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Abdominal hernias are common and characterised by the abnormal protrusion of a viscus through the wall of the abdominal cavity. The global incidence is 18.5 million annually and there are limited non-surgical treatments. To improve understanding of common hernia aetiopathology, we performed a six-stage genome-wide association study (GWAS) of 62,637 UK Biobank participants with either single or multiple hernia phenotypes including inguinal, femoral, umbilical and hiatus hernia. Additionally, we performed multivariable meta-analysis with metaUSAT, to allow integration of summary data across traits to generate combined effect estimates. On individual hernia analysis, we identified 3404 variants across 38 genome-wide significant (p < 5×10−8) loci of which 11 are previously unreported. Robust evidence for five shared susceptibility loci was discovered: ZC3H11B, EFEMP1, MHC region, WT1 and CALD1. Combined hernia phenotype analyses with additional multivariable meta-analysis of summary statistics in metaUSAT revealed 28 independent (seven previously unreported) shared susceptibility loci. These clustered in functional categories related to connective tissue and elastic fibre homeostasis. Weighted genetic risk scores also correlated with disease severity suggesting a phenotypic-genotypic severity correlation, an important finding to inform future personalised therapeutic approaches to hernia. [ABSTRACT FROM AUTHOR]

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA. Keeping osteoarthritis from getting out of hand: Keeping osteoarthritis from getting out of handOsteoarthritis (OA) is a debilitating medical condition with no treatments currently available. Here Zhu et al. identify variants in the ALDH1A2 gene, responsible for the synthesis of all-trans retinoic acid (atRA), in patients with severe hand OA and link risk alleles to cartilage injury and inflammation. They then show that administration of a retinoic acid metabolism blocking agent (RAMBA), talarozole, reduced cartilage injury and inflammation through a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism in both mouse and pig joints in vivo and ex vivo, respectively. These results implicate atRA in the development of OA and suggest that RAMBAs may be a viable therapeutic option for the treatment of this disease. —AW [ABSTRACT FROM AUTHOR]

Varicose veins affect one-third of Western society, with a significant subset of patients developing venous ulceration, costing $14.9 billion annually in the USA. Current management consists of either compression stockings, or surgical ablation for more advanced disease. Most varicose veins patients report a positive family history, and heritability is ~17%. We describe the largest two-stage genome-wide association study of varicose veins in 401,656 individuals from UK Biobank, and replication in 408,969 individuals from 23andMe (total 135,514 cases and 675,111 controls). Forty-nine signals at 46 susceptibility loci were discovered. We map 237 genes to these loci, several of which are biologically plausible and tractable to therapeutic targeting. Pathway analysis identified enrichment in extracellular matrix biology, inflammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis. Using a polygenic risk score (PRS) derived in an independent cohort, we demonstrate its predictive utility and correlation with varicose veins surgery. Although varicose veins are a common condition, the genetic basis is not well understood. Here, the authors find genetic variants associated with varicose veins and show that a higher polygenic risk score for varicose veins correlates with a greater likelihood of patients undergoing surgical treatment. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID‐19) pandemic has brought about many changes in the relationships between high‐income countries and partner organisations in low‐ or low–middle‐income countries, such as predominate in sub‐Saharan Africa. Medicine, surgery and in particular urology is no exception to the changes that COVID‐19 has demanded. Urolink represents the British Association of Urological Surgeons (BAUS) on the global urology stage and has been deleteriously impacted by the pandemic. Education, one of the pillars of Urolink's founding philosophies, has conventionally been delivered by face‐to face teaching, training, or mentoring by UK urologists at their host's site outside of the UK. As a consequence of the inability to travel due to the pandemic, BAUS Urolink has evolved a virtual on‐line webinar package evolved by, and delivered between, urologists in Lusaka, Zambia, and various centres in the UK. The aim was to deliver curricular‐based educational topics to trainees in both countries. This programme has generated a number of live webinars and archived recordings during the pandemic that has proven accessible and educationally acceptable to trainees in the UK and Zambia. This webinar series has also generated relationships between young urologists on different continents, given each a different view of healthcare delivery outside of their country of origin at no appreciable cost, and would appear to be an educational mechanism that is durable for, and applicable to, a wider participation in the post‐pandemic world. [ABSTRACT FROM AUTHOR]

Ninety per cent of the human population has been right-handed since the Paleolithic, yet the brain signature and genetic basis of handedness remain poorly characterized. Here, we correlated brain imaging phenotypes from ∼9000 UK Biobank participants with handedness, and with loci found significantly associated with handedness after we performed genome-wide association studies (GWAS) in ∼400 000 of these participants. Our imaging-handedness analysis revealed an increase in functional connectivity between left and right language networks in left-handers. GWAS of handedness uncovered four significant loci (rs199512, rs45608532, rs13017199, and rs3094128), three of which are in-or expression quantitative trait loci of-genes encoding proteins involved in brain development and patterning. These included microtubule-related MAP2 and MAPT, as well as WNT3 and MICB, all implicated in the pathogenesis of diseases such as Parkinson's, Alzheimer's and schizophrenia. In particular, with rs199512, we identified a common genetic influence on handedness, psychiatric phenotypes, Parkinson's disease, and the integrity of white matter tracts connecting the same language-related regions identified in the handedness-imaging analysis. This study has identified in the general population genome-wide significant loci for human handedness in, and expression quantitative trait loci of, genes associated with brain development, microtubules and patterning. We suggest that these genetic variants contribute to neurodevelopmental lateralization of brain organization, which in turn influences both the handedness phenotype and the predisposition to develop certain neurological and psychiatric diseases. [ABSTRACT FROM AUTHOR]

Background: Dupuytren's disease is a common, chronic, fibroproliferative disease of the palmar fascia. The cause is unclear but includes genetic predisposition alongside environmental factors. Several studies have suggested an association between Dupuytren's disease and excess mortality. The authors aimed to evaluate this association in adult patients in the United Kingdom and identify the causes of mortality., Methods: The authors used a large primary care database (Clinical Practice Research Datalink) linked to the Office of National Statistics to identify patients with Dupuytren's disease between January 1, 1995, and December 31, 2013. Each patient was matched by age, sex, and general practitioner to five control patients without the disease. Cox regression models were used to study the association between Dupuytren's disease and all-cause and cause-specific mortality, adjusting for confounders., Results: A total of 41,965 Dupuytren's disease patients and 209,825 control patients were identified. The all-cause mortality rate was increased in both unadjusted (hazard ratio, 1.48; 99% CI, 1.29 to 1.70; p < 0.0001) and multivariable adjusted (hazard ratio, 1.43; 99% CI, 1.25 to 1.65; p < 0.0001) models in patients with Dupuytren's disease, 12 years after diagnosis. Excess mortality was secondary to a wide range of causes, including cancer (hazard ratio, 1.66; 99% CI, 1.27 to 2.17; p < 0.0001), an effect that persisted after adjustment for confounders., Conclusions: There is excess mortality associated with Dupuytren's disease that can be partially explained through environmental factors. From time of diagnosis in primary care, there is a 12-year window of opportunity for intervention to reduce the impact of these factors. The authors observed an increased risk of cancer mortality independent of confounders, and hypothesize a shared genetic risk between Dupuytren's disease and cancer., Clinical Question/level of Evidence: Risk, II.

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45-60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted.

Background: Dupuytren's disease is a very common, highly heritable palmar fibromatosis. In a recent genome-wide association study, 26 single-nucleotide polymorphisms were found to be associated with development of Dupuytren's disease. The authors generated a weighted genetic risk score based on the genotype at these single-nucleotide polymorphisms. In two independent cohorts, they tested the association among high weighted genetic risk score, clinical features that predict a high risk of recurrence, and recurrence after surgery., Methods: Clinical data were obtained from patient questionnaires and clinical records, with missing data accounted for by imputation. Genotyping was performed as part of the recent genome-wide association study. Logistic regression was performed to study the association among weighted genetic risk score, high-risk clinical features, and recurrence, with a weighted genetic risk score analyzed as a continuous variable, and also grouped into four categories., Results: Using univariable logistic regression, a high weighted genetic risk score was associated with the presence of all high-risk clinical features: early age of onset, bilateral disease, ectopic disease, and a positive family history (p ≤ 0.004). After multivariable logistic regression accounting for these factors, an increased weighted genetic risk score was still associated with the need for repeated Dupuytren's disease surgery (p = 0.004)., Conclusions: The authors' results suggest that a weighted genetic risk score is useful in predicting the risk of disease recurrence, and may be used by surgeons to personalize prognostication. In the future, a weighted genetic risk score may be useful for determining the most appropriate initial surgical procedure in patients with Dupuytren's disease., Clinical Question/level of Evidence: Risk, III.