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Aims: Common genetic variations in the nitric oxide synthase‐1 adaptor protein (NOS1AP) gene are associated with QT‐interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT‐interval shortening in digoxin users. As QT‐interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. Methods: We included 11 377 individuals from the prospective population‐based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time‐dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose‐dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non‐users. Results: The median baseline age of the total study population was 62 (interquartile range [IQR] 58–71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow‐up of 11.5 (IQR 6.5–17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38–3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98–8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37–5.04] in the heterozygous TG and 2.56 [95%CI: 1.70–3.86] in the homozygous TT genotype groups. Compared to low‐ and moderate‐dose, high‐dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34–23.47]). Conclusions: Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin‐associated risk of SCD in a population of European ancestry. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We aimed to assess the effect of antidepressant use on dementia risk, cognitive decline, and brain atrophy. METHODS: In this prospective cohort study, we included 5511 dementia‐free participants (Mini‐Mental State Examination [MMSE] > 25) of the Rotterdam study (57.5% women, mean age 70.6 years). Antidepressant use was extracted from pharmacy records from 1991 until baseline (2002–2008). Incident dementia was monitored from baseline until 2018, with repeated cognitive assessment and magnetic resonance imaging (MRI) every 4 years. RESULTS: Compared to never use, any antidepressant use was not associated with dementia risk (hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.92–1.41), or with accelerated cognitive decline or atrophy of white and gray matter. Compared to never use, dementia risk was somewhat higher with tricyclic antidepressants (HR 1.36, 95% CI 1.01–1.83) than with selective serotonin reuptake inhibitors (HR 1.12, 95% CI 0.81–1.54), but without dose–response relationships, accelerated cognitive decline, or atrophy in either group. DISCUSSION: Antidepressant medication in adults without indication of cognitive impairment was not consistently associated with long‐term adverse cognitive effects. Highlights: Antidepressant medications are frequently prescribed, especially among older adults.In this study, antidepressant use was not associated with long‐term dementia risk.Antidepressant use was not associated with cognitive decline or brain atrophy.Our results support safe prescription in an older, cognitively healthy population. [ABSTRACT FROM AUTHOR]

The immune response–gut microbiota interaction is implicated in various human diseases, including cancer. Identifying the link between the gut microbiota and systemic inflammatory markers and their association with cancer will be important for our understanding of cancer etiology. The current study was performed on 8090 participants from the population‐based Rotterdam study. We found a significant association (false discovery rate [FDR] ≤0.05) between lymphocytes and three gut microbial taxa, namely the family Streptococcaceae, genus Streptococcus, and order Lactobacillales. In addition, we identified 95 gut microbial taxa that were associated with inflammatory markers (p < 0.05). Analyzing the cancer data, we observed a significant association between higher systemic immune‐inflammation index (SII) levels at baseline (hazard ratio (HR): 1.65 [95% confidence interval (CI); 1.10–2.46, p ≤ 0.05]) and a higher count of lymphocytes (HR: 1.38 [95% CI: 1.15–1.65, p ≤ 0.05]) and granulocytes (HR: 1.69 [95% CI: 1.40–2.03, p ≤ 0.05]) with increased risk of lung cancer after adjusting for age, sex, body mass index (BMI), and study cohort. This association was lost for SII and lymphocytes after additional adjustment for smoking (SII = HR:1.46 [95% CI: 0.96–2.22, p = 0.07] and lymphocytes = HR: 1.19 [95% CI: 0.97–1.46, p = 0.08]). In the stratified analysis, higher count of lymphocyte and granulocytes at baseline were associated with an increased risk of lung cancer in smokers after adjusting for age, sex, BMI, and study cohort (HR: 1.33 [95% CI: 1.09–1.62, p ≤0.05] and HR: 1.57 [95% CI: 1.28–1.92, p ≤0.05], respectively). Our study revealed a positive association between gut microbiota, higher SII levels, and higher lymphocyte and granulocyte counts, with an increased risk of developing lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies suggest that women are more susceptible to diuretic‐induced hyponatremia resulting in hospital admission than men. The aim of this study was to confirm whether these sex differences in hyponatremia‐related hospital admissions in diuretic users remain after adjusting for several confounding variables such as age, dose, and concurrent medication. Methods: In a case–control design nested in diuretic users, cases of hyponatremia associated hospital admissions between 2005 and 2017 were identified from the PHARMO Data Network. Cases were 1:10 matched to diuretic users as controls. Odds ratios (OR) with 95%CIs were calculated for women versus men and adjusted for potential confounders (age, number of diuretics, other hyponatremia‐inducing drugs, chronic disease score) using unconditional logistic regression analysis. A subgroup analysis was performed for specific diuretic groups (thiazides, loop diuretics and aldosterone antagonists). Results: Women had a statistically significantly higher risk of a hospital admission associated with hyponatremia than men while using diuretics (OR 1.86, 95%CI 1.64–2.11). Adjusting for the potential confounders resulted in an increased risk for women compared to men (ORadj 2.65, 95% CI 2.31–3.04). This higher risk in women was also seen in the three subgroup analyses after adjustment. Conclusion: Our findings show a higher risk of hyponatremia‐related hospital admission in women than men while using diuretics. Further research is needed to understand the underlying mechanism of this sex difference to be able to provide sex‐specific recommendations. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between proton pump inhibitors (PPIs) and risk of incident diabetes in a follow‐up study and to investigate its potential mechanisms. Methods: A total of 9531 individuals without type 2 diabetes (T2DM) at baseline were included from the Rotterdam Study, a prospective population‐based cohort of 14 926 individuals aged 45 years or older. During the study period (1 April 1997 to 1 January 2012) all incident cases of T2DM were enrolled. We used multivariable linear regression analysis to investigate the associations of baseline PPI use and various serum biomarkers (eg, serum magnesium, insulin‐like growth factor 1) which might modify the association. Thereafter, we excluded prevalent PPI users and performed a Cox proportional hazard regression analysis to explore the time‐varying effect of incident PPI use on T2DM during follow‐up. Results: Baseline use of a PPI was associated with increased serum levels of fasting insulin (0.091 pmoL/L, 95% confidence interval [CI] 0.049, 0.133), homeostasis model assessment‐insulin resistance (0.100, 95% CI 0.056, 0.145) and C‐reactive protein (0.29 mg/L, 95% CI 0.198, 0.384), but decreased levels of magnesium (−0.009 mmol/L, 95% CI −0.014, −0.004) and IGF‐1 (−0.805 nmoL/L, 95% CI −1.015, −0.595). After adjustment for risk factors such as physical activity and body mass index/waist‐to‐hip ratio, current use of PPI was associated with an increased risk of incident T2DM (hazard ratio [HR] 1.69, 95% CI 1.36‐2.10). The effect was dose‐dependent with the highest risk (HR 1.88, 95% CI 1.29‐2.75) in those on more than one defined daily dose. Conclusion: New users of PPIs during follow‐up had a significantly higher dose‐dependent risk of incident diabetes. We suggest vigilance regarding their potential adverse effect on glucose homeostasis. [ABSTRACT FROM AUTHOR]

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 < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. Conclusion: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response. [ABSTRACT FROM AUTHOR]

Objective: Clinical studies showing that non-central nervous system cancer patients can develop cognitive impairment have primarily focused on patients with specific cancer types and intensive treatments. To better understand the course of cognitive function in the general population of cancer patients, we assessed cognitive trajectories of patients before and after cancer diagnosis in a population-based setting.Methods: Between 1989 and 2014, 2211 participants from the population-based Rotterdam study had been diagnosed with cancer of whom 718 (32.5%) had undergone ≥1 cognitive assessment before and after diagnosis. Cognition was measured every 3 to 6 years using a neuropsychological battery. Linear mixed models were used to compare cognitive trajectories of patients before and after diagnosis with those of age-matched cancer-free controls (1:3).Results: Median age at cancer diagnosis was 70.3 years and 47.1% were women. Most patients (68.1%) had received local treatment only. Cognitive trajectories of patients before and after cancer diagnosis were largely similar to those of controls. After diagnosis, the largest difference was found on a memory test (patients declined with 0.14 units per year on the Word Learning Test: delayed recall [95% CI = -0.35; 0.07] and controls with 0.09 units [95% CI = -0.18;-0.00], p for difference = .59).Conclusions: In this longitudinal cohort, cancer did not appear to alter the trajectory of change in cognitive test results over time from that seen in similar individuals without cancer, although most cancer patients did not receive systemic therapies. Future studies should focus on identifying subgroups of patients who are at high risk for developing cognitive impairment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well‐established acute adverse effects on cognition. However, long‐term effects on dementia risk remain uncertain, and on subclinical imaging markers of neurodegeneration largely undetermined. Method: We included 5443 cognitively healthy participants (MMSE≥26) from the population‐based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005‐2008) was derived from ATC‐coded pharmacy records, from which we determined drug type (anxiolytics vs. sedative‐hypnotics vs. both) and cumulative dose. We determined the association of benzodiazepine use with dementia risk until 2020 using Cox regression, and with change in neuroimaging markers during 5‐yearly repeated brain MRI using linear mixed models. Models were adjusted for demographics, lifestyle factors and comorbidity, including presence of anxiety, depression and sleeping problems. Result: During a mean follow‐up of 11.2 years, 726 participants (13.3%) developed dementia. Benzodiazepine use occurred in 1675 (30.8%) participants, of whom 845 (50.4%) had used anxiolytics, 390 (23.3%) had used sedative‐hypnotics, and 440 (26.3%) had used both. Current use of any type of benzodiazepine at baseline, but not former use, was associated with an increased dementia risk during follow‐up (HR[95%CI] for current users: 1.56[1.17‐2.09]; and past users: 1.07[0.87‐1.31]). Excess risk in current users persisted after excluding a 2‐year lag‐time of benzodiazepine use prior to baseline. Dementia risk was dependent on cumulative dose (>median: HR[95%CI] 1.31[1.05‐1.63] vs. < = median: HR[95%CI] 1.01[0.78‐1.31]). Use was not associated with volume of grey matter, white matter, hippocampus, amygdala or thalamus at baseline. During follow up, high cumulative dose was associated with accelerated decrease in hippocampal volume (p = 0.021). Regarding drug type, dementia risk was increased with anxiolytics (overall HR[95%CI]: 1.37[1.10‐1.71]), which was paralleled by accelerated atrophy of grey matter (p = 0.036), albeit no dose‐response relationship was observed. Sedative‐hypnotics were not associated with dementia risk or brain atrophy. Combined use of anxiolytics and sedative‐hypnotics at baseline was associated with increased dementia risk (HR[95%CI]: 1.70[1.05‐2.76]), but this attenuated after excluding use during a 2‐year lag time before baseline (HR[95%CI]: 1.08[0.71‐1.64]), and was not associated with brain atrophy. Conclusion: Chronic use of benzodiazepines in a population of cognitively healthy older adults is associated with increased dementia risk. [ABSTRACT FROM AUTHOR]

Several studies found that the systemic immune‐inflammation index (SII) is a prognostic factor for mortality in patients with solid tumors. It is unknown whether an increased SII in generally healthy individuals reflects a risk for developing cancer. Our objective was to investigate the association between the SII and incident cancers in a prospective cohort study. Data were obtained from the Rotterdam Study; a population‐based study of individuals aged ≥45 years, between 2002 and 2013. The SII at baseline was calculated from absolute blood counts. The association between the SII and the risk of any solid incident cancer during follow‐up was assessed using Cox proportional hazard models. Individuals with a prior cancer diagnosis were excluded. Data of 8,024 individuals were included in the analyses. The mean age at baseline was 65.6 years (SD 10.5 years) and the majority were women. During a maximum follow‐up period of 10.7 years, 733 individuals were diagnosed with cancer. A higher SII at baseline was associated with a 30% higher risk of developing a solid cancer (HR of 1.30 [95% CI; 1.11–1.53]), after adjustment for age, sex, socioeconomic status, smoking, BMI and type 2 diabetes. The absolute cumulative 10‐year cancer risk increased from 9.7% in the lowest quartile of SII to 14.7% in the highest quartile (p‐value = 0.009). The risk of developing cancer was persistent over time and increased for individuals with the longest follow‐up. In conclusion, a high SII is a strong and independent risk indicator for developing a solid cancer. What's new? The systemic immune‐inflammation index (SII) incorporates blood counts of neutrophils, lymphocytes, and platelets. Several studies have found that the SII can help to predict mortality in patients with solid tumors. Might the SII also be useful in evaluating future cancer risk? In this prospective epidemiologic study, the authors found that an increased SII is independently associated with as much as a 30% higher risk of a future diagnosis of a solid cancer. These results indicate that inflammatory cells could play a role in the etiology of cancer. Further research is needed. [ABSTRACT FROM AUTHOR]

Aims: There are several epidemiological studies on the association between statins and incident diabetes, but most of them lack details. In this study, we aimed to investigate the association of statin use with glycaemic traits and incident type 2 diabetes. Methods: Using the prospective population‐based Rotterdam Study, we included 9535 individuals free from diabetes at baseline (>45 years) during the study period between 1997 and 2012. Linear regression analysis was applied to examine the cross‐sectional associations between statin use and glycaemic traits including fasting blood serum of glucose and insulin concentrations, and insulin resistance. In a longitudinal follow‐up study, we applied a Cox regression analysis to determine adjusted hazard ratios (HR) for incident type 2 diabetes in new users of statins. Results: The mean age at baseline was 64.3 ± 10.1 years and 41.7% were men. In the fully adjusted model, compared to never users of statins, baseline use of statins was associated with higher concentrations of serum fasting insulin (β = 0.07; 95% CI: 0.02–0.13) and insulin resistance (β = 0.09; 95% CI: 0.03–0.14). Ever use of statins was associated with a 38% higher risk of incident type 2 diabetes (HR = 1.38; 95% CI: 1.09–1.74). This risk was more prominent in subjects with impaired glucose homeostasis and in overweight/obese individuals. Conclusions: Individuals using statins may be at higher risk for hyperglycaemia, insulin resistance and eventually type 2 diabetes. Rigorous preventive strategies such as glucose control and weight reduction in patients when initiating statin therapy might help minimize the risk of diabetes. [ABSTRACT FROM AUTHOR]

Purpose Non‐steroidal anti‐inflammatory drugs (NSAIDs) are commonly used during pregnancy. Findings that prenatal NSAID exposure may affect offspring neurodevelopment have been inconsistent. We investigated the effect of prenatal NSAID exposure on childhood neurodevelopment and explored the susceptibility of our effect estimates to forms of bias via negative exposure, negative outcome, and multi‐informant analyses. Methods: In a cohort of pregnant women (n = 6876), perinatal NSAID use was assessed by prescriptions and self‐report. Primary neurodevelopmental outcomes included attention problems using maternal reports at 1½, 3, and 5 years. To explore potential systematic biases, we compared estimates from maternally reported attention problems to a teacher's report and a measure of nonverbal intelligence assessed at a clinic visit at age 6 years; we also used NSAID use before pregnancy and somatic problems as a "negative" exposure and outcome, respectively. Results: Maternal reports suggested that prenatal exposure to NSAIDs was associated with more attention problems at younger ages (eg, at age 3: mean difference in attention problems score: 0.30; 95% CI 0.12, 0.48). However, no strong association with attention problems was found in the teacher report, and a similarly strong association between prenatal NSAID exposure and somatic complaints suggests residual confounding by indication likely remains. Moreover, prenatal exposure to NSAIDs was not associated with an observed measure of IQ (mean difference in IQ score: −0.32; 95% CI: −1.82, 1.19). Conclusions: Jointly, our results suggest that the observed associations between prenatal exposure to NSAIDs and child attention problems reflect systematic biases of a null or small effect. [ABSTRACT FROM AUTHOR]

Purpose Hypomagnesaemia has been associated with various adverse outcomes. Loop and thiazide diuretics promote urinary magnesium excretion. However, it is unknown if this links to hypomagnesaemia. We study if loop or thiazide diuretic use affects serum magnesium levels and if it associates with hypomagnesaemia. In addition, we study the effect of combining a potassium‐sparing diuretic with a thiazide diuretic on the presence of hypomagnesaemia. Methods: The study performed a cross‐sectional analysis within 9820 participants from the prospective Rotterdam Study. Hypomagnesaemia was defined as a serum magnesium level ≤0.72 mmol/L. Participants were categorized by defined daily dose (DDD), and all analyses were adjusted for age, sex, BMI, eGFR, serum potassium levels, proton pump inhibitor use, and comorbidities. Results: Loop diuretic use was associated with higher serum magnesium levels (<1 DDD: 0.004 mmol/L 95% CI: −0.008; 0.017; 1 DDD: 0.023 mmol/L 95% CI: 0.013; 0.032; >1 DDD: 0.043 mmol/L 95% CI: 0.028; 0.057). Thiazide diuretic use was associated with lower serum magnesium levels (<1 DDD: −0.013 mmol/L 95% CI: −0.023; −0.002; ≥1 DDD: −0.018 mmol/L 95% CI: −0.028; −0.010), resulting in an increased odds ratio of hypomagnesaemia of 3.14 (95% CI: 1.67; 5.92) and 2.74 (95% CI: 1.57; 4.77), respectively. These effects were predominantly seen in participants using diuretics for more than 390 days. Combining thiazide diuretics with a potassium‐sparing agent was not associated with lower serum magnesium levels or hypomagnesaemia. Conclusions: Thiazide diuretic use is associated with lower serum magnesium levels and an increased risk of hypomagnesaemia. This increased risk is not seen in participants using a combination of thiazide diuretics with a potassium‐sparing agent. The use of loop diuretics is not associated with an increased risk of hypomagnesaemia. [ABSTRACT FROM AUTHOR]

Aims To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Methods Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time-varying β-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β-blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. Results In total 2917 participants encountered a fall during a total follow-up time of 89 529 years. Meta-analysis indicated no association between use of any β-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective β-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective β-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other β-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. Conclusion Our study suggests that use of a nonselective β-blocker, contrary to selective β-blockers, is associated with an increased fall risk in an older population. In clinical practice, β-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β-blocker in this age group, and the pros and cons for β-blocker classes should be taken into consideration. [ABSTRACT FROM AUTHOR]

Aims Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QTc prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults. Methods This study, which was part of the prospective Rotterdam Study (period 1991-2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QTcF (QT corrected according to Fridericia) measured during use of individual SSRIs with QTcF measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older. Results We included 12 589 participants with a total of 26 620 ECGs of which 436 ECGs were made during SSRI use. The mean QTcF was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QTc compared with ECGs recorded during non-use (+12.8 ms, 90% CI 7.5, 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg citalopram. Conclusions Although no SSRI class effect was observed, use of citalopram was associated with a longer QTcF, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QTcF prolongation. [ABSTRACT FROM AUTHOR]

Purpose Prolonged ventricular repolarization (measured as heart-rate corrected QT (QTc) prolongation or JT-interval prolongation) is a risk factor for ventricular arrhythmias and can be drug-induced. Drugs can be classified as having known or possible QTc-prolonging properties. Regulatory agencies recommend avoiding concomitant use of multiple QTc-prolonging drugs, but evidence is lacking to what degree ventricular repolarization is influenced by concomitant use of these drugs. Methods Within a population-based cohort of persons aged 45 years and older, with up to five electrocardiograms recorded per participant between 1991 and 2010, we used generalised estimating equations to study the association between concomitant use of multiple QTc-prolonging drugs and repolarization duration. Results The study population consisted of 13 009 participants with 26 908 electrocardiograms. With the addition of a second or third QTc-prolonging drug there was no substantial increase in QTc and JT interval and no increased risk of a prolonged QTc interval, compared to use of one QTc-prolonging drug. There was a large difference between the effect of one known or one possible QTc-prolonging drugs on QTc interval: 15 ms for known, and 3 ms for possible QTc-prolonging drugs. Conclusions In this study, the added prolongation in users of two or three QTc-prolonging drugs on QTc was small. There was a large difference in QTc prolongation between known and possible QTc-prolonging drugs. Further research in larger or high-risk populations is needed to establish whether it is safe to use multiple QTc-prolonging drugs concomitantly to prevent that the current advice might unnecessarily withhold beneficial drugs from patients. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim Electronic healthcare record (EHR)-based surveillance systems are increasingly being developed to support early detection of safety signals. It is unknown what the power of such a system is for surveillance among children and adolescents. In this paper we provide estimates of the number and classes of drugs, and incidence rates (IRs) of events, that can be monitored in children and adolescents (0-18 years). Methods Data were obtained from seven population-based EHR databases in Denmark, Italy, and the Netherlands during the period 1996-2010. We estimated the number of drugs for which specific adverse events can be monitored as a function of actual drug use, minimally detectable relative risk (RR) and IRs for 10 events. Results The population comprised 4 838 146 individuals (25 575 132 person years (PYs)), who were prescribed 2170 drugs (1 610 631 PYs drug-exposure). Half of the total drug-exposure in PYs was covered by only 18 drugs (0.8%). For a relatively frequent event like upper gastrointestinal bleeding there were 39 drugs for which an association with a RR ≥4, if present, could be investigated. The corresponding number of drugs was eight for a rare event like anaphylactic shock. Conclusion Drug use in children is rare and shows little variation. The number of drugs with enough exposure to detect rare adverse events in children and adolescents within an EHR-based surveillance system such as EU-ADR is limited. Use of additional sources of paediatric drug exposure information and global collaboration are imperative in order to optimize EHR data for paediatric safety surveillance. [ABSTRACT FROM AUTHOR]

Some studies suggest a favorable role of antioxidants on breast cancer risk but this is still inconclusive. The aim of this study was to assess whether overall dietary antioxidant capacity, as assessed by dietary ferric reducing antioxidant potential (FRAP), and individual dietary antioxidant intake were associated with breast cancer risk. Data was used from women participating in the Rotterdam Study, a prospective cohort study among subjects aged 55 years and older ( N = 3,209). FRAP scores and antioxidant intake ( i.e., vitamin A, C, E, selenium, flavonoids and carotenoids) was assessed at baseline by a food frequency questionnaire. Incident cases of breast cancer were confirmed through medical reports. During a median follow-up of 17 years, 199 cases with breast cancer were identified. High dietary FRAP score was associated with a lower risk of breast cancer [hazard ratio (HR): 0.68; 95% confidence intervals (CI): 0.49, 0.96]. No overall association between individual antioxidant intake and breast cancer risk was found. However, low intake of alpha carotene and beta carotene was associated with a higher risk of breast cancer among smokers (HR: 2.48; 95% CI: 1.21, 5.12 and HR: 2.31; 95% CI: 1.12, 4.76 for alpha and beta carotene, respectively) and low intake of flavonoids was associated with breast cancer risk in women over the age of 70 (HR: 1.80; 95% CI: 1.09, 2.99). These results suggest that high overall dietary antioxidant capacity is associated with a lower risk of breast cancer. Individual effects of dietary carotenoids and dietary flavonoids may be restricted to subgroups such as smokers and elderly. [ABSTRACT FROM AUTHOR]

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article discusses use of 5-alpha-reductase inhibitors, dutasteride and finasteride, indicated for treatment of male pattern hair loss and symptomatic benign prostatic hyperplasia, and contraindicated for use by women, in women in the Netherlands, as reported by the pharmacovigilance centre Lareb. Topics include their off-label use for treatment of women with alopecia or hirsutism; and a study to examine their dispensings to women of childbearing age who were on contraceptives concomitantly.

Background & Aims Little is known about the association of serum liver enzymes with long-term outcome in the elderly. We sought to clarify the association of serum gamma-glutamyltransferase ( GGT), alkaline phosphatase ( ALP), alanine aminotransferase ( ALT) and aspartate aminotransferase ( AST) with all-cause and cause-specific mortality in an elderly population. Methods This study was embedded in the Rotterdam Study, a large population-based cohort of persons aged 55 years or older. Cox-regression analyses were performed to examine the association of baseline serum GGT, ALP, and aminotransferase levels with mortality, adjusted for age, sex, education, smoking status, alcohol intake, hypertension, diabetes mellitus, body mass index and total cholesterol levels. Liver enzyme levels were categorized according to sample percentiles; levels <25th percentile were taken as a reference. Results During a follow-up of up to 19.5 years, 2997 of 5186(57.8%) participants died: 672 participants died of causes related to cardiovascular diseases ( CVD) and 703 participants died of cancer. All serum liver enzymes were associated with all-cause mortality (all P < 0.001). Moreover, GGT was associated with increased CVD mortality ( P < 0.001), and ALP and AST with increased cancer-related mortality ( P = 0.03 and P = 0.005 respectively). Participants with GGT and ALP in the top 5% had the highest risk for all-cause mortality ( HR1.55; 95% CI 1.30-1.85 and HR1.49; 95% CI 1.25-1.78 respectively). AST and ALT <25th percentile were also associated with a higher risk of all-cause mortality. Conclusions All serum liver enzymes were positively associated with long-term mortality in this elderly population. Why participants with low ALT and AST levels have higher risk of mortality remains to be elucidated. [ABSTRACT FROM AUTHOR]

Aim β-adrenoceptor blockers have been used with caution in patients with obstructive lung diseases such as asthma or chronic obstructive pulmonary disease ( COPD), due to the potentially increased airway reactivity and risk of bronchial obstruction. Cardioselective β-adrenoceptor blockers have a more beneficial profile than non-cardioselective β-adrenoceptor blockers and can be safely prescribed to patients with both cardiovascular disease and COPD. We hypothesized that cardioselective β-adrenoceptor blockers also affect pulmonary function. Methods This study was performed within the Rotterdam Study, a prospective population-based cohort study. Effects of cardioselective and non-cardioselective β-adrenoceptor blockers on pulmonary function were analysed using regression techniques with multivariable adjustment for potential confounders. Results Current use of non-cardioselective β-adrenoceptor blockers was significantly associated with a lower forced expiratory volume in 1 s ( FEV1) of −198 ml (95% CI −301, −96), with a lower forced vital capacity ( FVC) of −223 ml (95% CI −367, −79) and with a decreased FEV1 : FVC of −1.38% (95% CI −2.74, −0.13%). Current use of cardioselective β-adrenoceptor blockers was significantly associated with a lower FEV1 of −118 ml (95% CI −157, −78) and with a lower FVC of −167 ml (95% CI −222, −111), but did not affect FEV1 : FVC. After exclusion of patients with COPD, asthma and heart failure the effects of cardioselective β-adrenoceptor blockers remained significant for FEV1 (−142 ml [95% CI −189, −96]) and for FVC (−176 ml [95% CI −236, −117]). Conclusion In our study both non-cardioselective and cardioselective β-adrenoceptor blockers had a clinically relevant effect on both FEV1 and FVC. In contrast to cardioselective β-adrenoceptor blockers, use of non-cardioselective β-adrenoceptor blockers was associated with a significantly lower FEV1 : FVC. [ABSTRACT FROM AUTHOR]

Aims The assessment of heart rate-corrected QT ( QTc) interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic-pharmacodynamic (PKPD) relationships to characterize drug-induced QTc interval prolongation and explore the discrepancies between clinical trials and real-life conditions. Methods d,l- Sotalol data from healthy subjects and from the Rotterdam Study cohort were used to assess treatment response in a phase I setting and in a real-life conditions, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations. Results Inclusion criteria were shown to restrict the representativeness of the trial population in comparison to real-life conditions. A significant part of the typical patient population was excluded from trials due to weight and baseline QTc interval criteria. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes and myocardial infarction ( P < 0.01). Although drug effects do cause an increase in the relative risk of QTc interval prolongation, the presence of diabetes represented an increase from 4.0 [95% confidence interval (CI) 2.7-5.8] to 6.5 (95% CI 1.6-27.1), whilst for myocardial infarction it increased from 3.4 (95% CI 2.3-5.13) to 15.5 (95% CI 4.9-49.3). Conclusions Our findings show that drug effects on QTc interval do not explain the observed QTc values in the population. The prevalence of high QTc values in the real-life population can be assigned to co-morbidities and concomitant medications. These findings substantiate the need to account for these factors when evaluating the cardiovascular risk of medicinal products. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cardiovascular disease, disease outcome, drug treatment and drug response differ between men and women. WHAT THIS STUDY ADDS • Adverse drug reactions attributed to cardiovascular drugs that require hospital admission show differences between men and women, even after taking into account age and the total number of drug prescriptions. AIMS Cardiovascular disease in women is often underestimated. The effects of cardiovascular drugs differ between the sexes because of pharmacokinetic and pharmacodynamic differences. Adverse drug reactions (ADRs) within these drug classes may have serious consequences, leading to hospital admission. We aimed to study differences between men and women in hospital admissions for ADRs due to cardiovascular drugs. METHODS We conducted a nationwide study of all hospital admissions between 2000 and 2005 with data from the Dutch National Medical Register. Relative risks were calculated of hospital admissions due to ADRs to the different cardiovascular drug groups for women compared with men. By an ecological design, risks were adjusted for the total number of Dutch inhabitants and the total number of prescriptions. RESULTS In total, 14 207 of the hospital admissions (34% of all ADR-related admissions) were attributed to cardiovascular drugs [7690 in women (54%; 95% confidence interval 53-55%)]. 'Anticoagulants and salicylates' ( n= 8988), 'high- and low-ceiling diuretics' ( n= 2242) and 'cardiotonic glycosides' ( n= 932) were responsible for the majority of the ADR-related hospital admissions. The most pronounced sex differences were seen in users of low-ceiling diuretics (relative risk 4.02; 95% confidence interval 3.12-5.19), cardiotonic glycosides (relative risk 2.38; 95% confidence interval 2.06-2.74), high-ceiling diuretics (relative risk 2.10; 95% confidence interval 1.91-2.32) and coronary vasodilators (relative risk 0.77; 95% confidence interval 0.65-0.91). CONCLUSIONS Clear sex differences exist in ADRs requiring hospital admission for different cardiovascular drug groups. Sex differences should be taken into account in the prescription and evaluation of drugs. [ABSTRACT FROM AUTHOR]

