Distribution of age at natural menopause, age at menarche, menstrual cycle length, height and BMI in BRCA1 and BRCA2 pathogenic variant carriers and non-carriers: results from EMBRACE

BACKGROUND: Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited. METHODS: We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status. RESULTS: No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p = 0.003). CONCLUSION: Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.CC BY 4.0 Internationa

A novel, dominant disease mechanism of distal renal tubular acidosis with specific variants in ATP6V1B1

BACKGROUND AND HYPOTHESIS: ATP6V1B1 encodes a subunit of the vacuolar H+-ATPase and pathogenic variants are associated with autosomal recessive distal renal tubular acidosis (dRTA) with deafness. Heterozygous variants predicted to affect a specific amino acid, Arg394, have been recurrently reported in dRTA but their significance has been unclear. We hypothesised that these variants are associated with a dominant disease mechanism. METHODS: Retrospective analysis of cases identified in our genetic laboratories and through European nephrology organisations. Data regarding demographics, clinical presentation, laboratory findings, hearing and imaging studies of kidneys were collected from the index patient and, if available, from other family members. The potential disease mechanism was investigated through structural modelling in silico. RESULTS: Twenty index patients in total were included, of which 19 carried the variant c.1181G>A; p.(Arg394Gln) and one c.1180C>G; p.(Arg394Gly). In 7 families, more than one member was affected and the variant segregated with the disease in those with available information (15 affected, 6 unaffected), except for the unaffected mother of 2 affected children, who was mosaic. In no patient was a second causative variant in trans identified. In 8 sporadic patients and 1 affected parent, the variant was confirmed to be de novo. Both variants are absent in gnomAD. Sensorineural hearing loss was reported in 8 of the 22 patients with available information. Structural modelling supports a crucial role for Arg394 in nucleotide binding. CONCLUSION: We provide strong evidence for the pathogenicity of heterozygous variants affecting Arg394 and thus a novel inheritance modus for ATP6V1B1-associated dRTA. Clinically, this form differs from the recessive one by the lower prevalence of hearing loss. The prominent position of Arg394 in the nucleotide binding fold of the H+-ATPase structure is consistent with a dominant negative mechanism. Our findings inform the diagnosis and management of patients with dRTA and variants of Arg394.This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)New Full Text unavailable for 1 year from time of publication. Please click an article to explore additional access options

Chronic Kidney Disease Following Cardiac Arrest Manifesting as Dyspnoea and Peripheral Oedema in Cardiovascular Multimorbidity: Case Analysis and Brief Literature Review

BACKGROUND/AIM: Chronic kidney disease (CKD) contributes significantly to morbidity, mortality, and healthcare costs. CKD is not only an independent risk factor for cardiovascular disease (CVD) but also a severe complication for patients with CVD, impacting substantially their prognosis and quality of life. CASE REPORT: A 79-year-old male with a complex medical history, including asthma, hypertension, myocardial infarction, ischaemic heart disease, and recent atrial fibrillation, presented with new-onset exertional breathlessness and peripheral oedema following cardiac arrest and pacemaker insertion. Investigations, including medication reviews conducted shortly after in an outpatient setting, revealed severe renal impairment with creatinine levels at 250 μmol/l (reference range for adult males: 59-104), representing an initial acute kidney injury (AKI) that did not resolve and resulted in the diagnosis of stage 4 CKD (eGFR 25 ml/min/1.73 m(2)). The patient was treated with furosemide, dapagliflozin, and adjusted doses of ramipril and edoxaban. Following treatment, the patient's symptoms ameliorated and renal function slightly improved (eGFR 27 ml/min/1.73 m(2)). CONCLUSION: This case highlights the importance of individualised treatment for patients with CKD alongside complex cardiovascular multi-morbidity. The administration of dapagliflozin and furosemide, together with careful adjustments to ramipril, were instrumental in stabilising the patient's renal function and alleviating symptoms. This case demonstrates how a multifaceted approach, continuous monitoring, and patient education are essential for achieving optimal outcomes in patients with CKD and cardiovascular comorbidities.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international licenseRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

