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Abstract Background We aimed to investigate the longitudinal impact of COVID-19 and the effects of clinical and psychosocial factors, accounting for post-COVID conditions (PCC), on the mental and physical aspect of health-related quality of life (HRQoL) of patients diagnosed with COVID-19. Methods Data from the Nivel Corona Cohort were used, which includes individuals with an established SARS-CoV-2 infection that received four questionnaires over a year’s time with questions regarding HRQoL (SF-12), symptoms and social characteristics. PCC was determined based on questionnaire data. Data on medical history and healthcare utilization were obtained from electronic health records from general practice. A repeated measures linear mixed model was used to explore associations between clinical and social characteristics, and the course of mental and physical HRQoL after a SARS-CoV-2 infection, taking PCC into account. Results One hundred fifty-eight individuals of whom it was possible to determine whether they had PCC or not were included in this study. Seventy-six (48.1%) developed PCC, which was associated with a persistent reduction in both physical and mental HRQoL. Hospitalization during the acute phase of the infection had a negative impact on the physical HRQoL, which decreased over time. Females, people older than 53, and those with increased resilience and mental HRQoL before infection were more likely to report a more positive mental HRQoL over time. Conclusion The negative association PCC has with both mental and physical HRQoL for at least six months, calls for more research to support patients with PCC.

IntroductionAntihypertensive 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.MethodsEligible 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).ResultsIn 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.ConclusionThe 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.

Abstract Objective Drug non-adherence in primary preventive cardiovascular therapy is one of the most important modifiable drivers of cardiovascular events. The effect of deductibles in healthcare cost-sharing plans (the amount that has to be paid for healthcare services before the insurance company starts to pay) on such non-adherence in a European setting is unknown. Therefore, we estimated the association between deductibles and the adherence to primary preventive antihypertensive and antihyperlipidemic medication. Methods Using the claims database of Menzis Health Insurer in the Netherlands, we applied ordered beta regression mixed modelling to estimate the association between deductibles and adherence taking several demographic and social-economic factors, repeated measurements and within-patient variation into account. Results All in all, 106,316 patients starting primary preventive antihypertensive or antihyperlipidemic monotherapy were eligible for analysis. At index date, mean age of the study population was 58 years and 52% were male. Reaching the deductible limit and no need to pay for medication anymore increased the adherence [relative adherence ratio (RAR) 1.03, 95% confidence interval (95% CI): 1.00–1.05] for antihyperlipidemic therapy and 1.02 (95% CI: 1.00–1.04) for antihypertensive therapy. A larger deductible amount decreases the adherence of antihyperlipidemic and antihypertensive therapy (RAR 0.83; 95% CI: 0.69–1.00 and RAR 0.85, 95% CI: 0.74–0.98, respectively). Conclusion Independent of other risk factors for non-adherence, presence of deductibles in health insurance is associated with a small negative effect on the adherence to both primary preventive antihypertensive as well as antihyperlipidemic therapy. Further study is needed on the potential health-economic consequences.

Abstract Introduction The coronavirus disease 2019 (COVID-19) pandemic accelerated the provision of telepharmacy services. However, little is known about the knowledge, perception, and willingness of pharmacy students as future key players in telepharmacy adoption to provide such a service, particularly in a setting without well-established telepharmacy services before the COVID-19 pandemic. Objective With this survey we aimed to assess the level of knowledge, perception, and willingness to provide telepharmacy services and to identify associated factors among pharmacy students in Indonesia. Methods We applied a multicenter cross-sectional study design with convenience sampling technique among pharmacy students in three public universities in Bandung City, Surabaya City, and Special Region of Yogyakarta, Indonesia. The knowledge, perception, and willingness to provide telepharmacy services were assessed using an online questionnaire. Ordinal regression analysis was performed to determine factors associated with a high knowledge level, whereas binary logistic regression analyses were performed to determine factors associated with a positive perception of telepharmacy services. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Results Among 313 respondents, 83.4% were female, and the mean age was 20 years. Although only 13.2% showed a high knowledge level, 66.5% showed a positive perception of telepharmacy services and 97.4% were willing to provide telepharmacy services in the future. An increase in age (OR 1.33; 95% CI 1.14–1.54) and being advance in smartphone usage (OR 5.21; 95% CI 2.03–13.42) are associated with an increased likelihood of having a high knowledge level about telepharmacy services. Male students had a lower likelihood of having a positive perception of telepharmacy services than females (OR 0.46; 95% CI 0.24–0.85). Conclusion Despite limited knowledge of telepharmacy, the majority of pharmacy students reported a positive perception and willingness to provide telepharmacy services in their future careers. Therefore, telepharmacy practice models must be included as a subject course in the curriculum, better preparing future pharmacists to perform their roles effectively. Furthermore, student-specific factors such as age and expertise in smartphone usage that associated with knowledge and gender that associated with perception should be considered to facilitate telepharmacy adoption in Indonesia.

Abstract Background Numerous studies over the past four decades have revealed that breast cancer screening (BCS) significantly reduces breast cancer (BC) mortality. However, in BRICS-plus countries, the association between BCS and BC case fatality and disability are unknown. This study examines the association of different BCS approaches with age-standardized mortality, case-fatality, and disability-adjusted life years (DALYs) rates, as well as with other biological and sociodemographic risk variables, across BRICS-plus from a national and economic perspective. Methods In this ecological study applying mixed-effect multilevel regression models, a country-specific dataset was analyzed by combining data from the Global Burden of Disease study 2019 on female age-standardized BC mortality, incidence, and DALYs rates with information on national/regional BCS availability (against no such program or only a pilot program) and BCS type (only self-breast examination (SBE) and/or clinical breast examination (CBE) [SBE/CBE] versus SBE/CBE with mammographic screening availability [MM and/or SBE/CBE] versus SBE/CBE/mammographic with digital mammography and/or ultrasound (US) [DMM/US and/or previous tests] in BRICS-plus countries. Results Compared to self/clinical breast examinations (SBE/CBE) across BRICS-plus, more complex BCS program availability was the most significant predictor of decreased mortality [MM and/or SBE/CBE: − 2.64, p

Abstract Background Effective integration, one of the seven strategic priorities of the Immunization Agenda 2030, can contribute to increasing vaccination coverage and efficiency. The objective of the study is to measure and compare input costs of “non-selective” measles vaccination campaign as a stand-alone strategy and when integrated with another vaccination campaign. Methods We conducted a cost-minimization study using a matched design and data from five states of Nigeria. We carried-out our analysis in 3 states that integrated measles vaccination with Meningitis A and the 2 states that implemented a stand-alone measles campaign. The operational costs (e.g., costs of personnel, training, supervision etc.) were extracted from the budgeted costs, the financial and technical reports. We further used the results of the coverage surveys to demonstrate that the strategies have similar health outputs. Results The analysis of the impact on campaign budget (currency year: 2019) estimated that savings were up to 420,000 United States Dollar (USD) with the integrated strategies; Over 200 USD per 1,000 children in the target population for measles vaccination (0.2 USD per children) was saved in the studied states. The savings on the coverage survey components were accrued by lower costs in the integration of trainings, and through reduced field work and quality assurance measures costs. Conclusions Integration translated to greater value in improving access and efficiency, as through sharing of costs, more life-saving interventions are made accessible to the communities. Important considerations for integration are resource needs, micro-planning adjustments, and health systems delivery platforms.

Aims. To investigate the effect of serotonin transporter (5-HTT) polymorphisms on change in HbA1c levels six months after metformin initiation in type 2 diabetes patients. Materials and Methods. Participants of PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALidation of biomarkers) within the GIANTT (Groningen Initiative to ANalyse Type 2 Diabetes Treatment) cohort who initiated metformin were genotyped for combined 5-HTTLPR/rs25531 (L∗L∗, L∗S∗, and S∗S∗) and 5-HTT VNTR (STin 2.12, 12/-, and 10/-) polymorphisms, respectively. Multiple linear regression was applied to determine the change in HbA1c level from baseline date to six months across 5-HTTLPR/VNTR genotype groups, adjusted for baseline HbA1c, age, gender, triglyceride level, low-density lipoprotein level, and serum creatinine. Results. 157 participants were included, of which 56.2% were male. The average age was 59.3±9.23 years, and the mean baseline HbA1c was 7.49%±1.21%. 5-HTTLPR was characterized in 46 patients as L∗L∗, 70 patients as L∗S∗, and 41 patients as S∗S∗ genotypes. No significant association was found between 5-HTTLPR and 5-HTT VNTR genotypes and change in HbA1c after adjustments. Conclusions. 5-HTT polymorphisms did not affect HbA1c levels six months after the start of metformin. Further long-term studies in large samples would be relevant to determine which polymorphisms can explain the variation in response to metformin treatment.

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), I2=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), I2=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.

Pharmaceutical residues end up in surface waters, impacting drinking water sources and contaminating the aquatic ecosystem. Pharmacists can play a role in reducing pharmaceutical residues, yet this is often not addressed in pharmacy undergraduate education. Therefore, we developed the educational module “Reducing Pharmaceuticals in Water” for pharmacy students; this was integrated in our pharmacy simulation game for third year Master of Pharmacy students at the University of Groningen. In this study, we aim to evaluate the effects of the module on students’ knowledge of pharmaceutical residues in water, to describe students’ experiences in taking the module, and to explore their attitudes towards green pharmacy education in general. This mixed-methods study included quantitative measurements, before and after students took the module (intervention group) and in a control group which did not receive the module. Data were collected between February 2023 and June 2023. Overall, 29 students took the module and 36 students were in the control group. The knowledge score of students in the intervention group (N = 29) increased significantly from 9.3 to 12.9 out of 22 (p < 0.001). The knowledge score of the students in the control group was (8.9 out of 22). Students found the e-learning and the patient cases the most exciting part of this module. Students also recognized the need to including environmental issues in pharmacy education. In conclusion, the module contributes towards improved knowledge and increased awareness of the impact of pharmaceuticals found in water. It represents a promising strategy to strengthen pharmacist’s role in mitigating the amount and the effect of pharmaceuticals on water and the environment in the future.

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, 5770 (17.3%) patients experienced an acute CDT. The average follow-up time was 7.8±5.4 years. The 25-year incidence rate per 1000 person-years were 28.4, 25.2, 20.1, 28.4 and 25.2 for ACEI, ARB, BB, CCB and thiazide starters, respectively. Inverse probability weighted Cox regression showed that thiazide starters had lower hazards than the reference BB starters (HR: 0.88, 95%CI: 0.82 to 0.96). Among patients on diabetes drugs, risks were lower (HR: 0.58, 95%CI: 0.34 to 0.96). CCB starters had higher hazards than reference BB (HR: 1.26, 95% CI: 1.13 to 1.41). The overall estimated number needed to treat for thiazides compared with BBs to prevent one acute CDT in 25 years was 26, and five 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.

We aim to identify risk factors of major adverse cardio-cerebrovascular events (MACCE) using a proxy of drug treatment for a MACCE after the start of statin therapy in the primary cardiovascular prevention group, taking drug dose, persistency and adherence into account. We conducted a retrospective inception cohort study using data from the University of Groningen prescription database IADB.nl, covering patients in the Northern part of the Netherlands. We identified adult starters on primary preventive statin therapy as patients without any statin or cardiovascular drug prescription in the two years before the first statin dispensing and used a weighted Cox proportional hazard model to estimate hazard ratios (HR) with their 95 % confidence intervals (95 %CI). Among 39,487 primary preventive statin starters, 23% received drug treatment for a MACCE within a median follow-up period of four years. Increasing age, male gender and presence of diabetes drug treatment were significantly associated with the outcome (HR: 1.03; 95 %CI: 1.02–1.04; HR: 1.27; 95 %CI: 1.12–1.44 and HR: 1.39; 95 %CI: 1.24–1.56, respectively). If patients remained statin therapy persistent, adherence was no longer associated with drug treatment for a MACCE. In 23 % of the statin therapy initiators, incident drug treatment for a MACCE occurred with a median of four years. To reduce event rates in this group, older patients, males and diabetes patients should be closely monitored. Non-adherence in the early stage of treatment should be avoided to prevent non-persistence.

Abstract Background Deprescribing of preventive medication is recommended in older patients with polypharmacy, including people with type 2 diabetes (T2D). It seems that many patients in low-middle-income countries are not willing to have their medicines deprescribed. This study aims to assess attitudes of Indonesian patients with T2D towards deprescribing in general and regarding specific cardiometabolic medicines, and factors influencing their willingness to stop medicines. Methods Primary care patients with T2D of ≥60 years in Indonesia completed the revised Patients’ Attitudes Towards Deprescribing (rPATD) questionnaire. Attitudes in general and for cardiometabolic medicines were reported descriptively. Proportions of patients willing to stop one or more medicines when recommended by different healthcare professionals were compared with Chi-square test. Multiple regression analysis was used to analyse the influence between patient-related factors and the willingness to stop medicines. Results The survey was completed by 196 participants (median age 69 years, 73% female). The percentages willing to stop medicines were 69, 67, and 41%, when the general practitioner (GP), the specialist, or the pharmacist initiates the process (p-value

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.

Photosensitizing properties of hydrochlorothiazide may increase skin cancer risk. To date, study findings on the association between hydrochlorothiazide use and skin cancer risk are inconsistent, notably regarding confounding and dose-response. The aim of this study was to investigate the association between hydrochlorothiazide use and incidence of skin cancer in a cohort of unselected Caucasian adults, taking dosing into account. As part of the PharmLines Initiative, which links data from the Lifelines Cohort Study and prescription database IADB.nl, patients aged ≥ 40 years were included from Lifelines, a prospective population-based cohort study in the north of the Netherlands. Skin cancer incidence was compared between subjects starting hydrochlorothiazide treatment (n = 608), subjects starting treatment with other antihypertensives (n = 508), and non-antihypertensive long-term medication users (n = 1,710). Cox regression analyses were performed to obtain hazard ratios, adjusted for potential confounders. The risk of any skin cancer, keratinocyte carcinoma, basal cell carcinoma and squamous cell carcinoma was not significantly increased in general hydrochlorothiazide users. A clear association was observed between high cumulative hydrochlorothiazide use (≥ 5,000 defined daily dose; ≥ 125,000 mg) and the risk of any skin cancer (adjusted hazard ratio 5.32, 95% confidence interval (95% CI) 2.40–11.81), keratinocyte carcinoma (adjusted hazard ratio 7.31, 95% CI 3.12–17.13), basal cell carcinoma (adjusted hazard ratio 7.72, 95% CI 3.11–19.16) and squamous cell carcinoma (adjusted hazard ratio 19.63, 95% CI 3.12–123.56). These findings should lead to awareness with high use of hydrochlorothiazide in Caucasian adults.

Abstract Background Previously treated tuberculosis (TB) patients are a widely reported risk factor for multidrug-resistant tuberculosis. Identifying patients’ problems during treatment is necessary to control TB, especially in a high-burden setting. We therefore explored barriers to successful TB treatment from the patients’ perspective, aiming to identify potential patient-centred care strategies to improve TB treatment outcome in Indonesia. Methods A qualitative study was conducted in a province of Indonesia with high TB prevalence. Participants from various backgrounds (i.e., TB patients, physicians, nurses, pharmacists, TB activist, TB programmers at the district and primary care levels) were subject to in-depth interviews and focus group discussions (FGDs). All interviews and FGDs were transcribed verbatim from audio and visual recordings and the respective transcriptions were used for data analysis. Barriers were constructed by interpreting the codes’ pattern and co-occurrence. The information’s trustworthiness and credibility were established using information saturation, participant validation and triangulation approaches. Data were inductively analysed using the Atlas.ti 8.4 software and reported following the COREQ 32-items. Results We interviewed 63 of the 66 pre-defined participants and identified 15 barriers. The barriers were classified into three themes, i.e., socio-demography and economy; knowledge and perception and TB treatment. Since the barriers can be interrelated, we determined five main barriers across all barrier themes, i.e., lack of TB knowledge, stigmatisation, long distance to the health facility, adverse drug reaction and loss of household income. Conclusion The main treatment barriers can be considered to strengthen patient-centred care for TB patients in Indonesia. A multi-component approach including TB patients, healthcare providers, broad community and policy makers is required to improve TB treatment success.

Abstract Background From January to May 2019, large measles outbreaks affected Nigeria. Borno state was the most affected, recording 15,237 suspected cases with the state capital of Maiduguri having 1125 cases investigated and line-listed by March 2019. In Borno state, 22 of the 27 Local Government Areas (LGAs or Districts), including 37 internally displaced persons (IDPs) camps were affected. In response to the situation, an outbreak response immunization (ORI) campaign was conducted in the 13 most affected LGAs. In addition to conventional vaccination teams, special teams were deployed in security compromised areas, areas with migrants, and for nomadic and IDPs. Here we describe the outbreak and the ORI campaign. We also assess the measles-containing vaccine (MCV) coverage and vaccine effectiveness (VE) in order to quantify the population-level impact. Methods We reviewed the ORI activities, and conducted an analysis of the surveillance and the outbreak investigation reports. We assessed VE of MCV by applying the screening-method. Sensitivity analyses were also conducted to assess the effect of final classification of cases on the VE of MCV. The MCV coverage was assessed by a post-campaign coverage survey after completion of the ORI through a quantitative survey in the 12 LGAs that were accessible. Results Of the total 15,237 reported measles cases, 2002 cases were line-listed and investigated, and 737 were confirmed for measles by week 9 of 2019. Of the investigated cases 67.3% (n = 1348) were between 9 and 59 months of age. Among the 737 confirmed cases, only 9% (n = 64) stated being vaccinated with at least 1 dose of MCV. The overall VE for MCV was 98.4% (95%CI: 97.8–98.8). No significant differences were observed in the VE estimates of lab-confirmed and epi-linked cases when compared to the original estimates. The aggregated weighted vaccination coverage was 85.7% (95% CI: 79.6–90.1). Conclusion The experience in Borno demonstrates that adequate VE can be obtained in conflict-affected areas. In complex emergencies affected by measles outbreaks, health authorities may consider integration with other health strategies and the engagement of security personnel as part of the ORI activities.

Background: Community health centers (CHCs) are a backbone healthcare facility for tuberculosis (TB) services. Identifying barriers amongst TB service providers at the CHC level is required to help them deliver successful TB treatment.Aims: The current study aimed to analyze barriers to successful TB treatment from the perspective of TB service providers at the CHC level in a high prevalent TB country.Methods: A qualitative study was conducted using in-depth interviews and focus group discussions in a province of Indonesia with a high TB prevalence. Two districts representing rural and urban areas were selected to obtain information from TB service providers (i.e., physicians and nurses) at the CHC level. In addition, key informant interviews with TB patients, hospital TB specialists, pharmacists, and activists were conducted. The trustworthiness and credibility of the information were established using information saturation, participant validation, and triangulation approaches. The interviews were also transcribed for the inductive analysis using Atlas.ti 8.4 software.Results: We identified 210 meaning units from 48 participants and classified them into two main themes: organizational capacity and TB program activities. We identified the inadequacy of human resources, facility, and external coordination as the main barriers to organizational capacity. Furthermore, the barriers were identified regarding TB program activities, that is, inadequate TB case finding, diagnosis, drug supply chain and dispensing management, treatment and monitoring, case recording and reporting, and public-private collaboration.Conclusion: Strengthening CHCs in the management of TB is critical to reaching the national and global goals of TB eradication by 2035. These findings can be considered to develop evaluation strategies to improve the successful TB treatment in high prevalent TB countries, especially Indonesia.

BackgroundNonadherence to medication in tuberculosis (TB) hampers optimal treatment outcomes. Digital health technology (DHT) seems to be a promising approach to managing problems of nonadherence to medication and improving treatment outcomes. ObjectiveThis paper systematically reviews the effect of DHT in improving medication adherence and treatment outcomes in patients with TB. MethodsA literature search in PubMed and Cochrane databases was conducted. Randomized controlled trials (RCTs) that analyzed the effect of DHT interventions on medication adherence outcomes (treatment completion, treatment adherence, missed doses, and noncompleted rate) and treatment outcomes (cure rate and smear conversion) were included. Adult patients with either active or latent TB infection were included. The Jadad score was used for evaluating the study quality. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline was followed to report study findings. ResultsIn all, 16 RCTs were selected from 552 studies found, and 6 types of DHT interventions for TB were identified: 3 RCTs examined video directly observed therapy (VDOT), 1 examined video-observed therapy (VOT), 1 examined an ingestible sensor, 1 examined phone call reminders, 2 examined medication monitor boxes, and 8 examined SMS text message reminders. The outcomes used were treatment adherence, including treatment completion, treatment adherence, missed dose, and noncompleted rate, as well as clinical outcomes, including cure rate and smear conversion. In treatment completion, 4 RCTs (VDOT, VOT, ingestible sensor, SMS reminder) found significant effects, with odds ratios and relative risks (RRs) ranging from 1.10 to 7.69. Treatment adherence was increased in 1 study by SMS reminders (RR 1.05; 95% CI 1.04-1.06), and missed dose was reduced in 1 study by a medication monitor box (mean ratio 0.58; 95% CI 0.42-0.79). In contrast, 3 RCTs of VDOT and 3 RCTs of SMS reminders did not find significant effects for treatment completion. Moreover, no improvement was found in treatment adherence in 1 RCT of VDOT, missed dose in 1 RCT of SMS reminder, and noncompleted rate in 1 RCT of a monitor box, and 2 RCTs of SMS reminders. For clinical outcomes such as cure rate, 2 RCTs reported that phone calls (RR 1.30; 95% CI 1.07-1.59) and SMS reminders (OR 2.47; 95% CI 1.13-5.43) significantly affected cure rates. However, 3 RCTs found that SMS reminders did not have a significant impact on cure rate or smear conversion. ConclusionsIt was found that DHT interventions can be a promising approach. However, the interventions exhibited variable effects regarding effect direction and the extent of improving TB medication adherence and clinical outcomes. Developing DHT interventions with personalized feedback is required to have a consistent and beneficial effect on medication adherence and outcomes among patients with TB.

Background. Multiple studies and meta-analyses examined the role of traditional risk factors for cardiovascular events in statin treatment-naive patients. Nowadays, millions receive such therapy for the primary prevention of cardiovascular events (CVE). Objective. CVEs still occur in patients on primary preventive statin therapy. Therefore, further risk stratification within these patients is urgently needed. Methods. Using the unique linkage between biomedical data and prescription data from the PharmLines Initiative, we assessed the role of several risk factors used in cardiovascular risk models, using a time-dependent Cox PH model, in the occurrence of drug treatment of CVEs after initiation of statin therapy. Results. Among 602 statin therapy starters, 11% received drug treatment for CVE within an average follow-up period of 832 days. After multivariable modelling, cholesterol levels and blood pressure at baseline were no longer associated, whereas self-reported diabetes and increasing age were highly associated with the outcome when on statin therapy (hazard ratio (HR): 3.01, 95% confidence interval (95% CI): 1.48-6.12 and 1.04; 95% CI: 1.01-1.07, respectively). Males, smokers, and nonadherent patients had increased risks (HR 1.6, 1.12, and 1.18, resp.), though not statistically significant. Conclusion. Drug treatment for CVEs after statin initiation is increased in patients with diabetes type 2, in aged patients, males, smokers, and those with poor adherence, while there was no association with baseline cholesterol levels and blood pressure. These factors should be taken into account during the monitoring of statin therapy and may lead to changes in statin treatment or risk-related lifestyle factors.

Due to the expanding and ageing world population, the importance and use of medicines is expected to increase. However, this will lead to a greater impact on the ecosystem and our health in the long term.The concept of sustainability is rather slowly gaining traction and is currently still fragmented in the pharmaceutical field. A consortium of researchers from five European universities therefore advocates a global, systematic approach and places the emphasis on sustainability already in early stages of drug development, i.e. drug discovery. According to the researchers, the competent authorities, universities, research institutions and industrial organizations all need to take sustainability more into account. They summarized the most important opportunities on the basis of ten sustainability principles.

Mass spectrometry (MS) is increasingly used in clinical studies to obtain molecular evidence of chemical exposures, such as tobacco smoke, alcohol, and drugs. This evidence can help verify clinical data retrieved through anamnesis or questionnaires and may provide insights into unreported exposures, for example those classified as the same despite small but possibly relevant chemical differences or due to contaminants in reported exposure compounds. Here, we aimed to explore the potential of untargeted SWATH metabolomics to differentiate such closely related exposures. This data-independent acquisition MS-based profiling technique was applied to urine samples of 316 liver and 570 kidney transplant recipients from the TransplantLines Biobank and Cohort Study (NCT03272841), where we focused on the immunosuppressive drug mycophenolate, which is either supplied as a morpholino-ester prodrug or as an enteric-coated product, the illicit drug cocaine, which is usually supplied as an adulterated product, and the proton pump inhibitors omeprazole and esomeprazole. Based on these examples, we found that untargeted SWATH metabolomics has considerable potential to identify different (unreported) exposure or co-exposure metabolites and may determine variations in their abundances. We also found that these signals alone may sometimes be unable to distinguish closely related exposures, and enhancement of differentiation, for example by integration with pharmacogenomics data, is needed.

Objectives To evaluate the real-world association between varenicline and neuropsychiatric adverse events (NPAEs) in general and chronic obstructive pulmonary disease (COPD) population with and without psychiatric disorders compared with nicotine replacement therapy (NRT) to strengthen the knowledge of varenicline safety.Design A retrospective cohort study.Setting Prescription database IADB.nl, the Netherlands.Participants New users of varenicline or NRT among general (≥18 years) and COPD (≥40 years) population. Psychiatric subcohort was defined as people prescribed psychotropic medications (≥2) within 6 months before the index date.Outcome measures The incidence of NPAEs including depression, anxiety and insomnia, defined by new or naive prescriptions of related medications in IADB.nl within 24 weeks after the first treatment initiation of varenicline or NRT.Results For the general population in non-psychiatric cohort, the incidence of total NPAEs in varenicline (4480) and NRT (1970) groups was 10.5% and 12.6%, respectively (adjusted OR (aOR) 0.85, 95% CI 0.72 to 1.00). For the general population in psychiatric cohort, the incidence of total NPAEs was much higher, 75.3% and 78.5% for varenicline (1427) and NRT (1200) groups, respectively (aOR 0.82, 95% CI 0.68 to 0.99). For the COPD population (1598), there were no differences in the incidence of NPAEs between comparison groups in both the psychiatric cohort (aOR 0.97, 95% CI 0.66 to 1.44) and non-psychiatric cohort (aOR 0.81, 95% CI 0.54 to 1.20). Results from subgroup or sensitivity analyses also did not reveal increased risks of NPAEs but showed decreased risk of some subgroup NPAEs associated with varenicline.Conclusions In contrast to the concerns of a possible increased risk of NPAEs among varenicline users, we found a relative decreased risk of total NPAEs in varenicline users of the general population in psychiatric or non-psychiatric cohorts compared with NRT and no difference for NPAEs between varenicline and NRT users in smaller population with COPD.

Introduction: A pharmacist-led intervention in Community Health Centers (CHCs) in Indonesia targeted at patients with type 2 diabetes non-adherent to antihypertensive drugs resulted in a significant improvement in adherence to these drugs. The aim of this study was to evaluate the process of implementation this intervention intended to improve adherence to antihypertensive drugs from both the pharmacist and the patient perspective.Methods: Using the RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework, we conducted a focus group among pharmacists (N = 5) and a survey among patients with complete follow-up (N = 44) participating in the intervention group.Results: All pharmacists adopted the provided training and found support tools useful. The pharmacists implemented the intervention as intended (adequate intervention fidelity >69%). Factors relevant for implementation included having sufficient time and confidence, home visits for specific patients, multidisciplinary collaboration, and availability of a personal counseling room. To maintain the intervention, the need for practical guidance and support from health care authorities was mentioned. Most patients (96%) were satisfied with the information provided by the pharmacists and they believed the tailored counselling was helpful. Most patients (84%) reported that the duration of counselling was sufficient. The large majority of patients would like to receive the counselling regularly.Conclusion: Positive effects of the pharmacist-led intervention can be explained by adequate levels of reach, adoption and implementation in the participating CHCs. For successful implementation and maintenance in Indonesia or other low-and middle-income countries, sufficient training, resources, multidisciplinary collaboration, guidance and support from health care authorities are expected to be important.

BackgroundWhile Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.Methods and findingsWe used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = 4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.ConclusionsWe combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.

Abstract Background Since in low incidence TB countries population migration and complex treatment of drug-resistant tuberculosis (DR-TB) patients are major issues, we aimed to analyse patient risk factors associated with the incidence of poor outcome of TB treatment among DR-TB patients in the Netherlands. Methods This retrospective cohort study included adult patients with confirmed DR-TB treated from 2005 to 2015. We obtained data from a nationwide exhaustive registry of tuberculosis patients in the Netherlands. Predictors for unsuccessful TB treatment (defaulted and failed treatment) and TB-associated mortality were analysed using multivariate logistic regression. Results Among 10,303 registered TB patients, 545 patients with DR-TB were analysed. Six types of DR-TB were identified from the included patients, i.e. isoniazid mono- or poly-resistance (68%); rifampicin mono- or poly-resistance (3.1%); pyrazinamide mono-resistance (8.3%); ethambutol mono-resistance (0.1%); multidrug-resistance (18.9%); and extensively drug-resistance (0.7%). The majority of patients were foreign-born (86%) and newly diagnosed TB (89%) patients. The cumulative incidence of unsuccessful treatment and mortality were 5 and 1%, respectively. Among all DR-TB cases, patients with Multi Drug-Resistant Tuberculosis (MDR-TB) (OR 4.43; 95%CI 1.70–11.60) were more likely to have unsuccessful treatment, while miliary and central nervous system TB (OR 15.60; 95%CI 2.18–111.52) may also be predictors for TB mortality. Additionally, patients with substance abuse and homelessness tend to have unsuccessful treatment. Conclusions In recent years, we identified a low incidence of DR-TB as well as the poor outcome of DR-TB treatment. The majority of cases were primary drug-resistant and foreign-born. To further improve treatment outcome, special attention should be given to the high-risk DR-TB patients.

Abstract Aims The aim of this study was to explore the effect of insulin treatment initiation on weight by taking weight change prior to initiation into account. Materials and methods We performed an observational retrospective inception cohort study, concerning Dutch primary care. We identified all patients that initiated insulin treatment (n = 7967) and individually matched patients with a reference patient (n = 5213 pairs). We obtained estimated mean weight changes in the five years prior to five years post insulin therapy. We applied linear regression analysis on weight change in the first year after insulin therapy (T0 to T+1), with matched group as primary determinant adjusted for pre‐insulin weight change and additional covariates. Results Estimated mean weight increased in the five consecutive years prior to insulin therapy (−0.23 kg in year T‐5 to T‐4, 0.01 kg in year T‐4 to T‐3, 0.07 kg in year T‐3 to T‐2, 0.24 kg in year T‐2 to T‐1, and 0.46 kg in year T‐1 to T0) and continued to increase in the first year after, that is T0 to T+1, at a slightly lower rate (0.31 ± 3.9 kg). Pre‐insulin weight change had the highest explained variance and was inversely and independently associated with weight change (p

Antibiotic resistance has become a global health issue, negatively affecting the quality and safety of patient care, and increasing medical expenses, notably in Indonesia. Antibiotic stewardship programs (ASPs) aim to reduce resistance rates and their implementation in hospitals, has a high priority worldwide.We aimed to monitor the progress in the organizational implementation of ASPs in Indonesian hospitals by an Antimicrobial Resistance Control Program (ARCP) team and to identify possible hurdles. We conducted a cross-sectional study with structured interviews based on a checklist designed to assess the achievement of structural indicators at the organizational level in four private and three public hospitals in four regions (Surabaya, Sidoarjo, Mojokerto, Bangil) in East Java, Indonesia.The organizational structure of public hospitals scored better than that of private hospitals. Only three of the seven hospitals had an ARCP team. The most important deficiency of support appeared to be insufficient funding allocation for information technology development and lacking availability and/or adherence to antibiotic use guidelines. The studied hospitals are, in principle, prepared to adequately implement ASPs, but with various degrees of eagerness. The hospital managements have to construct a strategic plan and to set clear priorities to overcome the shortcomings.

Background: It is unknown whether population based single assessment of cardiovascular disease (CVD) risk and feedback to individuals and general practitioners results in initiation of preventive cardiovascular pharmacotherapy in those at risk. Methods: The population based cohort study Lifelines was linked to the IADB.nl pharmacy database to assess information on the initiation of preventive medication (N = 48,770). At the baseline visit, information on cardiovascular risk factors was collected and reported to the participants and their general practitioners. An interrupted-time-series-analysis was plotted, in which the start year of blood pressure and lipid lowering medication was displayed in years before or after the baseline visit. Subsequently, predictors of the initiation of pharmacotherapy were determined and possible reduction in cardiovascular events that could be achieved by optimal treatment of individuals at risk. Results: Before the Lifelines baseline visit, 34% (out of 1,527, 95% Confidence interval (CI) 32%–36%) and 30% (out of 1,991, 95%CI 28%–32%) of the individuals at risk had a blood pressure or lipid lowering drug prescription, respectively. In those at risk, the use of blood pressure lowering medication, increased substantially during the year of the baseline visit. Treating individuals at increased risk (≥5% 10-year risk) with lipid or blood pressure lowering medication (N = 8515 and N = 6899) would have prevented 162 and 183 CVD events, respectively, in the upcoming five years. Conclusion: Primary prevention of CVD in the general population appears suboptimal. Feedback of cardiovascular risk factors resulted in a substantial increase of blood pressure lowering medication and extrapolated health benefits.

Objectives To elicit key factors influencing physicians’ decision to prescribe statins.Design A qualitative study using a phenomenological approach within a pragmatism interpretive framework. A combination of purposive and snowball sampling was used to recruit physicians. Data were collected through face-to-face, semistructured interviews with physicians working in primary healthcare facilities in a capital of a province in Indonesia. We recorded and verbatim transcribed the interviews. Coding was done independently by two researchers and data were analysed using phenomenological data analyses. Key factors influencing physicians’ decision to prescribe statins were classified into factors at the microlevels, mesolevels and macrolevels according to the structural model by Scoggins et al.Participants and setting Physicians working in primary healthcare facilities in a capital of a province in Indonesia.Results Ten physicians were included in the study. Key factors at the microlevel were that physicians knew guidelines in general, but there was uncertainty how to take into account the level of total cholesterol in combination with other cardiovascular risk factors such as diabetes and hypertension. At the macrolevel, the new National Health Insurance System (NHIS) that appeared to facilitate the prescription of statins though more clinical information should be integrated in the system’s platform to support appropriate prescribing.Conclusions The findings indicate lack of awareness of specific details in current guideline recommendations. Appropriate prescribing of statins should be enhanced using the new NHIS.

IntroductionAlthough bacteria contribute significantly to acute exacerbations of chronic obstructive pulmonary disease (AECOPD), the added value of antibiotics remains controversial, especially in outpatient settings. Age may affect antibiotic effectiveness, but real-world evidence is lacking. We aimed to assess the influence of age on the effectiveness of doxycycline for AECOPD.MethodsA retrospective cohort study among outpatients with the first recorded AECOPD treated with oral corticosteroids was conducted using a large pharmacy dispensing database. The primary outcome was treatment failure within 15–31 days after treatment start. Secondary outcome was time to second exacerbation. All analyses were stratified by age groups.ResultsWe identified 6300 outpatients with the first AECOPD. 2261 (36%) received doxycycline and 4039 (64%) did not receive any antibiotic (reference group). Overall, there was no difference in treatment failure (adjusted OR: 0.97, 95% CI: 0.84 to 1.12) between two groups. Similarly, no difference in treatment failure was observed in younger groups. However, in patients with advanced age (≥75 years), treatment failure was significantly reduced by doxycycline compared with reference (16% vs 20%, adjusted OR: 0.77, 95% CI: 0.62 to 0.97). Overall, median time to second exacerbation was 169 days (95% CI: 158 to 182 days) in doxycycline group compared with 180 days (95% CI: 169 to 191 days) in reference group (adjusted HR: 1.06, 95% CI: 0.99 to 1.12). Although in older patients there was a trend within 3 months towards longer time of next exacerbation by doxycycline, it did not achieve statistical significance.ConclusionsOur findings showed short-term treatment benefit of doxycycline added to oral corticosteroids for chronic obstructive pulmonary disease patients with advanced age. This value remains unclear for persons aged under 75 years in current primary care. Long-term preventive benefits of doxycycline for the next exacerbation were not observed, irrespective of age.

