Evaluating DOAC dipstick testing in the management of acute stroke: protocol for a multicentre, prospective, observational registry study

Introduction
Direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prophylaxis in non-valvular atrial fibrillation. Yet, DOAC use is regarded as a contraindication for intravenous thrombolysis in acute ischaemic stroke. The stratification of patients into ‘on-therapy’ and ‘off-therapy’ categories based on their plasma DOAC concentrations is particularly crucial in the acute phase of stroke when decisions for thrombolysis or anticoagulation reversal are time-sensitive. The novel point-of-care DOAC dipstick assay (DOASENSE) rapidly assesses urine for clinically significant DOAC levels, potentially broadening eligibility for thrombolysis or targeted reversal therapy. This multicentre prospective observational registry study aims to evaluate the accuracy and clinical utility of DOAC dipstick testing compared with plasma DOAC assays in acute stroke management across regional Australian hospitals.

Methods and analysis
This multicentre, prospective, observational study will enrol participants presenting to hospitals across Victoria and Tasmania with acute ischaemic stroke or intracerebral haemorrhage with DOAC ingestion within 48 hours of presentation. Plasma DOAC concentrations measured by chromogenic assays will be compared with rapid urine dipstick results from DOASENSE testing. There is a target sample size of 146 participants. The primary outcomes are as follows: (1) proportion of ischaemic stroke participants with off-therapy plasma DOAC levels and (2) eligibility for reperfusion therapy based on DOASENSE and plasma DOAC concentrations. Secondary outcomes are follows: (1) ischaemic stroke aetiology for participants with on-therapy vs off-therapy DOAC levels; (2) proportion of participants meeting criteria for pharmacological DOAC reversal based on DOASENSE outcomes; (3) incidence of false-negative and false positive DOASENSE results in clinically significant DOAC plasma concentrations at a threshold of ≥30 ng/mL and (4) an exploratory analysis of any false negative DOASENSE assays to identify potential contributing factors.

Ethics and dissemination
Ethics approval has been granted by the Eastern Health Human Research Ethics Committee (reference number: 99628). Dissemination of findings will occur through peer-reviewed publications and academic conferences.

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Large-Core Paradox

Stroke, Ahead of Print. Recently, 6 randomized controlled trials of endovascular treatment (EVT) versus medical management in anterior circulation large vessel occlusion with large-core documented significant benefit of EVT on functional outcome. Moreover, one trial reported the benefit of EVT in the large-core category (Alberta Stroke Program Early Computed Tomography Score, 0–2). These results are considered paradoxical by some as they contradict the prevailing view that the presence of a large core precludes the possibility of good outcomes following reperfusion. They, in turn, led some investigators to question the applicability of the core/penumbra model in the case of large-core stroke and even its overall validity, specifically regarding the notion that the core reliably predicts tissue infarction. Here, we discuss the trial results and propose alternative explanations for the large-core paradox. First, although EVT does improve outcomes as compared with medical management, overall outcomes remain poor in ≈80% of the treated population. Second, the assessment of core extent on imaging, particularly with computed tomography, is potentially inaccurate, especially in the early time window. Third, consistent with observational studies, some randomized controlled trial substudies suggest that the benefit of EVT in this population derives at least in part from the salvage of penumbra, which appears to have been present in a large percentage of enrolled patients. Fourth, the markedly reduced perfusion that prevails within large cores facilitates the early development of vasogenic edema. This heterogeneity of tissue injury may, in turn, lead to an overestimation of true core/neuronal death as estimated with computed tomography and magnetic resonance imaging. Assessing patients with apparent large core should consider these notions when discussing eligibility for EVT. Early reperfusion of large-core patients is expected to both target any residual penumbra and prevent the development of vasogenic edema within the severely hypoperfused areas. These considerations underscore the need for more reliable methods to identify irreversible neuronal injury inside the imaging-based estimated core.

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Blood-Brain Barrier Disruption Predicts Poor Outcome in Subarachnoid Hemorrhage: A Dynamic Contrast–Enhanced MRI Study

Stroke, Ahead of Print. BACKGROUND:Spontaneous aneurysmal subarachnoid hemorrhage induces early blood-brain barrier permeability dysfunction, although its clinical relevance and underlying mechanisms remain poorly understood. We aimed to evaluate the association between blood-brain barrier disruption, quantified with dynamic contrast–enhanced magnetic resonance imaging at the end of the early brain injury period, circulating neuroinflammatory mediators, and long-term clinical outcomes.METHODS:We analyzed a prospective cohort of subarachnoid hemorrhage patients who underwent dynamic contrast–enhanced magnetic resonance imaging at a median (interquartile range) of 4 (2–6) days after clinical onset. Permeability maps were used to obtain K-trans values as a measure of increased blood-brain barrier permeability in the whole brain, gray matter, and white matter. Circulating neuroinflammatory molecules, including IL (interleukin) 8 and PDGF (platelet-derived growth factor), were measured using Multiplex-ELISA in blood samples collected concurrently with magnetic resonance imaging acquisition. Poor clinical outcome was defined as a modified Rankin Scale score of >2 at 90 days. Associations between K-trans values, neuroinflammatory mediators, and clinical outcomes were assessed using univariate and multivariate regression models.RESULTS:From 153 patients initially screened, 96 were finally included (63% females; median age, 55 years; 43% premorbid hypertension; 32% World Federation of Neurosurgical Societies grade 4–5; 31% poor outcome). In adjusted linear regression analyses, higher K-trans values were significantly associated with increased IL-8 (P=0.001) and PDGF (P=0.018) levels. In univariate analysis, K-trans values in white matter were significantly higher in patients with poor clinical outcome (median [interquartile range], 2.5 [2.07–6.09] ×10−3·min−1) compared with good clinical outcome (median [interquartile range], 2.0 [1.60–2.42] ×10−3·min−1;P

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Beyond the puff: qualitative insights into smoking behaviours and societal perceptions among university students in India

Objectives
The objective of the study was to understand the smoking behaviour of adults and how societal perceptions influence the smoking behaviour of university students.

Design
Qualitative study.

Setting
National Institute of Medical Sciences university, India.

Participants
20 face-to-face interviews were carried out among university students who were in the age group of 19–30 years using a combination of purposive sampling, followed by snowball sampling methods.

Results
Qualitative responses revealed that stress, cravings for cigarettes and mealtimes were key triggers for smoking behaviour. Many participants felt guilty about their smoking and often became irritated by advice from non-smoking friends. All participants had experienced negative health effects, including physical and sensory issues, as well as other adverse experiences. Students expressed a dislike for judgemental attitudes from society. They respected elders and found it difficult to smoke in front of them. Rather than being blamed for their smoking, they preferred supportive assistance to help them quit.

Conclusions
The study highlights the importance of understanding college students’ smoking behaviour, as it greatly influences their smoking habits. Cessation efforts should target this group and emphasise the negative experiences associated with smoking. Additionally, students recommend creating a non-judgemental and supportive environment to aid in quitting, rather than a judgemental and blaming society.

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Understanding disparities in access to and quality of surgical care for African, Caribbean and Black communities in high-income countries with universal healthcare: a scoping review protocol

Introduction
African, Caribbean and Black (ACB) communities experience disparities in health outcomes, with higher rates of chronic diseases, such as heart disease and stroke, and lower self-reported health status compared to their White counterparts. Barriers to timely access to healthcare services further exacerbate these inequities. Some studies link racialisation to surgical disparities and subpar surgical outcomes. However, the findings are diverse, and there is no synthesis of the evidence on disparities in surgical care for ACB patients in high-income countries with universal healthcare systems. The objective of the scoping review is to systematically describe, characterise and map the existing literature on disparities in the access to and quality of surgical care among ACB patients in high-income countries with universal healthcare systems, and to identify gaps in the literature on surgical access and quality of surgical care in ACB patients.

Methods and analysis
The scoping review will follow the Joanna Briggs Institute methodology and report according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. The search strategy will be customised for each database (MEDLINE, Embase, CINAHL, APA PsycINFO and Cochrane Library) using terms for ACB and surgery. Grey literature and references from included studies will be searched for additional sources, with no limitations on publication date or language. All study designs will be eligible. Two independent reviewers will screen titles, abstracts and full texts in duplicate for eligibility. One reviewer will chart data, with a second reviewer validating the data charted. The findings will be synthesised, quantitatively summarised using descriptive statistics and qualitatively analysed through thematic analysis.

Ethics and dissemination
Ethics approval is not required as the study utilises published data. The dissemination of the findings will inform future research and improve understanding of the surgical care experiences of ACB patients. Dissemination will target academics and healthcare professionals through publications, presentations and workshops.

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Fifty Years of Deciphering Stroke Pathophysiology

Stroke, Volume 56, Issue 7, Page 1947-1957, July 1, 2025. In the 2025 David G. Sherman Lecture, Jean-Claude Baron emphasizes the major role positron emission tomography played in the breakthroughs in ischemic stroke pathophysiology that took place in the last half-century and allowed major therapeutic advances. Based on his work using PET in both animal models and people with stroke spanning 4 decades, he details his main contributions to key milestones, including (1) the demonstration of the hemodynamic consequences of chronic carotid artery occlusion and the hemodynamic mechanism underlying some transient ischemic attacks; (2) the documentation of the existence of the ischemic penumbra in man and the formal validation, using stringent prespecified operational criteria, of the core/penumbra model; (3) the persistence of substantial penumbral volumes up to 17 hours after stroke onset in a substantial fraction of patients; (4) the demonstration that from early timepoints poststroke, a good fraction of patients do not show the extensive penumbral pattern but instead exhibit large cores or spontaneously reperfusion, indicating the importance of individual patient selection for trials and therapy based on physiological imaging instead of time since stroke onset; (5) the documentation that the salvaged penumbra may not be intact but is often affected by selective neuronal loss, which may impact functional outcome and represent a novel target for neuroprotection; and (6) the demonstration of remote metabolic effects of disconnection resulting in loss of excitatory input, such as crossed cerebellar diaschisis and thalamocortical diaschisis, which may represent additional targets for therapies aiming at adaptive plasticity.