Correction: UK corneal surgeons' attitudes towards splitting donor corneas between multiple recipients

This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text

FUT8 Is a Critical Driver of Prostate Tumour Growth and Can Be Targeted Using Fucosylation Inhibitors

BACKGROUND: An unmet clinical need requires the discovery of new treatments for men facing advanced prostate cancer. Aberrant glycosylation is a universal feature of cancer cells and plays a key role in tumour growth, immune evasion and metastasis. Alterations in tumour glycosylation are closely associated with prostate cancer progression, making glycans promising therapeutic targets. Fucosyltransferase 8 (FUT8) drives core fucosylation by adding α1,6-fucose to the innermost GlcNAc residue on N-glycans. While FUT8 is recognised as a crucial factor in cancer progression, its role in prostate cancer remains poorly understood. METHODS & RESULTS: Here, we demonstrate using multiple independent clinical cohorts that FUT8 is upregulated in high grade and metastatic prostate tumours, and in the blood of prostate cancer patients with aggressive disease. Using novel tools, including PhosL lectin immunofluorescence and N-glycan MALDI mass spectrometry imaging (MALDI-MSI), we find FUT8 underpins the biosynthesis of malignant core fucosylated N-glycans in prostate cancer cells and using both in vitro and in vivo models, we find FUT8 promotes prostate tumour growth, cell motility and invasion. Mechanistically we show FUT8 regulates the expression of genes and signalling pathways linked to prostate cancer progression. Furthermore, we find that fucosylation inhibitors can inhibit the activity of FUT8 in prostate cancer to suppress the growth of prostate tumours. CONCLUSIONS: Our study cements FUT8-mediated core fucosylation as an important driver of prostate cancer progression and suggests targeting FUT8 activity for prostate cancer therapy as an exciting area to explore.CC BY 4.0 (Creative Commons Attribution

How do we avoid over-treating skin cancer in people with severe frailty and limited life expectancy?

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Higher hospital volume reduces early failure rates in single-stage revision TKR for infection: An analysis of the United Kingdom National Joint Registry and National Administrative Databases

PURPOSE: Revision knee replacement (RevKR) for infection is rare but increasing. It is hypothesised that higher hospital volume reduces adverse outcomes. The aim was to estimate the association of surgical unit volume with outcomes following first, single-stage RevKR for infection. METHODS: This population-based cohort study merged data from the United Kingdom National Joint Registry, Hospital Episode Statistics, National Patient Reported Outcome Measures and the Civil Registrations of Death. Patients undergoing procedures between 1 January 2009 and 30 June 2019 were included. Early outcomes were chosen to reflect the quality of the surgical provision and included re-revision at 2 years, mortality, serious medical complications, length of stay and patient-reported outcome measures (PROMs). Adjusted fixed effect multivariable regression models were used to examine the association between surgical unit mean annual caseload and the risk of adverse outcomes. RESULTS: A total of 1477 patients underwent first-time single-stage RevKRs for infection across 267 surgical units and 716 surgeons. Following adjustment for age, gender, American Society of Anaesthesiologists grade, surgeon volume, year of surgery and operation funder and modelling surgical unit volume with restricted cubic spline, a greater mean annual volume was associated with a lower risk of re-revision at 2 years. The odds of re-revision in hospitals performing fewer than or equal to 12 cases per year was 2.53 (95% confidence interval = 1.50-4.31) times more likely than hospitals performing three to four cases per month. Annual variation in surgical unit volume was not associated with mortality and serious medical complications within 90 days. Only 99 out of 1477 (7%) of patients had linked PROMs which precluded subsequent analysis. CONCLUSION: Overall, higher volume surgical units had lower rates of early re-revision following the first RevKR for infection. We were unable to provide recommended specific volume thresholds for units; however, the probability of re-revision appears to be lowest in the highest volume units. LEVEL OF EVIDENCE: Level III, retrospective cohort study of prospectively collected data.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

A modified Delphi consensus statement on the role of biopsy in small renal masses

OBJECTIVE: To understand the variable utilisation of diagnostic biopsy for small renal masses (SRM) across the urology community, we worked with expert clinicians and patients to produce a consensus statement on the role of biopsy and to identify research gaps. METHODS: In phase I, qualitative interviews were performed to identify potential statements on the role of biopsy and research gaps. In phase II, an expert panel including patients scored statements on a 9-point scale through a modified Delphi process involving three rounds of web-based surveys. Consensus was considered to have been reached when 70% of participants scored a statement greater than or equal to seven. Panel members could propose additional statements for consideration after the first round. Following the second round, a moderation meeting was held to discuss statements where threshold of agreement was not met. RESULTS: In total, 35 participants were involved in this project and consisted of 23 clinicians and 12 patients, with 29 participants completing all three rounds. Overall, 18 statements reached consensus, 11 of which pertained to when and how a biopsy should be used in SRM management and 7 research recommendations to improve the evidence base for biopsy use. CONCLUSIONS AND CLINICAL IMPLICATIONS: This Delphi consensus statement, co-produced by patients and clinicians, provides best-practice guidance on the current role of renal tumour biopsy, including offering biopsy prior to active treatment if the outcome would affect management and offering a second attempt should the first biopsy be non-diagnostic. Priority areas for future research included studies to evaluate how a biopsy affects choice of treatment and patient anxiety.CC BY 4.0 Internationa

IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes

AIMS/HYPOTHESIS: Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study. METHODS: Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (n=192) and autoantibody-positive (n=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages. RESULTS: Compared with IA-2A(-) individuals, IA-2A(+) individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A(-) stage 1 individuals. Individuals at highest risk within the single-IA-2A(+) category included children (HR 14.2 [95% CI 1.9, 103.1], p=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], p<0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], p<0.001) and individuals with HLA DR4-positive status (HR 3.7 [95% CI 1.6, 8.3], p=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A(+) individuals and dysglycaemic IA-2A(-) individuals. CONCLUSIONS/INTERPRETATION: IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A(-). Approaches to incorporate IA-2A(+) status into monitoring strategies for autoantibody-positive individuals should be considered.Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text

Severe Asthma Questionnaire (SAQ) and Asthma Control Questionnaire (ACQ) as Early Predictors of Biologic Response in Severe Asthma

BACKGROUND: Biologic therapy in asthma can be life-changing and affect health-related quality of life, but symptoms are rarely used in the assessment of response. AIM: To examine the change in health-related quality of life and asthma control between starting a biologic and assessment of biologic response, assessing whether this change can provide early prediction of eventual clinical response at 12 months. METHODS: A service evaluation of severe asthmatics initiating a biologic at the Royal Devon NHS trust between 2019 and 22. Health-Related Quality of Life (Severe Asthma Questionnaire) and asthma control (Asthma Control Questionnaire-6) was captured at baseline, 8 weeks, 16 weeks and 12 months. Patients were classified as responder or non-responder using NICE Criteria for biologic response. Independent samples t-tests were used to determine statistical difference in change from baseline patient reported outcome measure scores between responder and non-responders. RESULTS: One hundred and eight initiations (103 patients) of biologic therapy were included. At 8 weeks and 16 weeks, responders had greater improvement in Severe Asthma Questionnaire & Severe Asthma Questionnaire Global compared to non-responders (p<0.05). Improvement in Asthma Control Questionnaire only achieved significance between all-responders and non-responders at 16 weeks (p<0.05). CONCLUSION: This study provides evidence of the early and sustained improvement in health-related quality of life and symptoms after starting biologic therapy. The findings support the use of the Severe Asthma Questionnaire and the Asthma Control Questionnaire as per the Core Outcome Measures Sets for Severe Asthma (COMSA). We have shown that health-related quality of life and asthma control can assist earlier assessment of response and non-response to biologics.CC BY 4.0 (Creative Commons Attribution