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De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome
No full textAround 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5' splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.https://www.nature.com/articles/s41586-024-07773-
Biomarkers associated with survival in patients with platinum-refractory urothelial carcinoma treated with paclitaxel
No full textBackground: Taxane- based chemotherapy is widely used in patients with platinum- and immunotherapy refractory, metastatic urothelial carcinoma (mUC). Outcomes are poor and biomarkers associated with outcome are lacking. We aim to identify cancer hallmarks associated with survival in patients receiving paclitaxel. Methods: Whole-transcriptome profiles were generated for a subset of patients enrolled in a randomised phase II study investigating paclitaxel and pazopanib in platinum refractory mUC (PLUTO, EudraCT 2011-001841-34). Estimates of gene expression were calculated and input into the Almac proprietary analysis pipeline and signature scores were calculated using ClaraT V3.0.0. Ten key gene signatures were assessed: Immuno-Oncology, Epithelial to Mesenchymal Transition, Angiogenesis, Proliferation, Cell Death, Genome Instability, Energetics, Inflammation, Immortality and Evading Growth. Hazard ratios were calculated using Cox regression model and Kaplan-Meier methods were used to estimate progression free survival (PFS) and overall survival (OS). Results: 38 and 45 patients treated with paclitaxel or pazopanib were included. Patients with high genome instability expression treated with paclitaxel had significantly improved survival with a HR of 0.29 (95% CI: 0.14-0.61, p=0.001) and HR 0.34 (95% CI: 0.17-0.69, p=0.003) for PFS and OS, respectively. Similarly, patients with high evading growth suppressor expression treated with paclitaxel had improved PFS and OS with a HR of 0.35 (95% CI: 0.19-0.77, p=0.007) and HR 0.46 (95% CI: 0.23-0.91, p=0.026), respectively. No other gene signatures had significant impact on outcome. In both paclitaxel and pazopanib cohorts, angiogenesis activation was associated with worse PFS and OS, and VEGF targeted therapy did not improve outcomes. Conclusion: High Genome-instability and Evading-growth suppressor biologies are associated with improved survival in patients with platinum refractory mUC receiving paclitaxel. These may refine mUC risk stratification and guide treatment decision in the future.https://dx.doi.org/10.1016/j.urolonc.2024.05.01
Apprenticeships and T-levels: an alternative pathway into health care
No full textThis article explores Northamptonshire Healthcare Foundation Trust’s (NHFT’s) innovative approach to addressing workforce challenges in the healthcare sector through apprenticeships and T-levels. NHFT offers various apprenticeship opportunities, ranging from entry-level healthcare support roles to pre-registration and post-registration nursing across different specialties. The article also looks at NHFT’s collaborations with local educational institutions and primary care training hubs to provide pathways for individuals who transitioned from different careers into nursing through apprenticeships. Additionally, the introduction of T-levels offers younger people practical experience in health care alongside classroom learning, opening pathways into nursing careers. The benefits of apprenticeships in providing financial support, practical experience, and career progression are highlighted. Overall, these alternative pathways play a crucial role in developing and retaining local healthcare professionals, addressing workforce challenges and reducing reliance on international recruitment.https://www.journalofpracticenursing.co.uk/journals/issue/06-2024/article/apprenticeships-and-t-levels-alternative-pathway-into-health-car
28-country global study on associations between cultural characteristics and Recovery College fidelity
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obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/Recovery Colleges (RCs) are learning-based mental health recovery communities, located globally. However, evidence on RC effectiveness outside Western, educated, industrialised, rich, and democratic (WEIRD) countries is limited. This study aimed to evaluate associations between cultural characteristics and RC fidelity, to understand how culture impacts RC operation. Service managers from 169 RCs spanning 28 WEIRD and non-WEIRD countries assessed the fidelity using the RECOLLECT Fidelity Measure, developed based upon key RC operation components. Hofstede's cultural dimension scores were entered as predictors in linear mixed-effects regression models, controlling for GDP spent on healthcare and Gini coefficient. Higher Individualism and Indulgence, and lower Uncertainty Avoidance were associated with higher fidelity, while Long-Term Orientation was a borderline negative predictor. RC operations were predominantly aligned with WEIRD cultures, highlighting the need to incorporate non-WEIRD cultural perspectives to enhance RCs' global impact. Findings can inform the refinement and evaluation of mental health recovery interventions worldwide.https://www.nature.com/articles/s44184-024-00092-
Ambulatory management of acute uncomplicated diverticulitis (AmbUDiv study): a multicentre, propensity score matching study.
Get PDFINTRODUCTION: Recent studies have suggested that ambulatory management is feasible for acute uncomplicated diverticulitis (AUD); however, there is still no consensus regarding the most appropriate management settings. This study presents a multi-centre experience of managing patients presenting with AUD, specifically focusing on clinical outcomes and comparing ambulatory treatment with in-patient management. METHODS: A retrospective multi-centre study was conducted across four hospitals in the UK and included all adult patients with computed tomography (CT) confirmed (Hinchey grade 1a) acute diverticulitis over a 12-month period (January - December 2022). Patient medical records were followed up for 1-year post-index episode, and outcomes were compared between those treated through the ambulatory pathway versus inpatient treatment using 1:1 propensity score matching (PSM). All statistical analysis was performed using the R Foundation for Statistical Computing, version 4.4. RESULTS: A total of 348 patients with Hinchey 1a acute diverticulitis were included (260 in-patients; 88 ambulatory pathway), of which nearly a third (31.3%) had a recurrent disease. Inpatient management was dominant (74.7%), with a median of 3 days of hospital stay. PSM resulted in 172 patients equally divided between the two care settings. Ambulatory management was associated with a lower readmission rate (P = 0.02 before PSM, P = 0.08 after PSM), comparable surgical (P = 0.57 before PSM, 0% in both groups after PSM) and radiological interventions (P = 0.99 before and after PSM) within one year. In both matched and non-matched groups, a strong association between readmissions and inpatient management was noted in univariate analysis (P = 0.03 before PSM, P = 0.04 after PSM) and multivariate analysis (P = 0.02 before PSM, P = 0.03 after PSM). CONCLUSION: Our study supports the safety and efficacy of managing patients with AUD through a well-designed ambulatory care pathway. In particular, hospital re-admission rates are lower and other outcomes are non-inferior to in-patient treatment. This has implications for substantial cost-savings and better utilisation of limited healthcare resources
The response of the secretary of state and the "supervised discharge" provision of the UK mental health bill 2022: Potential problems and opportunities in the wake of Secretary of State for Justice v MM [2018] UKSC 60
No full textThis article considers the legal regulation of discharge conditions that amount to deprivation of liberty (DoL) in the sense of Article 5 of the European Convention on Human Rights following the UK Supreme Court's decision in Secretary of State for Justice v MM in 2018. The 2019 response of the Secretary of State for Justice to the MM judgment and the proposed "Supervised Discharge" provision of the UK 2022 Mental Health Bill are reviewed from a critical perspective with several important problems identified. It is recommended that the advice of the Secretary of State to make use of leave provisions under s17 of the MHA in place of conditional discharge is considered cautiously as this may be liable to future legal challenge. The 2022 Draft Bill is likely to yield an effective solution but it is lacking important provisions to ensure accountability of healthcare providers where Supervised Discharge is authorised, opportunities for therapeutic relaxations of restrictions, and safe systems for the recall and conveyance of patients under the Supervised Discharge regime.https://www.sciencedirect.com/science/article/abs/pii/S0160252724000876?via%3Dihu
What validated instruments, that measure implementation outcomes, are suitable for use in the Paediatric Intensive Care Unit (PICU) setting? A systematic review of systematic reviews
Get PDFBACKGROUND/AIMS: The measurement of implementation outcomes can establish the success of implementing evidence into practice. However, implementation outcomes are seldom measured in acute healthcare settings, such as Paediatric Intensive Care Units (PICU), and if they are used, are likely to be non-validated, site or intervention-specific measures. To address this literature gap, this systematic review of systematic reviews aims to identify validated instruments to measure implementation outcomes of new EBP interventions in a PICU setting., METHODS: A systematic review of systematic reviews was conducted in two phases. Phase One: Five electronic databases were searched between 06/10/22 and 14/10/22. Systematic reviews were selected using pre-determined eligibility criteria. Methodological quality was assessed using the Critical Appraisal Skills Programme tool and a data extraction table was used to allow further synthesis. Phase Two: Secondary eligibility criteria were used to extract and review instruments from the systematic reviews selected in Phase One. Instruments were analysed and mapped to the Consolidated Framework of Implementation Research (CFIR)., RESULTS: Phase One: Searches resulted in 3195 unique papers. Five systematic reviews were eligible for inclusion. All examined the psychometric properties of each instrument, utilising different methods to do so; three considered their pragmatic or usability properties; and one identified instruments that were transferrable to different settings. Each systematic review identified that most included instruments had limited evidence of their validity or reliability and had poor psychometric properties. Phase two: 93 instruments were screened, and nine were eligible for analysis. After analysis and CFIR mapping, two instruments were identified as potentially adaptable to the PICU setting., CONCLUSIONS: The methodological quality of implementation outcome measurement instruments is inadequate, warranting further validation research. Two instruments were identified that cover multiple CFIR domains and have scope to be adapted for use when implementing evidence-based practice into the PICU. Further work is needed to adapt and further validate an instrument for use in practice., TRIAL REGISTRATION: For transparency of procedures and methods, the protocol for this systematic review was registered with PROSPERO (registration number CRD42022361638L). Copyright © 2024. The Author(s).https://doi.org/10.1186/s13012-024-01378-
Strategies to improve atrioventricular synchrony in patients with a Micra AV leadless pacemaker
Get PDF© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.The second generation of transcatheter pacing systems, called Micra AV, can provide atrioventricular (AV) synchronous pacing via a new pacing algorithm relying on sensing mechanical atrial contraction. Several novel programming parameters were introduced to enable AV synchronous pacing, including an A3 window and A4 window as well as a conduction mode switch and an activity mode switch. In addition to several automated features, manual programming optimization of some of the novel parameters is key to improving AV synchrony. A solid knowledge of the features and their programming is essential for electrophysiologists implanting or following patients with Micra AV devices. Differences in programming optimization might partially explain the high variability of AV synchrony published in real-world data reports. This article reviews the key programming parameters of Micra AV. Subsequently, optimal programming recommendations for defined patient profiles are presented. Those were established by consensus within an expert panel comprised of 11 European electrophysiologists from high-volume Micra AV centres. The patient profiles were (1) high degree AV block and slow sinus rhythm; (2) high degree AV block and fast sinus rhythm; and (3) intermittent AV block. The panel recommended to evaluate the mechanical atrial activity on transthoracic echocardiography prior to implant. It was also agreed that Auto A3 Threshold and Tracking Check should be turned off in all patients, AV conduction mode switch should be turned off in all patients with high degree AV block, and the lower rate should be programmed to 50 bpm with exceptions based on individual clinical assessment. Future studies will be useful to evaluate the strength of those recommendations to improve the AV synchrony.https://academic.oup.com/europace/article/26/3/euae060/762363
The role of day-case thoracoscopy at a district general hospital: A real world observational study
No full textObjective To assess the feasibility and safety of talc pleurodesis performed as part of day-case medical thoracoscopy. Methods A Richard Wolf® 5 mm mini thoracoscope through a 5.5 mm port was used with eligible cases having talc poudrage followed by insertion of indwelling pleural catheter (IPC). District nurses drain the IPC daily for the first 5 days. Once the drain output is <150 mL, the frequency is progressively reduced to once weekly. The drain is removed after two consecutive dry taps 1 week apart. Results Overall, 51 patients underwent day-case thoracoscopy. Median time to removal of IPC for our day-case protocol was 14 days. There were seven deaths within 70 days among 41 patients with malignant pleural effusion in the day-case cohort, compared to eight deaths in the 33 conventional thoracoscopy controls. Overall, the day-case cohort observed a statistically significant reduction in all-cause mortality at 180 days compared to the conventional cohort (log rank p = 0.024). The average cost per patient of the day-case and inpatient cohort was £1,328.0 ± 106.0 and £1,835.0 ± 295.0 (p = 0.961). Conclusion This study suggests that thoracoscopy and talc poudrage can be performed safely as a day-case procedure. Further data are needed to ascertain long-term outcomes.https://www.sciencedirect.com/science/article/pii/S2514664524015480?via%3Dihu
EFFECTIVENESS AND SAFETY OF BIOSIMILAR ETANERCEPT GP2015 IN PATIENTS WITH RHEUMATOID ARTHRITIS IN THE UK: RESULTS FROM THE COMPACT STUDY
Get PDFAbstract Background/Aims COMPACT is a non-interventional, multinational cohort study to evaluate effectiveness, safety and quality of life (QoL) outcomes in patients with rheumatic diseases treated with GP2015, an approved etanercept (ETN) biosimilar, under real-world conditions. Here, we present data from patients in the UK with rheumatoid arthritis (RA) enrolled in the COMPACT study, focusing on those who switched to GP2015 from reference ETN or another biosimilar ETN. Methods The COMPACT study included patients (≥18 years of age) with rheumatic diseases treated with GP2015. This analysis includes patients from the UK diagnosed with RA who were in treatment Group A (patients in clinical remission or low disease activity under treatment with reference ETN or other biosimilar ETN, who switched to GP2015 prior to study enrolment). Effectiveness and QoL outcomes were assessed using Disease Activity Score 28-joint count (DAS28) and health assessment questionnaire-disability index (HAQ-DI), respectively, and are presented up to Week 24. Safety outcomes were assessed, including rates of adverse events (AEs) and serious AEs (SAEs). Results A total of 112 patients with RA who switched to GP2015 from reference ETN or another biosimilar ETN (Group A) were enrolled in the UK. The mean ± standard deviation (SD) age was 62.9 ± 11.3 years and 74.1% of patients were female. The mean ± SD DAS28 score remained unchanged from baseline (2.6 ± 1.3) to Week 24 (2.5 ± 1.6). The mean ± SD HAQ-DI score displayed no major difference between baseline (1.2 ± 0.8) and Week 24 (0.9 ± 0.8). Overall, 67.9% (n = 76) of patients experienced ≥1 AE and 9.8% (n = 11) of patients experienced ≥1 SAE (Table). Conclusion Over 24 weeks of treatment with GP2015, disease activity remained low and stable in patients with RA previously switched from reference ETN or from another biosimilar ETN, with no new safety concerns observed. These results from a cohort of patients with RA treated in the UK are consistent with effectiveness, QoL and safety data reported previously for the total population in the COMPACT study.https://academic.oup.com/rheumatology/article/63/Supplement_1/keae163.157/7656056?login=tru