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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]

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.

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.)

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).)

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).)

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: 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.)

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.)

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.

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.

Study Objectives: Poor sleep is a risk factor for the development and recurrence of depression. Selective serotonin reuptake inhibitor (SSRI) use is consistently associated with good subjective sleep in clinically depressed patient populations. However, studies in the general population are lacking. Our objective was to investigate the association between SSRIs and subjective sleep in a middle-aged and elderly population in a daily practice setting., Methods: We included participants from the prospective Rotterdam Study cohort. Participants had up to two subjective sleep measurements assessed with Pittsburgh Sleep Quality Index ([PSQI], number of measurements = 14,770). SSRI use was based on pharmacy records. We assessed the association between SSRIs and PSQI score and its sub-components, with nonusers of any antidepressant as reference. Analyses were, among others, adjusted for presence of depressive symptoms and concurrent psycholeptic drug use., Results: We included 9,267 participants, average baseline age 66.3 y (standard deviation 10.6), and 57.6% women. SSRI use was significantly associated with a 0.78-point lower PSQI score (95% confidence interval [CI] -1.11; -0.44) which reflects better sleep, compared with non-use. The association was more prominent in continuous SSRI users (-0.71 points, 95% CI -1.18; -0.24). Of the sub-components, SSRIs were associated with 0.70-h longer sleep duration (95% CI 0.56; 0.85), higher sleep quality, higher sleep efficiency, and in contrast more daytime dysfunction., Conclusions: SSRI use was associated with better subjective sleep, after adjustment for depressive symptoms and concurrent psycholeptic drug use. This suggests that, in clinical practice in the middle-aged and elderly population, the sleep quality of some persons may benefit from, continued, SSRI use., (© 2016 American Academy of Sleep Medicine.)

Antidepressants are often only moderately successful in decreasing the severity of depressive symptoms. In part, antidepressant treatment response in patients with depression is genetically determined. However, although a large number of studies have been conducted aiming to identify genetic variants associated with antidepressant drug response in depression, only a few variants have been repeatedly identified. Within the present review, we will discuss the methodological challenges and limitations of the studies that have been conducted on this topic to date (e.g., 'treated-only design', statistical power) and we will discuss how specifically drug-gene interaction models can be used to be better able to identify genetic variants associated with antidepressant drug response in depression., Competing Interests: Financial & competing interests disclosure CL Avery and BH Stricker acknowledges funding from R01HL103612 (NIH). CL Avery also acknowledges funding from 15GPSPG239 (American Heart Association). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript

Background and Purpose: Serotonin-specific antidepressants may increase the risk of adverse bleeding events. In a previous cross-sectional study, we did not observe an association between antidepressant use and presence of subclinical cerebral bleedings. In this study, we investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds., Methods: In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds. Antidepressant use (yes versus no) was assessed between baseline and follow-up scan. In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors. We used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds., Results: Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31-3.76) than nonuse. When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53-6.17). Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence., Conclusions: Antidepressant use was associated with an increased risk of developing microbleeds. Our results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users., (© 2015 American Heart Association, Inc.)

Aims: Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QTc prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults., Methods: This study, which was part of the prospective Rotterdam Study (period 1991-2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QTc F (QT corrected according to Fridericia) measured during use of individual SSRIs with QTc F measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older., Results: We included 12 589 participants with a total of 26 620 ECGs of which 436 ECGs were made during SSRI use. The mean QTc F was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QTc compared with ECGs recorded during non-use (+12.8 ms, 90% CI 7.5, 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg citalopram., Conclusions: Although no SSRI class effect was observed, use of citalopram was associated with a longer QTc F, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QTc F prolongation., (© 2015 The British Pharmacological Society.)

