Correction to: Impact of risk minimisation measures on the use of strontium ranelate in Europe: a multi-national cohort study in 5 EU countries by the EU-ADR Alliance.

The original version of this article, published on 26 November 2019 contained a mistake.

Impact of risk minimisation measures on the use of strontium ranelate in Europe: a multi-national cohort study in 5 EU countries by the EU-ADR Alliance.

INTRODUCTION: In May 2013 and March 2014, the European Medicines Agency (EMA) issued two decisions restricting the use of strontium ranelate (SR). These risk minimisation measures (RMM) introduced new contraindications and limited the indications of SR therapy. The EMA required an assessment of the impact of RMMs on the use of SR in Europe. Methods design: multi-national, multi-database cohort Setting: electronic medical record databases based on hospital (Denmark) and primary care provenance (Italy, Spain, the Netherlands, UK). PARTICIPANTS: the database source populations were included for population-based analyses, and SR users for patient-level analyses. INTERVENTION: New RMMs included contraindications (ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, uncontrolled hypertension) and restricted SR indication to severe osteoporosis with initiation by experienced physician and not as first line anti-osteoporosis therapy. METHODS: Prevalence and incidence rates of SR use in the population; prevalence of contraindications and restricted indications in SR users, plus 1-year therapy persistence. Drug use measures were calculated in three periods for comparison: reference (2004 to May 2013), transition (June 2013 to March 2014) and assessment (from April 2014 to end 2016). RESULTS: The study population included 143 million person-years(PY) of follow-up and 76,141 incident episodes of SR treatment. Average monthly prevalence rates of SR use dropped by 86.4% from 62.6/10,000 PY (95 CI 62.4-62.9) in the reference to 8.5 (8.5-8.6) in the assessment period. Similarly, the incidence rate of SR use fell by 97.3% from 7.4/10,000 PY (7.4-7.4) to 0.2 (0.2-0.2) between the reference and assessment period. The prevalence of any contraindication decreased, whilst the prevalence of restricted indications increased in these periods. One-year persistence decreased in the assessment compared with reference period. CONCLUSIONS: Our study demonstrates a substantial impact of the regulatory action to restrict use of SR in Europe: SR utilisation overall decreased strongly. The proportion of patients fulfilling the restricted indications, without contraindications, increased after the proposed RMMs.

Use of antihistamines and risk of ventricular tachyarrhythmia: a nested case-control study in five European countries from the ARITMO project.

PURPOSE: After regulatory restrictions for terfenadine and astemizole in '90s, only scarce evidence on proarrhythmic potential of antihistamines has been published. We evaluate the risk of ventricular tachyarrhythmia (VA) related to the use of individual antihistamines. METHODS: A matched case-control study nested in a cohort of new users of antihistamines was conducted within the EU-funded ARITMO project. Data on 1997-2010 were retrieved from seven healthcare databases: AARHUS (Denmark), GEPARD (Germany), HSD and ERD (Italy), PHARMO and IPCI (Netherlands) and THIN (UK). Cases of VA were selected and up to 100 controls were matched to each case. The odds ratio (OR) of current use for individual antihistamines (AHs) was estimated using conditional logistic regression. RESULTS: For agents largely used to prevent allergic symptoms, such as cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine, we found no VA risk. A statistically significant, increased risk of VA was found only for current use of cyclizine in the pooled analysis (ORadj, 5.3; 3.6-7.6) and in THIN (ORadj, 5.3; 95% CI, 3.7-7.6), for dimetindene in GEPARD (ORadj, 3.9; 1.1-14.7) and for ebastine in GEPARD (ORadj, 3.3; 1.1-10.8) and PHARMO (ORadj, 4.6; 1.3-16.2). CONCLUSIONS: The risk of VA associated with a few specific antihistamines could be ascribable to heterogeneity in pattern of use or in receptor binding profile.

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures.

SUMMARY: There is evidence that the use oral bisphosphonates can lead to osteronecrosis of the jaws (ONJ). Although the occurrence of ONJ appears rare among oral bisphosphonates (BPs) users, it is important to know that it exists and can be opportunely minimized. INTRODUCTION: The purpose of this study is to evaluate the association between BPs prescribed for the secondary prevention of osteoporotic fractures and the occurrence of ONJ. METHODS: An Italian record linkage claims database with a target population of around 18 million individuals (6 million over 55 years of age) constituted the data source. We conducted a nested case-control study within a cohort of individuals aged 55+ years old, who were discharged from hospitals with a primary diagnosis of incident osteoporotic fracture. The date related to the discharge diagnosis of ONJ was the index date. Conditional logistic regression for matched data was fitted to estimate the odds ratio (OR) along with 95 % confidence intervals (95 % CI) for the likely association between use of BPs and the risk of ONJ. RESULTS: Any one of the 61 ascertained cases of ONJ (incidence rate, 36.6 per 100,000 person-years) was matched to 20 controls for a total of 1120 controls. When the exposure to BPs was modeled according to recency (i.e., exposure time window prior to the index date) of use, the adjusted OR (95 % CI) for current users was 2.8 (1.3-5.9) against never users. The cumulative use of BPs has shown to increase the incidence of ONJ among patients with primary osteoporotic fractures, although not statistically significant risk has been observed. CONCLUSIONS: Although the risk of BP-related ONJ appears low in non-oncological indications, it is important to be aware that it exists and to know how it may be predicted and possibly minimized.

Establishing in vitro to clinical correlations in the evaluation of cardiovascular safety pharmacology.

Preclinical studies are vital in establishing the efficacy and safety of a new chemical entity (NCE) in humans. To deliver meaningful information, experiments have to be well defined and provide outcome that is relevant and translatable to humans. This review briefly surveys the various preclinical experiments that are frequently conducted to assess drug effects on cardiac conductivity in early drug development. We examine the different approaches used to establish correlations between non-clinical and clinical settings and discuss their value in the evaluation of cardiovascular risk.

Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.

BACKGROUND: We estimated the multiple sclerosis (MS) incidence in the Netherlands for better active monitoring of potential vaccine safety signals. METHODS: A retrospective cohort study (1996-2008) was conducted using a population-based general practice research database containing electronic medical records. Additional information was collected to validate incident probable cases. RESULTS: In the source population (648,656 persons), 146 incident probable MS cases were identified. Overall incidence rate was 6.3/100,000 person years (py; 95% CI, 5.2-7.2). In the subgroup in which MS could be fully validated, the incidence increased from 4/100,000 py (95% CI, 3-5) in 1996-2004 to 9/100,000 py in 2007/8 (95% CI, 6-16). This increase was highest among women, but not statistically significantly different by gender. The median lag time between first recorded symptoms and MS diagnosis decreased from 32 months (<1998) to 2 months (>2005). CONCLUSIONS: MS is rare in the Netherlands. In recent years, there was a slight increase in the incidence especially among women during the fertile age. This increase coincided with a decrease in lag time between symptoms and diagnosis, both for men and women. This trend should be taken into account in the interpretation of MS cases occurring in a population where new vaccinations will be introduced shortly.

Tiotropium Handihaler and the risk of cardio- or cerebrovascular events and mortality in patients with COPD.

BACKGROUND: Tiotropium has been associated with an increased risk of mortality and/or cardiovascular events. Recent data from RCTs suggests tiotropium Handihaler to be safe, but its safety has not yet been fully investigated under real-life circumstances. METHODS: We conducted 2 nested case-control studies in a COPD cohort from the Dutch IPCI database. In the first case-control study, cases had a cardiovascular or cerebrovascular endpoint (CCVE): stroke and transient ischemic attack (TIA), myocardial infarction, heart failure and/or ventricular arrhythmia. In the second, cases were all patients who died. Cases were matched to controls on age, sex and index date. Conditional logistic regression analysis was used to calculate adjusted odds ratios (OR(adj)) with 95% confidence intervals (CI) for tiotropium vs. long-acting beta-agonists (LABA). RESULTS: Within a cohort of 6788 COPD patients, 784 CCVE's and 1032 deaths were reported. Compared to current LABA use, use of tiotropium Handihaler was neither associated with an increased risk of a CCVE (OR(adj) 0.89, 95% 0.55-1.44) nor with an increased risk of death (OR(adj) 0.79, 95% CI 0.49-1.28). CONCLUSIONS: In real life, use of tiotropium Handihaler in COPD patients is not associated with an increased risk of a CCVE or mortality compared to LABA.

Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT).

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making.

Estrogens and the risk of complex regional pain syndrome (CRPS).

OBJECTIVE: Since complex regional pain syndrome (CRPS) shows a clear female predominance, we investigated the association between the cumulative as well as current exposure to estrogens, and CRPS. METHODS: A population-based case-control study was conducted in the Integrated Primary Care Information (IPCI) project in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during a visit (using International Association for the Study of Pain Criteria), or had been diagnosed by a specialist. Controls were matched to cases on gender, age, calendar time, and injury. Measures of cumulative endogenous estrogen exposure were obtained by questionnaire and included age of menarche and menopause, menstrual life, and cumulative months of pregnancy and breast-feeding. Current estrogen exposure at CRPS onset was retrieved from the electronic medical records and determined by current pregnancy or by the use of oral contraceptive (OC) drugs or hormonal replacement therapy (HRT). RESULTS: Hundred and forty-three female cases (1493 controls) were included in analyses on drug use and pregnancies, while cumulative endogenous estrogen exposure was studied in 53 cases (58 controls) for whom questionnaire data were available. There was no association between CRPS and either cumulative endogenous estrogen exposure, OC, or HRT use. CRPS onset was increased during the first 6 months after pregnancy (OR: 5.6, 95%CI: 1.0-32.4), although based on small numbers. DISCUSSION: We did not find an association between CRPS onset and cumulative endogenous estrogen exposure or current OC or HRT use, but more powered studies are needed to exclude potential minor associations.

Referral and treatment patterns for complex regional pain syndrome in the Netherlands.

BACKGROUND: Patients with complex regional pain syndrome (CRPS) are seen and treated by a variety of physicians. The present study aims to describe referral and treatment patterns for CRPS patients in the Netherlands. METHODS: Patients, who were selected (1996-2005) from an electronic general practice (GP) database (Integrated Primary Care Information Project), were invited for study participation, involving diagnosis verification (International Association for the Study of Pain criteria) and assessment of referrals and treatment through information retrieved from GP journals, patients' questionnaires, pharmacy dispensing lists and specialist letters if available. RESULTS: One hundred and two patients were included. Sixty-one percent had presented first at the GP, while 80% subsequently consulted one or more medical specialists, most frequently an anesthetist (55% of the cases) or a specialist in rehabilitation medicine (41%). Over 90% of the patients received oral or topical pharmacotherapy, 45% received intravenous therapy, 89% received non-invasive therapy (i.e. physiotherapy) and 18% received nerve blocks. Analgesics and free radical scavengers were administered early during CRPS, while vasodilating drugs and drugs against neuropathic pain (antidepressants and anti-epileptics) were administered later on. Pharmacotherapy was usually initiated by a medical specialist. CONCLUSION: The Dutch treatment guidelines, issued in 2006, recommend free radical scavenger prescription (plus physiotherapy) as the initial treatment step for CRPS. Until 2005 only half of the patients received a scavenger within 3 months after disease onset, and the majority presents first at the GP, in particular GPs may be encouraged to initiate treatment with scavengers, while waiting for the results of further specialist consultation.

Prevalence and treatment of hypertensive patients with multiple concomitant cardiovascular risk factors in The Netherlands and Italy.

The Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA) trial demonstrated the benefits of combined antihypertensive/lipid-lowering treatment over antihypertensive treatment alone in hypertensive patients with > or =3 additional cardiovascular (CV) risk factors. We assessed the prevalence and treatment of patients with hypertension and > or =3 additional CV risk factors in The Netherlands and Italy in a retrospective cohort study using the Integrated Primary Care Information (IPCI) database in The Netherlands and the Health Search/Thales Database (HSD) in Italy. Patients aged > or =16 years, with 1 year of valid database history, diagnosed and/or treated for hypertension (>140/90 mmHg) during 2000-2002 were included in the study. The IPCI and HSD populations consisted of approximately 175000 and approximately 325000 patients, respectively. The prevalence of hypertension increased from 20.3 to 22.3% in the IPCI, and from 19.0 to 21.8% in the HSD during 2000-2002. The prevalence of > or =3 concomitant risk factors among hypertensive patients increased from 31.2 and 31.1% in 2000 to 34.2 and 39.3% in 2002 in the IPCI and HSD, respectively. From 2000 to 2002, among hypertensive patients with > or =3 CV risk factors and no prior symptomatic CV disease (CVD) approximately 54-57% in the IPCI and 80-83% in the HSD received antihypertensive treatment. In these patients, the use of combined antihypertensive and lipid-lowering treatment increased from 14.2 to 17.6% in the IPCI and from 15.5 to 17.4% in the HSD from 2000 to 2002. This study shows that primary prevention of CVD in hypertensive patients in The Netherlands and Italy could be improved.

