Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Effects of Ving Tsun Chinese Martial Art Training on Upper Extremity Muscle Strength and Eye-Hand Coordination in Community-Dwelling Middle-Aged and Older Adults: A Pilot Study

Objectives. To evaluate the effects of Ving Tsun (VT) martial art training on the upper extremity muscle strength and eye-hand coordination of middle-aged and older adults. Methods. This study used a nonequivalent pretest-posttest control group design. Forty-two community-dwelling healthy adults participated in the study; 24 (mean age ± SD = 68.5±6.7 years) underwent VT training for 4 weeks (a supervised VT session twice a week, plus daily home practice), and 18 (mean age ± SD = 72.0±6.7 years) received no VT training and acted as controls. Shoulder and elbow isometric muscle strength and eye-hand coordination were evaluated using the Lafayette Manual Muscle Test System and a computerized finger-pointing test, respectively. Results. Elbow extensor peak force increased by 13.9% (P=0.007) in the VT group and the time to reach peak force decreased (9.9%) differentially in the VT group compared to the control group (P=0.033). For the eye-hand coordination assessment outcomes, reaction time increased by 2.9% in the VT group and decreased by 5.3% in the control group (P=0.002). Conclusions. Four weeks of VT training could improve elbow extensor isometric peak force and the time to reach peak force but not eye-hand coordination in community-dwelling middle-aged and older adults

The clinical impact of chromosomal microarray on paediatric care in Hong Kong.

OBJECTIVE: To evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong. METHODS: We performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their "clinical actionability" based on established criteria. RESULTS: Thirty-seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p < 0.001). Nineteen out of the 28 management recommendations are "evidence-based" on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12). CONCLUSION: The application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ∼ 11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing

Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies

Abstract RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation

CNVs type in patients with clinically significant CNVs and patients with CNVs of unknown clinical significance.

<p>CNVs type in patients with clinically significant CNVs and patients with CNVs of unknown clinical significance.</p

Management recommendations for clinically significant CNVs and recommendation according to the level of evidence.

<p>Abbreviations: MCA = Multiple Congenital Anomalies; DD = Developmental Delay; ASD = Autism Spectrum Disorders; Dys = Dysmorphism; UCS = Uncertain Clinical Significance.</p><p>Abbreviations: S = Surveillance; R =  specialist Referral/assessment; D = Diagnostic testing; P = medical/surgical Procedure; M = Medication administration; L = Lifestyle recommendation; O = Other interventions.</p><p>* = pathogenic CNVs, ∧ = likely pathogenic CNVs.</p><p>N = not tested; Mat  =  maternal inheritance; Pat  =  paternal inheritance.</p><p>Management recommendations for clinically significant CNVs and recommendation according to the level of evidence.</p