Widening access to recombinant zoster vaccination in IBD

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Evaluating the return of additional findings from the 100,000 Genomes Project: A mixed methods study exploring participant experiences of receiving secondary findings from genomic sequencing

PURPOSE: 100,000 Genomes Project participants could consent to receive additional findings (AFs) for variants associated with susceptibility to cancer and familial hypercholesterolemia (FH). Here we evaluate stakeholder experiences to inform clinical practice. METHODS: Mixed-methods study conducted at 18 sites across England that comprised a cross-sectional survey and interviews with participants who received a positive AF (PAF), and interviews with participants who had no AFs (NAF). RESULTS: There were 146 surveys followed by 35 interviews with PAF participants, and 29 interviews with NAF participants. Surveys found that PAF results were seen as useful and would influence health management (82%). Most (90%) had shared their result with family members. Experiences differed by PAF type; cancer PAF participants were often initially shocked and anxious, and found telling family members challenging compared to participants with an FH PAF. Whilst most experiences of NAF results were positive, some misunderstandings were identified. Participants supported returning AFs when offering genome sequencing. CONCLUSION: Patient experiences of receiving AFs were primarily positive and there is support for offering AFs routinely. Considerations for offering AFs in clinical practice include adapting approaches tailored to individual conditions and greater support for people with a NAF result.CC BY 4.0 Internationa

Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder

PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a(-/-) mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).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

GRASS-UK: The Global Register of Alopecia areata disease Severity and treatment Safety- United Kingdom: importance of real-world data in alopecia areata

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High-Risk Outcomes in In Vitro Fertilization Pregnancies for Women of a Very Advanced Maternal Age: Insights from a Multi-Hospital Study in Greece

Background: In vitro fertilization (IVF) has transformed infertility treatment, yet it is associated with increased risks of adverse perinatal outcomes, particularly in women of advanced maternal age. This study aimed to investigate the prevalence of complications such as preeclampsia (PE), gestational diabetes mellitus (GDM), preterm labor (PTL), low birth weight (LBW), and placental abnormalities (PA) among women over 50 undergoing assisted reproductive technology (ART) in Greece, where the eligibility age limit has been recently raised to 54 years. Methods: We conducted a retrospective analysis of pregnancy outcomes in women over 50 compared to those under 50, utilizing medical records mainly from University Hospital of Ioannina but also from other public hospitals and private clinics in Greece. Results: Our findings indicate that women over 50 face an increased risk of developing preeclampsia (PE) by 4.61 times, GDM by 1.69 times, PTL by 1.82 times, LBW by 1.67 times, and PA by 3.92 times. Conclusions: These results underscore the need for heightened awareness and the monitoring of pregnancy complications in this demographic, informing clinical strategies to improve maternal and neonatal outcomes.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).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

Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

PURPOSE: ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited. METHODS: An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion. RESULTS: Although ATM is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. ATM GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history, ideally as part of a clinical trial, with existence of country-specific guidelines. For ATM GPV heterozygotes who develop cancer, radiation therapy decisions should not be influenced by the genetic result. Although poly-adenosine diphosphate ribose polymerase inhibitors are licensed for use in metastatic castration-resistant prostate cancer and ATM GPVs, the evidence-base is currently weak. CONCLUSION: Systematic prospective data collection is needed to establish the spectrum of ATM-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.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

Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity

BACKGROUND: We recently reported non-coding variants in a cis-regulatory element of the beta-cell disallowed gene hexokinase 1 (HK1) as a novel cause of congenital hyperinsulinism. These variants lead to a loss of repression of HK1 in pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed to determine the prevalence, genetics, and phenotype of HK1-hyperinsulinism by screening a large international cohort of patients living with the condition. METHODS: We screened the HK1 cis-regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories. RESULTS: We identified a HK1 variant in 89/1761 probands (5%) and 63 family members. Within the Exeter HI cohort, these variants accounted for 2.8% of all positive genetic diagnoses (n = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26 years (median: 7 days) with variable response to treatment; 80% were medically managed and 20% underwent pancreatic surgery due to poor response to medical therapy. Glycaemic outcomes varied from spontaneous remission to hypoglycaemia persisting into adulthood. Eight probands had inherited the variant from a parent not reported to have hyperinsulinism (median current age: 39 years), confirming variable penetrance. Two of the 23 novel HK1 variants allowed us to extend the minimal cis-regulatory region from 42 to 46 bp. CONCLUSIONS: Non-coding variants within the HK1 cis-regulatory region cause hyperinsulinism of variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood. Discovering variants in 89 families confirms HK1 as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made.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

A survey of perioperative medicine services with a focus on provision for older surgical patients in the UK and Republic of Ireland: SNAP-3

BACKGROUND: Perioperative medicine aims to improve care for high-risk patients, and is endorsed by national guidelines in the UK and Republic of Ireland (ROI). However, comprehensive perioperative medicine services are not yet uniformly available. This survey addressed the current state of perioperative medicine services for older surgical patients in the UK and ROI and how these services align with current national guidance. METHODS: A survey was distributed electronically to all publicly administered UK and ROI hospitals performing surgical procedures. The survey examined perioperative care against national recommendations regarding service organisation and conduct. RESULTS: Of 339 eligible hospitals, 54.9% (186/339) responded. A hospital frailty lead was appointed in 54% (101/186) of hospitals, and 9% (16/186) had a designated anaesthetist for cognitive impairment. Hospital anaesthetic services outside the theatre were focused on preoperative assessment clinics (146/172), with few reporting routine postoperative involvement (17/166). Nurse-led preoperative assessments of frailty, cognition, and delirium risk were conducted in 49.5% (90/182), 44.3% (78/176), and 13.7% (24/175) of hospitals, respectively. The Clinical Frailty Scale was used in 87.0% (147/169) of hospitals for frailty screening. The 4 'A's Test (45.7% [85/186]) and Abbreviated Mental Test (43.0% [80/186]) were the preferred cognitive assessment tools. CONCLUSIONS: The survey highlights the variation in perioperative medicine services that exist for older surgical patients despite national guidelines advocating their widespread implementation. Opportunity exists to develop interspecialty perioperative services further and promote identification of frailty, cognitive impairment, and delirium, all of which negatively impact postoperative outcomes for older surgical patients.Creative Commons CC BY 4.0 (open access

Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum

Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders. OBJECTIVE: To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum. METHODS: We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families. RESULTS: Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant. INTERPRETATION: This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025;97:611-628.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.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

Protocol update for the UK cohort study to investigate the prevention of parastomal hernia (the CIPHER study)

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