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Papers by Robert Reynolds

British journal of clinical pharmacology, Jan 27, 2015

Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long-acting antic... more Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long-acting anticholinergic agent. We aimed to analyse drug utilization, off-label usage, and generalizability of the TIOSPIR trial results for both devices. Patients aged ≥18 years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included in the analysis (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, sex, and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analysed. Between 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10,000 persons for HandiHaler® and between 1.5 and 9.3 per 10,000 persons for Respimat®. Only small differences regarding patient characteristics exist...

BMJ (online)

Objective To examine the rates of cardiac arrest and ventricular arrhythmia in patients with trea... more Objective To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls. Design Cohort study of outpatients using administrative data. Setting 3 US Medicaid programmes. Participants Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis. Main outcome measure Diagnosis of cardiac arrest or ventricular arrhythmia. Results Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses >600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038). Conclusions The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.

Ethnicity & disease

The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia ... more The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) was to estimate the prevalence and distribution of cardiovascular disease risk factors, including hypertension, hypercholesterolemia, diabetes, obesity, cigarette smoking, and physical inactivity, in the general population of both China and Thailand. A multistage cluster sampling method was used to select a nationally representative sample of 15,838 adults, aged 35-74 years, in China, and 5,350 similarly aged adults in Thailand. Data on medical history, cigarette smoking, alcohol consumption, diet, physical activity, and awareness and control of risk factors for cardiovascular disease, were collected. Blood pressure, body weight and height, and hip and waist circumferences, were measured using standard methods. Fasting blood specimens were collected to measure levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, and creatinine. All data w...

Pharmacoepidemiology and drug safety, Jan 6, 2015

The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic age... more The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic agents on the risk of acute liver injury using a self-controlled case series and case-crossover study and (ii) to compare the results between the case-only studies. For the self-controlled case series study relative incidence ratios (IRR) were calculated by dividing the rate of acute liver injury experienced during patients' periods of exposure to antibiotics to patients' rate of events during non-exposed time using conditional Poisson regression. For the case-crossover analysis we calculated Odds Ratios (OR) using conditional logistic regression by comparing exposure during 14- and 30-day risk windows with exposure during control moments. Using the self-controlled case series approach, the IRR was highest during the first 7 days after receipt of a prescription (10.01, 95% CI 6.59-15.18). Omitting post-exposure washout periods lowered the IRR to 7.2. The highest estimate in the case...

Pharmacoepidemiology and drug safety, Jan 7, 2015

Studies on drug utilization usually do not allow direct cross-national comparisons because of dif... more Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10 000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch ...

Pharmacoepidemiology and Drug Safety, 2015

There is widespread concern about increases in antibiotic use, but comparative data from differen... more There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries. Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1-year-period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic. The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0-9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty-nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin. Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries. © 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons, Ltd.

Pharmacoepidemiology and Drug Safety, 2015

The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in ... more The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables. To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied. CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30 days prior to first BZD exposure was also evaluated. In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP = 1.47 (1.29-1.67) and AORCPRD = 1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD. CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs. Copyright © 2015 John Wiley & Sons, Ltd.

Pharmacoepidemiology and Drug Safety, 2015

Results from observational studies may be inconsistent because of variations in methodological an... more Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs. Copyright © 2015 John Wiley & Sons, Ltd.

BMC pulmonary medicine, Jan 6, 2015

After the SMART trial evaluating the safety of salmeterol (long-acting beta-2-agonist (LABA)) in ... more After the SMART trial evaluating the safety of salmeterol (long-acting beta-2-agonist (LABA)) in asthma patients, regulatory actions were taken to promote a guideline-adherent prescribing of LABA only to patients receiving inhaled corticosteroids (ICS). We aim to analyse LABA- and ICS-related prescription patterns after the SMART trial in Germany. Patients documented in the Bavarian Association of Statutory Health Insurance Physicians database (approximately 10.5 million people) were included if they had a diagnosis of asthma and at least one prescription of LABA and/or ICS between 2004 and 2008. Annual period prevalence rates (PPRs) were estimated and Cochrane Armitage tests were used. Highest annual PPRs were found for budesonide and the fixed combination of salmeterol/fluticasone. The proportion of "concomitant LABA and ICS users" increased from 52 to 58% within the study period, whereas for "LABA users without ICS" a slight decrease from 6.5 to 5.4% was found...

Ethnicity & disease, 2004

The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia ... more The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) was to estimate the prevalence and distribution of cardiovascular disease risk factors, including hypertension, hypercholesterolemia, diabetes, obesity, cigarette smoking, and physical inactivity, in the general population of both China and Thailand. A multistage cluster sampling method was used to select a nationally representative sample of 15,838 adults, aged 35-74 years, in China, and 5,350 similarly aged adults in Thailand. Data on medical history, cigarette smoking, alcohol consumption, diet, physical activity, and awareness and control of risk factors for cardiovascular disease, were collected. Blood pressure, body weight and height, and hip and waist circumferences, were measured using standard methods. Fasting blood specimens were collected to measure levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, and creatinine. All data w...

Purpose Drug utilization studies have applied different methods to various data types to describe... more Purpose Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases.

PLoS ONE, 2014

Respiratory drugs are widely used in children to treat labeled and non-labeled indications but on... more Respiratory drugs are widely used in children to treat labeled and non-labeled indications but only some data are available quantifying comprehensively off-label usage. Thus, we aim to analyse drug utilisation and off-label prescribing of respiratory drugs focusing on age-and indication-related off-label use. Patients aged #18 years documented in the Bavarian Association of Statutory Health Insurance Physicians database (approx. 2 million children) between 2004 and 2008 were included in our study. Annual period prevalence rates (PPRs) per 10,000 children and the proportion of age-and indicationrelated off-label prescriptions were calculated and stratified by age and gender. Within the study period, highest PPRs were found for the fixed combination of clenbuterol/ambroxol (between 374-575 per 10,000 children) and the inhaled short acting beta-2-agonist salbutamol (between 378-527 per 10,000 children). Highest relative PPR increase was found for oral salbutamol (approx. 39-fold) whereas the most distinct decrease was found for oral long-acting beta-2-agonist clenbuterol (297%). Compound classes most frequently involved in off-label prescribing were inhaled bronchodilative compounds (91,402; 37.3%) and oral beta-2-agonists (26,850; 22.5%). The highest absolute number of off-label prescriptions were found for inhaled salbutamol (n = 67,084; 42.0%) and oral clenbuterol/ambroxol (fixed combination, n = 18,897; 20.7%). Off-label prescribing due to indication was of much greater relevance than age-related off-label use. Most frequently, bronchodilative compounds were used off-label to treat respiratory tract infections. Highest off-label prescription rates were found in the youngest patients without relevant gender-related differences. Off-label prescribing of respiratory drugs is common especially in young children. Bronchodilative drugs were most frequently used off-label for treating acute bronchitis or upper respiratory tract infections underlining the essential need for a more rational prescribing in this area.

All attendees at ICPE 2005 must wear their name badges to ALL events. A badge will be needed for ... more All attendees at ICPE 2005 must wear their name badges to ALL events. A badge will be needed for admission to meeting related functions such as scientific sessions, social events and the exhibit/poster hall. Badges will be included in the registration packet material. In some instances, tickets will be required. 6 Visit the ISPE website, www.pharmacoepi.org for meeting updates and information. August 21-24, 2005 | Gaylord Opryland Resort and Convention Center | Nashville, TN 7 I n t e r n a t i o n a l C o n f e r e n c e o n P h a r m a c o e p i d e m i o l o g y & T h e r a p e u t i c R i s k M a n a g e m e n t 2 2 n d Abstract Submission Deadline: February 15, 2006

