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Xuechun Li,1 Dennis Steenhuis,1 Maarten J Bijlsma,1,2 Stijn de Vos,1 Sumaira Mubarik,1 Jens HJ Bos,1 Catharina CM Schuiling-Veninga,1 Eelko Hak1 1Pharmacotherapy, Epidemiology and Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands; 2Laboratory of Population Health, Max Planck Institute for Demographic Research, Rostock, GermanyCorrespondence: Xuechun Li, PhD Research Fellow, Pharmacotherapy, Epidemiology and Economics, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, the Netherlands, Tel +31 649019602, Email xuechen.li@rug.nlPurpose: Anti-hyperlipidemic drug treatments are effective in reducing the risk of cardiovascular disease. In a long-term retrospective inception cohort study, we aimed to assess the real-world comparative effectiveness of anti-hyperlipidemic monotherapies for primary prevention of cardiovascular events.Patients and Methods: Patients aged 18 years and older, who initiated primary prevention with anti-hyperlipidemic monotherapy, were selected from the University of Groningen IADB.nl dispensing database. In intention-to-treat (ITT) analysis we included all patients, whereas in per-protocol (PP) analysis we included both all patients independent of adherence (PPIA) and adherent patients (PPA). Study outcome was the time to first prescription of acute cardiac drug therapy measured by valid drug proxies to identify a first major cardiovascular event. We applied inverse probability of treatment-weighted (IPTW) analysis using Cox regression and time-varying Cox regression with simvastatin as the reference category to estimate the average treatment effect hazard ratios (HR) and their corresponding 95% confidence intervals (CI).Results: Atorvastatin users had significantly higher hazards compared to simvastatin users (HR range: 1.27 to 1.47, 95% CI: 1.15 to 1.69). Similarly, Pravastatin users also exhibited increased hazards compared to simvastatin users (HR range: 1.41 to 1.56, 95% CI: 1.14 to 2.04). Similar patterns were observed in patients with diabetes, rheumatoid arthritis, and asthma/COPD. No differences were found in the hazards of rosuvastatin, fluvastatin, fibrates, and simvastatin.Conclusion: Atorvastatin and pravastatin users had higher long-term rates of cardiovascular events compared to simvastatin monotherapy in primary prevention, the difference may be attributed to the confounding by severity, but also possibly due to differences in drug mechanisms or patient response. These findings could influence current guideline recommendations, suggesting a potential preference for simvastatin in primary prevention, underscoring the need for further research to explore long-term impacts and underlying mechanisms, especially in diverse populations. Keywords: acute cardiac drug therapy, time-varying confounding, inverse probability treatment weighting, Cox regression

Irene Mommers,1 Job FM van Boven,2,3 Catharina CM Schuiling-Veninga,1 Jens HJ Bos,1 Marten Koetsier,1 Eelko Hak,1 Maarten J Bijlsma1,4 1Pharmacotherapy, Epidemiology and -Economics, University of Groningen, Groningen, the Netherlands; 2Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, the Netherlands; 3Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, the Netherlands; 4Laboratory of Population Health, Max Planck Institute for Demographic Research, Rostock, GermanyCorrespondence: Irene Mommers, University of Groningen, Department of Pharmacotherapy, -Epidemiology and -Economics, Antonius Deusinglaan 1, Building 3214, Room 0450, Groningen, 9713 AV, the Netherlands, Tel +31 50 36 32476, Email i.mommers@rug.nlPurpose: The Global Initiative for Asthma (GINA) suggests a step-wise approach for pharmacological treatment of asthma. Valid study of real-world treatment patterns using dispensing databases includes proper measurement of medication adherence. We aim to explore such patterns by applying a time-varying proportion of days covered (tPDC)-based algorithm.Patients and Methods: We designed a retrospective inception cohort study using the University of Groningen IADB.nl community pharmacy dispensing database. Included were 19,184 young adults who initiated asthma medication anywhere between 1994 and 2021, in the Netherlands. Main treatment steps were defined as: 1 - SABA/ICS-formoterol as needed, 2 - low dose ICS, 3 - low dose ICS + LABA or tiotropium, or intermediate dose ICS, 4 - intermediate to high dose ICS + LABA or tiotropium, triple therapy, or high dose ICS, 5 - treatment prescribed by a specialist. Changes in treatment steps were determined using a time-varying proportion of days covered (tPDC)-based algorithm. Individual drug treatment trajectories were visualized over time using a lasagna plot.Results: At initiation, of the 19,184 included individuals, 52%, 7%, 15%, 16%, and 10% started treatment in steps 1 to 5, respectively. The median (IQR) follow-up time was 3 (1– 7) years. Median (IQR) number of switches was 1 (0– 3). Comparing starting step to last observed step, 37% never switched between treatment steps, 20% of individuals stepped down and 22% stepped up.Conclusion: The low proportion of treatment switches between steps indicates that tailoring of treatment to patients’ needs might be suboptimal. The tPDC-based algorithm functions well in translating dispensing data into continuous drug-utilization data, enabling a more granular assessment of treatment patterns among asthma patients.Keywords: asthma management, respiratory disease, inhaler medication, personalized medicine, longitudinal, observational

Bianca Mulder,1 Maarten J Bijlsma,1 Catharina CM Schuiling-Veninga,1 Leonard P Morssink,2 Eugene van Puijenbroek,3,4 Jan G Aarnoudse,5 Eelko Hak,1 Tjalling W de Vries6 1Groningen Research Institute of Pharmacy, Unit PharmacoTherapy, Epidemiology & Economics, University of Groningen, Groningen, the Netherlands; 2Department of Obstetrics and Gynaecology, Medical Center Leeuwarden, Leeuwarden, the Netherlands; 3Netherlands Pharmacovigilance Centre Lareb, ´s-Hertogenbosch, the Netherlands; 4Unit of Pharmacotherapy and Pharmaceutical Care, Department of Pharmacy, University of Groningen, Groningen, the Netherlands; 5Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 6Department of Pediatrics, Medical Center Leeuwarden, Leeuwarden, the Netherlands Background: Understanding perception of risks and benefits is essential for informed patient choices regarding medical care. The primary aim of this study was to evaluate the perception of risks and benefits of 9 drug classes during pregnancy and associations with women’s characteristics.Methods: Questionnaires were distributed to pregnant women who attended a Dutch Obstetric Care facility (first- and second-line care). Mean perceived risk and benefit scores were computed for 9 different drug classes (paracetamol, antacids, antibiotics, antifungal medication, drugs against nausea and vomiting, histamine-2 receptor antagonists/proton pump inhibitors, antidepressants, nonsteroidal anti-inflammatory drugs, and sedatives/anxiolytics). For each participant, we computed weighted risk and benefit sum scores with principal component analysis. In addition, major concerns regarding medication use were evaluated.Results: The questionnaire was completed by 136 women (response rate 77%). Pregnant women were most concerned about having a child with a birth defect (35%), a miscarriage (35%), or their child developing an allergic disease (23%), respectively, as a result of drug use. The majority of studied drug classes were perceived relatively low in risk and high in benefit. Higher risk scores were reported if women were in their first trimesters of pregnancy (p=0.007). Lower benefit scores were reported if women were single (p=0.014), smoking (p=0.028), nulliparous (p=0.006), or did not have a family history of birth defects (p=0.005).Conclusion: Pregnant women’s concerns regarding potential drug adverse effects were not only focused on congenital birth defects but also included a wider range of adverse outcomes. This study showed that most of the studied drug classes were perceived relatively low in risk and high in benefit. Keywords: drugs, perception, risks, benefits, worries, pregnancy

