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Osteoporosis is a highly prevalent bone disease affecting more than 37.5 million individuals in the European Union (EU) and the United States of America (USA). It is characterized by low bone mineral density (BMD), impaired bone quality, and loss of structural and biomechanical properties, resulting in reduced bone strength. An increase in morbidity and mortality is seen in patients with osteoporosis, caused by the approximately 3.5 million new osteoporotic fractures occurring every year in the EU. Currently, different medications are available for the treatment of osteoporosis, including anti-resorptive and osteoanabolic medications. Bisphosphonates, which belong to the anti-resorptive medications, are the standard treatment for osteoporosis based on their positive effects on bone, long-term experience, and low costs. However, not only medications used for the treatment of osteoporosis can affect bone: several other medications are suggested to have an effect on bone as well, especially on fracture risk and BMD. Knowledge about the positive and negative effects of different medications on both fracture risk and BMD is important, as it can contribute to an improvement in osteoporosis prevention and treatment in general, and, even more importantly, to the individual’s health. In this review, we therefore discuss the effects of both osteoporotic and non-osteoporotic medications on fracture risk and BMD. In addition, we discuss the underlying mechanisms of action. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01625-8.

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway (MTHFR), cell transport (SLC19A1/ABCC2/ABCC4), intracellular metabolism (FPGS/GGH) and target enzymes (TYMS/DHFR/ATIC) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses.

Observational studies report a reduction of COPD exacerbations in patients treated with β-blockers. In contrast, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK COPD) randomised controlled trial which excluded COPD patients with cardiovascular conditions showed an increase in COPD exacerbations. It is unclear whether this discrepancy could be explained by underlying cardiovascular comorbidity. We examined whether the association between use of β-blockers and risk of COPD exacerbations differed between patients with and without a cardiovascular indication for β-blockers use. Within the Rotterdam Study, we followed COPD subjects until the first COPD exacerbation, or end of follow-up. Cardiovascular indication for β-blockers use was defined as a history of hypertension, coronary heart disease, atrial fibrillation and/or heart failure at baseline. The association between β-blockers use and COPD exacerbations was assessed using Cox proportional hazards models adjusted for age, sex, smoking, incident cardiovascular disease (i.e. heart failure, hypertension, atrial fibrillation and/or coronary heart disease during follow-up), respiratory drugs and nitrates. In total, 1312 COPD patients with a mean age of 69.7±9.2 years were included. In patients with a cardiovascular indication (n=755, mean age of 70.4±8.8 years), current use of cardioselective β-blockers was significantly associated with a reduced risk of COPD exacerbations (HR 0.69, 95% CI 0.57–0.85). In contrast, in subjects without a cardiovascular indication (n=557, mean age of 68.8±9.7 years), current use of cardioselective β-blockers was not associated with an altered risk of COPD exacerbations (HR 0.94, 95% CI 0.55–1.62). Use of cardioselective β-blockers reduced the risk of exacerbations in COPD patients with concomitant cardiovascular disease. Therefore, the potential benefits of β-blockers might be confined to COPD patients with cardiovascular disease., Use of cardioselective β-blockers reduces the risk of COPD exacerbations in patients with concomitant cardiovascular disease. The potential benefits of β-blockers might be restricted to COPD patients with cardiovascular disease. https://bit.ly/3bB1RGg

Purpose Current guidelines have no sex‐specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population‐based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data. Methods The mean daily starting doses of metoprolol in both sexes were compared with independent‐samples t‐tests and a linear regression analysis was used to adjust in the RS for co‐variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI‐database, adjustment was for age only. Results The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI −7.8, −1.8) and 4.6 mg (95%CI −5.3,‐4.0), respectively. Statistical significance remained after adjustment in both databases. Conclusions Women received lower starting doses of metoprolol than men in two independent data collections despite non‐sex specific cardiovascular guideline recommendations. This example of real‐life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.

Background: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. Objective: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. Methods: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population–based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. Results: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P

Aims: Hydroxychloroquine and chloroquine ([hydroxy]chloroquine) are drugs used to treat malaria and rheumatological disorders and were recently suggested as beneficial for prevention and treatment of patients with coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection. However, longitudinal studies to assess the electrocardiographic and cardiotoxic effects of these drugs are limited. In this study, we aimed to investigate the effect of these drugs on QTc-interval and incidence of sudden cardiac death (SCD). Methods We designed a longitudinal follow-up study of individuals within the prospective population-based Rotterdam Study. Eligible individuals had available data on medication and repeated ECG measurements. The study period was between 1 January 1991 and 1 January 2014. We studied on current and past use of [hydroxy]chloroquine as a time-varying exposure; high versus low daily dose of [hydroxy]chloroquine. QTc-interval duration, and the occurrence of SCD were the main outcomes. SCD was defined as an unexpected and sudden death due to cardiac arrhythmia within one hour of the onset of acute symptoms, and in patients without cardiac symptoms within 24 hours before death. Results Among the study population of 14 594 individuals (58.8% women) with an average age of 65 years, 346 patients used [hydroxy]chloroquine at any time during follow-up. The total number of SCD cases was 609. In a multiple linear mixed model analysis, the current use of [hydroxy]chloroquine was associated with a significantly increased duration of the QTc-interval of 8.1 ms (95% CI: 3.6; 12.6) compared with non-users. The association was stronger among current-high daily dosage [15.3 (95%CI: 7.0; 23.6)] compared with current-low daily dosage [5.5 (95%CI: 0.4; 10.7)] users. In a Cox proportional hazard regression analysis, the risk of SCD was significantly higher in participants who were current users of [hydroxy]chloroquine than in non-users [adjusted hazard ratio; 3.7 (95%CI: 1.1; 12.6)]. Conclusions In this longitudinal study, persons who received [hydroxy]chloroquine had an increased QTc-interval duration and the association was dose-dependent. [Hydroxy]chloroquine was associated with a significantly increased risk of SCD. As long as their activity against COVID-19 is controversial, cardiotoxicity is a strong argument against using these drugs to treat COVID-19 infections.