Pharmaceutics, 2013

Drug adverse event (AE) signal detection using the Gamma Poisson Shrinker (GPS) is commonly appli... more Drug adverse event (AE) signal detection using the Gamma Poisson Shrinker (GPS) is commonly applied in spontaneous reporting. AE signal detection using large observational health plan databases can expand medication safety surveillance. Using data from nine health plans, we conducted a pilot study to evaluate the implementation and findings of the GPS approach for two antifungal drugs, terbinafine and itraconazole, and two diabetes drugs, pioglitazone and rosiglitazone. We evaluated 1676 diagnosis codes grouped into 183 different clinical concepts and four levels of granularity. Several signaling thresholds were assessed. GPS results were compared to findings from a companion study using the identical analytic dataset but an alternative statistical method-the tree-based scan statistic (TreeScan). We identified 71 statistical signals across two signaling thresholds and two methods, including closely-related signals of overlapping diagnosis definitions. Initial review found that most ...

The objective of this study was to estimate the prevalence and distribution of hypertension and t... more The objective of this study was to estimate the prevalence and distribution of hypertension and to determine the status of hypertension awareness, treatment, and control in the general adult population in China. The International Collaborative Study of Cardiovascular Disease in ASIA (InterASIA), conducted in 2000 -2001, used a multistage cluster sampling method to select a nationally representative sample. A total

Schizophrenia Research, 2010

Background: Recent studies have suggested that early adverse events, such as childhood trauma, ac... more Background: Recent studies have suggested that early adverse events, such as childhood trauma, accentuate vulnerability for psychosis, and stressful life events, occurring later in the vulnerable individual may move the individual towards the tipping point of psychosis. This would, alongside the contribution of genetic factors, suggest that environment x environment (ExE) interactions play a decisive role in psychosis development, with vulnerability being determined by cascading events within the stress-trauma pathogen. However, establishing causality of these environmental dynamics requires prospective studies that are adequately powered, which are currently lacking in the literature. The Early Developmental Stages of Psychopathology (EDSP) study, a longitudinal study of a population sample of 3021 adolescents and young adults, was designed to provide answers about prevalence, incidence, risk factors, comorbidity and course of mental disorders. We used data from this study to examine whether there was a synergistic interaction between early life trauma and occurrence of later life events on the risk of outcome of psychosis, taking into account the moderating or mediating effects of cannabis abuse and urbanicity. Methods: We analyzed the association between childhood trauma (retrospectively assessed at T0), negative life events occurring between T0 and T2, and psychosis at T3, defined as either (i) having a total score above the 90th centile on the psychoticism subscale of the SCL-90, or (ii) having displayed impairment or helpseeking behavior in response to the occurrence of psychotic symptoms at T3, or (iii) being diagnosed as having a psychotic disorder at T3, according to the explicit diagnostic criteria of the DSM-IV. Associations were expressed as odds ratios from logistic regression models. All analyses were a priori adjusted for age, sex, urbanicity and cannabis abuse. Furthermore, all participants fulfilling criteria for psychosis liability prior to T3 were excluded from analysis. Results: The experience of life events between T0 and T2 significantly increased the risk to develop psychosis at T3 (OR: 2.37; 95% CI: 1.68-3.38; p = .000). This risk was larger in subjects who were exposed to trauma in their childhood (OR: 5.92; 95% CI: 2.41-14.57; p = .000), compared to those who did not experience childhood trauma (OR: 1.88; 95% CI: 1.25-2.82; p = .002). The observed risk difference in the trauma group was significantly larger than the risk difference in the non-trauma group (14,9% and 4,4% resp.; test for interaction: χ2(df = 1676) = 7.59, p = .006). Discussion: Results from this longitudinal study indicate that the occurrence of early life trauma moderates the effect of later life events on the risk of psychosis, taking into account the moderating

Schizophrenia Research, 2010

in-depth clinical interview to assess the relationship between psychotic symptoms and suicidality... more in-depth clinical interview to assess the relationship between psychotic symptoms and suicidality or other psychopathology. Methods: As part of a community study on suicidality in young people, a 50-minute self reported screening questionnaire which included one item designed to assess psychotic symptoms (auditory hallucinations) was administered to 1000 adolescents aged 14 years in community schools, in Cork, Ireland. The following question ("Have you ever heard voices or sounds that no one else can hear?") was used as it has been shown previously to show the best predictive power (Kelleher et al., 2009). Other screening questions assessed suicidality and other psychopathology. Detailed clinical interviews by experienced child and adolescent psychiatrists were subsequently carried out with a sample of these adolescents who endorsed a positive answer to screening questions. Results: We plan to calculate the sensitivity and specificity and positive predictive value for the specific screening symptom on auditory hallucinations and its relationship to suicidality, psychotic symptoms or psychopathology as verified on clinical interview. Discussion: Our results will be of value to those engaged in treating children and adolescents with psychiatric disorder and will inform on the clinical significance of a positive answer to a screening question on auditory hallucinations in adolescence.

Reproductive Health Matters, 1999

This revie~vof the literature examined the available evidence regarding the effects of lthat i\ t... more This revie~vof the literature examined the available evidence regarding the effects of lthat i\ t' cali 'female genital surgeries'on women's health and sexuality. It shows that the evidence on the consequences of female genital surgeries for health and sexuality is insufficient to support the powerful rhetoric thatpresents these practices as a grave danger to women's health. However, the scarcity of evidence is most likely due to the lack of concerted efforts to invcstigatc harmfill effects, rather than to the relative safety ofthese operations. There are f&studies that can provide estimates of the health risks associated with female genital surgeries. Complications are found to be more frequent for more extensive surgeries; the frequencies ofcomplications are around 1 per cent for serious, and Z-l8per cent for less serious, complications. The findings on sexuality are inconclusive but nonetheless suggest that many women who have had the surgeries have the capacity for sexual enjoyment. This review underscores the need for systematic studies ofthe health complications offemale genital operations, and emphasiscs the importance of understanding the meaning ofthese practices and the risks associated with them in the societies where they are prevalent, in order to inform discussions of the implications ofindividual choices and policy decisions. This paper is followed by responses from Seham Abd el Salam, Jocelyn De.long and Marie Basily Assaad, who each discuss the term 'female genital surgerics'as an alternative to 'female genital mutilation'. The,yalso discuss the subjective and symbolic USC of'thescpractices as a means ofsocial control ofwomen and women's sexuality; the relationship between research and advocacy work and what sorts ofinformation are needed for each ofthem; the methodological and ethical constraints in conducting studies on the harmful effects of these practices; the relationship between national and international advocacy work on FGM: and the importance of challenging the culture ofsilence on this subject and bringing discussion into the open In order to bring about change.

Menopause, 2004

To investigate the factors that influence therapeutic decisions at menopause, particularly those ... more To investigate the factors that influence therapeutic decisions at menopause, particularly those related to the burden of menopause symptoms, in a population of women living in Massachusetts, as part of the multisite DAMES (Decisions At Menopause Study). A survey using face-to-face interviews with a randomly selected sample of 293 women aged 45 to 55 who are members of the Fallon Community Health Plan in Central Massachusetts. The instrument combined closed- and open-ended questions and elicited information about a number of health topics, including the symptoms experienced by respondents over the preceding month and the decisions they made regarding therapies. Symptom reporting was found to be relatively high, with more than half of the sample reporting hot flashes, sleep disturbances, joint pains, and headaches in the month preceding the survey; one third to one half of the women reported palpitations, night sweats, fatigue, and numbness. The highest frequency of symptoms occurred during perimenopause. Nearly four fifths of the women consulted a healthcare provider, and one fifth used hormone therapy. More than half of the respondents said menopause is a difficult phase, and about half found decisionmaking about it to be difficult. This study documents a relatively heavy burden of symptoms in a relatively healthy population and provides an update on earlier studies in Massachusetts.

British journal of clinical pharmacology, Jan 27, 2015

Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long-acting antic... more Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long-acting anticholinergic agent. We aimed to analyse drug utilization, off-label usage, and generalizability of the TIOSPIR trial results for both devices. Patients aged ≥18 years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included in the analysis (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, sex, and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analysed. Between 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10,000 persons for HandiHaler® and between 1.5 and 9.3 per 10,000 persons for Respimat®. Only small differences regarding patient characteristics exist...

BMJ (online)

Objective To examine the rates of cardiac arrest and ventricular arrhythmia in patients with trea... more Objective To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls. Design Cohort study of outpatients using administrative data. Setting 3 US Medicaid programmes. Participants Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis. Main outcome measure Diagnosis of cardiac arrest or ventricular arrhythmia. Results Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses >600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038). Conclusions The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.

Ethnicity & disease

The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia ... more The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) was to estimate the prevalence and distribution of cardiovascular disease risk factors, including hypertension, hypercholesterolemia, diabetes, obesity, cigarette smoking, and physical inactivity, in the general population of both China and Thailand. A multistage cluster sampling method was used to select a nationally representative sample of 15,838 adults, aged 35-74 years, in China, and 5,350 similarly aged adults in Thailand. Data on medical history, cigarette smoking, alcohol consumption, diet, physical activity, and awareness and control of risk factors for cardiovascular disease, were collected. Blood pressure, body weight and height, and hip and waist circumferences, were measured using standard methods. Fasting blood specimens were collected to measure levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, and creatinine. All data w...

Pharmacoepidemiology and drug safety, Jan 6, 2015

The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic age... more The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic agents on the risk of acute liver injury using a self-controlled case series and case-crossover study and (ii) to compare the results between the case-only studies. For the self-controlled case series study relative incidence ratios (IRR) were calculated by dividing the rate of acute liver injury experienced during patients' periods of exposure to antibiotics to patients' rate of events during non-exposed time using conditional Poisson regression. For the case-crossover analysis we calculated Odds Ratios (OR) using conditional logistic regression by comparing exposure during 14- and 30-day risk windows with exposure during control moments. Using the self-controlled case series approach, the IRR was highest during the first 7 days after receipt of a prescription (10.01, 95% CI 6.59-15.18). Omitting post-exposure washout periods lowered the IRR to 7.2. The highest estimate in the case...

Pharmacoepidemiology and drug safety, Jan 7, 2015

Studies on drug utilization usually do not allow direct cross-national comparisons because of dif... more Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10 000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch ...

Pharmacoepidemiology and Drug Safety, 2015

There is widespread concern about increases in antibiotic use, but comparative data from differen... more There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries. Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1-year-period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic. The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0-9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty-nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin. Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries. © 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons, Ltd.

Pharmacoepidemiology and Drug Safety, 2015

The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in ... more The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables. To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied. CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30 days prior to first BZD exposure was also evaluated. In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP = 1.47 (1.29-1.67) and AORCPRD = 1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD. CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs. Copyright © 2015 John Wiley & Sons, Ltd.

Pharmacoepidemiology and Drug Safety, 2015

Results from observational studies may be inconsistent because of variations in methodological an... more Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs. Copyright © 2015 John Wiley & Sons, Ltd.

BMC pulmonary medicine, Jan 6, 2015

After the SMART trial evaluating the safety of salmeterol (long-acting beta-2-agonist (LABA)) in ... more After the SMART trial evaluating the safety of salmeterol (long-acting beta-2-agonist (LABA)) in asthma patients, regulatory actions were taken to promote a guideline-adherent prescribing of LABA only to patients receiving inhaled corticosteroids (ICS). We aim to analyse LABA- and ICS-related prescription patterns after the SMART trial in Germany. Patients documented in the Bavarian Association of Statutory Health Insurance Physicians database (approximately 10.5 million people) were included if they had a diagnosis of asthma and at least one prescription of LABA and/or ICS between 2004 and 2008. Annual period prevalence rates (PPRs) were estimated and Cochrane Armitage tests were used. Highest annual PPRs were found for budesonide and the fixed combination of salmeterol/fluticasone. The proportion of "concomitant LABA and ICS users" increased from 52 to 58% within the study period, whereas for "LABA users without ICS" a slight decrease from 6.5 to 5.4% was found...