Introduction: Antihypertensive drugs are used preventatively to lower the risk of cardiovascular disease events. Comparative effectiveness studies on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and thiazides have yielded inconsistent results and given little consideration to patient adherence. Using a longitudinal cohort and considering time-varying adherence and confounding factors, we aimed to estimate the real-world effectiveness of five major antihypertensive drug monotherapies in the primary prevention of cardiovascular events., Methods: Eligible patients for a retrospective inception cohort study were selected using information obtained from the University of Groningen IADB.nl pharmacy prescription database. Cohort 1 comprised adherent patients with a follow-up time exceeding 1 year, and cohort 2 comprised all patients independent of adherence. The exposures were ACEIs, ARBs, BBs, CCBs, and thiazides. The primary outcome was the time to the first prescription for an acute cardiac drug therapy (CDT) measured using valid drug proxies to identify the first major cardiovascular event. A per-protocol analytical approach was adopted with inverse probability of treatment weighted (IPTW), time-varying Cox regression analysis to obtain the hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: In cohort 1 ( n = 22,441), 1,294 patients (5.8%) were prescribed an acute CDT with an average follow-up time of 4.2 ± 2.8 years. Following IPTW, the hazard measures of ARBs and thiazides were lower than those of BBs (HRs: 0.79 and 0.80, respectively; 95% CIs: 0.64-0.97 and 0.69-0.94, respectively). Among drug-treated diabetic patients, the hazard measures were even lower, with HR point estimates of 0.43 (CI: 0.19-0.98) for ARBs and 0.32 (CI: 0.13-0.82) for thiazides. In cohort 2 ( n = 33,427) and sensitivity analysis, the comparative effectiveness results for thiazides and BBs were similar to those for cohort 1., Conclusion: The findings of this real-world analysis suggest that the incidence of CDT associated with long-term thiazide or ARB monotherapy is lower than the incidence of CDT with BBs, notably among high-risk patients. Incidences of CDT associated with ACEIs and CCBs were comparable relative to those associated with BBs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Bijlsma, de Vos, Bos, Mubarik, Schuiling-Veninga and Hak.)

Social relationships and genetic propensity are known to affect depression risk, but their joint effects are poorly understood. This study examined the association of a polygenic index for depression with time to antidepressant (AD) purchasing and the moderating role of partnership status. We analysed data from 30,192 Finnish individuals who participated in the FINRISK and Health 2000 and 2011 surveys and had register and medication data available. We measured genetic risk with a polygenic index (PGI) for depression. Depression was assessed through antidepressant purchases. We estimated an accelerated failure time model with partnership status as time-varying and different sets of confounder adjustments. The predicted cumulative hazard of antidepressant purchasing varied across PGI and partnership status. At follow-up year 10, being widowed was associated with the largest cumulative hazard of 0.34 (95%CI: 0.28-0.39) in the 80th and 0.20 (95%CI: 0.17-0.23) in the 20th PGI percentile, followed by divorced, single, married and cohabiting. Cohabiting was associated with a cumulative hazard of 0.19 (95%CI: 0.16-0.23) in the 80th and 0.11 (95%CI: 0.1-0.13) in the 20th PGI percentile. We found no evidence for an interaction between the PGI and partnership status. Results were robust to different model specifications, gender stratification, and the choice of PGI. Although antidepressant purchasing correlated with both PGI and partnership status, we found no evidence that partnership status could partially offset or amplify the association between the PGI for depression and antidepressant purchasing incidence., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We investigated whether socioeconomic inequalities in young adolescents' mental health are partially due to the unequal distribution of childhood obesity across socioeconomic positions (SEP), i.e. differential exposure, or due to the effect of obesity on mental health being more detrimental among certain SEPs, i.e. differential impact., Methods: We studied 4660 participants of the Generation R study, a population-based study in the Netherlands. SEP was estimated by mother's education and household income at age five of the child. We estimated the contribution of the mediating and moderating effects of high body fat percentage to the disparity in mental health. This was done through a four-way decomposition using marginal structural models with inverse probability of treatment weighting., Results: Comparing children with the least to most educated mothers and the lowest to highest household income, the total disparity in emotional problems was 0.98 points (95%CI:0.35-1.63) and 1.68 points (95%CI:1.13-2.19), respectively. Of these total disparities in emotional problems, 0.50 points (95%CI:0.15-0.85) and 0.24 points (95%CI:0.09-0.46) were due to the differential exposure to obesity. Obesity did not contribute to disparities in behavioural problems., Conclusion: Addressing the heightened obesity prevalence among children in low SEP families may reduce inequalities in emotional problems in early adolescence., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joost Oude Groeniger reports financial support was provided by Netherlands Organisation for Health Research and Development. Frank J van Lenthe reports financial support was provided by Netherlands Organisation for Health Research and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example., Study Design and Setting: A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies., Results: Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies., Conclusion: In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Alzheimer's disease (AD) is the most common cause of dementia, with a growing number of patients worldwide. The association between AD and treatment with drugs targeting the beta-adrenergic receptor is controversial. The aim of this study is to assess the association between the initiation of AD medication and beta-adrenoceptor antagonists (beta-blockers) in adults., Materials and Methods: We conducted a prescription sequence symmetry analysis using the University of Groningen IADB.nl prescription database. We determined the order of the first prescription for treating AD and the first prescription for beta-blockers, with the dispensing date of the first prescription for AD defined as the index date. Participants were adults over 45 years old starting any AD medication and beta-blockers within two years. We calculated adjusted sequence ratios with corresponding 95% confidence intervals., Results: We identified 510 users of both AD and beta-blockers, and 145 participants were eligible. The results were compatible with either a significant decrease in the incidence of AD after using beta-blockers (adjusted sequence ratio (aSR) = 0.52; 95% CI: 0.35-0.72) or, conversely, an increase in beta-blockers after AD medication (aSR = 1.96; 95% CI: 1.61-2.30)., Conclusions: There is a relationship between the use of beta-blockers and AD medications. Further research is needed with larger populations to determine whether drug therapy for AD increases the risk of hypertension or whether beta-blockers have potential protective properties against AD development.

