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Aims: The Gompertz law of mortality proclaims that human mortality rates in middle to old ages grow log-linearly with age and this law has been confirmed at multiple instances. We investigated if diabetes mortality in Germany also obeys to the Gompertz law and how this information helps to communicate diabetes mortality more intuitively. Methods: We analyzed all statutory health-insured persons in Germany in 2013 that were aged 30 years or older. Deaths in 2014 were recorded and given in 5-year age groups. We fitted weighted linear regression models (separately for females and males and for people with and without diabetes) and additionally computed the probability that a person with diabetes dies before a person of the same age and sex without diabetes, and the "diabetes age", that is, the additional years of mortality risk added to an individual's chronological age due to diabetes-related excess mortality. Results: We included N = 47,365,120 individuals, 6,541,181 of them with diabetes. In 2014, 763,228 deaths were recorded, among them 288,515 with diabetes. Diabetes mortality followed nearly perfectly Gompertz distributions. The probability that a person with diabetes dies before a person without diabetes was 61.9% for females and 63.3% for males. Conclusions: Diabetes mortality for females and males aged 30 years or older in Germany in 2014 followed the Gompertz law of mortality. The survival information of the population with diabetes during a large part of the lifespan can thus be reduced to the two parameters of the Gompertz distribution. [ABSTRACT FROM AUTHOR]

The aim was to investigate prevalence of dry eye syndrome (DES) in a population-based sample in Germany. The association between coexisting eye diseases and DES was also of interest. We recontacted participants of the Heinz Nixdorf Recall study between 2018 and 2021 by postal questionnaire that included the Women's Health Study questionnaire on DES. We estimated prevalence of DES and examined DES-associated factors among 2095 participants aged 62–91 years. We performed interaction analyses between sex and coexisting eye diseases in relation to the DES prevalence and performed bias analyses to examine the robustness of the results. The DES prevalence was 31.5% (34–36% after correction for potential non-response bias, 24.1% after correction for outcome misclassification) and it was almost 2.1-times higher in women than in men (women 42.3%, men 20.4%). Among DES subjects, 70.3% had received treatment in the previous 12 months. There was synergism between female sex and coexisting eye diseases (cataract, glaucoma, macular degeneration) in terms of DES prevalence. The extrapolated numbers of patients aged 62–91 years with DES in Germany are 1.1–1.3 million men and 6.1–6.8 million women. The observed synergism may be explained by differences in ocular physiology, subjective perception and response behavior. Women with eye diseases (cataract, glaucoma, macula degeneration) appear to have a markedly higher susceptibility to suffer from DES than men, so that a diagnostic workup of DES symptoms is particularly justified in women with these eye diseases. [ABSTRACT FROM AUTHOR]

Background/objectives: Findings from epidemiological studies showed controversial findings between dietary sugar intake and the development of diabetes. Most of these studies assessed dietary sugar intake by self-reports which might be prone to bias. Urinary sucrose, an objective biomarker of sucrose intake, might provide better insights into this association. Thus, the aim of this study was to investigate the associations between sucrose intake, measured via self-reports and urinary sucrose, with incident diabetes and to detect the impact of obesity on this association. Subjects/methods: Data of a sub-group (n = 2996) from the prospective EPIC-Norfolk cohort were investigated. Sucrose intake was assessed by self-reports (validated food frequency questionnaire (FFQ) and 7-day diet diaries (7DD)) and as an objective urinary sucrose biomarker. Cox proportional hazard models were conducted to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for the associations between urinary and dietary sucrose intake and incident diabetes. Mediation analysis was performed to investigate the mediated percentage of body mass index (BMI) and waist circumference (WC) on this association. Results: The mean age of the participants was 60.6 ± 9.5 years and 53% were women. After a mean follow-up of 11.2 ± 2.9 years, 97 participants developed diabetes. Findings suggested inverse associations regarding incident diabetes for self-reported sucrose intake per 50 g/d via 7DD [HR: 0.63 (95% CI: 0.43, 0.91)], and a tendency via FFQ [HR: 0.81 (95% CI: 0.46, 1.42)]. Urinary sucrose indicated a positive association with incident diabetes for each increase of 100 µM [HR: 1.14 (95% CI: 0.95, 1.36)]. The proportion mediated of BMI and WC for this association was 16 and 22%. Conclusions: These findings indicate that sucrose measured as objective urinary biomarker points to a positive association with incident diabetes. BMI might partly mediate this association. However, to obtain more precise results, more studies are warranted that consider this objective biomarker. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: There are two prerequisites for the precision medicine approach to be beneficial for treated individuals. First, there must be treatment heterogeneity; second, in the case of treatment heterogeneity, we need to detect clinical predictors to identify people who would benefit from one treatment more than from others. There is an established meta-regression approach to assess these two prerequisites that relies on measuring the variability of a clinical outcome after treatment in placebo-controlled randomised trials. Our aim was to apply this approach to the treatment of type 2 diabetes. Methods: We performed a meta-regression analysis using information from 174 placebo-controlled randomised trials with 178 placebo and 272 verum (i.e. active treatment) arms including 86,940 participants with respect to the variability of glycaemic control as assessed by HbA1c after treatment and its potential predictors. Results: The adjusted difference in log(SD) values between the verum and placebo arms was 0.037 (95% CI: 0.004, 0.069). That is, we found a small increase in the variability of HbA1c values after treatment in the verum arms. In addition, one potentially relevant predictor for explaining this increase, drug class, was observed, and GLP-1 receptor agonists yielded the largest differences in log(SD) values. Conclusions/interpretation: The potential of the precision medicine approach in the treatment of type 2 diabetes is modest at best, at least with regard to an improvement in glycaemic control. Our finding of a larger variability after treatment with GLP-1 receptor agonists in individuals with poor glycaemic control should be replicated and/or validated with other clinical outcomes and with different study designs. Funding: The research reported here received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Data availability: Two datasets (one for the log[SD] and one for the baseline-corrected log[SD]) to reproduce the analyses from this paper are available on https://zenodo.org/record/7956635. [ABSTRACT FROM AUTHOR]

The use of hazard ratios as the standard treatment effect estimators for randomized trials with time-to-event outcomes has been the subject of repeated criticisms in recent years, e.g., for its non-collapsibility or with respect to (causal) interpretation. Another important issue is the built-in selection bias, which arises when the treatment is effective and when there are unobserved or not included prognostic factors that influence time-to-event. In these cases, the hazard ratio has even been termed "hazardous" because it is estimated from groups that increasingly differ in their (unobserved or omitted) baseline characteristics, yielding biased treatment estimates. We therefore adapt the Landmarking approach to assess the effect of ignoring a gradually increasing proportion of early events on the estimated hazard ratio. We propose an extension called "Dynamic Landmarking". This approach is based on successive deletion of observations, refitting Cox models and balance checking of omitted but observed prognostic factors, to obtain a visualization that can indicate built-in selection bias. In a small proof-of-concept simulation, we show that our approach is valid under the given assumptions. We further use "Dynamic Landmarking" to assess the suspected selection bias in the individual patient data sets of 27 large randomized clinical trials (RCTs). Surprisingly, we find no empirical evidence of selection bias in these RCTs and thus conclude that the supposed bias of the hazard ratio is of little practical relevance in most cases. This is mainly due to treatment effects in RCTs being small and the patient populations being homogeneous, e.g., due to inclusion and exclusion criteria. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: To provide a systematic overview of the current body of evidence on high-risk phenotypes of diabetes associated with COVID-19 severity and death. Methods: This is the first update of our recently published living systematic review and meta-analysis. Observational studies investigating phenotypes in individuals with diabetes and confirmed SARS-CoV-2 infection with regard to COVID-19-related death and severity were included. The literature search was conducted from inception up to 14 February 2022 in PubMed, Epistemonikos, Web of Science and the COVID-19 Research Database and updated using PubMed alert to 1 December 2022. A random-effects meta-analysis was used to calculate summary relative risks (SRRs) with 95% CIs. The risk of bias was evaluated using the Quality in Prognosis Studies (QUIPS) tool and the certainty of evidence using the GRADE approach. Results: A total of 169 articles (147 new studies) based on approximately 900,000 individuals were included. We conducted 177 meta-analyses (83 on COVID-19-related death and 94 on COVID-19 severity). Certainty of evidence was strengthened for associations between male sex, older age, blood glucose level at admission, chronic insulin use, chronic metformin use (inversely) and pre-existing comorbidities (CVD, chronic kidney disease, chronic obstructive pulmonary disease) and COVID-19-related death. New evidence with moderate to high certainty emerged for the association between obesity (SRR [95% CI] 1.18 [1.04, 1.34], n=21 studies), HbA1c (53–75 mmol/mol [7–9%]: 1.18 [1.06, 1.32], n=8), chronic glucagon-like peptide-1 receptor agonist use (0.83 [0.71, 0.97], n=9), pre-existing heart failure (1.33 [1.21, 1.47], n=14), pre-existing liver disease (1.40 [1.17, 1.67], n=6), the Charlson index (per 1 unit increase: 1.33 [1.13, 1.57], n=2), high levels of C-reactive protein (per 5 mg/l increase: 1.07 [1.02, 1.12], n=10), aspartate aminotransferase level (per 5 U/l increase: 1.28 [1.06, 1.54], n=5), eGFR (per 10 ml/min per 1.73 m2 increase: 0.80 [0.71, 0.90], n=6), lactate dehydrogenase level (per 10 U/l increase: 1.03 [1.01, 1.04], n=7) and lymphocyte count (per 1×109/l increase: 0.59 [0.40, 0.86], n=6) and COVID-19-related death. Similar associations were observed between risk phenotypes of diabetes and severity of COVID-19, with some new evidence on existing COVID-19 vaccination status (0.32 [0.26, 0.38], n=3), pre-existing hypertension (1.23 [1.14, 1.33], n=49), neuropathy and cancer, and high IL-6 levels. A limitation of this study is that the included studies are observational in nature and residual or unmeasured confounding cannot be ruled out. Conclusions/interpretation: Individuals with a more severe course of diabetes and pre-existing comorbidities had a poorer prognosis of COVID-19 than individuals with a milder course of the disease. Registration: PROSPERO registration no. CRD42020193692. Previous version: This is a living systematic review and meta-analysis. The previous version can be found at https://link.springer.com/article/10.1007/s00125-021-05458-8 Funding: The German Diabetes Center (DDZ) is funded by the German Federal Ministry of Health and the Ministry of Culture and Science of the State North Rhine-Westphalia. This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). [ABSTRACT FROM AUTHOR]

Comment on "Drug-Drug Interaction of the Sodium Glucose Co-Transporter 2 Inhibitors with Statins and Myopathy: A Disproportionality Analysis Using Adverse Events Reporting Data" Drug-drug interaction of the sodium glucose co-transporter 2 inhibitors with statins and myopathy: a disproportionality analysis using adverse events reporting data. Interestingly, we recently saw a similar potentially protective drug-drug interaction for the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and statins on myopathy risk [[4]], and we refer to this previous letter for an explanation of the multiplicative model of Thakrar et al. [[2]]. [Extracted from the article]

Aims/hypothesis: No established blood-based biomarker exists to monitor diabetic sensorimotor polyneuropathy (DSPN) and evaluate treatment response. The neurofilament light chain (NFL), a blood biomarker of neuroaxonal damage in several neurodegenerative diseases, represents a potential biomarker for DSPN. We hypothesised that higher serum NFL levels are associated with prevalent DSPN and nerve dysfunction in individuals recently diagnosed with diabetes. Methods: This cross-sectional study included 423 adults with type 1 and type 2 diabetes and known diabetes duration of less than 1 year from the prospective observational German Diabetes Study cohort. NFL was measured in serum samples of fasting participants in a multiplex approach using proximity extension assay technology. DSPN was assessed by neurological examination, nerve conduction studies and quantitative sensory testing. Associations of serum NFL with DSPN (defined according to the Toronto Consensus criteria) were estimated using Poisson regression, while multivariable linear and quantile regression models were used to assess associations with nerve function measures. In exploratory analyses, other biomarkers in the multiplex panel were also analysed similarly to NFL. Results: DSPN was found in 16% of the study sample. Serum NFL levels increased with age. After adjustment for age, sex, waist circumference, height, HbA1c, known diabetes duration, diabetes type, cholesterol, eGFR, hypertension, CVD, use of lipid-lowering drugs and use of non-steroidal anti-inflammatory drugs, higher serum NFL levels were associated with DSPN (RR [95% CI] per 1-normalised protein expression increase, 1.92 [1.50, 2.45], p<0.0001), slower motor (all p<0.0001) and sensory (all p≤0.03) nerve conduction velocities, lower sural sensory nerve action potential (p=0.0004) and higher thermal detection threshold to warm stimuli (p=0.023 and p=0.004 for hand and foot, respectively). There was no evidence for associations between other neurological biomarkers and DSPN or nerve function measures. Conclusions/interpretation: Our findings in individuals recently diagnosed with diabetes provide new evidence associating higher serum NFL levels with DSPN and peripheral nerve dysfunction. The present study advocates NFL as a potential biomarker for DSPN. [ABSTRACT FROM AUTHOR]

Aims: Treatment effects from the large cardiovascular outcome trials (CVOTs) of new antidiabetic drugs are almost exclusively communicated as hazard ratios, although reporting guidelines recommend to report treatment effects also on an absolute scale, e.g. as numbers needed to treat (NNT). We aimed to analyse NNTs in CVOTs comparing dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or sodium–glucose cotransporter-2 (SGLT2) inhibitors to placebo. Methods: We digitalized individual time-to-event information for the primary outcome and all-cause mortality from 19 CVOTs that compared DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors to placebo. We estimated Weibull models for each trial and outcome and derived monthly NNTs. NNTs were summarized across all trials and within drug classes by random effects meta-analysis methods. Results: Treatment effects in the CVOTs appear smaller if they are reported as NNTs: Overall, 100 (95%-CI: 60, 303) patients have to be treated for 29 months (the median follow-up time across all trials) to avoid a single event of the primary outcome, and 128 (95%-CI: 85, 265) patients have to be treated for 39 months to avoid a single death. NNT time courses are very similar for GLP-1 receptor agonists and SGLT2 inhibitors, whereas treatment effects with DPP-4 inhibitors are smaller. Conclusions: We found that the respective treatment effects look less impressive when communicated on an absolute scale, as numbers needed to treat. For a valid overall picture of the benefit of new antidiabetic drugs, trial authors should also report treatment effects on an absolute scale. [ABSTRACT FROM AUTHOR]

Aims: Hemoglobin A1c (HbA1c) has been repeatedly questioned as a valid surrogate marker, especially for patient-relevant outcomes. The aim of this study was to validate the HbA1c value as a surrogate for all-cause mortality in people with type 2 diabetes. Methods: The effect estimates for HbA1c lowering after treatment as well as reductions in all-cause mortality of randomized trials were extracted from a systematic review and updated. For the measurement of actual surrogacy, weighted linear regression models with a random intercept for the study effect were used with the all-cause mortality estimate (risk difference and log relative risk) as the outcome and the estimate for HbA1c difference as the covariate. Surrogacy was assessed according to the criteria of Daniels and Hughes. Results: A total of 346 HbA1c-mortality-pairs from 205 single randomized trials were included in the analysis. Regarding the risk difference of all-cause mortality, there was no evidence for surrogacy of the HbA1c value. For the log relative risk, a small positive association between HbA1c and the all-cause mortality estimate (slope 0.129 [95% confidence interval −0.043; 0.302]) was observed. However, there was no sign of valid surrogacy. Conclusions: Based on the results of more than 200 randomized trials, HbA1c is not a valid surrogate marker for all-cause mortality in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: There is little evidence of the impact of diabetes risk scores on individual diabetes risk factors, motivation for behaviour changes and mental health. The aim of this study was to investigate the effect of applying a noninvasive diabetes risk score in primary care as component of routine health checks on physical activity and secondary outcomes. Methods: Cluster randomised trial, in which primary care physicians (PCPs), randomised (1:1) by minimisation, enrolled participants with statutory health insurance without known diabetes, ≥ 35 years of age with a body mass index ≥ 27.0 kg/m2. The German Diabetes Risk Score was applied as add-on to the standard routine health check, conducted in the controls. Primary outcome was the difference in participants' physical activity (International Physical Activity Questionnaire) after 12 months. Secondary outcomes included body mass index, perceived health, anxiety, depression, and motivation for lifestyle change. Analysis was by intention-to-treat principle using mixed models. Results: 36 PCPs were randomised; remaining 30 PCPs (intervention: n = 16; control: n = 14) recruited 315 participants (intervention: n = 153; controls: n = 162). A slight increase in physical activity was observed in the intervention group with an adjusted mean change of 388 (95% confidence interval: − 235; 1011) metabolic equivalents minutes per week. There were no relevant changes in secondary outcomes. Conclusions: The application of a noninvasive diabetes risk score alone is not effective in promoting physical activity in primary care. Clinical Trial Registration: ClinicalTrials.gov (NCT03234322, registration date: July 31, 2017). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine the mediation of body mass index (BMI) on the association between per capita sugar consumption and diabetes prevalence using country-related data. Research design and methods: In this ecological study, based on 192 countries, data on per capita sugar consumption were obtained from the Food and Agriculture Organization of the United Nations (FAO), on BMI from the World Health Organization and on diabetes prevalence from the International Diabetes Federation. Data on demography and economic factors were obtained from the Central Intelligence Agency, the United Nations and the FAO. Multiple linear regression analysis was performed to investigate the association between per capita sugar consumption and diabetes prevalence, and mediation analysis to detect the mediated percentage of BMI on this association. Results: Each increase of 100 kcal/day per capita sugar consumption was associated with a 1.62% higher diabetes prevalence [adjusted β-estimator (95% CI): 1.62 (0.71, 2.53)]. Mediation analysis using BMI as the mediator demonstrated an adjusted direct association of 0.55 (95% CI: − 0.22, 1.32) and an adjusted indirect association of 1.07 (95% CI: 0.54, 1.68). Accordingly, the BMI explained 66% (95% CI: 34%, 100%) of the association between per capita sugar consumption on diabetes prevalence. Conclusions: These findings indicate that the association between dietary sugar intake and the occurrence of diabetes is mediated by BMI to a large proportion. However, it seems that other mechanisms may explain the association between sugar consumption and development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

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Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In Germany, the nationwide population-based mammography screening program (MSP) was introduced in 2005 and is full-running since 2010. By 2014, incidence rates for invasive breast cancer were very similar to those of the pre-screening era. Therefore, the ongoing effect of the MSP on breast cancer surgery rates can now be investigated. We analyzed population-based breast-conserving (BCS) and mastectomy (MET) surgery rates (per 100,000) among women aged < 50, 50–69 (eligible for the MSP), and 70+ years among women with in situ and invasive breast cancer during 2005–2015. For invasive breast cancer, both BCS and MET rates slightly increased in the age group < 50 years (38.3 in 2005 vs 42.5 in 2015 and 15.7 vs 18.2, respectively). In contrast, MET rates considerably decreased among women aged 50–69 and 70+ years (92 vs 65.4 and 155.4 vs 122.1, respectively), while BCS rates increased in both age groups (210.6 vs 254.4 and 147.2 vs 187, respectively). For in situ breast cancer, MET rates slightly increased in all age groups. BCS rates slightly increased in women aged < 50, but nearly doubled for women aged 50–69 (26.9 vs 49.1) and markedly increased in the 70+ age group (11.5 vs 16.1). During and after the implementation of MSP, there was a strong shift towards BCS within the screening-eligible age group and for women aged 70+. Women with invasive breast cancer in these age groups may profit from screening with a decline of MET rates in favor of BCS rates at the expense of higher surgery rates for in situ breast cancer. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: 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.Methods: 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.Results: 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] <0.01). The greater decline in fasting glucose (CC/CT vs TT) in metformin monotherapy persisted after further adjusting for glucose values at diagnosis (genotype difference 1.0 mmol/l, p = 0.01; genotype×treatment interaction p = 0.06).Conclusions/interpretation: The variant rs8192675 in the SLC2A2 gene (C allele) is associated with an improved glucose response to metformin monotherapy during the first year after diagnosis in type 2 diabetes.Trial registration: ClinicalTrials.gov NCT01055093 [ABSTRACT FROM AUTHOR]

Purpose: To 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.Methods: A total of 425 male and 414 female patients aged 11-21 years 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.Results: Mean 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.Conclusions: Compared 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Wingless-type (Wnt) inducible signalling pathway protein-1 (WISP1) has been recently identified as a proinflammatory adipokine. We examined whether WISP1 expression and circulating levels are altered in type 2 diabetes and whether WISP1 affects insulin signalling in muscle cells and hepatocytes.Methods: Serum and visceral adipose tissue (VAT) biopsies, for analysis of circulating WISP1 levels by ELISA and WISP1 mRNA expression by real-time quantitative RT-PCR, were collected from normal-weight men (control group, n = 33) and obese men with (n = 46) and without type 2 diabetes (n = 56) undergoing surgery. Following incubation of primary human skeletal muscle cells (hSkMCs) and murine AML12 hepatocytes with WISP1 and insulin, insulin signalling was analysed by western blotting. The effect of WISP1 on insulin-stimulated glycogen synthesis and gluconeogenesis was investigated in hSkMCs and murine hepatocytes, respectively.Results: Circulating WISP1 levels were higher in obese men (independent of diabetes status) than in normal-weight men (mean [95% CI]: 70.8 [55.2, 86.4] ng/l vs 42.6 [28.5, 56.6] ng/l, respectively; p < 0.05). VAT WISP1 expression was 1.9-fold higher in obese men vs normal-weight men (p < 0.05). Circulating WISP1 levels were positively associated with blood glucose in the OGTT and circulating haem oxygenase-1 and negatively associated with adiponectin levels. In hSkMCs and AML12 hepatocytes, recombinant WISP1 impaired insulin action by inhibiting phosphorylation of insulin receptor, Akt and its substrates glycogen synthase kinase 3β, FOXO1 and p70S6 kinase, and inhibiting insulin-stimulated glycogen synthesis and suppression of gluconeogenic genes.Conclusions/interpretation: Circulating WISP1 levels and WISP1 expression in VAT are increased in obesity independent of glycaemic status. Furthermore, WISP1 impaired insulin signalling in muscle and liver cells. [ABSTRACT FROM AUTHOR]

Aims: 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. Methods: 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. Results: 4.459 patients (59.1%) were 65 years or older. Their HbA1c levels were similar to those with <65 years. 44.7% of patients ≥65 years had an HbA1c ≤7% (53 mmol/mol) and were treated with insulin or sulfonylureas, and 27.1% of them had ischaemic heart disease or congestive heart failure. Significantly more patients with heart disease had HbA1c values ≤7% (53 mmol/mol) and were treated more often with insulin or sulfonylureas compared to patients of the same age without heart disease. Conclusions: Most patients were treated according to guidelines valid at the time this large international patient sample was surveyed. Older and younger patients were at a similar level of metabolic control, and almost half of the patients with an age of ≥65 years and treated with insulin or sulfonylurea had HbA1c levels below the target range (≤7%) for younger patients. However, these patients have an increased risk of severe hypoglycaemic events with potentially dangerous complications, particularly in those with cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the association between the introduction of the nationwide mammography screening program (MSP) and breast cancer surgery rates in Germany 2005-2009. We used nationwide DRG hospitalization files (2005-2009) and analyzed surgery rates for the treatment of invasive and in situ breast cancer in Germany. We used actual numbers of screened women to model the influence of the introduction of the MSP on surgery rates. During 2005 through 2009, the rate of breast-conserving surgery for invasive and in situ breast cancer increased among all age groups. However, rate increases for invasive and in situ breast surgery were largest among women aged 50-69 years (invasive: rate difference [per 100,000] 95.1, 95 % CI 90.7; 99.5; in situ: rate difference 34.4, 95 % CI 32.6; 36.2). Mastectomy rates generally showed little change over time. Conditional on a 70 % participation in the MSP, our model predicts that the estimated increase of mastectomy rates for invasive and in situ breast cancer among women aged 50-69 years during the introductory phase of the MSP would be 4.2 (95 % CI −0.2; 8.6) and 6.1 per 100,000 (95 % CI 5.0; 7.1), respectively. The introduction of the nationwide MSP shows markedly rising rates of breast conserving surgery for women aged 50-69 years with invasive and in situ breast cancer. This increase is expected as a consequence of the first screening round. The model-based estimate for the increase of mastectomy rates, assuming a 70 % MSP participation, is lower than the reported increases observed in MSP in other countries. [ABSTRACT FROM AUTHOR]

Purpose: Few studies have examined the age-specific use of hysterectomy by indication. The aim of this study was to provide detailed nationwide age-specific prevalence-corrected hysterectomy rates for several indications in Germany, representing a population of 42 million women. Methods: Nationwide population-based diagnosis related group data of the years 2005 and 2006 were used to calculate the prevalence-corrected hysterectomy rates by age and indication group. Results: Prevalence-corrected age-standardized hysterectomy rates (any indication) was 362.9 (295.0 for benign diseases of the genital tract and 44.0 for primary malignant tumors of the genital tract) per 100,000 person-year. Corrected hysterectomy rates become increasingly greater than the uncorrected hysterectomy rates, such that they are about 68 % greater for women in the age groups 75-79, 80-84, and 85-89 years. Age-specific hysterectomy rates showed quite different patterns depending on the indication of hysterectomy. For example, hysterectomy rates closely follow the cancer incidence rates up to age 44 for cervical cancer and age 69 for uterine cancer, diverging noticeably in ages thereafter. Conclusions: The prevalence-corrected hysterectomy rates presented in this study provide a more accurate indication of the use of hysterectomy, which has implications in terms of costs and resource allocation. Understanding the role of hysterectomy in treating selected diseases across the age span is also important for patients and doctors as they consult together about an appropriate course of treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to provide population-based German-wide hysterectomy rates based on the national hospitalization file and to estimate the rate of conversion from laparoscopical or vaginal hysterectomy to open abdominal hysterectomy. Nationwide population-based DRG (diagnosis related groups) data of the years 2005 and 2006 were used to calculate hysterectomy rates by indication group and type of surgical approach. Overall 305,015 hysterectomies were performed during the study period (4.5 out of 1,000 women aged 20 years or more). The hysterectomy rate for benign diseases of the genital tract among women aged 20 years or more (3.6 out of 1,000 women) is higher than in Sweden but lower than in the US or Australia. Only 6 and 5% of all hysterectomies were performed by laparoscopically assisted vaginal hysterectomy and laparoscopic hysterectomy, respectively. Twenty-six percent of hysterectomies for benign diseases among women aged 50 years or more included bilateral oophorectomy. 10% of laparoscopical hysterectomies and 1% of vaginal hysterectomies necessitated a conversion to an abdominal hysterectomy. For both types of hysterectomies, the conversion rates were highest for primary malignant genital tract cancer and other cancers compared to the other indication groups. Whereas the conversion rate for laparoscopical hysterectomies increased by age, this rate did not change by age for vaginal hysterectomies. Conversion from laparoscopically or vaginal hysterectomy to open abdominal hysterectomy is associated with the indication and type of hysterectomy started with and is considerably higher for laparoscopic than vaginal hysterectomies. [ABSTRACT FROM AUTHOR]

Since its introduction into the biomedical literature, statistical significance testing (abbreviated as SST) caused much debate. The aim of this perspective article is to review frequent fallacies and misuses of SST in the biomedical field and to review a potential way out of the fallacies and misuses associated with SSTs. Two frequentist schools of statistical inference merged to form SST as it is practised nowadays: the Fisher and the Neyman-Pearson school. The P-value is both reported quantitatively and checked against the α-level to produce a qualitative dichotomous measure (significant/nonsignificant). However, a P-value mixes the estimated effect size with its estimated precision. Obviously, it is not possible to measure these two things with one single number. For the valid interpretation of SSTs, a variety of presumptions and requirements have to be met. We point here to four of them: study size, correct statistical model, correct causal model, and absence of bias and confounding. It has been stated that the P-value is perhaps the most misunderstood statistical concept in clinical research. As in the social sciences, the tyranny of SST is still highly prevalent in the biomedical literature even after decades of warnings against SST. The ubiquitous misuse and tyranny of SST threatens scientific discoveries and may even impede scientific progress. In the worst case, misuse of significance testing may even harm patients who eventually are incorrectly treated because of improper handling of P-values. For a proper interpretation of study results, both estimated effect size and estimated precision are necessary ingredients. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this present study was to evaluate Self-care Improvement through Oncology Nursing (SCION) program to reduce distressing anorexia, nausea, and emesis (ANE) in cancer patients undergoing chemotherapy.Methods: Two hundred eight patients receiving chemotherapy with moderate to high emetogenic potential participated in a cluster randomized trial on 14 wards in two German university hospitals. Additionally to standard antiemetic treatment, patients from the intervention wards received the SCION program consisting of four modules: advisory consultation, optimizing emesis prophylaxis, nutrition counseling, and relaxation. Patients from the control group received standard antiemetic treatment and standard care. Primary outcome was the group difference in ANE intensity assessed by Common Terminology Criteria for adverse events (CTCAE).Main Results: The SCION program did not result in a significant difference in the incidence of ANE symptoms as compared to standard care: mean difference on CTCAE scale was 0.24 pts (95%CI, -1.17 to 1.66 pts; P = 0.733). No difference could be found regarding patients' knowledge of side effects, self-care interventions, and agency. Health-related quality of life was significantly better for patients in the control group (mean difference 10.2 pts; 95%CI, 1.9 to 18.5; P = 0.017).Conclusions: Contrary to our expectations, the groups did not differ in ANE intensity caused by the overall low acute or delayed symptom intensity. Symptom hierarchy in cancer patients alters and challenges nursing interventions targeting the patients' self-care strategies. [ABSTRACT FROM AUTHOR]

Background: A reduced heart rate variability (HRV) is associated with worse prognosis, increased incidence of cardiovascular disease (CVD) and mortality. There are conflicting results and a lack of population-based data regarding the association of HRV with CVD risk factors and its potential role as independent cause or mediator of CVD risk. Methods: Cross-sectional data of a population-based cohort including 1,779 women and men aged 45–83 years were used to analyse associations of time and frequency domain measures of HRV (derived from 5-min ECG segments) with age, behavioural and biomedical risk factors and disease in the whole sample and in a “healthy” subgroup. Results: Age was inversely associated with all measures of HRV (mean standard deviation of normal intervals across 10-year age-groups 32.1, 26.9, 27.1 and 24.8 ms in women, 29.3, 25.9, 23.8 and 25.7 ms in men). There was no association of physical activity, current smoking or alcohol with HRV. In age-adjusted models, triglycerides, glucose, waist-to-hip ratio and diabetes were inversely associated with HRV in men and women, and low/high density cholesterol and hypertension in men only (up to 43% difference across risk factor quartiles). Multivariable adjustment and restriction to the “healthy” subgroup attenuated the associations. Conclusions: We found only weak and inconsistent associations of HRV with cardiovascular risk factors. However, these results as well as those from previous studies are still compatible with the hypothesis that short-term HRV may be a marker of ill health or a mediator of the effect of selected biomedical risk factors on CVD. [ABSTRACT FROM AUTHOR]

A missed protective drug-drug interaction of DPP-4 inhibitors and statins on myopathy risk The authors were especially interested in potential interactions between the two drugs and therefore refer to and use the approach of Thakrar et al. [[2]] which entails a multiplicative and an additive model to assess drug interactions. Additionally, researchers assessing drug-drug interactions by Thakrar's models should communicate and interpret the complete results of their analyses. [Extracted from the article]