Ethnicity & disease, 2004

The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia ... more The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) was to estimate the prevalence and distribution of cardiovascular disease risk factors, including hypertension, hypercholesterolemia, diabetes, obesity, cigarette smoking, and physical inactivity, in the general population of both China and Thailand. A multistage cluster sampling method was used to select a nationally representative sample of 15,838 adults, aged 35-74 years, in China, and 5,350 similarly aged adults in Thailand. Data on medical history, cigarette smoking, alcohol consumption, diet, physical activity, and awareness and control of risk factors for cardiovascular disease, were collected. Blood pressure, body weight and height, and hip and waist circumferences, were measured using standard methods. Fasting blood specimens were collected to measure levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, and creatinine. All data w...

Purpose Drug utilization studies have applied different methods to various data types to describe... more Purpose Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases.

PLoS ONE, 2014

Respiratory drugs are widely used in children to treat labeled and non-labeled indications but on... more Respiratory drugs are widely used in children to treat labeled and non-labeled indications but only some data are available quantifying comprehensively off-label usage. Thus, we aim to analyse drug utilisation and off-label prescribing of respiratory drugs focusing on age-and indication-related off-label use. Patients aged #18 years documented in the Bavarian Association of Statutory Health Insurance Physicians database (approx. 2 million children) between 2004 and 2008 were included in our study. Annual period prevalence rates (PPRs) per 10,000 children and the proportion of age-and indicationrelated off-label prescriptions were calculated and stratified by age and gender. Within the study period, highest PPRs were found for the fixed combination of clenbuterol/ambroxol (between 374-575 per 10,000 children) and the inhaled short acting beta-2-agonist salbutamol (between 378-527 per 10,000 children). Highest relative PPR increase was found for oral salbutamol (approx. 39-fold) whereas the most distinct decrease was found for oral long-acting beta-2-agonist clenbuterol (297%). Compound classes most frequently involved in off-label prescribing were inhaled bronchodilative compounds (91,402; 37.3%) and oral beta-2-agonists (26,850; 22.5%). The highest absolute number of off-label prescriptions were found for inhaled salbutamol (n = 67,084; 42.0%) and oral clenbuterol/ambroxol (fixed combination, n = 18,897; 20.7%). Off-label prescribing due to indication was of much greater relevance than age-related off-label use. Most frequently, bronchodilative compounds were used off-label to treat respiratory tract infections. Highest off-label prescription rates were found in the youngest patients without relevant gender-related differences. Off-label prescribing of respiratory drugs is common especially in young children. Bronchodilative drugs were most frequently used off-label for treating acute bronchitis or upper respiratory tract infections underlining the essential need for a more rational prescribing in this area.

All attendees at ICPE 2005 must wear their name badges to ALL events. A badge will be needed for ... more All attendees at ICPE 2005 must wear their name badges to ALL events. A badge will be needed for admission to meeting related functions such as scientific sessions, social events and the exhibit/poster hall. Badges will be included in the registration packet material. In some instances, tickets will be required. 6 Visit the ISPE website, www.pharmacoepi.org for meeting updates and information. August 21-24, 2005 | Gaylord Opryland Resort and Convention Center | Nashville, TN 7 I n t e r n a t i o n a l C o n f e r e n c e o n P h a r m a c o e p i d e m i o l o g y & T h e r a p e u t i c R i s k M a n a g e m e n t 2 2 n d Abstract Submission Deadline: February 15, 2006

Pharmaceutics, 2013

Drug adverse event (AE) signal detection using the Gamma Poisson Shrinker (GPS) is commonly appli... more Drug adverse event (AE) signal detection using the Gamma Poisson Shrinker (GPS) is commonly applied in spontaneous reporting. AE signal detection using large observational health plan databases can expand medication safety surveillance. Using data from nine health plans, we conducted a pilot study to evaluate the implementation and findings of the GPS approach for two antifungal drugs, terbinafine and itraconazole, and two diabetes drugs, pioglitazone and rosiglitazone. We evaluated 1676 diagnosis codes grouped into 183 different clinical concepts and four levels of granularity. Several signaling thresholds were assessed. GPS results were compared to findings from a companion study using the identical analytic dataset but an alternative statistical method-the tree-based scan statistic (TreeScan). We identified 71 statistical signals across two signaling thresholds and two methods, including closely-related signals of overlapping diagnosis definitions. Initial review found that most ...

The objective of this study was to estimate the prevalence and distribution of hypertension and t... more The objective of this study was to estimate the prevalence and distribution of hypertension and to determine the status of hypertension awareness, treatment, and control in the general adult population in China. The International Collaborative Study of Cardiovascular Disease in ASIA (InterASIA), conducted in 2000 -2001, used a multistage cluster sampling method to select a nationally representative sample. A total

Schizophrenia Research, 2010

Background: Recent studies have suggested that early adverse events, such as childhood trauma, ac... more Background: Recent studies have suggested that early adverse events, such as childhood trauma, accentuate vulnerability for psychosis, and stressful life events, occurring later in the vulnerable individual may move the individual towards the tipping point of psychosis. This would, alongside the contribution of genetic factors, suggest that environment x environment (ExE) interactions play a decisive role in psychosis development, with vulnerability being determined by cascading events within the stress-trauma pathogen. However, establishing causality of these environmental dynamics requires prospective studies that are adequately powered, which are currently lacking in the literature. The Early Developmental Stages of Psychopathology (EDSP) study, a longitudinal study of a population sample of 3021 adolescents and young adults, was designed to provide answers about prevalence, incidence, risk factors, comorbidity and course of mental disorders. We used data from this study to examine whether there was a synergistic interaction between early life trauma and occurrence of later life events on the risk of outcome of psychosis, taking into account the moderating or mediating effects of cannabis abuse and urbanicity. Methods: We analyzed the association between childhood trauma (retrospectively assessed at T0), negative life events occurring between T0 and T2, and psychosis at T3, defined as either (i) having a total score above the 90th centile on the psychoticism subscale of the SCL-90, or (ii) having displayed impairment or helpseeking behavior in response to the occurrence of psychotic symptoms at T3, or (iii) being diagnosed as having a psychotic disorder at T3, according to the explicit diagnostic criteria of the DSM-IV. Associations were expressed as odds ratios from logistic regression models. All analyses were a priori adjusted for age, sex, urbanicity and cannabis abuse. Furthermore, all participants fulfilling criteria for psychosis liability prior to T3 were excluded from analysis. Results: The experience of life events between T0 and T2 significantly increased the risk to develop psychosis at T3 (OR: 2.37; 95% CI: 1.68-3.38; p = .000). This risk was larger in subjects who were exposed to trauma in their childhood (OR: 5.92; 95% CI: 2.41-14.57; p = .000), compared to those who did not experience childhood trauma (OR: 1.88; 95% CI: 1.25-2.82; p = .002). The observed risk difference in the trauma group was significantly larger than the risk difference in the non-trauma group (14,9% and 4,4% resp.; test for interaction: χ2(df = 1676) = 7.59, p = .006). Discussion: Results from this longitudinal study indicate that the occurrence of early life trauma moderates the effect of later life events on the risk of psychosis, taking into account the moderating

Schizophrenia Research, 2010

in-depth clinical interview to assess the relationship between psychotic symptoms and suicidality... more in-depth clinical interview to assess the relationship between psychotic symptoms and suicidality or other psychopathology. Methods: As part of a community study on suicidality in young people, a 50-minute self reported screening questionnaire which included one item designed to assess psychotic symptoms (auditory hallucinations) was administered to 1000 adolescents aged 14 years in community schools, in Cork, Ireland. The following question ("Have you ever heard voices or sounds that no one else can hear?") was used as it has been shown previously to show the best predictive power (Kelleher et al., 2009). Other screening questions assessed suicidality and other psychopathology. Detailed clinical interviews by experienced child and adolescent psychiatrists were subsequently carried out with a sample of these adolescents who endorsed a positive answer to screening questions. Results: We plan to calculate the sensitivity and specificity and positive predictive value for the specific screening symptom on auditory hallucinations and its relationship to suicidality, psychotic symptoms or psychopathology as verified on clinical interview. Discussion: Our results will be of value to those engaged in treating children and adolescents with psychiatric disorder and will inform on the clinical significance of a positive answer to a screening question on auditory hallucinations in adolescence.

Reproductive Health Matters, 1999

This revie~vof the literature examined the available evidence regarding the effects of lthat i\ t... more This revie~vof the literature examined the available evidence regarding the effects of lthat i\ t' cali 'female genital surgeries'on women's health and sexuality. It shows that the evidence on the consequences of female genital surgeries for health and sexuality is insufficient to support the powerful rhetoric thatpresents these practices as a grave danger to women's health. However, the scarcity of evidence is most likely due to the lack of concerted efforts to invcstigatc harmfill effects, rather than to the relative safety ofthese operations. There are f&studies that can provide estimates of the health risks associated with female genital surgeries. Complications are found to be more frequent for more extensive surgeries; the frequencies ofcomplications are around 1 per cent for serious, and Z-l8per cent for less serious, complications. The findings on sexuality are inconclusive but nonetheless suggest that many women who have had the surgeries have the capacity for sexual enjoyment. This review underscores the need for systematic studies ofthe health complications offemale genital operations, and emphasiscs the importance of understanding the meaning ofthese practices and the risks associated with them in the societies where they are prevalent, in order to inform discussions of the implications ofindividual choices and policy decisions. This paper is followed by responses from Seham Abd el Salam, Jocelyn De.long and Marie Basily Assaad, who each discuss the term 'female genital surgerics'as an alternative to 'female genital mutilation'. The,yalso discuss the subjective and symbolic USC of'thescpractices as a means ofsocial control ofwomen and women's sexuality; the relationship between research and advocacy work and what sorts ofinformation are needed for each ofthem; the methodological and ethical constraints in conducting studies on the harmful effects of these practices; the relationship between national and international advocacy work on FGM: and the importance of challenging the culture ofsilence on this subject and bringing discussion into the open In order to bring about change.

Menopause, 2004

To investigate the factors that influence therapeutic decisions at menopause, particularly those ... more To investigate the factors that influence therapeutic decisions at menopause, particularly those related to the burden of menopause symptoms, in a population of women living in Massachusetts, as part of the multisite DAMES (Decisions At Menopause Study). A survey using face-to-face interviews with a randomly selected sample of 293 women aged 45 to 55 who are members of the Fallon Community Health Plan in Central Massachusetts. The instrument combined closed- and open-ended questions and elicited information about a number of health topics, including the symptoms experienced by respondents over the preceding month and the decisions they made regarding therapies. Symptom reporting was found to be relatively high, with more than half of the sample reporting hot flashes, sleep disturbances, joint pains, and headaches in the month preceding the survey; one third to one half of the women reported palpitations, night sweats, fatigue, and numbness. The highest frequency of symptoms occurred during perimenopause. Nearly four fifths of the women consulted a healthcare provider, and one fifth used hormone therapy. More than half of the respondents said menopause is a difficult phase, and about half found decisionmaking about it to be difficult. This study documents a relatively heavy burden of symptoms in a relatively healthy population and provides an update on earlier studies in Massachusetts.