Background: Comparing the impact of the COVID-19 pandemic on the incidence of newly diagnosed breast tumors and their tumor stage between the Netherlands and Norway will help us understand the effect of differences in governmental and social reactions towards the pandemic., Methods: Women newly diagnosed with breast cancer in 2017-2021 were selected from the Netherlands Cancer Registry and the Cancer Registry of Norway. The crude breast cancer incidence rate (tumors per 100,000 women) during the first (March-September 2020), second (October 2020-April 2021), and Delta COVID-19 wave (May-December 2021) was compared with the incidence rate in the corresponding periods in 2017, 2018, and 2019. Incidence rates were stratified by age group, method of detection, and clinical tumor stage., Results: During the first wave breast cancer incidence declined to a larger extent in the Netherlands than in Norway (27.7% vs. 17.2% decrease, respectively). In both countries, incidence decreased in women eligible for screening. In the Netherlands, incidence also decreased in women not eligible for screening. During the second wave an increase in the incidence of stage IV tumors in women aged 50-69 years was seen in the Netherlands. During the Delta wave an increase in overall incidence and incidence of stage I tumors was seen in Norway., Conclusion: Alterations in breast cancer incidence and tumor stage seem related to a combined effect of the suspension of the screening program, health care avoidance due to the severity of the pandemic, and other unknown factors., Competing Interests: Declaration of Competing Interest SS reports personal fees from the External Evaluation Committee: Public health master University of Nicosia and the Supervisory Board of PALGA (national Pathology laboratory Archive). VCGTH receives funding from AstraZeneca, E Lilly, Gilead, Novartis, Pfizer, and Roche. JW receives funding from Cancer Research UK, KWF Dutch Cancer Society, ZonMW, and AVL Investment Fund. The other authors have no relevant conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We aim to investigate to what extent gender inequality at the labor market explains higher depression risk for older US women compared to men. We analyze data from 35,699 US adults aged 50-80 years that participated in the Health and Retirement Study. The gender gap is calculated as the difference in prevalence in elevated depressive symptoms (score ≥ 3 on the 8-item Center for Epidemiological Studies Depression Scale) between women and men. We employ a dynamic causal decomposition and simulate the life course of a synthetic cohort from ages 50-80 with the longitudinal g-formula and introduce four nested interventions by assigning women the same probabilities of A) being in an employment category, B) occupation class, C) current income and D) prior income group as men, conditional on women's health and family status until age 70. The gender gap in depression risk is 2.9%-points at ages 50-51 which increases to 7.6%-points at ages 70-71. Intervention A decreases the gender gap over ages 50-71 by 1.2%-points (95%CI for change: 2.81 to 0.4), intervention D by 1.64%-points (95%CI for change: 3.28 to -0.15) or 32% (95%CI: 1.39 to 62.83), and the effects of interventions B and C are in between those of A and D. The impact is particularly large for Hispanics and low educated groups. Gender inequalities at the labor market substantially explain the gender gap in depression risk in older US adults. Reducing these inequalities has the potential to narrow the gender gap in depression., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the long-term effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events., Design: Retrospective inception cohort study covering a 25-year study period., Setting: University Groningen IADB.nl pharmacy prescription database with data from 1996 to 2020., Participants: Patients aged 18 years or older, free of any cardiovascular disease (CVD) drug therapies prior to initiation of a preventive antihypertensive monotherapy (ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs) and thiazides)., Outcome Measures: Primary outcome was the time to first prescription of acute cardiac drug therapy (CDT) measured by valid drug proxies to identify a first major CVD event in patients without a history of CVD., Results: Among 33 427 initiators, 5205 (15.6%) patients experienced an acute CDT. The average follow-up time was 7.9±5.5 years. The 25-year incidence rate per 1000 person-years were 25.3, 22.4, 18.2, 24.4 and 22.0 for ACEI, ARB, BB, CCB and thiazide starters, respectively. Inverse probability of treatment-weighted Cox regression showed that thiazide starters had lower hazards than the reference BB starters (HR: 0.88, 95% CI: 0.81 to 0.95). Among patients on diabetes drugs, risks were lower (HR: 0.49, 95% CI: 0.28 to 0.85). CCB starters had higher hazards than reference BB (HR: 1.21, 95% CI: 1.07 to 1.36). The overall estimated number needed to treat for thiazides compared with BBs to prevent one acute CDT in 25 years was 26, and four among patients on diabetes drugs., Conclusions: After adjustments for confounders, patients starting on monotherapy with thiazides had a lower incidence of CDT compared with those starting on BBs, notably among patients on diabetes drugs. Conversely, patients who began CCB monotherapy had a higher incidence of CDT compared with those starting on BBs. Other monotherapies had comparable incidence of cardiovascular disease compared with BBs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Current evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults., Design: Systematic review., Eligibility: Quantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease., Data Source: PubMed and Embase (1 January 2020-28 September 2022)., Risk of Bias: Cochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies of Interventions tools were applied to assess the quality of studies., Data Analysis: Meta-analyses for each eligible drug were performed if ≥2 similar study designs were available., Results: In all, 65 (25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: 0.82 (95% CI 0.74 to 0.90), I 2 =48%), a result largely driven by one clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I 2 =96%) and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate quality and of lower quality in observational studies., Conclusions: Results from our analysis are insufficient to support an evidence-based repurposed drug policy for SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable people are warranted to prevent the future waves of infection., Prospero Registration Number: CRD42021292797., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While the link between living in a low-socioeconomic status (SES) neighborhood and higher risk of adverse birth outcomes has been well established, the underlying mechanisms remain poorly understood. Using the parametric g-formula, we assessed the role of neighborhood crime as a potential mediator of the relationship between neighborhood SES and birth outcomes using data on singleton births occurring in the Netherlands between 2010 and 2017 (n = 1,219,470). We estimated total and mediated effects of neighborhood SES on small-for-gestational-age (SGA) birth, low birth weight (LBW), and preterm birth (PTB) for 3 types of crime (violent crimes, crimes against property, and crimes against public order). The g-formula intervention settings corresponded to a hypothetical improvement in neighborhood SES. A hypothetical improvement in neighborhood SES resulted in a 6.6% (95% CI: 5.6, 7.5) reduction in the proportion of SGA birth, a 9.1% (95% CI: 7.6, 10.6) reduction in LBW, and a 5.8% (95% CI: 5.7, 6.2) decrease in PTB. Neighborhood crime jointly accounted for 28.1% and 8.6% of the total effects on SGA birth and LBW, respectively. For PTB, we found no evidence of mediation. The most relevant pathways were crimes against property and crimes against public order. The results indicate that neighborhood crime mediates a meaningful share of the relationship between neighborhood SES and birth outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journalpermissions@oup.com.)

Background: The possible mediating role of cardiovascular disease (CVD) in the relationship between alcohol use disorders (AUD) and the risk of early-onset (

Background: More recent birth cohorts are at a higher depression risk than cohorts born in the early 20th century. We aimed to investigate to what extent changes in alcohol consumption, smoking, physical activity, and obesity contribute to these birth cohort variations., Methods: We analyzed panel data from US adults born 1916-1966 enrolled in the Health and Retirement Study (N = 163,760 person-years). We performed a counterfactual decomposition analysis by combining age-period-cohort models with g-computation. We thereby compared the predicted probability of elevated depressive symptoms (CES-D 8 score ≥3) in the natural course to a counterfactual scenario where all birth cohorts had the health behaviors of the 1945 birth cohort. We stratified analyses by sex and race-ethnicity., Results: We estimated that depression risk of the 1916-1949 and 1950-1966 birth cohort would be on average 2.0% (-2.3 to -1.7) and 0.5% (-0.9 to -0.1) higher with the alcohol consumption levels of the 1945 cohort. In the counterfactual with the 1945 BMI distribution, depression risk is on average 2.1% (1.8 to 2.4) higher for the 1916-1940 cohorts and 1.8% (-2.2 to -1.5) lower for the 1950-1966 cohorts. We find no cohort variations in depression risk for smoking and physical activity. The contribution of alcohol is more pronounced for Whites than for other race-ethnicity groups, and the contribution of BMI more pronounced for women than for men., Conclusion: Increased obesity levels were associated with exacerbated depression risk in recent birth cohorts in the United States, while drinking patterns only played a minor role., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: To test the hypothesis that the reduction in urinary kidney injury molecule-1 (KIM-1) observed with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein-1 (MCP-1) by assessing the proportion of the effect of canagliflozin on KIM-1 that is mediated through its effects on MCP-1 and UACR in patients with type 2 diabetes and albuminuric kidney disease., Material and Methods: We measured KIM-1 and MCP-1 levels in urine samples from the CANVAS trial at baseline and Week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM-1 and MCP-1 were standardized by urinary creatinine (Cr). The proportion of the effect of canagliflozin that is mediated through UACR and MCP-1/Cr on KIM-1/Cr was estimated with G-computation., Results: In total, 763 patients with micro- or macroalbuminuria (17.6% of the total cohort) were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At Year 1, canagliflozin compared to placebo reduced UACR, MCP-1/Cr and KIM-1/Cr by 40.4% (95% CI 31.0, 48.4), 18.1% (95% CI 8.9, 26.4) and 30.9% (95% CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM-1/Cr mediated by its effect on UACR and in turn on MCP-1/Cr was 15.2% (95% CI 9.4, 24.5)., Conclusion: Canagliflozin reduces urinary KIM-1, suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP-1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post hoc analysis suggests that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Young adulthood is a dynamic and demographically dense stage in the life course. This poses a challenge for research on the socioeconomic consequences of parenthood timing, which most often focuses on women. We chart the dynamics of delayed parenthood and its implications for educational and labor market trajectories for young adult women and men using a novel longitudinal analysis approach, the parametric g-formula. This method allows the estimation of both population-averaged effects (among all women and men) and average treatment effects (among mothers and fathers). Based on high-quality data from Finnish registers, we find that later parenthood exacerbates the educational advantage of women in comparison to men and attenuates the income advantage of men in comparison to women across young adult ages. Gender differences in the consequences of delayed parenthood on labor market trajectories are largely not explained by changes in educational trajectories. Moreover, at the time of entering parenthood, delayed parenthood improves the incomes of fathers more than those of mothers, thereby exacerbating existing gender differences. The results provide population-level evidence on how the delay of parenthood has contributed to the strengthening of women's educational position relative to that of men. Further, the findings on greater increases in fathers' than mothers' incomes at the time of entering parenthood, as followed by postponement, may help explain why progress in achieving gender equality in the division of paid and unpaid work in families has been slow., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Research suggests that work-related factors like job insecurity increases the risk of major depression (MD), although it is unclear whether the association is causal. Research further suggests that job insecurity increases sleep disturbances, which is also a risk factor for MD. Based on current knowledge, it is possible that job insecurity operates through sleep disturbances to affect MD, but this pathway has not been examined in the literature. The current study extends the literature by using two complementary, counterfactual approaches (i.e., random- and fixed-effects regression and a mediational g-formula) to examine whether job insecurity causes MD and whether sleep disturbances mediate the relationship. A methodological triangulation approach allowed us to adjust for unobserved and intermediate confounding, which has not been addressed in prior research. Findings suggest that the relationship between job insecurity and MD is primarily direct, that hypothetically intervening on job insecurity (in our g-formula) would reduce MD by approximately 10% at the population level, and this relationship operates via sleep disturbances to some degree. However, the indirect pathway had a high degree of uncertainty., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

One key objective of the population health sciences is to understand why one social group has different levels of health and well-being compared with another. Whereas several methods have been developed in economics, sociology, demography, and epidemiology to answer these types of questions, a recent method introduced by Jackson and VanderWeele (2018) provided an update to decompositions by anchoring them within causal inference theory. In this paper, we demonstrate how to implement the causal decomposition using Monte Carlo integration and the parametric g-formula. Causal decomposition can help to identify the sources of differences across populations and provide researchers with a way to move beyond estimating inequalities to explaining them and determining what can be done to reduce health disparities. Our implementation approach can easily and flexibly be applied for different types of outcome and explanatory variables without having to derive decomposition equations. We describe the concepts of the approach and the practical steps and considerations needed to implement it. We then walk through a worked example in which we investigate the contribution of smoking to sex differences in mortality in South Korea. For this example, we provide both pseudocode and R code using our package, cfdecomp. Ultimately, we outline how to implement a very general decomposition algorithm that is grounded in counterfactual theory but still easy to apply to a wide range of situations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Evidence suggests that contemporaneous labor force participation affects cognitive function; however, it is unclear whether it is employment itself or endogenous factors related to individuals' likelihood of employment that protects against cognitive decline. We exploit innovations in counterfactual causal inference to disentangle the effect of postponing retirement on later-life cognitive function from the effects of other life-course factors. With the U.S. Health and Retirement Study (1996-2014, n = 20,469), we use the parametric g-formula to estimate the effect of postponing retirement to age 67. We also study whether the benefit of postponing retirement is affected by gender, education, and/or occupation, and whether retirement affects cognitive function through depressive symptoms or comorbidities. We find that postponing retirement is protective against cognitive decline, accounting for other life-course factors (population: 0.34, 95% confidence interval (CI): 0.20,0.47; individual: 0.43, 95% CI: 0.26,0.60). The extent of the protective effect depends on subgroup, with the highest educated experiencing the greatest mitigation of cognitive decline (individual: 50%, 95% CI: 32%,71%). By using innovative models that better reflect the empirical reality of interconnected life-course processes, this work makes progress in understanding how retirement affects cognitive function., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 Published by Elsevier Ltd.)

