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Background: Relevant safety signals in the EU are regularly communicated in so-called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases.Objective: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands.Methods: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists.Results: For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings.Conclusions: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications. [ABSTRACT FROM AUTHOR]

Objective: Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives.Research Design and Methods: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant.Results: Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88-0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives.Conclusions: In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Isotretinoin is very effective in the treatment of severe acne. However, because of the teratogenic properties of this agent an isotretinoin Pregnancy Prevention Programme (PPP) was implemented in the Netherlands to guarantee that treatment is contraindicated in women of reproductive age unless at least one effective method of contraception is used. Furthermore, the PPP stipulates that isotretinoin treatment should be managed by physicians or specialists experienced in treatment with this drug and that only monthly prescriptions are issued.Objective: To assess compliance with the Dutch isotretinoin PPP in women of reproductive age during the study period of 1 January 2005 to 31 December 2008.Methods: Detailed information on dispensed medication and co-medication was available from the Dutch Foundation of Pharmaceutical Statistics. Four types of outcome were studied: concomitant dispensing of hormonal contraceptive with isotretinoin; the proportion of specialist prescribing of isotretinoin; prescribing of conventional acne therapy prior to isotretinoin initiation; and isotretinoin dispensing exceeding the maximum amount. The use of contraceptives in women aged between 15 and 45 years was defined as concomitant if the period of systemic contraceptive use overlapped the period of isotretinoin dispensing for at least 10 days, or if any dispensing of an intrauterine or intravaginal contraceptive was recorded since the year 2000. Dispensings were separated into those prescribed by either specialists or general practitioners (GPs). The use of antibacterials, antiandrogens or topical agents against acne was checked 4 months prior to an isotretinoin dispensing, and a possible excess of the maximum amount of isotretinoin was defined as prescriptions of more than 100 defined daily doses.Results: During the study period, data were available for 442 Dutch pharmacies encompassing 4881 women of reproductive age using isotretinoin at least once during study period. Among women of reproductive age, the use of isotretinoin increased during the study period. The proportion of isotretinoin initiation with concomitant oral hormonal or intrauterine contraceptives was low (59.3% [95% CI 57.6, 61.0]). Initiation of isotretinoin by a specialist increased the chance for concomitant contraception by 26% (95% CI 6.0, 49.0); in 78.2% (95% CI 76.8, 79.6) of women, isotretinoin was initiated by a specialist. Conventional acne therapy up to 16 months prior to isotretinoin initiation was found in 70% of the women (70.3% [95% CI 66.0, 74.6]). In 1.4% (95% CI 1.0, 1.8) of cases of treatment initiation, the amount of isotretinoin dispensed on one prescription seemed too high.Conclusion: Attention should be paid to improving the implementation of the isotretinoin PPP. Despite clear guidelines and warnings in the product information, our study strongly suggests that concomitant use of isotretinoin and contraceptives is too low. Even though we will have missed non-pharmacological forms of contraception, these results raise doubts about the safe use of isotretinoin in women of reproductive age in the Netherlands. Furthermore, isotretinoin does not seem to be used in cases of severe acne only. Reserving isotretinoin prescribing to specialists may improve adherence to the PPP. [ABSTRACT FROM AUTHOR]

BACKGROUND: Drug-drug interactions (DDIs) are responsible for a variety of adverse reactions, particularly in an elderly population. OBJECTIVE: To assess the frequency and potential clinical relevance of DDIs in a population aged >/=55 years. METHODS: Exposure to DDIs was assessed in 7842 people participating in the Rotterdam Study, a population-based cohort study. These people were followed between 1 January 1992 and 1 July 2005. The DDI list of the Royal Dutch Association for the Advancement of Pharmacy, in which DDIs are categorized by potential clinical relevance and quality of evidence, was used. Simultaneous use of interacting drug combinations was calculated on the basis of drug dispensing data from community pharmacies. RESULTS: The incidence of a first dispensing of DDIs in the study period was 10.5 per 100 person-years and 2.7 per 100 person-years for potentially life-threatening DDIs. The prevalence of DDIs in people aged >/=70 years increased from 10.5% in 1992 to 19.2% in 2005. Ten DDIs comprised two-thirds of the total exposure time to DDIs. The prevalence of potentially life-threatening DDIs in people aged >/=70 years increased from 1.5% to 2.9%. This increase was most likely caused by an increase in use of spironolactone combined with renin-angiotensin-aldosterone system inhibitors. CONCLUSION: A large number of people in the Netherlands aged >/=55 years are exposed to DDIs and this number has increased sharply between 1992 and 2005. Healthcare professionals should pay special attention to the potential risks of DDIs in these people, particularly if spironolactone is involved. [ABSTRACT FROM AUTHOR]

Abstract Background Alcohol use among adolescents has become a major public health problem in the past decade and has large short- and long-term consequences on their health. The aim of this systematic review was to provide an overview of longitudinal cohort studies that have analyzed the association between the parent–child relationship (PCR) and change in alcohol use during adolescence. Methods A search of the literature from 1985 to July 2011 was conducted in Medline, PsycINFO, and EMBASE in order to identify longitudinal, general population studies regarding the influence of the PCR on alcohol use during adolescence. The studies were screened, and the quality of the relevant studies was assessed. A best-evidence synthesis was used to summarize the results. Results Twenty-eight relevant studies were identified. Five studies found that a negative PCR was associated with higher levels of alcohol use. Another seven papers only found this association for certain subgroups such as boys or girls, or a specific age group. The remaining sixteen studies did not find any association. Conclusions We found weak evidence for a prospective association between the PCR and adolescent alcohol use. Further research to the association of the PCR with several types of alcohol use (e.g., initiation or abuse) and to the potential reversed causality of the PCR and alcohol use is required.

Abstract Background Intravenous (IV) artesunate is the treatment of choice for severe malaria. In Europe, however, no GMP-manufactured product is available and treatment data in European travellers are scarce. Fortunately, artesunate became available in the Netherlands and Belgium through a named patient programme. This is the largest case series of artesunate treated patients with severe malaria in Europe. Methods Hospitalized patients treated with IV artesunate between November 2007 and December 2010 in the Netherlands and Belgium were retrospectively evaluated. Patient characteristics, treatment and clinical outcome were recorded on a standardized form and mortality, parasite clearance times and the occurrence of adverse events were evaluated. Results Of the 68 treated patients, including 55 with severe malaria, two patients died (2/55 = 3.6%). The mean time to 50% parasite clearance (PCT50), 90% and 99% were 4.4 hours (3.9 - 5.2), 14.8 hours (13.0 - 17.2), and 29.5 hours (25.9 - 34.4) respectively. Artesunate was well tolerated. However, an unusual form of haemolytic anaemia was observed in seven patients. The relationship with artesunate remains uncertain. Conclusions Data from the named patient programme demonstrate that IV artesunate is effective and well-tolerated in European travellers lacking immunity. However, increased attention needs to be paid to the possible development of haemolytic anaemia 2-3 weeks after start of treatment. Treatment of IV artesunate should be limited to the period that IV treatment is required and should be followed by a full oral course of an appropriate anti-malarial drug.

Abstract Background Limited data exist documenting the degree to which travelers are inconvenienced by travelers' diarrhea (TD). We performed a prospective follow-up study at the travel clinic of Leiden University Medical Center in The Netherlands to determine the degree of inconvenience and to determine how experiencing TD affects travelers' perception. Methods Healthy adults who intended to travel to the (sub)tropics for less than two months were invited to take part. Participants filled out a web-based questionnaire before departure and after returning home. TD was defined as three or more unformed stools during a 24-hour period. Results 390 of 776 Eligible travelers completed both questionnaires. Participants' median age was 31 years and mean travel duration 23 days. Of 160 travelers who contracted TD (incidence proportion 41%, median duration of TD episode 2.5 days) the majority (107/160, 67%) could conduct their activity program as planned despite having diarrhea. However, 21% (33/160) were forced to alter their program and an additional 13% (20/160) were confined to their accommodation for one or more daylight days; 53 travelers (33%) used loperamide and 14 (9%) an antibiotic. Eight travelers (5%) consulted a physician for the diarrheal illness. When asked about the degree of inconvenience brought on by the diarrheal illness, 39% categorized it as minor or none at all, 34% as moderate and 27% as large or severe. In those who regarded the episode of TD a major inconvenience, severity of symptoms was greater and use of treatment and necessity to alter the activity program were more common. Travelers who contracted travelers' diarrhea considered it less of a problem in retrospect than they had thought it would be before departure. Conclusion Conventional definitions of TD encompass many mild cases of TD (in our study at least a third of all cases) for which treatment is unlikely to provide a significant health benefit. By measuring the degree of inconvenience brought on by TD, researchers and policy makers may be able to better distinguish 'significant TD' from mild TD, thus allowing for a more precise estimation of the size of the target population for vaccination or stand-by antibiotic prescription and of the benefit of such measures.

Abstract Background Clinical and research electives abroad offer medical students many unique experiences. However, participating in an unfamiliar health-care setting combined with limited medical experience may place students at risk of illness. To improve pre-and post-travel care, we assessed the health risks and the quality and comprehensiveness of pre-and post-travel care in a cohort of Dutch medical students returning form an elective abroad. Methods All medical students who had performed an elective in the tropics between July 2006 and December 2008 were sent an informative email asking them to complete a web-based questionnaire. Results 180 of 242 (74%) students completed the questionnaire. Regarding the risk of bloodborne viral infection: 67% of all students and 32% of junior students engaged in procedures that constitute a risk of exposure to bloodborne viral infection, often in countries with high HIV prevalence rates. None of nine students who experienced possible or certain mucosal or percutaneous exposure to potentially infectious body fluids reported the exposure at the time it occurred and none used PEP. Regarding other health risks: 8 of 40 (20%) students stopped using mefloquine due to adverse effects. This left a sizeable proportion unprotected in countries that are hyperendemic for malaria. Post-travel screening for schistosomiasis, tuberculosis (tuberculin skin test) and carriage of methicillin-resistant Staphylococcus aureus (MRSA) encompassed approximately half of all students who should have been screened. Conclusions Based on the results of this study we have adopted an integral set of measures to reduce the health risks associated with an elective abroad. The pre and post-travel consult has been centralized and standardized as well as the distribution of PEP. In addition we have developed a mandatory module on Global Health for all medical students planning an elective abroad.

Abstract Background To describe the epidemiology and trends of imported malaria in the Netherlands from 2000 through 2007. Methods Based on national surveillance data regarding all reported infections of imported malaria, diagnosed 2000 through 2007, incidence and trends of imported malaria in the Netherlands were estimated. Travellers statistics were used to estimate incidence, and data on malaria chemoprophylaxis prescriptions were used to estimate the number of unprotected travellers. Results Importation of malaria to the Netherlands is declining even as more travellers visit malaria-endemic countries. On average, 82% were acquired in sub-Saharan Africa, and 75% were caused by Plasmodium falciparum. The overall incidence in imported falciparum malaria fell from 21.5 to 6.6/10,000 of unprotected travellers. The percentage of unprotected travellers rose from 47% to 52% of all travellers. The incidence of imported falciparum infections is greatest from Middle and West Africa, and decreased from 121.3 to 36.5/10,000 travellers. The import of malaria from this region by immigrants visiting friends and relatives (VFR) decreased from 138 infections in 2000, to 69 infections in 2007. Conclusion The annual number of imported malaria shows a continuing declining trend, even with an increasing number of travellers visiting malaria endemic countries. VFR import less malaria than previously, and contribute largely to the declining incidence seen. The decline is not readily explained by increased use of chemoprophylaxis and may reflect a reduced risk of infection due to decreasing local malaria transmission as observed in some malaria endemic areas. Nevertheless, the increasing number of unprotected travellers remains worrisome.

Abstract Background The presence of ongoing local malaria transmission, identified though local surveillance and reported to regional WHO offices, by S-E Asian countries, forms the basis of national and international chemoprophylaxis recommendations in western countries. The study was designed to examine whether the strategy of using malaria transmission in a local population was an accurate estimate of the malaria threat faced by travellers and a correlate of malaria in returning travellers. Methods Malaria endemicity was described from distribution and intensity in the local populations of ten S-E Asian destination countries over the period 2003-2008 from regionally reported cases to WHO offices. Travel acquired malaria was collated from malaria surveillance reports from the USA and 12 European countries over the same period. The numbers of travellers visiting the destination countries was based on immigration and tourism statistics collected on entry of tourists to the destination countries. Results In the destination countries, mean malaria rates in endemic countries ranged between 0.01 in Korea to 4:1000 population per year in Lao PDR, with higher regional rates in a number of countries. Malaria cases imported into the 13 countries declined by 47% from 140 cases in 2003 to 66 in 2008. A total of 608 cases (27.3% Plasmodium falciparum (Pf)) were reported over the six years, the largest number acquired in Indonesia, Thailand and Korea. Four countries had an incidence > 1 case per 100,000 traveller visits; Burma (Myanmar), Indonesia, Cambodia and Laos (range 1 to 11.8-case per 100,000 visits). The remaining six countries rates were < 1 case per 100,000 visits. The number of visitors arriving from source countries increased by 60% from 8.5 Million to 13.6 million over the 6 years. Conclusion The intensity of malaria transmission particularly sub-national activity did not correlate with the risk of travellers acquiring malaria in the large numbers of arriving visitors. It is proposed to use a threshold incidence of > 1 case per 100,000 visits to consider targeted malaria prophylaxis recommendations to minimize use of chemoprophylaxis for low risk exposure during visits to S-E Asia. Policy needs to be adjusted regularly to reflect the changing risk.

Abstract Background Falciparum malaria remains a major occupational illness that accounts for several deaths per year and numerous lost working days among the expatriate population, working or living in high-risk malarious areas. Compliance to preventive strategies is poor in travellers, especially business travellers, expatriates and long-term travellers. Methods In this cross-sectional, web-based study the adherence to and outcome of a preventive malaria programme on knowledge, attitudes and practices, including the practice of self-diagnosis and standby treatment (curative malaria kit, CMK) was evaluated in 2,350 non-immune expatriates, who had been working in highly malaria endemic areas. Results One-third (N = 648) of these expatriates visited a doctor for malaria symptoms and almost half (29 of 68) of all hospitalizations were due to malaria. The mandatory malaria training for non-immunes was completed by 92% of those who visited or worked in a high risk malaria country; 70% of the respondents at risk also received the CMK. The malaria awareness training and CMK significantly increased malaria knowledge [relative risk (RR) of 1.5, 95%CI 1.2–2.1], attitudes and practices, including compliance to chemoprophylaxis [RR = 2.2, 95%CI 1.6–3.2]. Hospitalization for malaria tended to be reduced by the programme [RR = 0.4, 95%CI 0.1–1.1], albeit not significantly. Respondents who did not receive instructions on the rapid diagnostic test were two times [RR = 2.3, 95%CI 1.6–3.3] more likely to have difficulties. Those who did receive instructions adhered poorly to the timing of repeating the test. Moreover, 6% (31 of 513) of those with a negative test result were diagnosed with malaria by a local doctor. 77% (N = 393) of the respondents with a negative test result did not take curative medication. 57% (252 of 441) of the respondents who took the curative medication that was included in the kit did not have a positive self-test or clinical malaria diagnosis made by a doctor. Conclusion This survey demonstrated that a comprehensive programme targeting malaria prevention in expatriates can be effectively implemented and that it significantly increased malaria awareness.

Abstract A comparison was made between local malaria transmission and malaria imported by travellers to identify the utility of national and regional annual parasite index (API) in predicting malaria risk and its value in generating recommendations on malaria prophylaxis for travellers. Regional malaria transmission data was correlated with malaria acquired in Latin America and imported into the USA and nine European countries. Between 2000 and 2004, most countries reported declining malaria transmission. Highest API's in 2003/4 were in Surinam (287.4) Guyana (209.2) and French Guiana (147.4). The major source of travel associated malaria was Honduras, French Guiana, Guatemala, Mexico and Ecuador. During 2004 there were 6.3 million visits from the ten study countries and in 2005, 209 cases of malaria of which 22 (11%) were Plasmodium falciparum. The risk of adverse events are high and the benefit of avoided benign vivax malaria is very low under current policy, which may be causing more harm than benefit.

Purpose: The objective was to develop and evaluate the portability of a text mining algorithm for prospectively capturing disease progression in electronic health record (EHR) data of patients with metastatic non-small cell lung cancer (mNSCLC) treated with immunochemotherapy., Methods: This study used EHR data from patients with mNSCLC receiving immunochemotherapy (between October 1, 2018, and December 31, 2022) in four Dutch hospitals. A text mining algorithm for capturing disease progression was developed in hospitals 1 and 2 and then transferred to hospitals 3 and 4 to evaluate portability. Performance metrics were calculated by comparing its outcomes with manual chart review. In addition, data were simulated to come available over time to assess performance in real-time applications. Median progression-free survival (PFS) was calculated using the Kaplan-Meier method to compare text mining with manual chart review., Results: During development and portability, the text mining algorithm performed well in capturing disease progression, with all performance scores >90%. When real-time performance was simulated, the performance scores in all four hospitals exceeded 90% from week 15 after the start of follow-up. Although the exact progression dates varied in 46 patients of 157 patients with progressive disease, the number of patients labeled with progression too early (n = 24) and too late (n = 22) was well balanced with discrepancies ranging from -116 to 384 days. Nevertheless, the PFS curves constructed with text mining and manual chart review were highly similar for each hospital., Conclusion: In this study, an accurate text mining algorithm for capturing disease progression in the EHR data of patients with mNSCLC was developed. The algorithm was portable across different hospitals, and the performance over time was good, making this an interesting approach for prospective follow-up of multicenter cohorts.

Background: Hyponatremia is a common electrolyte disturbance and known adverse drug reaction of diuretics. Women tend to be more susceptible for diuretic associated hyponatremia. The aim of this study was to find more evidence whether women have a higher risk of diuretic associated hyponatremia than men measured at hospital admission for specific diuretic groups and whether there is a sex difference in risk of severity of hyponatremia., Methods: All patients using a diuretic and admitted for any reason to Tergooi MC and Haga Teaching hospital in the Netherlands between the 1st of January 2017 and the 31st of December 2021, with recorded sodium levels at admission were included in this study. Cases were defined as patients with a sodium level <135 mmol/L, while control patients had a sodium level ≥135 mmol/L at admission. Logistic regression analysis was used to calculate odds ratios (OR) with 95% CIs for women versus men and adjusted for potential confounding covariables (age, body mass index, potassium serum level, systolic and diastolic blood pressure, estimated glomerular filtration rate, number of diuretics, comedications and comorbidities). Stratified analyses were conducted for specific diuretic groups (thiazides, loop diuretics and aldosterone antagonists), and adjusted for dose. Furthermore, stratified analyses were performed by severity of hyponatremia (severe: <125 mmol/L), mild: 125-134 mmol/L)., Results: A total of 2,506 patients (50.0% women) were included, of which 516 had hyponatremia at admission (20.6%, 56.2% women). Women had a statistically significantly higher risk for hyponatremia at admission than men (OR 1.37; 95% CI 1.12-1.66) and after adjustment for potential risk factors (ORadj 1.55; 95% CI 1.22-1.98). Stratified analyses showed increased odds ratios for thiazides (ORadj 1.35; 95% CI 1.00-1.83) and loop diuretics (ORadj 1.62; 95% CI 1.19-2.19) among women. Use of aldosterone antagonists was also increased but not statistically significant (ORadj 1.15; 95% CI 0.73-1.81). Women had a statistically higher risk to develop mild and severe hyponatremia than men (ORadj 1.36; 95% CI 1.10-1.68 and ORadj 1.96; 95%CI 1.04-3.68, respectively)., Conclusion: Women have a higher risk of a hospital admission associated with hyponatremia while using diuretics than men. Further research is necessary to provide sex-specific recommendations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hendriksen, Mouissie, Herings, van der Linden and Visser.)