In the Netherlands, several reports have described a potentiation of acenocoumarol-induced anticoagulation by co-medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR) ≥ 6, until death, end of treatment, or end of the study period. The Andersen-Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55-2·55) and lansoprazole (HR 1·49, 95% CI 1·05-2·10). There was also a lower and non-significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co-medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: • To investigate the association between the use of inhaled anticholinergic drugs and the risk of acute urinary retention (AUR) under real life circumstances. PATIENTS AND METHODS: • We conducted a nested case-control study within a cohort of patients with chronic obstructive pulmonary disease (COPD; as AUR has been associated with the use of inhaled anticholinergic drugs, which are used as first-line treatment for COPD) from the Integrated Primary Care Information (IPCI) database. • The cohort consisted of all patients with COPD aged ≥ 45 years, registered between 1996 and 2006, with ≥ 12 months of valid history. Cases were patients with a first diagnosis of AUR. • To each case, controls were selected matched for age, gender and index date. • Multivariate conditional logistic regression analysis was used to calculate adjusted odds ratios (OR adj ) with 95% confidence intervals (95% CI). RESULTS: • Within the cohort of 22 579 patients with COPD, 209 cases were identified. • Current use of inhaled anticholinergic drugs was associated with a 40% increase in risk for AUR (OR adj 1.40; 95% CI 0.99–1.98) compared with non-users. • Among current users, the risk was highest for the recent starters (OR adj 3.11; 95% CI 1.21–7.98). The risk of long-acting anticholinergic drug tiotropium was not substantially different from that of the short-acting anticholinergic ipratropium. • The association was not dose-dependent, but changed by mode of administration, with nebulizers having the highest risk (OR adj 2.92; 95% CI 1.17–7.31). • In men with COPD and benign prostatic hyperplasia (BPH) the association was strongest (OR adj 4.67; 95% CI 1.56–14.0). CONCLUSION:• Current use of inhaled anticholinergic drugs increases the risk of AUR, especially in patients with BPH or if administered via a nebulizer. [ABSTRACT FROM AUTHOR]

Women are more at risk for developing adverse drug reactions (ADRs) due to differences in pharmacokinetics, pharmacodynamics and drug use. ADRs regularly lead to hospital admissions. There are differences between the sexes in hospital admissions attributed to ADRs. The risk of being hospitalized with an ADR varies between the sexes in the type of reaction and the causative drug. Adverse drug reactions (ADRs) are a major burden in health care, regularly leading to hospital admission, morbidity or death. Women tend to have a higher risk of adverse drug reactions with a 1.5 to 1.7-fold greater risk than men. Our primary aim was to study differences in ADR-related hospitalizations between the sexes. We conducted a nationwide study of all ADR-related hospitalizations in the period between 2000 and 2005 in the Netherlands, which were selected from all 9 287 162 hospital admissions in this period. ADR-drug group combinations with at least 50 admissions in one of the sexes were selected. Relative risks and confidence intervals were calculated with respect to total admissions and total prescriptions with men as reference. In total, 0.41% of the 4 236 368 admissions in men (95% CI 0.40, 0.42%) and 0.47% of the 5 050 794 admissions in women (95% CI 0.46, 0.48%) were attributed to an ADR by medical specialists (57% of all ADR-related admissions were in women). Differences between the sexes in risk for ADR-related hospitalization were found for antineoplastic and immunosuppressive drugs, antirheumatics, anticoagulants and salicylates, cardiovascular and neurological drugs, steroids and antibiotics. In certain drug categories, risks for hospitalization changed after taking into account total drug prescriptions. In all different drug classes, significant differences exist between the sexes in ADR-related hospital admissions. Cardiovascular drugs account for the most pronounced differences between men and women. More research is needed to explain the clear sex differences in ADR-related hospital admissions. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Drug-induced hepatic injury is one of the most important reasons for drug withdrawal in adults. • Very little is known about drug-induced hepatic injury in children and adolescents. WHAT THIS STUDY ADDS • The rate of hepatic injury as suspected adverse drug reactions in the paediatric population is low. • Drugs associated with hepatotoxicity in children and adolescents were mostly known to be associated with hepatotoxicity in adults as well. AIM To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. METHODS Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. RESULTS Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12-17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. CONCLUSIONS Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children. [ABSTRACT FROM AUTHOR]

Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene–drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene–drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted. [ABSTRACT FROM AUTHOR]

Kaur G, Verhamme KMC, Dieleman JP, Vanrolleghem A, van Soest EM, Stricker BHCh, Sturkenboom MCJM. Association between calcium channel blockers and gingival hyperplasia. J Clin Periodontol 2010; 37: 625–630. doi: 10.1111/j.1600-051X.2010.01574.x. Aim: To study the effect of the dose and type of calcium channel blockers (CCBs) on the risk of gingival hyperplasia and to quantify this association. Methods: The study was conducted within the Integrated Primary Care Information Project in The Netherlands. A nested case–control study was designed within a cohort of all patients who were new users of either CCBs or drugs interacting with the renin–angiotensin system (RAS). Cases were all individuals with a validated diagnosis of gingival hyperplasia. Controls were matched on age, gender and index date. Results: Within the study population, 103 cases of gingival hyperplasia were identified and matched to 7677 controls. The risk of gingival hyperplasia was higher in current users of CCBs [adjusted odds ratio (ORadj) 2.2, 95% confidence intervals (95% CI): 1.4–3.4], especially in dihydropyridines (ORadj 2.1, 95% CI: 1.3–3.5) and benzothiazepine derivatives (ORadj 2.9, 95% CI: 1.3–6.5) than in RAS drug users. The risk increased in patients using more than the recommended daily dose (ORadj 3.0, 95% CI: 1.6–5.5) and when the duration of current use was <1 month (ORadj 5.2, 95% CI: 2.1–12.6). Conclusion: This study shows that the risk of gingival hyperplasia is twofold higher in current users of CCBs than in users of RAS drugs. The association was dose dependent and the highest for dihydropyridines or benzothiazepine derivates. [ABSTRACT FROM AUTHOR]

