Gender diversity in the National Joint Registry

Aims Our primary aim was to establish the proportion of female orthopaedic consultants who perform arthroplasty via cases submitted to the National Joint Registry (NJR), which covers England, Wales, Northern Ireland, the Isle of Man, and Guernsey. Secondary aims included comparing time since specialist registration, private practice participation, and number of hospitals worked in between male and female surgeons. Methods Publicly available data from the NJR was extracted on the types of arthroplasty performed by each surgeon, and the number of procedures of each type undertaken. Each surgeon was cross-referenced with the General Medical Council (GMC) website, using GMC number to extract surgeon demographic data. These included sex, region of practice, and dates of full and specialist registration. Results Of 2,895 surgeons contributing to the NJR in 2023, 102 (4%) were female. The highest proportions of female surgeons were among those who performed elbow (n = 25; 5%), shoulder (n = 24; 4%), and ankle (n = 8; 4%) arthroplasty. Hip (n = 66; 3%) and knee arthroplasty (n = 39; 2%) had the lowest female representation. Female surgeons had been practising for a median of 10.4 years since specialist registration compared to 13.7 years for males (p < 0.001). Northern Ireland was the region with the highest proportion of female arthroplasty surgeons (8%). A greater proportion of male surgeons worked in private practice (63% vs 24%; p < 0.001) and in multiple hospitals (74% vs 40%; p < 0.001). Conclusion Only 4% of surgeons currently contributing cases to the NJR are female, with the highest proportion performing elbow arthroplasty (5%). Female orthopaedic surgeons in the NJR are earlier in their careers than male surgeons, and are less involved in private practice. There is a wide geographical variation in the proportion of female arthroplasty surgeons

High tie versus low tie of the inferior mesenteric artery: a protocol for a systematic review

In anterior resection of rectum, the section level of inferior mesenteric artery is still subject of controversy between the advocates of high and low tie. The low tie is the division and ligation to the branching of the left colic artery and the high tie is the division and ligation at its origin at the aorta. We intend to assess current scientific evidence in literature and to establish the differences comparing technique, anatomy and physiology. The aim of this protocol is to achieve a meta-analysis that tests safety and feasibility of the two procedures with several types of outcome measures

Identification of 4 novel human ocular coloboma genes ANK3, BMPR1B, PDGFRA, and CDH4 through evolutionary conserved vertebrate gene analysis

Purpose: Ocular coloboma arises from genetic or environmental perturbations that inhibit optic fissure (OF) fusion during early eye development. Despite high genetic heterogeneity, 70% to 85% of patients remain molecularly undiagnosed. In this study, we have identified new potential causative genes using cross-species comparative meta-analysis. Methods: Evolutionarily conserved differentially expressed genes were identified through in silico analysis, with in situ hybridization, gene knockdown, and rescue performed to confirm spatiotemporal gene expression and phenotype. Interrogation of the 100,000 Genomes Project for putative pathogenic variants was performed. Results: Nine conserved differentially expressed genes between zebrafish and mouse were identified. Expression of zebrafish ank3a, bmpr1ba/b, cdh4, and pdgfaa was localized to the OF, periocular mesenchyme cells, or ciliary marginal zone, regions traversed by the OF. Knockdown of ank3, bmpr1b, and pdgfaa revealed a coloboma and/or microphthalmia phenotype. Novel pathogenic variants in ANK3, BMPR1B, PDGFRA, and CDH4 were identified in 8 unrelated coloboma families. We showed BMPR1B rescued the knockdown phenotype but variant messenger RNAs failed, providing evidence of pathogenicity. Conclusion: We show the utility of cross-species meta-analysis to identify several novel coloboma disease-causing genes. There is a potential to increase the diagnostic yield for new and unsolved patients while adding to our understanding of the genetic basis of OF morphogenesis

Assessing the digenic model in rare disorders using population sequencing data

An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in different scenarios. We suggest that this approach will be relevant with the advent of new sequencing efforts including hundreds of thousands of samples

Human and mouse essentiality screens as a resource for disease gene discovery.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Colorectal and uterine movement and tension of the inferior hypogastric plexus in cadavers

Background: Hypotheses on somatovisceral dysfunction often assume interference by stretch or compression of the nerve supply to visceral structures. The purpose of this study is to examine the potential of pelvic visceral movement to create tension of the loose connective tissue that contains the fine branches of the inferior hypogastric nerve plexus. Methods: Twenty eight embalmed human cadavers were examined. Pelvic visceral structures were displaced by very gentle 5 N unidirectional tension and the associated movement of the endopelvic fascia containing the inferior hypogastric plexus that this caused was measured. Results: Most movement of the fascia containing the inferior hypogastric plexus was obtained by pulling the rectosigmoid junction or broad ligament of the uterus. The plexus did not cross any vertebral joints and the fascia containing it did not move on pulling the hypogastric nerve. Conclusions: Uterine and rectosigmoid displacement produce most movement of the fascia containing the hypogastric nerve plexus, potentially resulting in nerve tension. In the living this might occur as a consequence of menstruation, pregnancy or constipation. This may be relevant to somatovisceral reflex theories of the effects of manual therapy on visceral conditions.Ian P Johnso