position and there was a clear BP decline by consecutive measurement. Accordingly, the prevalence of hypertension depends strongly on the number and scheme of BP measurements taken to calculate the index values. Conclusions Thus, BP measurements should only be compared between studies applying equal measurement conditions and index calculation. Moreover, the first BP measurement should not be used to define hypertension since it overestimates BP. The mean of second and third measurement offers the advantage of better reproducibility over single measurements. Electronic supplementary material The online version of this article (doi:10.1186/s12872-017-0468-7) contains supplementary material, which is available to authorized users.

Objective: Early detection of diabetes and prediabetic states is beneficial for patients, but may be delayed by patientś being overly optimistic about their own health. Therefore, we assessed how persons without known diabetes perceive their risk of having or developing diabetes, and we identified factors associated with perception of diabetes risk. Research design and methods: 1,953 participants without previously known diabetes from the population-based, German KORA FF4 Study (59.1 years, 47.8% men) had an oral glucose tolerance test. They estimated their probability of having undiagnosed diabetes mellitus (UDM) on a six category scale, and assessed whether they were at risk of developing diabetes in the future. We cross-tabulated glycemic status with risk perception, and fitted robust Poisson regression models to identify determinants of diabetes risk perception. Results: 74% (95% CI: 65-82) of persons with UDM believed that their probability of having undetected diabetes was low or very low. 72% (95% CI: 69-75) of persons with prediabetes believed that they were not at risk of developing diabetes. In people with prediabetes, seeing oneself at risk of diabetes was associated with self-rated poor general health (prevalence ratio (PR) = 3.1 (95% CI: 1.4-6.8), parental diabetes (PR = 2.6, 1.9-3.4), high educational level (PR = 1.9 (1.4-2.5)), lower age (PR = 0.7, 0.6-0.8, per 1 standard deviation increase), female sex (PR = 1.2, 0.9-1.5) and obesity (PR = 1.5, 1.2-2.0). Conclusions: People with undiagnosed diabetes or prediabetes considerably underestimate their probability of having or developing diabetes. Contrary to associations with actual diabetes risk, perceived diabetes risk was lower in men, lower educated and older persons. Copyright: OA gold

Objectives The propensity score (PS) method is increasingly used to assess treatment effects in nonrandomized trials. Although there are several methods to use the PS for analysis, matching treated and untreated patients by the PS is recommended by most researchers among other reasons because this allows assessing covariate balance before and after matching. Although the standardized difference is commonly applied to compute a measure of balance, it has two deficiencies: its distribution depends on the sample size and one cannot compare standardized differences for baseline covariates on different scales, that is, continuous, binary, ordinal, or nominal covariates. Study Design and Setting We introduce the z -difference to measure covariate balance in matched PS analyses and illustrate it by a recent matched PS analysis from cardiac surgery. Results The z -difference is simple to calculate, can be used with second moments for continuous covariates, and in most cases can also be computed from published data. Its full advantage emerges after displaying z -differences in a Q – Q plot, which allows balance comparisons with respect to (1) a randomized trial and (2) a perfectly matched PS analysis in the sense of Rubin and Thomas. Conclusion The z -difference can be used to measure covariate balance in matched PS analyses.

Aim To validate the German Diabetes Risk Score within the population-based cohort of the Cardiovascular Disease – Living and Ageing in Halle (CARLA) study. Methods The sample included 582 women and 719 men, aged 45–83 years, who did not have diabetes at baseline. The individual risk of every participant was calculated using the German Diabetes Risk Score, which was modified for 4 years of follow-up. Predicted probabilities and observed outcomes were compared using Hosmer–Lemeshow goodness-of-fit tests and receiver–operator characteristic analyses. Changes in prediction power were investigated by expanding the German Diabetes Risk Score to include metabolic variables and by subgroup analyses. Results We found 58 cases of incident diabetes. The median 4-year probability of developing diabetes based on the German Diabetes Risk Score was 6.5%. The observed and predicted probabilities of developing diabetes were similar, although estimation was imprecise owing to the small number of cases, and the Hosmer–Lemeshow test returned a poor correlation (chi-squared = 55.3; P = 5.8*10-12). The area under the receiver–operator characteristic curve (AUC) was 0.70 (95% CI 0.64–0.77), and after excluding participants ≥66 years old, the AUC increased to 0.77 (95% CI 0.70–0.84). Consideration of glycaemic diagnostic variables, in addition to self-reported diabetes, reduced the AUC to 0.65 (95% CI 0.58–0.71). A new model that included the German Diabetes Risk Score and blood glucose concentration (AUC 0.81; 95% CI 0.76–0.86) or HbA1c concentration (AUC 0.84; 95% CI 0.80–0.91) was found to peform better. Conclusions Application of the German Diabetes Risk Score in the CARLA cohort did not reproduce the findings in the European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam study, which may be explained by cohort differences and model overfit in the latter; however, a high score does provide an indication of increased risk of diabetes.