Low childhood income is an established risk factor of self-harm in adolescence and young adulthood, and childhood income is additionally associated with various correlates of self-harm. How these correlates, such as psychiatric disorders, substance abuse, violent behaviour and school problems, mediate the effect of childhood income on self-harm, is less understood. The purpose of the current paper is to examine this mediation. The study is based on administrative register data on all Finnish children born in 1990-1995. An analytical sample of 384,121 children is followed from age 8 to 22. We apply the parametric g-formula to study the effect of childhood income on the risk of self-harm in young adulthood. Adolescent psychiatric disorders, substance abuse, prior self-harm, violent criminality and victimization, out-of-home placements, not being in education, employment or training and school performance are considered as potential mediators. We control for confounding factors related to childhood family characteristics. As a hypothetical intervention, we moved those in the lowest childhood income quintile to the second-lowest quintile, which resulted in a 7% reduction in hospital-presenting self-harm in young adulthood among those targeted by the intervention (2% reduction in the total population). 67% of the effect was mediated through the chosen mediators. The results indicate that increases in childhood material resources could protect from self-harm in young adulthood. Moreover, the large proportion of mediation suggests that targeted interventions for high-risk adolescents may be beneficial. To our knowledge, this is the first paper to use the parametric g-formula to study youth self-harm. Future applications are encouraged as the method offers several further opportunities for analysing the complex life course pathways to self-harm., Competing Interests: None., (© 2021 The Author(s).)

Background: Improving hypertension control is an important global health priority yet, to our knowledge, there is no direct evidence on the blood pressure (BP)-mortality relationship in sub-Saharan Africa. We investigate the BP-mortality relationship in South Africa and assess the comparative effectiveness of different care targets for clinical care and population-wide hypertension management efforts., Methods: We use country-wide population-based longitudinal data from five waves (2008 - 2017) of the South African National Income Dynamics Study (N = 4,993). We estimate the relationship between systolic BP (SBP) and six-year all-cause mortality and compare the mortality reductions associated with lowering SBP to different targets. We then estimate the number needed to treat to avert one death (NNT) under different hypothetical population-wide scale up scenarios., Findings: We found a weak, nonlinear, SBP-mortality relationship with larger incremental mortality benefits at higher SBP values: reducing SBP from 160 to 150 mmHg was associated with a mortality risk ratio of 0.95 (95% CI: 0.90, 0.99, p = 0.033), incrementally reducing SBP from 150 to 140 mmHg a risk ratio of 0.96 (95% CI: 0.91, 1.01, p = 0.12), with no evidence of incremental benefits of reducing BP below 140 mmHg. At the population level, reducing SBP to 150 mmHg among all those with an SBP > 150 mmHg had the lowest NNT (50) at 3.3 deaths averted (95% CI: -0.6, 0.3) per 1,000 population while requiring BP management for 16% (95% CI: 15.2, 17.3) of individuals., Interpretation: The SBP-mortality association is weaker in South Africa than in high-income and many low- and middle-income countries. As such, we do not find compelling evidence in support of targets below 140 mmHg and find that scaling up management based on a 150 mmHg target is more efficient in terms of the NNT compared to strategies to reduce SBP to lower values.

Background: The estimated effect of unemployment on depression may be biased by time-varying, intermediate, and time-constant confounding. One of the few methods that can account for these sources of bias is the parametric g-formula, but until now this method has required that all relevant confounders be measured., Methods: We combine the g-formula with methods to adjust for unmeasured time-constant confounding. We use this method to estimate how antidepressant purchasing is affected by a hypothetical intervention that provides employment to the unemployed. The analyses are based on an 11% random sample of the Finnish population who were 30-35 years of age in 1995 (n = 49,753) and followed until 2012. We compare estimates that adjust for measured baseline confounders and time-varying socioeconomic covariates (confounders and mediators) with estimates that also include individual-level fixed-effect intercepts., Results: In the empirical data, around 10% of person-years are unemployed. Setting these person-years to employed, the g-formula without individual intercepts found a 5% (95% confidence interval [CI] = 2.5%, 7.4%) reduction in antidepressant purchasing at the population level. However, when also adjusting for individual intercepts, we find no association (-0.1%; 95% CI = -1.8%, 1.5%)., Conclusions: The results indicate that the relationship between unemployment and antidepressants is confounded by residual time-constant confounding (selection). However, restrictions on the effective sample when using individual intercepts can compromise the validity of the results. Overall our approach highlights the potential importance of adjusting for unobserved time-constant confounding in epidemiologic studies and demonstrates one way that this can be done.

The available methodologies to estimate the obesity-attributable mortality fraction (OAMF) affect the levels found and hamper the construction of time series. Our aim was to assess the impact of using different techniques to estimate the levels and the trends in obesity-attributable mortality for The Netherlands between 1981 to 2013. Using Body Mass Index (BMI), all-cause and cause-specific mortality data, and worldwide and European relative risks (RRs), we estimated OAMFs using three all-cause approaches (partially adjusted, weighted sum, and the two combined) and one cause-of-death approach (Comparative Risk Assessment; CRA). We adjusted the CRA approach to purely capture obesity (BMI ≥ 30 kg/m²). The different approaches led to a range of estimates. The weighted sum method using worldwide RRs generated the lowest (0.9%) while the adjusted CRA approach using 2013 RRs generated the highest estimate (1.5%). Using European-specific RRs instead of worldwide RRs resulted in higher estimates. Most of the approaches revealed an increasing OAMF over the period 1981 to 2013 especially from 1993 onwards except for the adjusted CRA approach among women. Estimates of OAMF levels and trends differed depending on the method applied. Given the limited available data, we recommend using the weighted-sum method to compare obesity-attributable mortality across European countries over time.

