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Background Although dual antiplatelet therapy (DAPT) improves the outcomes of patients undergoing percutaneous coronary intervention (PCI), sex-specific differences in efficacy and safety of DAPT remain unresolved. We compared sex differences for DAPT outcomes and DAPT durations (1–3 months [short-term], 6 months [mid-term], and >12 months [extended] vs. 12 months). Methods We searched databases through 31 December 2023 for trials reporting DAPT after PCI. The endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), net adverse clinical and cerebrovascular events (NACCE), and any bleeding. Extracted data were pooled in a frequentist network and pairwise, random-effects meta-analysis. Results Twenty-two trials (99,591 participants, 25.2% female) were included. Female sex was significantly associated with a higher 1-year MACCE risk (hazard ratio 1.14 [95% confidence interval 1.02–1.28]) and bleeding (1.13 [1.00–1.28]), but not NACCE (1.12 [0.96–1.31]). In sub-analyses, the association between female sex and MACCE was related to use of clopidogrel as the second antiplatelet agent (1.11 [1.03–1.20]), whereas higher bleeding events were related to newer P2Y12 inhibitors (P2Y12i) (1.58 [1.01–2.46]). For DAPT duration, short-term DAPT followed by P2Y12i monotherapy was non-inferior for MACCE in females and males (0.95 [95% CI 0.83–1.10; and 0.96 [0.80–1.16]) but tended to be superior in males for NACCE versus 12-month DAPT (0.96 [0.91–1.01]); mid-term DAPT tended to be associated with a lower bleeding risk in males (0.43 [0.17–1.09]). Conclusions Female sex is associated with higher MACCE and bleeding when newer P2Y12i agents are used. Short-term DAPT followed by P2Y12i monotherapy is safe and effective in both sexes undergoing PCI. Clinical Trials Registration PROSPERO ID: CRD42021278663. Graphical Abstract Sex differences in outcomes of clinical trials of dual antiplatelet therapy (DAPT) after percutaneous coronary interventions (PCI).

The major pathophysiological symptom of the menopause affecting daily life is hot flushes, which are also associated with elevated cardiovascular disease risk. A hot flush is a sudden and intense heat sensation causing skin flushing and profuse sweating. Menopause-induced oestrogen deficiency could increase the sensitivity of skin blood vessels and sweat glands in postmenopausal women, which could result in more frequent and larger increases in skin blood flow in postmenopausal women consistent with hot flushes. Furthermore, oestrogen withdrawal could also alter the structure of the skin blood vessels and/or sweat glands which may also contribute to hot flushes. This trial aims to examine the function and structure of skin blood vessels and sweat glands in premenopausal and postmenopausal women. This is a single-centre multi-cohort observational study. Participants will attend the laboratory at Liverpool John Moores University (LJMU) on two separate occasions, ∼7 days apart. Visit 1 will consist of anthropometry, a blood sample and assessment of post-ganglionic skin blood vessel and sweat gland responsiveness via cutaneous microdialysis. At visit 2, participants will return for a skin punch biopsy. A between groups statistical analysis of the pre- and postmenopausal cohorts will be conducted in a blinded manner. The trial was approved by the North West - Greater Manchester South Research Ethics Committee (22/NW/0300) in the UK. The study adheres to The Declaration of Helsinki and is being conducted in accordance with the UK Policy Framework for Health and Social Care Research. Identifying functional and/or structural changes in skin blood vessels or sweat glands in women with hot flushes would increase our understanding of their cause(s) and side effects, and help to design effective treatments, including interventions that can manipulate the activity of the skin blood vessels and/or sweat glands via pharmacological or non-pharmacological methods. NCT06222073.

Background Low English language literacy is a common barrier to participation in clinical trials. Patient information leaflets (PILs) used in clinical trials are often lengthy, complex and have poor readability; this is a persistent and prevalent problem common to trials across the world. Simplifying the information provided in PILs can lead to improved understanding, comprehension and knowledge. The aim of this project was to develop recommendations for developing accessible PILs for clinical trials through a literature review of published and grey literature and co-working with marginalised communities, patients, and health and social care charities. Methods A literature review of MEDLINE, Embase and online resources was conducted, and recommendations for developing accessible PILs were extracted from eligible published and grey literature. Grey literature which contained insights into more inclusive forms of communication was also identified and summarised. Meetings were held with two racially marginalised community groups, two groups involving autistic adults and/or adults with learning difficulties and a patient advisory group. Examples of accessible PILs were shared and discussions held about the content and format of the PILs and suggestions for changes/improvements. National Voices, a coalition of health and social care charities in England, held a national online workshop with charities and lived experience partners. Recommendations identified from the multiple sources were coded, collated and refined to develop an overarching framework of recommendations. Results The framework consists of 74 recommendations for developing accessible PILs for clinical trials. Recommendations cover the five topics of formatting, information presentation, writing style, content and accessibility. Conclusions This project has developed a comprehensive framework of recommendations to guide researchers in the development of accessible PILs for clinical trials. Findings from previous research and from co-working with marginalised communities, patients and health and social care charities were collated to ensure that a diverse range of voices and experiences informed the framework. These recommendations aim to support researchers to develop better study information to reduce English language literacy as a barrier to participation in clinical trials.