Background/Aims: Dry weight estimation in hemodialysis patients is still a substantial problem. Despite meticulous clinical assessment, fluid overload is common, leading to hypertension and left ventricular hypertrophy (LVH). Segmental calf bioimpedance spectroscopy (cBIS) is a novel tool for dry weight assessment. Here we tested the hypothesis, that its clinical routine use reduces arterial hypertension and left ventricular mass. Methods: Left ventricular mass (determined by magnetic resonance imaging), blood pressure and antihypertensive medication (defined daily doses, ddd) were assessed at baseline (BL). Thereafter post-dialytic target weight was reduced until cBIS-defined dry weight was reached (DW). During a 6-month follow up, DW was re-evaluated monthly by cBIS and end-dialytic weight was adjusted correspondingly. At the end, left ventricular mass, blood pressure and antihypertensive medication were determined a 3rd time (follow-up, FU). Results: Eleven out of 15 patients were available for analysis after 6 months. Left ventricular mass showed a declining trend during the study period (Mean±SD; BL 145±54g; DW 142±55g; FU 137±52g; p=0.61, linear mixed model). Comparable results were obtained for systolic blood pressure (BL 158±18mmHg; DW 144±19mmHg; FU 149±21mmHg; p=0.07), and antihypertensive medication (BL 3.28±2.82ddd; DW 2.86±2.81ddd; FU 3.36±3.05ddd; p=0.37). Conclusions: We conclude that attainment of dry weight assessed by cBIS tends to reduce left ventricular mass and blood pressure while antihypertensive medication remains unchanged. While the study was underpowered, its results provide an important hypothesis generating data basis for the design of larger studies.

Aims The aim of this study was to investigate whether insulin sensitivity, beta-cell function or glycaemic control at diagnosis predict initiation of second-line treatment in newly diagnosed type 2 diabetes. Research design and methods Type 2 diabetes patients (n = 138) undergoing initial metformin monotherapy (age [mean ± SD], 52 ± 10 years; 67% males; BMI, 32 ± 6 kg/m2 ) from the prospective German Diabetes Study cohort (n = 398) were included. Patients remained under care of their general practitioners, yet underwent detailed metabolic characterization after diabetes diagnosis for study purposes (hyperinsulinemic-euglycemic clamp, M value; i.v. glucose tolerance test, incremental C-peptide area under the curve0-60 minutes, CP iAUC). The associations of baseline M value, CP iAUC, fasting glucose and HbA1c with time to second-line therapy were assessed using parametric survival analysis, accounting for interval-censoring. Results Second-line treatment was initiated in 26% of newly diagnosed type 2 diabetes patients within the first 3.3 years after diagnosis, using mostly DPP-4 inhibitors or GLP-1 receptor agonists (64%). In age-, sex- and BMI-adjusted survival models, higher baseline HbA1c and fasting glucose values were associated with earlier treatment intensification. Lower baseline M value and C-peptide secretion (CP iAUC) were also related to an earlier initiation of second-line treatment. In the best multivariable model, baseline HbA1c ≥ 7% (hazard ratio, HR; 95% CI: 3.18; 1.35-7.50) and fasting glucose ≥140 mg/dL (HR, 2.45; 95% CI, 1.04-5.78) were associated with shorter time to second-line therapy, adjusting for age, sex and BMI. Conclusions Baseline hyperglycaemia is a strong predictor of requirement of early intensification of glucose-lowering therapy in newly diagnosed type 2 diabetes.

Objectives Although transcatheter aortic valve implantation was the treatment of choice in inoperable and high-risk patients, the effect of transcatheter aortic valve implantation relative to conventional aortic valve replacement via ministernotomy in patients with moderate surgical risk remains unclear. Methods We consecutively enrolled patients who underwent minimally invasive aortic valve replacements via ministernotomy (n = 1929), transapical (n = 607), and transfemoral (n = 1273) aortic valve implantations from a single center during the period from July 2009 to July 2017. Of those, we conducted a 1:1:1 propensity score matching according to 23 preoperative risk factors. Results We were able to find 177 triplets (n = 531). The median European System for Cardiac Operative Risk Evaluation II was 3.0% versus 3.4% versus 2.9%, and Society of Thoracic Surgeons Predicted Risk of Mortality was 3.2% versus 3.6% versus 3.4%, respectively. According to the Valve Academic Research Consortium 2 criteria, there were no significant periprocedural differences regarding 30-day mortality (2.3% minimally invasive aortic valve replacement vs 4.5% transapical transcatheter aortic valve implantation vs 1.7% transfemoral transcatheter aortic valve implantation, P = .34), stroke (1.1% minimally invasive aortic valve replacement vs 0.6% transapical transcatheter aortic valve implantation vs 1.7% transfemoral transcatheter aortic valve implantation, P = .84), or myocardial infarction (0.6% minimally invasive aortic valve replacement vs 0.0% transapical transcatheter aortic valve implantation vs 0.0% transfemoral transcatheter aortic valve implantation, P = .83). Both intensive care and hospitalization times were significantly longer in the transapical group. Regarding midterm survival, transapical transcatheter aortic valve implantation was associated with a tendency toward a less favorable outcome (hazard ratio, 1.48; 95% confidence interval, 0.95-2.31; P = .17) compared with minimally invasive aortic valve replacement. Conclusions In this real-world propensity score–matched minimally invasive aortic valve replacement, transapical transcatheter aortic valve implantation, transfemoral transcatheter aortic valve implantation cohort of intermediate-risk patients, early mortality was not significantly different, whereas the rates of periprocedural complications were different depending on the approach. During follow-up, there was a tendency in the transapical transcatheter aortic valve implantation group toward a less favorable survival outcome, although there was no significant difference among the 3 groups.

The standardized protocol for performing the strip patch test has proven to be valid, but evidence on its reliability is still missing.To estimate the parallel-test reliability of the strip patch test as compared with the conventional patch test.In this multicentre, prospective, randomized, investigator-blinded reliability study, 132 subjects were enrolled. Simultaneous duplicate strip and conventional patch tests were performed with the Finn ChambersParallel-test reliability values of the three standard patch test preparations turned out to be acceptable, with slight advantages for the strip patch test. The differences in reliability were 9% (95%CI: -8% to 26%) for nickel sulfate and 23% (95%CI: -16% to 63%) for potassium dichromate, both favouring the strip patch test.The standardized strip patch test method for the detection of allergic contact sensitization in patients with suspected allergic contact dermatitis is reliable. Its application in routine clinical practice can be recommended, especially if the conventional patch test result is presumably false negative.

Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1–4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1–4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates β1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both β1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance. In mouse and human liver models, blood vessel perfusion and mechanical stretching release angiocrine signals from endothelial cells that lead to hepatocyte survival and liver growth.

Background Screening and detection of cases are a common public health priority for treatable chronic conditions with long subclinical periods. However, the validity of commonly-used metrics from surveillance systems for rates of detection (or case-finding) have not been evaluated. Methods Using data from a Danish diabetes register and a recently developed illness-death model of chronic diseases with subclinical conditions, we simulate two scenarios of different performance of case-finding. We report different epidemiological indices to assess case-finding in both scenarios and compare the validity of the results. Results The commonly used ratio of detected cases over total cases may lead to misleading conclusions. Instead, the ratio of undetected cases over persons without a diagnosis is a more valid index to distinguish the quality of case-finding. However, incidence-based measures are preferable to prevalence based indicators. Conclusion Prevalence-based indices for assessing case-finding should be interpreted with caution. If possible, incidence-based indices should be preferred. Electronic supplementary material The online version of this article (doi:10.1186/s12874-017-0328-2) contains supplementary material, which is available to authorized users.

Introduction: There is only limited quantitative information on the association between intake of sleep disturbing drugs and nocturnal sleep disturbances. Information on sleep disturbing effects of drugs mostly derives from clinical trials with highly selected patient collectives. As these patient collectives[for full text, please go to the a.m. URL], GMDS 2015; 60. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Objectives Aim was to examine the relationship between individually perceived changes in psychosocial stressors associated with German reunification and cardiovascular effects. We hypothesised that higher levels of psychosocial stress related to German reunification were associated with an increase in cardiovascular risk factors and cardiovascular diseases (CVDs). Design Cross-sectional data from 2 cohort studies in East Germany were used: Cardiovascular Disease, Living and Ageing in Halle Study (CARLA), and Study of Health in Pomerania (SHIP). Setting 2 populations in East Germany. Participants CARLA study: 1779 participants, aged 45–83 years at baseline (812 women), SHIP study: 4308 participants, aged 20–79 years at baseline (2193 women). Primary and secondary outcome measures Psychosocial stressors related to reunification were operationalised by the Reunification Stress Index (RSI; scale from 0 to 10). This index was composed of questions that were related to individually perceived changes in psychosocial stressors (occupational, financial and personal) after reunification. To examine the associations between the RSI and each stressor separately with cardiovascular risk factors and CVD, regression models were used. Results RSI was associated with CVD in women (RR=1.15, 95% CI 1.00 to 1.33). Cardiovascular risk factors were associated with RSI for both men and women, with strongest associations between RSI and diabetes in women (RR=1.10, 95% CI 1.01 to 1.20) and depressive disorders in men (RR=1.15, 95% CI 1.07 to 2.77). The change in occupational situation related to reunification was the major contributing psychosocial stressor. We observed a strong association with CVD in women who experienced occupational deterioration after reunification (RR=4.04, 95% CI 1.21 to 13.43). Conclusions Individually perceived deterioration of psychosocial stressors (occupational, financial and personal) related to German reunification was associated with cardiovascular risk factors and CVD. The associations were stronger for women than for men. An explanation for these findings could be that women were more often affected by unemployment after reunification. Morbidity and mortality follow-up of both cohorts could enhance the results.

OBJECTIVE: To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany. METHODS: Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison. RESULTS: Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups (

Descriptive epidemiologic features of testicular cancer suggest that the etiologies of seminoma and nonseminoma of the testis differ. To address this, the authors conducted a systematic review of 150 case-control and cohort studies of the etiology of testicular cancer including 1,148 relative risk estimates, stratified by histologic subgroup, reflecting 631 exposures. Their results do not support the hypothesis that seminoma and nonseminoma have different etiologies among adolescents and young men. To date, only descriptive epidemiologic features, including incidence age patterns and incidence time trends of seminoma and nonseminoma, provide evidence suggesting different etiologies, especially among newborns, infants, and elderly men.

Objective In a German multicenter case–control study of lumbar disc diseases, we calculated risk and rate advancement periods (RAP) for physical workload. Methods Patients aged 25–70 years with clinically and radiologically verified lumbar disc herniation (286 males, 278 females) or symptomatic lumbar disc narrowing (145 males, 206 females) were compared with population control subjects (453 males and 448 females). For this analysis, all manual handling of objects of about ≥5 kg and postures with trunk inclination of ≥20 °, as assessed by technical experts, were included in the calculation of cumulative lumbar load, determined by biomechanical model calculations. Logistic regression analysis was applied to calculate RAP, adjusted for region. Results We found a steep positive dose–response relationship between age and lumbar disc narrowing among men as well as women; however, we did not find a monotonic increase in lumbar disc herniation risk with age. As a monotonic increase in disease risk with age constitutes a fundamental assumption underlying the RAP concept, we restricted our RAP analysis to cases with symptomatic lumbar disc narrowing. Among men, there was a positive dose–response relationship between the cumulative lumbar load and the acceleration of lumbar disc narrowing. In the highest exposure category, a RAP of 28.0 years [95% confidence interval (95% CI) 9.7–46.3 years] was found. Among women, the RAP was 8.8 years (95% CI 2.4–15.2 years) in the highest exposure category. Conclusion This study emphasizes the conceptual importance of risk acceleration – causation not only comprises the occurrence of a disease (that without a specific exposure would not have occurred at all) but also the accelerated occurrence of a disease (that without exposure would have occurred later in life).

