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Animal muscles must maintain their function while bearing substantial mechanical loads. How muscles withstand persistent mechanical strain is presently not well understood. The basic unit of muscle is the sarcomere, which is primarily composed of cytoskeletal proteins. We hypothesized that cytoskeletal protein turnover is required to maintain muscle function. Using the flight muscles of Drosophila melanogaster, we confirmed that the sarcomeric cytoskeleton undergoes turnover throughout adult life. To uncover which cytoskeletal components are required to maintain adult muscle function, we performed an RNAi-mediated knockdown screen targeting the entire fly cytoskeleton and associated proteins. Gene knockdown was restricted to adult flies and muscle function was analyzed with behavioural assays. Here we analyze the results of that screen and characterize the specific muscle maintenance role for several hits. The screen identified 46 genes required for muscle maintenance: 40 of which had no previously known role in this process. Bioinformatic analysis highlighted the structural sarcomeric proteins as a candidate group for further analysis. Detailed confocal and electron microscopic analysis showed that while muscle architecture was maintained after candidate gene knockdown, sarcomere length was disrupted. Specifically, we found that ongoing synthesis and turnover of the key sarcomere structural components Projectin, Myosin and Actin are required to maintain correct sarcomere length and thin filament length. Our results provide in vivo evidence of adult muscle protein turnover and uncover specific functional defects associated with reduced expression of a subset of cytoskeletal proteins in the adult animal.

In a randomized trial, the routine use of cerebral embolic protection during TAVI did not reduce the incidence of stroke within 72 hours or before discharge from the hospital (if discharge occurred sooner).

Recent scholarship has begun to consider more seriously the effects of Tertullian of Carthage’s status as a colonized subject on his oeuvre. This article builds upon this groundwork, addressing Tertullian’s relationship to his North African identity by analyzing his use of Roman and North African history in his apologetic works. In particular, it examines Tertullian’s deployment of the Roman historiographic trope of exempla, narrative vignettes designed to emphasize the ideological goals of the historian, in the Apologeticum and his letter Ad Martyras with his colonial status in mind. Tertullian draws on certain exempla from the historical relationship between Carthage and Rome that prior Roman historians often used to bolster Rome’s claim to the divine right to rule. He reframes these stories in a manner that undermines these claims and places North Africa at the center of the historical narrative. In this way, Tertullian presents a view of history that privileges a North African narrative identity in which local Christians, especially martyrs, could imagine themselves as the latest participants.

Background Informed consent is considered a fundamental requirement for participation in trials, yet obtaining consent is challenging in a number of populations and settings. This may be due to participants having communication or other disabilities, their capacity to consent fluctuates or they lack capacity, or in emergency situations where their medical condition or the urgent nature of the treatment precludes seeking consent from either the participant or a representative. These challenges, and the subsequent complexity of designing and conducting trials where alternative consent pathways are required, contribute to these populations being underserved in research. Recognising and addressing these challenges is essential to support trials involving these populations and ensure that they have an equitable opportunity to participate in, and benefit from, research. Given the complex nature of these challenges, which are encountered by both adults and children, a cross-disciplinary approach is required. Discussion A UK-wide collaboration, a sub-group of the Trial Conduct Working Group in the MRC-NIHR Trial Methodology Research Partnership, was formed to collectively address these challenges. Members are drawn from disciplines including bioethics, qualitative research, trials methodology, healthcare professions, and social sciences. This commentary draws on our collective expertise to identify key populations where particular methodological and ethical challenges around consent are encountered, articulate the specific issues arising in each population, summarise ongoing and completed research, and identify targets for future research. Key populations include people with communication or other disabilities, people whose capacity to consent fluctuates, adults who lack the capacity to consent, and adults and children in emergency and urgent care settings. Work is ongoing by the sub-group to create a database of resources, to update NIHR guidance, and to develop proposals to address identified research gaps. Conclusion Collaboration across disciplines, sectors, organisations, and countries is essential if the ethical and methodological challenges surrounding trials involving complex and alternate consent pathways are to be addressed. Explicating these challenges, sharing resources, and identifying gaps for future research is an essential first step. We hope that doing so will serve as a call to action for others seeking ways to address the current consent-based exclusion of underserved populations from trials.

BackgroundLong covid describes a syndrome of persistent symptoms following COVID-19 and is responsible for substantial healthcare and economic burden. Currently, no effective treatments have been established. Ashwagandha (Withania somnifera (L.) Dunal) is a medicinal herb traditionally used in India for its immune-strengthening and anti-inflammatory properties. Withanolides, a family of steroid-derived molecules unique to Ashwagandha, have been shown to modulate inflammatory pathways in animal models, and several small randomised trials in humans support its effectiveness for reducing symptoms that are also associated with long covid. Therefore, this study aims to assess whether Ashwagandha is effective and safe for improving functional status and reducing symptom burden in adults living with long covid.MethodsA randomised double-blind placebo-controlled trial will be performed at participating general practice (GP) surgeries and long covid clinics across the UK. Individuals diagnosed with long covid will be screened for eligibility and then randomised 1:1 to take 1000 mg daily of Ashwagandha root extract tablets (standardised to <0.9% withanolides) or matching placebo tablets for 3 months (target, n = 2500). Monthly online surveys will be performed to collect patient-reported outcomes, and monthly safety monitoring, including liver function tests, will be conducted by clinical site teams. The primary outcome of the Post-COVID Functional Status Scale score at 3 months will be assessed by baseline-adjusted ordinal logistic regression, according to a pre-published statistical analysis plan. The secondary outcomes included validated quality of life and long covid symptom scales, work status and productivity and adverse events. The trial has been approved as a Clinical Trial of an Investigational Medicinal Produce by the Medicines and Healthcare Regulatory Authority and by the NHS Research Ethics Committee and Health Research Authority.DiscussionTreatments for long covid are urgently needed. This trial will robustly evaluate the safety and efficacy of a candidate treatment with a promising efficacy and safety profile. If found to be effective, the findings will likely influence treatment guidelines and improve health outcomes in those living with long covid.Trial registration numberThis trial was pre-registered on 15/08/2022: ISRCTN12368131

Plain English summary Patient and Public Involvement (PPI) describes the active involvement of patients and the public in the research process. Through PPI, patients and members of the public are increasingly involved in the design and conduct of clinical trials. PPI has been shown to improve the quality and relevance of research. During the COVID-19 pandemic, clinical trials have been playing a vital role in helping us find ways to prevent and treat the infection and improve our understanding of the virus. It is important that patients and the public are actively involved in deciding how COVID-19 research is carried out. Unfortunately, Research Ethics Committees in the UK have seen far less PPI for COVID-19 research studies compared with research before the pandemic. A key reason for this is that research is being designed much faster than normal and researchers may feel they do not have time to properly involve patients and the public. In this paper, we share our experiences of PPI for a COVID-19 clinical trial. We show that it is possible to rapidly involve patients and the public in COVID-19 clinical trials. We also explain how the design of the clinical trial was changed in response to feedback from public contributors. Lastly, we discuss the wider learning from this process which might be useful for researchers planning PPI activities for COVID-19 clinical trials in the future. Background: Clinical trials are playing a critical role in the global public health response to the COVID-19 pandemic. Despite the increasing recognition of the value of PPI in clinical trials, just 22% of the COVID-19 research proposals reviewed by Research Ethics Committees in the UK at the start of the pandemic reported PPI. There is a perception that PPI might result in delays in delivering research and therefore delays in obtaining important results. In this paper, we report our experience of rapid PPI for a COVID-19 clinical trial. Methods: RAPID-19 is a COVID-19 clinical trial which was planned to be submitted for fast-track ethics review in the United Kingdom. During the development of the trial protocol, the PPI Panel at the London School of Hygiene & Tropical Medicine Clinical Trials Unit was involved in the design of the study. The meeting with the PPI Panel lasted just over 1 h and was conducted by teleconference. Results: Although we only had a short period of time to explore the study with the PPI Panel, we were able to gain valuable insight into how the trial would be perceived by potential trial participants. Substantive changes were made to the trial to improve the acceptability of the research without compromising the study timelines. Having access to public contributors with relevant lived experience is an important resource for a Clinical Trials Unit and is critical for rapid PPI. The move to remote working due to lockdown required virtual discussions which helped to overcome some of the barriers to organising face-to-face meetings at short notice. Conclusions: PPI for clinical trials can be conducted in a time-efficient manner within the pressured environment of a pandemic. Involving PPI contributors at an early stage in protocol development maximised the opportunity to shape and influence the trial as well as limited potential delays which could occur if changes to the protocol had to be made at a later stage.