Objectives: To assess age, period, and birth cohort effects and patterns of obesity-attributable mortality in Czech Republic, Finland, France, Germany, Hungary, Italy, Poland, and the UK (UK)., Methods: We obtained obesity prevalence and all-cause mortality data by age (20-79), sex and country for 1990-2012. We applied Clayton and Schifflers' age-period-cohort approach to obesity-attributable mortality rates (OAMRs)., Results: Between 1990 and 2012, obesity prevalence increased and age-standardised OAMRs declined, although not uniformly. The nonlinear birth cohort effects contributed significantly (p < 0.01) to obesity-attributable mortality trends in all populations, except in Czech Republic, Finland, and among German women, and Polish men. Their contribution was greater than 25% in UK and among French women, and larger than that of the nonlinear period effects. In the UK, mortality rate ratios (MRRs) increased among the cohorts born after 1950. In other populations with significant birth cohort effects, MRRs increased among the 1935-1960 cohorts and decreased thereafter., Conclusions: Given its potential effects on obesity-attributable mortality, the cohort dimension should not be ignored and calls for interventions early in life next to actions targeting broader societal changes.

The effects of unemployment on depression are difficult to establish because of confounding and limited understanding of the mechanisms at the population level. In particular, due to longitudinal interdependencies between exposures, mediators and outcomes, intermediate confounding is an obstacle for mediation analyses. Using longitudinal Finnish register data on socio-economic characteristics and medication purchases, we extracted individuals who entered the labor market between ages 16 and 25 in the period 1996 to 2001 and followed them until the year 2007 (n = 42,172). With the parametric G-formula we estimated the population-averaged effect on first antidepressant purchase of a simulated intervention which set all unemployed person-years to employed. In the data, 74% of person-years were employed and 8% unemployed, the rest belonging to studying or other status. In the intervention scenario, employment rose to 85% and the hazard of first antidepressant purchase decreased by 7.6%. Of this reduction 61% was mediated, operating primarily through changes in income and household status, while mediation through other health conditions was negligible. These effects were negligible for women and particularly prominent among less educated men. By taking complex interdependencies into account in a framework of observed repeated measures data, we found that eradicating unemployment raises income levels, promotes family formation, and thereby reduces antidepressant consumption at the population-level., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Many methods have been proposed to solve the age-period-cohort (APC) linear identification problem, but most are not theoretically informed and may lead to biased estimators of APC effects. One exception is the mechanism-based approach recently proposed and based on Pearl's front-door criterion; this approach ensures consistent APC effect estimators in the presence of a complete set of intermediate variables between one of age, period, cohort, and the outcome of interest, as long as the assumed parametric models for all the relevant causal pathways are correct. Through a simulation study mimicking APC data on cardiovascular mortality, we demonstrate possible pitfalls that users of the mechanism-based approach may encounter under realistic conditions: namely, when (1) the set of available intermediate variables is incomplete, (2) intermediate variables are affected by two or more of the APC variables (while this feature is not acknowledged in the analysis), and (3) unaccounted confounding is present between intermediate variables and the outcome. Furthermore, we show how the mechanism-based approach can be extended beyond the originally proposed linear and probit regression models to incorporate all generalized linear models, as well as nonlinearities in the predictors, using Monte Carlo simulation. Based on the observed biases resulting from departures from underlying assumptions, we formulate guidelines for the application of the mechanism-based approach (extended or not).

Background and Aims: Understanding why inequalities in alcohol-related mortality trends by sex and country exist is essential for developing health policies. Birth cohort effects, indicative of differences by generation in drinking, have rarely been studied. This study estimated the relative contributions of birth cohorts to liver cirrhosis mortality trends and compared sex- and country-specific cohort patterns across eight European countries., Design: Time-series analysis of population-level mortality data., Setting: Austria, Finland, Hungary, Italy, the Netherlands, Poland, Spain and Sweden; 1950-2011., Participants: National populations aged 15-94 years., Measurements: We modelled country- and sex-specific liver cirrhosis mortality (from national vital registers) adjusting for age, period and birth cohort., Findings: Birth cohorts (adjusted for age and period) made statistically significant contributions to liver cirrhosis mortality in all countries and for both sexes (P < 0.001), and more so among women (average contribution to deviance reduction of 38.8%) than among men (17.4%). The observed cohort patterns were statistically different between all but two country pairs (P < 0.001). Sex differences existed overall (P < 0.001), but not in the majority of countries (P > 0.999). Visual inspection of birth cohort patterns reveals birth cohorts at higher risk of liver cirrhosis mortality., Conclusions: The inclusion of the birth cohort dimension improves the understanding of alcohol-attributable mortality trends in Europe. Birth cohorts at higher risk of liver cirrhosis mortality were born during 1935-49 in Sweden and Finland, around 1950 in Austria and the Netherlands and 1960 or later in Hungary, Italy, Poland and Spain., (© 2016 Society for the Study of Addiction.)

Influenza vaccine effectiveness (IVE) varies over different influenza seasons and virus (sub)types/lineages. To assess the association between IVE and circulating influenza virus (sub)types/lineages, we estimated the overall and (sub)type specific IVE in the Netherlands. We conducted a test-negative case control study among subjects with influenza-like illness or acute respiratory tract infection consulting the Sentinel Practices over 11 influenza seasons (2003/2004 through 2013/2014) in the Netherlands. The adjusted IVE was estimated using generalized linear mixed modelling and multiple logistic regression. In seven seasons vaccine strains did not match the circulating viruses. Overall adjusted IVE was 40% (95% CI 18 to 56%) and 20% (95% CI -5 to 38%) when vaccine (partially)matched and mismatched the circulating viruses, respectively. When A(H3N2) was the predominant virus, IVE was 38% (95% CI 14 to 55%). IVE against infection with former seasonal A(H1N1) virus was 83% (95% CI 52 to 94%), and with B virus 67% (95% CI 55 to 76%). In conclusion IVE estimates were particularly low when vaccine mismatched the circulating viruses and A(H3N2) was the predominant influenza virus subtype. Tremendous effort is required to improve vaccine production procedure and to explore the factors that influence the IVE against A(H3N2) virus., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the relationship between circulating influenza virus A types and subtypes and influenza B lineages, their match with the vaccine and the effectiveness of the influenza vaccine (IVE)., Design: Test negative case control study., Method: We used data from the Dutch Sentinel Practices of the Netherlands Institute for Health Services Research (NIVEL) Primary Care Database. Participating general practitioners took nose and throat swabs for viral studies from patients with influenza-like illness or another acute respiratory infection. Cases were those patients whose samples were positive for an influenza virus and controls were those whose samples were negative for influenza virus. We determined the IVE of 11 influenza seasons 2003/2004 to 2013/2014, for all seasons together and stratified by influenza virus type and to vaccine match or mismatch., Results: Over all seasons, the IVE was 29% (95% CI:11-43). In seven of the 11 seasons there was a mismatch between vaccine and circulating virus type. The IVE was 40% (95% CI: 18-56) for those seasons in which there was a vaccine match, and 20% (95% CI: - 5-38) for seasons with a mismatch. When the influenza A/H3N2 virus was dominant, the IVE was 38% (95% CI: 14-55). The IVE against the influenza virus A/H1N1, A/H1N1/pdm09 and against both influenza B lineages was 77% (95% CI: 37-92), 47% (95% CI: 22-64) and 64% (95% CI: 50-74), respectively., Conclusion: The IVE was particularly low when there was a mismatch between the vaccine and the circulating virus type and when A/H3N2 was the dominant influenza subtype.