Background and Purpose: Serotonin reuptake inhibiting antidepressants decrease platelet aggregation. This may cause an increased risk of intracerebral hemorrhage. However, the risk of subclinical microbleeds, which are highly prevalent in middle-aged and elderly people, is unknown. We studied whether serotonin reuptake inhibiting antidepressants increase the frequency of cerebral microbleeds and secondarily whether they lower the presence of ischemic vascular damage., Methods: Within the population-based Rotterdam Study, information on antidepressant use was obtained from continuously monitored pharmacy records. Brain MRI was available in 4945 participants (55% women, mean age 64 years) between 2005 and 2011. We categorized antidepressants based on affinity for the serotonin transporter: high, intermediate, or low. Microbleeds (presence and location) and ischemic lesions (lacunes, white matter lesions) were rated on MRI. Logistic and linear regression, adjusted for age, sex, depressive symptoms, and cardiovascular risk were used to study the association of antidepressants with microbleeds and ischemic vascular lesions., Results: Antidepressant use with strong serotonin reuptake inhibition was not associated with microbleed presence (odds ratio compared with nonuse, 1.03; confidence interval, 0.75-1.39) irrespective of microbleed location in the brain. Exclusion of antithrombotic users or persons with cortical infarcts did not change our results. Furthermore, serotonin reuptake inhibition was not related to ischemic vascular brain damage., Conclusions: In the general population, use of serotonin reuptake inhibiting antidepressants is not related to presence of cerebral microbleeds. This strengthens the idea that the platelet inhibitor effects of antidepressant drugs with affinity for serotonin are minimal and further supports the safety of selective serotonin reuptake inhibitors for nongastrointestinal bleedings., (© 2014 American Heart Association, Inc.)

Background: Recent studies suggest that overanticoagulation impairs renal function in patients on warfarin therapy, due to renal tubular obstruction from glomerular hemorrhage., Methods: Data from the Rotterdam Study (The Netherlands), a prospective population-based cohort study of patients 55 years and older, were used for this study. Information on vitamin K antagonist (VKA) therapy was obtained from the regional anticoagulation clinic, where prothrombin times were monitored every 1-6 weeks depending on target level and stability of the international normalized ratio (INR). Linear regression was performed to study the association between the cumulative number of instances of overanticoagulation (defined as a measurement of an INR >6.0) and the change in renal function between baseline and third examination round based on estimated glomerular filtration rate (CKD-EPI equation). Age, sex, baseline renal function, baseline and incident heart failure, and indication for VKA therapy were included as potential confounders., Results: Information was available for analysis on 2,802 study participants in whom overanticoagulation was significantly associated with a decline in renal function, after adjustment for confounding by age, sex, heart failure, baseline glomerular filtration rate and indication for VKA therapy (-0.180 ml/min per 1.73 m(2) per year per event for INR >6.0, p = 0.030)., Conclusions: Overanticoagulation (INR >6.0) is associated with a decline in renal function. Further studies are needed to evaluate the causal role of different degrees of overanticoagulation, including transient effects, in high-risk groups, and the association with the new oral anticoagulants.

Several statins are substrates for the multidrug resistance-associated protein 2 transporter, encoded by the ABCC2 gene. We analyzed in the Rotterdam Study whether the common polymorphisms -24C>T, 1249G>A and 3972C>T in the ABCC2 gene were associated with a dose decrease or switch to another cholesterol-lowering drug in simvastatin and atorvastatin users. These events could indicate an adverse effect or a too strong reduction in cholesterol level. We identified 1014 simvastatin and atorvastatin users during the period 1 January 1991 to 1 January 2010. Associations between genetic variation and the risk of these events were analyzed using Cox proportional hazards modelling. The ABCC2 -24C>T genotype (HR 1.32 95% CI 1.04-1.69) and the H12 haplotype versus the H2 haplotype (HR 1.49; 95% CI 1.06-2.09) were associated with these events in simvastatin users. A similar but not significant association was found in atorvastatin users. To conclude, genetic variation in the ABCC2 gene is associated with these events in simvastatin users.

Aims: Cardiovascular disease in women is often underestimated. The effects of cardiovascular drugs differ between the sexes because of pharmacokinetic and pharmacodynamic differences. Adverse drug reactions (ADRs) within these drug classes may have serious consequences, leading to hospital admission. We aimed to study differences between men and women in hospital admissions for ADRs due to cardiovascular drugs., Methods: We conducted a nationwide study of all hospital admissions between 2000 and 2005 with data from the Dutch National Medical Register. Relative risks were calculated of hospital admissions due to ADRs to the different cardiovascular drug groups for women compared with men. By an ecological design, risks were adjusted for the total number of Dutch inhabitants and the total number of prescriptions., Results: In total, 14 207 of the hospital admissions (34% of all ADR-related admissions) were attributed to cardiovascular drugs [7690 in women (54%; 95% confidence interval 53-55%)]. 'Anticoagulants and salicylates' (n= 8988), 'high- and low-ceiling diuretics' (n= 2242) and 'cardiotonic glycosides' (n= 932) were responsible for the majority of the ADR-related hospital admissions. The most pronounced sex differences were seen in users of low-ceiling diuretics (relative risk 4.02; 95% confidence interval 3.12-5.19), cardiotonic glycosides (relative risk 2.38; 95% confidence interval 2.06-2.74), high-ceiling diuretics (relative risk 2.10; 95% confidence interval 1.91-2.32) and coronary vasodilators (relative risk 0.77; 95% confidence interval 0.65-0.91)., Conclusions: Clear sex differences exist in ADRs requiring hospital admission for different cardiovascular drug groups. Sex differences should be taken into account in the prescription and evaluation of drugs., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Background: The enzyme CYP1A2 (cytochrome 1A2) is involved in the metabolism of certain drugs and caffeine, and its activity can be influenced by factors such as sex, age, and smoking. The single nucleotide polymorphism (SNP) rs762551A>C, which has also been studied for its modifying effect on cardiovascular disease, has been reported to alter enzyme activity., Objective: The objective was to study the effect of CYP1A2, sex, age, and smoking on coffee intake., Design: Within the Rotterdam Study, a population-based cohort, all coffee drinkers for whom genome-wide association data were available were selected. Because SNP rs762551 was not on the Illumina 550 platform, SNP rs2472299 was used as a proxy, with the A allele of rs762551 linked to the G allele of rs2472299. Linear regression analyses were used to determine the effect and interaction of rs2472299, sex, age, and smoking on coffee intake. Adjusted geometric means of coffee intake were calculated per genotype for the different smoking and sex strata by using multivariable general linear models. A combined analysis, with the use of a "risk score," was performed to determine the contribution of each separate factor., Results: rs2472299G>A, female sex, and nonsmoking were significantly inversely related to coffee intake. Coffee intake was lowest in nonsmoking women homozygous for rs2472299G>A (3.49 cups/d; ∼436 mL). All factors contributed almost linearly to the intake of coffee, with the highest coffee intake in smoking men without the A allele (5.32 cups/d; ∼665 mL)., Conclusion: rs2472299G>A, linked to rs762551A>C, sex, age, and smoking significantly contribute to coffee intake.

Background: The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known., Objectives: In the present study, the effects of these polymorphisms on the risk of underanticoagulation and overanticoagulation over time after the start of acenocoumarol were investigated., Patients/methods: In three cohorts, we analyzed the relationship between the CYP2C9 and VKORC1 genotypes and the incidence of subtherapeutic or supratherapeutic International Normalized Ratio (INR) values (< 2 and > 3.5) or severe overanticoagulation (INR > 6) for different time periods after treatment initiation., Results: Patients with polymorphisms in CYP2C9 and VKORC1 had a higher risk of overanticoagulation (up to 74%) and a lower risk of underanticoagulation (down to 45%) in the first month of treatment with acenocoumarol, but this effect diminished after 1-6 months., Conclusions: Knowledge of the patient's genotype therefore might assist physicians to adjust doses in the first month(s) of therapy., (© 2012 International Society on Thrombosis and Haemostasis.)

Aims/hypothesis: Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study., 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. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes., Results: Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified., Conclusion/interpretation: Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.

Aim: The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment., Methods: All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) ≥6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated., Results: The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine., Conclusion: Fluvoxamine and venlafaxine were associated with a more than double risk of INR values ≥6 in acenocoumarol treated subjects., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

What Is Already Known About This Subject: Women are more at risk for developing adverse drug reactions (ADRs) due to differences in pharmacokinetics, pharmacodynamics and drug use. ADRs regularly lead to hospital admissions., What This Study Adds: There are differences between the sexes in hospital admissions attributed to ADRs. The risk of being hospitalized with an ADR varies between the sexes in the type of reaction and the causative drug., Aim: Adverse drug reactions (ADRs) are a major burden in health care, regularly leading to hospital admission, morbidity or death. Women tend to have a higher risk of adverse drug reactions with a 1.5 to 1.7-fold greater risk than men. Our primary aim was to study differences in ADR-related hospitalizations between the sexes., Methods: We conducted a nationwide study of all ADR-related hospitalizations in the period between 2000 and 2005 in the Netherlands, which were selected from all 9,287,162 hospital admissions in this period. ADR-drug group combinations with at least 50 admissions in one of the sexes were selected. Relative risks and confidence intervals were calculated with respect to total admissions and total prescriptions with men as reference., Results: In total, 0.41% of the 4,236,368 admissions in men (95% CI 0.40, 0.42%) and 0.47% of the 5,050,794 admissions in women (95% CI 0.46, 0.48%) were attributed to an ADR by medical specialists (57% of all ADR-related admissions were in women). Differences between the sexes in risk for ADR-related hospitalization were found for antineoplastic and immunosuppressive drugs, antirheumatics, anticoagulants and salicylates, cardiovascular and neurological drugs, steroids and antibiotics. In certain drug categories, risks for hospitalization changed after taking into account total drug prescriptions., Conclusion: In all different drug classes, significant differences exist between the sexes in ADR-related hospital admissions. Cardiovascular drugs account for the most pronounced differences between men and women. More research is needed to explain the clear sex differences in ADR-related hospital admissions., (© 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.)

The organic cation transporter 1, encoded by the SLC22A1 gene, is responsible for the uptake of the anti-hyperglycaemic drug, metformin, in the hepatocyte. We assessed whether a genetic variation in the SLC22A1 gene is associated with the glucose-lowering effect of metformin. Incident metformin users in the Rotterdam Study, whose HbA1c measurements were available, were identified. Associations between 11 tagging single nucleotide polymorphisms in the SLC22A1 gene and change in the HbA1c level were analyzed. A total of 102 incident metformin users were included in this study sample. Except for the rs622342 A>C polymorphism, no significant differences in metformin response were observed. For each minor C allele at rs622342, the reduction in HbA1c levels was 0.28% less (95% CI 0.09-0.47, P=0.005). After Bonferroni correction, the P-value was 0.050. To conclude, genetic variation at rs622342 in the SLC22A1 gene was associated with the glucose-lowering effect of metformin in patients with diabetes mellitus.

Aim: To study the effect of the CYP2D6*4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)]., Methods: In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined (n= 76). Multivariate linear regression was used to study the association between CYP2D6*4 and serum sodium concentration., Results: CYP2D6 poor metabolizers (PMs) (*4/*4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (*1/*1) [difference -3.9 mmol l(-1); 95% confidence interval (CI) -0.86, -7.03; P= 0.013]. In CYP2D6*4 heterozygotes (*1/*4) serum sodium concentration was 1.7 mmol l(-1) (95% CI -3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant (P= 0.077)., Conclusions: The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia.

Background: CYP2C9 enzymes are involved in non-steroidal anti-inflammatory drug (NSAID) metabolism. Therefore, we investigated whether CYP2C9*2 and *3 variant alleles, encoding for enzymes with lower activity, increased the protective effect of NSAIDs on colorectal cancer., Methods: Individual and combined associations of NSAIDs and CYP2C9*2 and *3 variant alleles with colorectal cancer were studied in 7757 Caucasian individuals of The Rotterdam Study, a population-based prospective cohort since 1990. Additive and multiplicative effect modification models were used to examine drug-gene interactions., Results: There were 212 incident cases of colorectal cancer during follow-up. A reduced risk of colorectal cancer was observed in individuals who used NSAIDs for more than a year (HR 0.45; 95% CI 0.28 to 0.71), and in carriers of an CYP2C9 variant allele associated with lower enzymatic activity (HR 0.67; 95% CI 0.47 to 0.96). The combination of both determinants was associated with a further risk reduction but without synergy., Conclusion: Both NSAID use and CYP2C9*2 and/ or *3 carriage are associated with a reduced risk of colorectal cancer. However, no interaction between the determinants was found, which might indicate independent pathophysiological mechanisms.

Objective: Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin., Research Design and Methods: We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Associations between 12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed., Results: One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 G>A SNP was significantly associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669, the A1C reduction was 0.30% (95% CI -0.51 to -0.10; P = 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045., Conclusions: The rs2289669 G>A SNP is associated with a reduction in A1C level, consistent with a reduction in MATE1 transporter activity. These results suggest that the transporter MATE1, encoded by SLC47A1, may have an important role in the pharmacokinetics of metformin, although replication is necessary.

Aim: Recently, a polymorphism in the NOS1AP gene (rs10494366), a regulator of neuronal nitric oxide synthase (nNOS), was associated with QTc prolongation. Both nNOS and calcium channel blockers (CCBs) regulate intracellular calcium levels and have an important role in cardiovascular homeostasis. The aim was to investigate whether this polymorphism is associated with cardiovascular mortality in users of CCBs., Methods: The data from the Rotterdam study, a population-based closed cohort study of Caucasian individuals of > or =55 years of age, were used. We identified 1113 participants in the Rotterdam Study who were prescribed CCBs for the first time between 1991 and 2005. All-cause and cardiovascular mortality was assessed in participants who were prescribed CCBs with different NOS1AP rs10494366 genotypes using Cox proportional hazard models., Results: In participants starting on dihydropyridine CCBs (amlodipine, nifedipine and others) all-cause mortality (n = 79) risks were higher in participants with the TG [hazard ratio (HR) 2.57, 95% confidence interval (CI) 1.24, 5.34] or the GG genotype (HR 3.18, 95% CI 1.18, 8.58) than in participants with the referent TT genotype. Cardiovascular mortality (n = 54) risks were 3.51 (95% CI 1.41, 8.78) for the TG genotype and 6.00 (95% CI 1.80, 20.0) for the GG genotype. No differences in all-cause mortality or cardiovascular mortality were seen in participants starting with the nondihydropyridine CCBs verapamil or diltiazem., Conclusion: The minor G allele of rs10494366 in the NOS1AP gene is associated with increased all-cause and cardiovascular mortality in Caucasian users of dihydropyridine CCBs. The mechanism underlying the observed association is unknown.

Objective: Besides effects on hemostasis, vitamin K-dependent proteins play a role in bone mineralization and arterial calcification. We investigated the association between the VKORC1 1173C>T polymorphism and calcification of the aortic far wall in a large population-based cohort., Methods and Results: Aortic calcification was diagnosed by radiographic detection of calcified deposits in the abdominal aorta. In all cohort members for whom DNA was available, the C1173T SNP of VKORC1 (rs9934438) was determined. With multivariable logistic regression analysis the association between this polymorphism and the risk of aortic calcification was calculated, adjusted for potential confounders. The T allele frequency of the VKORC1 1173C>T polymorphism was 38.8%. 1185 (37.2%) persons were homozygous CC, 1529 (48,0%) were heterozygous CT and 473 (14.8%) were homozygous TT. Persons with at least one T-allele had a statistically significant 19% (95% CI 2 to 40%) risk increase of calcification of the aortic far wall compared to CC homozygous persons, adjusted for age and gender., Conclusions: The T-allele of the VKORC1 1173C>T polymorphism was associated with a significantly higher risk of aortic calcification in Whites.

What Is Already Known About This Subject: * Most antidepressants are metabolized by CYP2D6. The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. * Reduced enzyme activity potentially leads to increased toxicity of antidepressants, but the relevance of genotyping for clinical practice is unclear. Most clinical studies suffer from small numbers of patients., What This Study Adds: * This large population-based cohort study in 1198 elderly Dutch patients examines the influence of the CYP2D6*4 polymorphism on intolerability of antidepressants. * The risk of switching to another antidepressant in tricyclic antidepressant users is higher in poor metabolizers (PMs), but not in SSRI users. PMs require a lower maintenance dose of antidepressants compared with extensive metabolizers (EMs). * Antidepressants were initiated in a relatively low dose, with gradual dose increments thereafter, reducing the risk of adverse drug reactions. Therefore, the question remains whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy., Aims: To study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy., Methods: The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t-tests and repeated measurements analyses., Results: In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02)., Conclusions: The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.

Some medical textbooks on drug interactions take note of the potential interaction between laxatives and coumarin anticoagulants, but epidemiological evidence that this interaction is of practical importance is lacking. We conducted a follow-up study in a large population-based cohort to investigate which laxatives are associated with overanticoagulation during therapy with coumarins. Of the 1124 patients in the cohort, 351 developed an International Normalized Ratio > or = 6.0. The only laxative with a moderate but significantly increased relative risk of overanticoagulation was lactulose (relative risk 3.4, 95% confidence interval 2.2, 5.3). In view of the widespread use of lactulose, especially among the elderly, awareness of this potential drug interaction is required.

Aims: To establish the frequency with which NSAIDs were prescribed to elderly patients after admission to hospital for serious gastrointestinal complications and to study which factors are determinants of the prescription of these contraindicated drugs., Methods: A retrospective cohort study of patients from The Rotterdam Elderly Study, a prospective population-based cohort study of people older than 55 years of age was carried out. Elderly patients with a hospital admission for serious gastrointestinal complications were followed until prescription of an NSAID, death, removal to another area or end of the study period, whichever came first. The following baseline determinants for receiving a contraindicated prescription were studied: gender, age, presence of rheumatoid arthritis or osteoarthritis, presence of cardiovascular risk factors, number of GP visits, number of visits to a medical specialist, cognitive function and the prescriber being a GP or a medical specialist., Results: Prescriptions of an NSAID after discharge from hospital, were identified in 73 patients (73%). Fifty-one percent were prescribed aspirin of whom the large majority used it as an antithrombotic agent, and 49% were prescribed a nonaspirin NSAID after discharge from hospital. Twenty percent of the patients used more than one NSAID on one or more occasions after discharge. For patients who were prescribed NSAIDs before admission as well as after discharge, the proportion of contraindicated prescriptions with concomitant use of antiulcer drugs rose significantly from 0.19 before discharge to 0.60 after discharge for aspirin and from 0.11 to 0.61 for nonaspirin NSAIDs. In the multivariate analysis the only remaining factor with prognostic influence on prescription of NSAIDs was a history of NSAID use before cohort enrollment. A history of rheumatoid arthritis or osteoarthritis was not associated with NSAID prescription after discharge., Conclusions: Contraindicated NSAIDs are prescribed to a great extent in elderly patients, despite their greater vulnerability for life-threatening gastrointestinal blood loss. It is remarkable that a history of rheumatoid arthritis or osteoarthritis is no significant determinant for receiving a contraindicated prescription, which suggests that these drugs are mainly prescribed for uncomplicated arthralgia.

In Spain mumps vaccine is given at the age of 15 months together with measles and rubella vaccines since 1982. Increased numbers of cases and outbreaks of mumps appeared in several autonomous communities in 1995. An outbreak of mumps in the province of.

Typhoid ileal perforation remains a frequently fatal illness in the developing world. The purpose of a retrospective review of 195 cases was to ascertain prognostic indices and therapeutic options influencing outcome. The overall mortality rate of 31% was worsened by extremes of age (p less than 0.025), generalized peritonitis (p less than 0.025), lower white blood cell count (p less than 0.05), increased number of perforations (p less than 0.005), and postoperative enterocutaneous fistula (p less than 0.005). Double-layer closure of the perforation lowered the mortality rate compared with single-layer closure (p less than 0.01). Broader-spectrum antibiotics, in the form of chloramphenicol with gentamycin, metronidazole, or both, reduced the mortality rate compared with chloramphenicol alone (p less than 0.05). Based on these findings, a prospective series was initiated in which all patients were treated with two-layer closure and chloramphenicol, gentamycin, and metronidazole. The mortality rate of 8% for the 26 patients treated in this manner confirmed the improved survival with these treatment modalities. Improved survival from typhoid perforation is possible with simple, low-cost measures.

From a screening of several Kluyveromyces strains, the yeast Kluyveromyces marxianus CBS 6556 was selected for a study of the parameters relevant to the commercial production of inulinase (EC 3.2.1.7). This yeast exhibited superior properties with respect to growth at elevated temperatures (40 to 45 degrees C), substrate specificity, and inulinase production. In sucrose-limited chemostat cultures growing on mineral medium, the amount of enzyme decreased from 52 U mg of cell dry weight at D = 0.1 h to 2 U mg of cell dry weight at D = 0.8 h. Experiments with nitrogen-limited cultures further confirmed that synthesis of the enzyme is negatively controlled by the residual sugar concentration in the culture. High enzyme activities were observed during growth on nonsugar substrates, indicating that synthesis of the enzyme is a result of a derepression/repression mechanism. A substantial part of the inulinase produced by K. marxianus was associated with the cell wall. The enzyme could be released from the cell wall via a simple chemical treatment of cells. Results are presented on the effect of cultivation conditions on the distribution of the enzyme. Inulinase was active with sucrose, raffinose, stachyose, and inulin as substrates and exhibited an S/I ratio (relative activities with sucrose and inulin) of 15 under standard assay conditions. The enzyme activity decreased with increasing chain length of the substrate.