Organoid cell culture methodologies are enabling the generation of cell models from healthy and diseased tissue. Patient-derived cancer organoids that recapitulate the genetic and histopathological diversity of patient tumours are being systematically generated, providing an opportunity to investigate new cancer biology and therapeutic approaches. The use of organoid cultures for many applications, including genetic and chemical perturbation screens, is limited due to the technical demands and cost associated with their handling and propagation. Here we report and benchmark a suspension culture technique for cancer organoids which allows for the expansion of models to tens of millions of cells with increased efficiency in comparison to standard organoid culturing protocols. Using whole-genome DNA and RNA sequencing analyses, as well as medium-throughput drug sensitivity testing and genome-wide CRISPR-Cas9 screening, we demonstrate that cancer organoids grown as a suspension culture are genetically and phenotypically similar to their counterparts grown in standard conditions. This culture technique simplifies organoid cell culture and extends the range of organoid applications, including for routine use in large-scale perturbation screens.

BackgroundHumans display an age-related decline in cerebral blood flow and increase in blood pressure (BP), but changes in the underlying control mechanisms across the lifespan are less well understood. We aimed to; (1) examine the impact of age, sex, cardiovascular disease (CVD) risk, and cardio-respiratory fitness on dynamic cerebral autoregulation and cardiac baroreflex sensitivity, and (2) explore the relationships between dynamic cerebral autoregulation (dCA) and cardiac baroreflex sensitivity (cBRS).Methods206 participants aged 18–70 years were stratified into age categories. Cerebral blood flow velocity was measured using transcranial Doppler ultrasound. Repeated squat-stand manoeuvres were performed (0.10 Hz), and transfer function analysis was used to assess dCA and cBRS. Multivariable linear regression was used to examine the influence of age, sex, CVD risk, and cardio-respiratory fitness on dCA and cBRS. Linear models determined the relationship between dCA and cBRS.ResultsAge, sex, CVD risk, and cardio-respiratory fitness did not impact dCA normalised gain, phase, or coherence with minimal change in all models (P > 0.05). cBRS gain was attenuated with age when adjusted for sex and CVD risk (young–older; β = − 2.86 P < 0.001) along with cBRS phase (young–older; β = − 0.44, P < 0.001). There was no correlation between dCA normalised gain and phase with either parameter of cBRS.ConclusionAgeing was associated with a decreased cBRS, but dCA appears to remain unchanged. Additionally, our data suggest that sex, CVD risk, and cardio-respiratory fitness have little effect.

IntroductionPatients with node-positive breast cancer having primary surgery currently undergo axillary node clearance (ANC) to reduce the risk of breast cancer recurrence. Evidence that this highly morbid procedure improves survival is lacking, but approximately 30% of patients will develop lifelong complications which significantly impact their quality of life.Targeted axillary dissection (TAD) may be a safe, less morbid alternative to ANC and will be evaluated in the upcoming Targeted Axillary Dissection versus axillary node clearance in patients with POsitive axillary Lymph nodes in Early breast cancer (TADPOLE) randomised controlled trial.TAD is not currently routine practice in patients having primary surgery, so it is vital that the procedure is performed in an agreed upon, standardised way within the trial and procedure fidelity monitored to ensure the results are generalisable and will be accepted by the surgical community. Robust surgical quality assurance (SQA) is essential. Here we describe the first phase of the TADPOLE SQA, a consensus process with the breast surgical community to agree upon how (1) surgery should be performed and standardised; (2) procedure fidelity will be monitored and (3) requirements for surgeon credentialling within the trial.Methods and analysisThe consensus process will have three phases:Generation of a long list of possible components of TAD from a scoping review and expert opinion. Identified items will be categorised and formatted into Delphi consensus questionnaire items.At least two rounds of an online Delphi survey in which at least 100 breast cancer surgeons will rate the importance of mandating/prohibiting, standardising and/or monitoring each component.A consensus meeting with surgeons to discuss, agree upon and ratify the approach to SQA within TADPOLE.Ethics and disseminationEthical approval has been obtained from the University of Bristol Faculty of Health Sciences Ethics Committee. Educational materials including videos and webinars will be developed and shared with surgeons participating in TADPOLE. Results will be presented at national/international meetings and published in peer-reviewed journals.

BackgroundImplant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure following mastectomy. IBBR techniques are evolving rapidly, with mesh-assisted subpectoral reconstruction becoming the standard of care and more recently, prepectoral techniques being introduced. These muscle-sparing techniques may reduce postoperative pain, avoid implant animation and improve cosmetic outcomes and have been widely adopted into practice. Although small observational studies have failed to demonstrate any differences in the clinical or patient-reported outcomes of prepectoral or subpectoral reconstruction, high-quality comparative evidence of clinical or cost-effectiveness is lacking. A well-designed, adequately powered randomised controlled trial (RCT) is needed to compare the techniques, but breast reconstruction RCTs are challenging. We, therefore, aim to undertake an external pilot RCT (Best-BRA) with an embedded QuinteT Recruitment Intervention (QRI) to determine the feasibility of undertaking a trial comparing prepectoral and subpectoral techniques.Methods and analysisBest-BRA is a pragmatic, two-arm, external pilot RCT with an embedded QRI and economic scoping for resource use. Women who require a mastectomy for either breast cancer or risk reduction, elect to have an IBBR and are considered suitable for both prepectoral and subpectoral reconstruction will be recruited and randomised 1:1 between the techniques.The QRI will be implemented in two phases: phase 1, in which sources of recruitment difficulties are rapidly investigated to inform the delivery in phase 2 of tailored interventions to optimise recruitment of patients.Primary outcomes will be (1) recruitment of patients, (2) adherence to trial allocation and (3) outcome completion rates. Outcomes will be reviewed at 12 months to determine the feasibility of a definitive trial.Ethics and disseminationThe study has been approved by the National Health Service (NHS) Wales REC 6 (20/WA/0338). Findings will be presented at conferences and in peer-reviewed journals.Trial registration numberISRCTN10081873.

Purpose The aim of this study was to examine if catechin‐rich green tea abrogates the negative effects of 7‐days of physical inactivity and excessive calorie‐intake on insulin homeostasis and peripheral vascular function. Methods Using a randomized, double‐blind, crossover design, twelve healthy men (29 ± 6 yrs) underwent 7‐days unhealthy lifestyle (UL), including physical inactivity (−50% steps/day) and overfeeding (+50% kcal/day). This was combined with green tea consumption (UL‐tea; 3 doses/day) or placebo (UL‐placebo). Before and after each intervention, we examined postprandial blood glucose and insulin (3‐h after a 1,202 kcal meal) and upper and lower limb vascular function (flow‐mediated dilation (FMD%)) and carotid artery reactivity (CAR%). Results UL‐placebo increased postprandial glucose and insulin, while UL‐tea decreased postprandial glucose and insulin (Time*Intervention interaction effects: both p < 0.05). UL‐placebo decreased CAR% and femoral FMD%, while UL‐tea prevented these effects (Time*Intervention interaction effects of p < 0.04 and p < 0.001, respectively). There was no main effect of Time or Time*Intervention interaction (both p > 0.05) for brachial FMD%. Conclusion Seven days of physical inactivity and overfeeding impair insulin homeostasis and vascular function. These effects were mitigated by a daily intake of catechin‐rich green tea. The aim of this study was to examine if catechin‐rich green tea abrogates the negative effects of short‐term physical inactivity and excessive calorie‐intake on insulin homeostasis and peripheral vascular function. Twelve healthy men (29 ± 6 yrs) underwent 7‐days unhealthy lifestyle (UL), including physical inactivity (−50% steps/day) and overfeeding (+50% kcal/day) combined with green tea consumption (UL‐tea; 3 doses/day) or placebo (UL‐placebo). UL‐placebo increased post‐prandial glucose and insulin, while UL‐tea decreased post‐prandial glucose and insulin. UL‐placebo decreased carotid artery reactivity and lower limb vascular function, while UL‐tea prevented these effects. Seven days of physical inactivity‐ and overfeeding‐induced impairments in insulin homeostasis and vascular function were mitigated by daily intake of catechin‐rich green tea.

AimTo explore parent and general practitioner (GP) understanding and beliefs about food allergy testing for children with eczema.Design and settingQualitative interview study in UK primary care within the Trial of Eczema allergy Screening Tests feasibility trial.ParticipantsSemi-structured interviews with parents of children with eczema taking part in the feasibility study and GPs at practices hosting the study.Results21 parents and 11 GPs were interviewed. Parents discussed a range of potential causes for eczema, including a role for food allergy. They believed allergy testing to be beneficial as it could potentially identify a cure or help reduce symptoms and they found negative tests reassuring, suggesting to them that no dietary changes were needed. GPs reported limited experience and uncertainty regarding food allergy in children with eczema. While some GPs believed referral for allergy testing could be appropriate, most were unclear about its utility. They thought it should be reserved for children with severe eczema or complex problems but wanted more information to advise parents and help guide decision making.ConclusionsParents’ motivations for allergy testing are driven by the desire to improve their child’s condition and exclude food allergy as a possible cause of symptoms. GPs are uncertain about the role of allergy testing and want more information about its usefulness to support parents and help inform decision making.Trial registration numberISRCTN15397185.