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The quantification of diffuse input loads of nutrients to rivers is a challenge due to limited observed data. This study aimed to develop a simple model that can relate in-stream nutrient concentrations due to diffuse sources with land cover categories within a catchment affecting a river reach. A previously developed point-diffuse model was used to distinguish the diffuse nutrient signature within South African Department of Water Affairs historical monitoring flow and water quality data for selected river gauges. The diffuse signature was related to land cover categories within respective catchments using Principal Component Analysis (PCA), and influential land cover categories were used to construct land cover models relating land cover categories with in-stream nutrient concentrations. Generally, the land cover categories affecting diffuse signatures of nutrients as indicated by PCA were expected. Using land cover information, the developed land cover models performed well in re-creating the diffuse in-stream nutrient signature as determined by the point-diffuse model.

Evapotranspiration (ET) is one of the least understood components of the water cycle, particularly in data scarce areas. In a context of climate change, evaluating water vapour fluxes of a particular area is crucial to help understand dynamics in water balance. In data scarce areas, ET modelling becomes vital. The study modelled ET using the Penman-Monteith- Leuning (PML) equation forced by Moderate Resolution Imaging Spectroradiometer (MODIS) leaf area index (LAI) and MODIS albedo with ancillary meteorological data from an automatic weather station. The study area is located on the Albany Thicket (AT) biome of South Africa and the dominant plant species is Portulacaria afra. The biggest challenge to the implementation of the PML is the parameterisation of surface and stomatal conductance. We tested the use of volumetric soil water content (fswc), precipitation and equilibrium evaporation ratio (fzhang) and soil drying after precipitation (f) approaches to account for the fraction (f) of evaporation from the soil. ET from the model was validated using an eddy covariance system (EC). Post processing of eddy covariance data was implement using EddyPro software. The fdrying method performed better with a root mean square observations standard deviation ratio (RSR) of 0.97. The results suggest that modelling ET over the AT vegetation is delicate owing to strong vegetation phenological control of the ET process. The convergent evolution of the vegetation has resulted in high plant available water than the model can detect. It is vital to quantify plant available water in order to improve ET modelling in thicket vegetation.

Determining water and carbon fluxes over a vegetated surface is important in a context of global environmental changes and the fluxes help in understanding ecosystem functioning. Pursuant to this, the study measured evapotranspiration (ET) using an eddy covariance (EC) system installed over an intact example of the Albany Thicket (AT) vegetation in the Eastern Cape, South Africa. Environmental constraints to ET were also assessed by examining the response of ET to biotic and abiotic factors. The EC system comprised of an open path Infrared Gas Analyser and Sonic anemometer and an attendant weather station to measure bi-meteorological variables. Post processing of eddy covariance data was conducted using EddyPro software. Quality assessment of fluxes was also performed and rejected and missing data were filled using the method of mean diurnal variations (MDV). Much of the variation in ET was accounted for by the leaf area index (LAI, p < 0.001, 41%) and soil moisture content (SWC, p < 0.001, 32%). Total measured ET during the experiment was greater than total rainfall received owing to the high water storage capacity of the vegetation and the possibility of vegetation accessing ground water. Most of the net radiation was consumed by sensible heat flux and this means that ET in the area is essentially water limited since abundant energy was available to drive turbulent transfers of energy. Understanding the environmental constraints to ET is crucial in predicting the ecosystem response to environmental forces such as climate change.

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.A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System (1999-2009). Children and adolescents (19 years) with at least 2 insulin dispensings from community pharmacies (T1D cohort, N = 925) were matched by age and sex (reference cohort without insulin use, N = 3591). The 5-year prevalence of psychiatric medication use (psycholeptics [ATC N05] and psychoanaleptics [ATC N06]) before and after onset of T1D were estimated, compared, and stratified by age, sex, and medication subgroup.The mean age of study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2% vs 4.7%, respectively; P = .002) with the same pattern after developing T1D (10.4% vs 7.9%, respectively; P = .015). In both cohorts, adolescents (15-19 years) and boys had higher prevalences of use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (predominantly anxiolytics).Children with T1D were more likely to use psychiatric medication in the years before and after the onset of T1D which was mainly driven by psycholeptic use.

Objective: Three online surveys explored compliance with the PPP by pharmacists and dermatologists, in the Netherlands. In 2007 and 2011, two pharmacist surveys were conducted to assess improvement over time. Methods: In 2007, survey was sent to members of the Utrecht Pharmacy Panel for Education & Research (UPPER) network (n = 1000) and in 2011, to the research group of the Dutch Association of Pharmacists (KNMP) (n = 556). In 2010, a survey was sent to 564 dermatologists of the Dutch Association of Dermatology and Venereology (NVDV). Results: Both pharmacists' questionnaires had response rates of 20% and the dermatologist questionnaire of 28%. Pharmacists' checks on 30-day dispensing remained 82%, but a check whether the prescription is out-of-date decreased (61 to 53%). Pharmacists asked the patient for a negative pregnancy test in 15%, but use of contraception was checked by 44 - 49%. One hundred and five dermatologists (64%) always prescribe contraception; 35 (22%) occasionally. Ninety-three percent of the dermatologists were of the opinion that they performed the PPP. Analysis of different elements of the PPP showed that 41 (25%) were compliant. Conclusions: The observed non-adherence to the isotretinoin PPP calls for careful evaluation of risk minimisation plans and participation of all stakeholders in the development of these plans.

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 Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP-4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9–2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6–17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism.

PURPOSE: For optimal decision making on access to and regulations around biologicals availability of national utilisation data is a prerequisite. This study characterises the main categories of critical issues in collecting available national utilisation data on tumour necrosis factor alpha (TNFalpha) inhibitors in different European countries. METHODS: Data were collected on characteristics of the nature of TNFalpha usage data and on usage of TNFalpha itself (2003-2007). Utilisation rates were expressed as defined daily doses (DDDs)/1000 inhabitants/day. Data from Denmark, Finland, Ireland, the Netherlands, Norway and Portugal were included. RESULTS: Characteristics of TNFalpha (usage settings and ways of distribution to patients) and databases (type of data collected, public availability and data sources) influenced the way data were collected and determined the type of research and policy questions that can validly be addressed. The prevailing differences in the structure of national databases are prohibitive for critical aspects of medicines utilisation studies. An increase in TNFalpha usage over time was observed in all countries and varied widely from 0.32 (Portugal) to 1.89 (Norway) DDDs/1000 inhabitants/day (2007). CONCLUSIONS: In the European countries studied data on national TNFalpha usage is not easily, if at all accessible. Intercountry collaboration and sharing of technical resources will facilitate harmonisation of data collection allowing independent, population based, health and outcomes research. (aut. ref.)

Introduction: A periodic safety update report (PSUR), composed by marketing authorization holders and submitted to regulatory authorities on predetermined time points, provides an update of the worldwide safety experience of a pharmaceutical. Information is lacking on how PSURs contribute to safety related regulatory actions. Aim: The objective of the study is to analyze the contribution of PSUR evaluations to the initiation of safety related regulatory actions of biopharmaceuticals. Methods: We performed a retrospective analysis of all safety related type II variations of biological products centrally approved in the European Union (since 1995) for which ≥1 safety-related Direct Health Healthcare Professional Communication (DHPC) was issued until December 2009. An evaluation of the role of PSUR assessments in the initiation of safety associated regulatory actions was performed through an analysis of European Public Assessment Reports and updates of the Summary of Product Characteristics (SPC). We compared “urgent” variations, defined as variations accompanied by the distribution of a DHPC, with “less urgent” variations, i.e. safety related SPC variations for which no DHPC was distributed. For each variation we determined if any reference was made to the contribution of PSUR evaluations. We determined the data source and nature of the safety issues included in the variations. Each variation could include ≥1 safety issue and ≥1 data source could contribute in a single variation. Results: We identified 133 safety related type II variations for 15 biological products. Reference to PSUR evaluations was made in 2/24 (8.4%) of all urgent type II variations and 48/109 (44.0%) of the less urgent variations (x2, p

Prevailing notions of foodweb structure and trophic relations in fresh waters are based on research undertaken in a limited range of latitudes or habitat types. This limitation had led to the general view that stream food webs are detritus-based with short food chains and simple interactions that often are dominated by a few key species. We used gut-content analyses and stable-isotope signatures to characterize feeding relationships and foodweb attributes of benthic communities in riffles in 2 forest streams in Hong Kong. We compared them with existing data on foodweb structure from pools in 1 of the streams and data from the literature. The 2 approaches to dietary analyses yielded complementary results, providing confidence that trophic relations and foodweb structure were adequately characterized. Food webs in both streams were remarkably similar regardless of habitat (riffle vs pool). Consumers in both streams depended primarily on autochthonous resources, as has been reported from some other t...

Small dams represent an important local-scale resource designed to increase water supply reliability in many parts of the world where hydrological variability is high. There is evidence that the number of farm dams has increased substantially over the last few decades. These developments can have a substantial impact on downstream flow volumes and patterns, water use and ecological functioning. The study reports on the application of a hydrological modelling approach to investigate the uncertainty associated with simulating the impacts of farm dams in several South African catchments. The focus of the study is on sensitivity analysis and the limitations of the data that would be typically available for water resources assessments. The uncertainty mainly arises from the methods and information that are available to estimate the dam properties and the water use from the dams. The impacts are not only related to the number and size of dams, but also the extent to which they are used for water supply...

Background: Drugs for rare diseases, so-called orphan drugs, are often intended for serious or chronically debilitating diseases. Safety information is more limited at the time of approval for orphan drugs as a result of various factors, such as the limited number of patients in clinical trials, quality of the clinical trials and special approval procedures. Several studies have been conducted on safety-related regulatory actions for drugs, but none of these have specifically focused on orphan drugs. Objective: To determine the frequency and nature of safety-related regulatory actions for orphan drugs in the US and EU. Methods: This cohort study examined publicly available data from the websites of US and EU regulatory authorities on orphan drugs approved in the US and/or the EU between January 2000 and December 2007. The main outcome measures were the nature, frequency and timing of safety-related regulatory actions, defined as (i) safety withdrawals; (ii) ‘black-box’ warnings; and (iii) written communications to healthcare professionals issued by the US FDA or the European Medicines Agency between January 2000 and June 2008. Results: Ninety-five orphan drugs were approved during the study period (75 in the US, 44 in the EU, and 24 in both regions). Ten products (10.5%) received a safety-related regulatory action. No safety withdrawals, four black-box warnings and 12 written communications were identified. The probability of a first safety-related regulatory action for orphan drugs was 20.3% after 8 years of follow-up. Orphan drugs approved by accelerated approval (relative risk [RR] 3.32; 95% CI 1.06, 10.42), oncological products (RR 7.83; 95% CI 0.96, 63.82) and products for gastrointestinal and metabolism indications (RR 10.44; 95% CI 1.25, 87.27) may have a higher risk for a safety-related regulatory action. Conclusions: The probability of a first safety-related regulatory action for an orphan drug was slightly lower than that reported in the literature for biologicals in one study and new molecular entities in another study. However, detection of safety issues may be complicated by the limited experience with orphan drugs in practical use due to the low prevalences of the diseases they are used for. Doctors and pharmacists should therefore be vigilant with regard to the occurrence of a safety-related issue for orphan drugs.

Purpose Real-life experience with anti-obesity drugs has shown that psychiatric and cardiovascular diseases may be reported as adverse drug reactions. For adequate risk assessment of these drugs knowledge on baseline risks of patients starting anti-obesity drugs and insight in patterns of use is needed. The aim was to assess whether baseline characteristics of patients starting anti-obesity drugs differ from those not being prescribed these drugs, and to study patterns of anti-obesity drug use. Methods A population-based cohort study was conducted in the IPCI database (1995–2007). The index cohort comprised all persons who started an anti-obesity drug. The reference cohort comprised up to six randomly sampled patients from the same GP practice with same index date. Baseline characteristics were assessed for both cohorts. The index cohort was followed for 1 year to study patterns of drug use. Unconditional logistic regression was used to calculate crude odds ratios and 95% confidence intervals. Results The index and reference cohort comprised 1471 and 8736 persons, respectively. Both cardiovascular and psychiatric co-morbidities were more prevalent among starters compared to non-starters. 77.7% of the patients stopped using anti-obesity drugs within 90 days. Users of amphetamine-like drugs differed from patients using orlistat or sibutramine, whereas users of orlistat and sibutramine were highly comparable. Conclusions The increased prevalence of co-morbidities constitutes a baseline risk which may translate in higher occurrence of psychiatric and cardiovascular diseases during use of anti-obesity drugs, independent of the drugs. The limited period of use might reduce possible cardiovascular benefits of weight reduction induced by these drugs. Copyright © 2009 John Wiley & Sons, Ltd.

The introduction of recombinant DNA and hybridoma techniques more than 25 years ago enabled the large-scale production of biopharmaceuticals, which resulted in important new treatments for a variety of chronic and sometimes life-threatening diseases [4,18]. The recent expiration of patents of some biopharmaceuticals, like growth hormones, granulocyte colony-stimulating factors, and erythropoietin, makes it possible for pharmaceutical companies to produce so-called “biosimilars”, which are also called “biogenerics” or “follow-on biologics” [13]. Biosimilars are defined by the European Medicines Agency (EMEA) as biopharmaceuticals claimed to be similar to a reference medicinal product based on the demonstration of the similar nature of the two products, in terms of quality, safety and efficacy. Biosimilars are approved on the basis of an abbreviated dossier, in which comparability between the reference product and the biosimilar has been shown both for efficacy and safety. In addition, it is possible to extrapolate therapeutic comparability shown for one indication to other indications of the reference medicinal product [2,3] as was done for the recombinant derived growth hormone Valtropin. For Valtropin it was agreed that data obtained in a comparative double-blind phase III study, where the reference product Humatrope was compared with Valtopin, for the indication ‘Children with growth hormone deficiency’ could be extrapolated to all indications for which the reference product Humatrope had already been approved [8]. Requirements for the dossier of the marketing application for different active substance is laid down in product specific guidelines [2,3]. Compared to small molecules biopharmaceuticals in general, have different characteristics and therefore may carry specific risks. Small molecules are synthesized chemically, whereas biopharmaceuticals are large-complicated molecules which are manufactured in living cells [4,18]. Biopharmaceuticals have a very complex production and purification process involving multiple steps. This carries the risk of influencing the characteristics of the end product, and possibly the safety profile of the end product, at

The wide availability of economic evaluations and their increasing importance for decision making emphasises the need for economic evaluations that are methodologically sound. The aim of this review was to provide users of economic evaluations of cholesterol-lowering drugs with an insight into the quality of these evaluations. By focusing on the most relevant studies, the gap between research and policy making may be narrowed. A systematic review was conducted. All Dutch and English publications on economic evaluations of cholesterol-lowering drugs were identified by searching PubMed, the Centre for Reviews and Dissemination database (CRD), the NHS Economic Evaluation Database (NHS EED), the Health Technology Assessment database (HTA) and the Database of Abstracts of Reviews of Effects (DARE). A search strategy was set up to identify the articles to be included. The quality of these articles was assessed using Drummond's checklists. The scoring was performed by at least two reviewers. When necessary, disagreement between these reviewers was decided upon in a consensus meeting. We calculated an average quality score for the included articles. The search identified 1390 articles, of which 23 were included. Most studies measured the costs per life-year gained. The overall score per study was disappointing and varied between 2.7 and 7.7, with an average of 5.5. Most studies scored high on the measurement of costs and consequences, whereas the establishment of effectiveness left room for improvement. Only two studies included a well performed incremental analysis. This study noted an increase of quality of economic evaluations over time, suggesting the value of cost-effectiveness studies for policy decisions increases over time. In general, piggy-back evaluations tended to score higher on quality and may therefore be more valuable in decision making.

The aim of the present study was to provide an insight into the characteristics and follow-up of postmarketing studies of medicines that were conditionally authorized in the European Union (EU).We compiled a list of all postmarketing studies attached as specific obligations to the licence of medicines that were granted conditional marketing authorization from January 2006 to April 2014. Studies were characterized based on their objective, design, status upon marketing authorization (MA) and due data set by authorities. They were linked to online study registrations (Clinicaltrials.gov, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines, and determined whether studies were completed on time.A total of 59 postmarketing studies were requested for 21 conditionally authorized medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting postmarketing studies were 'long-term follow-up' and 'increase data on subpopulations'. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed on time. Actual completion time took a median (interquartile range) of 274 (-121 to 556) days longer than expected.Our results indicated that most postmarketing studies attached to a conditional marketing authorization were eventually completed but that half were completed with a substantial delay. The observations suggest caution when broadening the use of postmarketing studies for resolving uncertainties about benefits and risks after MA.

Aim To assess dosing and determinants of the choice of statins among starters of statins. Methods Data were obtained from the PHARMO database comprising pharmacy and linked hospital discharge records of approximately 300 000 subjects in the Netherlands. All new users of statins in 1998 were selected. Patient characteristics and drug regimens were compared between starters of different statins. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression modelling, using the start of simvastatin therapy as reference category. Results In 1998, 1738 patients started using simvastatin (41.1%), pravastatin (23.1%), fluvastatin (11.9%), atorvastatin (22.8%) or cerivastatin (1.0%). Compared with starters with simvastatin [mean dose 1.02 ± 0.39 defined daily doses (DDDs)], starters with pravastatin (1.27 ± 0.56 DDDs) and atorvastatin (1.43 ± 0.59 DDDs) received higher doses (P

Macrobrachium hainanense is a large palaemonid shrimp (total length up to 7 cm) present at high densities (>2 individuals m−2) in pools of low-order forested streams in Southern China. The present study investigated the reproductive biology and sexual dimorphism of this shrimp in Tai Po Kau Forest Stream (TPK) and Tai Shing Stream (TSS), Hong Kong. Recruitment occurred during the wet season (May to August). Macrobrachium hainanense, a truly freshwater species, has abbreviated larval development, and the study populations had smaller broods than euryhaline species of this genus. Most females probably produced only a single brood of 20–75 eggs each breeding season. They showed no size-specific fecundity. Egg development in the laboratory took over 53 days, and eggs grew larger during development. The reproductive output (RO) of females was 11% for each brood, lower than for most other species of Macrobrachium. Lifetime RO was 21%, assuming a single brood in each of two seasons. The population male-...

A food web based on the gut contents of consumers (invertebrates and fishes) in pools of Tai Po Kau Forest Stream (TPKFS), Hong Kong (southern China), indicated the importance of periphyton and fine organic particles; coarse particulate organic matter was a less important food source despite its higher relative abundance in this shaded hillstream. Stable isotope analysis of consumer tissues was undertaken to confirm this result. IsoSource software was used to model n-isotope and >n + 1-sources, so that the relative contribution of the potential food sources could be determined. Results of an IsoSource mixed model of δ15N and δ13C stable isotope signatures of primary consumers generally supported evidence from gut content analyses about the importance of autochthonous resources. Inconsistencies between the results of gut content analysis and isotope signatures of consumer tissues occurred in a few cases but could be explained either by small sample size or the wide range of feasible solutions provi...

Summary 1. Macrobrachium hainanense is a predatory palaemonid shrimp (total length >7 cm) that can be abundant [density 3–5 m−2; biomass 484–606 mg ash-free dry mass (AFDM) m−2] in forest streams in Hong Kong, China. This study investigated the growth and production of M. hainanense during 2001 and 2002 in pools of two forested streams (one third- and one fourth-order). 2. The growth of tagged individuals was recorded in situ and compared with that of tagged and untagged shrimps in laboratory tanks. Field and laboratory estimates yielded similar growth rates of 0.7 mm carapace length (CL) per month, and instantaneous growth rate was 0.004 g AFDM g−1 day−1. Tagging did not affect growth in the laboratory. Cohort analysis of field populations produced similar estimates of growth to that of tagged individuals, and the growth of M. hainanense was generally slower than has been reported for other Macrobrachium species. Mass-specific growth rate of M. hainanense in the field varied with size and was two to five times higher in small individuals (

Summary 1. Macrobrachium hainanense is a large predatory palaemonid shrimp, present at high densities in pools of low-order forested streams in Hong Kong. The present study investigated the impacts of M. hainanense on benthic community structure and functions in pools of two streams: Tai Po Kau Forest Stream and Tai Shing Stream. 2. Repeated whole-pool experiments involving shrimp density manipulations (removal, control and addition) were conducted in both streams between October 2000 and April 2002, and included a wet (May to September) and two dry (October to April) seasons. The three objectives of the study were to determine the effects of M. hainanense predation on benthic macroinvertebrate abundance and species richness, rates of leaf litter breakdown because of effects on detritivores, and periphyton standing stocks by way of an effect on herbivores. 3. Wet season results showed consistent reductions in benthos densities and species richness following heavy rainfall, irrespective of shrimp manipulation. These results suggested that spate-induced disturbances might override biotic effects and play a dominant role in structuring benthic communities in stream pools in Hong Kong. 4. No significant, reproducible effects on any of the response variables measured in either stream were found during the dry season. Litter breakdown was reduced in the absence of shrimps during one experiment only, suggesting it might be a type I error. These results signified no effect of shrimp removal on benthic communities, or on the functional processes of litter breakdown, or on periphyton accumulation. The large scale of the experimental units (8–40 m2), refuge availability, and the presence of benthic predatory fishes that cropped excess prey made available by removal of M. hainanense, may have contributed to the lack of any effect, despite the abundance of the predatory shrimps.

Macrobrachium hainanense is a large palaemonid shrimp (total length >7cm), present at high densities (>2 individuals m -2 ) in pools of low-order forested streams in Hong Kong, Southern China. The present study investigated the diet and trophic status of this shrimp in pools of Tai Po Kau Forest Stream (TPK) and Tai Shing Stream (TSS). Macrobrachium hainanense was a generalist predator that fed selectively on sedentary and slow-moving prey (snails, chironomid larvae and calamoceratid caddisflies) eating them disproportionately relative to their abundance in pool benthic communities. Shrimp diets varied by size of the individual, by season and by stream. The diet of large males was dominated by the thiarid snail Brotia hainanensis, and ovigerous females had guts that were half as full as large females although their diet was similar to other life stages. Gut fullness was reduced in shrimps that had molted recently. Over 80 % of the food items eaten by M. hainanense at TPK during the wet season were B. hainanensis, while the dry season diet included a greater number of taxa including tube-dwelling Chironomidae (31 %), Trichoptera (25 %) and Ephemeroptera (24 %). This pattern of seasonal variation was less noticeable at TSS than at TPK. TPK M. hainanense had less full guts (∼ 50 %) than those at TSS (∼ 70 %), but, at both sites, shrimps with empty guts were encountered only during the wet season. The predaceous nature of M. hainanense through all life stages is in contrast to the omnivorous or detritivorous habit of other Macrobrachium species. The results of δ 15 N and δ 13 C stable isotope analysis of samples from TPK confirmed the predatory trophic status of M. hainanense. All life stages had isotopic signatures that were higher than to sympatric predatory invertebrates (e. g. Odonata). Allochthonous detritus made no direct contribution to the assimilated tissue of M. hainanense.

BACKGROUND: Persistence with lipid-lowering drug use is important in order for patients to gain full treatment benefit. The withdrawal of cerivastatin from the market may have affected persistence due to the fear of serious adverse effects. OBJECTIVE: To assess failure of patients to continue lipid-lowering drug use following the withdrawal of cerivastatin. METHODS: A cohort study including 3.5 months follow-up after the withdrawal of cerivastatin in August 2001 was conducted using data from community pharmacies in The Netherlands, covering a population of approximately 600,000 subjects. Patients selected for inclusion in the index group were current users of cerivastatin on August 10, 2001 (the date that cerivastatin was withdrawn from the market). Reference patients were gender, age and pharmacy or region matched patients who were using any HMG-CoA reductase inhibitor other than cerivastatin on the same date. The main outcome measure was discontinuation of lipid-lowering drug use. To assess whether discontinuation had increased in the reference group, discontinuation rates were compared with discontinuation rates in the previous year. Data on these rates in 2000 were obtained from the population-based PHARMO record linkage system. RESULTS: A total of 31 pharmacies of the research network (response rate 86.1%) provided medication histories of 234 current users of cerivastatin and 431 matched patients using any other HMG-CoA reductase inhibitor. In addition, 352 current users of cerivastatin and 704 matched patients using any other HMG-CoA reductase inhibitor were obtained from the PHARMO database. Overall, 13.7% of subjects in the cerivastatin group (n=586) and 9.5% in the reference group (n=1135) discontinued lipid-lowering medication (adjusted odds ratio [OR] 1.44; 95% CI 1.04-2.00). The rate of discontinuation in the reference group was comparable to this rate in the previous year. Discontinuation was more prevalent in women who had been taking cerivastatin (adjusted OR 1.74; 95% CI 1.09-2.78), those receiving low doses of cerivastatin (adjusted OR 2.45; 95% CI 1.20-4.97), those who received their last cerivastatin prescription from a specialist (adjusted OR 1.92; 95% CI 1.02-3.60) and those who had recently started using cerivastatin (adjusted OR 2.80; 95% CI 0.98-7.98), although the latter was not statistically significant. CONCLUSIONS: Failure to continue lipid-lowering drug use was higher in patients using cerivastatin than in users of other HMG-CoA reductase inhibitors, especially in women, those using low doses of HMG-CoA reductase inhibitors and recent starters of lipid-lowering medication. The prevention of unwarranted discontinuation of drugs due to market withdrawal should be a joint task of healthcare providers, industry and regulatory bodies.

Discontinuation and poor adherence to therapy are major problems during long-term treatment, particularly with cholesterol lowering drugs. Several studies have indicated that the cholesterol lowering effect of statins differs according to apolipoprotein (apo)E genotypes. Low-density lipoprotein-cholesterol lowering capacity appears to be smaller in subjects with the epsilon(4) allele. To assess whether the use of statins in daily practice differs according to apoE genotypes, we used data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or more. During follow-up, there were 798 subjects who started to use statins. We used a Cox proportional hazard model to determine the rate of discontinuation in the first 3 years of statin use. Subjects on statin therapy with epsilon(2)epsilon(2) and epsilon(4)epsilon(4) genotypes showed a trend towards higher dosages than subjects with the other genotypes. Relative to subjects with the epsilon(2)epsilon(3) genotype, those with the epsilon(4)epsilon(4) genotype had a risk of 2.28 [95% confidence interval (CI) 1.02-5.12] to discontinue statins within 3 years. In women, this relative risk was 1.70 (CI 0.53-5.42) versus 3.18 (CI 1.01-10.03) in men. The apoE genotype is associated with discontinuation of statins. This suggests that subjects who are genetically prone to develop hypercholesterolemia show the highest risk of discontinuation of treatment.

Aims To assess the level of undertreatment of hypercholesterolaemia in the general population, taking intra-person variability in serum cholesterol concentrations into account, and to identify determinants of undertreatment of hypercholesterolaemia. Methods In this cross-sectional study, data from two population-based surveys on cardiovascular disease risk factors conducted between 1987 and 1997 in the Netherlands were used. For all 64 757 respondents aged 20‐59 years, treatment eligibility for lipid-lowering drug use was established according to the Dutch Cholesterol Consensus. Multivariate logistic models were used to identify determinants of undertreatment. Results During the study period, 56.8% of the study population had undesirable cholesterol concentrations (serum total cholesterol > 5 mmol l - 1 ) and 5.5% of those were eligible for pharmacological treatment based on their absolute risk of coronary heart disease. Of those eligible for pharmacological treatment, 16.3% were treated, and 19.6% of those treated had their serum total cholesterol concentration controlled. Only 3.2% of those eligible for pharmacological treatment were both treated and controlled. We identified several determinants for undertreatment, e.g. male gender and younger age for primary prevention and female gender and older age for secondary prevention. Treatment has improved slightly in more recent years. Conclusions Over 95% of the population eligible for the pharmacological treatment of hypercholesterolaemia was either untreated or was uncontrolled. To decrease undertreatment, identification of high-risk patients should be increased. Those who are treated with lipid-lowering medication could further benefit from more aggressive treatment, especially with statins.

Hoebert JM, Souverein PC, Mantel-Teeuwisse AK, Leufkens HGM, Van Dijk L. Benzodiazepinegebruik daalt als de gebruiker zelf betaalt. Huisarts Wet 2012;55(7):286-8

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.

OBJECTIVE: To estimate the number of expected cases of myopathy based on the prevalence of lipid-lowering drug use, and to compare this number with the observed number of cases of myopathy due to lipid-lowering drug use in the Netherlands. METHODS: Prevalence of lipid-lowering drug use in 1998 was estimated by using data from the PHARMO record linkage system comprising pharmacy records linked to hospital admission data. The expected number of cases of myopathy was calculated by multiplying the total number of person-years of lipid-lowering drug use by the excess incidence rates of myopathy due to those drugs as reported in the literature. The observed number of cases was obtained from PHARMO and the Dutch Pharmacovigilance Foundation Lareb. RESULTS: Based on the estimated prevalence of lipid-lowering drug use in the Netherlands in 1998 (n = 520 800), we expected 60 cases of idiopathic myopathy due to hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) or fibric acid derivatives (fibrates). This low number was confirmed by data from PHARMO (n = 11; none of these were related to current use of lipid-lowering drugs) and Lareb (n = 43). CONCLUSIONS: The expected number of statin- or fibrate-related idiopathic myopathy is low and observed numbers are even lower in the Netherlands. This should, therefore, not compromise continued use of lipid-lowering drugs.

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.

To assess the trends in the incidence and prevalence rates of type 1 diabetes (T1D) among children and adolescents in the Netherlands.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).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).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.

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.

Es wird uber 3 Patienten im Alter von 12, 14 Wochen und 4 Jahren mit Atemnot berichtet, bei denen die thorakale Sonografie eine bronchogene Zyste aufdeckte. In allen 3 Fallen zeigte die Thoraxaufnahme nur eine unspezifische Uberblahung beider Lungen mit nur fraglicher Weichteildichte. Die laterale Thoraxaufnahme zeigte eine Verdrangung von Osophagus und Trachea in 2 Fallen, wahrend thoraxsonografisch in allen 3 Fallen eine echoarme, glatt begrenzte Struktur ohne Dopplerflus zwischen Pulmonalarterie und Aorta descendens darstellbar war. Diese Struktur wurde im Computertomogramm (CT) bestatigt. Bronchoskopisch war eine Vorwolbung der Pars membranacia typisch. Es erfolgte die chirurgische Resektion der Zysten, die histologisch als bronchogene Zysten bestatigt wurden. In 1 Fall trat 3 Monate postoperativ wieder Atemnot auf. Bronchoskopisch und mittels NMR wurde ein Rezidiv der bronchogenen Zyste festgestellt. Es erfolgte die erfolgreiche Abtragung eines Rezidivs der Zyste mittels Lasertechnik uber die Bronchoskopie. Schlusfolgerung: Bei Atemwegsobstruktion ist an eine bronchogene Zyste mit der Moglichkeit einer Darstellung durch die Sonografie zu denken. Postoperativ kommen Rezidive vor, die einer Laserbehandlung zuganglich sind.

Background The European legislation prohibits prescription-only medicines' advertising but allows pharmaceutical companies to provide information to the public on health and diseases, provided there is no direct or indirect reference to a pharmaceutical product. Various forms of promotion have become increasingly common in Europe including “disease-oriented” campaigns. Objectives To explore examples of disease awareness campaigns by pharmaceutical companies in the Netherlands, by assessing their compliance with the World Health Organization (WHO) Ethical Criteria for medicinal drug promotion and the Dutch guidelines for provision of information by pharmaceutical companies. Methods Materials referring to health/disease and treatments published in the most widely circulated newspapers and magazines were collected from March to May 2012. An evaluation tool was developed based on relevant underlying principles from the WHO ethical criteria and Dutch self-regulation guidelines. Collected disease awareness advertisements were used to pilot the evaluation tool and to explore the consistency of information provided with the WHO and Dutch criteria. Findings Eighty materials met our inclusion criteria; 71 were published in newspapers and 9 in magazines. The large majority were news items but 21 were disease awareness advertisements, of which 5 were duplicates. Fifteen out of the 16 disease awareness campaigns were non-compliant with current guidelines mainly due to lack of balance (n = 12), absence of listed author and/or sponsor (n = 8), use of misleading or incomplete information (n = 5) and use of promotional information (n = 5). None mentioned a pharmaceutical product directly. Conclusion Disease Awareness Campaigns are present in Dutch printed media. Although no brand names were mentioned, the lack of compliance of disease awareness campaigns with the current regulations is alarming. There were information deficiencies and evidence of information bias. A key concern is that the context in which the information is provided, mostly through indirect referral, is likely to support treatment with the sponsor's product.

The risk for occupational exposure to HIV is a serious public health problem that is well characterized in the developed world, but less so in the developing countries such as Ghana. This study was undertaken to examine the characteristics of occupational exposure to HIV and the utilization of a risk assessment system (RAS)–based postexposure prophylaxis (PEP) among health care workers (HCWs) and health care students (HCSs) in the Korle-Bu Teaching Hospital (KBTH). During the study period (January 2005–December 2010), a total of 260 and 35 exposures were reported by HCWs and HCSs, respectively. Ward attendants reported the highest incidence rate of 6.46 of 100 person-years (P-Y). The incidence of high-risk exposures was 0.33 of 100 P-Y (n = 65); 60.0% occurred during a procedure of disposing of a needle and 24.6% during a cannula insertion. A total of 289 of the 295 individuals were administered PEP, of which 181 (62.6%) completed the 6-month follow-up testing schedule and none sero-converted. This shows that with a good RAS in place, it is possible to deploy an effective PEP program in a typical African teaching hospital like the KBTH in Accra, Ghana.

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.

Objectives Continuous provision of appropriate medicines of assured quality, in adequate quantities, and at reasonable prices is a concern for all national governments. A national medicines policy (NMP) developed in a collaborative fashion identifies strategies needed to meet these objectives and provides a comprehensive framework to develop all components of a national pharmaceutical sector. To meet the health needs of the population, there is a general need for medicine policies based on universal principles, but nevertheless adapted to the national situation. This review aims to provide a quantitative and qualitative (describing the historical development) study of the development process and evolution of NMPs. Methods The number of NMPs and their current status has been obtained from the results of the assessment of WHO Level I indicators. The policy formulation process is examined in more detail with case studies from four countries: Sri Lanka, Australia, former Yugoslav Republic of Macedonia and South Africa. Results The number of NMPs worldwide has increased in the last 25 years with the highest proportional increase in the last 5–10 years in high-income countries. Higher income countries seem to have more NMP implementation plans available and have updated their NMP more recently. The four case studies show that the development of a NMP is a complex process that is country specific. In addition, it demonstrates that an appropriate political window is needed for the policy to be passed (for South Africa and the FYR Macedonia, a major political event acted as a trigger for initiating the policy development). Policy-making does not stop with the official adoption of a policy but should create mechanisms for implementation and monitoring. The NMPs of the FYR Macedonia and Australia provide indicators for monitoring. Conclusions To date, not all countries have a NMP since political pressure by national experts or non-governmental organizations is generally needed to establish a NMP. Case studies in four countries showed that the policy process is just as important as the policy document since the process must create a mechanism by which all stakeholders are brought together and a sense of collective ownership of the final policy may be achieved.

Background We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products is associated with sponsors deciding to apply for an orphan designation at the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Methods All metabolic diseases with a genetic cause and prevalence of less than 10 patients per 1 million of the population were selected from the ‘Orphanet database of Rare diseases’. The outcome of interest was the application for an orphan designation at FDA or EMA. The level of publicly available knowledge of the disease and drug candidate before an orphan designation application was defined as whether the physiological function corresponding with the pathologic gene and initiation of the pathophysiological pathway was known, whether an appropriate animal study was identified for the disease, whether preclinical proof of concept was ascertained and the availability of data in humans. Other determinants included in the study were metabolic disease class, the prevalence of the disease, prognosis and time of first description of the disease in the literature. Univariate relative risks (RRs) and 95% confidence intervals (CIs) of an orphan designation application were calculated for each of these determinants. In addition, a multivariate Cox regression analysis was conducted (Forward LR). Results In total, 166 rare metabolic genetic diseases were identified and included in the analysis. For only 42 (25%) of the diseases an orphan designation application was submitted at either FDA or EMA before January 2012. The multivariate analysis identified preclinical proof of concept of a potential medicinal product as major knowledge related determinant associated with an orphan designation application (RRadj 3.9, 95% CI 1.9-8.3) and confirmed that prevalence of the disease is also associated with filing an application for an orphan designation (RRadj 2.8, 95% CI 1.4-5.4). Conclusion For only one out of four known exceptionally rare metabolic inherited diseases sponsors applied for an orphan designation at FDA or EMA. These applications were found to be associated with the prevalence of the rare disease and the level of available scientific knowledge on the proof of concept linking possible drug candidates to the disease of interest.

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.

Land cover change analysis was performed for three catchments in the rural Eastern Cape, South Africa, for two time steps (2000 and 2014), to characterize landscape conversion trajectories for sustained landscape health. Land cover maps were derived: (1) from existing data (2000); and (2) through object-based image analysis (2014) of Landsat 8 imagery. Land cover change analysis was facilitated using land cover labels developed to identify landscape change trajectories. Land cover labels assigned to each intersection of the land cover maps at the two time steps provide a thematic representation of the spatial distribution of change. While land use patterns are characterized by high persistence (77%), the expansion of urban areas and agriculture has occurred predominantly at the expense of grassland. The persistence and intensification of natural or invaded wooded areas were identified as a degradation gradient within the landscape, which amounted to almost 10% of the study area. The challenge remains to determine significant signals in the landscape that are not artefacts of error in the underlying input data or scale of analysis. Systematic change analysis and accurate uncertainty reporting can potentially address these issues to produce authentic output for further modelling.