The human gene connectome as a map of short cuts for morbid allele discovery

High-throughput genomic data reveal thousands of gene variants per patient, and it is often difficult to determine which of these variants underlies disease in a given individual. However, at the population level, there may be some degree of phenotypic homogeneity, with alterations of specific physiological pathways underlying the pathogenesis of a particular disease. We describe here the human gene connectome (HGC) as a unique approach for human Mendelian genetic research, facilitating the interpretation of abundant genetic data from patients with the same disease, and guiding subsequent experimental investigations. We first defined the set of the shortest plausible biological distances, routes, and degrees of separation between all pairs of human genes by applying a shortest distance algorithm to the full human gene network. We then designed a hypothesis-driven application of the HGC, in which we generated a Toll-like receptor 3-specific connectome useful for the genetic dissection of inborn errors of Toll-like receptor 3 immunity. In addition, we developed a functional genomic alignment approach from the HGC. In functional genomic alignment, the genes are clustered according to biological distance (rather than the traditional molecular evolutionary genetic distance), as estimated from the HGC. Finally, we compared the HGC with three state-of-the-art methods: String, FunCoup, and HumanNet. We demonstrated that the existing methods are more suitable for polygenic studies, whereas HGC approaches are more suitable for monogenic studies. The HGC and functional genomic alignment data and computer programs are freely available to noncommercial users from http://lab.rockefeller.edu/casanova/HGC and should facilitate the genome-wide selection of disease-causing candidate alleles for experimental validation.     

Prospective clinical trial comparing outcome measures between Furlow and von Langenbeck Palatoplasties for UCLP

The goal of this prospective randomized clinical trial was to compare 2 cohorts of standardized cleft patients with regard to functional speech outcome and the presence or absence of palatal fistulae. The 2 cohorts are randomized to undergo either a conventional von Langenbeck repair with intravelar velarplasty or the double-opposing Z-plasty Furlow procedure. A prospective 2 × 2 × 2 factorial clinical trial was used in which each subject was randomly assigned to 1 of 8 different groups: 1 of 2 different lip repairs (Spina vs. Millard), 1 of 2 different palatal repair (von Langenbeck vs. Furlow), and 1 of 2 different ages at time of palatal surgery (9-12 months vs. 15-18 months). All surgeries were performed by the same 4 surgeons. A cul-de-sac test of hypernasality and a mirror test of nasal air emission were selected as primary outcome measures for velopharyngeal function. Both a surgeon and speech pathologist examined patients for the presence of palatal fistulae. In this study, the Furlow double-opposing Z-palatoplasty resulted in significantly better velopharyngeal function for speech than the von Langenbeck procedure as determined by the perceptual cul-de-sac test of hypernasality. Fistula occurrence was significantly higher for the Furlow procedure than for the von Langenbeck. Fistulas were more likely to occur in patients with wider clefts and when relaxing incisions were not used.     

Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19

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The bone response to non-weight-bearing exercise is sport-, site-, and sex-specific.

OBJECTIVE: To examine whether skeletal adaptations to chronic non-weight-bearing exercise depend on the type of aquatic exercise (swimming or water polo) as well as on sex (men or women). DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study at the Laboratory of Nutrition and Clinical Dietetics, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece. A total of 43 water polo players, 26 swimmers, and 30 sedentary individuals, aged 17 to 34 years, were recruited (52 men, 47 women). MAIN OUTCOME MEASURES: Bone mineral content (BMC) and areal bone mineral density (aBMD) of the total body and of various subregions. RESULTS:: Compared with controls, swimmers had lower leg and total aBMD (P < 0.05), whereas water polo players had lower leg but higher arm and trunk aBMD (all P < 0.05). Swimmers and water polo athletes differed at the arms (men only), trunk, and total body (all higher in water polo players, at P < 0.05). Bone adaptations to water polo playing were unaffected by sex. Female swimmers, but not male swimmers, had 13% higher arm BMC than controls (P < 0.05), whereas male swimmers, but not female swimmers, had 12% lower leg BMC than controls (P < 0.05). CONCLUSIONS: Athletes participating in long-term water polo playing and swimming have substantially different total and regional aBMD. The effect is not mediated by sex in water polo players; however, sex may mediate the differences between swimmers and controls. Whether the observed differences between athlete groups and sexes arise from different bone adaptations to activity or from other factors cannot be answered by the current data. CLINICAL RELEVANCE: Water polo playing may be preferable over swimming for maintaining bone health; both types of aquatic exercise at the elite level of participation, however, have unfavorable effects on the lower limb bones.     

Assessing surgeons' disclosure of risk information before carotid endarterectomy

BACKGROUND: To make an informed decision about treatment, patients need accurate information about the benefits and risks of treatment and 'non-treatment' options. A survey was conducted to determine patients' recall of the extent and effect of preoperative disclosure by surgeons to patients of risks about carotid endarterectomy (CEA). METHODS: A self-administered questionnaire was given to 133 patients undergoing elective CEA in New South Wales. The primary outcome measures were patient recall of preoperative discussion, self-assessed estimates of stroke risk with and without surgery and receipt of written information before CEA. RESULTS: A significantly higher proportion of patients recalled that their surgeon discussed the short-term stroke risk (i.e. within 30 days) if they decided to undergo CEA (86.2%) than if they decided not to have the procedure (76.9%) (P = 0.04). Of those patients who recalled the surgeon discussing their short-term stroke risk with CEA, only 24 (18.0%) were accurately able to quantify this risk. Patients were significantly more likely to recall their surgeon discussing their long-term stroke risk (i.e. within 2 years) if they decided not to have CEA (72.4%) than if they decided to have the CEA (31.5%) (P < 0.0001). CONCLUSIONS: Patients recalled discussions with their surgeon about short-term stroke risk. Only a minority, however, accurately quantified their postoperative stroke risk. In view of variable patient recall, decision aids could assist.