David Pache

Monitoring salivary melatonin concentrations in children with sleep disorders using liquid chromatography-tandem mass spectrometry

Background: Melatonin is synthesized in the pineal gland and is an important circadian phase marker, especially in the determination of sleep patterns. Both temporary and permanent abnormal sleep patterns occur in children; therefore, it is desirable to have methods for monitoring melatonin in biological fluids in the diagnosis and treatment of such disorders. Objective: The objective of the study is to develop a liquid chromatography–tandem mass spectrometry method for the determination of melatonin in saliva and to apply it to monitoring salivary concentrations in children with sleep disorders. Methods: A deuterated internal standard (d7-melatonin) was added to a diluted saliva sample (20 µL) in an autosampler vial insert, and 50 µL were injected. Plasticware was strictly avoided, and all glassware was scrupulously cleaned and then baked at 120°C for at least 48 hours to obtain satisfactory performance. Reverse-phase chromatography was performed on a C8 column using a linear gradient elution profile comprising mobile phases A (0.1% aqueous formic acid) and B (15% methanol in acetonitrile containing 0.1% formic acid), pumped at a total flow rate of 0.8 mL/min. The run time was 8 minutes. After atmospheric pressure chemical ionization, mass spectrometric detection was in positive ion mode. Mass detection was by selected reaction monitoring mode with the following mass transitions used for quantification: melatonin, m/z 233.0 → 173.8 and d7-melatonin, m/z 240.0 → 178.3. Results: Linearity (r > 0.999) was established from 3.9 to 1000 pg/mL. Imprecision (coefficient of variation percent) was less than 11%, and accuracy was 100–105% (7.0–900 pg/mL). The method was selective, and the mean (range) ratio of the slopes of calibrations in water to those in daytime saliva samples collected from 10 healthy adult subjects was 0.989 (0.982–0.997), indicating negligible matrix effects. The application of the assay was demonstrated in healthy adults and in children being clinically investigated for sleep disturbances. Conclusions: A validated liquid chromatography–tandem mass spectrometry method suitable for monitoring salivary melatonin in children with circadian rhythm sleep disorders is reported. The method also has potential application to pediatric population pharmacokinetic studies using sparse sampling of saliva as the biological sample matrix.

Prolonged anticholinergic delirium following antihistamine overdose

Objective: A case of anticholinergic delirium in a female adolescent is described, exploring the pharmacokinetic reasons for the prolonged time course and reviewing the management provided. Conclusion: A 14 year old female hospitalised for depression ingested large quantities of promethazine and cyproheptadine. A severe anticholinergic delirium ensued which resolved after six days, much longer than the expected duration. The likely cause of the prolonged delirium was the interaction of promethazine and fluvoxamine through the inhibition of the CYP2D6 enzyme. The patients young age, the severity of the poisoning and the use of drugs with anticholinergic properties to manage the delirium may also have contributed. The delirium may have been reversed had a cholinesterase inhibitor been provided soon after the overdose.

Therapeutic Options in the Management of Sleep Disorders in Visually Impaired Children: A Systematic Review

BACKGROUND Treatment of sleep disorders in visually impaired children is complicated by a complex pathophysiology, a high incidence of sleep disorders in this population, and a dearth of management options. The significant impact on the health of these children and distress to their caregivers warrant a systematic assessment of the published literature on therapeutic approaches. OBJECTIVE This systematic review aims to assess the current therapeutic options in the management of sleep disorders in visually impaired children to identify knowledge gaps and guide future research. METHODS A search of primary literature was conducted using the bibliographic databases PubMed (1980-August 2010), EMBASE (1990-August 2010), Science Citation Index Expanded (1990-August 2010), and CINHAL (1992-August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL). Additional studies were identified through snowballing search techniques (manually by searching retrieved references and electronically by using citation-tracking software). Search terms included behavioral treatment, children, circadian rhythm, hypnosedatives, intellectual disability, light therapy, melatonin, phototherapy, random allocation, randomized controlled trial (RCT), sleep disorder, and visual impairment. Randomized and quasi-randomized clinical trials of therapeutic options (behavioral treatment, light therapy, melatonin, or hypnosedatives) used in participants aged 3 months to 18 years who had both a visual impairment and a sleep disorder were included. Independent extraction of articles was performed by 2 authors using predefined data fields, including quality of the therapeutic options, based on the Strength of Recommendation Taxonomy evidence-rating system. RESULTS Two RCTs were retrieved for melatonin, with improved effect on sleep latency (P = 0.019 and P < 0.05, respectively). However, separate analysis for visual impairment was not conducted. No RCTs were retrieved for behavioral intervention, light therapy, or hypnosedatives. Three studies using behavioral therapy (2 case reports and 1 case series) anecdotally showed improvement in sleep habit. No improvement in sleep rhythm was observed with a case series applying light therapy as an intervention. CONCLUSIONS Children with visual impairment and sleep disorders are a heterogeneous patient group, making diagnosis and treatment difficult. RCTs on treatment options remain in their infancy, with a lack of evidence for appropriate therapeutic strategies. Trials across a range of selected diagnoses need to be conducted with adequate sample populations to differentiate the efficacy of 4 different treatment modalities (behavioral therapy, light therapy, melatonin, and hypnosedatives) as agents for improving sleep.

Does consumer medicines interest reflect medicines use? An Australian observational study comparing medicines call center queries with medicines use

Background: Consumers have questions about their medication but the nature of these concerns and how they reflect medication use is unknown. Objectives: To determine the characteristics and medicines interests of callers to an Australian medicines call center and whether the medicines interest of callers corresponds with medicines utilization. Methods: Data from consumers who contacted a national medicines call center between September 2002 and June 2010 were analyzed. Patterns of consumer medicines interest were described. Medicines were class‐matched by Anatomical Therapeutic Classification, and compared with dispensed use (January 2006–June 2010). Results: In total 125,951 calls were received between 2002 and 2010. Callers were mainly female (76.8%), median age 48 years, calling for themselves (71.7%). Motivation to call related to safety (34.7%), efficacy (24.1%) and interactions (14.9%). For the comparison with medicines utilization, 85,416 calls with 124,177 individual medicine counts were analyzed (2006 and 2010). There were 976 unique ‘medicines of interest’. Half (49.4%) of these questions involved just fifty unique medicines. Nervous system medicines (antiepileptics, psycholeptics, analgesics) and antibacterials consistently ranked highest for interest compared with use. Conversely, agents acting on the renin‐angiotensin system, statins and drugs for acid related disorders ranked low for interest despite widespread use. Conclusions: Consumer questions about medicines correlate poorly with overall medicines utilization. To promote quality health outcomes, clinicians should target their education to the relatively small number of medicines of real concern to patients.

Dopamine agonists: time pattern of adverse effects reporting in Australia

Background: One previous study of our group reported that acid suppressive drug use during pregnancy is associated with an increased risk for the development of atopic dermatitis in children. However, reported associations could have been confounded by unmeasured risk factors. Objectives: The aim of this study was to assess the association between prenatal exposure to acid-suppressive drugs and the development of atopic dermatitis in children by using a confounding minimizing crossover design. Methods: We conducted a bidirectional case-crossover study within the Clinical Practice Research Database in which 1,445 children with atopic dermatitis were randomly matched to one of their own siblings without atopic dermatitis. Children were defined as having atopic dermatitis if they had a diagnosis of atopic dermatitis and at least 3 prescriptions for ointments containing steroids or calcineurin inhibitors in the year after diagnosis. We applied conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (95%CI). Results: The percentage of exposure to acid suppressive drugs amongst cases was 21.5% compared to 18.8% amongst controls. After adjustments for gender, birth order and maternal age at delivery the exposure to any acid suppressive drug during pregnancy increased the odds for developing atopic dermatitis by 34% (aOR 1.34; 95%CI: 1.05-1.71). Though not significant, exposure to the subgroup proton pump inhibitors conferred an increased risk of 72% (aOR 1.72 95% CI: 0.62-4.79). Conclusions: This study supports previous findings of a small association between gastric acid suppression during pregnancy and the development of atopic dermatitis in children.Background: After extensive media attention on thromboembolic adverse drug reactions (TE-ADRs) and the use of cyproterone/ethinylestradiol (CE), the Netherlands Pharmacovigilance Centre Lareb received a high number of reports about this association, which prompted for detailed analyses. Objectives: To analyse reports of thromboembolic events associated with the use of cyproterone/ ethinylestradiol submitted to Lareb, focusing on the indication of use, presence of risk factors and time between the initial symptoms and the actual diagnosis of the TE. Methods: Reports submitted to Lareb till 11 February 2014 were analysed. The analysis was focussed on reporter type, seriousness of the reaction, age of the patient, BMI, indication, ADRs classified as arterial thrombosis and venous thrombosis, pulmonary embolism, latency period, outcome of the reaction, treatment of the ADR, delay between the first symptoms and diagnosis of the ADR, presence of risk factors. Results: On 11 February 2014, Lareb had received a total of 786 reports about CE, including 41 cases with a fatal outcome. Of all reports, 438 reports considered TE-ADRs which were analysed in more detail. Reported ADRs consisted of arterial thrombosis (N = 74), venous thrombosis (N = 63), pulmonary embolism (N = 219) and thrombosis with an unspecified location (N = 172). Patients mean age was 30.5 years (range 14-57 years). The primary indications for use were acne (N = 193), oral contraceptive (N = 181), hirsutism (N = 13), other (N = 18) or the indication was unknown (N = 33). The median time to onset was 4 years, although many patients reported a longer latency period. There was no distinction between the time of onset in respect to the reported ADR. No differences in risk factors seem to exist between labeled and off-label indications. In 382 out of 438 reports (87%), the reporter was a consumer. Some reports mentioned the fact that thrombosis or embolism were not recognized in an early stage. Conclusions: The reported thromboembolic ADRs are a known risk related to the use of CE, but may be misdiagnosed initially. From the reports that Lareb received it is evident that off-label use is frequent.Background: Recent studies have reported an increased risk of asthma in children after prenatal exposure to antibiotics, notably during third trimester due to altered vaginal bacterial flora. Associations could have been influenced by unmeasured confounders. Objectives: To assess the association between antibiotic use during pregnancy and the development of toddler asthma with a confounding minimizing crossover(casesibling) design. Secondary we wanted to assess the influence of time-invariant confounding by comparing results with a case-control design. Methods: We conducted this study using a linked mother-infant subset of the University Groningen prescription database IADB.nl. We conducted both a crossover study in which 1,228 children with asthma were compared to their own siblings without asthma, and a traditional matched case-control study. Maternal exposure was defined as at least 1 day of supply of systemic antibiotics during pregnancy. Children were considered to have asthma if they received at least 3 prescriptions for anti-asthma medication within a year before the fifth birthday. Conditional logistic regression was used to estimate crude and adjusted odds ratios (aOR). Sensitivity analyses were performed to estimate the potential influence of unobserved timevarying confounders. Results: The crossover analysis only showed an increase in the toddlers asthma risk if antibiotics were used in the third trimester of pregnancy (aOR 1.37 (95%CI 1.02-1.83)). The matched case-control study yielded a similar increase in the toddlers asthma risk after exposure in the third trimester (aOR 1.40(95%CI 1.15-1.47)). In addition, use of antibiotics, independent of trimester of pregnancy, was associated with an aOR of 1.46 (95%CI 1.33-1.58) in the matched case-control study. Conclusions: Prenatal exposure to antibiotics in the third trimester of pregnancy is associated with a small increased risk of childhood asthma. This association did not appear to be influenced by time-invariant confounders such as genetic predisposition. However the influence of time-variant confounders, such as disease severity, cannot be ruled out.Background: The use of anti-epileptic drugs (AEDs) during pregnancy is associated with an increased risk of birth defects. Since epilepsy itself is also associated with potential risks for mother and child, an optimal AED treatment is needed. Over the past years, the introduction of new AEDs and the amendments of guidelines have changed the use of AEDs in this vulnerable group of patients. The extend of the changes over time in the Netherlands has not been studied before. Objectives: To compare the use of different AEDs in pregnant women over the past 10 years in the Netherlands. Methods: This retrospective cohort study data is based on data from the register that is being used to submit Dutch cases to the EURAP study. Pregnancies were included in which women were exposed to an AED between January 2003 and December 2012 either preconceptionally or during the first trimester. Binary logistic regression analysis was used to compare the proportion of various AEDs annually. Dependent variable was the year in which conception took place; the AED and type of epilepsy were covariates. In addition, the mean number of concomitantly used AEDs were calculated per year and analyzed by ANOVA. Results: A total number of 1,733 pregnancies in were included in the analysis. The proportion of use of levetiracetam and lamotrigine showed an upwards trend from 6.2 and 16.0% in 2003 till 25.0 and 33.5% in 2012, with corresponding adjusted Odds Ratio (OR) of 4.89 (95% CI 2.65-9.06) and 2.77 (95% CI 1.76-4.34) respectively. The proportion of use of valproate and carbamazepine decreased from 28.4 and 28.4% in 2003 till 9.3 and 17.3% in 2013, with an adjusted OR of 0.28 (95% CI 0.16-0.48) and from 0.44 (95%CI 0.28-0.70) respectively. The use of other miscellaneous AEDs decreased from 20.9% to 14.9%, OR 0.61 (95%CI 0.38-0.98). The average number of AEDs being used was 1.30 in 2003 and 1.24 in 2012 (p>0.05). Conclusions: The use of relatively safer AEDs gradually increased over the past 10 years compared to drugs more frequently associated with congenital defects. The mean number of AEDs used remained stable of the years. Our findings are in line with advice provided in the literature on the use of AEDs.Background: This study was part of the Pharmacoepidemiological Research on Outcomes (PROTECT) project which aims at monitoring of the benefit-risk of medicines in Europe. Few epidemiological studies have investigated the association between calcium channel blockers (CCB) and cancer, and have provided contradictory evidence. Objectives: To investigate whether CCB exposure is associated with cancer risk and whether the risk varies according to cancer subtype and duration of exposure. Methods: A population-based matched-cohort study was conducted using data from the Clinical Practice Research Datalink and National Cancer Registration System. Eligible patients (18 to 79 years, over two years primary care and prescription history) with ≥1 CCB prescription between 1996 and 2009 (CCBC) were compared with two CCB unexposed cohorts: 1) patients without CCB exposure (NCCBC), and; 2) patients with no CCB and ≥1 other antihypertensive prescription (AHTC). CCBC was compared with NCCBC and AHTC according to cancer outcomes. Conditional logistic cox-regression models estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI). Results: There were 150,750 patients in the CCBC, 557,931 in the NCCBC, and 156,966 in the AHTC. Cancer rates (crude per 1000 person-years) were 16.51, 15.75 and 10.62 for the CCBC, NCCBC and AHTC respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC and AHTC were 0.88 (0.86-0.89) and 1.01 (0.98-1.04) respectively. Adjusted HRs (CI) of breast, prostate, and colon cancer for the CCBC compared to the AHTC were 0.95 (0.87-1.04), 1.07 (0.98-1.16) and 0.89 (0.81-0.98) respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC were 0.88 (0.85-0.91), 0.98 (0.93-1.04), and 1.11 (0.98-1.27) for 0 to 5years, 5 to 10years, and ≥10 years of cumulative drug exposure respectively. Conclusions: This study showed strong evidence that CCB use is not associated with cancer. Shorter periods of CCB exposure showed a small protective effect for cancer, as did CCB exposure for colon cancer. Results will be discussed in relation to other findings from PROTECT work package two.Background: Instrumental variable (IV) analysis with physicians prescribing preference (PPP) as an IV has been used to control for unobserved confounding in pharmacoepidemiology. PPP can be defined in several ways, but it is unclear how different PPPs perform across databases. Objectives: To assess the validity of the IV PPP in two general practice (GP) databases in the study of inhaled long-acting beta2-agonist (LABA) use and the risk of acute myocardial infarction (AMI). Methods: Information on adult patients with a diagnosis of asthma and/or COPD and at least one prescription of an inhaled short-acting beta2-agonist (SABA)/LABA/ muscarinic antagonist (MA) was extracted from the British Clinical Practice Research Datalink (CPRD, n = 490499), and the Dutch Mondriaan (n = 27459) GP databases. Conventional Cox model and two-stage IV analysis were applied to estimate the effect of LABA vs. non-LABA (SABA/MA) on the risk of AMI. PPPs were defined by the proportion of LABA prescriptions per practice (PLP) or previous single (PPP1), or five (PPP5), or ten (PPP10) prescriptions by a physician. Quantitative methods (e.g. correlation (r), odds ratio (OR), standardized difference (SDif)) were used to assess the validity of the IVs. 95% confidence intervals (CI) for IV estimates were estimated using bootstrapping. Results: LABA was not associated with an increased risk of AMI, adjusted hazard ratio 0.96 [95%CI 0.89-1.02] (CPRD) and 1.18 [0.97-1.43] (Mondriaan) in conventional Cox model and 0.95 [0.55-1.63], 1.24 [0.40-3.60], and 1.24 [0.47-3.09] in IV analyses with PPP10 for CPRD, and PPP5 and PPP10 for Mondriaan, respectively. PLP, PPP1 and PPP5 in the CPRD and PPP1 in Mondriaan were weakly associated with LABA (r0.10) across PLP levels in Mondriaan. Conclusions: LABA use was not associated with an increased risk of AMI compared to non-LABA. Validity of IV depends on the definition of IV and the database in which it is applied. We recommend researchers to generate several possible IVs, assess their validity, and report the estimate(s) from the most valid IV.Background: Results from several cohort studies have indicated that long-term low-dose aspirin (acetylsalicylic acid, ASA) use markedly increases the risk for neovascular age-related macular degeneration (nAMD). nAMD is a serious condition that causes rapid decline in central-field vision over the course of days to weeks. The studies currently available obtained data from questionnaires, therefore lacking high-quality information regarding exposure to low-dose ASA, and had few nAMD cases. Objectives: To quantify the risk for nAMD associated with long-term low-dose ASA use. Methods: A case-control study was conducted, including all cases of nAMD in the period 1 January 1987 - 31 December 2012 aged 50 years and older from the UK Clinical Practice Research Datalink (CPRD) database. Cases were matched to up to five controls on age, gender and general practice. Conditional logistic regression was used to estimate odds ratios for the risk of nAMD associated with increasing durations of low-dose ASA use, adjusting for smoking status, obesity, glaucoma, hypercholesterolaemia, and lipid lowering medication, and cardiovascular diseases. Results: 4,125 cases were matched to 20,173 controls. Cases had a median age of 80.1 years and were in majority female (64.7%). Overall, the risk for nAMD associated with low-dose ASA use was a small but significantly increased adjusted risk of 1.12 (95% confidence interval 1.03 - 1.21). We observed a trend for increasing risk with prolonged use: odds ratios were 1.06 (use for less than twoand- a-half years; 95% CI 0.96 - 1.17), 1.07 (twoand- a-half to five years; 95% CI 0.94 - 1.21), 1.17 (five to ten years; 95% CI 1.04 - 1.31), 1.23 (ten to fifteen years; 95% CI 1.05 - 1.45), and 1.33 (more than fifteen years; 95% CI 1.08 - 1.63), compared to no ASA use. Conclusions: Long-term use of low-dose ASA is associated with an increased risk for nAMD. This risk is lower than previously observed and small compared to other risk factors and the benefit-risk balance of low-dose ASA for the prevention of cardiovascular disease will not be impacted.Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.Background: Unmeasured confounding is one of the principal problems in observational pharmacoepidemiologic studies. Prior event rate ratio (PERR) adjustment method has been proposed to control for unmeasured confounding. Objectives: To assess the performance of the PERR method in realistic pharmacoepidemiologic settings. Methods: Simulation studies were performed in several scenarios with varying effects of prior events on the probability of subsequent exposure, incidence rates, strength of confounders in prior and post periods, and rate of mortality/dropout. Exposure effects were estimated using conventional rate ratio (RR) and PERR adjustmentmethods. For the PERR method, the exposure effect is a ratio of two RRs: RR post exposure initiation and RR prior to initiation of exposure. In each simulation, the sample size was 100000 and each scenario was replicated 10000 times. 95% confidence intervals were estimated in a non-parametric way using the 2.5 and 97.5 percentiles of the 10000 estimates. Results: The exposure effects from the PERR adjustment method are highly biased when “prior” events influence the probability of subsequent exposure or when confounding differs considerably between prior and post periods. For example, the RR ranged from 1.52 to 1.10 (true RR= 2.00) when the effect of prior events on the exposure was RR 1.25 to 1.70, respectively. With a strong effect of prior events on the exposure (e.g. RR= 1.70), the bias of the estimates were more pronounced for PERR method than for the conventional method. In such case, even with a null exposure effect (RR = 1.00), the estimates shifted away from the null. In all settings, the confidence intervals of the estimates were wider for the PERR method than for the conventional method. Conclusions: The PERR adjustment method has significant limitations; in particular situations, e.g. when prior events strongly influence the probability of subsequent exposure, it can be more biased than conventional methods. Hence, caution should be exercised when applying this method and theoretical justification should be provided for underlying assumptions of the PERR.Background: At the time of marketing, knowledge on the safety of the use of drugs during pregnancy is still limited, as pregnant women are not included in pre-marketing research. Also after marketing, collecting information on drug use during pregnancy can be bothersome. In 2013 the pREGnant project started in order to develop and implement a national register for medical drug use during pregnancy in the Netherlands. This register will be used for signal detection and conducting epidemiological studies. In February 2014, a pilot study was started to test and validate this register. Objectives: To describe the first results of the pilot phase of the pREGnant register. Methods: In pREGnant, exposure to medical drugs and other potential risk factors are monitored prospectively. Data are collected by means of web-based questionnaires and completed by pregnant women, focusing on medical drug use, the health of the pregnant woman, pregnancy complications and outcomes, and the health of the child. In the pilot phase, different schemes for data collection are introduced in order to choose the best practice for inclusion. During the pilot phase, inclusion takes place at midwiferies and hospitals. Results: The method and approaches applied will be discussed as well as the number and type of inclusions. Based on the initial results of the validation studies and the experiences with implementing data from other data sources, possibilities for the definite system for pREGnant be discussed. Conclusions: The current lack of knowledge on the teratogenic risks of many medical drug use often hampers healthcare professionals in making evidencebased decisions on whether or not the beneficial effects of treatment outweigh the possible risks for the developing foetus and the pregnant woman. The pREGnant register will enable a systematic collection of information and may fill this gap of knowledge.Background: There is no recent data on the epidemiology of type 1 diabetes (T1D) in Dutch children and adolescents. To assess the incidence and prevalence of T1D in children, which is reasonably rare, a large population has to be monitored. Objectives: To assess trends in the incidence and prevalence of T1D in Dutch children and adolescents aged 0-19 years. Methods: A population-based cohort study was conducted in the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions (1998-2010). Insulin prescriptions were used as a proxy to identify cases of T1D. All children and adolescents aged 0-19 years with at least two insulin prescriptions were identified and the numbers of incident and prevalent cases of T1D (numerators) were calculated in each year. The incidence and prevalence of T1D were calculated overall and for different sexes and age categories (age bands: 0-4, 5-9, 10-14, 15-19, and 0-14 years) using the data from the Dutch Central Bureau of Statistics as denominator. Results: In 2010, the incidence and prevalence of T1D was 31.6/100,000 person-years and 195.2/100,000 children, respectively. From 1998 to 2010, the overall incidence and prevalence of T1D in Dutch children increased by 62.9% and 87.9%, respectively. A similar increasing pattern was observed for boys and girls. The largest increase in the incidence and prevalence of T1D was perceived for 15-19 years adolescents (140% and 93%, respectively). A sensitivity analysis restricted to children 0-14 years showed a plateau and even a gradual decrease in the incidence of T1D, mainly driven by a decreasing trend in the 0-4 year old children. Overall, there was an increase in the mean age at the onset of T1D (from 10.9 in 1999 to 13.1 years in 2010). Conclusions: Our study is the most recent populationbased study to investigate the incidence and prevalence of T1D in Dutch children and adolescents. Both incidence and prevalence of T1D nearly doubled from 1998 to 2010. The increase in the number of new cases and older age at the onset of the disease warrants further research to identify environmental triggering factors of T1D.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: ACEI-induced ADRs are the main reason to discontinue ACEI treatment. In prescription databases, information on ADRs is not available; therefore it is necessary to identify proxies for ADRs in such databases to study risk factors for ADRs. Objectives: To study prescription patterns for ACEIs as potential marker for ACEI-induced ADRs. Methods: A cohort of patients starting ACEI from 2000 to 2011 was identified within the Rotterdam Study, (a prospective population-based cohort study of approximately 15,000 individuals aged 45 years and older). Medication dispensing data on daily basis were obtained from the fully computerized linked pharmacies. Participants were followed from the start of ACEI treatment until the end of study period, death or moving out of the area, whichever came first. Patients were classified into 4 mutually exclusive groups: continuous users, discontinued users, switchers to angiotensin receptor blockers (ARBs), and switchers to other antihypertensives. For continuous use or switching, the maximum time interval between two prescription periods was set at 3 or 6months. Patients without a prescription for antihypertensives, 3 or 6months after the end date of the last ACEI prescription were classified as discontinued users. Primary care physician files were searched for reasons of ACEI discontinuation for patients who discontinued or switched ACEIs. Clinical events were classified as definite ADRs (73.5% cough, 3% angioedema, 23.5%others), probable ADRs, possible ADRs and definite non-ADRs. Positive predictive values (PPVs) of the prescription patters of the 3 groups for ADRs were calculated. Results: Totally 1132 patients were included. The PPV for a definite ADR was 56.1% in switchers to ARBs, while the PPVs for switchers to other antihypertensives, and discontinued users were 39.5% and 19.5%. Including probable and possible ADRs, increased the PPVs for switchers to ARBs to 68.3% and 90.5%. A 6-month time interval gave slightly higher PPVs compared to a 3-month interval (maximum 6.1% higher). Conclusions: This study showed that switching from ACEI to ARB is the best marker for ACEI-induced ADRs in prescription databases.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: Results from multiple observational studies on inhaled long-acting beta-2-agonists (LABA) and the risk of acute myocardial infarction (AMI) are conflicting, due to variations in methodological, clinical and health care characteristics. To some extent, the discrepancies in the design might limit the comparability of the results encountered. Objectives: To determine the risk of AMI in inhaled LABA users in two European electronic primary care databases using a common study protocol. Methods: Patients from the Dutch Mondriaan (1.4 Million) and the UK CPRD (5 Million) databases were included if they had a diagnosis of asthma and/or COPD, and were prescribed at least one inhaled LABA, a short-acting beta-2-agonist (SABA), or a short- or long-acting muscarinic antagonist (SAMA, LAMA) during the study period (2002 to 2009). LABA episodes were divided into current, recent (1. Effect of Statin Use on Acute Kidney Injury Following Elective Cardiothoracic Surgery: A Population Cohort Study in Denmark J Bradley Layton, Malene K Hansen, Carl-Johan Jakobsen, Jan J Andreasen, Vibeke E Hjortdal, Bodil S Rasmussen, Abhijit V Kshirsagar, Ross J Simpson, Christian F Christiansen. Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Clinical Epidemiology, Aarhus Univeristy Hosptial, Aarhus, Denmark; Anesthesia and Intensive Care, Aarhus University Hospital, Aarhus, Denmark; Cardiothoracic Surgery, Aalborg University Hospital, Aalborg, Denmark; Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark; Anaesthesia and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark; Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC,Background: Limited quantitative data exist on the burden of chronic comorbidities in children and adolescents with type 1 diabetes (T1D). Such knowledge is necessary for the development of guidelines and prevention programs. Objectives: To determine the incidence of chronic comorbidities in children and adolescents with T1D and to compare the risks with the diabetes-free children. Methods: A population-based cohort study was conducted using the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions. Insulin prescriptions were used as a proxy to identify incident cases of T1D. All patients (Background: Pregnancy-induced hypertension (PIH) is possibly caused by an increased activity of the sympatic nervous system. Previous studies have suggested that inhibition of the re-uptake of serotonin and norepinephrine by selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) could contribute to this increased activity. Objectives: To assess the association between the use of antidepressants (ADs) and the development of pregnancyinduced hypertension. Methods: Using the prescription database IADB.nl we conducted a case-control study among pregnant women between 1995 and 2012. Cases were defined as>1 dispensed prescription of an antihypertensive drug (methyldopa, dihydralazine, ketanserin, labetalol, nifidepine) after 20weeks of gestation. Controls were matched for age at time of giving birth. Only first and singleton pregnancies of women not using any antihypertensive drug during 6months before pregnancy till 20weeks of gestation were included. Exposure was defined as>1 dispensed prescription of an antidepressant during pregnancy. Logistic regression analysis was used to estimate odds ratios (OR) and their corresponding 95% confidence intervals (95% CIs). Subanalyses were conducted for class of AD (TCA, SSRI, other) and duration of AD use (1-30, ≥ 31 Defined Daily Doses (DDDs)). As the exact duration of gestation was unknown, all analysis were conducted for 3 theoretical gestational ages (36, 38, 40weeks). Results: A total of 312 PIH cases and 12480 controls were included in the analysis (gestational age 36 weeks). The exposure rate among case and control pregnancies was 3.2% and 1.5% respectively. The use of AD increased the risk for developing PIH more than twice (OR [95% CI] 2.24 [1.17-4.27]). Significant associations (OR [95% CI]) were also found for the subgroups TCA (3.39 [1.04-11.08]), SSRI (2.23 [1.03-4.81]) and ≥ 31 DDDs (2.38 [1.16-4.90]). Increasing the theoretical gestational age showed comparable results. Conclusions: Prolonged use of ADs during pregnancy appeared to be associated with an increased risk of developing PIH. When balancing the benefit and risks of using these drugs during pregnancy, this should be taken into account.Background: In observational studies of time-varying treatment, conditioning on time-dependent confounders that are affected by previous treatment using conventional regression methods may adjust-away(indirect) treatment effects.In the presence of unmeasured common causes of confounders and outcome, it can also induce collider-stratification bias. Objectives: To compare time-dependent propensity scores, conventional Cox and marginal structural models (MSM) in a study of selective serotonin reuptake inhibitors (SSRI) and the risk of hip fracture (HF). Methods: A cohort of patients with a first prescription for antidepressants (AD, SSRI or tricyclic antidepressants, TCA) was extracted from the Dutch Mondriaan GP database in the period 2001-2009.Potential confounders were ascertained when antidepressant use changed over time or at six month intervals. Follow-up began with the first day of AD prescription and ended at the occurrence of HF, death, unregistration with the GP, or end of the study.Treatment effects were estimated using time-varying Cox regression, PS stratification, covariate adjustment, and inverse probability weighting (MSM) to control for confounding. In MSMs, censoring was accounted for by including inverse probability of censoring weights (IPCW). Results: The crude HR of HF in current SSRI users versus non-current SSRI users was 1.70 [95%CI 1.09-2.65]. Effects increased after confounder adjustment, PS stratification, and PS adjustment: HR 2.28 [1.45-3.59], 2.47 [1.54-3.95], and 2.51 [1.54-4.09], respectively.When MSMs with stabilized weights were used, the HR was 1.34 [0.65-2.76] and 1.53 [0.81-2.93] with and without accounting for censoring, respectively. After weight truncation, the HR became 2.09 [1.31-3.35] and 2.37 [1.49-3.78] with and without accounting for censoring, respectively. Conclusions: When treatment and confounders are time-varying, accounting for informative censoring can materially influence effect estimates in addition to the potential collider-stratification and confounding bias that arise due conditioning or stratification on time-dependent confounders.Hence, the use of methods such as MSMs is recommended.