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Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 ‘DSDnet’ was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV) or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case.

Background\ud \ud Patients with rare diseases face health disparities and are often challenged to find accurate information about their condition. We aimed to use the best available evidence and community partnerships to produce patient education materials for congenital hypogonadotropic hypogonadism (CHH) and the olfacto-genital (Kallmann) syndrome (i.e., CHH and defective sense of smell), and to evaluate end-user acceptability. Expert clinicians, researchers and patients co-created the materials in a multi-step process. Six validated algorithms were used to assess reading level of the final product. Comprehensibility and actionability were measured using the Patient Education Materials Assessment Tool via web-based data collection. Descriptive statistics were employed to summarize data and thematic analysis for analyzing open-ended responses. Subsequently, translation and cultural adaption were conducted by clinicians and patients who are native speakers.\ud Results\ud \ud Co-created patient education materials reached the target 6th grade reading level according to 2/6 (33%) algorithms (range: grade 5.9–9.7). The online survey received 164 hits in 2 months and 63/159 (40%) of eligible patients completed the evaluation. Patients ranged in age from 18 to 66 years (median 36, mean 39 ± 11) and 52/63 (83%), had adequate health literacy. Patients scored understandability at 94.2% and actionability at 90.5%. The patient education materials were culturally adapted and translated into 20 languages (available in Additional file 1).\ud Conclusions\ud \ud Partnering with patients enabled us to create patient education materials that met patient- identified needs as evidenced by high end-user acceptability, understandability and actionability. The web-based evaluation was effective for reaching dispersed rare disease patients. Combining dissemination via traditional healthcare professional platforms as well as patient-centric sites can facilitate broad uptake of culturally adapted translations. This process may serve as a roadmap for creating patient education materials for other rare diseases.

This paper deals with an analysis of performances of the HL (Hyperloop) transport system considered as an advanced transport alternative to the existing APT (Air Passenger Transport) and HSR (High Speed Rail) systems. The considered performances are operational, financial, social and environmental. The operational performance include capacity and quality of service provided to the system’s users-passengers with attributes such as door-to-door travel time consisting of the access and egress time, schedule delay, in-vehicle time, and interchange time. The economic performances embrace the costs and revenues of operating the system. The costs include that for infrastructure, vehicles, traffic management facilities and equipment, and employees. The revenues embrace earnings from pricing users/passengers. The environmental performances include energy consumption and related emissions of GHGs (Green House Gases), and land use. The social performances are considered to be noise and safety. The analytical models of indicators of these performances are developed and applied to the scenario of operating the HL system on the short- to medium-haul travel distances/routes. These are then compared to the corresponding performances of the HSR and APT. This comparison has shown that the HL system may possess some advantages but also disadvantages regarding particular performances.

Context:\ud Only about 85% of patients with clinical diagnosis complete androgen insensitivity syndrome (CAIS) and less than 30% with partial androgen insensitivity syndrome (PAIS) can be explained by inactivating mutations in the androgen receptor (AR) gene.\ud Objective:\ud To clarify this discrepancy by in-vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls.\ud Design:\ud Quantification of dihydrotestosterone (DHT)-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GF) (APOD-assay) and next generation sequencing (NGS) of the complete coding - and non-coding AR-locus.\ud Setting:\ud University Hospital Endocrine research laboratory\ud Patients:\ud GF from 169 individuals were studied encompassing control males (N=68), molecular defined DSD other than AIS (N=18), AR-mutation positive AIS (N=37) and previously undiagnosed DSD including patients with clinical suspicion of AIS (N=46).\ud Intervention(s):\ud None.\ud Main Outcome Measure(s):\ud DHT-dependent APOD-expression in cultured GF and AR-mutation status in 169 individuals.\ud Results:\ud The APOD-assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff

Summary: Transportation origin-destination analysis is investigated through the use of Poisson mixtures by introducing covariate-based models which incorporate different transport modelling phases and also allow for direct probabilistic inference on link traffic based on Bayesian predictions. Emphasis is placed on the Poisson-inverse Gaussian model as an alternative to the commonly used Poisson-gamma and Poisson-log-normal models. We present a first full Bayesian formulation and demonstrate that the Poisson-inverse Gaussian model is particularly suited for origin-destination analysis because of its desirable marginal and hierarchical properties. In addition, the integrated nested Laplace approximation is considered as an alternative to Markov chain Monte Carlo sampling and the two methodologies are compared under specific modelling assumptions. The case-study is based on 2001 Belgian census data and focuses on a large, sparsely distributed origin-destination matrix containing trip information for 308 Flemish municipalities. © 2014 Royal Statistical Society.

Introduction. Als parameter voor de kwaliteit van de hulpverlening door gespecialiseerde kinderdiabetescentra wordt naar de metabole controle (HbA1c) ook het gezondheidsgerelateerd algemeen welbevinden, welke zowel het fysiek, mentaal, emotioneel en sociaal als schools functioneren omvat, voorgesteld. Adolescentie is een periode van zowel minderen metabole controle als een minder algemeen welbevinden bij kinderen met diabetes. Aim. In deze studie willen we het algemeen (AW) en diabetes-gerelateerd welbevinden (DW) bij adolescenten met diabetes mellitus type 1 (DM1) nagaan en de invloed van het geslacht, leeftijd, etnische origine, gezinssituatie (één- of twee oudergezin), gezinsinkomen en metabole controle onderzoeken. Method. De 310 DM1 adolescenten (12-18 jaar), opgevolgd in het UZ Brussel en UZ Gent, werden na geïnformeerde toestemming telefonisch en schriftelijk uitgenodigd om de Pediatric Quality of Life Inventory (PedsQL) vragenlijst en een demografische vragenlijst in te vullen. Het gemiddelde van de 3 laatste HbA1c bepalingen werd berekend. Results. 133 patiënten (71 meisjes, 120 autochtone origine, 81 uit het UZ Gent, 20 behandeld met insuline pomp, 107 uit twee-ouder gezin, 68 met ouderlijk maandinkomen boven de 3000 euro) stuurden ingevulde vragenlijsten terug. Mediane (range) leeftijd en diabetesduur was 15.2 (range 12.4 – 18.8) en 5 jaar (range 1 – 16). Gemiddelde (SD) HbA1c was 7.9% (1.0), vergelijkbaar tussen de ziekenhuizen, maar significant (p < .001) lager dan bij de niet deelnemende adolescenten (8.4(1.2)%). De gemiddelde (SD) AW en DW totaal scores waren 82 (12) en 74 (14), vergelijkbaar tussen de geslachten en de ziekenhuizen en sterk gecorreleerd (r = .676, p < .001). Voor fysiek, psychosociaal, emotioneel, sociaal en schools functioneren hadden respectievelijk 9.0%, 14.3%, 15.0%, 9.8%, en 20.3% een afwijkende score. HbA1c (r = -.230, p < .01) en leeftijd (r = -.180, p < .05) correleerden negatief met DW score, doch niet met AW score. Autochtone diabetici hadden, in vergelijking met allochtone, een significant hogere DW score (p < .005), maar een vergelijkbare AW score. DW en AW score van patiënten uit één-ouder gezinnen waren significant lager in vergelijking met twee-ouder gezinnen (p < .005). Elke sub-score van AW varieerde significant in functie van het gezinsinkomen (p < .005). Met diabetesduur en type behandeling (pen versus pomp) werd geen correlatie gevonden. Enkel gezinsinkomen was een significante voorspellen voor AW (p < .05) en etniciteit voor DW (p < .05) in multipele regressie analyse. Conclusion. Het algemeen welbevinden bij Vlaamse DM1 adolescenten is vergelijkbaar met deze gerapporteerd in andere landen. In hoofdzaak werd een minder gunstig schools functioneren vastgesteld. In de rapportering van het welbevinden dient met gezinsinkomen en de etnische origine rekening gehouden te worden bij de vergelijking van diabetescentra.