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Aims Studies on adherence and persistence with non-vitamin K oral anticoagulant (NOAC) treatment have relied on data from the early years of NOAC availability. We aimed to study long-term adherence and persistence with NOACs and their association with stroke risk. Methods and results From the Stockholm Healthcare database, we included 21 028 atrial fibrillation patients claiming a first NOAC prescription from July 2011 until October 2018, with more than 1000 patients having more than 5 years of follow-up (median: 2.0, interquartile range: 1.0–3.2). Persistence rates, defined as continuing to claim NOAC prescriptions within a 90-day gap, decreased to 70% at the end of follow-up. However, 85% of the patients were treated at the end of the study due to reinitiations. Adherence, calculated as medication possession rate (MPR) in 3 and 6-month intervals among persistent users, remained stable at 90%, with 75% of patients having an MPR >95% throughout the study period. Using a case–control design, we calculated associations of persistence and adherence with stroke risk, adjusting for potential confounders. The outcome was a composite of ischaemic or unspecified stroke and transient ischaemic attack. Non-persistence and poor adherence were both associated with increased stroke risk [non-persistence adjusted odds ratio (aOR): 2.05; 95% confidence interval (CI): 1.49–2.82, 1% reduction MPR aOR: 1.03; CI: 1.01–1.05]. There was no association between non-persistence or poor adherence and the falsification endpoints; fractions and respiratory infections, indicating no ‘healthy-adherer’ effect. Conclusion Persistence rates decreased slowly over time, but persistent patients had high adherence rates. Both non-persistence and poor adherence were associated with an increased stroke risk.

Aims To analyse 90-day mortality in atrial fibrillation (AF) patients after a stroke or a severe bleed and assess associations with the type of antithrombotic treatment at the event. Methods and results From the Stockholm Healthcare database, we selected 6017 patients with a known history of AF who were diagnosed with ischaemic stroke, 3006 with intracranial haemorrhage, and 4291 with a severe gastrointestinal bleed (GIB). The 90-day mortality rates were 25.1% after ischaemic stroke, 31.6% after intracranial haemorrhage, and 16.2% after severe GIB. We used Cox regression and propensity score-matched analyses to test the association between antithrombotic treatment at the event and 90-day mortality. After intracranial haemorrhage, there was a significantly higher mortality rate in warfarin compared to non-vitamin K oral anticoagulant (NOAC)-treated patients [adjusted hazard ratio (aHR) 1.36, 95% confidence interval (CI) 1.04–1.78]. After an ischaemic stroke and a severe GIB, patients receiving antiplatelets or no antithrombotic treatment had significantly higher mortality rates compared to patients on NOACs, but there was no difference comparing warfarin to NOACs (aHR 0.84, CI 0.63–1.12 after ischaemic stroke, aHR 0.91, CI 0.66–1.25 after severe GIB). Propensity score-matched analysis yielded similar results. Conclusion Mortality rates were high in AF patients suffering from an ischaemic stroke, an intracranial haemorrhage, or a severe GIB. NOAC treatment was associated with a lower 90-day mortality after intracranial haemorrhage than warfarin.

Aims To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. Methods and results We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. Results Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. Conclusion Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.

BACKGROUND: Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. Because there is limited information on the association between type 1 diabetes (T1D) and psychiatric disorders (including psychiatric medication use) in children and adolescents, we assessed frequency of use of these medications before and after the onset of T1D. METHODS: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System (1999-2009). Children and adolescents (

We aimed to quantify the effects of antidepressant (AD) use in oral anticoagulant (OAC)-treated patients with atrial fibrillation (AF). Using the Stockholm Healthcare database, we analyzed AF patients initiated with an OAC. Outcomes were severe bleeds and strokes and were analyzed using Cox models. We included 17,210 patients claiming warfarin and 13,385 claiming a non-vitamin K OAC. The number of patients that claimed an AD during follow-up was 4,303. Concomitant OAC and AD use was associated with increased rates of severe bleeds (4.7 vs. 2.7 per 100 person-years) compared with OAC treatment alone (adjusted hazard ratio (aHR) 1.42, confidence interval (CI): 1.12-1.80), but not significantly associated with increased stroke rates (3.5 vs. 2.1 per 100 person-years, aHR 1.23, CI: 0.93-1.62). No significant differences in risks were observed between different OAC classes or different AD classes. In conclusion, concomitant use of an OAC and an AD is associated with an increased bleeding risk.

Accurately quantifying actual evapotranspiration (ETa) over wetlands is important for the improved management of these ecosystems, since 65% of them are threatened by clearing or drainage in South Africa. This study evaluated a range of available estimates of ETa over six palmiet wetlands, which are key ecological structures in terms of water regulation and sediment trapping. The research compared three remote sensing based products (a local product, FruitLook, and two global data products, MOD16 ET and EEFlux) across different rainfall years (2008 to 2019). Their outputs were validated, where possible, with limited ground-based scintillometer data on the Krom palmiet wetland, which indicated that MOD16 and EEFlux were most representative of ground-based measurements. We also compared the small pixel size EEFlux data over three wetlands with ETa over increasing buffers of land cover (100, 500, 1000 m) in order to validate the perception of these wetlands being high water users. While larger wetlands had slightly higher evaporative demands than adjacent areas, ETa over a small wetland was similar to neighboring land cover. The results indicate that palmiet wetland ETa is highly variable and dependent on external factors such as climate, wetland size and seasonality.

Background Anticoagulation treatment reduces the risk of stroke but increases the risk of bleeding in atrial fibrillation (AF) patients. There is little data on survival after a stroke or a severe bleed. Objective To analyze 90-day mortality in AF patients after an ischemic stroke, an intracranial hemorrhage (ICH) or a gastrointestinal bleed (GIB) and assess associations with the type of antithrombotic treatment preceding the event. Methods From the Stockholm Healthcare database (n=2.3 million inhabitants) we selected all AF patients suffering from an ischemic stroke, an intracranial bleed, or a severe GIB requiring acute hospital care between July 2011 and August 2018 and assessed 90-day mortality rates. We assessed current use of warfarin, non-vitamin K oral anticoagulants (NOAC), or antiplatelet agents at the time of the event. We used a Cox regression to calculate adjusted hazard ratios (aHRs), adjusting for components of the Charlson Comorbidity Index, the CHADsVASc score, the HAS-BLED score, comedication, and year of inclusion, for the association between treatment preceding the event and mortality. In addition, we performed log-rank tests in propensity score matched cohorts. Results Of 105 313 patients with AF, 6 017 were included after an ischemic stroke, 3 006 after an ICH, and 4 291 after a GIB. 90-day mortality rates were 25.1%, 31.6% and 16.2%, respectively. Patients suffering from an ischemic stroke were the oldest at 81.6±9.8 (S.D:) years of age followed by patients suffering from an ICH (80.2±9.8 years) or a GIB (78.7±10.5 years). A large proportion of patients suffering ischemic stroke (72%) had no anticoagulant treatment preceding the event. After ICH, there was a significantly increased risk of mortality in warfarin compared to NOAC treated patients after adjusting for confounders (aHR: 1.36 CI: 1.04–1.78). Patients receiving antiplatelets or no treatment had significantly higher mortality rates than patients on NOAC treatment, both after an ischemic stroke and a GIB, but there was no significant difference between warfarin and NOACs (aHR 0.84 CI: 0.63–1.12 after ischemic stroke, aHR 0.91 CI: 0.66–1.25 after GIB). Propensity score matched analyses yielded similar results. Survival curves after event Conclusion Mortality rates are high in AF patients suffering from an ischemic stroke, an ICH, or a GIB. NOAC treatment was associated with a lower 90-day mortality after ICH than warfarin, but no such difference was found after ischemic stroke or GIB. After ischemic stroke and GIB, mortality rates were higher in antiplatelet treated and untreated patients compared to NOAC treated patients. Acknowledgement/Funding Swedish Heart Lung Foundation

Background Anticoagulation treatment reduces the risk of stroke but increases the risk of bleeding in atrial fibrillation (AF) patients. Antidepressants use is associated with increased risk for stroke and bleeds. Objective To assess the association between antidepressant use in AF patients with oral anticoagulants and bleeding and stroke risk. Methods All AF patients newly prescribed with an oral anticoagulant in the Stockholm Healthcare database (n=2.3 million inhabitants) from July 2011 until 2016 were included and followed for one year or shorter if they stopped claiming oral anticoagulant treatment or had an outcome of interest. Outcomes were severe bleeds and strokes, requiring acute hospital care. During follow-up, patients were considered exposed to antidepressant after claiming a prescription for the duration of the prescription. With a time-varying Cox regression, we assessed the association between antidepressant use and strokes and bleeds, adjusting for confounders (i.e., age, sex, comorbidities, comedication, and year of inclusion). In addition, we performed a propensity score matched analysis to test the robustness of our findings. Results Of the 30,595 patients included after claiming a prescription for a NOAC (n=13,506) or warfarin (n=17,089), 4 303 claimed a prescription for an antidepressant during follow-up. A total of 712 severe bleeds and 551 strokes were recorded in the cohort. Concomitant oral anticoagulant and antidepressant use was associated with increased rates of severe bleeds (4.7 vs 2.7 per 100 person-years) compared to oral anticoagulant treatment without antidepressant use (aHR 1.42, 95% CI: 1.12–1.80), but not significantly associated with increased stroke rates (3.5 vs 2.1 per 100 person-years, aHR 1.23, 95% CI: 0.93–1.62). No significant differences were observed between different oral anticoagulant classes (i.e., warfarin or NOAC) or different antidepressant classes (i.e., SSRI, TCA, or other antidepressant). Additional propensity-score matched analyses yielded similar results but showed a significantly increased risk for stroke (HR: 1.47, 95% CI: 1.08–2.02). Incidence rates of strokes and bleeds Conclusion Concomitant use of an oral anticoagulant and an antidepressant, irrespective of type, is associated with an increased bleeding risk. Increased awareness and a critical consideration for the need of an antidepressant is recommended in this population. Acknowledgement/Funding Swedish Heart Lung Foundation

Purpose To evaluate the association between the use of streptomycin, amikacin, kanamycin and capreomycin in tuberculosis (TB) treatment and the pharmacovigilance reporting of ototoxicity (deafness or hearing loss, tinnitus and vertigo). Second, to analyze patient demographic and geographic factors that influence the reporting of ototoxicity in TB treatment. Methods A case/non-case disproportionality analysis of the VigiBase® individual case safety reports (ICSRs) of patients treated for TB using multidrug regimens that contain either of streptomycin, amikacin, kanamycin or capreomycin. Cases were reports of ototoxicity; non-cases were other adverse drug reactions (ADRs). The unit of analysis was the drug–ADR pair. We calculated reporting odds ratios (RORs) and their 95% confidence intervals (CI). The referent drug was streptomycin. Results By June 2014, there were 3361 drug–ADR pairs in VigiBase® (1693 ICSRs) where the parenteral administration of the four drugs for TB treatment was suspected of causing the reported ADRs. Deafness, tinnitus and vertigo were reported in 576 drug–ADR pairs (cases), the rest being other ADRs (non-cases). Reporting of deafness was most disproportionately associated with amikacin use (ROR 9.3; 95%CI 3.8–23.0), followed by kanamycin use (ROR 4.3; 95%CI 1.3–14.2). Reporting of vertigo was inversely associated with capreomycin use (ROR 0.1; 95%CI 0.01–0.4). Geographic region affected the reporting of ototoxicity while age and sex did not. Conclusion Spontaneous reporting of deafness cases within VigiBase® was most disproportionately associated with amikacin use, followed by kanamycin. There were regional variations in the global reporting of ototoxicity. These findings should be verified through a follow up study. Copyright © 2016 John Wiley & Sons, Ltd.

In this issue of Pharmacoepidemiology and Drug Safety, several research papers address the safe and appropriate use of opioids. This is important, given the critical situation on opioid use in the United States (US). According to preliminary data from the Centers for Disease Control and Prevention (CDC), more than 72 000 people in the United States died because of drug overdose in 2017 with over two‐thirds involving opioids.1 This situation has been declared a “national public health emergency.”2 To address the so‐called opioid epidemic, the House and Senate recently passed new legislation that aims to increase access to opioid dependence treatment and to prevent illicit opioids from entering the market, and supports research on other treatment options for pain besides opioids.3, 4 Experts and activists are skeptical whether this agreement will solve the opioid crisis, at least in part because of limited funding.3

textabstractAim The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. Methods A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. Results In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). Conclusions Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity.

Background and Purpose— The purpose of this study was to investigate the impact of improved antithrombotic treatment in atrial fibrillation after the introduction of non–vitamin K antagonist oral anticoagulants on the incidence of stroke and bleeding in a real-life total population, including both primary and secondary care. Methods— All resident and alive patients with a recorded diagnosis for atrial fibrillation during the preceding 5 years in the Stockholm County Healthcare database (Vårdanalysdatabasen) were followed for clinical outcomes during 2012 (n=41 008) and 2017 (n=49 510). Results— Pharmacy claims for oral anticoagulants increased from 51.6% to 73.8% (78.7% among those with CHA 2 DS 2 -VASc ≥2). Non–vitamin K antagonist oral anticoagulant claims increased from 0.4% to 34.4%. Ischemic stroke incidence rates decreased from 2.01 per 100 person-years in 2012 to 1.17 in 2017 (incidence rate ratio, 0.58; 95% CI, 0.52–0.65). The largest increases in oral anticoagulants use and decreases in ischemic strokes were seen in patients aged ≥80 years who had the highest risk of stroke and bleeding. The incidence rates for major bleeding (2.59) remained unchanged (incidence rate ratio, 1.00; 95% CI, 0.92–1.09) even in those with a high bleeding risk. Poisson regression showed that 10% of the absolute ischemic stroke reduction was associated with increased oral anticoagulants treatment, whereas 27% was related to a generally decreased risk for all stroke. Conclusions— Increased oral anticoagulants use contributed to a marked reduction of ischemic strokes without increasing bleeding rates between 2012 and 2017. The largest stroke reduction was seen in elderly patients with the highest risks for stroke and bleeding. These findings strongly support the adoption of current guideline recommendations for stroke prevention in atrial fibrillation in both primary and secondary care.