Background: As a modification of patch testing, the strip patch test was established to obtain more sensitive and reliable test results. Comparative data on diagnostic accuracy for both tests are missing. Objectives: To compare the diagnostic accuracy of strip patch tests and patch tests in detecting sensitizations in patients with suspected allergic contact dermatitis by using patient history as the reference standard. Patients/methods: In a multicentre, prospective, investigator-blinded study 790 patients were enrolled. The defined reference standard was established prior to patch testing. Patch tests were performed with nickel sulfate, potassium dichromate, and lanolin alcohol. Duplicate tests were simultaneously performed on both sides of the back, of which one randomly chosen side was tape stripped beforehand, according to a standardized procedure. Primary outcome was the difference in sensitivity between strip patch test and patch test. Results: Seven hundred and eighty-seven patients were included in the analysis. Strip patch tests detected considerably more sensitization to nickel sulfate and potassium dichromate than patch tests: differences of sensitivities were 16.4% (95% CI, 8.7–24.1%) for nickel sulfate and 25.0% (95% CI, 8.9–41.0%) for potassium dichromate, both favouring the strip patch test. Conclusions: The standardized strip patch test proved to be accurate and clinically safe and is promising to improve diagnosis of allergic contact dermatitis beyond the patch test.

Background: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. Methods: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m−2 over 30 min), oxaliplatin (65 mg m−2) and 5-FU (1500 mg m−2 over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. Results: Response rates were 19% (95% CI: 6–32%) and 23% (95% CI: 9–37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6–12.4) and 9.9 months (95% CI: 7.5–12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. Conclusion: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

Summary Background Tape stripping the skin prior to patch testing (strip patch test, SPT) may enhance percutaneous penetration of test substances and increase skin reactivity to test substances. Objective To evaluate the test sensitivity of SPT in compliance with our recently presented practical method vs. conventional patch test (PT) in nickel- and dichromate-sensitive subjects. Methods Thirty subjects participated in the prospective, randomized, controlled, investigator-blind study. Serial dilution tests of nickel sulphate (10 000–50 ppm aq.) and potassium dichromate (1000–5 ppm aq.) were used. Tests were applied in duplicate to both sides of the upper back of the subject, where one, randomly chosen side was tape stripped. Results According to the estimated test sensitivities, SPT is more sensitive than PT in nickel- and dichromate-sensitive subjects, regardless of the interindividual different numbers of tape strips. The superiority of the SPT grows with diminishing concentrations of the allergens. Conclusion Test sensitivity of SPT vs. PT is increased. If no positive results are obtained by PT, the SPT could help to detect hidden allergens in case of weak sensitization or low concentration and poor percutaneous penetration of the test substances. Conflict of Interest None declared.

In patients with cardiovascular disease or organ failure, elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are associated with an increased risk of future cardiovascular events. We aimed to investigate elevated plasma ADMA concentrations as a prospective risk marker for adverse events in patients undergoing noncardiac surgery.Prospective observational study.Two tertiary care centers.Four hundred and two patients scheduled for elective noncardiac surgery.None.Patients were followed for 30 days after surgery for a predefined composite end point (death, myocardial infarction/acute coronary syndrome, acute heart failure, severe arrhythmia, embolism, or thrombosis). Plasma ADMA concentrations at baseline were determined by high-performance liquid chromatography. ADMA was only weakly (-0.2tau0.2) correlated with other risk markers and risk scores. In univariate logistic regression, per 0.1-micromol/L increment in plasma ADMA concentration, the odds ratio to experience the primary end point increased by 1.26 (95% confidence interval 1.10-1.45, p = .001). In a multivariate logistic regression model adjusting for age, gender, current smoking, plasma creatinine, hypertension, diabetes, ischemic heart disease, highly sensitive C-reactive protein, revised cardiac risk index, type of surgery, high-risk surgery, ASA class, and study center, ADMA was found to be an independent risk marker. The odds ratio to experience the primary end point was 1.33 (95% confidence interval 1.12-1.59, p = .001) per 0.1-micromol/L increase in the plasma ADMA concentration.Elevated plasma ADMA concentrations are independently associated with a higher risk for adverse events in the peri- and postoperative periods.