Multiple factors may contribute to the decision to initiate methylphenidate treatment in children such as maternal sociodemographic factors of which relatively little is known. The objective was to investigate the association between these factors and methylphenidate initiation. The study population included 4243 children from the Generation R Study in the Netherlands. Maternal sociodemographic characteristics were tested as determinants of methylphenidate initiation through a time-dependent Cox regression analysis. Subsequently, we stratified by mother-reported ADHD symptoms (present in 4.2% of the study population). When ADHD symptoms were absent, we found that girls (adjusted HR 0.25, 95%CI 0.16–0.39) and children born to a mother with a non-western ethnicity (compared to Dutch-Caucasian) (adjusted HR 0.42, 95%CI 015–0.68) were less likely to receive methylphenidate. They were more likely to receive methylphenidate when their mother completed a low (adjusted HR 2.29, 95%CI 1.10–4.77) or secondary (adjusted HR 1.71, 95%CI 1.16–2.54) education. In conclusion, boys and children born to a mother of Dutch-Caucasian ethnicity were more likely to receive methylphenidate, irrespective of the presence of ADHD symptoms. Electronic supplementary material The online version of this article (10.1007/s10578-020-01016-2) contains supplementary material, which is available to authorized users.

Cancer diagnoses which are not confirmed by pathology are often under-registered in cancer registries compared to pathology-confirmed diagnoses. It is unknown how many patients have a non pathology-confirmed cancer diagnosis, and whether their characteristics and survival differ from patients with a pathology-confirmed diagnosis. Participants from the prospective population-based Rotterdam Study were followed between 1989 and 2013 for the diagnosis of cancer. Cancer diagnoses were classified into pathology-confirmed versus non pathology-confirmed (i.e., based on imaging or tumour markers). We compared participant characteristics and the distribution of cancers at different sites. Furthermore, we investigated differences in overall survival using survival curves adjusted for age and sex. During a median (interquartile range) follow-up of 10.7 (6.3–15.9) years, 2698 out of 14,024 participants were diagnosed with cancer, of which 316 diagnoses (11.7%) were non pathology-confirmed. Participants with non pathology-confirmed diagnoses were older, more often women, and had a lower education. Most frequently non pathology-confirmed cancer sites included central nervous system (66.7%), hepato-pancreato-biliary (44.5%), and unknown primary origin (31.2%). Survival of participants with non pathology-confirmed diagnoses after 1 year was lower compared to survival of participants with pathology-confirmed diagnoses (32.6% vs. 63.4%; risk difference of 30.8% [95% CI 25.2%; 36.2%]). Pathological confirmation of cancer is related to participant characteristics and cancer site. Furthermore, participants with non pathology-confirmed diagnoses have worse survival than participants with pathology-confirmed diagnoses. Missing data on non pathology-confirmed diagnoses may result in underestimation of cancer incidence and in an overestimation of survival in cancer registries, and may introduce bias in aetiological research. Electronic supplementary material The online version of this article (10.1007/s10654-019-00592-5) contains supplementary material, which is available to authorized users.

Background The objective of this retrospective single-center study was to report the initial and the long-term outcome after stent-assisted angioplasty of occlusive disease at the common femoral artery. Materials and Methods Between 1995 and 2015, 94 limbs in 79 consecutive patients (54 men; mean age 70 ± 8.6 years) underwent angioplasty with self-expanding stent implantation in 94 common femoral arteries. Critical limb ischemia was present in 15 limbs (16%); the other patients had claudication. Results Technical success was 99%. Complications occurred in 5/94 interventions (5.3%): puncture site hematomas (2), arteriovenous fistula (1), cholesterol embolism (1), and dissection of the access site artery (1). The intervention was outpatient-based in 98%. Median follow-up was 53 months. Ankle–brachial index (ABI) rose from 0.71 ± 0.17 to 1.0 ± 0.2 (p p Conclusions SAA of the CFA resulted in high immediate success and a low complication rate. Restenosis rate was moderate, and target lesions could easily be retreated by angioplasty. The main hazard was not restenosis, but death during follow-up.

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Purpose We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS313) and other, nongenetic risk factors. Methods Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS(313)was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS(313)and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. Results In total, 320 women developed BC. The PRS(313)was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. Conclusions The effect size of the PRS(313)is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.

Background and aims: COPD is associated with an increased risk of cardiovascular morbidity and mortality, potentially by mechanisms of atherosclerosis. Insight into location-specific vulnerability to atherosclerosis in COPD, including intracranial arteries, is lacking. We aimed to investigate the relation between COPD and atherosclerosis in multiple vessel beds within a large population-based cohort study. Methods: From 2003 to 2006, a random sample of 2187 elderly participants (mean age, 69.6 +/- 6.8 years; 50.9% female; 11.7% COPD) from the population-based Rotterdam Study underwent computed tomography to quantify atherosclerotic coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial carotid artery calcification (ECAC), and intracranial carotid artery calcification (ICAC). We investigated the association of COPD [ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) < 70%] with the presence of calcification and with calcification volumes in each vessel bed using logistic and linear regression, with adjustments for cardiovascular risk factors including smoking. Results: The prevalence of CAC, AAC and ECAC was significantly higher in subjects with COPD compared to those without. After adjusting for age and smoking, COPD remained associated with the presence of ECAC (odds ratio 1.46 [95% confidence interval, 1.02-2.07, p = 0.037]). COPD was significantly associated with larger calcification volumes in all four vessel beds in people in whom calcification was present. Conclusions: The results of this study suggest that COPD plays a role in extracranial carotid artery atherosclerosis initiation and systemic atherosclerosis aggravation.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Background The majority of prevalence studies on deep vein thrombosis (DVT) in severe COVID-19 patients are retrospective with DVT assessment based on clinical suspicion. Our aim was to prospectively and systematically estimate the occurrence of DVT in critically ill mechanically ventilated patients, and to identify potential risk factors for DVT occurrence and mortality. Methods All patients with COVID-19 admitted to our 45-beds intensive care unit (ICU) between March 6, 2020 and April 18, 2020 requiring invasive ventilatory support were daily screened for DVT with lower extremities and jugular veins ultrasonography. Univariate and multivariable logistic regression models were performed in order to identify predictors of DVT and mortality. Results Seventy-six patients were included in the final analysis (56 men, mean age 67 years, median SOFA 7 points, median SAPS II 41 points, median PaO2/Fi02 10.8 kPa). The period prevalence of DVT was 40.8%. Thirty-one DVTs were diagnosed. Twenty-five DVTs (80.6% of total DVTs) were catheter-related, mainly in the jugular veins. Twentysix DVTs (83.9%) occurred in patients receiving enhanced antithrombotic prophylaxis. No independent variable was predictive of DVT occurrence. Twenty-eight patients (36.8%) died during the ICU stay. Age and SOFA score were independently associated with mortality. Conclusions A high number of critically ill mechanically ventilated COVID-19 patients developed a DVT. The majority of DVTs were catheter-related and occurred under intensive prophylactic anticoagulation. Routine ultrasound of the jugular veins should be suggested in this patient population, and in particular in presence of a central venous catheter.