Background There is limited information on patterns of treatment change among new initiators of highly active antiretroviral therapy (HAART) in the regions most affected by HIV/AIDS. This makes it difficult to identify the determinants of treatment change. In this retrospective cohort study, we examined treatment change patterns over a five-year period among initiators of HAART. Methods De-identified data were obtained from the Fevers’ Unit Database at the Korle-Bu Teaching Hospital. All adult treatment-naive patients who started treatment with first line HAART between 1st January, 2008 and 31st December, 2012 were followed over a minimum period of three months. The main outcome was the first treatment change, defined as the first substitution/switch in accordance with the standard treatment guidelines. Data were analyzed stratified by year of treatment initiation. Crude and adjusted hazard ratios were calculated. Results A total of 3933 patients were followed with almost equal numbers of initiators per year. The mean age (standard deviation) at treatment initiation was 39 (10.3) years. The most prescribed HAART combination was AZT/3TC/EFV and overall for initiators zidovudine combination therapy was about 60%. Utilization of stavudine containing HAART increased gradually until 2010 and then dropped to zero. Over the study period, 44.9% of recorded deaths were from those initiated with a stavudine backbone, 41.1% from a zidovudine backbone, and 11.5% from a tenofovir backbone. Females had a significantly higher rate of treatment change compared to males (p-value = 0.0002), and d4T/3TC/EFV and d4T/3TC/NVP recorded independent treatment change hazard ratios of 12.05 (CI 9.58 to 15.16) and 12.03 (CI 9.27 to 15.61) respectively.. Kaplan-Meier curves showed that treatment change was higher among those who started treatment later in the study period compared with those who started earlier. Conclusion A major treatment change in the utilization of antiretroviral medicines in Ghana occurred during the study period which was associated with type of treatment, year of treatment, gender and disease stage. The influence of a policy change during the period may have made a significant impact.. For diseases involving life-long treatment in particular, it is important to monitor and periodically evaluation treatment utilization patterns.

OBJECTIVE: To assess the trends in the incidence and prevalence rates of type 1 diabetes (T1D) among children and adolescents in the Netherlands. METHODS: A population-based cohort study was conducted in the Dutch PHARMO record linkage system (1998-2011). All children and adolescents aged ≤19 yr with at least one insulin dispensing (as a proxy for T1D) were identified and the numbers of incident and prevalent cases (numerators) were calculated. Overall age-adjusted (0-19 yr) incidence and prevalence rates together with age- and sex-specific rates of T1D and their 95% confidence intervals (CI) were calculated using data from the Dutch Central Bureau of Statistics as denominator. Trends over time were assessed using Joinpoint regression software (National Cancer Institute, Bethesda, MD, USA). RESULTS: In 2011, the overall age-adjusted incidence and prevalence rates of T1D were 25.2/100 000 (95% CI, 23.7-26.8) person-years (PY) and 174.4/100 000 (95% CI, 170.2-178.5) children, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence and prevalence rate was 3.7% (95% CI, 1.8-5.7) and 3.8% (95% CI, 2.4-5.2), respectively. While during the study period the largest increases in the incidence and prevalence rates of T1D were observed for the oldest age groups (10-14 and 15-19 yr), a decreasing trend was detected for the 0- to 4-yr-old category (with AAPCs of -1.8 (95% CI, -9.9 to 7.1) and -6.9% (95% CI, -11.5 to -2.1) for incidence and prevalence, respectively). CONCLUSION: Age-adjusted incidence (1999-2011) and prevalence rates (1998-2011) of T1D in Dutch children (aged 0-19 yr) continued to increase and a shift was observed to a later onset of the disease.

Uncertainties associated with General Circulation Models (GCMs) and the downscaling methods used for regional or local scale hydrological modelling can result in substantial differences in estimates of future water resources availability. This paper assesses the skill of nine statistically downscaled GCMs in reproducing historical climate for 15 catchments in five regions of South Africa. The identification of skilled GCMs may reduce the uncertainty in future predictions and the focus is on rainfall skill as the GCMs show very similar patterns of change in temperature. The skill tests were designed to assess whether the GCMs are able to realistically reproduce precipitation distribution statistics and patterns of seasonality, persistence and extremes. Some models are consistently less skilful for the regions assessed, while some are generally more skilful with some regionally specific exceptions. There are differences in the GCMs skill across the different regions and in the skill ranking between coastal areas and inland regions. However, only a limited reduction in uncertainty is achieved when using only the downscaled GCM outputs identified as being skilled in a hydrological model for one of the regions. Further modelling studies are required to determine the general applicability of this observation.

Antiretroviral Therapy (ART) is effective in reducing morbidity and mortality in patients living with HIV/AIDS (PLWHA). However, Adverse Effects (AEs) to ART pose major problems and threaten adherence to therapy. We evaluated the knowledge and attitudes of patients to ART following routine adherence counselling and education in the Korle Bu Teaching Hospital in Accra, Ghana. This cross-sectional study was conducted by administering a questionnaire on socio-demographics, knowledge of AEs of antiretrovirals and attitude to AEs to 98 patients who were on antiretroviral therapy. A 3-point Likert-scale was used to assess knowledge of AEs of ART and a 5 point Likert-scale to assess attitudes to AEs. Mean rated scores for attitude to AEs were estimated and factor analysis was used to reduce the dimensions of the attitudes observed to identify relevant latent constructs. Sixty one percent of participants were females and most of the participants were aged 35-44 years (35%). Ninety nine percent of participants answered that they had been counselled on unpleasant effects of their medicines and 93% knew that all medicines could cause some unpleasant effects. Concerning attitude, 90% of study participants strongly agreed that they benefit from their medicines and get better taking them (mean rated score=4.87 ± 0.49) whilst 27% strongly agreed that medicines may have side effects (mean rated score=3.12 ± 1.55). Majority of the study participants (74%) strongly disagreed that there was no need to tell their doctor/pharmacist about AEs to antiretrovirals (mean rated score=4.60 ± 0.83). Factor analysis yielded two underlying dimensions (cognitive and behavioural/affective aspects) that described participants’ attitude towards AEs. Study participants rating for participants’ knowledge on AEs was good and exhibited positive attitudes to AEs of ART. Adherence counselling and education provided to PLWHA before initiation of antiretroviral therapy is beneficial and should be continued.