BackgroundDrug-drug interaction (DDI) is one of the main contributors to adverse drug reactions and therefore, it is important to study its frequency in the population. We aimed to investigate frequency and concordance on CYP2D6, CYP2C19, and CYP2C9 (CYP2D6/2C19/2C9)-mediated potential DDIs at the Lifelines cohort and linked data from the pharmacy database IADB.nl.MethodsAs part of the University of Groningen PharmLines Initiative, data were collected on CYP2D6/2C19/2C9-related substrate/inhibitors from entry questionnaires of Lifelines participants and linked information from the pharmacy database IADB.nl. CYP2D6/2C19/2C9 related co-prescriptions were divided based on the type of drugs i.e. chronically used medication (CM) or occasionally used medication (OM). This resulted in the combination of two chronically used drugs (CM-CM), chronically and occasionally used medication (CM-OM), and two occasionally used drugs (OM-OM). To measure the agreement level, cohen’s kappa statistics and test characteristics were used. Results were stratified by time window, gender, and age.ResultsAmong 80,837 medicine users in the Lifelines, about 1–2 per hundred participants were exposed to a CYP2D6/2C19/2C9-mediated potential DDI. Overall, the overlapping time window of three months produced the highest mean kappa values between the databases i.e. 0.545 (95% CI:0.544–0.545), 0.512 (95% CI:0.511–0.512), and 0.374 (95% CI:0.373–0.375), respectively. CM-CM had a better level of agreement (good) than CM-OM (fair to moderate) and OM-OM combination (poor to moderate). The influence of gender on concordance values was different for different CYPs. Among older persons, agreement levels were higher than for the younger population.ConclusionsCYP2D6/2C19/2C9-mediated potential DDIs were frequent and concordance of data varied by time window, type of combination, sex and age. Subsequent studies should rather use a combination of self-reported and pharmacy database information.

BackgroundBrain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, and its dysregulation has been associated with the pathogenesis of mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone which is also produced as a cytokine by immune cells and could be a neurotrophic factor regulating the functional activity of stress-related mechanisms.AimTo investigate the possible relationship between depressive state and BDNF and PRL genotypes or levels with special reference to severity of depression.MethodsParticipants of 18–70 years with a clinical diagnosis of depressive disorder of at least moderate severity were included. These patients had not been treated with antidepressant drugs before admission to hospital during the preceding period of the last 6 months, and 54.5% had never been treated with antidepressant drugs during their entire life. The DNA was genotyped for rs1341239 within the prolactin and for rs6265, rs7124442, and rs11030104 within the BDNF gene. Rs11030104 violated the Hardy-Weinberg equilibrium distribution and was excluded from further analyses. BDNF and prolactin concentration was measured in serum by MAGPIX multiplex analyzer (Luminex, USA) using MILLIPLEX® MAP kit (Merck, Germany). Genetic associations were determined by sequentially regressing prolactin, BDNF, 17-items Hamilton's Depression (HAMD-17) and Clinical Global Impression scale, Severity (CGI-S) ratings, and depression (absent/present) on the available SNPs. Genetic associations were evaluated assuming an additive model.ResultsA total of 186 depressed patients (of which 169 were women) and 94 healthy controls (67 women) were genotyped. After excluding subjects without genetic information on all three study SNPs, 217 remained of whom 138 suffered from depression. Within depressed patients we observed an association of rs6265 with HAMD-17: mean difference (MD) 2.33 (95%CI 0.49; 4.16; p = 0.014) and CGI-S: MD 0.38 (95%CI 0.09; 0.66; p = 0.011). No significant association was observed between the prolactin SNP rs1341239 and prolactin levels. Similarly the mean differences of BDNF SNPs did not show an association with BDNF: rs6265 −0.042 ln(pg/ml) (95%CI −0.198; 0.113), and rs7124442 0.006 ln(pg/ml) (95%CI −0.117; 0.130). No other association reached statistical significance.ConclusionWe observed a significant association between BDNF gene variant rs6265 and the severity of depression in newly admitted, antidepressant treatment-free, depressed patients. Actual PRL and BDNF levels were not elevated sufficiently in depressed patients to reach statistical significance and were not associated with the studied genotypes.

Background and aims: Acute ST-elevation myocardial infarction (STEMI) is a potentially fatal presentation of coronary artery disease (CAD). Evidence of the impact of acute pharmacological interventions in non-reperfused STEMI patients on subsequent events is limited. We aimed to assess the association between adherence to guideline-recommended preventive medications and in-hospital mortality among this high-risk patient population. Methods: We conducted a cohort study using data obtained from the Jakarta Acute Coronary Syndrome (JAC) Registry database from a tertiary care academic hospital in Indonesia. We included 1132 of 2694 patients with STEMI recorded between 1 January 2014 and 31 December 2016 who did not undergo acute reperfusion therapy. Adherence to guideline-recommended preventive medications was defined as the combined administration of aspirin, clopidogrel, anticoagulants and statins after hospital admission. The main outcome measure was in-hospital mortality. Results: Overall, 778 of 1132 patients (69%) received the combination of preventive medications. The guideline non-adherent group had significantly more patients with earlier onset of STEMI, higher Killip class and thrombolysis in myocardial infarction (TIMI) score. After adjustments for measured characteristics using logistic regression modeling, exposure to the combination of preventive therapies was associated with a statistically significant lower risk for in-hospital mortality (adjusted odds ratio: 0.46, 95% confidence interval: 0.30–0.70). Conclusions: Adherence to guideline-recommended preventive medications was associated with lower risk of in-hospital mortality in non-reperfused STEMI patients. The predictors of not receiving these medications need to be confirmed in future research.

Abstract Background Prior studies reported that exposure to antidepressants during pregnancy may be associated with gestational hypertension. The aim of this study is to assess the association between the use of antidepressants during pregnancy and the risk of developing gestational hypertension. Methods A retrospective cohort study using the prescription database IADB.nl was conducted among nulliparous women with singleton pregnancies between 1994 and 2015 in the Netherlands. Logistic regression analysis was used to estimate odds ratios (OR), adjusted OR (aOR) and their corresponding 95% confidence intervals (95% CI). Gestational hypertension as main outcome measure was defined as at least one dispensed record of an antihypertensive drug (methyldopa, nifedipine, labetalol, ketanserin, nicardipine) after 20 weeks of gestation until 14 days after delivery. Sub-analyses were conducted for class of antidepressant, duration and amount of use of antidepressant (≤30, ≥30 Defined Daily Doses or DDDs), and maternal age. Sensitivity analyses to assess uncertainties were conducted. Results Twenty-eight thousand twenty women were included, of which 539 (1.92%) used antidepressants. The risk of gestational hypertension was doubled for women using antidepressant (aOR 2.00 95% CI 1.28–3.13). Significant associations were also found for the subgroup selective serotonin reuptake inhibitors (SSRIs) (aOR 2.07 95% CI 1.25–3.44), ≥30 DDDs (aOR 2.50 95% CI 1.55–3.99) and maternal age of 30–34 years (aOR 2.59 95% CI 1.35–4.98). Varying the theoretical gestational age showed comparable results. Conclusion Prolonged use of antidepressants during the first 20 weeks of gestation appeared to be associated with an increased risk of developing gestational hypertension. When balancing the benefits and risks of using these drugs during pregnancy, this should be taken into account.

