High-resolution geospatial mapping of zero-dose and under-immunized children following Nigeria's 2021 multiple indicator cluster survey/national immunization coverage survey (MICS/NICS).

BACKGROUND: The "zero-dose" children are those without any routine vaccination or lacking the first dose of the diphtheria-tetanus-pertussis-containing vaccine. As per 2022 WHO/UNICEF estimates, globally, Nigeria has the highest number of zero-dose with over 2.3 million unvaccinated. METHODS: We used data from the 2021 Nigeria Multiple Indicator Cluster Survey - National Immunisation Coverage Survey to identify zero-dose and under-immunized children. Geospatial modelling techniques were employed to determine the prevalence of zero-dose children and predict risk areas with under-immunized at a high resolution of 1x1 km. RESULTS: Both zero-dose and under-immunized children are more prevalent in socially deprived groups. Univariate and multivariate Bayesian analyses showed positive correlations between the prevalence of zero-dose and under-immunized children with factors like stunting, contraceptive prevalence, and literacy. The prevalence of zero-dose and under-immunized children varies significantly by region and ethnicity, with higher rates observed in the country's northern parts. Significant heterogeneity in the distribution of under-vaccinated children was observed. CONCLUSIONS: Nigeria needs to enhance its immunization system and coverage. Geospatial modelling can help deliver vaccines effectively to underserved communities. By adopting this approach, countries can ensure equitable vaccine access and contribute to global vaccination objectives.

Sex disparities in treatment patterns after metformin initiation among patients with type 2 diabetes mellitus.

PURPOSE: To assess sex differences in treatment patterns after metformin initiation among type 2 diabetes mellitus (T2D) patients. METHODS: A cohort study was conducted using the Groningen Initiative to ANalyze Type 2 diabetes Treatment (GIANTT) primary care database. Patients aged ≥18 years initiating metformin were followed 2-5 years. Markov modeling was conducted to estimate treatment transition rates and calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI) comparing men with women adjusted for age, HbA1c level at initiation, and cardiovascular disease history. Kaplan-Meier analyses and Cox proportional-hazards models were used to determine the time to and likelihood of getting treatment intensification. HbA1c levels at initiation and intensification were compared using Mann-Whitney U tests. RESULTS: In total, 11 508 metformin initiators were included (50.1% women). The most common transition after initiation was a dose increase (probability women 0.52, men 0.59, no significant difference). Women were more likely than men to switch to any other non-insulin hypoglycemic agent after initiation (aHR 1.66; 95% CI 1.31-2.12), after dose increase (aHR 1.48; 95% CI 1.10-1.98) and after dose decrease (aHR 2.64; 95% CI 1.28-5.46). Time to intensification was longer, time to switching was shorter, and HbA1c levels at initiation and intensification were lower for women than men. CONCLUSIONS: Sex disparities were observed in treatment transitions after metformin initiation. Women more often switched treatment than men, which suggest that prescribers acknowledge more tolerance or other problems for metformin in women. Men intensified treatment earlier and at higher HbA1c levels, indicative of a higher need for treatment intensification.

Chronic Use of Hydrochlorothiazide and Risk of Skin Cancer in Caucasian Adults: A PharmLines Initiative Inception Cohort Study.

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.

A systematic literature review and meta-analysis of community pharmacist-led interventions to optimise the use of antibiotics.

AIMS: The aim of this systematic review is to assess the effects of community pharmacist-led interventions to optimise the use of antibiotics and identify which interventions are most effective. METHODS: This review was conducted according to the PRISMA guidelines (PROSPERO: CRD42020188552). PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched for (randomised) controlled trials. Included interventions were required to target antibiotic use, be set in the community pharmacy context, and be pharmacist-led. Primary outcomes were quality of antibiotic supply and adverse effects while secondary outcomes included patient-reported outcomes. Risk of bias was assessed using the 'Cochrane suggested risk of bias criteria' and narrative synthesis of primary outcomes conducted. RESULTS: Seventeen studies were included covering in total 3822 patients (mean age 45.6 years, 61.9% female). Most studies used educational interventions. Three studies reported on primary outcomes, 12 on secondary outcomes and two on both. Three studies reported improvements in quality of dispensing, interventions led to more intensive symptom assessment (up to 30% more advice given) and a reduction of over-the-counter supply up to 53%. Three studies led to higher consumer satisfaction, effects on adherence from nine studies were mixed (risk difference 0.04 [-0.02, 0.10]). All studies had unclear or high risks of bias across at least one domain, with large heterogeneity between studies. CONCLUSIONS: Our review suggests some positive results from pharmacist-led interventions, but the interventions do not seem sufficiently effective as currently implemented. This review should be interpreted as exploratory research, as more high-quality research is needed.

Decomposing the heterogeneity of depression at the person-, symptom-, and time-level: latent variable models versus multimode principal component analysis.

BACKGROUND: Heterogeneity of psychopathological concepts such as depression hampers progress in research and clinical practice. Latent Variable Models (LVMs) have been widely used to reduce this problem by identification of more homogeneous factors or subgroups. However, heterogeneity exists at multiple levels (persons, symptoms, time) and LVMs cannot capture all these levels and their interactions simultaneously, which leads to incomplete models. Our objective is to briefly review the most widely used LVMs in depression research, illustrating their use and incompatibility in real data, and to consider an alternative, statistical approach, namely multimode principal component analysis (MPCA). METHODS: We applied LVMs to data from 147 patients, who filled out the Quick Inventory of Depressive Symptomatology (QIDS) at 9 time points. Compatibility of the results and suitability of the LVMs to capture the heterogeneity of the data were evaluated. Alternatively, MPCA was used to simultaneously decompose depression on the person-, symptom- and time-level and to investigate the interactions between these levels. RESULTS: QIDS-data could be decomposed on the person-level (2 classes), symptom-level (2 factors) and time-level (2 trajectory-classes). However, these results could not be integrated into a single model. Instead, MPCA allowed for decomposition of the data at the person- (3 components), symptom- (2 components) and time-level (2 components) and for the investigation of these components' interactions. CONCLUSIONS: Traditional LVMs have limited use when trying to define an integrated model of depression heterogeneity at the person, symptom and time level. More integrative statistical techniques such as MPCA can be used to address these relatively complex data patterns and could be used in future attempts to identify empirically-based subtypes/phenotypes of depression.

The Association between Deductibles and Cardiovascular Medication Adherence: A Retrospective Inception Cohort Study.

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.

Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation.

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.

Comparative effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events-a real-world longitudinal inception cohort study.

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

Risk factors for drug-treated major adverse cardio-cerebrovascular events in patients on primary preventive statin therapy: A retrospective cohort study.

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.

Association between Incidence of Prescriptions for Alzheimer's Disease and Beta-Adrenoceptor Antagonists: A Prescription Sequence Symmetry Analysis.

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.

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis.

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.

Community Use of Repurposed Drugs Before and During COVID-19 Pandemic in the Netherlands: An Interrupted Time-Series Analysis.

Background: Repurposing registered drugs could reduce coronavirus disease (COVID-19) burden before novel drugs are authorized. Little is known about how the pandemic and imposed restrictions changed their dispensing. We aimed to investigate the impact of COVID-19 pandemic on repurposed drugs dispensing in the Netherlands. Methods: We performed interrupted time-series study using University of Groningen prescription database IADB.nl to evaluate dispensing trends of 24 repurposed drugs before (2017-February 2020) and after (March 2020-2021) the pandemic' start. Primary outcomes were monthly prevalence and incidence rates. An autoregressive integrated moving average model assessed the effect of pandemic and stringency index (measuring strictness of government's restriction policies). Results: Annual number of IADB.nl population ranged from 919,697 to 952,400. Generally, dispensing of common long-term-used drugs was not significantly affected by pandemic. The prevalence of antibacterials (-4.20 users per 1000 people), antivirals (-0.04), corticosteroids (-1.29), prednisolone (-1.32), calcium channel blocker (-0.41), and diuretics (-1.29) was lower than expected after the pandemic's start, while the prevalence of ivermectin (0.07), sulfonylureas (0.15), sodium-glucose co-transporter-2 (SGLT2) inhibitor (0.17), and anticoagulants (1.95) was higher than expected. The pandemic was associated with statistically significant decreases in the incidence of antibacterials (-1.21), corticosteroids (-0.60), prednisolone (-0.64) and anticoagulants (-0.02), and increases in ivermectin (0.02), aggregated antidiabetic drugs (0.13), and SGLT2 inhibitors (0.06). These trends were positively associated with pandemic and negatively associated with stringency index. Conclusion: Dispensing of most drugs was not significantly associated with pandemic and government's response. Despite some statistically significant disruptions, these were not necessarily clinically relevant due to small absolute differences observed.

Role of Traditional Cardiovascular Risk Factors after Initiation of Statin Therapy: A PharmLines Inception Cohort Study.

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.

Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer's Disease: A Retrospective Inception Cohort Study.

BACKGROUND: Animal studies suggested that ß2-Adrenergic receptors (ß2AR) may be a potential target for the treatment of Alzheimer's disease (AD). OBJECTIVE: This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the ß2AR and the risk of starting treatment for AD in older adults. METHODS: A retrospective inception cohort study was conducted among older adults who initiated either non-selective ßAR antagonists or selective ß2AR agonists using the University Groningen IADB.nl prescription database (study period 1994-2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR). RESULTS: The risk of developing AD was elevated among patients exposed to non-selective ßAR antagonists (A: aHR 3.303, 95% CI 1.230-8.869, B: aHR 1.569, 95% CI 0.560-4.394) and reduced among patients exposed to selective ß2AR agonists (A: aHR 0.049, 95% CI 0.003-0.795, B: aHR 0.834, 95% CI 0.075-9.273) compared to reference patients. CONCLUSION: These findings suggest that exposure to non-selective ßAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective ß2AR agonists.

Antidepressant use during pregnancy and development of preeclampsia: A focus on classes of action and specific transporters/receptors targeted by antidepressants.

OBJECTIVE: The association between antidepressants and preeclampsia has been inconsistently reported. Given the compound-specific variable affinity for different transporters/receptors, their effect on preeclampsia risk could differ. Our study examined the risk of preeclampsia (and its subtypes) following exposure to different classes of antidepressants, also accounting for specific transporters/receptors targeted by antidepressants. METHODS: We conducted a cohort study, combining data from the Netherlands Perinatal Registry and the PHARMO Database Network. Exposure to antidepressants was examined from conception to week 20 of gestation; extended use thereafter was also studied. Antidepressants were categorized according to classes [selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressants] and according to target transporters/receptors. Women not using any antidepressants during 15 months before delivery were included as reference. RESULTS: We included 2,103 exposed and 95,376 reference women. Preeclampsia occurred in 70 exposed women (15 early-onset, 55 late-onset) and in 2,582 reference women (387 early-onset, 2,195 late-onset). TCA monotherapy (214 women) was associated with an increased risk of preeclampsia (n = 15, RR 2.46, 95% CI 1.51-4.02) and late-onset preeclampsia (n = 12, RR 2.41, 95% CI 1.39-4.17, early-onset could not be evaluated). No association was detected with SSRIs, SNRIs and MAOIs. We did observe an increased risk of early-onset preeclampsia following exposure to 5-HT2A antagonizing antidepressants (6/405 women, excluding TCA users, RR 3.56, 95% CI 1.60-7.94). CONCLUSIONS: Our results support an increased risk of preeclampsia and the late-onset subtype among TCA users. The association between 5-HT2A antagonists and the early-onset subtype needs to be interpreted with caution based on the relatively small number of exposed cases.

Sex disparities in the effect of statins on lipid parameters: The PharmLines Initiative.

ABSTRACT: Real-world evidence on a potential statin effect modification by sex is inconclusive, especially for the primary prevention of cardiovascular disease (CVD). We aimed to quantify the differences in the effect of statins on lipid parameters between men and women.The PharmLines Initiative linked the Lifelines Cohort Study and the IADB.nl prescription database. This database covers a representative population from the Netherlands. We selected participants aged ≥40 years at the index date: the date of the first prescription of any statin monotherapy in the study period 2006 to 2017. Multivariate regression modeling was used to compare the difference of the mean percentage change of lipid parameters (% mean difference [MD]) from baseline to follow-up measurement between the sexes.Out of 5366 statin users from approximately 50,000 participants available in the final linked database, 685 were statin initiators. At baseline, women had significantly higher levels of mean total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) than men (all P values <.01). At follow-up, women had a significantly higher mean percentage change of HDL-C compared to men (adjusted % MD 5.59, 95% confidence interval [CI] 2.42-8.75, P < .01). There was no significant sex difference in other parameters, nor in the proportion of men and women who achieved LDL-C ≤2.5 mmol/L.Statins appear to have a greater effect on increasing HDL-C levels in women than men while showing similar effect on other lipid parameters in both sexes. Men should not be treated differently than women.

Association between adherence to statin therapy and low-density lipoprotein cholesterol (LDL-c) response in first-time users of standard-dose and low-dose statins: the PharmLines initiative.

OBJECTIVE: To investigate whether statin adherence (defined as proportion days covered, PDC) is associated with LDL-c response in statin initiators on standard and low starting doses of statins, and to detect a possible interaction with sex. METHODS: An inception cohort study was conducted using the PharmLines Initiative, a linkage between the Lifelines Cohort Study and the University of Groningen's IADB.nl (prescription database). First-time statin users were followed from baseline to follow-up measurement. We matched participants (1:1) between the standard-dose and the low-dose group of statin users on the duration of follow-up. Multiple linear regression analysis was used to model the association. RESULTS: In univariate analysis, PDC was significantly associated with LDL-c response similarly (slope = -0.021), in both the standard-dose group (N = 115, p < .001) and the low-dose group (N = 115, p = .003). In the standard-dose group, the same level of PDC appeared to be significantly associated with a greater LDL-c level reduction in women (slope = -0.027, N = 48, p < .001) than in men (slope = -0.017, N = 67, p < .001). Meanwhile, in the low-dose group, the reduction of LDL-c level from baseline seemed to be greater in men (slope = -0.023, N = 56, p < .001) than in women (slope = -0.020, N = 59, p < .001) for the same level of PDC. In multiple regression analysis, the significant association between PDC and LDL-c with a similar pattern to the univariate result was maintained only in the standard-dose group. CONCLUSIONS: Adherence is significantly associated with LDL-c response to statins at follow-up. Sex appears to significantly modify this association. At a similar adherence level, women seem to experience a better LDL-c response to standard-dose statins compared to men in a real-world setting.

A Transdiagnostic Network Approach to Psychosis.

Our ability to accurately predict development and outcome of early expression of psychosis is limited. To elucidate the mechanisms underlying psychopathology, a broader, transdiagnostic approach that acknowledges the complexity of mental illness is required. The upcoming network paradigm may be fruitful here. In this study, we applied a transdiagnostic network approach to psychosis. Data pertain to the third wave (second follow-up) of a sample of adolescents originally recruited at age 7-8 years. At baseline, N = 347 children with auditory verbal hallucinations (AVH) and N = 347 control children were included. N = 293 of these N = 694 children participated in the second follow-up (mean age 18.9 years; 59% women). Participants completed the Community Assessment of Psychic Experiences (CAPE) and the Depression, Anxiety and Stress Scale (DASS-21). A specific type of network model, the Ising model, was applied to dichotomized CAPE and DASS items. Interconnections of experiences within the same domain were observed, as well as interconnections between experiences of multiple domains of psychopathology. Quantitative and qualitative differences in network architecture were found in networks of psychopathological experiences in individuals with or without AVH at age 7-8 years. Although adolescents with or without previous AVH did not differ in their current CAPE scores, differences in the interconnectedness of psychopathology items were still found, possibly mirroring a difference in psychosis liability. This study showed that it is possible to map transdiagnostic experiences of psychopathology as a network and that important information can be derived from this approach in comparison to regular approaches.