Purpose Simvastatin and atorvastatin are metabolized by the CYP3A4 enzyme and transported by the ABCB1 transporter. We studied whether the polymorphism CYP3A4*1B and the polymorphisms C1236T, G2677A/T and C3435T in the ABCB1 gene were associated with a decrease of the prescribed dose or a switch to another cholesterol lowering drug during simvastatin and atorvastatin therapy. These events may indicate that statin plasma levels were too high and resulted in an adverse drug reaction or a too strong reduction in cholesterol level. Methods We identified 1239 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations between the polymorphisms in the CYP3A4 and ABCB1 gene and the time to a decrease in dose or a switch to another cholesterol lowering drug were studied using Cox proportional hazards. Results Simvastatin and atorvastatin users with the CYP3A4*1B variant G allele had a lower risk (HR 0.46; 95%CI 0.24-0.90) for these events than users with the wild-type AA genotype. No significant associations were found for the ABCB1 polymorphisms. The association with the CYP3A4*1B polymorphism was found in women (HR 0.33; 95%CI 0.12-0.89) and was non-significant in men (HR 0.69 95%CI 0.28-1.70). This association was stronger in patients with the ABCB1 3435T variant allele versus the G allele. Conclusion In simvastatin and atorvastatin users, the CYP3A4*1B G allele is associated with a lower risk of elevated statin plasma levels, particularly in women and in users with the ABCB1 3435T variant allele. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Thyroid hormone free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death. • The association between hyperthyroidism and ventricular arrhythmias or sudden cardiac death has been reported in several case reports. WHAT THIS STUDY ADDS • We investigated in a prospective population-based cohort study and in a case–control study whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of sudden cardiac death. • Use of antithyroid drugs was associated with a threefold increased risk of sudden cardiac death. • Although this might be due to antithyroid drug use, it could be more readily explained by underlying hyperthyroidism. AIM Thyroid free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death (SCD). Hyperthyroidism has been associated with SCD in case reports, but there are no population-based studies confirming this. The aim was to investigate whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of SCD. METHODS We studied the occurrence of SCD in a two-step procedure in two different Dutch populations. First, the prospective population-based Rotterdam Study including 7898 participants (≥55 years old). Second, we used the Integrated Primary Care Information (IPCI) database, which is a longitudinal general practice research database to see whether we could replicate results from the first study. Drug use at the index date was assessed with prescription information from automated pharmacies (Rotterdam Study) or drug prescriptions from general practices (IPCI). We used a Cox proportional hazards model in a cohort analysis, adjusted for age, gender and use of QTc prolonging drugs (Rotterdam Study) and conditional logistic regression analysis in a case–control analysis, matched for age, gender, practice and calendar time and adjusted for arrhythmia and cerebrovascular ischaemia (IPCI). RESULTS In the Rotterdam Study, 375 participants developed SCD during follow-up. Current use of antithyroid drugs was associated with SCD [adjusted hazard ratio 3.9; 95% confidence interval (CI) 1.7, 8.7]. IPCI included 1424 cases with SCD and 14 443 controls. Also in IPCI, current use of antithyroid drugs was associated with SCD (adjusted odds ratio 2.9; 95% CI 1.1, 7.4). CONCLUSIONS Use of antithyroid drugs was associated with a threefold increased risk of SCD. Although this might be directly caused by antithyroid drug use, it might be more readily explained by underlying poorly controlled hyperthyroidism, since treated patients who developed SCD still had low thyroid-stimulating hormone levels shortly before death. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several antidepressants are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). • The variant allele CYP2D6* 4 is the main polymorphism resulting in decreased enzyme activity in Caucasians. • Decreased CYP2D6 enzyme activity potentially leads to higher plasma concentrations of antidepressants. • Consequently, patients carrying the * 4 allele are more likely to suffer from adverse drug reactions such as hyponatraemia. WHAT THIS STUDY ADDS • The association between CYP2D6 genotype and serum sodium concentration in users of antidepressants has not been examined thoroughly, and most studies suffer from small numbers of poor metabolizers (PMs) of CYP2D6. • This study shows that serum sodium concentrations in users of tricyclic antidepressive drugs are lower in CYP2D6 PMs than in extensive metabolizers. AIM To study the effect of the CYP2D6* 4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)]. METHODS In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined ( n= 76). Multivariate linear regression was used to study the association between CYP2D6* 4 and serum sodium concentration. RESULTS CYP2D6 poor metabolizers (PMs) (* 4/* 4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (* 1/* 1) [difference −3.9 mmol l−1; 95% confidence interval (CI) −0.86, −7.03; P= 0.013]. In CYP2D6* 4 heterozygotes (* 1/* 4) serum sodium concentration was 1.7 mmol l−1 (95% CI −3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant ( P= 0.077). CONCLUSIONS The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia. [ABSTRACT FROM AUTHOR]

Purpose In epidemiological studies, non-response may introduce bias and limit generalizability. In genetic pharmacoepidemiological research, collection of DNA might be a major reason for non-response. We determined reasons for non-response and compared characteristics of non-responders and responders in a pharmacogenetic case-control study. Methods Myocardial infarction (MI) cases and controls, who were antihypertensive drug users, were recruited through community pharmacies that participate in the Pharmaco-Morbidity-Record-Linkage-System (PHARMO). The PHARMO database comprises drug dispensing histories of about 2 000 000 subjects from a representative sample of Dutch community pharmacies linked to the national registry of hospital discharges. Independent samples t-test and ANOVA-statistics were used to analyse the differences in continuous variables between responders and non-responders. χ2 statistics and logistic regression were used to compare categorical variables. Results We approached 1871 cases and 14 102 controls of whom 794 MI cases (42.4%) and 4997 controls (35.4%) responded. We could not approach 2194 patients of whom 63.1% had died and 31.2% moved to another pharmacy. Main reasons for non-response were health problems or hospital stays (16.2%, OR 1.47; 95%CI: 1.00-2.16). Other reasons were old age or dementia (16.9%, OR 1.82; 95%CI: 1.24-2.65). Only a small percentage (1.1%, OR 1.43; 95%CI: 0.41-5.03) mentioned DNA sampling as a reason. About 30% of the non-responders did not give a reason. Women were statistically significantly ( p < 0.0005) less willing to participate than men (38.8% versus 31.3%). An association with age was also found (mean age 64.6 versus 66.5 yrs) ( p < 0.0005). Conclusion In a pharmacogenetic case-control study fear for genetic screening was not a major reported reason for non-response. Females were less willing to participate than males. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We studied the hypothesis that the BclI polymorphism of the glucocorticoid receptor gene is associated with an increased probability of being a (heavy) smoker and a decreased ability to quit smoking. The study cohort consisted of all subjects in the Rotterdam Study, a Dutch population-based cohort of people aged 55 years and older, for whom BclI genotyping and smoking status at baseline were available. In prospective analyses, the smoking status was reassessed during three additional examination rounds. Logistic regression analysis was used to study the association between BclI polymorphism and being a smoker or a heavy smoker at baseline. Furthermore, the relationship between BclI polymorphism and incident smoking cessation was tested with Cox proportional hazards analysis within those who smoked at baseline. In total, 6358 subjects were included in the study. The presence of a G-allele was not associated with current smoking at baseline [odds ratio (OR) = 0.96, 95%confidence interval (CI): 0.85–1.09] or with the incidence of smoking cessation during follow-up [hazard ratio (HR) = 0.98, 95%CI: 0.80–1.19]. Within current smokers, having a G-allele was not significantly associated with the risk of being a heavy smoker when measured by pack-years smoked (OR = 1.07, 95%CI: 0.85–1.35) or daily consumption of tobacco (OR = 1.10, 95%CI: 0.88–1.37). We were not able to replicate the earlier findings indicating that the proportion of current smokers is lower among carriers of the CC-genotype of the BclI glucocorticoid receptor. Furthermore, the BclI glucocorticoid receptor polymorphism did not predict the incidence of smoking cessation in the general elderly population. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Neuronal nitric oxide synthase (nNOS) regulates intracellular calcium handling • A polymorphism in the NOS1AP gene (rs10494366), a regulator of nNOS, is associated with QTc prolongation • Calcium channel blockers also affect calcium handling by blocking the L-type calcium channel WHAT THIS STUDY ADDS • We assessed the association between the polymorphism rs10494366 in the NOS1AP gene and mortality in calcium channel blocker users • The TG and GG genotype are associated with increased cardiovascular mortality in dihydropyridine calcium channel blocker users AIM Recently, a polymorphism in the NOS1AP gene (rs10494366), a regulator of neuronal nitric oxide synthase (nNOS), was associated with QTc prolongation. Both nNOS and calcium channel blockers (CCBs) regulate intracellular calcium levels and have an important role in cardiovascular homeostasis. The aim was to investigate whether this polymorphism is associated with cardiovascular mortality in users of CCBs. METHODS The data from the Rotterdam study, a population-based closed cohort study of Caucasian individuals of ≥55 years of age, were used. We identified 1113 participants in the Rotterdam Study who were prescribed CCBs for the first time between 1991 and 2005. All-cause and cardiovascular mortality was assessed in participants who were prescribed CCBs with different NOS1AP rs10494366 genotypes using Cox proportional hazard models. RESULTS In participants starting on dihydropyridine CCBs (amlodipine, nifedipine and others) all-cause mortality ( n = 79) risks were higher in participants with the TG [hazard ratio (HR) 2.57, 95% confidence interval (CI) 1.24, 5.34] or the GG genotype (HR 3.18, 95% CI 1.18, 8.58) than in participants with the referent TT genotype. Cardiovascular mortality ( n = 54) risks were 3.51 (95% CI 1.41, 8.78) for the TG genotype and 6.00 (95% CI 1.80, 20.0) for the GG genotype. No differences in all-cause mortality or cardiovascular mortality were seen in participants starting with the nondihydropyridine CCBs verapamil or diltiazem. CONCLUSION The minor G allele of rs10494366 in the NOS1AP gene is associated with increased all-cause and cardiovascular mortality in Caucasian users of dihydropyridine CCBs. The mechanism underlying the observed association is unknown. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all-cause mortality in elderly people. DESIGN: Prospective study. SETTING: Community based. PARTICIPANTS: Five thousand sixty-four subjects from the Rotterdam study aged 55 and older. MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mmHg or more or a decline in diastolic blood pressure of 10 mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing. RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow-up, 668 subjects had coronary heart disease (CHD) (mean follow-up 6.0 ± 3.5 years), and 1,835 subjects died (mean follow-up period 7.8 ± 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR)=1.31, 95% confidence interval (CI)=1.08–1.57) and all-cause mortality (HR=1.22, 95% CI=1.09–1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all-cause mortality were 1.80 (95% CI 1.25–2.60), 1.13 (0.89–1.42), and 1.27 (95% CI=1.11–1.44), in the first, second, and third tertile of age, respectively. CONCLUSION: Orthostatic hypotension increases the risk of CHD and all-cause mortality in elderly people. The risk of CVD and mortality is strongest in younger and very old subjects. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Benzodiazepine use increases the risk of fracture in the elderly. • It is controversial which conditions of use are most risky, e.g. use of short- or long-acting benzodiazepines, dose and duration of use. • The well-known Beers criteria include statements about inappropriate benzodiazepine use in elderly and the risk of fracture, but their clinical value has never been tested in an outcome study. WHAT THIS STUDY ADDS • Inappropriate benzodiazepine use according to the Beers criteria is not associated with an increased risk of fracture. • Daily dose and duration of use is associated with higher risk of fracture, not the type of benzodiazepine prescribed as the Beers criteria state. AIMS The Beers criteria for prescribing in elderly are well known and used for many drug utilization studies. We investigated the clinical value of the Beers criteria for benzodiazepine use, notably the association between inappropriate use and risk of fracture. METHODS We performed a nested case–control study within the Rotterdam Study, a population-based cohort study in 7983 elderly. The proportion of ‘inappropriate’ benzodiazepine use according to the Beers criteria was compared between fracture patients and controls. ‘Inappropriate’ use for elderly implies use of some long-acting benzodiazepines and some intermediate/short-acting ones exceeding a suggested maximum daily dose. Also, alternative criteria were applied to compare the risk of fracture. Cases were defined as persons with incident fracture between 1991 and 2002 who were current benzodiazepine users on the fracture date. Controls were matched on fracture date and were also current benzodiazepine users. RESULTS The risk of fracture in ‘inappropriate’ benzodiazepine users according to the Beers criteria was not significantly different from ‘appropriate’ users [odds ratio (OR) 1.07, 95% confidence interval (CI) 0.72, 1.60]. However, a significantly higher risk of fracture was found in ‘high dose’ users and a longer duration of use (14–90 days), irrespective of the type of benzodiazepine (OR 3.45, 95% CI 1.38, 8.59). CONCLUSIONS These findings suggest that inappropriate benzodiazepine use according to the Beers criteria is not associated with increased risk of fracture. Daily dose and longer duration of use (>14 days) is associated with higher risk of fracture, irrespective of the type of benzodiazepine prescribed. [ABSTRACT FROM AUTHOR]