The studyHerrett E, Williamson E, Brack K, et al. The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs. Health Technol Assess 2021;25:16.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/statins-not-likely-to-cause-muscle-pain-stiffness/

Animal muscles must maintain their function and structure while bearing substantial mechanical loads. How muscles withstand persistent mechanical strain is presently not well understood. Understanding the mechanisms by which tissues maintain their complex architecture is a key goal of cell biology. This dataset represents a systematic screen through the Drosophila melanogaster cytoskeleton to identify genes that are required to maintain tissue, specifically muscle, architecture. Using RNA interference (RNAi), we knocked down 238 genes in Drosophila and assayed for climbing ability with a robust behavioural assay. Here we present the summary of the screen and provide the complete results of the assays. We have uncovered a number of novel hits that would reward further study. The data are easy to use: the raw data are provided to allow researchers to perform their own analysis and analysed results are given indicating whether or not the genes are required for muscle maintenance. This dataset will allow other researchers to identify candidate genes for more detailed study and lead to better understanding of muscle maintenance.

Out-of-hospital cardiac arrest (OHCA) is a global public health issue. There is wide variation in both regional and inter-hospital survival rates from OHCA and overall survival remains poor at 7%. Regionalization of care into cardiac arrest centers (CAC) improves outcomes following cardiac arrest from ST elevation myocardial infarction (STEMI) through concentration of services and greater provider experience. The International Liaison Committee on Resuscitation (ILCOR) recommends delivery of all post-arrest patients to a CAC, but that randomized controlled trials are necessary in patients without ST elevation (STE). Following completion of a pilot randomized trial to assess safety and feasibility of conducting a large-scale randomized controlled trial in patients following OHCA of presumed cardiac cause without STE, we present the rationale and design of A Randomized tRial of Expedited transfer to a cardiac arrest center for non-ST elevation OHCA (ARREST). In total 860 patients will be enrolled and randomized (1:1) to expedited transfer to CAC (24/7 access to interventional cardiology facilities, cooling and goal-directed therapies) or to the current standard of care, which comprises delivery to the nearest emergency department. Primary outcome is 30-day all-cause mortality and secondary outcomes are 30-day and 3-month neurological status and 3, 6 and 12-month mortality. Patients will be followed up for one year after enrolment. Post-arrest care is time-critical, requires a multi-disciplinary approach and may be more optimally delivered in centers with greater provider experience. This trial would help to demonstrate if regionalization of post-arrest care to CACs reduces mortality in patients without STE, which could dramatically reshape emergency care provision.

We studied the translational cardioprotective potential of P2Y12 inhibitors against acute myocardial ischemia/reperfusion injury (IRI) in an animal model of acute myocardial infarction and in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). P2Y12 inhibitors may have pleiotropic effects to induce cardioprotection against acute myocardial IRI beyond their inhibitory effects on platelet aggregation. We compared the cardioprotective effects of clopidogrel, prasugrel, and ticagrelor on infarct size in an in vivo rat model of acute myocardial IRI, and investigated the effects of the P2Y12 inhibitors on enzymatic infarct size (48-h area-under-the-curve (AUC) troponin T release) and clinical outcomes in a retrospective study of STEMI patients from the CONDI-2/ERIC-PPCI trial using propensity score analyses. Loading with ticagrelor in rats reduced infarct size after acute myocardial IRI compared to controls (37 ± 11% vs 52 ± 8%, p < 0.01), whereas clopidogrel and prasugrel did not (50 ± 11%, p > 0.99 and 49 ± 9%, p > 0.99, respectively). Correspondingly, troponin release was reduced in STEMI patients treated with ticagrelor compared to clopidogrel (adjusted 48-h AUC ratio: 0.67, 95% CI 0.47–0.94). Compared to clopidogrel, the composite endpoint of cardiac death or hospitalization for heart failure within 12 months was reduced in STEMI patients loaded with ticagrelor (HR 0.63; 95% CI 0.42–0.94) but not prasugrel (HR 0.84, 95% CI 0.43–1.63), prior to PPCI. Major adverse cardiovascular events did not differ between clopidogrel, ticagrelor, or prasugrel. The cardioprotective effects of ticagrelor in reducing infarct size may contribute to the clinical benefit observed in STEMI patients undergoing PPCI.