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Background National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. Methods In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). Results Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. Conclusion The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation. [ABSTRACT FROM AUTHOR]

Objective To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. Design Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. Results Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. Conclusion The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry. [ABSTRACT FROM AUTHOR]

Since December 2019, the coronavirus (COVID19) outbreak has impacted everyone's daily lives globally, especially those experiencing mental health issues. The well-being and mental healthcare of patients, families, and health-care professionals who have been directly or indirectly affected by this pandemic has not been well addressed. Governments have asked their citizens to take actions, some of which include making sacrifices that may result in dignity violations and moral injury, a term originating in the military to describe the psychological distress that results from actions, or the lack of them, which violate a person's moral or ethical code. Health professionals, individuals, and communities have changed their way of life and working to decrease coronavirus infectivity, causing additional stress and increasing potential for moral injury. It is important to hear the first-hand experience of people affected to understand the new psychosocial stressors that they face in their day to day lives and what they found helpful in managing these. This global survey carried out by the World Dignity Project in collaboration with the Global Mental Health Peer Network is to ensure that the voices of people with lived experience of mental health, their families, and professionals that work with them are heard. Aims: * To understand the impact of the coronavirus pandemic on mental health, well-being, and dignity, what has helped and what lessons can be learned to support coping in future. Materials and Methods: * Online qualitative and quantitative survey (April 15-June 15, 2020) * Participants gave narrative responses to several questions, posting photos or images. Analysis: Narrative responses were analyzed using the Gioia approach, a systematic inductive approach to develop concepts that help make sense of socially constructed worlds. Visual ethnographic data was used to give insight into the participant's socio-cultural context. [ABSTRACT FROM AUTHOR]

Background: Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma.Methods/design: Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom.Trial Registration: ISRCTN84434175. Registered 12 November 2018. [ABSTRACT FROM AUTHOR]

Aim: To determine UK genetic counselors' (UKGCs) opinion regarding 'the psychosocial component of the UKGC remit in the new genomics era'. Methods: Facilitated discussions at a national conference (2016) using interactive methodologies (58 participants). Results: UKGCs recognized the rapid rate of change emerging with advances in genomic science. Change will be required to the UKGC remit and the roles, rules, relationships and responsibilities that underpin it (29 topics identified). UKGCs supported their 'unique selling point'; integrating knowledge and the explicit focus on psychosocial aspects of genomic healthcare. By 2019, some of the aspirations have been achieved. Conclusion: UKGCs should proactively position themselves to capitalize on the challenges and opportunities of genomic healthcare to maximize patient benefit. [ABSTRACT FROM AUTHOR]

Background: The effects of exposure to chemical warfare agents in humans are topical. Porton Down is the UK's centre for research on chemical warfare where, since WWI, a programme of experiments involving ~30 000 participants drawn from the UK armed services has been undertaken. Objectives: Our aim is to report on exposures to nerve agents, particularly sarin, using detailed exposure data not explored in a previous analysis. Methods: In this paper, we have used existing data on exposures to servicemen who attended the human volunteer programme at Porton Down to examine exposures to nerve agents in general and to sarin in particular. Results: Six principal nerve agents were tested on humans between 1945 and 1987 Of all 4299 nerve agent tests recorded, 3511 (82%) were with sarin, most commonly in an exposure chamber, with inhalation being the commonest exposure route (85%). Biological response to sarin exposure was expressed as percentage change in cholinesterase activity and, less commonly, change in pupil size. For red blood cell cholinesterase, median inhibition for inhalation tests was 41% (interquartile range 28-51%), with a maximum of 87%. For dermal exposures the maximum inhibition recorded was 99%. There was a clear association between increasing exposure to sarin and depression of cholinesterase activity but the strength and direction of the association varied by exposure route and the presence of chemical or physical protection. Pupil size decreased with increased exposure but this relationship was less clear when modifiers, such as atropine drops, were present. Conclusions: These results, drawn from high quality experimental data, offer a unique insight into the effects of these chemical agents on humans. [ABSTRACT FROM AUTHOR]

Purpose: Real-time symptom monitoring using a mobile phone is potentially advantageous for patients receiving oral chemotherapy. We therefore conducted a pilot study of patient dose adaptation using mobile phone monitoring of specific symptoms to investigate relative dose intensity of capecitabine, level of toxicity and perceived supportive care. Methods: Patients with breast or colorectal cancer receiving capecitabine completed a symptom, temperature and dose diary twice a day using a mobile phone application. This information was encrypted and automatically transmitted in real time to a secure server, with moderate levels of toxicity automatically prompting self-care symptom management messages on the screen of the patient's mobile phone or in severe cases, a call from a specialist nurse to advise on care according to an agreed protocol. Results: Patients ( n = 26) completed the mobile phone diary on 92.6 % of occasions. Twelve patients had a maximum toxicity grade of 3 (46.2 %). The average dose intensity for all patients as a percentage of standard dose was 90 %. In eight patients, the dose of capecitabine was reduced, and in eight patients, the dose of capecitabine was increased. Patients and healthcare professionals involved felt reassured by the novel monitoring system, in particular, during out of hours. Conclusion: It is possible to optimise the individual dose of oral chemotherapy safely including dose increase and to manage chemotherapy side effects effectively using real-time mobile phone monitoring of toxicity parameters entered by the patient. [ABSTRACT FROM AUTHOR]

Background: Hermansky-Pudlak syndrome 2 (HPS2; OMIM #608233) is a rare, autosomal recessive disorder caused by loss-of-function genetic variations affecting AP3B1, which encodes the β3A subunit of the adaptor-related protein complex 3 (AP3). Phenotypic characteristics include reduced pigmentation, absent platelet dense granule secretion, neutropenia and reduced cytotoxic T lymphocyte (CTL) and natural killer (NK) cell function. To date HPS2 has been associated with non-synonymous, stop-gain or deletion-insertion nucleotide variations within the coding region of AP3B1. Case presentation: We describe a consanguineous female infant with reduced pigmentation, neutropenia and recurrent infections. Platelets displayed reduced aggregation and absent ATP secretion in response to collagen and ADP, indicating a platelet dense granule defect. There was increased basal surface expression of CD107a (lysosomeassociated membrane protein 1(LAMP-1)) on NK cells and CTLs from the study subject and a smaller increase in the percentage of CD107a positive cells after stimulation compared to most healthy controls. Immunoblotting of protein extracts from EBV-transformed lymphoblasts from the index case showed absent expression of full-length AP-3 β3A subunit protein, confirming a phenotypic diagnosis of HPS2. The index case displayed a homozygous pericentric inv(5)(p15.1q14.1), which was also detected as a heterozygous defect in both parents of the index case. No loss of genetic material was demonstrated by microarray comparative genome hybridisation at 60kb resolution. Fluorescence in-situ hybridisation using the 189.6kb probe RP11-422I12, which maps to 5q14.1, demonstrated dual hybridisation to both 5q14.1 and 5p15.1 regions of the inverted Chr5. The RP11-422I12 probe maps from intron 1 to intron 16 of AP3B1, thus localising the 5q inversion breakpoint to within AP3B1. The probe RP11-211K15, which corresponds to an intergenic region on 5p also showed dual hybridisation, enabling localisation of the 5p inversion breakpoint. Conclusion: This case report extends the phenotypic description of the very rare disorder HPS2. Our demonstration of a homozygous Chr5 inversion predicted to disrupt AP3B1 gene provides a novel pathogenic mechanism for this disorder. [ABSTRACT FROM AUTHOR]

Background There has been a Human Volunteer Programme at the British chemical weapons research facility at Porton Down since the First World War, in which some of the participants were exposed to chemical warfare agents.Aim To identify any striking specific morbidity patterns in members of the Porton Down Veterans Support Group (PDVSG).Methods A self-completed postal questionnaire was prepared including health immediately after the visits to Porton Down, subsequent diagnoses and hospital admissions, symptoms in, and after, the first 5 years after the visits, fatigue symptoms and current quality of life, measured using the SF-36.Results Responses were received from 289 of 436 (66%). Results reported here relate to 269 male respondents of mean age 66.8 years. Sixty-six per cent reported their first visit to Porton Down in the 1950s. The most common diagnoses or hospital admissions reported were diseases of the circulatory system. In the first 5 years after their visits the most common symptoms were headache, irritability or outbursts of anger and feeling un-refreshed after sleep. In the later period, most common symptoms were fatigue, feeling un-refreshed after sleep and sleeping difficulties. Sixty-five per cent met the definition for a case of ‘fatigue’. Current quality of life dimensions were consistently lower than age-specific estimates from general population samples.Conclusions Members of the PDVSG responding to this survey reported poorer quality of life than the general population. Despite there being no clear pattern of specific morbidities, we cannot rule out ill-health being potentially associated with past experience at Porton Down. [ABSTRACT FROM AUTHOR]

Presents an abstract of the article "A Study of Patient Experience of the Pre-Clinic Home Visit Consultation Provided by Genetic Counselors in Liverpool," by Claire Brooks, G. Mannion, J. Birch, P. Harris, J. Daly, C. Knightley and C. Higgins.