Purpose: To explore the use of the biological tumour necrosis factor alpha (TNFalpha) inhibitors used in the treatment of rheumatoid arthritis as a measure of access to treatment with new medicines. In addition, characteristics both related to national health systems and spending will be assessed to explore possible differences in international utilisation. Methods: Data from four European countries were included: Ireland, The Netherlands, Norway and Portugal. Annual utilisation rates of TNFalpha inhibitors (2003-2007) were expressed as defined daily doses (DDD5)/1000 inhabitants/day. Qualitative data such as country characteristics, national health policy characteristics, guidelines were obtained from the literature. In addition, interviews were held with leading rheumatologists of each country to put obtained results into (cultural) context. Results: Utilisation of TNFalpha inhibitors varied widely from 0.32 (Portugal) to 1.89 (Norway) DDD5/1000 inhabitants/day (2007). A major driver for the utilisation of TNFalpha inhibitors seemed to be the country's total health expenditure (R-2 = 0.81). When the use of TNFalpha inhibitors became more established, the association seemed stronger. Differences in health expenditure were nevertheless not the only determinant of usage. Cultural aspects such as difference in recognition of guidelines also come into play when looking at differences in TNFalpha utilisation between countries. Conclusions: The prospects of patients receiving TNFalpha inhibitor treatment depend on the country where they are living. In case uniformity of management and treatment would be considered to provide health benefits, the extent and the causes of variation should feature prominently on future public health agendas. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Objective: A level of 95% adherence to antiretroviral therapy (ART) has been found to benefit HIV/AIDS patients. Low adherence may lead to treatment failure, and may subsequently result in treatment change. The main objective of this study was to evaluate the effect of ART adherence on treatment change Methods: Data were extracted from available written clinical and pharmacy records, and the electronic database at the Korle-Bu Teaching Hospital. Cases comprised all those (≥15 years) who experienced a first treatment change after starting first-line ART between 1/1/2004 and 31/12/2009. Controls (who did not change treatment) were sampled from the same cohort of ART starters and matched to cases on date ART was started. Adherence was determined using the proportion of days covered (PDC) approach and poor adherence was defined as PDC levels below 95%. Measures of effect were calculated using conditional logistic regression. Results: The 298 cases and 298 matched controls were similar in most baseline characteristics. Among cases 20.1% (60/298) switched to second-line therapy and the rest had treatment substitutions. Overall, 88.9% of controls compared with 79.9% of cases had adherence levels greater than or equal to 95% (p=0.003). After adjusting for possible confounders, an adherence level below 95% was associated with almost four times (ORadj=3.56 (95% CI 1.60 to 7.88)) the likelihood of having a treatment change. Conclusion: This study showed that insufficient ART adherence was associated with about four times the likelihood of treatment change. Policy makers must partner researchers to engage patients more often, to unravel the causes of non-adherence, and make the necessary interventions for patients to achieve maximum benefits from dispensed medicines.

Aims To assess time trends in lipid lowering drug use in The Netherlands. Methods Data were obtained from the PHARMO-database, comprising pharmacy records of approximately 300 000 people in The Netherlands. In the period from 1991–98, we estimated prevalence of lipid lowering drug use on the first Wednesday of October. A patient was defined as incident user if (s)he filled a prescription for lipid lowering medication after a 360 days lipid lowering drug free interval. Both prevalence and incidence estimates were weighted for the sex and age distribution of the general Dutch population. Results From 1991 to 1998, the prevalence of lipid lowering drug use increased from 0.5% (95% confidence interval (CI): 0.5, 0.6) to 2.3% (95% CI: 2.2, 2.4) in women and from 0.6% (95% CI: 0.6, 0.6) to 2.9% (95% CI: 2.8, 3.0) in men. Prevalence increased with increasing age and was highest in the age category 60–69 years (in 1998: 9.9% (95% CI: 9.4, 10.4) in women and 11.6% (95% CI: 11.0, 12.1) in men). In 1992, the estimated incidence of lipid lowering drug use was 251(95% CI: 226, 277)/100 000 person years in women and 251(95% CI: 225, 276)/100 000 person years in men. The largest incidence estimates were observed in 1996 (685(95% CI: 644, 726)/100 000 person years in women and 881(95% CI: 834, 928)/100 000 person years in men). After 1996, incidence stabilized in 1997 and decreased in 1998 to 599(561, 637)/100 000 person years in women and 731(688, 773)/100 000 person years in men. Most of the patients (approximately 95%) were treated with one lipid lowering agent. Statins were used by over 90% of patients from 1996 onwards. In 1998, 35% of the patients started with a statin that was not a first choice drug (mainly atorvastatin). Conclusions In the period from 1991–98, prevalence of lipid lowering drug use significantly increased in The Netherlands. However, incidence stabilized and decreased after 1996 which may be explained by the fact that the number of patients eligible for treatment was reached. The question remains whether lipid lowering medication was targeted to the appropriate patients.

Many drugs besides lipid-lowering drugs affect serum lipid levels in either a potentially harmful or beneficial way, and may therefore increase or decrease the risk of cardiovascular disease. Diuretics, beta-blocking agents, progestogens, combined oral contraceptives containing 'second generation' progestogens, danazol, immunosuppressive agents, protease inhibitors and enzyme-inducing anticonvulsants adversely affect the lipid profile. They increase total cholesterol, low density lipoprotein cholesterol and triglycerides by up to 40, 50 and 300%, respectively, and decrease high density lipoprotein cholesterol by a maximum of 50%. Conversely, alpha-blocking agents, estrogens, hormone replacement therapy, combined oral contraceptives containing 'third generation' progestogens, selective estrogen receptor modulators, growth hormone and valproic acid show mostly beneficial effects on the lipd profile. Some drugs, for example, isotretinoin, acitretin and antipsychotics, mainly elevate triglyceride levels. Adverse or beneficial effects on serum cholesterol levels do not always translate into a higher or lower, respectively, incidence of cardiovascular disease. because these drugs may influence cardiovascular risk through multiple pathways. In some cases, excessive cholesterol levels occur, for example, with protease inhibitor therapy, and several cases of pancreatitis attributable to drug-induced hypertriglyceridaemia have been reported. Some general guidelines on the management of drug-induced dyslipidaemia can be given. Replacement of the dyslipidaemia-inducing drug by an equivalent alternative therapy is preferred. However, such alternatives are often difficult to find. If there is no equivalent alternative and treatment with the dyslipidaemia-inducing drug must be initiated, monitoring of serum lipid levels is important. If drug use is expected to be long term, the existing guidelines for the management of dyslipidaemia in the general population can be applied to drug-induced dyslipidaemia. In cases of extreme hyperlipidaemia, medication use should be reassessed.

In settings such as Namibia with a high prevalence of human immunodeficiency virus (HIV) and drug-resistant (DR) tuberculosis (TB) co-infection, interactions and adverse events associated with second-line anti-TB and antiretroviral medicines pose a unique challenge in the treatment of both infections.The main objective of this study was to compare the absolute risks and risk factors for commonly observed adverse events (occurring in20 % of patients) during DR-TB treatment in HIV-infected and HIV-uninfected patients.This was a retrospective cohort analysis of patients treated for DR-TB between January 2008 and February 2010 at the Kondja DR-TB ward in Walvis Bay, Namibia. Data were anonymously collected from patients' treatment records, using a structured form. The data were then analyzed using descriptive statistics, while 2 × 2 contingency tables stratified by HIV status were employed to examine specific risk factor and adverse event relationships, using Epi Info 3.4.3 statistical software. Eighteen adverse events were studied but, because of the small sample size of patients, only the four most frequent ones (occurring in20 % of patients) were included in the risk factor analysis. The risk factors were a treatment period of4 weeks; treatment with any highly active antiretroviral therapy (HAART) regimen; specific treatment with a zidovudine (AZT)-based HAART regimen, a cycloserine-based DR-TB regimen or an amikacin-based DR-TB regimen; female gender; baseline body weight ≤ 45 kg; and age 30 ≥ years.Of the 57 DR-TB patients who were included in the analysis, 31 (53 %) were co-infected with HIV. When stratified by HIV status, DR-TB patients had similar exposure to specific DR-TB medicines and comparable demographic and clinical characteristics, except for age, as HIV-infected patients were on average 6.5 years older than HIV-uninfected patients (P = 0.007). Of the 18 studied adverse events, tinnitus (40 %), joint pain (26 %), hearing loss (23 %) and nausea (21 %) were the four most commonly observed events. Only for abdominal pain was there a statistically significant difference in the risk of occurrence between HIV-infected patients and HIV-uninfected patients (26 versus 4 %, P = 0.02). The risk ratios (RRs) for the association between treatment with a cycloserine-based DR-TB regimen and occurrence of joint pain did not differ much between HIV-infected and HIV-uninfected patients (RR 4.3 in HIV-infected patients, P = 0.03; RR 5 in HIV-uninfected patients, P = 0.08). Similarly, although some differences in the RRs were observed between the two HIV status groups, the differences were not statistically significant for tinnitus, hearing loss or nausea. In some instances, HIV status appeared to modify the effect of the association of some of the risk factors and adverse event occurrence, but the wide and overlapping confidence intervals were inconclusive.Generally, the absolute risks and risk factors for adverse events were similar between HIV-infected and HIV-uninfected patients treated for DR-TB in our Namibian cohort of 57 patients. Although our findings of comparable adverse event risks between DR-TB and DR-TB/HIV co-infected patients are encouraging, they are inconclusive because of the low statistical power of our study. We recommend a prospective study with a larger sample size that would increase the power and therefore the confidence in the results.

BACKGROUND Tracheotomy in the pediatric patient has become a routine procedure since the late 19th century, when it was used in treating diphtheria. Although underlying diseases have changed, the child with an artificial airway still faces numerous risks. This study investigates fatal complications in 280 patients with tracheostomy who were seen in the Dr. von Haunersches Kinderspital for laryngo-tracheo-bronchoscopy. METHOD Data was acquired from patients' records of the Dr. von Haunersches Kinderspital and communications with other institutions. RESULTS Nineteen deaths were investigated. Three patients died of acute cannula obstruction although hospitalized in different institutions. Two patients who died at home may also have suffered cannula obstruction, although this could not be verified. The majority of patients succumbed to the underlying disease. CONCLUSIONS Permanent close supervision or monitoring at all times is critical to prevent cannular related deaths. Our results are compared with major series in other studies. In addition, we propose a booklet for the pediatric tracheotomy patient to document patient data and examination findings, e. g. type and size of cannula, duration of cannulation, laryngotracheometry, and complications. Its purpose will be to support communication between patients, parents, pediatricians, pediatric surgeons, and otolaryngologists. Furthermore, this booklet will help in evaluating risks, which may encounter pediatric tracheostomy patients, thereby enabling future studies.

Pulmonary sling (PS) is a congenital condition in which the left pulmonary artery (LPA) arises from the right pulmonary artery (RPA), forming a sling around the trachea causing tracheal compression. The incidence is not so rare as initially thought. Symptoms of severe airway obstruction often begin in the newborn or young infant. Echo-colour-Doppler may reveal the PS but emphysema can mask the typical findings. Deviation of fluid-filled lungs may be detected prenatally. Chest radiographs show unusual air distribution, deviation of heart and mediastinum and altered tracheobronchial angles. Bronchography and bronchoscopy demonstrate the high incidence of associated tracheal anomalies such as cartilagenous rings and long tracheal stenosis. Anterior oesophageal indentation is not always seen in the oesophogram. Magnetic resonance imaging (MRI) and computed tomography (CT) reveal the PS, but cautious interpretation is necessary because of different levels of the anomalous LPA. PS and associated cardiovascular malformations can be clearly detected by angiography. Associated extrathoracic anomalies are common. Early diagnosis and therapy of PS is mandatory and consists of reimplantation of the LPA into the pulmonary trunk and division of the ligamentum arteriosum. The postoperative course may be cumbersome necessitating bronchological interventions. Tracheal resection may be necessary but restenosis is frequent. A one-stage repair has been proposed in such cases and was successfully done in a few reported cases. Relief of respiratory obstruction is often complete when there are no associated tracheobronchial anomalies. Late postoperative course is favourable but respiratory obstructive attacks may occur with decreasing incidence over time and tracheal growth.

Item does not contain fulltext AIMS: Gouty arthritis is a frequent and disabling complication in heart failure patients. This study aimed to investigate which factors are associated with the occurrence of gouty arthritis in these patients. METHODS AND RESULTS: A case-control study was performed in heart failure patients (February 2007 to October 2009). Cases were defined as patients with gouty arthritis. Factors that are possibly associated with gouty arthritis and/or heart failure were evaluated. Echocardiographic dimensions and laboratory values including glomerular filtration rate (GFR) and fractional excretion of uric acid (FEUA) were measured. Logistic regression analysis was used to determine crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for possibly associated factors. In total, 188 patients (59 with gouty arthritis) were included. Spironolactone use was associated with a decreased occurrence of gouty arthritis (OR 0.32, 95% CI 0.13-0.77). Independently associated with an increased occurrence of gouty arthritis were hypertensive heart failure (OR 3.6, 95% CI 1.6-8.2), New York Heart Association (NYHA) class III/IV (OR 4.5, 95% CI 1.8-11.0), lower GFR (P < 0.001), and FEUA

The combined information of drug exposure and laboratory test results on an individual patient level obtained in daily clinical practice can add important information about the safety of a drug. Thrombocytopenia is a known adverse drug reaction of rituximab, which has already been identified during the preregistration trials, but knowledge on incidence and risk factors in clinical practice is limited. We, therefore, aimed to estimate the incidence and explore the risk factors for the development of rituximab-induced thrombocytopenia (a platelet count

Calculating the exact measures of laryngeal tumours will be crucial for the next generation of the TNM System. Furthermore, cross-sectional area and length of a laryngotracheal stenosis are of major interest for clinical management. It is the aim of this study to assess these parameters endoscopically in a more detailed and exact manner. For this purpose a Hopkins Endoscope (Karl Storz, Tuttlingen, Germany) and a slide caliper are combined. This new instrument is called laryngometer (Fig. 1a u. b). It helps to measure the lengths of a stenosis or neoplasm. In addition it defines the level of a given object and provides a standard in a two-dimensional video sequence. Thus the laryngometer allows to digitally analyse cross-sectional areas and distances as well as to evaluate craniocaudal parameters.

In the past 15 years, infants and children with laryngeal stenosis have also been successfully treated with laryngotracheoplasty. From 1991 to 1993 we performed a surgical treatment in 20 pediatric patients with subglottic stenosis. The anterior cricoid split procedure should always be considered in children who cannot be extubated before undergoing tracheotomy, especially because in case of failure there are no disadvantages for any further operative measurements. By modifying the technique described by Cotton and Seid (1980), we performed an endoscopically controlled anterior cricoid split in 5 children via an endolaryngeal approach. 4 of these patients were extubated within 10 days after using a nasotracheal tube for splinting the cricoid level. In 14 patients with a tracheostoma we used a modification of Rethi's division of the posterior lamina of the cricoid by the placement of a autogenous costal cartilage graft. A 6-week-period of stenting is required for sufficient healing and stability of the reconstructed airway.

Background: Biologicals have specific characteristics, as compared with the small molecule drugs, and carry specific risks. Safety problems, for example infliximab and the risk for tuberculosis, have been identified via spontaneous reports of suspected adverse drug reactions (ADRs). However, in general there is limited data on the nature of spontaneously reported suspected ADRs for biologicals. Objective: To map the safety profile of biologicals as compared with all other drugs. In addition, mechanistic classes of biologicals will be compared. Methods: Data was obtained from the ADR database (VigiBase) maintained by the WHO Collaborating Centre for International Drug Monitoring. A disproportionality analysis was performed in which case reports for biologicals and all other drugs (the reference group), reported between January 1995 and December 2008, were selected. Vaccines were not included in the analysis. Suspected ADRs were classified according to Medical Dictionary for Regulatory Activities (MedDRA®) version 12.0 at the System Organ Class (SOC) level. Biologicals were classified into mechanistic classes: antibodies, cytokines, enzymes, growth factors, hormones (reference group), interferons, receptors and others/various. The safety profile of the biologicals versus all other drugs in the database and of the various mechanistic classes of biologicals was compared using the proportional reporting ratio (PRR). Results: 19 1004 case reports containing 546474 suspected ADRs were reported for 62 different biologicals, and 2 556 209 case reports containing 8 761 522 suspected ADRs were reported for all other drugs (the reference group). It was found that two-thirds of all suspected ADRs reported for biologicals were reported for five active substances: etanercept (20.3%), interferon-β-1a (15.6%), infliximab (11.6%), teriparatide (10.7%) and adalimumab (9.0%). Comparison of the safety profile of biologicals and the reference group showed that suspected ADRs for biologicals were more frequently reported in the SOCs ‘Infections and infestations’ (PRR 4.5), ‘Surgical and medical procedures’ (PRR 2.4) and ‘Neoplasms benign, malignant and unspecified’ (PRR 2.1), and less frequently reported in the SOCs ‘Psychiatric disorders’ (PRR 0.4), ‘Vascular disorders’ (PRR 0.4) and ‘Pregnancy, puerperium and perinatal conditions’ (PRR 0.4). Regarding the differences in safety profile between various mechanistic classes of biologicals, compared with hormones (reference group), ‘Infections and infestations’ were more frequently reported for receptors and antibodies. ‘Neoplasms benign, malignant and unspecified’ were more frequently reported for antibodies, cytokines, interferons and receptors, and less frequently for enzymes as compared with the reference group. Conclusions: In VigiBase, five biologicals comprise two-thirds of the suspected ADRs reported for biologicals, which might distort the relation found between a specific biological and a specific adverse event in case of quantitative signal detection. Therefore the choice of reference group to be used in case of quantitative signal detection should be considered very carefully. This study confirmed that biologicals have a different safety profile compared with all other drugs in the database and, within the group of biologicals, differences exist between mechanistic classes. Infections are, for example, frequently reported for receptors and antibodies, which often have an immune compromising effect. Such predictable safety issues should be specifically studied by preregistration clinical trials and/or targeted pharmacovigilance. In addition, since not all adverse reactions can be predicted or detected during development, spontaneous reporting remains an important tool for the early detection of signals.

Obesity and physical inactivity are associated with several diseases such as diabetes, cardiovascular diseases, musculoskeletal complaints, osteoporosis, certain types of cancer and depression. However, few data are available on the specific types of medication associated with obesity and physical inactivity.The aim of this study was to determine the independent association of body mass index (BMI) and physical inactivity with use of specific classes of prescription drugs, and the interaction between BMI and physical inactivity.The Doetinchem Cohort Study is a population-based longitudinal study. We analyzed cross-sectional data of 1703 men and 1841 women, examined between 1998 and 2002, for whom drug-dispending data were available from the PHARMO database. Drugs were coded according to the WHO Anatomical Therapeutic Chemical (ATC) classification system. Body weight was measured during the physical examination. Physical activity was assessed using an extensive questionnaire. Persons were defined as a user of a certain drug class if they filed at least one prescription in the year around (+/-6 months) the examination.Compared with normal weight persons (BMI 18.5-25 kg m(-2)), obese persons (BMI30 kg m(-2)) had a higher use of prescription drugs of several drug classes, especially cardiovascular drugs (OR (95% CI): 3.83 (2.61-5.64) in men and 2.80 (2.03-3.86) in women) and diabetes drugs (OR (95% CI): 5.72 (2.32-14.14) in men and 3.92 (1.80-8.54) in women). In women, physical inactivity was also associated with higher use of certain drug classes, such as drugs for blood and blood-forming organs (OR (95% CI): 2.11 (1.22-3.65)) and musculoskeletal drugs (OR (95% CI): 2.07 (1.45-2.97)), whereas in men this was not the case. We found no interaction between BMI and physical inactivity with respect to use of prescription drugs.In both men and women, obesity was associated with a higher use of several types of prescription drugs, whereas physical inactivity was only associated with a higher use of certain drug classes in women.

Background: Statins [3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors] and antiplatelet therapy reduce the risk of atherosclerotic disease. Besides a reduction of lipid levels, statins might also have antithrombotic and anti-inflammatory properties, and anti-platelet therapy reduces clot formation. We have studied the risk of venous thrombosis with use of statins, other lipid-lowering medication, and antiplatelet therapy. Materials and methods: Patients with a first episode of deep vein thrombosis in the leg or pulmonary embolism between March 1999 and September 2004 were included in a large population-based case–control study (MEGA study). Control subjects were partners of patients (53%) or recruited via a random-digit-dialing method (47%). Participants reported different all-medication use in a questionnaire. Results: Of 4538 patients, 154 used statins (3.3%), as did 354 of 5914 control subjects (5.7%). The use of statins [odds ratio (OR) 0.45; 95% confidence interval (CI) 0.36–0.56] but not other lipid-lowering medications (OR 1.22; 95% CI 0.62–2.43), was associated with a reduced venous thrombosis risk as compared with individuals who did not use any lipid-lowering medication, after adjustment for age, sex, body mass index, atherosclerotic disease, antiplatelet therapy and use of vitamin K antagonists. Different types and various durations of statin therapy were all associated with a decreased venous thrombosis risk. Antiplatelet therapy also reduced venous thrombosis risk (OR 0.56; 95% CI 0.42–0.74). However, sensitivity analyses suggested that this effect is most likely explained by a so-called ‘healthy user effect’. Simultaneous use of medication most strongly reduced venous thrombosis risk. Conclusion: These results suggest that the use of various types of statins is associated with a reduced risk of venous thrombosis, whereas antiplatelet therapy and other lipid-lowering medications are not.