Abstract Background Current influenza vaccines, based on antibodies against surface antigens, are unable to provide protection against newly emerging virus strains which differ from the vaccine strains. Therefore the population has to be re-vaccinated annually. It is thus important to develop vaccines which induce protective immunity to a broad spectrum of influenza viruses. This trial is designed to evaluate the immunogenicity and safety of FLU-v, a vaccine composed of four synthetic peptides with conserved epitopes from influenza A and B strains expected to elicit both cell mediated immunity (CMI) and humoral immunity providing protection against a broad spectrum of influenza viruses. Methods In a single-center, randomized, double-blind and placebo-controlled phase IIb trial, 222 healthy volunteers aged 18–60 years will be randomized (2:2:1:1) to receive two injections of a suspension of 500 μg FLU-v in saline (arm 1), one dose of emulsified 500 μg FLU-v in Montanide ISA-51 and water for injection (WFI) followed by one saline dose (arm 2), two saline doses (arm 3), or one dose of Montanide ISA-51 and WFI emulsion followed by one saline dose (arm 4). All injections will be given subcutaneously. Primary endpoints are safety and FLU-v induced CMI, evaluated by cytokine production by antigen specific T cell populations (flow-cytometry and ELISA). Secondary outcomes are measurements of antibody responses (ELISA and multiplex), whereas exploratory outcomes include clinical efficacy and additional CMI assays (ELISpot) to show cross-reactivity. Discussion Broadly protective influenza vaccines able to provide protection against multiple strains of influenza are urgently needed. FLU-v is a promising vaccine which has shown to trigger the cell-mediated immune response. The dosages and formulations tested in this current trial are also estimated to induce antibody response. Therefore, both cellular and humoral immune responses will be evaluated. Trial registration EudraCT number 2015–001932-38 ; retrospectively registered clinicaltrials.gov NCT02962908 (November 7th 2016).

Abstract Background Pharmacogenetics is an emerging field currently being implemented to improve safety when prescribing drugs. While many women who take drugs during pregnancy would likely benefit from such personalized drug therapy, data is lacking on the awareness towards pharmacogenetics among women. We aim to determine the level of knowledge and acceptance of formerly pregnant women in the Netherlands regarding pharmacogenetics and its implementation, and their interest in pharmacogenetic research. Methods A population-based survey using postal questionnaires was conducted among formerly pregnant women in the Northern parts of the Netherlands. A total of 986 women were invited to participate. Results Of the 219 women who returned completed questionnaires (22.2% response rate), only 22.8% had heard of pharmacogenetics, although the majority understood the concept (64.8%). Women who had experience with drug side-effects were more likely to know about pharmacogenetics [OR = 2.06, 95% CI 1.16, 3.65]. Of the respondents, 53.9% were positive towards implementing pharmacogenetics in their future drug therapy, while 46.6% would be willing to participate in pharmacogenetic research. Among those who were either not willing or undecided in this regard, their concerns were about the consequences of the pharmacogenetic test, including the privacy and anonymity of their genetic information. Conclusion The knowledge and attitude regarding the concept of pharmacogenetics among our population of interest is good. Also, their interest in pharmacogenetic research provides opportunities for future research related to drug use during pregnancy and fetal outcome.

Abstract Background There is no conclusive evidence that stimulants have beneficial effects on major associated outcome parameters, particularly school performance. We assessed the differences in school performance among children using methylphenidate at the end of primary school in relation to various parameters of methylphenidate use. Methods We linked children from a pharmacy prescription database with standardized achievement test results at the end of primary school. We explored differences in test scores between current methylphenidate users versus never users and methylphenidate users who stopped treatment at least 6 months before the test, early versus late starters, different dosage of methylphenidate, and concurrent antipsychotic or asthma treatment. Results Out of the 7736 children, 377 (4.9%) children were treated with methylphenidate at the time of the test. After adjusting for confounders the methylphenidate users (532.58 ± .48) performed significantly lower on the test than never users (534.72 ± .11). Compared with late starters of methylphenidate treatment (536.94 ± 1.51) we found significantly lower test scores for the early starters (532.33 ± .50). Conclusion Our study indicates that children using methylphenidate still perform less at school compared to their peers. Our study also suggests that earlier start of methylphenidate treatment is associated with a lower school performance compared to children starting later with the treatment. This result could either indicate a limited effect of long term treatment or a more strongly affected group of early starters.

BACKGROUND AND PURPOSE:Polypharmacy is becoming increasingly common owing to the ageing population, which can pose problems for patients and society. We investigated the trends in polypharmacy and underlying drug groups among adults in the Netherlands from 1999 to 2014 stratified by age, and compared these with findings from the United States (US). METHODS:We conducted a repeated cross-sectional study using the Dutch IADB.nl prescription database. All patients aged 20 years and older in the period 1999 to 2014 were included. Polypharmacy was defined as the dispensing of five or more chronic drugs at the pharmacological subgroup level. Chi-square tests were applied to calculate the p-value for trends. Changes in prevalences were compared between the Netherlands and the US. RESULTS:The prevalence of polypharmacy increased from 3.1% to 8.0% (p-value for trend

BackgroundAdherence to antihypertensive drugs in patients with diabetes is important. To support adherence, attention should be paid to the dynamic process of implementation, persistence and reinitiation of these drugs. We assessed non-adherence, non-persistence and reinitiation patterns for antihypertensive drugs in patients on oral diabetes drugs and identified pharmacy-based predictors of these processes.MethodsWe conducted a cohort study in patients on oral diabetes drugs who initiated antihypertensive drugs between 1995-2015, as registered in the IADB.nl pharmacy database. Non-adherence was defined as a medication possession ratio < 80% and non-persistence as a gap > 180 days. We defined reinitiation as the dispensing of an antihypertensive drug within one year following discontinuation. We provide descriptive statistics for different time periods and applied logistic and Cox regressions to assess associations with sociodemographic and drug-related factors.ResultsOf 6,669 initiators, non-adherence rates in persistent patients decreased from 11.0% in the first year to 8.5% and 7.7% in the second and third years, respectively. Non-persistence rates decreased from 18.0% in the first year to 3.7% and 2.9% in the second and third years, respectively. Of the 1,201 patients who discontinued in the first year, 22.0% reinitiated treatment within one year. Non-adherence and non-persistence rates were lower in the more recent time period. Predictors of non-adherence were secondary prevention (OR: 1.45; 95% CI: 1.10-1.93) and diuretics as initial drug class (OR: 1.37; 95% CI: 1.08-1.74). Predictors of non-persistence were female gender (HR: 1.18; 95% CI: 1.05-1.32), older age (HR: 1.33; 95% CI: 1.08-1.63) and diuretics, beta-blocking agents or calcium channel blockers as initial drug class. Longer duration of persistence was a predictor of reinitiation.ConclusionsAdherence to antihypertensive drugs in patients on oral diabetes drugs has improved over time. The first year after initiation is the most crucial with regard to non-adherence and non-persistence, and the risk groups are different for both processes. Early non-persistence is a risk factor for not reinitiating treatment.

Abstract 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.

Background: a large number of studies have linked vitamin B6 to inflammation and cardiovascular disease in the general population. However, it remains uncertain whether vitamin B6 is associated with cardiovascular outcome independent of inflammation. Methods: we measured plasma pyridoxal 5’-phosphate (PLP), as an indicator of vitamin B6 status, at baseline in a population-based prospective cohort of 6249 participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study who were free of cardiovascular disease. As indicators of low-grade systemic inflammation, we measured high-sensitivity C-reactive protein and GlycA; Results: median plasma PLP was 37.2 (interquartile range, 25.1–57.0) nmol/L. During median follow-up for 8.3 (interquartile range, 7.8–8.9) years, 409 non-fatal and fatal cardiovascular events (composite outcome) occurred. In the overall cohort, log transformed plasma PLP was associated with the composite outcome, independent of adjustment for age, sex, smoking, alcohol consumption, body mass index (BMI), estimated glomerular filtration rate (eGFR), total cholesterol:high-density lipoprotein (HDL)-cholesterol ratio, and blood pressure (adjusted hazard ratio per increment of log plasma PLP, 0.66; 95% confidence interval (CI), 0.47–0.93). However, adjustment for high-sensitivity C-reactive protein and GlycA increased the hazard ratio by 9% and 12% respectively, to non-significant hazard ratios of 0.72 (95% confidence interval, 0.51–1.01) and 0.74 (95% confidence interval, 0.53–1.05). The association of plasma PLP with cardiovascular risk was modified by gender (adjusted Pinteraction = 0.04). When stratified according to gender, in women the prospective association with cardiovascular outcome was independent of age, smoking, alcohol consumption, high-sensitivity C-reactive protein, and GlycA (adjusted hazard ratio, 0.50, 95% confidence interval, 0.27–0.94), while it was not in men (adjusted hazard, 0.99, 95% confidence interval, 0.65–1.51). Conclusions: in this population-based cohort, plasma PLP was associated with cardiovascular outcome, but this association was confounded by traditional risk factors and parameters of inflammation. Notably, the association of low plasma PLP with high risk of adverse cardiovascular outcome was modified by gender, with a stronger and independent association in women.

Prescription sequence symmetry analysis (PSSA), a case-only design introduced in 1996, has been increasingly used to identify unintentional drug effects, and has potential applications as a hypothesis-testing and a hypothesis-generating method, due to its easy application and effective control of time-invariant confounders. The aim of this study is to systematically compare effect estimates from the PSSA to effect estimates from conventional observational parallel group study designs, to assess the validity and constraints of the PSSA study design. We reviewed the MEDLINE, EMBASE, and Web of Science databases until February 2016 to identify studies that compared PSSA to a parallel group design. Data from the eligible articles was extracted and analyzed, including making a Bland-Altman plot and calculating the number of discrepancies between the designs. 63 comparisons (from two studies) were included in the review. There was a significant correlation (p < 0.001) between the effect estimates of the PSSA and the parallel group designs, but the bias indicated by the Bland-Altman plot (0.20) and the percentage of discrepancies (70-80%) showed that this correlation was not accompanied by a considerable similarity of the effect estimates. Overall, the effect estimates of the parallel group designs were higher than those of the PSSA, not necessarily further away from 1, and the parallel group designs also generated more significant signals. However, these results should be approached with caution, as the effect estimates were only retrieved from two separate studies. This review indicates that, even though PSSA has a lot of potential, the effect estimates generated by the PSSA are usually lower than the effect estimates generated by parallel group designs, and PSSA mostly has a lower power than the conventional study designs, but this is based on limited comparisons, and more comparisons are needed to make a proper conclusion.

Streptococcus pneumoniae causes morbidity and mortality among all ages in The Netherlands. To reduce this burden, infants in The Netherlands receive the 10-valent pneumococcal conjugated vaccine (PCV10), but older persons are not targeted. We assessed the impact and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23) or 13-valent PCV (PCV13) among all those aged 60, 65 or 70 and/or in combination with replacing PCV10 with PCV13 in the infant vaccination programme.A static cost-effectiveness model was parameterized including projected trends for invasive pneumococcal disease (IPD) and hospitalised community acquired pneumonia (CAP). The different strategies were evaluated using vaccine list prices and a 10-year time horizon. Incremental cost-effectiveness ratios (ICER) were calculated with the current strategy (infant vaccination program with PCV10) as reference.Compared to the reference, the largest impact on pneumococcal disease burden was projected with a combined use of PCV13 among infants and PPV23 at 60, 65 and 70 years, preventing 1,635 cases of IPD and 914 cases of CAP. The most cost-effective strategy was vaccinating with PPV23 at 70 years only with similar low ICERs at age 60 and 65. The impact of the use of PCV13 among infants depends strongly on the projected herd-immunity effect on serotype 19A. Vaccinating elderly with either PCV13 or PPV23 was dominated by PPV23 in all investigated scenarios, mainly due to the lower price of PPV23.Under the current assumptions, the best value for money is the use of PPV23 for elderly, with a single dose or at five year increment between age 60 to age 70.

Obtaining approval for a multinational vaccine trial from an ethics committee and the national competent authority of different Member States of the European Union (EU) is challenging under clinical trial Directive 2001/20/EC because of the differences in the implementation of the directive in national laws of Member States. In this review the national differences in requirements for ethical and competent authority approval are illustrated. The national ethical and competent authority review procedures in Finland, Hungary, The Netherlands, Norway and Slovenia are described under the EU trial directive after discussing the provisions of the trial directive related to both review procedures. The review illustrates the differences between the countries in the documents that have to be submitted for the review procedures, the submission procedures and the language requirements of the documents, the organization of the ethics committees and the role of the competent authority in the approval procedure.

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.

BACKGROUND:A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins. METHODS:A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB.nl, a pharmacy prescription database. RESULTS:Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies. CONCLUSIONS:Some of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures.

BACKGROUND AND OBJECTIVES:QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials. METHODS:A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality. RESULTS:Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04-6.24). No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10-15.35 and RR 2.55, 95% CI 1.41-4.59, respectively). ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08-10.97). CONCLUSIONS:Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. This meta-analysis is limited by the relatively small number of individuals recruited in the included trials, especially in the control groups.

To evaluate the effectiveness of the 7-valent pneumococcal conjugate vaccine (PCV7) program, we conducted a cross-sectional observational study on nasopharyngeal carriage of Streptococcus pneumoniae 3 years after implementation of the program in the Netherlands. We compared pneumococcal serotypes in 329 prebooster 11-month-old children, 330 fully vaccinated 24-month-old children, and 324 parents with age-matched pre-PCV7 (unvaccinated) controls (ages 12 and 24 months, n = 319 and n = 321, respectively) and 296 of their parents. PCV7 serotype prevalences before and after PCV7 implementation, respectively, were 38% and 8% among 11-month-old children, 36% and 4% among 24-month-old children, and 8% and 1% among parents. Non-PCV7 serotype prevalences were 29% and 39% among 11-month-old children, 30% and 45% among 24-month-old children, and 8% and 15% among parents, respectively; serotypes 11A and 19A were most frequently isolated. PCV7 serotypes were largely replaced by non-PCV7 serotypes. Disappearance of PCV7 serotypes in parents suggests strong transmission reduction through vaccination.

In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV-7) was implemented in a 3+1-dose schedule in the national immunization program for infants born after April 1, 2006. To assess the vaccine’s effectiveness, we compared disease incidence before and after vaccine implementation (June 2004–June 2006 and June 2006–June 2008, respectively). We serotyped 2,552 invasive pneumococcal isolates from throughout the Netherlands, covering 25% of the country’s population. Clinical characteristics were extracted from hospital records. After June 2006, vaccine-serotype invasive pneumococcal disease (IPD) decreased 90% (95% confidence interval [CI] 68%–97%) in children age eligible for PCV-7; simultaneously, however, non–vaccine-serotype IPD increased by 71% (not significant), resulting in a 44% total net IPD reduction (95% CI 7%–66%). IPD rates did not change for other age groups. In the Netherlands, PCV-7 offered high protection against vaccine-serotype IPD in vaccinated children, but increases of non–vaccine-serotype IPD reduced net vaccine benefits.