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BackgroundStandardised home-based pulmonary rehabilitation (PR) programmes offer an alternative model to centre-based supervised PR for which uptake is currently poor. We determined if a structured home-based unsupervised PR programme was non-inferior to supervised centre-based PR for participants with COPD.MethodsA total of 287 participants with COPD who were referred to PR (187 male, mean (SD) age 68 (8.86) years, FEV1% predicted 48.34 (17.92)) were recruited. They were randomised to either centre-based PR or a structured unsupervised home-based PR programme including a hospital visit with a healthcare professional trained in motivational interviewing, a self-management manual and two telephone calls. Fifty-eight (20%) withdrew from the centre-based group and 51 (18%) from the home group. The primary outcome was dyspnoea domain in the chronic respiratory disease questionnaire (Chronic Respiratory Questionnaire Self-Report; CRQ-SR) at 7 weeks. Measures were taken blinded. We undertook a modified intention-to-treat (mITT) complete case analysis, comparing groups according to original random allocation and with complete data at follow-up. The non-inferiority margin was 0.5 units.ResultsThere was evidence of significant gains in CRQ-dyspnoea at 7 weeks in both home and centre-based groups. There was inconclusive evidence that home-based PR was non-inferior to PR in dyspnoea (mean group difference, mITT: −0.24, 95% CI −0.61 to 0.12, p=0.18), favouring the centre group at 7 weeks.ConclusionsThe standardised home-based programme provides benefits in dyspnoea. Further evidence is needed to definitively determine if the health benefits of the standardised home-based programme are non-inferior or equivalent to supervised centre-based rehabilitation.Trial registration numberISRCTN81189044.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV1], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV1, worse dyspnoea and higher ADO index compared to other clusters (p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.

Background: The incremental shuttle walk test (ISWT) assesses exercise capacity in chronic obstructive pulmonary disease (COPD) patients. Guidelines suggest that 2 ISWTs should be performed. However, in inpatients with an acute exacerbation, it is unknown if 2 ISWTs are required. Objective: To investigate if a practice ISWT is needed for inpatients with an acute COPD exacerbation. Methods: Patients admitted to hospital with an acute exacerbation completed 2 ISWTs prior to discharge. Patients provided informed consent and were included if they used the same oxygen and mobility aid (if any) between tests. Results: Thirty-nine inpatients with COPD were included with a mean (SD) forced expiratory volume in 1 s (FEV 1 ) of 1.1 litres (0.5) [42.5% predicted (13.2)] and a median (interquartile range) Medical Research Council dyspnoea grade of 4 (3-5). Participants achieved 88.2 m (96.7) on ISWT1, and there was a statistically significant increase of 14.1 m (28.4) for ISWT2 (p < 0.05). Multiple regression explained 98.8% of the variance (F (8-22) p < 0.001, R 2 = 0.988) between ISWTs using age, FEV 1 /forced vital capacity (FVC)%, FVC, resting oxygen saturation, resting heart rate (HR), ISWT1 distance, ISWT1 post-HR and post-Rated Perceived Exertion (p < 0.05). Using this equation to calculate predicted ISWT2, there was good agreement and no significant difference between this and actual ISWT2 (0.01 m, p > 0.05). Conclusions: There was a small but statistically significant increase between ISWTs, which was below the minimal clinically important difference but would have had consequences for exercise prescription. This exploratory work has shown that we may be able to predict the difference between ISWTs using a multiple regression equation which could substitute the need for a second ISWT; this needs to be confirmed prospectively.

De novo assembly of a human genome using nanopore long-read sequences has been reported, but it used more than 150,000 CPU hours and weeks of wall-clock time. To enable rapid human genome assembly, we present Shasta, a de novo long-read assembler, and polishing algorithms named MarginPolish and HELEN. Using a single PromethION nanopore sequencer and our toolkit, we assembled 11 highly contiguous human genomes de novo in 9 d. We achieved roughly 63× coverage, 42-kb read N50 values and 6.5× coverage in reads >100 kb using three flow cells per sample. Shasta produced a complete haploid human genome assembly in under 6 h on a single commercial compute node. MarginPolish and HELEN polished haploid assemblies to more than 99.9% identity (Phred quality score QV = 30) with nanopore reads alone. Addition of proximity-ligation sequencing enabled near chromosome-level scaffolds for all 11 genomes. We compare our assembly performance to existing methods for diploid, haploid and trio-binned human samples and report superior accuracy and speed. High contiguity human genomes can be assembled de novo in 6 h using nanopore long-read sequences and the Shasta toolkit.

Clinical decision support (CDS) is one strategy to increase evidence-based practices by clinicians. Despite its potential, CDS tools produce mixed results and are often disliked by clinicians. Principles from behavioral economics such as \"nudges\" may improve the effectiveness and clinician satisfaction of CDS tools. This paper outlines a pragmatic approach grounded in implementation science to identify and prioritize how to incorporate different types of nudges into CDS tools. The purpose of this paper is to describe a systematic and pragmatic approach grounded in implementation science to identify and prioritize how best to incorporate different types of nudges into CDS tools. We provide a case example of how this systematic approach was applied to design a CDS tool to improve guideline-concordant prescribing of mineralocorticoid receptor antagonists for patients with heart failure and reduced ejection fraction. We applied the Messenger, Incentives, Norms, Defaults, Salience, Priming, Affect, Commitments, and Ego nudge framework and the Practical, Robust Implementation and Sustainability Model implementation science framework to systematically and pragmatically identify and prioritize different types of nudges for CDS tools. To illustrate how these frameworks can be applied in a real-life scenario, we use a case example of a CDS tool to improve guideline-concordant prescribing for patients with heart failure. We describe a process of how these frameworks can be used pragmatically by clinicians and informaticists or more technical CDS builders to apply nudge theory to CDS tools. We defined four iterative steps guided by the Practical, Robust Implementation and Sustainability Model: (1) engage partners for user-centered design, (2) develop a shared understanding of the nudge types, (3) determine the overarching CDS format, and (4) brainstorm and prioritize nudge types to address each modifiable contextual issue. These steps are iterative and intended to be adapted to align with the local resources and needs of various clinical scenarios and settings. We provide illustrative examples of how this approach was applied to the case example, including who we engaged, details of nudge design decisions, and lessons learned. We present a pragmatic approach to guide the selection and prioritization of nudges, informed by implementation science. This approach can be used to comprehensively and systematically consider key issues when designing CDS to optimize clinician satisfaction, effectiveness, equity, and sustainability while minimizing the potential for unintended consequences. This approach can be adapted and generalized to other health settings and clinical situations, advancing the goals of learning health systems to expedite the translation of evidence into practice.

ObjectivesTo identify barriers and facilitators to implementing an electronic shared decision-making tool for managing anticoagulant-related drug-drug interactions that affect bleeding risk in routine clinical care.DesignPreimplementation qualitative study using semistructured interviews.SettingThree academic medical centres in the southeastern and western USA. Interviews were conducted between 27 March and 25 September 2024.Participants36 participants, including 19 clinicians involved in prescribing or managing anticoagulants and seventeen patients prescribed anticoagulants, were recruited using purposive and convenience sampling.ResultsParticipants identified multiple barriers and facilitators to tool implementation. Common barriers included limited visit time, challenges integrating the tool into existing workflows, role and scope-of-practice constraints, and variation in patient digital literacy. Facilitators included clear visualisation of bleeding risk, access to supporting evidence, familiar interface design and perceived potential to support patient engagement and shared decision-making. Several determinants functioned as both barriers and facilitators, depending on clinical context and user role.ConclusionsThis preimplementation qualitative study identified context-specific determinants that influence the adoption of an electronic shared decision-making tool for anticoagulant-related drug–drug interactions. Findings highlight the importance of early attention to workflow integration, role alignment and usability to support uptake in routine care. Addressing these factors during design and implementation may inform strategies to support adoption and future evaluation in real-world clinical settings.

Since the coronavirus disease pandemic response began in March 2020, tests, vaccinations, diagnoses, and treatment initiations for sexual health, HIV, and viral hepatitis in England have declined. The shift towards online and outreach services happened rapidly during 2020 and highlights the need to evaluate the effects of these strategies on health inequalities.

Michael Talkowski and colleagues analyze balanced chromosomal abnormalities in 273 individuals by whole-genome sequencing. Their findings suggest that sequence-level resolution improves prediction of clinical outcomes for balanced rearrangements and provides insight into pathogenic mechanisms such as altered gene regulation due to changes in chromosome topology. Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C , a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies 1 – 3 . Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity 4 , 5 , its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T reg ) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T reg cells. Accordingly, in mouse models, PI3Kδi decreased the number of T reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T reg cells, accompanied by expansion of pathogenic T helper 17 (T H 17) and type 17 CD8 + T (T C 17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity. A study using a mouse solid tumour model suggests that adjusting the dosing frequency of the PI3Kδ inhibitor AMG319 in the treatment of human cancers could decrease tumour growth with fewer adverse effects.