Long segment malacia of the trachea or main stem bronchi in children is not always suitable for surgical correction; patients may therefore remain ventilator-dependent and/or experience severe obstructive crises. We treated 7 children (ages, 4 months to 9 years) with extreme structural central airway obstruction with stent implantations. Six were mechanically ventilated; 5 had frequent life-threatening obstructive spells requiring deep sedation or paralysis. Diagnoses were: syndrome-associated tracheobronchomalacia (n = 4), malignancy infiltrating the carina (n = 1), congenital tracheal stenosis (n = 1), and tracheobronchial compression by a malpositioned aorta (n = 1). Six tracheal and 13 bronchial stents were endoscopically placed. The prostheses included mesh titan (n = 5), the newer shape memory material nitinol (n = 13), and 1 Y-shaped carina stent. Follow-up was reported for 7 weeks to 72 months. All patients showed marked improvement of their respiratory obstruction. Six children were weaned at least temporarily from ventilation. No significant bleeding, stenosis, or perforation was observed. Seven stents were changed after up to 14 months. Three children are well and at home. In 2 children airway stabilization was successful, but they later died from causes unrelated to stent placement, and 2 children died due to generalized airway disease. Soft metal mesh airway stents can offer a therapeutic option in life-threatening inoperable obstruction of the trachea and main stem bronchi in children.

Three newborns with congenital tracheoesophageal fistula were treated by endoscopic laser coagulation. After radiologic and endoscopic diagnosis, laser coagulation of the mucosal layer of the fistula followed using Nd:YAG laser light transferred through an uncovered quartz fiber of 600 microns diameter. The successful and uneventful course in two cases contrasts with the incomplete obliteration in one case caused by inadequate energy application and/or early localized instillation of contrast medium for radiologic control examination. The advantages of this method include elimination of an operative procedure, exclusion of operative complications, and the possibility of repetition in recurrent cases. Care must be taken to prevent esophageal and tracheal damage by use of this method.

The value of endoscopic techniques in surgery has changed. For several years only a diagnostic procedure, endoscopy is now being used in surgical therapy, especially in the esophagus and the trachea. In general surgery, for example, the recanalization of tumorous obstructions in trachea or esophagus or in the treatment of malignant tracheoesophageal fistula are carried out by surgical endoscopists [14,16,24].

Tracheobronchial endoluminal reconstruction and stenting has become a valuable palliative tool in adults with intrathoracic tumors compromising the airways. Tracheobronchial balloon dilatation has been recently used in children and even neonates. We report a case of severe airway obstruction requiring emergency intubation and artificial ventilation in a 5-year-old child with intrathoracic recurrence of a rhabdomyosarcoma. Endoscopic balloon dilatation through the endotracheal tube with subsequent implantation of a non self-expanding metal mesh stent was used successfully, allowing extubation and discharge of the child from ICU.

In August 2001, the lipid lowering drug cerivastatin was withdrawn from the market after its use was associated with the deaths of 52 patients due to rhabdomyolysis. Our aim was to assess the patterns of lipid lowering drug use after the withdrawal of cerivastatin. A total of 36 Dutch community pharmacies were invited to extract medication histories from all patients who were prevalent users of cerivastatin (index group) on August 10, 2001 (index date), and from two age and gender matched controls. The controls had to be a prevalent user of any other statin at the index date. Medication histories were complete for a follow up period of 3.5 months (November 26, 2001: last day of the study). Logistic regression models were used to assess the association between patient and medication characteristics and discontinuation of lipid lowering drug use, defined as no prescription refilled for any lipid lowering drug after the index date and before end of the study. Of the 36 community pharmacies, 31 participated in the study (response rate 86.1%). Medication histories were available for 234 index patients and 431 matched controls. On the last day of the study, 37 patients in the index group (15.8%) and 41 controls (9.5%) had not refilled a prescription for any lipid lowering drug, and were therefore assumed to have discontinued lipid lowering drug use (OR = 1.8; 95% CI 1.1, 3.0). In men, the risk of discontinuation was similar for both users of cerivastatin and users of any other statin (OR = 0.9; 95% CI 0.5, 1.9), whereas in women the risk of discontinuation was higher for those using cerivastatin (OR = 3.4; 95% CI 1.7, 6.8). Stratification by age showed that discontinuation was more pronounced in those younger than 50 years of age (OR = 3.8; 95% CI 0.7, 22.4) than in older age categories (ORs ranging from 1.6 to 1.8, none statistically significant). Stratification by prescribed daily dose at the index date (expressed as defined daily doses (DDD)) showed that discontinuation was also more prevalent in those with the lowest doses of statins, < 1.00 DDDs day−1 (OR = 5.3; 95% CI 1.8, 15.6), compared with 1.00–1.99 DDDs day−1 (OR = 1.1; 95% CI 0.5, 2.5) and 2.00 DDDs day−1 (OR = 1.8; 95% CI 0.8, 3.7). In the cerivastatin group, 130 patients (66.0%) filled a new prescription for a lipid lowering drug before the theoretical end date of the prevalent prescription at the index date compared with 139 (35.6%) controls (OR = 3.5; 95% CI 2.5,5.1). Most of the patients who were on cerivastatin therapy switched to other lipid lowering drugs before they ran out of tablets. However, discontinuation of lipid lowering drug use was more prevalent in these patients than in users of other statins, especially in women, younger patients and those with low doses of statin therapy.

Prevalence of undertreatment of patients with hypercholesterolaemia is high and it remains uncertain which patients receive treatment. The aim was to identify determinants of non-use of lipid lowering drugs among those eligible for pharmacological treatment. Data were obtained from two population-based surveys (n = 65,428) on cardiovascular disease risk factors conducted from 1987–1997 in The Netherlands. All respondents (age 20–59 years) completed a questionnaire which contained questions on demographic variables, cardiovascular disease (CVD) risk factors and medication use. Blood pressure, total-cholesterol and HDL-cholesterol levels were measured. Treatment eligibility was established for all respondents according to the Dutch Consensus Cholesterol 1998. This standard indicates pharmacological treatment in secondary prevention (unless Tc160 mmHg or diastolic blood pressure >95 mmHg) (OR = 13.4; 7.0–25.8) current smoking (OR = 11.7; 6.4–21.2) were most strongly associated with non-use of lipid lowering drugs, while non-use decreased with concomitant anticoagulant drug use (OR = 0.05; 0.01–0.19). For age, we found an increase in risk of 1.26 (1.21–1.32) per year of age. This study indicates that many subpopulations of respondents eligible for treatment with lipid lowering drugs but not receiving medication can be identified. Attention should be focused on the elderly, men (especially in primary prevention), patients with diabetes mellitus and untreated hypertensives.

Objective To evaluate the potential of MRI in the assessment of tracheal stenosis due to tracheal or vascular malformations, 45 children with severe respiratory distress were examined prospectively during a period of 1 year. Five of these children had tracheal stenosis due to a sling left pulmonary artery (SLPA). Materials and Methods Magnetic resonance examinations of the anesthetized children were performed with a 1.5 T Siemens MR imager using electro-cardiographically gated Tl-weighted SE sequences in transverse and sagittal slice orientations. Slice thickness was 3 mm and each sequence was repeated after shifting the slice position by 1 mm. Monitoring during the examinations included ECG, oscillatory blood pressure, respiratory rate, and oxygen concentration. Magnetic resonance findings were compared with esophagography, selective pulmonary angiography, bronchoscopy, Doppler sonography, and surgery. All examinations were repeated after surgical therapy to assess the improvement in tracheal stenoses and the patency of the ligated and reimplanted left pulmonary arteries. Results Magnetic resonance imaging clearly revealed the course of the SLPA and its topographic relationship to the trachea as well as the coexistence of cardiovascular and tracheobronchial or esophageal malformations. The degree and length of tracheal stenoses, which were measured in the pre- and postoperative axial slices and graphically displayed, as well as the angles of the right and left main stem bronchi, could be accurately determined. Conclusion Magnetic resonance imaging in combination with bronchoscopy yielded the necessary and sufficient information for diagnosis and aided the surgeon in planning operative strategy and in postoperative follow-up.

16 infants with severe distal tracheal stenosis (TS) seen from 1978-1988 are reviewed. Diagnosis was established by endoscopy and confirmed by radiographic methods, including magnetic resonance imaging (MRI) in three cases. Types of TS ranged from segmental stenosis to complex lesions involving the carina and bronchi. Associated vascular anomalies were found in nine patients (56%). All patients needed long-term intubation or a tracheostomy (seven cases) for stenting of the airway. Patients with congenital TS (CTS) were treated by tracheal resection (two survivors), dilatation (one survivor, two non-survivors), or observation (two non-survivors). Patients with pulmonary artery sling (PAS) were treated by division of the vascular sling (three survivors, one non-survivor), or combined vascular and tracheal surgery (one non-survivor). One patient with dilated pulmonary arteries compressing both main bronchi died in spite of oxygen therapy. Two cases of compression by an anomalous aorta were managed with dilatation (one survivor, one non-survivor). One patient with a severe stricture after a tracheal resection was successfully treated by dilatation. The overall mortality was 50%. We conclude that 1. endoscopic examination of the tracheobronchial tree and thorough evaluation of associated anomalies is mandatory in symptomatic patients; 2. if indicated surgical correction is the treatment of choice for tracheal stenosis; 3. dilatation and stenting of the stenosis are invaluable tools in the management of these infants.

Magnetic resonance imaging of the trachea was performed in 21 children with congenital or acquired narrowing of the trachea or main bronchi. Diagnosis included aortic arch anomalities, innominate artery compression, pulmonary artery compression and tracheomalacia. All patients were examined after bronchoscopy. The demonstration of the trachea and the surrounding tissue and vessels on MR images enables the cause of tracheal compression and the degree and location of collapse to be evaluated. MRI is a modality well suited to characterizing tracheal narrowing without employing ionizing radiation or intravenous contrast medium. All MRI examinations were carried out with the patient under general anaesthesia so as not to risk pulmonary deterioration during sedation. In the cases presented MRI is the diagnostic step of choice after tracheo-bronchoscopy and broadens the diagnostic potential in extrinsic tracheal or bronchial stenosis in paediatric patients.

This is a report on 35 cases of innominate artery compression of the trachea and its surgical correction by means of aortotruncopexy. Diagnostic procedures of choice were tracheoscopy and magnetic resonance imaging, which offers representative images of inspiration and expiration, shows the anatomical relations between aortic arch and trachea and reveals the extent of tracheal compression. Surgical treatment is indicated if narrowing of the tracheal lumen exceeds 70%. By fixation of the aortic arch and the proximal innominate artery to the back of the sternum, tracheal compression is relieved. There was no unsuccessful operation in the 35 children. One late death occurred from cardiac failure, unrelated to tracheal compression.

Three cases of male infants with hypoplasia and aplasia of the right lung and dextrocardia are reported. The infants developed increasing obstructive respiratory distress in the first 4 months of life. In all three cases, there was an opaque right hemithorax with overinflation of the left lung, a posterior deviation of the trachea with pulsatile stenosis, and a posteriorly located aortic arch. Hypoplasia (two cases) or aplasia (one case) of the right pulmonary artery and an absence or a remnant of the right main bronchus were also observed. Associated malformations were esophageal atresia with an abnormal high pouch of the proximal esophagus in case 1, and hypertelorismus syndrome in case 2. Because of severe respiratory distress in all three patients, an aortopexy was performed at the ages of 5 months (one infant) and 10 months (two infants). The obstructive respiratory signs disappeared postoperatively in the following weeks. It has been observed that tracheal stenosis in aplasia or hypoplasia of the right lung may be caused by the dislocated aortic arch. An aortopexy can release the airway compression in such cases. Because of associated malformations, a careful evaluation of the airway and vessels is recommended.

A case of asymmetrical thoraco-omphalo-ischiopagus tripus will be reported. Anal atresia, ruptured omphalocele with lesion of the small intestine made an artificial anus necessary. Recurrent adhesion ileus made three further operations necessary. After precise preliminary examinations we separated these twins at the age of\(2{\raise0.5ex\hbox{$\scriptstyle 1$}\kern-0.1em/\kern-0.15em\lower0.25ex\hbox{$\scriptstyle 2$}}\) years. After 7 and 9 months both children had to be reoperated because of fistula of the small intestine. Twin R. died at the age of 3 years and 8 months in consequence of a candida sepsis. Twin P. now lives with his parents.

Upper airway obstruction is common in neonates and infants, even more by to-days obstructive lesions after prolonged intubation with or without intermittent positive pressure ventilation (IPPV). These patients are often high-risk babies. Nevertheless it is essential to establish the cause of airway obstruction, because it may prove fatal unless treated correctly. So general anaesthesia for laryngo-tracheoscopy in neonates and infants must provide as well good endoscopic possibilities as it must be safe for these little patients.

Prolonged endotracheal intubation and congenital malformations are the most common causes of distal narrowing of the trachea in infancy and childhood (Mansfield 1980; O’Neill 1984). Resection of the stenosis with subsequent end-to-end anastomosis has proved to be the treatment of choice in older patients (Grillo 1976) and was first successfully performed in the paediatric age group by Carcassonne et al. (1973). We report on a case with postintubational distal tracheal stenosis where resection of one-third of the trachea and subsequent primary anastomosis were successfully performed.

It has long been known that children with esophageal atresia may suffer from respiratory problems for years (Daum 1970). Studies revealed that esophageal atresia is frequently associated with tracheal malacia (Benjamin et al. 1976), with anatomical disturbances of the tracheal skeleton and the tracheal mucosa (Emery and Haddadin 1971). It was suspected that the large upper pouch impeded tracheal growth within the narrow upper thoracic aperture (Davies and Cywes 1978), but no therapeutic conclusions were drawn, although life-threatening apneic and hypoxic spells had been observed. Several investigators found that a considerable number of patients operated on for esophageal atresia had external tracheal obstruction by the innominate artery (Berdon et al. 1969; Fearon and Shortreed 1963; Filler et al. 1976; Gross and Neuhauser 1948; Mustard et al. 1969). Therapeutic consequences among our own patients are discussed here and compared with reports in the literature.

Bericht uber ein 10jahriges Kind, das 1971 an einer Leukamie erkrankt war. Wahrend einer Vollremission entwikkelte es eine Pneumonie, die klinisch und rontgenologisch an eine Pneumocystis Carinii-Pneumonie denken lies. Die Diagnose wurde durch eine Bronchialspulung mit Nachweis von Pneumocystis Carinii im Spulwasser gesichert. Das Kind wurde mit Pentamidin und Bactrim behandelt und geheilt.