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Importance: Development of myocardial fibrosis in patients with aortic stenosis precedes left ventricular decompensation and is associated with an adverse long-term prognosis., Objective: To investigate whether early valve intervention reduced the incidence of all-cause death or unplanned aortic stenosis-related hospitalization in asymptomatic patients with severe aortic stenosis and myocardial fibrosis., Design, Setting, and Participants: This prospective, randomized, open-label, masked end point trial was conducted between August 2017 and October 2022 at 24 cardiac centers across the UK and Australia. Asymptomatic patients with severe aortic stenosis and myocardial fibrosis were included. The final date of follow-up was July 26, 2024., Intervention: Early valve intervention with transcatheter or surgical aortic valve replacement or guideline-directed conservative management., Main Outcomes and Measures: The primary outcome was a composite of all-cause death or unplanned aortic stenosis-related hospitalization in a time-to-first-event intention-to-treat analysis. There were 9 secondary outcomes, including the components of the primary outcome and symptom status at 12 months., Results: The trial enrolled 224 eligible patients (mean [SD] age, 73 [9] years; 63 women [28%]; mean [SD] aortic valve peak velocity of 4.3 [0.5] m/s) of the originally planned sample size of 356 patients. The primary end point occurred in 20 of 113 patients (18%) in the early intervention group and 25 of 111 patients (23%) in the guideline-directed conservative management group (hazard ratio, 0.79 [95% CI, 0.44-1.43]; P = .44; between-group difference, -4.82% [95% CI, -15.31% to 5.66%]). Of 9 prespecified secondary end points, 7 showed no significant difference. All-cause death occurred in 16 of 113 patients (14%) in the early intervention group and 14 of 111 (13%) in the guideline-directed group (hazard ratio, 1.22 [95% CI, 0.59-2.51]) and unplanned aortic stenosis hospitalization occurred in 7 of 113 patients (6%) and 19 of 111 patients (17%), respectively (hazard ratio, 0.37 [95% CI, 0.16-0.88]). Early intervention was associated with a lower 12-month rate of New York Heart Association class II-IV symptoms than guideline-directed conservative management (21 [19.7%] vs 39 [37.9%]; odds ratio, 0.37 [95% CI, 0.20-0.70])., Conclusions and Relevance: In asymptomatic patients with severe aortic stenosis and myocardial fibrosis, early aortic valve intervention had no demonstrable effect on all-cause death or unplanned aortic stenosis-related hospitalization. The trial had a wide 95% CI around the primary end point, with further research needed to confirm these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT03094143.

Background: Clinical trials are fundamental to healthcare, however, they also contribute to anthropogenic climate change. Following previous work to develop and test a method and guidance to calculate the carbon footprint of clinical trials, we have now applied the guidance to 10 further UK and international, academically sponsored clinical trials to continue the identification of hotspots and opportunities for lower carbon trial design., Methods: 10 collaborating clinical trial units (CTUs) self-identified and a trial was selected from their portfolio to represent a variety of designs, health areas and interventions. Trial activity data was collated by trial teams across 10 modules spanning trial setup through to closure, then multiplied by emission factors provided in the guidance to calculate the carbon footprint. Feedback was collected from trial teams on the process, experience and ease of use of the guidance., Results: We footprinted 10 trials: 6 investigational medicinal product trials, 1 nutritional, 1 surgical, 1 health surveillance and one complex intervention trial. Six of these were completed and four ongoing (two in follow-up and two recruiting). The carbon footprint of the 10 trials ranged from 16 to 765 tonnes CO 2 e. Common hotspots were identified as CTU emissions, trial-specific patient assessments and trial team meetings and travel. Hotspots for specific trial designs were also identified. The time taken to collate activity data and complete carbon calculations ranged from 5 to 60 hours. The draft guidance was updated to include new activities identified from the 10 trials and in response to user feedback., Discussion: There are opportunities to reduce the impact of trials across all modules, particularly trial-specific meetings and travel, patient assessments and laboratory practice. A trial's carbon footprint should be considered at the design stage, but work is required to make this common place., Competing Interests: Competing interests: JG, LF, JB and PRW have received NIHR funding to undertake this study (support for the manuscript). FA is the paid chair of the Sustainable Healthcare Coalition. RA-SS reports clinical study grants from the British Heart Foundation and Chief Scientist Office Health Improvement, Protection and Services Research Committee Project Grant; consulting fees from Recursion Pharmaceuticals and Bioxodes, and payment from European Stroke Masters (European Stroke Organisation). RA-SS participates on the Novo Nordisk NN9931-4553 and NN9931-4554 endpoint adjudication committee and is the clinical director of the UK Clinical Research Collaboration network of registered Clinical Trials Units. CA is the Vice President of the World Stroke Organisation, Editor-in-chief of Cerebrovascular Diseases and Associate Editor of International Journal of Stroke; reports grants or contracts from National Health and Medical Research Council (NHMRC) of Australia, Medical Research Council (MRC) of the UK, Medical Research Foundation (MRF) of the UK, Penumbra and Takeda; consulting fees from AstraZeneca Advisory Board and participation on Dutch DIST trial. CG is supported by the NIHR CTU efficiency call. KG receives consulting fees from Boehringer & Ingelheim (unrelated to this work) and is Chair of the ICTMC 2024 Scientific Committee. KH is the Deputy Chair of the NIHR Research Professors panel and was previously a member of the NIHR HTA General Committee. CN is an unpaid information specialist in a priority setting partnership for adults living with type 1 diabetes. SP reports grants or contracts from ViiV Healthcare, Gilead Sciences, NIH, MRC, EDCTP and Janssen-Cilag and is a DSMB member for the academic NIHR–funded trial TIPAL. SO’R, LM and JM are supported by funding from Health Research Board (HRB) Ireland MRSy is an independent unpaid member of many Independent Data Monitoring Committees for academic sponsors; reports grants or contracts from Astellas, Clovis Oncology, Janssen, Pfizer, Novartis and Sanofi-Aventis; consulting fees from Eli Lilly; speaker fees from Janssen and AstraZeneca, and payment from Eisai, all unrelated to the topic of this comment. EM, AB, DC, FY, LW, XC, CM, PD, NM, AP, KM, EB, FD and CK report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: The majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death., Methods: TARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. After myocardial infarction and clear alternative diagnoses have been ruled out, participants with intermediate cardiac troponin concentrations (5 ng/L to 99th centile upper reference limit) will be randomised 1:1 to outpatient CTCA plus standard of care or standard of care alone. The primary endpoint is myocardial infarction or cardiac death. Secondary endpoints include clinical, patient-centred, process and cost-effectiveness. Recruitment of 2270 patients will give 90% power with a two-sided P value of 0.05 to detect a 40% relative risk reduction in the primary endpoint. Follow-up will continue until 97 primary outcome events have been accrued in the standard care arm with an estimated median follow-up of 36 months., Discussion: This randomised controlled trial will determine whether high-sensitivity cardiac troponin-guided CTCA can improve outcomes and reduce subsequent major adverse cardiac events in patients presenting to the emergency department who do not have myocardial infarction., Trial Registration: ClinicalTrials.gov Identifier: NCT03952351. Registered on May 16, 2019., (© 2023. The Author(s).)

In 2019, just one-half of Americans received their influenza vaccine, despite it being safe, effective, and important in preventing serious infection, hospitalization, and death. Black children receive fewer influenza vaccines than their White counterparts. Vaccine hesitancy can hinder influenza vaccine uptake and is partially fueled by ongoing systemic racism and historical abuse leading to medical mistrust in communities of color. Building trust may enhance the transfer of reliable vaccine information and may move people along the spectrum of vaccine intention. We sought to partner with faith-based organizations through a community influenza vaccination event to increase vaccination rates. By leveraging the reach and expertise of trusted voices, such as church "first ladies" and local community leaders, we were able to administer 600 pediatric influenza vaccines between 2016 and 2019. In addition, this event served as a platform to assess whether youth attendees had a place for regular medical care ("medical home") (>80% did in each year assessed) and to conduct preventive screenings. Most children, as reported by their caregivers, had recent medical check-ups (85% in 2016, 84% in 2017, and 82% in 2018). Of the children screened, more than one-third had an abnormal body mass index and one-half had abnormal dentition. By partnering with organizations that are well-embedded in the local community, such as faith-based organizations, health care groups may be able to maximize the impact of their health promotion campaigns., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Patients with suspected acute coronary syndrome in whom myocardial infarction has been excluded are at risk of future adverse cardiac events., Objectives: This study evaluated the usefulness of high-sensitivity cardiac troponin I (hs-cTnI) to select patients for further investigation after myocardial infarction has been excluded., Methods: This is a prospective cohort study of patients presenting to the emergency department with suspected acute coronary syndrome and hs-cTnI concentrations below the sex-specific 99th percentile. Patients were recruited in a 2:1 fashion, stratified by peak hs-cTnI concentration above and below the risk stratification threshold of 5 ng/L. All patients underwent coronary computed tomography angiography (CCTA) after hospital discharge., Results: Overall, 250 patients were recruited (61.4 ± 12.2 years 31% women) in whom 62.4% (156 of 250 patients) had coronary artery disease (CAD). Patients with intermediate hs-cTnI concentrations (between 5 ng/L and the sex-specific 99th percentile) were more likely to have CAD than those with hs-cTnI concentrations <5 ng/L (71.9% [120 of 167 patients] vs 43.4% [36 of 83 patients]; odds ratio: 3.33; 95% CI: 1.92-5.78). Conversely, there was no association between anginal symptoms and CAD (63.2% [67 of 106 patients] vs 61.8% [89 of 144 patients]; odds ratio: 0.92; 95% CI: 0.48-1.76). Most patients with CAD did not have a previous diagnosis (53.2%; 83 of 156 patients) and were not on antiplatelet and statin therapies (63.5%; 99 of 156 patients) before they underwent CCTA., Conclusions: In patients who had myocardial infarction excluded, CAD was 3× more likely in those with intermediate hs-cTnI concentrations compared with low hs-cTnI concentrations. In such patients, CCTA could help to identify those with occult CAD and to target preventative treatments, thereby improving clinical outcomes., Competing Interests: Funding Support and Author Disclosures Dr Lee was supported by a British Heart Foundation (BHF) Clinical Research Training Fellowship (FS/18/25/33454). Drs Bularga and Wereski and Mr. Doudesis were supported by the Medical Research Council (MR/N013166/1, MR/V007017/1, MR/V007254/1). Dr Williams was supported by the British Heart Foundation (FS/ICRF/20/26002). Dr van Beek was supported by the Scottish Imaging Network. Dr Mills was supported by a Chair Award (CH/F/21/90010), Programme Grant (RG/20/10/34966), and Research Excellence Award (RE/18/5/34216) from the British Heart Foundation. Dr Lee has received honoraria from Abbott Diagnostics. Dr van Beek is founder/owner of QCTIS Ltd; has received honoraria from Aidence NV, Roche Diagnostics, AstraZeneca, and Mentholatum; and has received research support from Siemens Healthineers. Dr Mills has received honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics, and LumiraDx; and the University of Edinburgh has received research grants from Abbott Diagnostics and Siemens Healthineers. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Apathy is prevalent in dementia, such as behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and Alzheimer disease (AD). As a multidimensional construct, it can be assessed and subsumed under a Dimensional Apathy Framework. A consistent apathy profile in bvFTD and PPA has yet to be established. The aim was to explore apathy profiles and awareness in bvFTD, PPA, and AD. A total of 12 patients with bvFTD, 12 patients with PPA, 28 patients with AD, and 20 matched controls, as well as their informants/carers, were recruited. All participants completed the Dimensional Apathy Scale (DAS), assessing executive, emotional, and initiation apathy subtypes, a 1-dimensional apathy measure, depression measure, and functional and cognitive screens. Apathy subtype awareness was determined through DAS informant/carer and self-rating discrepancy. Apathy profile comparison showed patients with bvFTD had significantly higher emotional apathy than patients with AD ( P < .01) and significantly higher apathy over all subtypes than patients with PPA ( P s < .05). Additionally, patients with bvFTD had significantly lower awareness for emotional apathy ( P < .01) when compared to patients with AD and PPA. All patient groups had significant global apathy over all subtypes compared to controls. The emergent apathy profile for bvFTD seems to be emotional apathy (indifference or emotional/affective neutrality), with lower self-awareness in this subtype. Further, lower self-awareness for executive apathy (lack of motivation for planning, organization, or attention) differentiates bvFTD from PPA. Future research should investigate the cognitive and neural correlates as well as the practical impact of apathy subtypes.

Cognitive dysfunction is present in up to 70% of patients with multiple sclerosis (MS) and has been reported at all stages and in all subtypes of the disease. These deficits have been reported across a variety of cognitive domains, but are generally under-recognized and incompletely evaluated in routine clinical practice. The aim of this study was to investigate the spectrum of cognitive impairment in patients with MS presenting to a specialist MS clinic using the Cambridge Neuropsychological Test Automated Battery (CANTAB), administered on a touchscreen platform. Ninety MS patients completed computerized CANTAB tasks assessing working memory, executive function, processing speed, attention, and episodic memory. Scores were adjusted for age, sex, and level of education and classified as normal or impaired based on comparison with a large normative data pool. We also investigated the impact of clinical and demographic variables which could potentially influence cognitive performance including patient educational level (a proxy for cognitive reserve), disease status (duration, course, and severity of MS), and depression. CANTAB testing detected cognitive impairment in 40 patients (44% of the sample). The most frequently impaired domain was executive function, present in 55% of cognitively impaired individuals. Disease duration and severity were significantly associated with performance across various cognitive domains. Patients with depressive symptoms were also more likely to exhibit impaired processing speed. Results from this study confirm that cognitive impairment is common and occurs across a range of domains among MS patients attending routine clinical visits. CANTAB tasks provide a sensitive and practical approach to cognitive testing in MS patients as part of a holistic patient assessment.

Chronic pelvic pain (CPP) affects 2.1-24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700 mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women's experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012-2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07-3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97-6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial.