PEDIA: prioritization of exome data by image analysis.

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

Weiterentwicklung von Deponieabdichtungssystemen. Teilvorhaben 20: Langzeitverhalten von Erdstoffschichten in Deponiebasisabdichtungen, Feuchtehaushalt unter Temperatureinwirkung

The sealing properties of the earthen layers in landfill liners depend on water content, which is not constant but changes according to the moisture conditions of the landfill and the adjacent soil. Earthen layers in landfill liners tend to lose water over the course of time and this may result in desiccation cracking. To study the behaviour of soils undergoing desiccation, test devices and methods were developed to evaluate the water transport characteristics of soil samples. Measurement of the temporal and spatial changes in moisture distribution within the cylindrical soil sample was accompanied by a calculation in which diffusion coefficients were iteratively varied so as to reach optimum agreement with the observed moisture distribution. Overburden pressure can to some extent prevent desiccation. Therefore test devices were developed which made it possible to load soil samples simultaneously by vertical stress and by suction. (orig./SR)Die Dichtigkeit von Erdstoffschichten in Deponieabdichtungen haengt vom Wassergehalt ab, der nicht konstant ist, sondern sich entsprechend dem Feuchtehaushalt von Deponie und umgebendem Boden aendert. Die Erdstoffabdichtungssschichten tendieren langfristig zum Trocknerwerden, wodurch es zu Rissen kommen kann. Um das Austrocknungsverhalten zu untersuchen, wurden Versuchsgeraete und -verfahren zur Bestimmung von Wassertransportkennwerten an Bodenproben entwickelt. Die Messung der zeitlichen und oertlichen Aenderung der Feuchteverteilung in der zylindrischen Bodenprobe wurde durch eine Rechnung begleitet, in der die eingegebenen Diffusionskoeffizienten iterativ variiert wurden, bis optimale Uebereinstimmung mit der gemessenen Feuchteverteilung erreicht war. Auflast kann Austrocknung bis zu einem gewissen Grad verhindern. Deshalb wurden Geraete entwickelt, in denen Bodenproben gleichzeitig einer Wasserspannung und einer vertikalen Spannung ausgesetzt werden koennen. (orig./SR)SIGLEAvailable from TIB Hannover: F97B1024+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

A novel THz source based on a two-color Nd: LSB microchip laser and a LT-GaAsSb photomixer

The prognostic impact of multifocal upper-tract urothelial carcinoma (UTUC) is poorly understood.To investigate the association between tumor multifocality and clinicopathologic features and outcomes of UTUC in patients managed by radical nephroureterectomy (RNU).The study included 2492 patients treated with either open or laparoscopic RNU. Tumor and patient characteristics included tumor stage, tumor grade, lymph node status, lymphovascular invasion (LVI), tumor architecture, tumor location, unifocal or multifocal disease, gender, age, history of bladder cancer (BCa), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adjuvant chemotherapy. tumor multifocality of UTUC was defined as the synchronous presence of multiple tumors in the renal pelvis or ureter.All patients were treated with either open or laparoscopic RNU.Univariable and multivariable models tested the effect of tumor multifocality on disease progression and cancer-specific mortality.Five hundred ninety patients (23.7%) had tumor multifocality at the time of RNU. The median follow-up was 45 mo (interquartile range [IQR]: 0-101). Tumor multifocality was significantly associated with a history of previous BCa (p=0.032), lymph node involvement (p=0.036), tumor location in the ureter (p=0.003), higher tumor stage (p<0.001), higher tumor grade (p<0.001), sessile tumor architecture (p=0.003), and LVI (p=0.001). In organ-confined patients, tumor multifocality was an independent predictor of both disease progression (hazard ratio [HR]: 1.43; p=0.019) and cancer-specific mortality (HR: 1.46; p=0.027). When assessed in all patients, tumor multifocality was associated with both disease progression and cancer-specific mortality in univariable (p=0.005 and p=0.006, respectively) but not in multivariable analyses (p=0.468 and p=0.798, respectively). The main limitation is the retrospective design of the study.Tumor multifocality is an independent prognosticator of disease progression and cancer-specific mortality in patients with organ-confined UTUC treated with RNU. Multifocal organ-confined patients with UTUC may need closer follow-up. Integration of tumor multifocality with other factors may help identify those patients who would benefit from multimodal therapy

Thermal behavior of mortars with incorporation of Phase Change Materials (PCM) in the Portuguese climate

Atualmente, os elevados consumos energéticos constituem uma das maiores preocupações da sociedade e da comunidade científica. A União Europeia definiu várias estratégias para atenuar este problema até 2020, passando pela redução das emissões de CO2, redução do consumo de energia primária e aumento do consumo de energia proveniente de fontes renováveis. O sector da construção é responsável por elevados consumos energéticos durante a fase de construção e utilização dos edifícios. Assim, torna-se importante utilizar soluções construtivas funcionais, que minimizem os consumos energéticos nos edifícios. A incorporação de materiais de mudança de fase (PCM) em materiais de construção permite a regulação da temperatura no interior dos edifícios com recurso à sua capacidade de armazenamento e libertação de energia. Desta forma, o principal objetivo deste estudo consistiu na caracterização do desempenho térmico de argamassas com incorporação de microcápsulas de PCM e comparação com argamassas de referência (0% PCM). Para tal, foram desenvolvidas 8 composições distintas, à base de diferentes ligantes, sendo estes a cal aérea, cal hidráulica, cimento e gesso. Para cada ligante foi desenvolvida uma composição de referência (0% PCM) e uma composição com incorporação de 40% de PCM, em substituição da massa de agregado. As propriedades avaliadas foram a trabalhabilidade, microestrutura, comportamento mecânico e desempenho térmico. Foi possível observar que a utilização de microcápsulas de PCM em argamassas contribui para uma melhoria da eficiência energética dos edifícios, através da diminuição das temperaturas extremas, do desfasamento temporal das temperaturas extremas e da diminuição das necessidades de climatização dos edifícios.Nowadays, the high energetic consumption is one of the biggest concerns of the modern society and scientific community. The European Union defined strategies for 2020 in order to reduce this problem, through the decrease of CO2 emissions, decrease the primary energy consumption and increase the energy consumption from renewable sources. The construction sector is responsible for high energetic consumptions during the production and utilization of buildings. Thus, it becomes important to use constructive solutions that allow minimize the energy consumption in buildings. The incorporation of phase change materials (PCM) in construction materials allows regulate the temperature inside the buildings, due to their capability of storage and release energy. The main objective of this study was to characterize the thermal performance of mortars with incorporation of PCM microcapsules. It were developed 8 different compositions based in different binders. The studied binders were aerial lime, hydraulic lime, cement and gypsum. For each binder a reference mortar (0% PCM) and a mortar with incorporation of 40% of PCM were developed. It was evaluated properties such as workability, microstructure, mechanical and thermal performance. It was possible to observe that the in-corporation of PCM microcapsules in mortars effectively contributes to improving the energy efficiency of buildings, through the decrease of extreme temperatures, lag time delay of extreme temperatures and decrease of climatization needs of the buildings.Os autores desejam expressar os seus agradecimentos à Fundação para a Ciência e Tecnologia (FCT) pelo financiamento deste trabalho no âmbito da bolsa de doutoramento SFRH/BD/95611/2013.info:eu-repo/semantics/publishedVersio

Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations

Contains fulltext : 154784.pdf (publisher's version ) (Closed access)FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications" did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis

PRUNE1 deficiency: Expanding the clinical and genetic spectrum.

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations.Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reportedmissensemutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene.Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature