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BackgroundTelephone triage is used to facilitate efficient and adequate acute care allocation, for instance in out-of-hours primary care services (OPCSs). Remote assessment of health problems is challenging and could be impeded by a patient’s ambiguous formulation of his or her healthcare need. Socioeconomically vulnerable patients may experience more difficulty in expressing their healthcare need. We aimed to assess whether income differences exist in the patient’s presented symptoms, assessed urgency and allocation of follow-up care in OPCS.MethodData were derived from Nivel Primary Care Database encompassing electronic health record data of 1.3 million patients from 28 OPCSs in 2017 in the Netherlands. These were linked to sociodemographic population registry data. Multilevel logistic regression analyses (contacts clustered in patients), adjusted for patient characteristics (eg, age, sex), were conducted to study associations of symptoms, urgency assessment and follow-up care with patients’ income (standardised for household size as socioeconomic status (SES) indicator).ResultsThe most frequently presented symptoms deduced during triage slightly differed across SES groups, with a larger relative share of trauma in the high-income groups. No SES differences were observed in urgency assessment. After triage, low income was associated with a higher probability of receiving telephone advice and home visits, and fewer consultations at the OPCS.ConclusionsSES differences in the patient’s presented symptom and in follow-up in OPCS suggest that the underlying health status and the ability to express care needs affect the telephone triage process . Further research should focus on opportunities to better tailor the telephone triage process to socioeconomically vulnerable patients.

PURPOSE: In 2009 a Dutch guideline was published containing recommendations to reduce Hospital Admissions Related to Medications (HARMs). This study aims to examine time-trends of HARMs and their potential preventability between 2008 and 2013 in The Netherlands.METHODS: A retrospective prevalence study was conducted using the Dutch PHARMO Database Network. A semi-automated pre-selection was used to make a crude identification of possible HARMs of which four samples were selected. These were independently assessed with respect to causality and potential preventability by a physician and pharmacist. The results were stratified by age into 18-64 years and 65 years and older. For these groups the net prevalences and incidence rates of HARMs and potentially preventable HARMs were calculated for the years 2008, 2009, 2011 and 2013.RESULTS: Four samples of 467 (2008), 447 (2009), 446 (2011) and 408 (2013) admissions were assessed. The net prevalence of HARMs in the 18-64 years group was approximately four times smaller compared to the older group with a mean prevalence of 2.7% (95% confidence interval [CI]:2.4%-3.0%) and 10.2% (95%CI: 9.7%-10.7%) respectively. The potential preventability was 25.1% (18.4%-31.8%) and 48.3% (95%CI: 44.8%-51.8%), respectively. The prevalence of HARMs in both groups did not change significantly between 2008 and 2013 with 2.4% (95%CI: 1.9%-3.0%) and 10.0% (95%CI: 9.0%-11.0%) in 2008 and 3.1% (2.7%-3.5%) and 10.4% (95%CI: 9.4%-11.4%) in 2013, respectively.CONCLUSION: Despite efforts to reduce HARMs, the prevalence did not decrease over time. Additional measures are therefore necessary, especially in the elderly population.

Background Low socioeconomic position (SEP) is related to higher healthcare use in out-of-hours primary care services (OPCSs). We aimed to determine whether inequalities persist when taking the generally poorer health status of socioeconomically vulnerable individuals into account. To put OPCS use in perspective, this was compared with healthcare use in daytime general practice (DGP). Methods Electronic health record (EHR) data of 988 040 patients in 2017 (251 DGPs, 27 OPCSs) from Nivel Primary Care Database were linked to socio-demographic data (Statistics, The Netherlands). We analyzed associations of OPCS and DGP use with SEP (operationalized as patient household income) using multilevel logistic regression. We controlled for demographic characteristics and the presence of chronic diseases. We additionally stratified for chronic disease groups. Results An income gradient was observed for OPCS use, with higher probabilities within each lower income group [lowest income, reference highest income group: odds ratio (OR) = 1.48, 95% confidence interval (CI): 1.45–1.51]. Income inequalities in DGP use were considerably smaller (lowest income: OR = 1.17, 95% CI: 1.15–1.19). Inequalities in OPCS were more substantial among patients with chronic diseases (e.g. cardiovascular disease lowest income: OR = 1.60, 95% CI: 1.53–1.67). The inequalities in DGP use among patients with chronic diseases were similar to the inequalities in the total population. Conclusions Higher OPCS use suggests that chronically ill patients with lower income had additional healthcare needs that have not been met elsewhere. Our findings fuel the debate how to facilitate adequate primary healthcare in DGP and prevent vulnerable patients from OPCS use.

Background: Patients with primary hypothyroidism are treated with levothyroxine (LT4) to normalize their serum thyrotropin (TSH). Finding the optimal dosage is a long-lasting process, and a small change can have major impact. Currently, limited data are available on the impact of dose-equivalent substitution between brands. This study aimed to determine the effect of the shortage of the LT4 brand Thyrax® in the Netherlands and the resulting dose-equivalent switch to another brand on plasma TSH concentrations in a large cohort of patients. Methods: Observational cohort study. Two registries representative for the Dutch population containing prescription and laboratory test data: the Nivel Primary Care Database and the PHARMO Database Network. Patients using at least 25 μg Thyrax daily for one year or longer were included. Two cohorts were formed: a switch cohort consisting of patients who switched from Thyrax to an alternative brand, and a Thyrax cohort including patients who continued to use Thyrax. Patients in the switch cohort did switch from Thyrax to a different brand of LT4 in 2016 and had two consecutive TSH measurements on the same dose of LT4, one before and one 6 weeks after the switch. Patients in the Thyrax cohort had two consecutive TSH measurements on the same dose of Thyrax that were 6 weeks apart. Results: In the Thyrax cohort, 19% of euthyroid patients using ≤100 μg had a TSH level outside the reference range at the subsequent measurement compared with 24% in the switch cohort (p < 0.0001). For patients using >100 μg Thyrax, these figures were 24% and 63%, respectively (p < 0.0001). Furthermore, patients using >50 μg Thyrax were four to five times more likely to become hyperthyroid after a dose-equivalent switch to a different brand compared with patients who stayed on Thyrax. Conclusions: In euthyroid patients continuing the LT4 product Thyrax at the same dose, TSH was out of range in 19-24% at least 6 weeks later. A dose-equivalent switch from Thyrax to other LT4 brands induced biochemical signs of overdosing in an even larger proportion (24-63%) of patients. The results indicate that a dose-equivalent LT4 brand switch may necessitate a dose adjustment in a large number of patients.

BackgroundLow-value pharmaceutical care exists in general practice. However, the extent among Dutch GPs remains unknown.AimTo assess the prevalence of low-value pharmaceutical care among Dutch GPs.Design and settingRetrospective cohort study using data from patient records.MethodThe prevalence of three types of pharmaceutical care prescribed by GPs between 2016 and 2019 were examined: topical antibiotics for conjunctivitis, benzodiazepines for non-specific lower back pain, and chronic acid-reducing medication (ARM) prescriptions. Multilevel logistic regression analysis was performed to assess prescribing variation and the influence of patient characteristics on receiving a low-value prescription.ResultsLarge variation in prevalence as well as practice variation was observed among the types of low-value pharmaceutical GP care examined. Between 53% and 61% of patients received an inappropriate antibiotics prescription for conjunctivitis, around 3% of patients with lower back pain received an inappropriate benzodiazepine prescription, and 88% received an inappropriate chronic ARM prescription during the years examined. The odds of receiving an inappropriate antibiotic or benzodiazepine prescription increased with age (PPPPPConclusionThe results show that the prevalence of low-value pharmaceutical GP care varies among these three clinical problems. Significant variation in inappropriate prescribing exists between different types of pharmaceutical care — and GP practices.

Background Guidelines recommend to prescribe a laxative with an opioid to prevent constipation. We aimed to determine the adherence by general practitioners (GPs) to this recommendation and to explore which GP- and patient related factors were associated with it from the perspective of the GP. Methods We conducted an observational study using GPs’ prescription data from the Nivel Primary Care Database combined with a questionnaire asking for reasons of non-adherence. The proportion of first opioid prescriptions prescribed together with a laxative was determined as primary outcome. Possible explanatory factors such as the quality of registration, the level of collaboration with the pharmacy, familiarity with the recommendation and use of a clinical decision support system were explored, as were the self-reported reasons for non-adherence (classified as either GP-related or patient-related). We assessed the association of factors with the primary outcome using univariable multilevel logistic regression analysis. Results The recommendation was measured in 195 general practices. The median proportion of first opioid prescriptions prescribed together with a laxative in these practices was 54% (practice range 18–88%). None of the determinants was consistently associated with the primary outcome. GPs from 211 practices filled out the questionnaire and the most frequently mentioned reason not to prescribe a laxative was that the patient has laxatives in stock, followed by that the patient doesn’t want a laxative; both were patient-related factors. Conclusion There was room for improvement in following the guideline on laxative prescribing in opioid use. A main reason seemed to be that the patient refuses a laxative. Improvement measures should therefore focus on communication between GPs and patients on the relevance of co-using a laxative with opioids. Future studies need to establish the effect of such improvement measures, and determine whether reasons for non-adherence to the guideline changed over time.

BACKGROUND Real-world data from electronic health records (EHRs) represent a wealth of information for studying the benefits and risks of medical treatment. However, they are limited in scope and should be complemented by information from the patient perspective. OBJECTIVE The aim of this study is to develop an innovative research infrastructure that combines information from EHRs with patient experiences reported in questionnaires to monitor the risks and benefits of medical treatment. METHODS We focused on the treatment of overactive bladder (OAB) in general practice as a use case. To develop the Benefit, Risk, and Impact of Medication Monitor (BRIMM) infrastructure, we first performed a requirement analysis. BRIMM’s starting point is routinely recorded general practice EHR data that are sent to the Dutch Nivel Primary Care Database weekly. Patients with OAB were flagged weekly on the basis of diagnoses and prescriptions. They were invited subsequently for participation by their general practitioner (GP), via a trusted third party. Patients received a series of questionnaires on disease status, pharmacological and nonpharmacological treatments, adverse drug reactions, drug adherence, and quality of life. The questionnaires and a dedicated feedback portal were developed in collaboration with a patient association for pelvic-related diseases, Bekkenbodem4All. Participating patients and GPs received feedback. An expert meeting was organized to assess the strengths, weaknesses, opportunities, and threats of the new research infrastructure. RESULTS The BRIMM infrastructure was developed and implemented. In the Nivel Primary Care Database, 2933 patients with OAB from 27 general practices were flagged. GPs selected 1636 (55.78%) patients who were eligible for the study, of whom 295 (18.0% of eligible patients) completed the first questionnaire. A total of 288 (97.6%) patients consented to the linkage of their questionnaire data with their EHR data. According to experts, the strengths of the infrastructure were the linkage of patient-reported outcomes with EHR data, comparison of pharmacological and nonpharmacological treatments, flexibility of the infrastructure, and low registration burden for GPs. Methodological weaknesses, such as susceptibility to bias, patient selection, and low participation rates among GPs and patients, were seen as weaknesses and threats. Opportunities represent usefulness for policy makers and health professionals, conditional approval of medication, data linkage to other data sources, and feedback to patients. CONCLUSIONS The BRIMM research infrastructure has the potential to assess the benefits and safety of (medical) treatment in real-life situations using a unique combination of EHRs and patient-reported outcomes. As patient involvement is an important aspect of the treatment process, generating knowledge from clinical and patient perspectives is valuable for health care providers, patients, and policy makers. The developed methodology can easily be applied to other treatments and health problems. CLINICALTRIAL

ObjectivePart of the funding of Dutch General Practitioners (GPs) care is based on pay-for-performance, including an incentive for appropriate prescribing according to guidelines in national formularies. Aim of this paper is to describe the development of an indicator and an infrastructure based on prescription data from GP Electronic Health Records (EHR), to assess the level of adherence to formularies and the effects of the pay-for-performance scheme, thereby assessing the usefulness of the infrastructure and the indicator.MethodsAdherence to formularies was calculated as the percentage of first prescriptions by the GP for medications that were included in one of the national formularies used by the GP, based on prescription data from EHRs. Adherence scores were collected quarterly for 2018 and 2019 and subsequently sent to health insurance companies for the pay-for-performance scheme. Adherence scores were used to monitor the effect of the pay-for-performance scheme.Results75% (2018) and 83% (2019) of all GP practicesparticipated. Adherence to formularies was around 85% or 95%, depending on the formulary used. Adherence improved significantly, especially for practices that scored lowest in 2018.DiscussionWe found high levels of adherence to national formularies, with small improvements after one year. The infrastructure will be used to further stimulate formulary-based prescribing by implementing more actionable and relevant indicators on adherence scores for GPs.

Inleiding Er zijn aanwijzingen dat gezamenlijke besluitvorming onnodig voorschrijven van antibiotica kan verminderen. De onderzoekers gingen na of in huisartsenpraktijken waar meer gezamenlijke besluitvorming plaatsvindt, minder vaak antibiotica worden voorgeschreven. Methode De onderzoekers maten het niveau van gezamenlijke besluitvorming met een gevalideerde vragenlijst (SDM-Q9). Ze legden deze voor aan patienten die lid waren van het Nivel Consumentenpanel Gezondheidszorg en tevens waren ingeschreven bij een van de vijftien huisartsenpraktijken binnen Nivel Zorgregistraties eerste lijn. Per huisartsenpraktijk bepaalden ze de gemiddelde SDM-score en verzamelden ze gegevens uit de elektronische patientendossiers over alle episodes van hoesten, neusbijholteontsteking of urineweginfectie. Per episode bepaalden ze of er volgens de relevante NHG-Standaarden een indicatie was voor antibiotica en of er een antibioticum was voorgeschreven. Met multilevel logistische regressieanalyses onderzochten ze het verband tussen samen beslissen en het voorschrijven van antibiotica. Resultaten Wanneer er geen duidelijke indicatie was, maar antibiotica konden worden overwogen, kregen patienten tussen 18 en 39 jaar oud minder antibioticavoorschriften in praktijken waar meer gezamenlijke besluitvorming plaatsvond. Voor andere leeftijdsgroepen vonden de onderzoekers dit verband niet. Conclusie Gezamenlijke besluitvorming blijkt gerelateerd te zijn aan voorschrijven van antibiotica en kan wellicht bijdragen aan het terugdringen van antibioticagebruik.

Background: Depression is common among patients with cardiovascular disease and has been associated with both drug non-adherence and increased mortality. Non-adherence can occur because of non-initiation, suboptimal implementation, or non-persistence. We aimed to determine if depression increased the risk of any of these components of non-adherence among older patients prescribed cardiovascular drugs in primary care.Methods: A longitudinal analysis of routine primary care data from the Nivel Primary Care Database was performed using data for 2011-2013. A total of 1512 patients aged >= 60 years diagnosed with depression in 2012 were compared with age-and sex-matched groups with either other psychological diagnoses (N = 1457) or mentally healthy controls (N = 1508), resulting in the inclusion of 4477 patients. Non-adherence was classified as non-initiation, suboptimal implementation, or non-persistence. Regression analyses were performed to determine the association between mental health status and non-initiation, suboptimal implementation, and non-persistence.Results: Mixed-effects logistic regression analyses showed increased odds for suboptimal implementation of beta-blockers among depressed patients (2.18; 95% CI 1.29-3.69). For non-persistence, a clustered Cox regression analysis demonstrated that, compared with controls, there was an increased hazard ratio for depressed patients to discontinue beta-blockers (2.31; 95% CI 1.58-3.37) and calcium antagonists (1.74; 95% CI 1.23-2.46).Conclusions: It is likely that older patients in primary care diagnosed with depression are at increased risk of non-persistence with cardiovascular drug therapy. Because non-adherence is associated with increased cardiovascular mortality, it is important that physicians ensure that older depressed patients persevere with therapy. (c) 2018 Published by Elsevier B.V.

Background: Depression is common among older adults and is typically treated with antidepressants.Objective: To determine the non-adherence rates to antidepressants among older adults in primary care, based on non-initiation, suboptimal implementation or non-persistence.Methods: We selected all patients aged ≥60 years and diagnosed with depression in 2012, from the Netherlands Institute for Health Services Research (NIVEL) Primary Care Database. Non-initiation was defined as no dispensing within 14 days of the first prescription; suboptimal implementation, as fewer than 80% of the days covered by dispensed dosages; and non-persistence, as discontinuation within 294 days after first dispense. First, we determined the antidepressant non-initiation, suboptimal implementation and non-persistence rates. Second, we examined whether comorbidity and chronic drug use were associated with non-adherence by mixed-effects logistic regression (non-initiation or suboptimal implementation as dependent variables) and a clustered Cox regression (time to non-persistence).Results: Non-initiation, suboptimal implementation and non-persistence rates were 13.5%, 15.2% and 37.1%, respectively. As the number of chronically used drugs increased, the odds of suboptimal implementation (odds ratio, 0.89; 95% confidence interval, 0.83-0.95) and of non-persistence (hazard ratio, 0.87; 95% confidence interval, 0.82-0.92) reduced.Conclusions: Non-adherence to antidepressants is high among older patients with depression in primary care settings. Adherence is better when patients are accustomed to taking larger numbers of prescribed drugs, but this only provides partial explanation of the variance. GPs should be aware of the high rates of non-adherence. Emphasizing the importance of adhering to the optimal length of antidepressant therapy might be prudent first steps to improving adherence.

Background Increasing antibiotic resistance is recognized as a major threat to global health and is related to antibiotic prescription rates in primary care. Shared decision-making (SDM), the process in which patients and doctors participate together in making decisions, is argued to possibly promote more appropriate use of antibiotics and reduce prescribing. However, it is unknown whether in practice fewer antibiotics are prescribed where more SDM takes place. Objectives To investigate whether more SDM is related to less antibiotic prescribing and whether this relationship differs between subgroups of patients (male/female and age groups). Patients and methods A questionnaire survey was conducted among 2670 members of the Dutch Health Care Consumer Panel to measure SDM (response rate 45%). Average practice-level SDM scores were calculated for 15 general practices. Data from routine electronic health records of 8192 adult patients of these general practices participating in the Nivel Primary Care Database were used to assess relevant illness episodes (acute cough, acute rhinosinusitis and urinary tract infection), the indication for antibiotics and antibiotic prescriptions. Logistic multilevel regression analyses were performed to investigate the relationship between practice-level SDM and patient-level antibiotic prescriptions. Results In practices where more SDM takes place, general practitioners prescribed fewer antibiotics for adult patients under the age of 40 years in preference-sensitive situations (i.e. situations in which antibiotics could be considered according to clinical guidelines). Conclusions SDM can be a framework to reduce the prescribing of antibiotics and thus to control antibiotic resistance. (aut. ref.)

Background Patient gender as well as doctor gender are known to affect doctor-patient interaction during a medical consultation. It is however not known whether an interaction of gender influences antibiotic prescribing. This study examined GP’s prescribing behavior of antibiotics at the first presentation of patients with sore throat symptoms in primary care. We investigated whether GP gender, patient gender and gender concordance have an effect on the GP’s prescribing behavior of antibiotics in protocolled and non-protocolled diagnoses. Methods We analyzed electronic health record data of 11,285 GP practice consultations in the Netherlands in 2013 extracted from the Nivel Primary Care Database. Our primary outcome was the prescription of antibiotics for throat symptoms. Sore throat symptoms were split up in ‘protocolled diagnoses’ and ‘non-protocolled diagnoses’. The association between gender concordance and antibiotic prescription was estimated with multilevel regression models that controlled for patient age and comorbidity. Results Antibiotic prescription was found to be lower among female GPs (OR 0.88, CI 95% 0.67–1.09; p = .265) and female patients (OR 0.93, 95% 0.84–1.02; p = .142), but observed differences were not statistically significant. The difference in prescription rates by gender concordance were small and not statistically significant in non-protocolled consultations (OR 0.92, OR 95% CI: 0.83–1.01; p = .099), protocolled consultations (OR 1.00, OR 95% CI: 0.68–1.32; p = .996) and all GP practice consultations together (OR 0.92, OR 95% CI: 0.82–1.02; p = .118). Within the female GP group, however, gender concordance was associated with reduced prescribing of antibiotics (OR 0.85, OR 95% CI: 0.72–0.99; p = 0.034). Conclusions In this study, female GPs prescribed antibiotics less often than male GPs, especially in consultation with female patients. This study shows that, in spite of clinical guidelines, gender interaction may influence the prescription of antibiotics with sore throat symptoms.

Purpose Complex medication management in older people with multiple chronic conditions can introduce practice variation in polypharmacy prevalence. This study aimed to determine the inter-practice variation in polypharmacy prevalence and examine how this variation was influenced by patient and practice characteristics. Methods This cohort study included 45,731 patients aged 55 years and older with at least one prescribed medication from 126 general practices that participated in NIVEL Primary Care Database in the Netherlands. Medication dispensing data of the year 2012 were used to determine polypharmacy. Polypharmacy was defined as the chronic and simultaneous use of at least five different medications. Multilevel logistic regression models were constructed to quantify the polypharmacy prevalence variation between practices. Patient characteristics (age, gender, socioeconomic status, number, and type of chronic conditions) and practice characteristics (practice location and practice population) were added to the models. Results After accounting for differences in patient and practice characteristics, polypharmacy rates varied with a factor of 2.4 between practices (from 12.4% to 30.1%) and an overall mean of 19.8%. Age and type of conditions were highly positively associated with polypharmacy, and to a lesser extent a lower socioeconomic status. Conclusions Considerable variation in polypharmacy rates existed between general practices, even after accounting for patient and practice characteristics, which suggests that there is not much agreement concerning medication management in this complex patient group. Initiatives that could reduce inappropriate heterogeneity in medication management can add value to the care delivered to these patients. Copyright © 2016 John Wiley & Sons, Ltd.

Background Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene–environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. Methods Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. Results No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10−8) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10−7). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10−7) and rs4542757 (intronic to DCC, P = 7.31 × 10−7). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10−10; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. Conclusions Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

BackgroundMajor depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.MethodWe performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).ResultsOne single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.ConclusionsDespite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

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Governments have several options to reduce the increasing costs of healthcare, including restrictions for the reimbursement of medicines. Next to the intended effect of reduced costs for medicines, reimbursement restriction can have unintended effects such as patients refraining from their treatment which may lead to health problems and increased use of health care. An example of a reimbursement restriction is the one for proton pump inhibitors (PPIs) that became effective in the Netherlands in January 2012. A major unintended effect of this measure could be the that high-risk patients who start with non-steroidal anti-inflammatory drugs (NSAIDs) or low dose aspirin (aspirin), and who have an increased risk of gastric complications for which they are prescribed PPIs refrain from this PPI treatment. The aim of this study was to evaluate the effect of the reimbursement restriction among high-risk users of NSAIDs or aspirin. Do these patients refrain from their PPI treatment and if so do they have an increased risk of gastric complications? Part of the patients starting with NSAIDs or aspirin have an increased risk of gastric complications due to their age, comorbidities or co-medication. The incidence of PPI use during the two years before the reimbursement restriction (2010 and 2011) and two years after the introduction of the reimbursement restriction was compared for patients on NSAIDs or aspirin with an increased risk of developing gastric complications. Impact of age, sex and social economic status was taken into account. Hospital admissions due to gastric complications were studied over the same period (2010-2013). Data were obtained from a large population-based primary care database and a hospital database. The use of PPIs in patients with an increased risk of gastric complications who started NSAID/aspirin increased from 40% in 2010 to 55% in 2013. No impact was found of age, sex or social economic status. There was no increase in hospital admissions due to gastric complications after the reimbursement restriction. The reimbursement restriction on PPIs was not associated with any detectable unintended effects for patients with an increased risk of gastric complications.

Background Adequate record keeping of medication adverse events in electronic health records systems is important for patient safety. Events that remain unrecorded cannot be communicated from one health professional to another. In the absence of a gold standard, we investigate the variation between Dutch general practices in the extent to which they record medication adverse events. Methods Data were derived from electronic health records (EHR) of Dutch general practices participating in NIVEL Primary Care Database (NIVEL-PCD) in 2014, including 308 general practices with a total practice population of 1,256,049 listed patients. Medication adverse events were defined as recorded ICPC-code A85 (adverse effect medical agent). Between practice variation was studied using multilevel logistic regression analysis corrected for age, gender, number of different medicines prescriptions and number of chronic diseases. Results In 2014 there were 8330 patients with at least one medication adverse event recorded. This corresponds to 6.9 medication adverse events per 1000 patients and is higher for women, elderly, patients with polypharmacy and for patients with comorbidity. Corrected for these patient characteristics the median odds ratio (MOR = 1.92) suggests an almost twofold difference between general practices in recorded medication adverse events. Conclusion Our results suggest that improvement in terms of uniformity in recording medication adverse events is possible, preventing potential damage for patients. We suggest that creating a learning health system by individual practice feedback on the number of recordings of adverse events would help practitioners to improve their recording habits.

Background One perceived barrier to adherence to guidelines is the existence of patient preferences which may conflict with them. We examined whether patient preferences influence the prescription of antibiotics in general practice, and how this affects adherence to guidelines. We hypothesised that preferences play a greater role in prescribing antibiotics if the guideline allows for patient preferences to be taken into account, i.e. if prescribing antibiotics is an option which can be considered rather than a clear guideline recommendation to prescribe or not. We included three guidelines: acute cough, acute rhinosinusitis, and urinary tract infections. Methods Data from the NIVEL Primary Care Database (NIVEL PCD) were used to assess antibiotic indications and prescriptions. These data were combined with a questionnaire among members of NIVEL’s Dutch Health Care Consumer Panel in order to examine patient preferences. According to the NIVEL PCD, 286 of these members contacted their GP in 2015 for acute cough, acute rhinosinusitis or urinary tract infections. A logistic multilevel regression analysis was performed to test our hypothesis. Results Patient preferences do play a role in GPs’ prescribing of antibiotics but only in situations where in accordance with the guideline their use is an option which could be considered (interaction between indication and preference: p = 0.049). If patients ask for antibiotics themselves in such situations, then GPs prescribe antibiotics more often. Conclusions Patient preferences only play a role if the guideline provides room for these preferences to be taken into account. Therefore, our results do not suggest a conflict between applying guideline recommendations and including patient preferences. Further research is recommended to examine whether this conflict exists in other situations. Key messages •Patient preferences do play a role in GPs’ prescribing of antibiotics but only in situations where in accordance with the guideline their use is an option which could be considered. •Our results do not suggest a conflict between applying guideline recommendations and including patient preferences. Research is recommended to examine whether this conflict exists in other situations. (aut. ref.)

Introduction Chlamydia prevalence remains high despite scaled-up control efforts and recurrent infection frequently occurs. Objective We investigated the potential of direct partner treatment for chlamydia related to current practice and attitude of GPs towards partner notification (PN) and partner treatment (PT). Methods Four data-sources were combined: 1) Information on current practice via two short questionnaires at a national GP conference; 2) GPs’ attitudes towards PN/PT were explored in a vignette questionnaire study among GPs in NIVEL Primary Care Database (NIVEL-PCD); 3) Quantitative data on (potential) PT were obtained from prescriptions in electronic patient data of NIVEL-PCD; 4) GP recorded questionnaires related to STI consultations in the sentinel practices of NIVEL-PCD. Results Questionnaires showed that the large majority of GPs (>95%) discuss PN of current and ex-partner(s) with chlamydia-patients. Usually, GPs leave further steps to the patients (83%); partners are rarely treated directly (4%), except when partners are registered in the same practice (16%). In the vignette study, 16-20% of GPs indicated willingness to provide direct PT, depending on patient/partner profile, and 24-45% if possible after patient-initiated PN. Prescription data showed that double dosages of Azithromycin were prescribed in 1-2% of cases. STI consultation data revealed PT in 6/100 cases, via partner prescription or double doses for the index. Conclusions At present, GPs in the Netherlands rarely treat partners of chlamydia cases directly, except for partners registered in the same practice. GPs may be open to options for direct PT, provided there are clear guidelines to arrange this adequately. Key messages: •At present, GPs in the Netherlands rarely treat partners of chlamydia cases directly, except for partners registered in the same practice. •GPs may be open to options for direct PT, provided there are clear guidelines to arrange this legally and practically. (aut. ref.)

BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10(-9)).CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

Ongeveer de helft van alle medicatiegerelateerde acute ziekenhuisopnames is potentieel te voorkomen. Van deze ziekenhuisopnames is 18% het gevolg van symptomen als syncope, vallen en duizeligheid. Deze symptomen zijn geassocieerd met het gebruik van (meerdere) antihypertensiva. Nieuw onderzoek van het Erasmus MC en het Nivel richt zich op de vraag of afbouwen van antihypertensiva bij ouderen het aantal ziekenhuisopnames door vallen en duizeligheid kan voorkomen en daarmee de kwaliteit van leven bij ouderen kan verhogen.

Summary Context The hypothalamic-pituitary-adrenal (HPA) axis is one of the body's main systems that controls response to stress. It acts through the hormone cortisol. While the dysregulation of cortisol has been associated with anxiety disorders, the evidence is inconsistent. Moreover, only a few small studies have assessed this relationship in older adults. Objective To determine whether in adults aged 65 years and over there is a difference in daily cortisol pattern between those with and without an anxiety disorder. Methods The study population comprised 1788 older adults from a population-based cohort. The Munich version of the Composite International Diagnostic Interview was used to diagnose anxiety disorders (generalized anxiety disorder, social phobia, specific phobia, agoraphobia and panic disorder). The cortisol awakening response and total cortisol secretion over the day were calculated from cortisol levels in four saliva samples taken over the course of one day (at awakening, 30 min after awakening, at 1700 h, at bedtime). Results Older adults with an anxiety disorder (n = 145, median duration since first symptoms 41 years) had a lower cortisol awakening response (p = 0.02) than those without such a disorder (n = 1643). This association was most prominent in those with generalized anxiety disorder (p = 0.008), but was not associated with the extent of chronicity of anxiety disorders. Conclusion Older adults from the general population with long-lasting anxiety disorders had a lower cortisol awakening response than those without. This is consistent with the notion that chronic anxiety may result in downregulation of HPA-axis activity. Longitudinal studies are needed to confirm this mechanism.

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values

Anxiety disorder is a common psychiatric problem during late-life, and frequently co-occurs with depression. High comorbidity between anxiety and depression may partly be explained by the definition of the disorders and the assessment of both disorders with one instrument at the same time. The current study investigates the relation of current and past depression with anxiety disorders in the Rotterdam Study, a large population-based cohort study of older adults in the Netherlands (n study population = 5565). DSM-IV anxiety disorder was ascertained with the Munich version of the Composite International Diagnostic Interview. DSM-IV depression was diagnosed with the Schedules for Clinical Assessment of Neuropsychiatry (SCAN) on a different day. Past depression was assessed from general practitioners' records, self-report, and a prior SCAN interview. Of the 457 persons with an anxiety disorder, 11.6% had a comorbid major depression, and another 6.3% had other depressive syndromes. However, 49.3% of persons with an anxiety disorder experienced or had in the past experienced a depressive episode. Our study suggests that comorbid depression in older adults with anxiety disorders may be less prevalent than previously suggested. However, the relation of current anxiety disorders with past depression is substantial. Copyright © 2011 John Wiley & Sons, Ltd.

The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to similar to 0.7% of the variance in depression in Rotterdam Study and up to similar to 1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples. Molecular Psychiatry (2011) 16, 773-783; doi:10.1038/mp.2010.65; published online 22 June 2010

Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors likely contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a novel susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging and animal models suggest a novel pathophysiological mechanism for MD that may be accessible to drug targeting.