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The randomised thoracoscopic talc poudrage+indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC): study protocol for a randomised controlled trial
No full textINTRODUCTION: Malignant pleural effusion (MPE) is common, with 50 000 new cases per year in the UK. MPE causes disabling breathlessness and indicates advanced disease with a poor prognosis. Treatment approaches focus on symptom relief and optimising quality of life (QoL). Patients who newly present with MPE commonly require procedural intervention for both diagnosis and therapeutic benefit.Thoracoscopic pleural biopsies are highly sensitive in diagnosing pleural malignancy. Talc poudrage may be delivered at thoracoscopy (TTP) to prevent effusion recurrence by effecting pleurodesis. Indwelling pleural catheters (IPCs) offer an alternative strategy for fluid control, enabling outpatient management and are often used as 'rescue' therapy following pleurodesis failure or in cases of 'trapped lung'. It is unknown whether combining a TTP with IPC insertion will improve patient symptoms or reduce time spent in the hospital.The randomised thoracoscopic talc poudrage + indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC) is the first randomised controlled trial (RCT) to examine the benefit of a combined TTP and IPC procedure, evaluating cost-effectiveness and patient-centred outcomes such as symptoms and QoL. The study remains in active recruitment and has the potential to radically transform the pathway for all patients presenting with MPE. METHODS AND ANALYSIS: TACTIC is an unblinded, multicentre, RCT comparing the combination of TTP with an IPC to TTP alone. Co-primary outcomes are time spent in the hospital and mean breathlessness score over 4 weeks postprocedure. The study will recruit 124 patients and aims to define the optimal pathway for patients presenting with symptomatic MPE. ETHICS AND DISSEMINATION: TACTIC is sponsored by North Bristol NHS Trust and has been granted ethical approval by the London-Brent Research Ethics Committee (REC ref: 21/LO/0495). Publication of results in a peer-reviewed journal and conference presentations are anticipated. TRIAL REGISTRATION: ISRCTN 11058680.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Phenotypic effect of GBA1 variants in individuals with and without Parkinson's disease: The RAPSODI study
No full textBACKGROUND: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. OBJECTIVES: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. METHODS: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. RESULTS: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups. CONCLUSIONS: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.Published version, submitted versionRDUH can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Exercise-based cardiac rehabilitation for adults with heart failure - 2023 Cochrane systematic review and meta-analysis
No full textAIMS: Despite strong evidence, access to exercise-based cardiac rehabilitation (ExCR) remains low across global healthcare systems. We provide a contemporary update of the Cochrane review randomized trial evidence for ExCR for adults with heart failure (HF) and compare different delivery modes: centre-based, home-based (including digital support), and both (hybrid). METHODS AND RESULTS: Databases, bibliographies of previous systematic reviews and included trials, and trials registers were searched with no language restrictions. Randomized controlled trials, recruiting adults with HF, assigned to either ExCR or a no-exercise control group, with follow-up of ≥6 months were included. Two review authors independently screened titles for inclusion, extracted trial and patient characteristics, outcome data, and assessed risk of bias. Outcomes of mortality, hospitalization, and health-related quality of life (HRQoL) were pooled across trials using meta-analysis at short-term (≤12 months) and long-term follow-up (>12 months) and stratified by delivery mode. Sixty trials (8728 participants) were included. In the short term, compared to control, ExCR did not impact all-cause mortality (relative risk [RR] 0.93; 95% confidence interval [CI] 0.71-1.21), reduced all-cause hospitalization (RR 0.69; 95% CI 0.56-0.86, number needed to treat: 13, 95% CI 9-22), and was associated with a clinically important improvement in HRQoL measured by the Minnesota Living with Heart Failure Questionnaire (MLWHF) overall score (mean difference: -7.39; 95% CI -10.30 to -4.47). Improvements in outcomes with ExCR was seen across centre, home (including digitally supported), and hybrid settings. A similar pattern of results was seen in the long term (mortality: RR 0.87, 95% CI 0.72-1.04; all-cause hospitalization: RR 0.84, 95% CI 0.70-1.01, MLWHF: -9.59, 95% CI -17.48 to -1.50). CONCLUSIONS: To improve global suboptimal levels of uptake for HF patients, global healthcare systems need to routinely recommend ExCR and offer a choice of mode of delivery, dependent on an individual patient's level of risk and complexity.Published version, accepted version, submitted versionRDUH can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Cognitive Load Management: An Invaluable Tool for Safe and Effective Surgical Training
No full textThis article highlights the importance of considering Cognitive Load (CL) and Cognitive Load Theory (CLT) during surgical training, focusing on the acquisition of intra-operative skills. It describes the basis of CLT with the overarching aim of describing CLT-based techniques to enhance current training strategies and surgical performance, many of which are instinctively already employed in surgical practice. Currently, methods of feedback and assessment are imperfect - typically subjective, unsystematic, opportunistic, or retrospective, and at risk of human bias. Surgical Sabermetrics, the advanced analytics of surgical and audio-visual data, aims to enhance this feedback by providing objective, real-time, digital-based feedback. This article introduces the benefit of real-time measurement of CL to enhance feedback and its applications to surgical performance that follow the ethos of Surgical Sabermetrics.(1) The 2022 theme for ICOSET was Making it Better." Cognitive Load and Surgical Sabermetrics principles provide tools to make Surgical training better, with the goal of higher quality care for patients."0Supports Open Acces
Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
No full textWe evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.Published version, accepted versionThis article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site
Genetic association analysis of 77,539 genomes reveals rare disease etiologies
No full textThe genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.Accepted version (6 months embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium
No full textOBJECTIVE: The optimal approach to the surveillance of non-functioning pituitary microadenomas (micro-NFPAs) is not clearly established. Our aim was to generate evidence on the natural history of micro-NFPAs to support patient care. DESIGN: Multi-centre, retrospective, cohort study involving 23 endocrine departments (UK NFPA consortium). METHODS: Clinical, imaging, and hormonal data of micro-NFPA cases between January, 1, 2008 and December, 21, 2021 were analysed. RESULTS: Data for 459 patients were retrieved [median age at detection 44 years (IQR 31-57)-152 males/307 females]. Four hundred and nineteen patients had more than two magnetic resonance imagings (MRIs) [median imaging monitoring 3.5 years (IQR 1.71-6.1)]. One case developed apoplexy. Cumulative probability of micro-NFPA growth was 7.8% (95% CI, 4.9%-8.1%) and 14.5% (95% CI, 10.2%-18.8%) at 3 and 5 years, respectively, and of reduction 14.1% (95% CI, 10.4%-17.8%) and 21.3% (95% CI, 16.4%-26.2%) at 3 and 5 years, respectively. Median tumour enlargement was 2 mm (IQR 1-3) and 49% of micro-NFPAs that grew became macroadenomas (nearly all >5 mm at detection). Eight (1.9%) patients received surgery (only one had visual compromise with surgery required >3 years after micro-NFPA detection). Sex, age, and size at baseline were not predictors of enlargement/reduction. At the time of detection, 7.2%, 1.7%, and 1.5% patients had secondary hypogonadism, hypothyroidism, and hypoadrenalism, respectively. Two (0.6%) developed hypopituitarism during follow-up (after progression to macroadenoma). CONCLUSIONS: Probability of micro-NFPA growth is low, and the development of new hypopituitarism is rare. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of tumour growth or clinical manifestations is a safe approach for micro-NFPA surveillance.Accepted version, submitted versionThis article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site
Comprehensive analysis of alternative splicing across multiple transcriptomic cohorts reveals prognostic signatures in prostate cancer
No full textBACKGROUND: Alternative splicing (AS) plays a crucial role in transcriptomic diversity and is a hallmark of cancer that profoundly influences the development and progression of prostate cancer (PCa), a prevalent and potentially life-limiting cancer among men. Accumulating evidence has highlighted the association between AS dysregulation and the onset and progression of PCa. However, a comprehensive and integrative analysis of AS profiles at the event level, utilising data from multiple high-throughput cohorts and evaluating the prognosis of PCa progression, remains lacking and calls for thorough exploration. RESULTS: We identified a differentially expressed retained intron event in ZWINT across three distinct cohorts, encompassing an original array-based dataset profiled by us previously and two RNA sequencing (RNA-seq) datasets. Subsequent in-depth analyses of these RNA-seq datasets revealed 141 altered events, of which 21 demonstrated a significant association with patients' biochemical recurrence-free survival (BCRFS). We formulated an AS event-based prognostic signature, capturing six pivotal events in genes CYP4F12, NFATC4, PIGO, CYP3A5, ALS2CL, and FXYD3. This signature effectively differentiated high-risk patients diagnosed with PCa, who experienced shorter BCRFS, from their low-risk counterparts. Notably, the signature's predictive power surpassed traditional clinicopathological markers in forecasting 5-year BCRFS, demonstrating robust performance in both internal and external validation sets. Lastly, we constructed a novel nomogram that integrates patients' Gleason scores with pathological tumour stages, demonstrating improved prognostication of BCRFS. CONCLUSIONS: Prediction of clinical progression remains elusive in PCa. This research uncovers novel splicing events associated with BCRFS, augmenting existing prognostic tools, thus potentially refining clinical decision-making.UnknownRDUH can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Colon cancer care is changing and not before time
No full textAccepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design
No full textBACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP(3) ) receptor type 1 (IP(3) R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP(3) -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Published version, accepted versionRDUH can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted