Type 2 Diabetes, the Epidemic: Trends in Prevalence and Incidence, 2004-2020.

Aims/Hypothesis: Only a few studies reported the incidence of type 2 diabetes (T2D). Understanding recent trends in diabetes is vital for planning future diabetes care. This study updated national trends in the prevalence and incidence of type 2 diabetes (T2D) in the Netherlands from 2004-2020. Methods: The DIAbetes, MANagement and Treatment (DIAMANT) cohort was used. A cross-sectional design with yearly measurements for the study period was used. The prevalence was calculated by dividing the total number of people with T2D by the total number of all residents. The incidence was calculated by dividing new cases of T2D by the resident population at risk during the calendar year of interest. Results: Among men, the prevalence of T2D in the Netherlands increased from 2.3% in 2004 to 6.3% in 2020. Women's prevalence increased from 2.3% in 2004 to 5.3% in 2020. During 2005-2009, the incidence rate for both men and women was relatively stable Between 2010 and 2020, the incidence rate fell about 1.5 per 1000 in both men and women. Conclusion: From 2004-2020, the prevalence of T2D in the Netherlands more than doubled, with a decreasing incidence from 2010 onwards.

Research in context What is already known about this subject? Many studies have reported the increasing prevalence of type 2 diabetes (T2D). However, only a few studies reported the incidence.In a recent systematic review of all these studies, the incidence fell in over a third of the most high-income populations and increased in a minority of populations. Data from the Netherlands were included, but they date back to 1996.Understanding recent trends in diabetes, the prevalence and incidence are vital for planning future diabetes care.What is the key question? To update national trends in the prevalence and incidence of T2D in the Netherlands for 2004-2020.What are the new findings? During 2004-2020, the prevalence of T2D in the Netherlands more than doubled, with a decreasing incidence from 2010 onwards.How might this impact on clinical practice in the foreseeable future? It demonstrates the effectiveness of preventive strategies, public health education and awareness campaigns contributing to this trend.

The yield of routine laboratory examination in osteoporosis evaluation in primary care.

This study evaluated the yield of routine laboratory examination in a large population of older women in primary care. The prevalence of laboratory abnormalities was low and the clinical consequences in follow-up were limited. There was a weak association of laboratory abnormalities with osteoporosis but no association with vertebral fractures and recent fractures. PURPOSE: Most osteoporosis guidelines advice routine laboratory examination. We have investigated the yield of laboratory examinations in facture risk evaluation of elderly women in primary care. METHODS: We assessed the prevalence of laboratory abnormalities and their association with risk factors for fractures, recent fractures, low bone mineral density (BMD), and prevalent vertebral fracture in 8996 women ≥ 65 years of age participating in a primary care fracture risk screening study. In a sample of 2208 of these participants, we also evaluated the medical consequences in the medical records during a follow-up period of ≥ 1 year. RESULTS: Vitamin D deficiency (< 30 nmol/L) was present in 13% and insufficiency (< 50 nmol/L) in 43% of the study sample. The prevalence of other laboratory abnormalities (ESR, calcium, creatinine, FT4) was 4.6% in women with risk factors for fractures, 6.1% in women with low BMD (T-score ≤ - 2.5), 6.0% after a prevalent vertebral fracture, 5.2% after a recent fracture and 2.6% in the absence of important risk factors for fractures. Laboratory abnormalities other than vitamin D were associated with low BMD (OR 1.4, 95%CI 1.1-1.8) but not with prevalent vertebral fractures nor recent fractures. Low BMD was associated with renal failure (OR 2.0, 95%CI 1.3-3.4), vitamin D insufficiency (OR 1.2, 95%CI 1.0-1.3) and deficiency (OR 1.3, 95%CI 1.1-.5). In the follow-up period, 82% of the laboratory abnormalities did not result in a new diagnosis or treatment reported in the medical records. CONCLUSIONS: We identified a low prevalence of laboratory abnormalities in a primary care population of older women and the majority of these findings had no medical consequences.

Challenges and lessons learned from a long-term postauthorisation safety study programme of rivaroxaban in Europe.

OBJECTIVES: To describe opportunities and challenges experienced from the four pharmacoepidemiological database studies included in the rivaroxaban post authorisation safety study (PASS) programme and propose ways to maximise the value of population-based observational research when addressing regulatory requirements. DESIGN: PASS programme of rivaroxaban carried out as part of the regulatory postapproval commitment to the European Medicines Agency. SETTING: Clinical practice in Germany, the Netherlands, Sweden and the UK (electronic health records)-undertaken by pharmacoepidemiology research teams using country-specific databases with different coding structures. PARTICIPANTS: 355 152 patients prescribed rivaroxaban and 338 199 patients prescribed vitamin K antagonists. RESULTS: Two major challenges that were encountered throughout the lengthy PASS programme were related to: (1) finalising country-tailored study designs before the extent of rivaroxaban uptake was known, and (2) new research questions that arose during the programme (eg, those relating to an evolving prescribing landscape). RECOMMENDATIONS: We advocate the following strategies to help address these major challenges (should they arise in any future PASS): conducting studies based on a common data model that enable the same analytical tools to be applied when using different databases; maintaining early, clear, continuous communication with the regulator (including discussing the potential benefit of studying drug use as a precursor to planning a safety study); consideration of adaptive designs whenever uncertainty exists and following an initial period of data collection; and setting milestones for the review of study objectives.

Risk of cardiovascular events after an exacerbation of chronic obstructive pulmonary disease: results from the EXACOS-CV cohort study using the PHARMO Data Network in the Netherlands.

BACKGROUND: People living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations. METHODS: Persons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1-7, 8-14, 15-30, 31-180 and 181-365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome. RESULTS: 8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease [range of HR: from 15.3 (95% confidence interval 11.8-20.0) in days 1-7 to 1.3 (1.0-1.8) in days 181-365]. After a moderate exacerbation, the risk was increased over the first 180 days [HR 2.5 (1.3-4.8) in days 1-7 to 1.6 (1.3-2.1) in days 31-180]. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation [HR 48.6 (36.9-64.0) in days 1-7 down to 1.6 (1.0-2.6) in days 181-365]. Increase in risk concerned all categories of severe CV events. CONCLUSIONS: Among incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.

Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study.

INTRODUCTION: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. OBJECTIVES: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions. METHODS: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.01.2010-31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures. RESULTS: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention -7.7%), Spain (-11.3%), and UK (-5.9%) and a non-significant decline in the Netherlands (-3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07). CONCLUSION: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future.

Safety and effectiveness of rivaroxaban for prevention of stroke in patients with nonvalvular atrial fibrillation: analysis of routine clinical data from four countries.

BACKGROUND: The safety and effectiveness of rivaroxaban versus vitamin K antagonists (standard of care [SOC]) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) was evaluated in Europe. RESEARCH DESIGN AND METHODS: Observational studies were conducted in the UK, the Netherlands, Germany, and Sweden. Primary safety outcomes were hospitalization for intracranial hemorrhage, gastrointestinal bleeding, or urogenital bleeding among new users of rivaroxaban and SOC with NVAF; outcomes were analyzed using cohort (rivaroxaban or SOC use) and nested case-control designs (current vs nonuse). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. RESULTS: Overall, 162,919 rivaroxaban users and 177,758 SOC users were identified. In the cohort analysis, incidence ranges for rivaroxaban users were 0.25-0.63 events per 100 person-years for intracranial bleeding, 0.49-1.72 for gastrointestinal bleeding, and 0.27-0.54 for urogenital bleeding. Corresponding ranges for SOC users were 0.30-0.80, 0.30-1.42, and 0.24-0.42, respectively. In the nested case-control analysis, current SOC use generally presented a greater risk of bleeding outcomes than nonuse. Rivaroxaban use (vs nonuse) was associated with a higher risk of gastrointestinal bleeding, but a similar risk of intracranial or urogenital bleeding, in most countries. Ischemic stroke incidence ranged from 0.31 to 1.52 events per 100 person-years for rivaroxaban users. CONCLUSIONS: Incidences of intracranial bleeding were generally lower with rivaroxaban than with SOC, whereas incidences of gastrointestinal and urogenital bleeding were generally higher. The safety profile of rivaroxaban for NVAF in routine practice is consistent with findings from randomized controlled trials and other studies.

Time Trends in Patient Characteristics of New Rivaroxaban Users with Atrial Fibrillation in Germany and the Netherlands.

BACKGROUND: Use of the direct oral anticoagulant rivaroxaban has strongly increased in Europe since its market approval for non-valvular atrial fibrillation in 2011. Patients characteristics of rivaroxaban initiators may have changed over time but this has not been investigated so far. OBJECTIVE: We aimed to describe time trends of patient baseline characteristics among new rivaroxaban users with non-valvular atrial fibrillation from 2011 to 2016/17 in two European countries. METHODS: We used data from Germany (German Pharmacoepidemiological Research Database) and the Netherlands (PHARMO Database Network). We included new rivaroxaban users with (i) a first dispensing between 2011 and 2016/17, (ii) ≥ 2 years of age, and (iii) a diagnosis of non-valvular atrial fibrillation and described their baseline medication and comorbidity prior to starting rivaroxaban stratified by year of inclusion. RESULTS: Overall, 130,652 new rivaroxaban users were included during the study period (Germany: N = 127,743, the Netherlands: N = 2909). The sex ratio and median age remained relatively stable over time. The proportion of patients without prior use of oral anticoagulants before initiation of rivaroxaban increased in both countries between 2011 and 2016/17 (Germany: from 51 to 76%, the Netherlands: from 57 to 85%). In Germany, we observed a relative decrease by 27% in the proportion of new rivaroxaban users with a history of ischemic stroke and by 18% in the proportion with a transient ischemic attack at baseline. No such a pattern was observed in the Netherlands. The proportion of patients with heart failure at baseline showed a three-fold increase in the Netherlands, while there was a relative decrease by 12% in Germany. CONCLUSIONS: Patient characteristics of new rivaroxaban users with non-valvular atrial fibrillation changed between 2011 and 2016/17, but changes differed between countries. These patterns have methodological implications. They have to be considered in the interpretation of observational studies comparing effectiveness and safety of oral anticoagulants, especially regarding potential bias due to unmeasured confounding.

Completeness and Representativeness of the PHARMO General Practitioner (GP) Data: A Comparison with National Statistics.

Purpose: When using incomplete or non-representative real-world data (RWD), bias is more likely to occur. The aim of the current study was to assess the completeness and representativeness of the PHARMO GP data for the Dutch population. Patients and Methods: A cross-sectional study was performed. The PHARMO GP data comprise data from electronic health records registered by GPs. Data on the Dutch population were obtained from Statistics Netherlands (CBS), which offers publicly available data on several themes. The standardized difference (std.diff) was used to compare proportions between the PHARMO GP population and the Dutch population. An absolute std.diff >0.2 was considered a difference. Results: On January 1st, 2018, 3,466,321 persons were included in the PHARMO GP data (mean age: 41.6 years, 49.7% males). The sex and age distribution was similar to the Dutch population. The PHARMO GP data captured less not urbanized areas compared to the Dutch population (not urbanized areas: 9.4% vs 17.1% [std.diff: -0.23]). Regarding medication use, only the pharmacological subgroups "viral vaccines" and "hormonal contraceptives for systemic use" differed (std.diff >0.2); use in the GP data was more complete than in the Statistics Netherlands (CBS) data. No differences were observed regarding diagnoses. Conclusion: The PHARMO GP data are representative of the Dutch population with regard to the demographic characteristics and diagnoses in primary care. Medication data in the PHARMO GP data are more complete than national statistics, and differences are related to reimbursement. Use of the data and interpretation of results based on these sources should be done with experts on the data sources, the Dutch healthcare system and (pharmaco)epidemiology.

The DIAbetes MANagement and Treatment (DIAMANT) Cohort.

Introduction: The increasing number of people with diabetes and the unclear long-term safety and effectiveness of newer and older blood-glucose-lowering treatments emphasize the need for more pharmaco-epidemiological studies in this field. A prospective, regularly updated cohort of people with diabetes would provide quick and up-to-date information regarding prevalence, treatment, safety and effectiveness. The current aim was to describe the design of the DIAbetes MANagement and Treatment (DIAMANT) cohort. Methods: The DIAMANT cohort is a population-based, dynamic, prospective cohort of persons with diabetes. It contains real-world data (RWD) from general practitioners (GP), including diagnoses, symptoms, examinations, communication to/from specialists and medication. Diabetes is defined as a recorded diabetes diagnosis or a prescription of drugs used in diabetes. The cohort is part of the national infrastructure of "Stichting Informatievoorziening voor Zorg en Onderzoek" (STIZON) and is linked to other data sources. Results: Currently, the cohort enables access to information of 89,883 patients in 2004 to 344,914 in 2020 (6% T1D, 84% T2D and 10% unclassified type of diabetes), with 193,931 participants still registered as being present in the GP practice (active) in 2020. The frequency of follow-up of persons with diabetes is practice dependent. The Dutch guidelines advise 2-4 contacts per year with a more extensive yearly check-up. The DIAMANT cohort is updated several times a year. Anonymised data from the DIAMANT cohort are available to researchers. Discussion: The DIAMANT cohort provides the opportunity to gain RWD insights into the treatment and outcomes among people with diabetes in daily general practice. The data can be enriched by established linkages to other data sources (eg, hospital data, the Perinatal Registry, the Cancer Registry). The DIAMANT cohort serves as a start of a national infrastructure to study, manage and provide personalised care in order to ultimately improve care and outcomes for people with diabetes.

Myocarditis and pericarditis associated with SARS-CoV-2 vaccines: A population-based descriptive cohort and a nested self-controlled risk interval study using electronic health care data from four European countries.

Background: Estimates of the association between COVID-19 vaccines and myo-/pericarditis risk vary widely across studies due to scarcity of events, especially in age- and sex-stratified analyses. Methods: Population-based cohort study with nested self-controlled risk interval (SCRI) using healthcare data from five European databases. Individuals were followed from 01/01/2020 until end of data availability (31/12/2021 latest). Outcome was first myo-/pericarditis diagnosis. Exposures were first and second dose of Pfizer, AstraZeneca, Moderna, and Janssen COVID-19 vaccines. Baseline incidence rates (IRs), and vaccine- and dose-specific IRs and rate differences were calculated from the cohort The SCRI calculated calendar time-adjusted IR ratios (IRR), using a 60-day pre-vaccination control period and dose-specific 28-day risk windows. IRRs were pooled using random effects meta-analysis. Findings: Over 35 million individuals (49·2% women, median age 39-49 years) were included, of which 57·4% received at least one COVID-19 vaccine dose. Baseline incidence of myocarditis was low. Myocarditis IRRs were elevated after vaccination in those aged < 30 years, after both Pfizer vaccine doses (IRR = 3·3, 95%CI 1·2-9.4; 7·8, 95%CI 2·6-23·5, respectively) and Moderna vaccine dose 2 (IRR = 6·1, 95%CI 1·1-33·5). An effect of AstraZeneca vaccine dose 2 could not be excluded (IRR = 2·42, 95%CI 0·96-6·07). Pericarditis was not associated with vaccination. Interpretation: mRNA-based COVID-19 vaccines and potentially AstraZeneca are associated with increased myocarditis risk in younger individuals, although absolute incidence remains low. More data on children (≤ 11 years) are needed.

The Association Between the Kyphosis Angle and Physical Performance in Community-Dwelling Older Adults.

BACKGROUND: We investigated prospectively among community-dwelling older adults aged 65 years and older whether a larger kyphosis angle is associated with poorer physical performance (balance, muscle strength, or both), and whether this association is unidirectional. METHODS: Male and female participants performed a multicomponent physical performance test with subscores for gait, muscle strength, and balance at baseline and after 2 years. Hand grip strength was also measured at baseline and at follow-up. The Cobb angle was measured on DXA-based Vertebral Fracture Assessments, made at the baseline and follow-up visit. Through linear and logistic regression analysis, we investigated the association between the kyphosis angle and physical performance and vice versa. We stratified for sex, and tested for effect modification by age and study center. RESULTS: The mean kyphosis angle was 37° and 15% of the participants (n = 1 220, mean age 72.9 ± 5.7 years) had hyperkyphosis (Cobb angle ≥50°). A larger kyphosis angle at baseline was independently associated with a poorer total physical performance score in women of the oldest quartile (≥77 years) in both the cross-sectional and longitudinal analyses (baseline B -0.32, 95% confidence interval [CI] -0.56-0.08; follow-up B 0.32, 95% CI -0.55-0.10). There was no association between physical performance at baseline and kyphosis progression. CONCLUSION: A larger kyphosis angle is independently associated with a poorer physical performance at baseline and over time, and the direction of this association is unidirectional. These results emphasize the importance of early detection and treatment of hyperkyphosis to prevent further worsening of the kyphosis angle, thereby potentially preserving physical performance.

The association between hyperkyphosis and fall incidence among community-dwelling older adults.

Hyperkyphosis, an increased kyphosis angle of the thoracic spine, was associated with a higher fall incidence in the oldest quartile of a large prospective cohort of community-dwelling older adults. Hyperkyphosis could serve as an indicator of an increased fall risk as well as a treatable condition. INTRODUCTION: Hyperkyphosis is frequently found in adults aged 65 years and older and may be associated with falls. We aimed to investigate prospectively in community-dwelling older adults whether hyperkyphosis or change in the kyphosis angle is associated with fall incidence. METHODS: Community-dwelling older adults (n = 1220, mean age 72.9 ± 5.7 years) reported falls weekly over 2 years. We measured thoracic kyphosis through the Cobb angle between the fourth and 12th thoracic vertebra on DXA-based vertebral fracture assessments and defined hyperkyphosis as a Cobb angle ≥ 50°. The change in the Cobb angle during follow-up was dichotomized (< 5 or ≥ 5°). Through multifactorial regression analysis, we investigated the association between the kyphosis angle and falls. RESULTS: Hyperkyphosis was present in 15% of the participants. During follow-up, 48% of the participants fell at least once. In the total study population, hyperkyphosis was not associated with the number of falls (adjusted IRR 1.12, 95% CI 0.91-1.39). We observed effect modification by age (p = 0.002). In the oldest quartile, aged 77 years and older, hyperkyphosis was prospectively associated with a higher number of falls (adjusted IRR 1.67, 95% CI 1.14-2.45). Change in the kyphosis angle was not associated with fall incidence. CONCLUSIONS: Hyperkyphosis was associated with a higher fall incidence in the oldest quartile of a large prospective cohort of community-dwelling older adults. Because hyperkyphosis is a partially reversible condition, we recommend investigating whether hyperkyphosis is one of the causes of falls and whether a decrease in the kyphosis angle may contribute to fall prevention.

Effectiveness of COVID-19 Vaccines in Adults with Diabetes Mellitus: A Systematic Review.

Persons with diabetes mellitus may have an increased risk of severe illness or death from COVID-19 compared to persons without diabetes. Prior studies indicate that immune response and thus vaccine effectiveness might be lower in persons with diabetes. We aimed to systematically review the effectiveness of COVID-19 vaccines in adults with diabetes. Pubmed, Embase, Web of Science and Cochrane Library were searched for studies that evaluated the effectiveness of COVID-19 vaccines in adults with diabetes, published before 4 March 2022. Risk of bias in the included studies was evaluated using the ROBINS-I tool. At least two reviewers conducted the study selection, data extraction, and risk of bias assessment independently. After screening of 2196 studies, a total of 17 articles were included. Six different COVID-19 vaccines (Ad5-nCoV-S, AZD1222, BNT162b2, CoronaVac, JNJ-78436735, and mRNA-1273) were included in the synthesis. Vaccine effectiveness was reported for SARS-CoV-2 infection, symptomatic COVID-19, hospitalization, and death, and ranged from 24 to 96% in persons with diabetes, and from 33 to 97% in total study populations; effectiveness was generally lower for persons with diabetes. Odds ratios for breakthrough infection or severe COVID-19 ranged from 1.03 to 2.41 in vaccinated persons with diabetes compared to persons without diabetes. Even though the included studies were very heterogeneous, results from the synthesis indicate that effectiveness of COVID-19 vaccines might be lower in persons with diabetes. More research is needed on the comparison of vaccine effectiveness between persons with and without diabetes, and the effectiveness of repeat COVID-19 vaccinations.

Predicting hospital admissions from individual patient data (IPD): an applied example to explore key elements driving external validity.

OBJECTIVE: To explore factors that potentially impact external validation performance while developing and validating a prognostic model for hospital admissions (HAs) in complex older general practice patients. STUDY DESIGN AND SETTING: Using individual participant data from four cluster-randomised trials conducted in the Netherlands and Germany, we used logistic regression to develop a prognostic model to predict all-cause HAs within a 6-month follow-up period. A stratified intercept was used to account for heterogeneity in baseline risk between the studies. The model was validated both internally and by using internal-external cross-validation (IECV). RESULTS: Prior HAs, physical components of the health-related quality of life comorbidity index, and medication-related variables were used in the final model. While achieving moderate discriminatory performance, internal bootstrap validation revealed a pronounced risk of overfitting. The results of the IECV, in which calibration was highly variable even after accounting for between-study heterogeneity, agreed with this finding. Heterogeneity was equally reflected in differing baseline risk, predictor effects and absolute risk predictions. CONCLUSIONS: Predictor effect heterogeneity and differing baseline risk can explain the limited external performance of HA prediction models. With such drivers known, model adjustments in external validation settings (eg, intercept recalibration, complete updating) can be applied more purposefully. TRIAL REGISTRATION NUMBER: PROSPERO id: CRD42018088129.

Discovery of predictors of sudden cardiac arrest in diabetes: rationale and outline of the RESCUED (REcognition of Sudden Cardiac arrest vUlnErability in Diabetes) project.

INTRODUCTION: Early recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information. AIM: To describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA. METHODS: The RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA. CONCLUSION: The RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.

Predicting negative health outcomes in older general practice patients with chronic illness: Rationale and development of the PROPERmed harmonized individual participant data database.

The prevalence of multimorbidity and polypharmacy increases significantly with age and are associated with negative health consequences. However, most current interventions to optimize medication have failed to show significant effects on patient-relevant outcomes. This may be due to ineffectiveness of interventions themselves but may also reflect other factors: insufficient sample sizes, heterogeneity of population. To address this issue, the international PROPERmed collaboration was set up to obtain/synthesize individual participant data (IPD) from five cluster-randomized trials. The trials took place in Germany and The Netherlands and aimed to optimize medication in older general practice patients with chronic illness. PROPERmed is the first database of IPD to be drawn from multiple trials in this patient population and setting. It offers the opportunity to derive prognostic models with increased statistical power for prediction of patient-relevant outcomes resulting from the interplay of multimorbidity and polypharmacy. This may help patients from this heterogeneous group to be stratified according to risk and enable clinicians to identify patients that are likely to benefit most from resource/time-intensive interventions. The aim of this manuscript is to describe the rationale behind PROPERmed collaboration, characteristics of the included studies/participants, development of the harmonized IPD database and challenges faced during this process.

Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial.

BACKGROUND & AIMS: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk. METHODS: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 µg) and vitamin-B12 (500 µg) versus placebo (n = 2,919). Primary outcome was verified self-reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease. RESULTS: A total of 1,298 individuals (44.5%) participated in the second follow-up round with median of 54 months [51-58], (n = 662 and n = 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic- and any fracture (p = 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 µmol/l). No age-dependent effects were present. CONCLUSIONS: This study supports and extends previous null-findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated.

A prognostic model predicted deterioration in health-related quality of life in older patients with multimorbidity and polypharmacy.

OBJECTIVES: To develop and validate a prognostic model to predict deterioration in health-related quality of life (dHRQoL) in older general practice patients with at least one chronic condition and one chronic prescription. STUDY DESIGN AND SETTING: We used individual participant data from five cluster-randomized trials conducted in the Netherlands and Germany to predict dHRQoL, defined as a decrease in EQ-5D-3 L index score of ≥5% after 6-month follow-up in logistic regression models with stratified intercepts to account for between-study heterogeneity. The model was validated internally and by using internal-external cross-validation (IECV). RESULTS: In 3,582 patients with complete data, of whom 1,046 (29.2%) showed deterioration in HRQoL, and 12/87 variables were selected that were related to single (chronic) conditions, inappropriate medication, medication underuse, functional status, well-being, and HRQoL. Bootstrap internal validation showed a C-statistic of 0.71 (0.69 to 0.72) and a calibration slope of 0.88 (0.78 to 0.98). In the IECV loop, the model provided a pooled C-statistic of 0.68 (0.65 to 0.70) and calibration-in-the-large of 0 (-0.13 to 0.13). HRQoL/functionality had the strongest prognostic value. CONCLUSION: The model performed well in terms of discrimination, calibration, and generalizability and might help clinicians identify older patients at high risk of dHRQoL. REGISTRATION: PROSPERO ID: CRD42018088129.

Effect of Genetically Low 25-Hydroxyvitamin D on Mortality Risk: Mendelian Randomization Analysis in 3 Large European Cohorts.

The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15⁻1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80⁻2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

The association between apathy, decline in physical performance, and falls in older persons.

BACKGROUND: Symptoms of apathy are common in older persons. Negative effects on physical performance and fall risk are plausible, considering the pathophysiology of apathy. However, literature is scarce. AIM: To longitudinally assess the association between apathy and (1) decline of physical performance and (2) the number of falls in older community-dwelling persons. METHODS: The 'B vitamins for the PRevention Of Osteoporotic Fractures' study provided data on 2919 older persons over a period of 2 years. Apathy was assessed using the Geriatric Depression Scale 3. A physical performance score (PPS) was calculated using three performance tests. Falls were registered prospectively. We calculated adjusted odds ratios (ORs), Incidence Rate Ratios (IRRs), and their 95% confidence intervals. Effect modification by age and gender was investigated. We also investigated mediation by baseline PPS for the association between apathy and the number of falls. RESULTS: Apathy and decline of PPS were independently associated. After stratification, the effect only remained in men. Age was an effect modifier; higher ORs for decreasing age. Apathy was also independently associated with the number of falls. After stratification, women had higher IRRs than men. Age modified the association in the opposite direction: higher IRRs for increasing age. Baseline PPS was a mediator in the association. CONCLUSION: The impact of apathy on physical performance and fall incidents varied with age and gender. Potentially, in older individuals with apathy, fall risk is preceded by a decline in physical performance. In clinical practice, identifying apathy in older persons might be useful to target mobility preserving interventions.