What is already known about this subject • Most antidepressants are metabolized by CYP2D6. The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. • Reduced enzyme activity potentially leads to increased toxicity of antidepressants, but the relevance of genotyping for clinical practice is unclear. Most clinical studies suffer from small numbers of patients. What this study adds • This large population-based cohort study in 1198 elderly Dutch patients examines the influence of the CYP2D6* 4 polymorphism on intolerability of antidepressants. • The risk of switching to another antidepressant in tricyclic antidepressant users is higher in poor metabolizers (PMs), but not in SSRI users. PMs require a lower maintenance dose of antidepressants compared with extensive metabolizers (EMs). • Antidepressants were initiated in a relatively low dose, with gradual dose increments thereafter, reducing the risk of adverse drug reactions. Therefore, the question remains whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy. Aims To study the effect of CYP2D6* 4 on antidepressant dose, switching and discontinuation of therapy. Methods The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6* 4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t-tests and repeated measurements analyses. Results In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:* 4/* 4) compared with extensive metabolizers (EMs:* 1/* 1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02). Conclusions The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The risk of adverse events due to chronic benzodiazepine use is high in the elderly. • Cross-sectional studies have shown that increasing age, female gender and poor physical and mental health are associated with benzodiazepine use. • When users were re-examined some years later, chronic somatic disease, pain and stress seemed to contribute to the continuation of benzodiazepine use. WHAT THIS STUDY ADDS • This is the first longitudinal study that analyzed the determinants of new-onset chronic benzodiazepine use in community-dwelling elderly. • Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new-onset chronic use. Living alone was found to decrease the risk of chronic use. AIMS The risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related factors that predict new-onset chronic benzodiazepine use in community-dwelling elderly. METHODS This study was embedded in an ongoing cohort study among 5364 persons aged ≥57 years. Drug-dispensing medication records were available for the period between 1991 and 2003. We defined chronic benzodiazepine use as use during at least 180 days in a period of 365 consecutive days. The association of various social, psychiatric and somatic variables with new-onset chronic benzodiazepine use was studied with a Cox proportional hazards analysis. RESULTS Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new-onset chronic use. In the subsample of participants who had filled at least one prescription in the follow-up period, of these variables only pain related joint complaints increased the risk of new-onset chronic use. Living alone protected against chronic benzodiazepine use. CONCLUSIONS The elderly with poor mental and physical health are at an increased risk of chronic benzodiazepine use. Living alone was found to decrease the risk of chronic use, which suggests that social factors may determine drug usage patterns. Very few characteristics predicted chronic benzodiazepine use once patients had received their first prescription. For clinicians, identification of patients at high risk is therefore not straightforward. [ABSTRACT FROM AUTHOR]

The article focuses on a study which aims to investigate whether renin-angiotensin system (RAS) inhibitors and/or angiotensin I-converting enzyme (ACE) inhibitors genotypes were linked with an altered risk of colorectal, lung, breast and prostate cancer. It notes that angiotensin II is the biologically active peptide of the RAS and is a vital regulator of blood pressure. It concludes that the use of RAS inhibitors was linked with a decreased risk of cancer in people with the DD genotype.

Purpose To compare adjusted effects of drug treatment for hypertension on the risk of stroke from propensity score (PS) methods with a multivariable Cox proportional hazards (Cox PH) regression in an observational study with censored data. Methods From two prospective population-based cohort studies in The Netherlands a selection of subjects was used who either received drug treatment for hypertension ( n = 1293) or were untreated 'candidates' for treatment ( n = 954). A multivariable Cox PH was performed on the risk of stroke using eight covariates along with three PS methods. Results In multivariable Cox PH regression the adjusted hazard ratio (HR) for treatment was 0.64 (CI95%: 0.42, 0.98). After stratification on the PS the HR was 0.58 (CI95%: 0.38, 0.89). Matching on the PS yielded a HR of 0.49 (CI95%: 0.27, 0.88), whereas adjustment with a continuous PS gave similar results as Cox regression. When more covariates were added (not possible in multivariable Cox model) a similar reduction in HR was reached by all PS methods. The inclusion of a simulated balanced covariate gave largest changes in HR using the multivariable Cox model and matching on the PS. Conclusions In PS methods in general a larger number of confounders can be used. In this data set matching on the PS is sensitive to small changes in the model, probably because of the small number of events. Stratification, and covariate adjustment, were less sensitive to the inclusion of a non-confounder than multivariable Cox PH regression. Attention should be paid to PS model building and balance checking. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine whether outcomes of tilt-table tests improved after withdrawal of fall-risk-increasing drugs (FRIDs). DESIGN: Prospective cohort study. SETTING: Geriatric outpatient clinic. PARTICIPANTS: Two hundred eleven new, consecutive outpatients, recruited from April 2003 until December 2004. MEASUREMENTS: Tilt-table testing was performed on all participants at baseline. Subsequently, FRIDs were withdrawn in all fallers in whom it was safely possible. At a mean follow-up of 6.7 months, tilt-table testing was repeated in 137 participants. Tilt-table testing addressed carotid sinus hypersensitivity (CSH), orthostatic hypotension (OH), and vasovagal collapse (VVC). Odds ratios (ORs) of tilt-table-test normalization according to withdrawal (discontinuation or dose reduction) of FRIDs were calculated using multivariate logistic regression analysis. RESULTS: After adjustment for confounders, the reduction of abnormal test outcomes (ORs) according to overall FRID withdrawal was 0.34 (95% confidence interval (CI)=0.06–1.86) for CSH, 0.35 (95% CI=0.13–0.99) for OH, and 0.27 (95% CI=0.02–3.31) for VVC. For the subgroup of cardiovascular FRIDs, the adjusted OR was 0.13 (95% CI=0.03–0.59) for CSH, 0.44 (95% CI=0.18–1.0) for OH, and 0.21 (95% CI=0.03–1.51) for VVC. CONCLUSION: OH improved significantly after withdrawal of FRIDs. Subgroup analysis of cardiovascular FRID withdrawal showed a significant reduction in OH and CSH. These results imply that FRID withdrawal can cause substantial improvement in cardiovascular homeostasis. Derangement of cardiovascular homeostasis may be an important mechanism by which FRID use results in falls. [ABSTRACT FROM AUTHOR]

Purpose To estimate the association between use of typical and atypical antipsychotics and all-cause mortality in a population of demented outpatients. Methods The study cohort comprised all demented patients older than 65 years and registered in the Integrated Primary Care Information (IPCI) database, during 1996-2004. First, mortality rates were calculated during use of atypical and typical antipsychotics. Second, we assessed the association between use of atypical and typical antipsychotics and all-cause mortality through a nested case-control study in the cohort of demented patients. Each case was matched to all eligible controls at the date of death by age and duration of dementia. Odds ratios were estimated through conditional logistic regression analyses. Results The crude mortality rate was 30.1 (95%CI: 18.2-47.1) and 25.2 (21.0-29.8) per 100 person-years (PY) during use of atypical and typical antipsychotics, respectively. No significant difference in risk of death was observed between current users of atypical and typical antipsychotics (OR = 1.3; 95%CI: 0.7-2.4). Both types of antipsychotics were associated with a significantly increased risk of death as compared to non-users (OR = 2.2, 1.2-3.9 for atypical antipsychotics; OR=1.7, 1.3-2.2 for typical antipsychotics). Conclusions Conventional antipsychotic drug should be included in the FDA's Public Health advisory, which currently warns only of the increased risk of death with the use of atypical antipsychotics in elderly demented persons. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

What is already known about this subject • In observational studies, several drugs have been associated with an increased fall risk. A meta-analysis in 1999 found a significant association for neuroleptics, antidepressants, sedatives, diuretics, type IA antiarrhythmics, and digoxin. • Nevertheless, knowledge on the effect of withdrawal of these drugs on fall risk is scarce. Only one randomized controlled trial has been carried out in 1999, showing a significantly lowered fall risk after withdrawal of sedatives and antidepressants in community-dwelling older persons. What this study adds • This study indicates that withdrawal of all fall-risk-increasing drugs, including both cardiovascular and psychotropic drugs, is an effective intervention for lowering of falls incidence. This effect appears to be highest for withdrawal of cardiovascular drugs. Aims Falling in older persons is a frequent and serious clinical problem. Several drugs have been associated with increased fall risk. The objective of this study was to identify differences in the incidence of falls after withdrawal (discontinuation or dose reduction) of fall-risk-increasing drugs as a single intervention in older fallers. Methods In a prospective cohort study of geriatric outpatients, we included 139 patients presenting with one or more falls during the previous year. Fall-risk-increasing drugs were withdrawn, if possible. The incidence of falls was assessed within 2 months of follow-up after a set 1 month period of drug withdrawal. Multivariate adjustment for potential confounders was performed with a Cox proportional hazards model. Results In 67 patients, we were able to discontinue a fall-risk-increasing drug, and in eight patients to reduce its dose. The total number of fall incidents during follow-up was significantly lower in these 75 patients, than in those who continued treatment (mean number of falls: 0.3 vs. 3.6; P value 0.025). The hazard ratio of a fall during follow-up was 0.48 (95% confidence interval (CI) 0.23, 0.99) for overall drug withdrawal, 0.35 (95% CI 0.15, 0.82) for cardiovascular drug withdrawal and 0.56 (95% CI 0.23, 1.38) for psychotropic drug withdrawal, after adjustment for age, gender, use of fall-risk-increasing drugs, baseline falls frequency, comorbidity, Mini-Mental State Examination score, and reason for referral. Conclusions Withdrawal of fall-risk-increasing drugs appears to be effective as a single intervention for falls prevention in a geriatric outpatient setting. The effect was greatest for withdrawal of cardiovascular drugs. [ABSTRACT FROM AUTHOR]

See Original Article I here i See Comment I here i We welcome the comments on our article "Associations of statin use with glycemic traits and incident type 2 diabetes1" by Sansome DJ et al, which express the importance of bile acid (BA) as an important metabolic regulator in the association of statins and glycaemic control in type 2 diabetes (T2D). From the date of baseline centre visit and during follow-up, prevalent and incident T2D cases were defined as a fasting serum glucose concentration of >=7.0 mmol/L or the use of glucose-lowering medications. Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin. [Extracted from the article]

Background: Mefloquine, a drug used for treatment and prophylaxis of malaria, is known for its neuropsychiatric adverse effects. We hypothesized that neuropsychiatric adverse effects of mefloquine are associated with polymorphisms in the MDR1/ABCB1 gene that encodes for the efflux pump P-glycoprotein.Methods: The association between MDR1 C1236T, G2677T, and C3435T single-nucleotide polymorphisms and the occurrence of neuropsychiatric adverse effects was examined in a prospective cohort study of 89 healthy white travelers taking mefloquine.Results: Of the subjects, 27 (28%) reported neuropsychiatric adverse effects, women significantly more frequently than men. Allele frequencies of the C1236T, G2677T, and C3435T polymorphisms were similar to those found in other white populations, and there was no significant association between any of the individual polymorphisms and neuropsychiatric adverse effects. However, women with the 1236TT, 2677TT, and 3435TT genotypes had a higher risk of neuropsychiatric adverse effects than the reference groups of women with heterozygous and homozygous CC or GG genotypes, with odds ratios of 6.3 (95% confidence interval [CI], 1.1-36.9), 10.5 (95% CI, 1.1-100.6), and 5.4 (95% CI, 1.1-30.0), respectively. The association for women homozygous for the 1236-2677-3435 TTT haplotype was even stronger (P = .004) than the effect of any of the individual polymorphisms. No associations with mefloquine blood levels were observed.Conclusion: In this study the MDR1 1236TT, 2677TT, and 3435TT genotypes, along with the 1236-2677-3435 TTT haplotype, were associated with neuropsychiatric adverse effects of mefloquine in women. MDR1 polymorphisms may play an important role in predicting the occurrence of neuropsychiatric adverse effects of mefloquine, particularly in female travelers.Clinical Pharmacology & Therapeutics (2006) 80, 367–374; doi: 10.1016/j.clpt.2006.07.003 [ABSTRACT FROM AUTHOR]