Unlicensed and off-label drug use in a Swiss paediatric university hospital.

BACKGROUND: Many medicines used in newborns, infants, children and adolescents are not licensed ("unlicensed") or are prescribed outside the terms of the marketing authorization ("off-label"). Several studies have shown that this is a common practice in various healthcare settings in the USA, Europe and Australia, but data are scarce in Switzerland. OBJECTIVES: The aim of our prospective study was to determine the proportion of unlicensed or off-label prescriptions in paediatric patients. METHODS: This pilot study was conducted prospectively over a six month period in the department of paediatrics of a university hospital. RESULTS: Sixty patients aged from three days to 14 years were included in the study. A total of 483 prescriptions were written for the patients. More than half of all prescriptions (247; 51%) followed the terms of the marketing authorization. 114 (24%) were unlicensed and 122 (25%) off-label. All patients received at least one unlicensed or offlabel medicine. CONCLUSION: The use of unlicensed or off-label medicines to treat children was found to be common. Co-operation between the pharmaceutical industry, national regulatory authorities, clinical researchers, healthcare professionals and parents is required in order to ensure that children do not remain "therapeutic orphans"

Statistical modelling of the snow depth distribution in open alpine terrain

The spatial distribution of alpine snow covers is characterised by large variability. Taking this variability into account is important for many tasks including hydrology, glaciology, ecology or natural hazards. Statistical modelling is frequently applied to assess the spatial variability of the snow cover. For this study, we assembled seven data sets of high-resolution snow-depth measurements from different mountain regions around the world. All data were obtained from airborne laser scanning near the time of maximum seasonal snow accumulation. Topographic parameters were used to model the snow depth distribution on the catchment-scale by applying multiple linear regressions. We found that by averaging out the substantial spatial heterogeneity at the metre scales, i.e. individual drifts and aggregating snow accumulation at the landscape or hydrological response unit scale (cell size 400 m), that 30 to 91% of the snow depth variability can be explained by models that are calibrated to local conditions at the single study areas. As all sites were sparsely vegetated, only a few topographic variables were included as explanatory variables, including elevation, slope, the deviation of the aspect from north (northing), and a wind sheltering parameter. In most cases, elevation, slope and northing are very good predictors of snow distribution. A comparison of the models showed that importance of parameters and their coefficients differed among the catchments. A "global" model, combining all the data from all areas investigated, could only explain 23% of the variability. It appears that local statistical models cannot be transferred to different regions. However, models developed on one peak snow season are good predictors for other peak snow seasons

Margrit Frölich, Klaus Gronenborn, Karsten Visarius (Hg.): A Star Is Born. Ruhm im Kino

Proxy-indicators in lake sediments provide the only approach by which the dynamics of in-lake methane cycling can be examined on multi-decadal to centennial time scales. This information is necessary to constrain how lacustrine methane production, oxidation and emissions are expected to respond to global change drivers. Several of the available proxies for reconstructing methane cycle changes of lakes rely on interpreting past changes in the abundance or relevance of methane oxidizing bacteria (MOB), either directly (e.g. via analysis of bacterial lipids) or indirectly (e.g. via reconstructions of the past relevance of MOB in invertebrate diet). However, only limited information is available about the extent to which, at the ecosystem scale, variations in abundance and availability of MOB reflect past changes in in-lake methane concentrations. We present a study examining the abundances of fatty acids (FAs), particularly of C-13-depleted FM known to be produced by MOB, relative to methane concentrations in 29 small European lakes. 39 surface sediment samples were obtained from these lakes and FA abundances were compared with methane concentrations measured at the lake surface, 10 cm above the sediments and 10 cm within the sediments. Three of the FAs in the surface sediment samples, C-16(:1 omega 7c), C-16(:1 omega 5c/t), and C-18(:1 omega 7c) were characterized by lower delta C-13 values than the remaining FAs. We show that abundances of these FM, relative to other short-chain FAs produced in lake ecosystems, are related with sedimentary MOB concentrations assessed by quantitative polymerase chain reaction (qPCR). We observed positive relationships between methane concentrations and relative abundances of C-16:1 omega 7c, C-16:1 omega 5c/t, and C-18:1 omega 7c and the sum of these FAs. For the full dataset these relationships were relatively weak (Spearman's rank correlation (r(s)) of 0.34-0.43) and not significant if corrected for multiple testing. However, noticeably stronger and statistically significant relationships were observed when sediments from near-shore and deep-water oxic environments (r(s) = 0.57 to 0.62) and those from anoxic deep-water environment (r(s)= 0.55 to 0.65) were examined separately. Our results confirm that robust relationships exist between in-lake CH 4 concentrations and 13 C-depleted groups of FAs in the examined sediments, agreeing with earlier suggestions that the availability of MOB-derived, C-13-depleted organic matter for aquatic invertebrates increases with increasing methane concentrations. However, we also show that these relationships are complex, with different relationships observed for oxic and anoxic sediments and highest values measured in sediments deposited in oxic environments overlain with relatively methane-rich water. Furthermore, although all three C-13-depleted FA groups identified in our survey are known to be produced by MOB, they also receive contributions by other organism groups, and this will have influenced their distribution in our dataset. (C) 2018 Elsevier Ltd. All rights reserved

Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome

Tourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by motor and vocal tics. Imaging studies found alterations in caudate (Cd) and putamen volumes. To investigate possible alterations in cell populations, postmortem basal ganglia tissue from individuals with TS and normal controls was analyzed by using unbiased stereological techniques. A markedly higher total neuron number was found in the globus pallidus pars interna (GPi) of TS. In contrast, a lower neuron number and density was observed in the globus pallidus pars externa and in the Cd. An increased number and proportion of the GPi neurons were positive for the calcium-binding protein parvalbumin in tissue from TS subjects, whereas lower densities of parvalbumin-positive interneurons were observed in both the Cd and putamen of TS subjects. This change is consistent with a developmental defect in tangential migration of some GABAergic neurons. The imbalance in striatal and GPi inhibitory neuron distribution suggests that the functional dynamics of cortico-striato-thalamic circuitry are fundamentally altered in severe, persistent TS

Identification Of A Founder Mutation In Tpm3 In Nemaline Myopathy Patients Of Turkish Origin

To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the gamma-tropomyosin gene (TPM3) encoding slow skeletal muscle alpha-tropomyosin, a known NM gene. Sequencing revealed homozygous deletion of the first nucleotide of the last exon, c.913delA of TPM3 in both families. The mutation removes the last nucleotide before the stop codon, causing a frameshift and readthrough across the termination signal. The encoded alpha Tm-slow protein is predicted to be 73 amino acids longer than normal, and the extension to the protein is hypothesised to be unable to form a coiled coil. The resulting tropomyosin protein may therefore be non-functional. The affected children in both families were homozygous for the mutation, while the healthy parents were mutation carriers. Both of the patients in Family 1 had the severe form of NM, and also an unusual chest deformity. The affected children in Family 2 had the intermediate form of NM. Muscle biopsies showed type 1 (slow) fibres to be markedly smaller than type 2 (fast) fibres. Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population.WoSScopu

The clinical, histologic, and genotypic spectrum of SEPN1 -related myopathy

International audienceObjective: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series.Methods: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades.Results: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification.Conclusion: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease