Polygenic threshold model with sex dimorphism in adolescent idiopathic scoliosis: The Carter effect

Background: Idiopathic clubfoot is approximately twice as common in males than in females. The reason for this discrepancy is unclear butmay represent an inherent difference in the susceptibility to thedeformity. If this difference is due to genetic factors it is predicted that in order to inherit clubfoot, females need to have a greater number of susceptibility genes than males. Females would also be more likely to transmit the disease to their children and have siblings with clubfoot. This phenomenon is known as the Carter effect, and the presence of such an effect supports a multifactorial threshold model of inheritance. Methods: Ninety-seven multiplex families with more than one individual with idiopathic clubfoot were studied. The study included1093 individuals: 291with clubfoot and802unaffected relatives. Ratesof transmissionby the thirty-seven affected fathers and twenty-six affected mothers were calculated, and the prevalence among siblings was determined in the nuclear families of affected persons

Kinesin family member 6 (kif6) is necessary for spine development in zebrafish

Author Posting. © The Author(s), 2014. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in Developmental Dynamics 243 (2014): 1646–1657, doi:10.1002/dvdy.24208.Idiopathic scoliosis is a form of spinal deformity that affects 2–3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in part due to the lack of a relevant animal model. We performed a forward mutagenesis screen in zebrafish to identify new models for idiopathic scoliosis. We isolated a recessive zebrafish mutant, called skolios, which develops isolated spinal curvature that arises independent of vertebral malformations. Using meiotic mapping and whole genome sequencing, we identified a nonsense mutation in kinesin family member 6 (kif6gw326) unique to skolios mutants. Three additional kif6 frameshift alleles (gw327, gw328, gw329) were generated with transcription activator-like effector nucleases (TALENs). Zebrafish homozygous or compound heterozygous for kif6 frameshift mutations developed a scoliosis phenotype indistinguishable from skolios mutants, confirming that skolios is caused by the loss of kif6. Although kif6 may play a role in cilia, no evidence for cilia dysfunction was seen in kif6gw326 mutants. Overall, these findings demonstrate a novel role for kif6 in spinal development and identify a new candidate gene for human idiopathic scoliosis.2015-11-1

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND

The role of supportive supervision on immunization program outcome - a randomized field trial from Georgia

<p>Abstract</p> <p>Background</p> <p>One of the most common barriers to improving immunization coverage rates is human resources and its management. In the Republic of Georgia, a country where widespread health care reforms have taken place over the last decade, an intervention was recently implemented to strengthen performance of immunization programs. A range of measures were taken to ensure that immunization managers carry out their activities effectively through direct, personal contact on a regular basis to guide, support and assist designated health care facility staff to become more competent in their immunization work. The aim of this study was to document the effects of "supportive" supervision on the performance of the immunization program at the district(s) level in Georgia.</p> <p>Methods</p> <p>A pre-post experimental research design is used for the quantitative evaluation. Data come from baseline and follow-up surveys of health care providers and immunization managers in 15 intervention and 15 control districts. These data were supplemented by focus group discussions amongst Centre of Public Health and health facility staff.</p> <p>Results</p> <p>The results of the study suggest that the intervention package resulted in a number of expected improvements. Among immunization managers, the intervention independently contributed to improved knowledge of supportive supervision, and helped remove self-perceived barriers to supportive supervision such as availability of resources to supervisors, lack of a clear format for providing supportive supervision, and lack of recognition among providers of the importance of supportive supervision. The intervention independently contributed to relative improvements in district-level service delivery outcomes such as vaccine wastage factors and the DPT-3 immunization coverage rate. The clear positive improvement in all service delivery outcomes across both the intervention and control districts can be attributed to an overall improvement in the Georgian population's access to health care.</p> <p>Conclusion</p> <p>Provider-based interventions such as supportive supervision can have independent positive effects on immunization program indicators. Thus, it is recommended to implement supportive supervision within the framework of national immunization programs in Georgia and other countries in transition with similar institutional arrangements for health services organization.</p> <p>Abstract in Russian</p> <p>See the full article online for a translation of this abstract in Russian.</p

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine