A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation

BACKGROUND: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)). RESULTS: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire–revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient’s quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was −48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). CONCLUSIONS: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride

Community readiness to address disparities in access to cancer, palliative and end-of-life care for ethnic minorities

Background Inequalities in cancer, palliative, and end-of-life care services remain a significant challenge, particularly for ethnic minorities who face systemic barriers such as limited awareness, cultural stigmas, and language differences. These disparities hinder equitable access to essential services and contribute to poorer health outcomes for affected communities. Addressing these challenges requires targeted, culturally sensitive initiatives that promote both awareness and uptake of care. Community readiness is a critical factor in the success of such interventions, as it reflects the willingness and capacity of a community to engage with and support change. Methods A mixed-methods approach was used, combining individual interviews and two focus groups with key informants (N = 14). This study, conducted in the ethnically and geographically diverse region of Bedfordshire, Luton, and Milton Keynes in southeast England, aimed to assess community readiness to embrace initiatives designed to reduce health inequalities in cancer, palliative, and end-of-life care. The key informants, including faith leaders and professional stakeholders, rated community readiness on five anchored scales: Knowledge of efforts, Leadership, Knowledge of the issue, Community Climate, and Resources. The focus groups facilitated a discussion of the ratings, providing deeper insights into community dynamics and barriers. Results Overall, the community was identified as being at the pre-planning stage of readiness to address disparities in cancer, palliative, and end-of-life care for ethnic minorities. Quantitatively, faith and religious leaders assessed readiness at the vague awareness stage (mean: 3.88), while professional stakeholders rated it at the pre-planning stage (mean: 4.87). Qualitative findings highlighted limited community knowledge, passive leadership with potential for ‘community champions’ to foster openness, a positive climate influenced by younger generations, widespread misconceptions, language barriers, and resource constraints affecting service accessibility. Conclusions The Community Readiness Model provides an insight into the community’s position regarding disparities in access to cancer, palliative and end-of-life services. In order to ensure that continuing efforts are successful in addressing existing inequalities rather than exacerbating them, this study emphasises how critical it is to evaluate the readiness of the community in order to avoid widening inequalities in access and use of services

Bridging inequities in palliative and end-of-life care: the role and experiences of community connectors

Background: The Community Connectors programme is a UK pilot initiative designed to bridge gaps between cancer, palliative, and end-of-life care services and diverse ethnic and faith communities. Community Connectors are local individuals with strong cultural insight who enhance two-way communication, increase awareness of care services, and address the unique needs of seldom-heard groups, including South Asian, Black African-Caribbean, and Eastern European communities. By engaging trusted community members, the programme aims to foster relationships, empower communities, and improve understanding of cancer and palliative care pathways among underserved populations. Objective: To explore the experiences and perspectives of Community Connectors implementing this model, with a focus on feasibility, acceptability, and perceived impact within target communities. Methods: A qualitative longitudinal design was employed using linked interviews and reflective diaries. A qualitative descriptive approach was used to explore evolving perceptions of the role, community engagement, and barriers to care access. Semi-structured interviews (N = 3) were conducted between July 2023 and April 2024, focusing on emerging themes and changes in perceptions. In addition, Community Connectors (N = 4) kept diaries and activity logs to document their community interactions, challenges, and key observations throughout their involvement in the project. Results: Community Connectors reported success in building trust and relationships within the community, emphasising that trust, integrity, and passion for the role were more important than financial reward. Initially, there was confusion about the role, with expectations of marketing work evolving into a focus on research and engagement. They faced several challenges, including time constraints linked to the part-time nature of the role, as well as cultural sensitivities, language barriers, and stigma around cancer. Despite difficulties in measuring impact, Connectors reported personal growth, strong community relationships, and a sense of reward from their involvement. Conclusion: The Community Connector model is a feasible and culturally responsive approach to improving access to cancer and palliative care in underserved communities. Future programmes should provide clearer role definitions, sustained funding, and training in emotional resilience and cultural competence. Further research is needed to assess the long-term impact of this model on health outcomes and its integration into mainstream health services.gold o

Position statement and considerations for remotely delivered pulmonary rehabilitation services.

Statement and methods of development The challenge of access to pulmonary rehabilitation (PR) and meeting associated service demand is certainly not new. However, the COVID-19 pandemic set an unprecedented challenge evoking rapid adaptation of services. An inherent spotlight has been placed on remotely delivered services. As we look beyond the height of this pandemic, it is important to reflect and consider what has been learnt, and emerging perspectives on the future of PR service delivery. This document updates the ‘ACPRC statement and considerations for the remote delivery of pulmonary rehabilitation services during the COVID-19 pandemic’ (1) and seeks to provide pragmatic practical guidance for remotely delivered models of PR for healthcare professionals that should be used alongside local guidance. The recommendations provided are for guidance only, and may be updated in response to further national guidelines and new evidence. An online survey of PR healthcare professionals (ACPRC pulmonary rehabilitation provision during COVID-19 and beyond!) was conducted in the development of this document to scope current practice in PR services across the U.K. Informed by queries received by the ACPRC, the survey was first conducted in 2020 and repeated in July 2021 with the aim of capturing a snapshot of practice, one-year post onset of the COVID-19 pandemic. The survey was publicised and disseminated via Twitter using the @theACPRC handle, with request that one team member completed on behalf of their service. A summary of the 21 responses can be found in Appendix 1 which served to inform the content of this document. A literature review was undertaken to identify and integrate relevant published trials since the 2021 Cochrane review of telerehabilitation for people with chronic respiratory disease (2). Details of the search strategy can be found in Appendix 2 and summary of study characteristics and outcomes in Appendix 3. Anonymous feedback from four PR services was collated and analysed to identify common themes in experiences of remotely delivered PR services. A summary of this process and collated feedback can be found in Appendix 4. Key terms Remotely delivered models – the delivery of pulmonary rehabilitation services at a distance; the interaction between healthcare professional and participant using communication and information technologies, that may take place in real-time (synchronously) or asynchronously (1). It may be delivered by a virtual platform, an online web application or programme, or referred to as telerehabilitation (note: this terminology is used where studies have reported it). Field walking tests are commonly employed to evaluate exercise capacity, prescribe exercise, and evaluate treatment response in chronic respiratory diseases (3). The most valid, reliable and responsive ones are the six-minute walk test (6MWT), incremental (ISWT) and endurance walk test (ESWT). NACAP – the National Asthma and COPD Audit Programme is commissioned by the Healthcare Quality Improvement Partnership (HQIP), as part of the National Clinical Audit and Patient Outcomes Programme (NCAPOP), and currently covers England and Wales. The programme is led by the Royal College of Physicians (RCP) and includes a pulmonary rehabilitation workstream. PRSAS – the Pulmonary Rehabilitation Services Accreditation Scheme was launched in April 2018, and is run by the Royal College of Physicians (RCP)

Post-prandial effects of a meal rich in long-chain omega-3 fatty acids on indicators of cardiovascular risk

Funding was provided through a joint funding initiative from the Institute for Health & Welfare Research at RGU and QMUIntroduction Evidence from epidemiological studies indicates that the regular consumption of oily fish may be protective against the risk of cardiovascular disease. The benefits appear to be related to the content of long-chain omega-3 fatty acids (LC n-3 PUFA), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Current UK dietary guidelines therefore recommend the consumption of two portions of fish per week, one of which should be oily (1), which equates to 0.45g LC n-3 PUFA per day. Although there is limited information about intakes of EPA and DHA in Scotland, recent studies show that they are consistently below recommendations (2). Further review of the dietary intake data indicates that the consumption of oily fish is sporadic and inconsistent (3) despite attempts to promote regular intake. Several of the mechanisms involved in the development of cardiovascular disease (CVD) involve endothelial function. Post-prandial hyperlipidaemia has been linked to an increased risk of CVD (4), which is largely attributed to the transient (2-6 hour) decrease in endothelial function (5). Changes in endothelial function have also been shown to be associated with superoxide production (6), implicating oxidative stress as a possible mechanism for endothelial dysfunction. The long-term effects of LC n-3 PUFA on oxidative stress and inflammation are well established, however little is known about their immediate post-prandial effects. Identifying the possible benefits of consumption of a single meal rich in LC n-3 PUFA may provide a new perspective on which to promote dietary changes. The aim of this pilot project was therefore to identify post-prandial changes in markers of cardiovascular risk, assessed by measurement of arterial compliance, whole blood fatty acid profile, plasma glucose and insulin, markers of endothelial dysfunction, oxidative stress and antioxidant status in response a test meal naturally rich LC n-3 PUFA compared with a control meal.sch_dieunpub2825unpu

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings. Keywords: children; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor

Individual Health Trainers to support health and wellbeing for people under community supervision in the criminal justice system: the STRENGTHEN pilot RCT

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