Background Macrolides are widely prescribed antibiotics for many different indications. However, there are concerns about adverse effects such as ototoxicity. Objectives To investigate whether macrolide use is associated with tinnitus and hearing loss in the general population. Methods Cross-sectional (n = 4286) and longitudinal (n = 636) analyses were performed within the population-based Rotterdam Study. We investigated with multivariable logistic regression models the association between macrolides and tinnitus, and with multivariable linear regression models the association between macrolides and two different hearing thresholds (both ears, averaged over 0.25, 0.5, 1, 2, 4 and 8 kHz and 2, 4 and 8 kHz). Both regression models were adjusted for age, sex, systolic blood pressure, alcohol, smoking, BMI, diabetes, education level, estimated glomerular filtration rate and other ototoxic or tinnitus-generating drugs. Cumulative exposure to macrolides was categorized according to the number of dispensed DDDs and duration of action. Results In the fully adjusted model, ever use of macrolides was associated with a 25% higher likelihood of prevalent tinnitus (OR = 1.25; 95% CI 1.07–1.46). This association was more prominent in participants with a cumulative dose of more than 14 DDDs and among users of intermediate- or long-acting macrolides. Macrolide use in between both assessments was associated with more than a 2-fold increased risk on incident tinnitus. No general association between macrolides and hearing loss was observed. A borderline significant higher hearing threshold in very recent users (≤3 weeks) was found. Conclusions Macrolide use was significantly associated with both prevalent and incident tinnitus. Macrolide-associated tinnitus was likely cumulative dose-dependent.

Background: We explored whether total exposure to pemetrexed predicts effectiveness and toxicity in advanced non–small-cell lung cancer (NSCLC). Furthermore, we investigated alternative dosing schedules. Methods: In this prospective cohort study, patients with advanced NSCLC receiving first- or second-line pemetrexed(/platinum) were enrolled. Plasma sampling was performed weekly (cyclePK) and within 24 h (24hPK) after pemetrexed administration. With population pharmacokinetic/pharmacodynamic modelling, total exposure to pemetrexed during cycle 1 (area under the curve during chemotherapy cycle 1 [AUC1]) was estimated and related to progression-free survival (PFS)/overall survival (OS). We compared mean AUC1 (mg·h/L) in patients with and without severe chemotherapy-related adverse events (AEs) during total treatment. Second, different dosing schedules were simulated to minimise the estimated variability (coefficient of variation [CV]) of AUC. Results: For 106 of 165 patients, concentrations of pemetrexed were quantified (24hPK, n = 15; cyclePK, n = 106). After adjusting for prognostic factors, sex, disease stage and World Health Organisation performance score, AUC1 did not predict PFS/OS in treatment-naive patients (n = 95) (OS, hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.00–1.11; PFS, HR = 1.03, 95% CI: 0.98–1.08). Patients with severe chemotherapy-related AEs (n = 55) had significantly higher AUC1 values than patients without them (n = 51) (226 ± 53 vs 190 ± 31, p < 0.001). Compared with body surface area–based dosing (CV: 22.5%), simulation of estimated glomerular filtration rate (eGFR)–based dosing (CV 18.5%) and fixed dose of 900 mg with 25% dose reduction, if the eGFR

Background: Chronic obstructive pulmonary disease (COPD) has been associated with atrial fibrillation (AF). More insight into the epidemiology and underlying mechanisms is required to optimize management. Methods: The Rotterdam Study is a large, population-based cohort study with long-term follow-up. Time dependent Cox proportional hazard models were constructed to study the effect of COPD on incident AF, adjusted for age, sex and pack years of cigarette smoking, and additionally stratified according to exacerbation frequency, left atrial size and baseline systemic inflammatory levels. Results: 1369 of 10,943 subjects had COPD, of whom 804 developed AF. The AF incidence rate was 14 per 1000 person years in COPD and 8 per 1000 person years in subjects without COPD. The adjusted hazard ratio (HR) for COPD subjects to develop AF as compared to subjects without COPD was 1.28 (95% CI [1.04, 1.57]). COPD subjects with frequent exacerbations had a twofold increased AF risk (HR 1.99 [1.42, 2.79]) and COPD subjectswith a left atrial size >= 40 mm also had an elevated AF risk (HR 1.77 [1.07, 2.94]). COPD subjects with baseline systemic inflammatory levels above the median had significantly increased AF risks (hsCRP=1.83 mg/L: HR 1.51 [1.13, 2.03] and IL6 >= 1.91 ng/L: HR 2.49 [1.18, 5.28]), whereas COPD subjects below the median had in both analyses no significantly increased AF risk. Conclusions: COPD subjects had a 28% increased AF risk, which further increased with frequent exacerbations and an enlarged left atrium. The risk was driven by COPD subjects having elevated systemic inflammatory levels.

BACKGROUND To operationalize the National Institute on Aging - Alzheimer's Association (NIA-AA) Research Framework for Alzheimer's Disease 6-stage continuum of clinical progression for persons with abnormal amyloid. METHODS The Mayo Clinic Study of Aging is a population-based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross-sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months. RESULTS Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44-59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short-term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1). INTERPRETATION The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145-1156.

Sarcopenia is a heterogeneous skeletal muscle disorder involving the loss of muscle mass and function. However, the prevalence of sarcopenia based on the most recent definition remains to be determined in older people with chronic airway diseases. The aim was to evaluate sarcopenia prevalence and association with chronic airway diseases and its lung function in an older population, using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. We performed a cross-sectional analysis in 5082 participants (mean age 69.0±8.8 years, 56% females) from the Rotterdam Study. Participants with interpretable spirometry and an available assessment of sarcopenia were included. The appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS) were assessed using dual-energy X-ray absorptiometry (DXA) and a hydraulic hand dynamometer, respectively. We analysed the association between sarcopenia and chronic airway diseases by using regression models adjusted for age, sex, smoking status, total fat percentage and other relevant confounders. Participants with chronic airway diseases had higher prevalence of probable sarcopenia (12.0%, 95% CI 10.2–13.8) and confirmed sarcopenia (3.0%, 95% CI 2.1–3.9) than without. Chronic airway diseases were associated with “probable sarcopenia” (OR 1.28, 95% CI 1.02–1.60), “confirmed sarcopenia” (OR 2.13, 95% CI 1.33–3.43), reduced HGS (β −0.51 (−0.90–−0.11)) and reduced ASMI (β −0.19 (−0.25–−0.14)). Forced expiratory volume in 1 s, Probable and confirmed sarcopenia prevalence among the older population with chronic airway diseases is higher than in those without. Given this prevalence, it could be essential to screen for sarcopenia in primary care units for older patients. https://bit.ly/34Fhc56

Background: Whether liraglutide use improves cardiometabolic risk factors in different subsets of subjects with coronary artery disease (CAD) remains unclear. In a systematic review and meta-analysis, we quantified the effects of liraglutide on cardiometabolic risk profile in subjects with CAD with or without type 2 diabetes mellitus (T2D).Methods: Online database searches were conducted in PubMed, Scopus, EMBASE, Web of Science, Cochrane library, and Google Scholar from incept up to 15th January 2021. We identified randomized controlled trials (RCTs) assessing the effects of liraglutide compared to placebo on cardiometabolic risk profile. We used the random- or fixed-effect models to pool the weighted mean differences (WMDs) and 95% confidence intervals (CIs).Results: Out of a total of 7,320 citations, six articles (seven RCTs) with 294 subjects with CAD (mean age, 61.21 years; 19% women) were included. Our findings presented as WMD and 95% CI showed a statistical significant decrease in hemoglobin A1c (HbA1c) [−0.36%; −0.47; −0.26, p < 0.001; I2 = 0.0% (with 6 RCTs)], body mass index (BMI) [−0.61 kg/m2; −1.21; −0.01, p = 0.047; I2 = 72.2% (with five RCTs)], and waist circumference [−2.41 cm; −3.47; −1.36, p < 0.001; I2 = 0.0% (with three RCTs)]. Through a set of subgroup analyses, we found a significant reduction in BMI in CAD patients with T2D [WMD = −1.06; 95% CI, −1.42, −0.70, p < 0.001; I2 = 0.0% (with three RCTs)] compared to CAD only patients [WMD = −0.08; 95% CI, −0.45, 0.29, p = 0.66; I2 = 0.0% (with two RCTs)] in the liraglutide group compared with the placebo group. No significant changes in heart rate, blood pressure, and lipid profiles were observed.Conclusions: Among people with established CAD, liraglutide significantly improved HbA1c, BMI, and waist circumference values. The effect of liraglutide on BMI was more robust in individuals with T2D compared to those without.

Aim The aim of this study was to investigate occurrence and determinants of asthma exacerbations in an ageing general population. Methods Subjects aged 45 years or above with physician-diagnosed asthma in the Rotterdam Study, a population-based prospective cohort from January 1991 to May 2018, were assessed for asthma exacerbations. Exacerbations were defined as acute episodes of worsening asthma treated with oral corticosteroids. Cox proportional hazards analysis was used to investigate risk factors for a future exacerbation. Results Out of 763 participants with asthma (mean age 61.3 years, 69.2% female), 427 (56.0%) experienced at least one exacerbation, in a mean follow-up time of 13.9 years. The mean annual exacerbation rate was 0.22. Most exacerbations occurred during winter months. Risk factors for exacerbations were a history of previous exacerbations (HR 4.25; 95% CI 3.07–5.90, p, Most middle-aged and older adults with asthma suffer from at least one severe exacerbation. Risk factors are previous exacerbations, use of SABA without concomitant controller medication, respiratory complaints, obesity, airway obstruction and depression. https://bit.ly/3gcTO6t

Since chronic cough has common neurobiological mechanisms and pathophysiology with chronic pain, both clinical disorders might be interrelated. Hence, we examined the association between chronic cough and chronic pain in adult subjects in the Rotterdam Study, a large prospective population-based cohort study.Using a standardised questionnaire, chronic pain was defined as pain lasting up to 6 months and grouped into a frequency of weekly/monthly or daily pain. Chronic cough was described as daily coughing for at least 3 months duration. The longitudinal and cross-sectional associations were investigated bi-directionally.Of 7141 subjects in the study, 54% (n=3888) reported chronic pain at baseline. The co-prevalence of daily chronic pain and chronic cough was 4.4%. Chronic cough was more prevalent in subjects with daily and weekly/monthly chronic pain compared with those without chronic pain (13.8% and 10.3%versus8.2%; pChronic cough and chronic pain confer risk on each other among adult subjects, indicating that both conditions might share common risk factors and/or pathophysiologic mechanisms.

Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None

Background: While observational studies suggest a reduced risk of exacerbation in COPD patients treated with β-blockers (BB), there is reluctance to prescribe BB in patients with cardiovascular disease (CVD) and concomitant COPD. Recently, the BLOCK COPD trial reported an increased risk of exacerbation in metoprolol treated COPD patients without a therapeutic indication (TI) for such drug. The current discrepancy between findings from observational studies and the BLOCK COPD trial might result in even less prescribing BB in COPD patients with a cardiac indication. Aim: To examine whether the association between use of BB and risk of COPD exacerbations differed between patients with and without a TI for BB use. Methods: Within the Rotterdam Study, we followed 1,312 COPD subjects until the first COPD exacerbation or end of follow-up. We defined TI for BB use as having hypertension, coronary heart disease, atrial fibrillation, or heart failure at baseline. The association between BB use, as a time-varying variable, and COPD exacerbations was assessed using Cox proportional hazards models adjusted for age, sex, smoking, and other potential confounders. Results: In patients with a TI for BB (n=755, mean age=70.4±9) current use of cardioselective BB (CSBB) was associated with a reduced risk of COPD exacerbations (HR=0.69, 95%CI:0.57-0.85). In contrast, in subjects without a TI for BB (n=557, mean age=68.8±10) use of CSBB was not associated with an altered risk of COPD exacerbations. Conclusion: Use of CSBB reduced the risk of exacerbations only in COPD patients with concomitant CVD. Our results could explain the discordant findings between the BLOCK COPD trial and observational studies.

Background: Low lean mass is a highly prevalent condition in the elderly population. In patients with COPD, lean mass declines further with advancing age. In asthmatic patients, the age-dependent lean mass loss is less well-studied. We aimed at determining the degree of longitudinal change in appendicular skeletal muscle mass observed in elderly individuals with COPD and asthma. Methods: All 492 prevalent COPD cases, 186 prevalent asthma cases and 2556 participants without COPD or asthma, with more than two dual-energy X-ray absorptiometry scans (11.6 years of follow-up) were included. A linear mixed-effects model was fitted for appendicular lean mass, with natural cubic splines for age and their interactions with sex and chronic respiratory diseases, adjusted for smoking status, corticosteroids use and body mass index (BMI). Results: Asthma participants had a lower trajectory of appendicular lean mass at younger ages than those without either respiratory disease, irrespective of sex, smoking status, oral corticosteroids use and BMI (β=-1.14, 95% CI -1.84, -0.44, p=0.033). Trajectories of appendicular lean mass in participants with COPD were linear for both sexes while those of participants with asthma were curved (Figure 1). Conclusion: Our study confirms the longitudinal linear age-dependent muscle loss in COPD participants and adds that asthmatic subjects had a significantly non-linear loss of appendicular lean mass. Figure 1: Longitudinal changes in appendicular lean mass according to sex and chronic respiratory diseases. Red lines show the change in the coefficient (β) of appendicular lean mass over years of age with 95% CIs which are indicated by black dot lines.

Background There are detectable cognitive differences in cognitively unimpaired (CU) individuals with preclinical Alzheimer's disease (AD). Objective To determine whether cross-sectional performance on the Cogstate Brief Battery (CBB) and Auditory Verbal Learning Test (AVLT) could identify 1) CU participants with preclinical AD defined by neuroimaging biomarkers of amyloid and tau, and 2) incident mild cognitive impairment (MCI)/dementia. Method CU participants age 50+ were eligible if they had 1) amyloid (A) and tau (T) imaging within two years of their baseline CBB or 2) at least one follow-up visit. AUROC analyses assessed the ability of measures to differentiate groups. We explored the frequency of cross-sectional subtle objective cognitive impairment (sOBJ) defined as performance ≤-1 SD on CBB Learning/Working Memory Composite (Lrn/WM) or AVLT delayed recall using age-corrected normative data. Results A+T+ (n = 33, mean age 79.5) and A+T- (n = 61, mean age 77.8) participants were older than A-T- participants (n = 146, mean age 66.3), and comparable on sex and education. Lrn/WM did not differentiate A + T+or A+T- from A-T- participants. AVLT differentiated both A+T+ and A+T- from A-T- participants; 45% of A+T+ and 25% of A+T- participants met sOBJ criteria. The follow-up cohort included 150 CU individuals who converted to MCI/dementia and 450 age, sex, and education matched controls. Lrn/WM and AVLT differentiated between stable and converter CU participants. Conclusion Among CU participants, AVLT helped differentiate A+T+ and A+T- from A-T- participants. The CBB did not differentiate biomarker subgroups, but showed potential for predicting incident MCI/dementia. Results inform future definitions of sOBJ.

Background Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. Methods We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. Results There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10− 4 in the discovery and OR = 1.30, P = 1.8 × 10− 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52–2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94–1.20). Conclusions Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.

Highlights • In a population-based setting we studied brain structure before cancer diagnosis. • Brain structure was not altered before non-CNS cancer diagnosis. • The effect of cancer on the brain before clinical manifestation is not supported., Purpose Many studies have shown that patients with non-central nervous system (CNS) cancer can have brain abnormalities, such as reduced gray matter volume and cerebral microbleeds. These abnormalities can sometimes be present even before start of treatment, suggesting a potential detrimental effect of non-CNS cancer itself on the brain. In these previous studies, psychological factors associated with a cancer diagnosis and selection bias may have influenced results. To overcome these limitations, we investigated brain structure with magnetic resonance imaging (MRI) prior to cancer diagnosis. Patients and methods Between 2005 and 2014, 4,622 participants from the prospective population-based Rotterdam Study who were free of cancer, dementia, and stroke, underwent brain MRI and were subsequently followed for incident cancer until January 1st, 2015. We investigated the association between brain MRI measurements, including cerebral small vessel disease, volumes of global brain tissue, lobes, and subcortical structures, and global white matter microstructure, and the risk of non-CNS cancer using Cox proportional hazards models. Age was used as time scale. Models were corrected for e.g. sex, intracranial volume, educational level, body mass index, hypertension, diabetes mellitus, smoking status, alcohol use, and depression sum-score. Results During a median (interquartile range) follow-up of 7.0 years (4.9–8.1), 353 participants were diagnosed with non-CNS cancer. Results indicated that persons who develop cancer do not have more brain abnormalities before clinical manifestation of the disease than persons who remain free of cancer. The largest effect estimates were found for the relation between presence of lacunar infarcts and the risk of cancer (hazard ratio [HR] 95% confidence interval [CI] = 1.39 [0.97–1.98]) and for total brain volume (HR [95%CI] per standard deviation increase in total brain volume = 0.76 [0.55–1.04]). Conclusion We did not observe associations between small vessel disease, brain tissue volumes, and global white matter microstructure, and subsequent cancer risk in an unselected population. These findings deviate from previous studies indicating brain abnormalities among patients shortly after cancer diagnosis.

Background: Various studies show an inverse relation between Alzheimer disease and cancer, but findings are likely to be biased by surveillance and survival bias. Plasma amyloid-β (Aβ) is defined as a preclinical feature of Alzheimer disease, with lower levels of Aβ42 being associated with a higher risk of Alzheimer disease. To get more insight into the biological link between Alzheimer disease and cancer, we investigated plasma Aβ levels in relation to the risk of cancer. Methods: Between 2002 and 2005, we measured plasma Aβ40 and Aβ42 levels in 3,949 participants from the population-based Rotterdam Study. These participants were followed until the onset of cancer, all-cause dementia, death, loss to follow-up, or January 1, 2014, whichever came first. We used Cox proportional hazards models to investigate the association between plasma Aβ40 and Aβ42 levels, and the risk of cancer. Analyses were stratified by cancer site. Results: During a median (interquartile range) follow-up of 9.0 years (6.9–10.1), 560 participants were diagnosed with cancer. Higher levels of log2 plasma Aβ40 and Aβ42 were associated with a higher risk of cancer [hazard ratio per standard deviation increase for Aβ40 = 1.12 (95% confidence interval, CI = 1.02–1.23) and Aβ42 = 1.12 (95% CI = 1.03–1.23)]. These effect estimates were most pronounced for hematologic cancers, urinary tract cancers, and cancers of unknown primary origin. Conclusions: We found that higher levels of both plasma Aβ40 and Aβ42 were associated with a higher risk of cancer. Impact: Our study suggests a potential biological link between Alzheimer disease and cancer. The pathophysiologic role of Aβ in cancer and its causality warrant further investigation.

Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

ObjectiveObservational data can be used to attempt to emulate a target trial of statin use and estimate analogues of intention-to-treat and per protocol effects on dementia risk.MethodsUsing data from a prospective cohort study in the Netherlands, we conceptualized a sequence of “trials” in which eligible individuals ages 55–80 years were classified as statin initiators or noninitiators for every consecutive month between 1993 and 2007 and were followed until diagnosis of dementia, death, loss to follow-up, or the end of follow-up. We estimated 2 types of effects of statin use on dementia and a combined endpoint of dementia or death: the effect of initiation vs no initiation and the effect of sustained use vs no use. We estimated risk by statin treatment strategy over time via pooled logistic regression. We used inverse-probability weighting to account for treatment-confounder feedback in estimation of per-protocol effects.ResultsOf 233,526 eligible person-trials (6,373 individuals), there were 622 initiators and 232,904 noninitiators. Comparing statin initiation with no initiation, the 10-year risk differences (95% confidence interval) were −0.1% (−2.3% to 1.8%) for dementia and 0.3% (−2.7% to 3.3%) for dementia or death. Comparing sustained statin use vs no use, the 10-year risk differences were −2.2% (−5.2% to 1.6%) for dementia and −5.1% (−10.5% to −1.1%) for dementia or death.ConclusionsIndividuals with sustained statin use, but not statin initiation alone, had reduced 10-year risks of dementia and dementia or death. Our results should be interpreted with caution due to the small number of initiators and events and potential for residual confounding.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p

BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS: We identified a genome-wide significant (P < 5 × 10(–8)) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10(–)12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. CONCLUSIONS: In this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies. FUNDING: This project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 – STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

Background Little is known on the prevalence and characteristics of asthma in middle-aged and older adults, since previous studies mainly focused on children and young adults. Therefore, the aim was to investigate the prevalence of physician-diagnosed asthma and its comorbidities, in a population-based cohort of adults 45 years of age and over. Methods We identified participants with physician-diagnosed asthma in the Rotterdam Study; a prospective population-based cohort in the Netherlands. Pulmonary function measurements and comorbidities of the asthma cases were assessed at baseline and compared to those of the general population. Results Out of 14,621 participants (mean age 65.5 years; 59% women), 524 subjects (31.5%males) had physician-diagnosed asthma at study entry, implicating an asthma prevalence of 3.6% [95% Confidence Interval (CI) 3.3%–3.9%] (2.8% in males and 4.2% in females). Asthmatic subjects had a significantly higher prevalence of obesity and depressive symptoms (Odds Ratio [OR]: 2,02 [95% CI 1,66-2,47] and [OR]: 2,01 [95% CI 1,52-2,66] respectively). Longer duration of asthma and current smoking were associated with lower lung function in asthmatic subjects. Conclusion Four percent of middle-aged and older adults have physician-diagnosed asthma. These adult asthmatics suffer more frequently from obesity and depression than subjects without obstructive lung disease.

ObjectivesBurdensome and futile interventions with the aim of prolonging life should be avoided in dying patients. However, current clinical practice has hardly been investigated.We examined the number and type of diagnostic and therapeutic medical interventions in hospitalised patients with cancer in their last days of life. In addition, we investigated if physician awareness of impending death affected the use of these interventions.MethodsQuestionnaire study and medical record study. Attending physicians of patients who died in a university hospital between January 2010 and June 2012 were asked whether they had been aware of the patient’s impending death. The use of diagnostic and therapeutic interventions and medications was assessed by studying patients’ charts. We included 131 patients.ResultsIn the last 72 and 24 hours of life, 59% and 24% of the patients received one or more diagnostic interventions, respectively. Therapeutic interventions were provided to 47% and 31%. In the last 24 hours of life, patients received on average 5.8 types of medication.Awareness of a patient’s impending death was associated with a significant lower use of diagnostic interventions (48% vs 69% in the last 72 hours; 11% vs 37% in the last 24 hours) and several medications that potentially prolong life (eg, antibiotics and cardiovascular medication).ConclusionsMany patients with cancer who die in hospital receive diagnostic and therapeutic interventions in the last days of life of which their advantages are questionable. To improve end-of-life care, medical care should be adapted.

BackgroundSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies.MethodsWe carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA.ResultsNo variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in highrisk populations and the general community.

Introduction.In patients with advanced non–small-cell lung cancer, the treatment benefits and risks need to be constantly weighed. We explored patient-reported satisfaction with therapy (SWT) and assessed its value in addition to quality of life (QoL) and adverse events (AEs).Patients and methods.In a prospective multicenter cohort study, patients with stage IIIB/IV non–small-cell lung cancer received platinum-pemetrexed chemotherapy. They completed the World Health Organization Quality of Life-BREF (WHOQoL-BREF) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) before and during chemotherapy. After the last cycle, patients reported on SWT, expectations of therapy, and feelings about side effects (FSE) using the Cancer Therapy Satisfaction Questionnaire. The explained variance (R2) of QoL after treatment by SWT was calculated. Using multivariable linear regression, we examined the association of SWT with patient- and treatment-related variables, FSE, and AEs.Results.Eighty-nine patients finished 4 cycles of chemotherapy, 65 of whom completed the Cancer Therapy Satisfaction Questionnaire. Fifty-six patients (86.2%) would probably or definitely decide to undergo the same treatment again, regardless of deterioration or improvement in QoL or a high or low frequency of AEs during chemotherapy. The explained variance of QoL by SWT was greatest for the EORTC QLQ C-30 global health status/QoL scale (R2 = 0.170). Patient age (β = 0.43; 95% confidence interval [CI], 0.05-0.82), FSE (β = 0.17; 95% CI, 0.06-0.29), and tumor response (β = 7.93; 95% CI (1.64 to 14.22)) were independently associated with SWT.Conclusion.SWT could provide important supplementary information in addition to QoL assessments and treatment toxicities. Tumor response, older age, and FSE score were associated with better SWT. These insights could affect decision-making during palliative chemotherapy

Background: Adrenal adenomas are incidentally diagnosed in 7% of adults undergoing abdominal imaging. Mild autonomous cortisol secretion is present in 50% of adrenal adenomas, and even “nonfunctioning” adrenal adenomas demonstrate abnormal steroid profile. We aimed to 1) investigate the prevalence of mental and sleep disorders in patients with adrenal adenomas and to 2) determine the risk of mental and sleep disorders after the diagnosis of adrenal adenoma in patients compared to the referent subjects from the same population Methods: Using a medical records linkage system, we identified adult patients living in the Olmsted County, MN diagnosed with an adrenal adenoma during 1995–2017. Patients with overt hormone excess were excluded. Every patient with adenoma was matched by sex and age to a referent subject from the same population. Subjects were followed until death or end of the study. Mental health related comorbidities and sleep disorders were assessed at baseline and during follow up. Results: Our cohort included 1004 patients with adrenal adenomas and 1004 referent subjects (58% women, median age of 63 years). Patients were more likely to smoke (70% vs 54%, p

Controversy exists regarding the potential association between taking calcium channel blockers (CCBs) and the development of breast cancer. As a positive association would have important public health implications due to the widespread use of CCBs, this study aimed to incorporate new evidence to determine whether an association is likely to exist. We searched MEDLINE, EMBASE and the Cochrane Library to 28 June 2016 for relevant literature. References and citing articles were checked and authors contacted as necessary. Two authors independently selected articles and extracted data. Twenty-nine studies were reviewed; 26 were non-randomised studies (NRS). Meta-analysis of study data where adjustment for 'confounding by indication' was judged to be present suggests that an association, if any, is likely to be modest in magnitude (pooled odds/risk ratio 1.09 (95% confidence interval (CI) 1.03-1.15, I2=0%, 8 sub-studies; pooled hazard ratio 0.99 (95% CI 0.94-1.03, I2=35%, 9 sub-studies)). There are credible study data showing an increased relative risk with long-term use of CCBs, but the results of our meta-analysis and of meta-regression of log relative risk against minimum follow-up time are mixed. The current summative evidence does not support a clear association between taking CCBs and developing breast cancer. However, uncertainty remains, especially for long-term use and any association might not be uniform between different populations and/or breast cancer sub-types. We thus recommend further NRS in settings where CCB use is highly prevalent and population-based cancer, prescription and health-registries exist, to resolve this continuing uncertainty. PROSPERO, CRD42015026712.

We aimed to evaluate the criterion validity of the 2015 food-based Dutch dietary guidelines, which were formulated based on evidence on the relation between diet and major chronic diseases. We studied 9701 participants of the Rotterdam Study, a population-based prospective cohort in individuals aged 45 years and over [median 64.1 years (95%-range 49.0–82.8)]. Dietary intake was assessed at baseline with a food-frequency questionnaire. For all participants, we examined adherence (yes/no) to fourteen items of the guidelines: vegetables (≥200 g/day), fruit (≥200 g/day), whole-grains (≥90 g/day), legumes (≥135 g/week), nuts (≥15 g/day), dairy (≥350 g/day), fish (≥100 g/week), tea (≥450 mL/day), ratio whole-grains:total grains (≥50%), ratio unsaturated fats and oils:total fats (≥50%), red and processed meat (

Benzodiazepines and benzodiazepine-related medications (BBRMs) are anxiolytics and hypnotics acting on γ-amino butyric acid (GABA)A receptors. BBRMs are assumed to have a low potential for major congenital malformations, but research on more subtle and protracted developing symptoms of these medications is lacking. Therefore, we prospectively investigated the association between BBRM use in pregnancy and long-term effects on child behavior in a large population-based cohort study. The study population consisted of 104 children prenatally exposed to BBRM, 527 children exposed to maternal prenatal anxiety or phobic anxiety symptoms (without exposure to BBRM), and 5609 control children. At child age, 6 years, Oppositional Defiant Disorder (ODD), Aggressive Behavior and Anxiety Problems were assessed by the Child Behavior Checklist (CBCL) reported by the mother and the Teacher Report Form (TRF). Children prenatally exposed to BBRM had higher scores of ODD and aggressive behavior, but not of anxiety. However, these associations were explained by maternal anxiety symptoms during pregnancy. Moreover, prenatal exposure to anxiety (without exposure to BBRM) was associated with increased scores of child ODD, aggressive behavior, and anxiety. In conclusion, the current study demonstrates that prenatal BBRM exposure was not independently associated with ODD and aggressive behavior in childhood when prenatal anxiety symptoms were taken into account.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P

SEE BREEN AND LANG DOI101093/AWW321 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: At the time of clinical diagnosis, patients with Parkinson's disease already have a wide range of motor and non-motor features that affect their daily functioning. However, the temporal sequence of occurrence of these features remains largely unknown. We studied trajectories of daily functioning and motor and non-motor features in the 23 years preceding Parkinson's disease diagnosis by performing a nested case-control study within the prospective Rotterdam study. Between 1990 and 2013, we repeatedly performed standardized assessments of daily functioning (Stanford Health Assessment Questionnaire, Lawton Instrumental Activities of Daily Living Scale), potential prediagnostic motor (hypo- and bradykinesia, tremor, rigidity, postural imbalance, postural abnormalities) and non-motor features of Parkinson's disease, including cognition (Mini-Mental State Examination, Stroop Test, Letter-Digit-Substitution Test, Word Fluency Test), mood (Center for Epidemiological Studies-Depression Scale, Hamilton Anxiety and Depression Scale), and autonomic function (blood pressure, laxative use). In addition, the cohort was followed-up for the onset of clinical Parkinson's disease using several overlapping modalities, including repeated in-person examinations, as well as complete access to medical records and specialist letters of study participants. During follow-up, 109 individuals were diagnosed with Parkinson's disease, and each case was matched to 10 controls based on age and sex (total n = 1199). Subsequently, we compared prediagnostic trajectories of daily functioning and other features between Parkinson's disease cases and controls. From 7 years before diagnosis onwards, prediagnostic Parkinson's disease cases more commonly had problems in instrumental activities of daily functioning, and more frequently showed signs of movement poverty and slowness, tremor and subtle cognitive deficits. In the past 5 years, Parkinson's disease cases developed additional motor features (postural imbalance, rigidity, and postural abnormalities) and increasingly reported problems in basic daily activities. Parkinson's disease cases also increasingly reported anxiety symptoms, depressive symptoms, and use of laxatives throughout study follow-up, although differences with controls only became statistically significant in the last years before diagnosis. In conclusion, in patients with prediagnostic Parkinson's disease, impairments in instrumental daily activities, which require both motor and non-motor skills, pre-date difficulties in more physically oriented daily activities.media-1vid110.1093/brain/aww291_video_abstractaww291_video_abstract.

Item does not contain fulltext BACKGROUND: Parkinsonism is a common neurodegenerative syndrome in middle-aged and elderly persons. The etiology is multifactorial with a possible vascular contribution, but this has not been comprehensively studied. OBJECTIVE: To determine whether selected markers of subclinical vascular pathology are associated with the risk of all-cause parkinsonism in the general population. METHODS: We assessed a range of markers of subclinical vascular pathology (ankle-brachial index, carotid plaques and intima media thickness, retinal arteriolar and venular calibers) in 6199 persons from the population-based Rotterdam Study, who were free of parkinsonism and dementia at baseline. We followed these persons up till onset of parkinsonism, dementia, and death for 89,387 person-years until January 1, 2013. Hazard ratios (HRs) for all-cause parkinsonism and separately for Parkinson disease (PD) versus non-PD were estimated from competing risk regression models adjusting for potential confounders. RESULTS: During follow-up, we identified 211 cases of parkinsonism (110 had PD). None of the five markers of subclinical pathology was associated with all-cause parkinsonism. Only low ankle-brachial index was associated with a higher risk of non-PD parkinsonism (HR = 0.79, 95%CI: 0.68-0.92), but not with the risk of PD. CONCLUSION: We did not find a consistent pattern of associations between systemic vascular pathology markers with parkinsonism, suggesting that the potential involvement of vascular pathology is not prominent or needs further evaluation in studies with an even larger sample size.

Purpose In March 2013, regulatory warnings concerning the potential risks of domperidone caused considerable media attention in the Netherlands. The aim of the study was to assess the effect of regulatory warnings and the resulting media hype on the frequency of electrocardiogram (ECG) monitoring of inpatients using domperidone. We also studied the effect on the frequency of prescribing domperidone by physicians. Methods A 2-centre, observational, retrospective cohort study was performed. Inpatients using domperidone in 2 hospitals in the Netherlands during a period of 384 days before and after the media hype were included. The main outcomes were (1) the proportion of domperidone users with ECGs before and/or during domperidone treatment, (2) the proportion of patients with an ECG before and during treatment, and (3) the proportion of patients with an ECG during treatment. Secondary outcome was the proportion of domperidone prescriptions comparing the before- and after-period. Results Four hundred twenty-eight patients were included. The main outcomes [respectively (1) relative risk (RR) 1.02, 95% confidence interval (CI), 0.85-1.21; (2) RR 1.06, 95% CI, 0.60-1.85; and (3) RR 1.27, 95% CI, 0.80-2.01) were not different. After stratifying for hospital, no significant differences were found. A statistically significant decrease (RR 0.40, 95% CI, 0.35-0.45) in numbers of prescriptions was found for the university medical centre only. Conclusions No effect of the media hype was found on the intensity of ECG monitoring in domperidone users. In the university medical centre, domperidone prescriptions were reduced.

Aims/hypothesis Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk. Methods Within the population-based Rotterdam Study, we used Cox models, adjusted for age, sex, lifestyle factors, comorbidities, kidney function, serum levels of electrolytes and diuretic use, to study the association between serum magnesium and prediabetes/diabetes. In addition, we performed two mediation analyses: (1) to study if common genetic variation in eight magnesium-regulating genes influence diabetes risk through serum magnesium levels; and (2) to quantify the proportion of the effect of serum magnesium levels on diabetes that is mediated through insulin resistance (quantified by HOMA-IR). Results A total of 8555 participants (mean age, 64.7 years; median follow-up, 5.7 years) with normal glucose levels (mean ± SD: 5.46 ± 0.58 mmol/l) at baseline were included. A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation in CLDN19, CNNM2, FXYD2, SLC41A2, and TRPM6 significantly influenced diabetes risk (p

Background Pulmonary hypertension is a progressive heterogeneous syndrome, characterized by elevated pulmonary arterial pressure which can lead to right ventricular failure. Although the presence of elevated pulmonary arterial systolic pressure (PASP) in patients with a lung disease is a well-known occurrence, little is known about the association between pulmonary function and PASP in the general population. We hypothesized that pulmonary function and PASP are associated, irrespective of airflow limitation. Methods This study was performed within the Rotterdam Study, a prospective population-based cohort. We included 1660 participants with spirometry, performed and interpreted according to ATS/ERS-guidelines, and echocardiography performed according to the ASE/EAE/CSE-guidelines. We analyzed the association of Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), FEV1/FVC and diffusion capacity (DLCO) with estimated PASP (ePASP). Furthermore, we investigated the association between spirometry measures, COPD, and echocardiographic pulmonary hypertension. Results A 10% absolute decrease in FEV1 was associated with an ePASP increase of 0.46 mmHg (95%CI: 0.31; 0.61). Similarly, per absolute 10% decrease, FVC was significantly associated with an increased ePASP of 0.42 mmHg (95%CI: 0.25; 0.59). FEV1/FVC showed an association of 1.01 mmHg (95%CI: 0.58; 1.45) increase in ePASP per 10% absolute decrease. A decrease in DLCO (in mL/min/kPa) was associated with an increased ePASP (0.46 mmHg, 95%CI: 0.17; 0.76). We found significant associations for FEV1 and FVC with echocardiographic pulmonary hypertension. Importantly, an increased ePASP was significantly associated with mortality (Hazard Ratio: 1.042 per mmHg [95%CI: 1.023–1.062; p Conclusion We observed a clearly graded association between pulmonary function and ePASP and pulmonary hypertension, even in individuals without airflow limitation.