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OBJECTIVES: Describe and evaluate a method for assessing whether physical restraint prevalence differs by timing and frequency of data collection and to determine the minimum period of observation necessary to provide accurate prevalence estimates on both Intensive Care Unit (ICU) and medical-surgical units. DESIGN: Two-period, cross-sectional design with repeated observations in year 1 for 18 consecutive days and in year 2 for 21 consecutive days with method modifications. Setting: 400-bed urban teaching hospital. PARTICIPANTS: All beds on general medical, surgical, and intensive care units. MEASUREMENT: Direct observation of patients, nurse interview, and medical record review conducted by trained observers. RESULTS: There were no significant differences in mean restraint use prevalence rates comparing: (a) morning and evening periods; (b) weekdays and weekend days; and (c) observation periods of 7, 14, or 21 consecutive days or for 7 days using every 3rd day on either medical-surgical units or ICUs. Analyses using data from an increasing number of days of observation indicates that the mean prevalence rate stabilizes after 16 days. There were larger mean differences for comparisons on ICU-ventilator units and lack of significant differences may be due to low statistical power. CONCLUSION: Direct observation by trained observers, supplemented by nurse report and medical record documentation over brief monitoring periods, results in accurate, nonintrusive, cost-efficient estimates of physical restraint prevalence. As few as seven consecutive or nonconsecutive days in measuring restraint prevalence is sufficient to obtain accurate estimates, although the number of days may vary depending on patient mix and unit type. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterised by ataxia, slow saccadic eye movements and opthalmoparesis. SCA2 is caused by expansion of the CAG repeat tract in exon 1 of the ataxin-2 gene (12q24). Normal alleles have between 16-30 repeats with 1-3 CAA interruptions. Pathogenic alleles have 36-52 repeats with no CAA interruptions. Intermediate alleles are extremely rare, however two SCA2 patients have been previously reported with CAA interrupted tracts of 34 repeats. Age of onset is inversely proportional to the length of the expansion. We present a patient with SCA2 symptoms and an intermediate allele. An 83 year old man was referred to us having developed cerebellar ataxia. Analysis found a CAG tract of 32 repeats at the SCA2 locus. Sequencing showed the allele to contain 2 CAA interruptions. All other SCA loci tested normal. Little is known about the pathogenicity of intermediate alleles and it is thought they may be incompletely penetrant. The presence of CAA interruptions should have no effect at the protein level as both CAA and CAG codons encode for glutamine but at the DNA level they confer stability on transmission. This intermediate allele in our elderly patient caused difficulties in counselling as it is not clear whether the intermediate allele was the cause of the patient's symptoms. We discuss some of the issues raised by the case. [ABSTRACT FROM AUTHOR]

Purpose: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs., Methods: An observational study in an area representing one-fifth of England., Results: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF., Conclusion: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Study Aim: This study aims to describe the transition-in-care work process for sepsis survivors going from hospitals to home health care (HHC) and identify facilitators and barriers to enable practice change and safe care transitions using a human factors and systems engineering approach., Background: Despite high readmission risk for sepsis survivors, the transition-in-care work process from hospitals to HHC has not been described., Methods: We analyzed semi-structured needs assessment interviews with 24 stakeholders involved in transitioning sepsis survivors from two hospitals and one affiliated HHC agency participating in the parent implementation science study, I-TRANSFER. The qualitative data analysis was guided by the Systems Engineering Initiative for Patient Safety (SEIPS) framework to describe the work process and identify work system elements., Results: We identified 31 tasks characterized as decision making, patient education, communication, information, documentation, and scheduling tasks. Technological and organizational facilitators lacked in HHC compared to the hospitals. Person and organization elements in HHC had the most barriers but few facilitators. Additionally, we identified specific task barriers that could hinder sepsis information transfer from hospitals to HHC., Conclusion: This study explored the complex transition-in-care work processes for sepsis survivors going from hospitals to HHC. We identified barriers, facilitators, and critical areas for improvement to enable implementation and ensure safe care transitions. A key finding was the sepsis information transfer deficit, highlighting a critical issue for future study., Application: We recommend using the SEIPS framework to explore complex healthcare work processes before the implementation of evidence-based interventions.

A dedicated sepsis coordinator role at Penn Medicine Lancaster General Hospital led initiatives to improve sepsis core measure compliance by 40% during the course of 4 years with submission of all sepsis cases. Chart abstraction and analysis of noncompliant cases identified areas for improvement: early recognition education, order set revisions, documentation support, and the implementation of a nurse-driven 24/7 sepsis monitoring process. The cooperative work with Penn Medicine affiliates, sharing best practices, improves overall sepsis bundle compliance and transitions of care. Ongoing achievements acknowledge the value of building relationships and leading improvements through the collaborative efforts of interprofessional teams., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Patients with episodes of supraventricular tachycardia (SVT), a common heart arrhythmia, are often attended by ambulance services. International guidelines advocate treatment with the Valsalva manoeuvre (VM), but this simple physical treatment has a low success rate, with most patients requiring conveyance to hospital. The Valsalva Assist Device (VAD) is a simple device that might help practitioners and patients perform a more effective VM and reduce the need for patients to be taken to hospital., Methods and Analysis: This stepped wedge cluster randomised controlled trial, conducted within a UK ambulance service, compares the current standard VM with a VAD-delivered VM in stable adult patients presenting to the ambulance service with SVT. The primary outcome is conveyance to hospital; secondary outcomes measures include cardioversion rates, duration of ambulance care and number of subsequent episodes of SVT requiring ambulance service care. We plan to recruit approximately 800 patients, to have 90% power to detect an absolute reduction in conveyance rate of 10% (from 90% to 80%) between the standard VM (control) and VAD-delivered VM (intervention). Such a reduction in conveyance would benefit patients, the ambulance service and receiving emergency departments. It is estimated potential savings would pay for devices for the entire ambulance trust within 7 months., Ethics and Dissemination: The study has been approved by the Oxford Research Ethics Committee (reference 22/SC/0032). Dissemination will be through peer-reviewed journal publication, presentation at national and international conferences and by the Arrhythmia Alliance, a patient support charity., Trial Registration Number: ISRCTN16145266., Competing Interests: Competing interests: AA, on behalf of the Royal Devon University Healthcare NHS Foundation Trust (RDUFT), introduced the concept of the Valsalva Assist Device to Meditech Systems Limited and advised on refinements to the device in light of initial volunteer studies. RDUFT has a royalty agreement on future sales of the device. Any money received can only be used for patient care or further research., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice., Competing Interests: Competing interests: RC has received speakers' honoraria from Novartis and Ipsen; DM has received speakers' honoraria from Roche and MSD and speakers' honoraria and consulting fees from Bristol Myers Squib., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: The Strengthening And stretching for Rheumatoid Arthritis of the Hand (SARAH) program is a tailored, 12-week hand and arm exercise program recommended in the National Institute for Health and Care Excellence guidelines. It includes seven mobility exercises and four strength exercises against resistance. An online version of the SARAH program (mySARAH) has been developed to allow direct access for people with rheumatoid arthritis., Purpose: The purpose of this study was to assess the feasibility, acceptability, and clinical impact of mySARAH in people with rheumatoid arthritis., Study Design: This is a mixed-method, proof-of-concept study., Methods: mySARAH is a self-guided, online version of the SARAH program with six exercise training and review sessions. Participants were observed as they worked through four of the six online sessions. They were also asked to demonstrate the SARAH exercises. Participants undertook two sessions independently at home. At the baseline and 12 weeks, hand pain, hand function, and grip strength were measured. At 12 weeks, feedback on mySARAH, and perceived recovery were also collected. Approximately one month later, a telephone follow-up was conducted to explore participants' experiences with mySARAH. Pain, hand function, and perceived recovery were also assessed., Results: Eleven participants (males/females: 3/8) with a median (interquartile range) age of 63 (17) years took part. Six participants completed all mySARAH sessions. About 512 exercise and load-setting demonstrations were observed and 491 (96%) were performed correctly. Improvements in grip strength and hand function were observed with no increase in pain. Most of the participants reported improvement and provided positive feedback. All participants perceived mySARAH as a useful resource. Features to improve the online exercise diary such as recording and tracking exercise dose and face-to-face or remote support by phone or Skype from health professionals were suggested to optimize user engagement., Conclusions: Initial evaluation of mySARAH indicates that mySARAH was feasible, acceptable, and beneficial to participants. Further iteration and evaluation are needed before large-scale implementation., (Copyright © 2020 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.)

Objective: The autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate >300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities., Methods: Probands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy., Results: Biallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and >45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes., Conclusions: This study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.

Background: Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized., Methods: We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age., Results: Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6-18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (<3-gland) resection resulted in decreased disease-free outcomes versus subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months versus not reached; P = .005). Pancreaticoduodenal neuroendocrine tumors developed in ∼35% of patients, of whom >70% had nonfunctioning tumors, >35% had insulinomas, and <5% had gastrinomas, with ∼15% having metastases and >55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel., Conclusion: Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic and pituitary tumors, and is due to mutations in the coding region of the MEN1 gene, which encodes menin. We investigated a family with identical twins that had MEN1, with different MEN1 tumors. DNA sequence analysis of the MEN1 coding region had not identified any abnormalities and we hypothesized that deletions and mutations involving the untranslated regions may be involved. Informed consent and venous blood samples were obtained from five family members. Sanger DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses were performed using leukocyte DNA. This revealed a heterozygous 596bp deletion (Δ596bp) between nucleotides -1087 and -492 upstream of the translation start site, located within the MEN1 5' untranslated region (UTR), and includes the core promoter and multiple cis-regulatory regions. To investigate the effects of this 5'UTR deletion on MEN1 promoter activity, we generated luciferase reporter constructs, containing either wild-type 842bp or mutant 246bp MEN1 promoter, and transfected them into human embryonic kidney HEK293 and pancreatic neuroendocrine tumor BON-1 cells. This revealed the Δ596bp mutation to result in significant reductions by 37-fold (p < 0.0001) and 16-fold (p < 0.0001) in luciferase expression in HEK293 and BON-1 cells, respectively, compared to wild-type. The effects of this 5'UTR deletion on MEN1 transcription and translation were assessed using qRT-PCR and Western blot analyses, respectively, of mRNA and protein lysates obtained from Epstein-Barr-virus transformed lymphoblastoid cells derived from affected and unaffected individuals. This demonstrated the Δ596bp mutation to result in significant reductions of 84% (p < 0.05) and 88% (p < 0.05) in MEN1 mRNA and menin protein, respectively, compared to unaffected individuals. Thus, our results report the first germline MEN1 5'UTR mutation and highlight the importance of investigating UTRs in MEN1 patients who do not have coding region mutations. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)