Background: The COVID-19 pandemic underscored the criticality and complexity of decision making for novel treatment approval and further research. Our study aims to assess potential decision-making methodologies, an evaluation vital for refining future public health crisis responses., Methods: We compared 4 decision-making approaches to drug approval and research: the Food and Drug Administration's policy decisions, cumulative meta-analysis, a prospective value-of-information (VOI) approach (using information available at the time of decision), and a reference standard (retrospective VOI analysis using information available in hindsight). Possible decisions were to reject, accept, provide emergency use authorization, or allow access to new therapies only in research settings. We used monoclonal antibodies provided to hospitalized COVID-19 patients as a case study, examining the evidence from September 2020 to December 2021 and focusing on each method's capacity to optimize health outcomes and resource allocation., Results: Our findings indicate a notable discrepancy between policy decisions and the reference standard retrospective VOI approach with expected losses up to $269 billion USD, suggesting suboptimal resource use during the wait for emergency use authorization. Relying solely on cumulative meta-analysis for decision making results in the largest expected loss, while the policy approach showed a loss up to $16 billion and the prospective VOI approach presented the least loss (up to $2 billion)., Conclusion: Our research suggests that incorporating VOI analysis may be particularly useful for research prioritization and treatment implementation decisions during pandemics. While the prospective VOI approach was favored in this case study, further studies should validate the ideal decision-making method across various contexts. This study's findings not only enhance our understanding of decision-making strategies during a health crisis but also provide a potential framework for future pandemic responses., Highlights: This study reviews discrepancies between a reference standard (retrospective VOI, using hindsight information) and 3 conceivable real-time approaches to research-treatment decisions during a pandemic, suggesting suboptimal use of resources.Of all prospective decision-making approaches considered, VOI closely mirrored the reference standard, yielding the least expected value loss across our study timeline.This study illustrates the possible benefit of VOI results and the need for evidence accumulation accompanied by modeling in health technology assessment for emerging therapies., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Dijk reports grants from the Gordon and Betty Moore Foundation during the conduct of the study and grants from the German Innovation Fund outside the submitted work. Dr. Krijkamp reports grants and personal fees from the Society for Medical Decision Making fellowship through a grant from the Gordon and Betty Moore Foundation (GBMF7853) outside the submitted work. Dr. Kunst has nothing to disclose. Dr. Gross reports grants from the American Cancer Society, Johnson & Johnson, Pfizer, Flatiron Health, and Genentech outside the submitted work. Dr. Labrecque is supported by an NWO/ZonMW Veni grant (09150162010213). Mrs. Pandit has nothing to disclose. Ms. Lu has nothing to disclose. Dr. Visser has nothing to disclose. Dr. Wong has nothing to disclose. Dr. Hunink reports grants from the Gordon and Betty Moore Foundation during the conduct of the study; other support from the European Society of Radiology, the European Institute for Biomedical Imaging Research, and Cambridge University Press; grants from the American Diabetes Association, the Netherlands Organization for Health Research and Development, the German Innovation Fund, and the Netherlands Educational Grant (“Studie Voorschot Middelen”) outside the submitted work. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the Gordon and Betty Moore Foundation through grant GBMF9634 to Johns Hopkins University to support the work of the Society for Medical Decision Making COVID-19 Decision Modeling Initiative. The funding sources played no role in the writing or submission of this article. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report.

Introduction: Polypharmacy is common in older adults with cancer and is associated with drug related problems (DRPs) and potentially inappropriate medication (PIM). We introduced a medication optimization care pathway for older adults with advanced cancer and a limited life expectancy and studied the prevalence of DRPs and PIMs as well as the adherence to medication-related recommendations and the patient satisfaction., Materials and Methods: A medication review was performed in patients aged ≥65 years with polypharmacy and a life expectancy of <24 months. Recommendations on adjustments of medication were discussed in a multidisciplinary team including a pharmacist, an oncologist, and a geriatrician. Implementation of the recommendations was left to the discretion of the oncologist. Four weeks after the implementation, the patient filled a questionnaire to assess satisfaction., Results: One hundred twenty patients were included. The mean age was 75 years and 39% were female. A mean of 12 medications was used. The median number of DRP was 6.0 per patient and median number of PIMs was 3.0 per patient. Overtreatment accounted for 26% of DRP and the most frequently involved drug classes were antihypertensive medication (22%), non-opioid analgesics (22%), and antilipemics (12%). The multidisciplinary team accepted 78% of the recommendations of the pharmacist and the oncologist implemented 54% of the recommendations. Overall, patients were satisfied or very satisfied with the intervention., Discussion: DRPs and PIMs are highly prevalent in this population and can be reduced by a multidisciplinary medication optimization intervention. Patients appreciate the medication optimization intervention and are satisfied with the intervention., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Remdesivir is a registered treatment for hospitalised patients with COVID-19 that has moderate clinical effectiveness. Anecdotally, some patients' respiratory insufficiency seemed to recover particularly rapidly after initiation of remdesivir. In this study, we investigated if this rapid improvement was caused by remdesivir, and which patient characteristics might predict a rapid clinical improvement in response to remdesivir., Methods: This was a multicentre observational cohort study of hospitalised patients with COVID-19 who required supplemental oxygen and were treated with dexamethasone. Rapid clinical improvement in response to treatment was defined by a reduction of at least 1 L of supplemental oxygen per minute or discharge from the hospital within 72 h after admission. Inverse probability of treatment-weighted logistic regression modelling was used to assess the association between remdesivir and rapid clinical improvement. Secondary endpoints included in-hospital mortality, ICU admission rate and hospitalisation duration., Results: Of 871 patients included, 445 were treated with remdesivir. There was no influence of remdesivir on the occurrence of rapid clinical improvement (62% vs 61% OR 1.05, 95% CI 0.79-1.40; p = 0.76). The in-hospital mortality was lower (14.7% vs 19.8% OR 0.70, 95% CI 0.48-1.02; p = 0.06) for the remdesivir-treated patients. Rapid clinical improvement occurred more often in patients with low C-reactive protein (≤ 75 mg/L) and short duration of symptoms prior to hospitalisation (< 7 days) (OR 2.84, 95% CI 1.07-7.56)., Conclusion: Remdesivir generally does not increase the incidence of rapid clinical improvement in hospitalised patients with COVID-19, but it might have an effect in patients with short duration of symptoms and limited signs of systemic inflammation., (© 2023. The Author(s).)

Purpose: Recent studies suggest that women are more susceptible to diuretic-induced hyponatremia resulting in hospital admission than men. The aim of this study was to confirm whether these sex differences in hyponatremia-related hospital admissions in diuretic users remain after adjusting for several confounding variables such as age, dose, and concurrent medication., Methods: In a case-control design nested in diuretic users, cases of hyponatremia associated hospital admissions between 2005 and 2017 were identified from the PHARMO Data Network. Cases were 1:10 matched to diuretic users as controls. Odds ratios (OR) with 95%CIs were calculated for women versus men and adjusted for potential confounders (age, number of diuretics, other hyponatremia-inducing drugs, chronic disease score) using unconditional logistic regression analysis. A subgroup analysis was performed for specific diuretic groups (thiazides, loop diuretics and aldosterone antagonists)., Results: Women had a statistically significantly higher risk of a hospital admission associated with hyponatremia than men while using diuretics (OR 1.86, 95%CI 1.64-2.11). Adjusting for the potential confounders resulted in an increased risk for women compared to men (ORadj 2.65, 95% CI 2.31-3.04). This higher risk in women was also seen in the three subgroup analyses after adjustment., Conclusion: Our findings show a higher risk of hyponatremia-related hospital admission in women than men while using diuretics. Further research is needed to understand the underlying mechanism of this sex difference to be able to provide sex-specific recommendations., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: This study was designed to investigate the impact of age on the effectiveness and immune-related adverse events (irAEs) of programmed death-(ligand)1 [PD-(L)1] inhibitors in patients with non-small cell lung cancer (NSCLC) using a novel text-mining technique., Methods: This retrospective study included patients with stage III/IV NSCLC treated with a PD-(L)1 inhibitor (nivolumab, pembrolizumab, atezolizumab and durvalumab) at Leiden University Medical Centre and Haga Teaching hospital, (both in The Netherlands) from September 2016 to May 2021. All the relevant data was extracted from the structured and unstructured fields of the Electronic Health Records using a novel text-mining tool. Effectiveness [progression-free survival (PFS) and overall survival (OS)] and safety (the incidence of nine potentially fatal irAEs and systemic corticosteroid requirement) outcomes were compared across age subgroups (young: < 65 years, Middle-aged: 65-74 years, and old: ≥ 75 years) after adjustment for confounding., Results: Of 689 patients, 310 patients (45.0%) were < 65 years, 275 patients (39.9%) were aged between 65 and 74 years, and 104 patients (15.1%) were ≥ 75 years. There was no significant difference between younger and older patients regarding PFS (median PFS 12, 8, 13 months respectively; Hazard ratio (HR) middle-aged  = 1.14, 95% CI 0.92-1.41; HR old  = 1.10, 95% CI 0.78-1.42). This was also the case for OS (median OS 19, 14, 18 months respectively; HR middle-aged  = 1.22, 95% CI 0.96-1.53; HR old  = 1.10, 95% CI 0.79-1.52). Safety analysis demonstrated a higher incidence of pneumonitis among patients aged 65-74. When all the investigated irAEs were pooled, there was no statistically significant difference found between age and the incidence of potentially fatal irAEs., Conclusions: The use of PD-(L)1 inhibitors is not associated with age related decrease of PFS and OS, nor with increased incidence of serious irAEs compared to younger patients receiving these treatments. Chronological age must therefore not be used as a predictor for the effectiveness or safety of ICIs., (© 2023. The Author(s).)

Objective: Cervical cancer can be prevented by regular screening; however, screening rates are low in developing countries. We evaluated the proportion of women screened, modalities of screening utilized, and factors influencing uptake among Ghanaian women with access to free screening services., Methods: Participants were women aged 25-65 in Asokore-Mampong, Ghana. A structured questionnaire collected socio-demographic characteristics, risk factors, knowledge of, and utilization of cervical cancer screening. Adjusted logistic regression evaluated predictors of screening., Results: Of 710 participants, the majority had heard of cervical cancer (64.6%) and screening (57.7%). Screening utilization was 24.6%. Visual inspection with acetic acid was the most common screening method (97.1%). For those who had never been screened, common reasons were believing they were healthy (21.7%), fearing pain (12.9%), lacking awareness of screening (11.8%), and being too busy (11.6%). Participants who were aged 35-44 (aOR 1.82; 95% CI 1.09-3.03; p = 0.023), married (aOR 3.98; 95% CI 1.68-9.40; p = 0.002), formally employed (aOR 9.31; 95% CI 2.86-30.35; p <0.001), and had higher cervical cancer knowledge (aOR 3.98; 95% CI 2.64-6.02; p <0.001) were more likely to have been screened., Conclusion: Despite geographic proximity to a health center that provides free cervical cancer screening, screening uptake among Ghanaian women remains low., (© 2022 International Federation of Gynecology and Obstetrics.)

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: To compare the real-world safety profile of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors between younger and older patients., Materials and Methods: All patients receiving pembrolizumab, nivolumab, atezolizumab or durvalumab between September 2016 and September 2019 at Haga Teaching Hospital, The Hague, The Netherlands were included in this retrospective study. Immune-related adverse drug reactions (irADRs) were manually retrieved from the electronic patient files. The cumulative incidence of irADRs were compared between younger (<65 years) and older (≥65 years) patients using a Pearsons Chi-square test., Results: We identified 217 patients who were treated with at least one dose of PD-(L)1 inhibitor. 58% were 65 years or older at the start of immunotherapy. 183 patients (84.3%) received monotherapy PD-(L)1 inhibitors and 34 (15.7%) received chemo-immunotherapy. A total of 278 irADRs were registered. Cutaneous irADRs (53.9%), thyroid gland disorders (20.3%), and non-infectious diarrhoea/colitis (17.5%) were the most frequently reported irADRs. The majority of the irADRs were mild to moderate and no fatal irADRs were observed. 61 (21.9%) of the irADRs needed systemic treatment, of which 19 (6.8%) required treatment with corticosteroids. 18 irADRs (6.5%) were severe and resulted in hospitalisation. The cumulative incidence of cutaneous irADRs was different between the age groups: 45.7% of the patients <65 years and in 60.0% of the patients ≥65 years (p = 0.036). No statistical difference was found in the cumulative incidence of other irADRs between the two age groups., Discussion: Advanced age is not associated with immune-related adverse drug reactions of PD-1 and PD-L1 inhibitors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Hypokalaemia is a potentially life-threatening adverse event of flucloxacillin with unknown incidence. The risk of flucloxacillin-induced hypokalaemia has recently been suggested to be increased among females compared to males. The aim of this study is to describe the incidence and to determine the influence of sex and other risk factors on flucloxacillin-induced hypokalaemia., Methods: A retrospective single-centre cohort study was performed. Patients treated with intravenous flucloxacillin for >24 hours between January 2017 and October 2020, a baseline potassium level of ≥3.5 mmol/L and potassium measurement during treatment were included. The primary endpoint was incidence of hypokalaemia defined as the percentage of patients with a potassium measurement <3.5 mmol/L during flucloxacillin treatment. Logistic regression modelling was used to establish risk factors for hypokalaemia., Results: A total of 835 patients were included, 58.2% male and median age 71.0 years (interquartile range 61.0-81.0). The incidence of hypokalaemia was 23.7% (28.4% in females vs 20.4% in males). A dose-dependent relation between sex and the incidence of hypokalaemia was found. The risk of hypokalaemia was 4.41 (95% confidence interval 1.47-13.24) times higher in females compared to males when receiving a flucloxacillin dose of >8 g/24 h. No sex differences were found for lower daily doses. Other risk factors for hypokalaemia were older age, concomitant antibiotic use, lower bodyweight, lower baseline plasma potassium concentration and longer treatment duration., Conclusion: Hypokalaemia is a frequent complication in patients treated with intravenous flucloxacillin. Females receiving >8 g intravenous flucloxacillin per day are more prone to develop hypokalaemia compared to males., (© 2022 British Pharmacological Society.)

Background: Metoprolol, a beta-blocker, is used to reduce the heart rate. Although it has been demonstrated that the metoprolol plasma concentration is higher in women than in men, the same dose is recommended. In this study, we investigated whether the metoprolol concentration was associated with a stronger heart-rate reduction and bradycardia in women than in men. Methods: This study is part of the Rotterdam Study (RS), a population-based prospective cohort study. Blood samples from a random subset of 2000 participants were used to assess metoprolol plasma levels. An analysis of heart rate (beats per minute, bpm) and bradycardia (<60 bpm) was performed in metoprolol users with an ECG at the day of blood collection to study sex-specific differences in heart rate and the risk of bradycardia. Results: In total, 40 women and 39 men were included. There was a statistically significant association between metoprolol concentration and heart rate in women (p-value: 0.014) but not in men (p-value: 0.639). Furthermore, women in the highest concentration group had a more than 15-times-higher risk of bradycardia than women in the lowest concentration group (OR = 15.6; 95% CI = 1.1, 217.3); however, this was not seen in men (OR = 1.3; 95% CI = 0.1, 12.4). After adjustment for age, BMI, time between blood sample and ECG, hypertension, myocardial infarction, heart failure, atrial fibrillation, digoxin use, and calcium channel blocker use, the association between concentration and bradycardia in women remained statistically significant. Conclusions: Women, but not men, had a statistically significantly lower heart rate at higher metoprolol plasma concentration and a statistically significantly increased risk of bradycardia.

The anti-IL-5 biologic reslizumab for the treatment of severe eosinophilic asthma is administered intravenously. In the current study home administration of intravenous reslizumab was evaluated in 24 patients included between 2019 (July) and 2020 (July). This is the first study to show that intravenous reslizumab can be administered safely and successfully in an outpatient setting. Notably, not all patients prefer home administration and severe asthma patients may have different needs when it comes to choosing treatment at home or in the hospital., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan-Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8-20.7), 16.3 months (95%CI, 9.3-not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4-NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1-50.9 months), 39.3 months (95%CI, 29.5-NE) for pazopanib, and 28.1 months (95%CI, 7.0-NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Laar, Gombert-Handoko, Groenwold, van der Hulle, Visser, Houtsma, Guchelaar and Zwaveling.)

Background: The severity of COVID-19 after SARS-CoV-2 infection is unpredictable. Angiotensin-converting enzyme-2 (ACE2) is the receptor responsible for coronavirus binding, while subsequent cell entry relies on priming by the serine protease TMPRSS2 (transmembrane protease, serine 2). Although renin-angiotensin-aldosterone-system (RAAS) blockers have been suggested to upregulate ACE2, their use in COVID-19 patients is now considered well tolerated. The aim of our study was to investigate parameters that determine COVID-19 severity, focusing on RAAS-components and variation in the genes encoding for ACE2 and TMPRSS2., Methods: Adult patients hospitalized due to SARS-CoV-2 infection between May 2020 and October 2020 in the Haga Teaching Hospital were included, and soluble ACE2 (sACE2), renin, aldosterone (in heparin plasma) and polymorphisms in the ACE2 and TMPRSS2 genes (in DNA obtained from EDTA blood) were determined., Measurements and Main Results: Out of the 188 patients who were included, 60 were defined as severe COVID-19 (ICU and/or death). These patients more often used antidiabetic drugs, were older, had higher renin and sACE2 levels, lower aldosterone levels and a lower aldosterone/renin ratio. In addition, they displayed the TMPRSS2-rs2070788 AA genotype less frequently. No ACE2 polymorphism-related differences were observed. Multivariate regression analysis revealed independent significance for age, sACE2, the aldosterone/renin ratio, and the TMPRSS2 rs2070788 non-AA genotype as predictors of COVID-19 severity, together yielding a C-index of 0.79. Findings were independent of the use of RAAS blockers., Conclusion: High sACE2, a low aldosterone/renin ratio and having the TMPRSS2 rs2070788 non-AA genotype are novel independent determinants that may help to predict COVID-19 disease severity., Trial Registration: retrospectively registered., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Polypharmacy is common in older adults with cancer and deprescribing potentially inappropriate medications becomes very relevant when life expectancy decreases due to metastatic disease. Especially preventive medications may no longer be beneficial, because they may decrease quality of life and reduction in morbidity and mortality may be futile. Although deprescribing of preventive medication is common in the last period of life, it is still unusual during active cancer treatment for advanced disease, although life expectancy is often limited to less than 1 to 2 years in that stage. We performed a systematic search of the literature in Pubmed and Embase on the discontinuation of commonly utilized groups of preventive medication and evaluated the evidence of potential benefits and harms in patients aged 65 years or older with cancer and a limited life expectancy (LLE). From 21 included studies, it can be concluded that deprescribing lipid lowering drugs, antihypertensive drugs, osteoporosis drugs and antihyperglycemic drugs is feasible in a considerable part of patients with a LLE. Discontinuation may be performed safely, without the occurrence of serious adverse events or decrease of survival. The only study that addressed quality of life after deprescribing showed that discontinuation of statins improves quality of life in patients with a LLE. Recurrence of symptoms requiring reintroduction occurred in 0-13% of patients on antihyperglycemic treatment and 8-60% of patients using antihypertensive drugs. In order to reduce pill burden and futile treatment clinicians should discuss deprescribing of preventive medication with older patients with advanced cancer and a LLE.

Objectives: Medications at the end of life should be used for symptom control. Medications which potential adverse effects outweigh their expected benefits are called 'potentially inappropriate medications' (PIMs). PIMs are related with adverse drug events and reduced quality of life. In this study, we investigated to what extent PIMs are dispensed to older patients with lung cancer in the last month of life., Methods: We selected patients with lung cancer, aged 65+, diagnosed between 2009 and 2014, and who died before April 1st 2015 from the population-based Netherlands Cancer Registry (NCR). The NCR is linked to the PHARMO Database Network, that includes medications dispensed by community pharmacies in the Netherlands. The eight PIM groups were based on the OncPal Deprescribing Guideline: aspirin, dyslipidaemia medications, antihypertensives, osteoporosis medications, peptic ulcer prophylaxis, oral hypoglycaemics, vitamins and minerals., Results: Data of 7864 patients with lung cancer were analyzed. Median age was 74 year (IQR = 70-79) and 67% was male. 45% of all patients received at least one PIM in their last month of life. Taking into account all dispensed medications, patients receiving PIMs received more different medications compared to those receiving no PIMs, respectively 10 (SD = 5) vs. 3 (SD = 4) different medications (P < 0.001)., Conclusion: Almost half of the older patients with lung cancer in the Netherlands received PIMs in their last month of life. Since PIM use is associated with reduced quality of life, it is important that health care professionals continue to critically assess which medication can be discontinued at the end of life., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of disease and lead to frequent doctor visits. Children with recurrent RTIs generally have no significant alterations or deficits in systemic immunity. In an attempt to treat the assumed bacterial component involved, they are often treated with prolonged courses of prophylactic antibiotics taken on a daily basis. Despite its common use, there is no evidence that this is beneficial. Studies assessing the clinical effectiveness of antibiotic prophylaxis as well as potential adverse effects and antibiotic resistance development, are therefore urgently needed., Methods and Analysis: We present a protocol for a randomised double-blind placebo-controlled trial comparing co-trimoxazole with placebo treatment in children with recurrent RTIs. A total of 158 children (aged 6 months-10 years) with recurrent RTIs without significant comorbidity will be enrolled from a minimum of 10 Dutch hospitals. One group receives co-trimoxazole 18 mg/kg two times per day (36 mg/kg/day) and the other group receives a placebo two times per day for a period of 3 months. The main objective is to determine whether antibiotic prophylaxis is more effective than placebo to prevent/reduce respiratory symptoms in children with recurrent RTIs. Respiratory symptoms will be scored by parents on a daily basis in both study arms by the use of a mobile phone application. Our primary outcome will be the number of days with at least two respiratory symptoms during the treatment., Ethics and Dissemination: Ethics approval was obtained from the Medical Ethics Research Committee Zuidwest Holland/LDD. A manuscript with the study results will be submitted to a peer-reviewed journal. All participants will be informed about the study results. The results of the study will inform clinical guidelines regarding the prophylactic treatment of children with recurrent RTIs., Trial Registration Number: NL7044., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Current guidelines have no sex-specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population-based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data., Methods: The mean daily starting doses of metoprolol in both sexes were compared with independent-samples t-tests and a linear regression analysis was used to adjust in the RS for co-variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI-database, adjustment was for age only., Results: The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI -7.8, -1.8) and 4.6 mg (95%CI -5.3,-4.0), respectively. Statistical significance remained after adjustment in both databases., Conclusions: Women received lower starting doses of metoprolol than men in two independent data collections despite non-sex specific cardiovascular guideline recommendations. This example of real-life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology., (© 2021 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Adverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5-1.7 times more likely to develop ADRs. The main objective was to identify sex differences in the types and number of ADRs leading to hospital admission., Methods: ADR-related hospital admissions between 2005 and 2017 were identified from the PHARMO Database Network using hospital discharge diagnoses. Patients aged ≥ 16 years with a drug possibly responsible for the ADR and dispensed within 3 months before admission were included. Age-adjusted odds ratios (OR) with 95% CIs for drug-ADR combinations for women versus men were calculated., Results: A total of 18,469 ADR-related hospital admissions involving women (0.35% of all women admitted) and 14,678 admissions involving men (0.35% of all men admitted) were included. Most substantial differences were seen in ADRs due to anticoagulants and diuretics. Anticoagulants showed a lower risk of admission with persistent haematuria (ORadj 0.31; 95%CI 0.21, 0.45) haemoptysis (ORadj 0.47, 95%CI 0.30,0.74) and subdural haemorrhage (ORadj 0.61; 95%CI 0.42,0.88) in women than in men and a higher risk of rectal bleeding in women (ORadj 1.48; 95%CI 1.04,2.11). Also, there was a higher risk of admission in women using thiazide diuretics causing hypokalaemia (ORadj 3.03; 95%CI 1.58, 5.79) and hyponatraemia (ORadj 3.33, 95%CI 2.31, 4.81) than in men., Conclusions: There are sex-related differences in the risk of hospital admission in specific drug-ADR combinations. The most substantial differences were due to anticoagulants and diuretics.

Multiple factors may contribute to the decision to initiate methylphenidate treatment in children such as maternal sociodemographic factors of which relatively little is known. The objective was to investigate the association between these factors and methylphenidate initiation. The study population included 4243 children from the Generation R Study in the Netherlands. Maternal sociodemographic characteristics were tested as determinants of methylphenidate initiation through a time-dependent Cox regression analysis. Subsequently, we stratified by mother-reported ADHD symptoms (present in 4.2% of the study population). When ADHD symptoms were absent, we found that girls (adjusted HR 0.25, 95%CI 0.16-0.39) and children born to a mother with a non-western ethnicity (compared to Dutch-Caucasian) (adjusted HR 0.42, 95%CI 015-0.68) were less likely to receive methylphenidate. They were more likely to receive methylphenidate when their mother completed a low (adjusted HR 2.29, 95%CI 1.10-4.77) or secondary (adjusted HR 1.71, 95%CI 1.16-2.54) education. In conclusion, boys and children born to a mother of Dutch-Caucasian ethnicity were more likely to receive methylphenidate, irrespective of the presence of ADHD symptoms.

Objectives: Numerous studies have examined determinants contributing to methylphenidate adherence and persistence, but these were mainly conducted in adults. These determinants are likely to be different in children as they usually rely on their parents to provide them with the care they need. The objective was to study child and family characteristics as determinants of methylphenidate adherence and persistence in children. Methods: The study population consists of 307 children from the Generation R Study in the Netherlands, who had at least one dispensing record of methylphenidate until the age of 16 years. Adherence was defined as a medication possession ratio ≥0.80 up to 2 years after treatment initiation. Persistence was defined as the duration of treatment until a discontinuation period of ≥6 months. Family and child characteristics were tested as determinants of adherence with multivariable logistic regression analysis. Persistence was evaluated using a Kaplan-Meier analysis. Results: Children of mothers with one child (adjusted odds ratio [OR]: 2.31, 95% confidence interval [CI]: 1.17-4.54) or of mothers with an average household income (compared to high) were more likely to be adherent (adjusted OR: 3.45, 95% CI: 1.43-8.31). Children who started treatment at the age of 12-16 years (compared to <12 years) (adjusted hazard ratio [HR]: 3.55, 95% CI: 2.54-4.98) and girls (adjusted HR: 1.44, 95% CI: 1.07-1.95) were more often nonpersistent. Conclusion: Both child and family characteristics may play a role in methylphenidate treatment adherence. Furthermore, gender and the start age of treatment were found to be associated with nonpersistence. These findings may be important for health care professionals when initiating methylphenidate treatment in children.

In the past decade, the leading international cardiology societies have released statements that emphasize the importance of sex-specific reporting of the findings of clinical trials in cardiovascular research. To find out whether this has led to improvement, we compared sex-specific reporting of efficacy and safety outcomes for trials of cardiovascular drug interventions presented at the major clinical trials sessions of the European Society of Cardiology (ESC), American Heart Association (AHA) and the American College of Cardiology (ACC) before and after publication of these statements. We found that sex-specific efficacy and safety outcomes of the most influential cardiovascular intervention trials are still not systematically presented., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background Sex differences in efficacy and safety of dual antiplatelet therapy remain uncertain because of the underrepresentation of women in cardiovascular trials. The aim of this study was to perform a sex-specific analysis of the pooled efficacy and safety data of clinical trials comparing a high potent P2Y 12 inhibitor+aspirin with clopidogrel+aspirin in patients with acute coronary syndrome. Methods and Results A systematic literature search was performed. Randomized clinical trials that compared patients following percutaneous coronary intervention/acute coronary syndrome who were taking high potent P2Y 12 inhibitors+aspirin versus clopidogrel+aspirin were selected. Random effects estimates were calculated and relative risks with 95% CIs on efficacy and safety end points were determined per sex. We included 6 randomized clinical trials comparing prasugrel/ticagrelor versus clopidogrel in 43 990 patients (13 030 women), with a median follow-up time of 1.06 years. Women and men had similar relative risk (RR) reduction for major cardiovascular events (women: RR, 0.89 [95% CI, 0.80-1.00; men: RR, 0.84 [95% CI, 0.79-0.91) ( P for interaction=0.39). Regarding safety, women and men had similar risk of major bleeding by high-potency dual antiplatelet therapy (RR, 1.18 [95% CI, 0.98-1.41] versus RR, 1.03 [95% CI, 0.93-1.14]) ( P for interaction=0.20). Conclusions The small and statistically insignificant difference in efficacy and safety estimates of high-potency dual antiplatelet therapy between women and men following percutaneous coronary intervention/acute coronary syndrome do not justify differential dual antiplatelet therapy treatment for both sexes.

Objectives: To estimate the number of patients who started methylphenidate during childhood and continued treatment beyond the age of 18 years and to study the determinants that may be associated with continuing treatment. Methods: Patients 17 years of age and younger who have received at least one prescription of methylphenidate were identified in the Integrated Primary Care Information database (1996-2017). Logistic regression analyses were performed to assess the association between potential determinants and continuation with methylphenidate treatment at the age of 18 years. Results: Fifty-three percent of all methylphenidate users ( n  = 1020) continued their treatment after the age of 18 years. Patients were more likely to continue treatment with methylphenidate if they started treatment at the age of 15-17 years compared with patients of 11 years and younger (adjusted odds ratio [OR]: 5.74, 95% confidence interval [CI]: 1.48-22.31), if they had a medication possession ratio (MPR) between 0.80 and 1.00 compared with a low MPR (adjusted OR: 2.18, 95% CI: 1.23-3.85) and if they lived in an area with a medium level of urbanization (adjusted OR: 1.98, 95% CI: 1.06-3.69). Furthermore, a relatively high number of patients had a MPR >1.0 (24.8%), of whom 91.3% started their treatment when they were between 15 and 17 years of age. Conclusions: Methylphenidate treatment initiated during childhood was continued in half of the study population when reaching the age of 18, where adolescents were more likely to continue treatment than young children. We also found that ∼25% of our study population had a MPR >1, mainly patients 15-17 years of age, which may suggest misuse or abuse of methylphenidate.

Background There is increasing interest in outpatient parenteral antimicrobial treatment. Objective To evaluate the added value of consultation of an infectious diseases expert team (consisting of two internist-infectious diseases specialists and a microbiologist) for advice regarding type, administration route and duration of antibiotic treatment. Setting A retrospective case series was performed at the Haga Teaching Hospital, a 700-bed regional teaching hospital in The Hague, The Netherlands. Methods Complication rate and mortality was evaluated during 60 days of follow-up. Therapeutic rationality regarding outpatient parenteral antimicrobial treatment was determined by presenting randomly selected paper cases from the database to two independent infectious diseases specialists who were blinded to patient's treatment and outcomes. The concordance between the two advices were analysed using Cohen's kappa. For those with discordance, an infectious diseases expert team meeting was organized to reach consensus. The final recommendation was compared to the actual given antibiotic treatment. Main outcome measure Discrepancy between the infectious disease expert team recommendations upon type, administration route and duration of antibiotics and the real outpatient parenteral antimicrobial treatment practice. Results Out of 89 included cases, 50 were randomly selected for review by the infectious diseases specialists. The kappa statistic regarding antimicrobial policy was 0.581 (P < 0.001). In 78% (39/50 cases), they had complete agreement upon all aspects of antibiotic treatment. The remaining 11 cases were reviewed by the expert team. Comparing the consensus of 50 cases to actual practice, in 14(28%) cases there was a discrepancy suggesting potential room for improvement. Comparing the cases in whom an individual infectious diseases specialist was involved in real practice to those cases without, there was 18% versus 42% discrepancy with the recommendations of the expert team (OR 3.4; 95% CI: 0.9-12.5, P = 0.06). Complication rate was 19% including unplanned readmissions and side effects of antimicrobial agent or administration route. Conclusion Though outpatient parenteral antimicrobial treatment policies in the Netherlands appear to be safe, consultation of an ID expert team, rather than an individual ID specialist, has the potential to optimize antimicrobial treatment in patients considered suitable for outpatient parenteral antimicrobial treatment.

Background Children are still prescribed age contraindicated drugs, but information about the number and type of these drugs dispensed for children in the Netherlands is limited. Objective To determine the incidence and prevalence of contraindicated drugs that were dispensed for the use by children. Setting The study was conducted in the Netherlands with routinely collected data from 95% of all community pharmacies. Method We performed a one-year nationwide observational study where all patients aged 17 years or younger who have received at least one prescription in 2016 were included. Contraindicated drugs were selected, according to the 5th level of ATC code, using different information sources. Main outcome measure The proportion of (newly) contraindicated drugs that were dispensed to children. Results In total, 3.9% of all children received at least one drug that was contraindicated for their age. The highest percentage of contraindicated drugs that was dispensed, was observed in patients aged 1-2 years and 13-17 years (7.0 and 5.7%, respectively) and the percentage of contraindicated drugs that were dispensed was higher in female than in male patients (4.3 and 3.6%, respectively; p value < 0.001). Conclusion The results of this study show that a substantial percentage of children received a drug that was conta-indicated for their age, and it happes more in female than in male patients. Furthermore, the information about this type of contraindications is limited and inconsistent.