A novel programme to evaluate and communicate 10-year risk of CHD reduces predicted risk and improves patients' modifiable risk factor profile.

AIMS: We assessed whether a novel programme to evaluate/communicate predicted coronary heart disease (CHD) risk could lower patients' predicted Framingham CHD risk vs. usual care. METHODS: The Risk Evaluation and Communication Health Outcomes and Utilization Trial was a prospective, controlled, cluster-randomised trial in nine European countries, among patients at moderate cardiovascular risk. Following baseline assessments, physicians in the intervention group calculated patients' predicted CHD risk and were instructed to advise patients according to a risk evaluation/communication programme. Usual care physicians did not calculate patients' risk and provided usual care only. The primary end-point was Framingham 10-year CHD risk at 6 months with intervention vs. usual care. RESULTS: Of 1103 patients across 100 sites, 524 patients receiving intervention, and 461 receiving usual care, were analysed for efficacy. After 6 months, mean predicted risks were 12.5% with intervention, and 13.7% with usual care [odds ratio = 0.896; p = 0.001, adjusted for risk at baseline (17.2% intervention; 16.9% usual care) and other covariates]. The proportion of patients achieving both blood pressure and low-density lipoprotein cholesterol targets was significantly higher with intervention (25.4%) than usual care (14.1%; p < 0.001), and 29.3% of smokers in the intervention group quit smoking vs. 21.4% of those receiving usual care (p = 0.04). CONCLUSIONS: A physician-implemented CHD risk evaluation/communication programme improved patients' modifiable risk factor profile, and lowered predicted CHD risk compared with usual care. By combining this strategy with more intensive treatment to reduce residual modifiable risk, we believe that substantial improvements in cardiovascular disease prevention could be achieved in clinical practice.

Adherence to gastroprotection and the risk of NSAID-related upper gastrointestinal ulcers and haemorrhage.

BACKGROUND: Upper gastrointestinal (UGI) complications are a well-recognized risk of NSAID treatment, requiring preventive measures in high-risk patients. Adherence to gastroprotective agents (GPAs) in NSAID users has been suggested to be suboptimal. AIM: To investigate the association between adherence to GPAs (proton pump inhibitors or H(2)-receptor antagonists) and the risk of NSAID-related UGI ulcers or haemorrhage in high-risk patients. METHODS: A population-based nested case-control study was conducted within a cohort of new NSAID users with at least one risk factor for a NSAID-related UGI complication, identified in the Dutch IPCI database during 1996-2005. Adherence to GPAs was calculated as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Multivariate conditional logistic regression analysis was used to calculate odds ratios with 95% confidence intervals (95% CI). RESULTS: Fifteen percent of the non-selective NSAID users received GPAs. The risk of a NSAID-related UGI complication among NSAID users increased 16% for every 10% decrease in adherence. Compared to patients with a PDC of >80%, patients with PDCs of 20-80% and <20% had a 2.5-fold (95% CI: 1.0-6.7) respectively 4.0-fold (95% CI: 1.2-13.0) increased risk. CONCLUSION: There is a strong inverse relationship between adherence to GPAs and the risk of UGI complications in high-risk NSAID users.

[Increased risk of gastrointestinal bleeding or ulcers when using spironolactone: a case-control study]. / Toegenomen kans op gastro-intestinale bloedingen of ulcera bij gebruik van spironolacton: patiënt-controlestudie.

OBJECTIVE: To study the association between the use of spironolactone and the risk of upper gastrointestinal bleeding or ulcers. DESIGN: Case-control study. METHOD: The study used the computerized 'integrated primary care information' (IPCI) database in the Netherlands. All persons, 18 years or older during the study period from January 1st 1996 through September 30th 2003 with at least one year of valid case history were included. Patients with a medical history of alcoholism or gastrointestinal cancer were excluded. For each case of gastroduodenal ulcer or upper gastrointestinal bleeding, 10 controls were sampled from the same database, matched on age (year of birth), gender and index date. The association between the use ofspironolactone, calculated from the number of general practitioners' prescriptions, and the occurrence of an upper gastrointestinal event (upper gastrointestinal bleeding or ulcers) was analysed by means of a conditional logistic regression analysis. RESULTS: Within the source population of 306,645 patients, 523 cases with gastric or duodenal ulcers or upper gastrointestinal bleeding were identified and matched with 5,230 controls. Current use of spironolactone was associated with a 2.7-fold (adjusted odds ratio (OR); 95% CI: 1.2-6.0) increased risk of gastrointestinal events. This risk was higher in patients on high dosages and was the highest in patients using spironolactone in combination with an ulcerogenic drug (NSAIDs, platelet aggregation inhibitors, corticosteroids or vitamin K antagonist) (adjusted OR: 7.3; 95% CI: 2.9-18.7). CONCLUSION: The risk of upper gastrointestinal bleeding or ulcer was increased 2.7 times when spironolactone was used.

Persistence and adherence to proton pump inhibitors in daily clinical practice.

BACKGROUND: Proton pump inhibitors are widely used, but little is known about the usage pattern in different indications. AIM: To analyse proton pump inhibitor usage patterns in the general population. METHODS: A cohort of 16 311 incident proton pump inhibitor users was identified in the Integrated Primary Care Information database, a Dutch general practice research database. Persistence and adherence were calculated by indication. Risk factors were identified by logistic regression analysis. RESULTS: One-year persistence was 31% in patients using proton pump inhibitors for gastro-oesophageal reflux. Persistence was higher in oesophagitis grade A/B (54%), grade C/D (73%) and Barrett's oesophagus (72%), compared to patients with only reflux symptoms (27%). Approximately 25% of patients with non-reflux dyspepsia or Helicobacter pylori-associated indications used proton pump inhibitors for more than 6 months. Half of all patients used proton pump inhibitors <80% of time indicating intermittent use, which was independent of indication. Exception were patients with Barrett's oesophagus, who were most adherent. CONCLUSIONS: A substantial proportion of patients with indications not requiring long-term treatment use proton pump inhibitors for an extended period. Half of the patients used proton pump inhibitors on-demand or intermittently. Such usage pattern is probably sufficient for most patients, but may be inadequate if proton pump inhibitors are used for serious diseases, such as severe oesophagitis or Barrett's oesophagus.

Real life data on incidence and risk factors of severe asthma exacerbations in children in primary care.

Real-life data on the incidence rates (IR) and risk factors of severe asthma exacerbations in children are sparse. We aimed to assess IR and risk factors of severe asthma exacerbations in children in real life. We conducted a population-based cohort study using a Dutch GP database containing complete medical records of >1 million patients. All records of children with physician-diagnosed asthma aged 5-18 years between 2000 and 2012 were examined for exacerbations, defined as either hospitalization, emergency department visit or need of systemic steroids for asthma. IR was expressed as number of exacerbations per person year (PY). We identified 14,303 asthmatic children with 35,118 PY of follow-up and 732 exacerbations. The overall IR was 2.1/100PY (95% CI 1.9-2.2), 4.1/100PY (3.8-4.4) for children on asthma treatment. Re-exacerbation occurred in 2% (1.3-4.3) of patients within 1 month, in 25% (20.6-28.8) within 1 year. Predictors for (frequent) exacerbations were age, medication use and prior exacerbations (all p < 0.001). The overall IR of severe asthma exacerbations was 4/100PY in children on asthma treatment, highest in spring and fall. 25% of the patients with an exacerbation will experience a next exacerbation within 1 year. More severe asthma is a predictor of subsequent and future exacerbations.

Minocycline and lupuslike syndrome in acne patients.

BACKGROUND: Recently several case reports described the association between minocycline and lupuslike syndrome. Minocycline, one of the tetracyclines, is widely used to treat acne. We aimed to examine the association of exposure to minocycline and other tetracyclines with the development of lupuslike syndrome. METHODS: We conducted a nested case-control study in a cohort of 27 688 acne patients aged 15 to 29 years, using data automatically recorded on general practitioners' office computers in the United Kingdom. Controls were matched to cases on age, sex, and practice. The main outcome was lupuslike syndrome defined as the occurrence of polyarthritis or polyarthralgia of unknown origin, with negative rheumatoid factor or latex agglutination test, positive or unmeasured antinuclear factor, elevated or unmeasured erythrocyte sedimentation rate, and absence of or unmeasured antinative DNA antibody levels. RESULTS: We identified 29 cases and selected 152 controls. Current single use of minocycline was associated with an 8.5-fold (95% confidence interval [CI], 2.1-35) increased risk of developing lupuslike syndrome compared with non-users and past users of tetracyclines combined. The risk of past exposure to any of the tetracyclines was closely similar to nonuse (relative risk, 1.3; 95% CI, 0.5-3.3). Current use of doxycycline, oxytetracycline, or tetracycline combined was associated with a 1.7-fold (95% CI, 0.4-8.1) increase of risk. The risk increased with longer use. CONCLUSION: Current use of minocycline increased the risk of developing lupuslike syndrome 8.5-fold in the cohort of young acne patients. The effect was stronger in longer-term users. However, the absolute risk of developing lupuslike syndrome seems to be relatively low.

Application of a Systems Pharmacology-Based Placebo Population Model to Analyze Long-Term Data of Postmenopausal Osteoporosis.

Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.

Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events.

OBJECTIVES: We performed a prospective, double-blind, randomized study to compare the occurrence of neuropsychiatric adverse events and concentration impairment during prophylactic use of either mefloquine or atovaquone plus chloroguanide (INN, proguanil). METHODS: Our potential study population consisted of all persons who were included in the MAL30010 trial at the Travel Clinic, Rotterdam, The Netherlands. All subjects were randomized to receive either active atovaquone (250 mg) plus chloroguanide (100 mg) daily plus a placebo for mefloquine weekly or active mefloquine (250 mg) weekly plus a placebo for atovaquone plus chloroguanide daily. Each subject was followed up from a baseline screening visit up to the index date, 7 days after he or she left the malaria-endemic area. We measured the interindividual and intraindividual changes in mood disturbance by means of the Dutch shortened Profile of Mood States and 3 domains of the Neurobehavioral Evaluation System, which included sustained attention, coding speed, and visuomotor accuracy between baseline and follow-up visit. RESULTS: The cohort consisted of 119 subjects with a mean age of 35 years. A significant deterioration in depression, anger, fatigue, vigor, and total mood disturbance domains occurred during use of mefloquine but not during use of atovaquone plus chloroguanide. Stratification for sex showed between-treatment differences in female patients but not in male patients. In both treatment groups, sustained attention deteriorated after travel, especially with increased duration of stay. CONCLUSIONS: Prophylactic use of mefloquine was associated with significantly higher scores on scales for depression, anger, and fatigue and lower scores for vigor than prophylactic use of atovaquone plus chloroguanide.

Multiple sclerosis and antecedent infections: a case-control study.

OBJECTIVES: To determine whether there is an excess of respiratory tract infections in the 5-week, 3-month, and 12-month periods before MS symptom onset and if there is an association between MS and a history of infectious mononucleosis (IM). BACKGROUND: The etiology of MS remains unknown, but infection is frequently suggested as a putative etiologic agent. Epidemiologic studies have produced inconsistent evidence for an etiologic role of respiratory tract infections (RTI) and IM in MS. METHODS: The authors performed a case-control study using the General Practice Research Database from the United Kingdom. There were 225 subjects with definite or probable MS, and 900 controls matched for age, sex, and physician practice. Using computerized patient records, the authors compared the mean rates of RTI per patient in the 5-week, 3-month, and 12-month periods before the date of onset of the first symptoms compatible with MS (index date). They also compared histories of IM. RESULTS: In all periods, an increased frequency of RTI was associated with a significantly increased risk of MS. A history of IM was associated with greater than five times the risk of MS (OR = 5.5 [95% CI 1.5 to 19.7]). CONCLUSIONS: These results support an association between a history of IM and subsequent MS. Respiratory tract infections may precipitate disease onset.