OBJECTIVES Cardiopulmonary bypass (CPB) is associated with a disturbed immune response, e.g., impaired HLA-DR expression on monocytes and the release of pro- and anti-inflammatory cytokines. Cytokine release plays a role in the pathogenesis of postoperative systemic inflammatory response syndrome (SIRS) and immune system deterioration, e.g., impaired monocyte and polymorphonuclear neutrophil (PMN) function, factors that ultimately lead to an increased susceptibility to infections. To gain a further understanding, we investigated HLA-DR expression on monocytes and on B- and T-lymphocytes. In addition, we investigated the IN VITRO effect of the immunostimulating hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) on HLA-DR expression of these cell types. Neither HLA-DR expression on B- and T-lymphocytes nor the effects of GM-CSF in cardiac surgical patients have been studied before. METHODS In 16 patients undergoing elective cardiac surgery with CPB, counts of circulating leukocyte subsets as well as HLA-DR expression on monocytes, B- and T-lymphocytes were measured by flow cytometry before, immediately after CPB, and on the 2nd and 10th postoperative days. Treatment with GM-CSF was performed IN VITRO in whole blood cultures with 100 ng/ml recombinant human GM-CSF for 20 h. RESULTS Monocyte HLA-DR expression was attenuated immediately after CPB (125 +/- 4 mean channel fluorescence [MCF] vs. 143 +/- 2 MCF preoperatively, mean +/- SEM, P < 0.001). HLA-DR expression further decreased on the 2nd day after CPB and did not normalize until the 10th day after the operation. In contrast, HLA-DR expression on T-cells was unchanged, whereas HLA-DR expression on B-cells did not decrease before the 2nd day after CPB (152 +/- 3 MCF vs. 170 +/- 2 MCF preoperatively, P < 0.001). IN VITRO GM-CSF treatment increased HLA-DR expression on monocytes prepared after CPB to a degree comparable to preoperative values. HLA-DR expression on B-lymphocytes could not be restored by GM-CSF. CONCLUSIONS Immune system suppression after cardiac surgery is reflected in prolonged diminished HLA-DR expression on monocytes and B-lymphocytes. Suppression is not irreversible but can - at least IN VITRO - be overridden by the immunostimulating compound GM-CSF.

Background: Combinations of gemcitabine–oxaliplatin, gemcitabine–5-fluorouracil (5-FU) and 5-FU–oxaliplatin have synergistic activity and nonoverlapping adverse effect profiles. This trial assessed efficacy and safety of the triple combination gemcitabine–oxaliplatin and infusional 5-FU in patients with locally advanced (n = 11) or metastatic (n = 32) pancreatic adenocarcinoma. Patients and methods: A total of 43 eligible patients were treated with intravenous infusions of gemcitabine (900 mg/m2 over 30 min), followed by oxaliplatin (65 mg/m2 over 2 h) and 5-FU (1500 mg/m2 over 24 h) on days 1 and 8 of a 21-day cycle. Results: Among all 43 patients, the tumor response rate was 19% [95% confidence interval 7% to 30%]. Nine patients were nonassessable for response because they did not complete the first two cycles of chemotherapy due to rapid disease progression, early death or treatment refusal. One patient was lost to follow-up. Median time to progression and overall survival were 5.7 and 7.5 months. Principal grade III/IV toxic effects were leucopenia in 11 (2%), thrombocytopenia in 13 (2%), nausea in 13 (0%), anorexia 16 (7%) and sensory neuropathy in 18 (0%) of patients. Unexpected cardiotoxicity was observed in this trial. Conclusion: Response rates and survival of the three-drug combination compare favorably with single-agent gemcitabine, but do not exceed results for doublets.

The number needed to treat (NNT) is a popular measure to describe the absolute effect of a new treatment compared with a standard treatment or placebo in clinical trials with binary outcome. For use of NNT measures in epidemiology to compare exposed and unexposed subjects, the terms 'number needed to be exposed' (NNE) and 'exposure impact number' (EIN) have been proposed. Additionally, in the framework of logistic regression a method was derived to perform point and interval estimation of NNT measures with adjustment for confounding by using the adjusted odds ratio (OR approach). In this paper, a new method is proposed which is based upon the average risk difference over the observed confounder values (ARD approach). A decision has to be made, whether the effect of allocating an exposure to unexposed persons or the effect of removing an exposure from exposed persons should be described. We use the term NNE for the first and the term EIN for the second situation. NNE is the average number of unexposed persons needed to be exposed to observe one extra case; EIN is the average number of exposed persons among one case can be attributed to the exposure. By means of simulations it is shown that the ARD approach is better than the OR approach in terms of bias and coverage probability, especially if the confounder distribution is wide. The proposed method is illustrated by application to data of a cohort study investigating the effect of smoking on coronary heart disease.