Objective: To inform development of guidelines for hypertension management in Vietnam, we evaluated the cost-effectiveness of different strategies on screening for hypertension in preventing cardiovascular disease (CVD)., Methods: A decision tree was combined with a Markov model to measure incremental cost-effectiveness of different approaches to hypertension screening. Values used as input parameters for the model were taken from different sources. Various screening intervals (one-off, annually, biannually) and starting ages to screen (35, 45 or 55 years) and coverage of treatment were analysed. We ran both a ten-year and a lifetime horizon. Input parameters for the models were extracted from local and regional data. Probabilistic sensitivity analysis was used to evaluate parameter uncertainty. A threshold of three times GDP per capita was applied., Results: Cost per quality adjusted life year (QALY) gained varied in different screening scenarios. In a ten-year horizon, the cost-effectiveness of screening for hypertension ranged from cost saving to Int$ 758,695 per QALY gained. For screening of men starting at 55 years, all screening scenarios gave a high probability of being cost-effective. For screening of females starting at 55 years, the probability of favourable cost-effectiveness was 90% with one-off screening. In a lifetime horizon, cost per QALY gained was lower than the threshold of Int$ 15,883 in all screening scenarios among males. Similar results were found in females when starting screening at 55 years. Starting screening in females at 45 years had a high probability of being cost-effective if screening biannually was combined with increasing coverage of treatment by 20% or even if sole biannual screening was considered., Conclusion: From a health economic perspective, integrating screening for hypertension into routine medical examination and related coverage by health insurance could be recommended. Screening for hypertension has a high probability of being cost-effective in preventing CVD. An adequate screening strategy can best be selected based on age, sex and screening interval.

Background: To determine the clinical effectiveness of statins on cardiovascular mortality in practice, observational studies are needed. Control for confounding is essential in any observational study. Falsification end-points may be useful to determine if bias is present after adjustment has taken place., Methods: We followed starters on statin therapy in the Netherlands aged 46 to 100 years over the period 1996 to 2012, from initiation of statin therapy until cardiovascular mortality or censoring. Within this group (n = 49,688, up to 16 years of follow-up), we estimated the effect of adherence to statin therapy (0 = completely non-adherent, 1 = fully adherent) on ischemic heart diseases and cerebrovascular disease (ICD10-codes I20-I25 and I60-I69) as well as respiratory and endocrine disease mortality (ICD10-codes J00-J99 and E00-E90) as falsification end points, controlling for demographic factors, socio-economic factors, birth cohort, adherence to other cardiovascular medications, and diabetes using time-varying Cox regression models., Results: Falsification end-points indicated that a simpler model was less biased than a model with more controls. Adherence to statins appeared to be protective against cardiovascular mortality (HR: 0.70, 95 % CI 0.61 to 0.81)., Conclusions: Falsification end-points helped detect overadjustment bias or bias due to competing risks, and thereby proved to be a useful technique in such a complex setting.

Purpose: Accurate measurement of drug adherence is essential for valid risk-benefit assessments of pharmacologic interventions. To date, measures of drug adherence have almost exclusively been applied for a fixed-time interval and without considering changes over time. However, patients with irregular dosing behaviour commonly have a different prognosis than patients with stable dosing behaviour., Methods: We propose a method, based on the proportion of days covered (PDC) method, to measure time-varying drug adherence and drug dosage using electronic records. We compare a time-fixed PDC method with the time-varying PDC method through detailed examples and through summary statistics of 100 randomly selected patients on statin therapy., Results: We demonstrate that time-varying PDC method better distinguishes an irregularly dosing patient from a stably dosing patient and demonstrate how the time-fixed method can result in a biassed estimate of drug adherence. Furthermore, the time-varying PDC method may be better used to reduce certain types of confounding and misclassification of exposure., Conclusions: The time-varying PDC method may improve longitudinal and time-to-event studies that associate adherence with a clinical outcome or (intervention) studies that seek to describe changes in adherence over time., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: A bridging study of plasma and DBS concentrations for therapeutic drug monitoring of antidepressants was performed. RESULTS & METHODOLOGY: Potassium-based hematocrit analysis was included. In addition, we defined acceptance criteria based on the differences between individual data points of plasma and DBS concentrations. These criteria were applied to test acceptability of error found in predicted nortriptyline plasma concentrations. Potassium-based hematocrit predicted a negative bias for DBS concentrations of amitriptyline, but not for the other compounds. To predict plasma concentrations of antidepressants based on DBS concentrations, a factor of 0.8, 0.65, 0.84 and 0.78 was found for nortriptyline, desmethylclomipramine, venlafaxine and desmethylvenlafaxine, respectively., Discussion & Conclusion: Application of the factor and newly formulated acceptance criteria demonstrated prediction of nortriptyline plasma concentrations based on DBS concentrations.

Background: We assessed the contribution of statin use to the decline in cardiovascular mortality for The Netherlands over the period 1994-2010., Methods: We combined aggregated mortality data from Statistics Netherlands with dispensing data from a representative drug dispensing database. We estimated mortality as if prevalence of statin use had remained at its observed 1994 levels throughout the period 1994-2010 for acute myocardial infarction, other ischemic heart disease, and cerebrovascular disease using Poisson models adjusted for various confounders., Results: We estimated that keeping prevalence of statin use at observed 1994 levels would have resulted in 6.3 (95% confidence interval [CI] = 4.9, 7.8), 1.6 (95% CI = 0.8, 2.6), and 3.4 (95% CI = 2.2, 4.6) more acute myocardial infarction, ischemic heart disease, and cerebrovascular deaths per 10,000 person-years, respectively., Conclusion: The findings indicate that statin therapy was associated with decreasing national cardiovascular mortality rates in the period 1994 to 2010.

Background and Objectives: Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits., Design, Setting, Participants, & Measurements: This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements., Results: Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone., Conclusions: Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials., (Copyright © 2015 by the American Society of Nephrology.)

Objectives: To investigate how birth cohorts can confound population-based intervention effect estimates., Study Design and Setting: Interrupted time series design was applied to study the prevalence of statin use in Dutch diabetes patients over the period 1998-2011. Effects of guideline changes on the outcome were estimated using a Poisson regression model with and without the birth cohort dimension modeled through random intercepts., Results: Both models estimated a stronger increase in prevalence of statin use after influential studies were published in 2003 for patients aged below 50 and above 70 years. The model that controlled for birth cohort also estimated an effect for patients aged 50-70 years from 2003 onward. The magnitude of the intervention effect for patients aged above 70 years when we controlled for birth cohort was reduced from 0.078 [95% confidence interval (CI): 0.065, 0.091] to 0.027 (95% CI: 0.013, 0.041). Similarly, for patients aged below 50 years, the estimated guideline effect was reduced from 0.070 (95% CI: 0.048, 0.092) to 0.055 (95% CI: 0.035, 0.075)., Conclusion: In this case study, the birth cohort dimension appeared to confound population-level effect estimates of guideline changes on prevalence of statin use in patients with diabetes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The application of test-negative design case-control studies to assess the effectiveness of influenza vaccine has increased substantially in the past few years. The validity of these studies is predicated on the assumption that confounding bias by risk factors is limited by design. We aimed to assess the effectiveness of influenza vaccine in a high-risk group of elderly people., Methods: We searched the Cochrane library, Medline, and Embase up to July 13, 2014, for test-negative design case-control studies that assessed the effectiveness of seasonal influenza vaccine against laboratory confirmed influenza in community-dwelling people aged 60 years or older. We used generalised linear mixed models, adapted for test-negative design case-control studies, to estimate vaccine effectiveness according to vaccine match and epidemic conditions., Findings: 35 test-negative design case-control studies with 53 datasets met inclusion criteria. Seasonal influenza vaccine was not significantly effective during local virus activity, irrespective of vaccine match or mismatch to the circulating viruses. Vaccination was significantly effective against laboratory confirmed influenza during sporadic activity (odds ratio [OR] 0·69, 95% CI 0·48-0·99) only when the vaccine matched. Additionally, vaccination was significantly effective during regional (match: OR 0·42, 95% CI 0·30-0·60; mismatch: OR 0·57, 95% CI 0·41-0·79) and widespread (match: 0·54, 0·46-0·62; mismatch: OR 0·72, 95% CI 0·60-0·85) outbreaks., Interpretation: Our findings show that in elderly people, irrespective of vaccine match, seasonal influenza vaccination is effective against laboratory confirmed influenza during epidemic seasons. Efforts should be renewed worldwide to further increase uptake of the influenza vaccine in the elderly population., Funding: None., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

To estimate the effect of the introduction of the 7- and 10-valentpneumococcal vaccines in 2006 and 2011, respectively in the Netherlands, we assessed respiratory antibiotic use in one to nine year-old children between 2002 and 2013. Seasonal autoregressive integrated moving-average models were applied to estimate the percentage reduction in respiratory antibiotic use. When compared with the pre-vaccination period, the proportion of respiratory antibiotic prescriptions fell by 4.94% (95% CI: 4.63 to 5.26) and 9.02% (95% CI: 2.83 to 14.82) after the introduction of the 7-valent vaccine in children aged three and four years, respectively. After the introduction of the 10-valent vaccine, we observed a reduction of 13.04% (95% CI: 2.76 to 22.23), 20.31% (95% CI: 13.50 to 26.58), 16.92% (95% CI: 3.07 to 28.80), 22.34% (95% CI: 3.73 to 37.35), 23.75% (95% CI: 2.37 to 40.44) in two, three, four, six and seven year-old children, respectively. Thus, our results indicate a reduction in respiratory antibiotic prescriptions in young children after introduction of the pneumococcal vaccines. As only children in our study population aged one and two years born after March 2011 had received the 10-valent vaccine, the effects of the 10-valent vaccine in children aged three to nine years likely reflect the effects of the 7-valent vaccine and herd immunity.

The creation of places of remembrance in virtual space constitutes a new ritual to commemorate the dead. The purpose of this study is to explore for whom individual Web memorials are meaningful places, who are commemorated, and whether they constitute a community of support. We analyzed 181 Dutch Web memorials and conducted content analysis of messages posted in four guestbooks. We found that parents, and in particular mothers, create Web memorials in remembrance of their deceased children. The memorials provide access to a community of social support, consisting primarily of strangers and/or people who have experienced a similar loss.

Purpose: The aim of this study was to investigate whether including the birth cohort dimension in time series analysis leads to a more accurate estimation of the (long-term) effect of a guideline change on the trend of benzodiazepine use., Methods: We calculated age-specific (20-84 years) and sex-specific prevalence of benzodiazepine use per 1000 population per quarter year (1998 to 2008) using a prescription database set in the Netherlands. We studied the prevalence over time by age group and within birth cohorts through interrupted time series analyses to estimate the effect of the guideline change in 2001., Results: From 1998 to 2008, the overall age-standardized prevalence of benzodiazepine use per 1000 population declined from ~54 for men and ~107 for women to ~45 for men and ~85 for women. The relative change increased significantly after 2001 for both sexes and for the majority of age groups. Within birth cohorts, the prevalence increased with age until the year 2001 and leveled thereafter. The age-period approach overall had worse model fit indicators than the within-cohort approach and predicted larger long-term effects than the within-cohort approach. The age-period projection estimated 36% decline in benzodiazepine use relative to 2008, whereas the birth-cohort projection estimated 8% decline., Conclusion: Explicitly following birth cohort trajectories led to models with better fit; the conventional approach estimated a stronger long-term guideline effect. This has important implications for professional practice., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objective: Including the birth cohort dimension improves trend studies of mortality and health. We investigated the effect of including the birth cohort dimension in trend studies of prescription drug use by studying prevalence of statin use among adults., Study Design and Setting: Data from a drug prescription database in the Netherlands (IADB.nl) were used to obtain the number of users of statin per 1,000 population (prevalence) in the age range 18-85 years from 1994 to 2008. We applied descriptive graphs and standard age-period-cohort (APC) models., Results: From 1994 to 2008, the prevalence increased from ∼10 to ∼90 users per 1,000 population, with the peak in prevalence shifting from age 63 to 78 years. The APC model shows patterns that were masked in the age-period (AP) model. The prevalence rate ratio increased from the 1911 birth cohort to the 1930 birth cohort and then declined. Similar for both sexes, adding nonlinear period effects contributed ∼4.4% to reductions in deviance, whereas adding nonlinear birth cohort effects contributed ∼12.9%., Conclusion: Adding the birth cohort dimension to AP analysis is valuable for academic and professional practice as trends can be more accurately described and explained and it can help improve projections of future trends., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We develop a theory describing neutral atom scattering at low energies in an optical lattice. We show that, for a repulsive interaction, as the microscopic scattering length increases the effective scattering amplitude approaches a limiting value which depends only on the lattice parameters. In the case of attractive interaction a geometric resonance occurs before reaching this limit. Close to the resonance, the effective interaction becomes repulsive and supports a weakly bound state, which can extend over several lattice sites.