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Assessing the impact of novel social media policies in the USA restricting youth exposure to food and beverage advertisements: a protocol for a difference-in-difference study

Introduction
Social media is the most prominent source of online food and beverage advertisements (ads) seen by adolescents. Companies target adolescent social media users with ads that feature calorie-dense, nutrient-poor products, and exposure to ads drives poor diet and risk for future diet-related diseases. Black, Hispanic and lower socio-economic status youth are exposed to significantly more ads than White peers. Several state-level policies in the USA have passed restricting youth from accessing social media without parental approval, and some policies have banned advertising to youth. This protocol paper describes a current study that aims to understand the impact of such policies in two states, Louisiana and Texas, as they were among the first to be implemented with racially/ethnically diverse populations.

Methods and analysis
This study employs a repeated cross-sectional difference-in-difference design in which 700 youth ages 13–17 years are being recruited each year for 5 years (Louisiana n=175, Texas n=175, matched comparisons from other states n=350). Youth screen record their mobile devices for 60 minutes while they browse social media platforms (eg, TikTok, Instagram) or use the internet. They also complete a brief survey about a variety of topics (eg, health behaviours, mental health). Adolescents are compensated for screen recording ($75) and the survey ($25). Study team members are coding recordings for several characteristics, including media platforms used, appearances of food or beverages, and food or beverage type. We will estimate the impact of policies on food and beverage ads seen per hour using Ordinary Least Squares regression models and heterogeneity-robust standard errors clustered at the state level (by year and cumulatively). We will run additional models with interaction terms with income and race/ethnicity, separately, to test the role of the policies on health disparities.

Ethics and dissemination
Study procedures have been approved by the Institutional Review Board of the NYU Grossman School of Medicine. We will distribute findings in peer-reviewed journals and at local and national conferences. To complement traditional dissemination pathways, we will create infographics to share with relevant community stakeholders. We will also share findings with policymakers in states that have passed or considered similar policies.

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Safety and feasibility of allogeneic cord blood-derived cell therapy in preterm infants with severe brain injury (ALLO trial): a phase-1 trial protocol

Introduction
Severe intraventricular haemorrhage (IVH) and white matter injury (WMI) are major neurological complications in preterm infants, leading to long-term neurodevelopmental impairments. Despite advances in neonatal care, effective treatments are lacking. Umbilical cord blood cell (UCBC) therapy shows neuroprotective potential, with autologous sources ideal but often not feasible due to the unpredictability of preterm births. Allogeneic UCBCs offer an alternative, although immunogenicity and human leucocyte antigen (HLA) compatibility present challenges with knowledge gaps in their relevance in neonatal populations. This study aims to assess the feasibility and safety of partially HLA-matched allogeneic UCBC therapy in preterm infants with severe brain injury.

Methods
The ALLO trial is an open-label, phase I, single-arm feasibility and safety study conducted at Monash Children’s Hospital, Victoria, Australia. Preterm infants born before 28 weeks (ALLO-1) or between 28 weeks and 36+6 weeks (ALLO-2) gestational age with severe brain injury identified on neuroimaging will be enrolled. Severe brain injury is defined as grade 3 or 4 IVH or significant WMI. Exclusion criteria include major congenital anomalies or redirection to comfort care. Eligible infants will receive a single intravenous infusion of unrelated, allogeneic, partially HLA-matched (4/6 or 5/6 HLA match) UCBCs sourced from a public cord blood bank. The target dose is 50 million total nucleated cells per kilogram body weight. Infusion will occur within 2–3 weeks of confirmation of eligibility, contingent on clinical stability and absence of active sepsis. Primary outcome includes: (1) feasibility, defined as having more than 60% of enrolled infants with an eligible allogeneic partially matched cord blood unit available and (2) safety, defined as absence of severe adverse events within 48 hours of infusion or graft-versus-host disease within 3 months of infusion. Secondary outcomes include survival, neonatal morbidities, neurodevelopmental assessments and serum cytokine analysis.

Ethics and dissemination
Monash HREC has granted full ethics approval (RES-23-0000-297A) for the study, including the research use of allogeneic cord blood from compassionate donations by healthy donors, facilitated through the Bone Marrow Donor Institute Cord Blood Bank within the AusCord network. Findings will be disseminated through peer-reviewed publications and conference presentations, contributing to the development of novel neuroreparative therapies for preterm brain injury.

Trial registration number
ACTRN12623001352695 (The Australian New Zealand Clinical Trials Registry).

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Heated tobacco product use prevalence and temporal trends among the German population: a series of representative cross-sectional household surveys, 2018-2023

Objectives
Heated tobacco products (HTPs) are electronic devices that heat tobacco instead of burning it to produce an inhalable aerosol. This study aimed to investigate usage patterns, sociodemographic and socioeconomic factors, as well as co-use characteristics of people who use HTPs within the German population to inform interventions and preventive measures.

Methods
We conducted analysis with pooled cross-sectional data from the German Study on Tobacco Use (DEBRA) from June 2018 till November 2023. We estimated weighted, descriptive and bimonthly data on current and ever HTP usage and descriptive data on user patterns. To analyse the variance between people who ever versus people who never used HTPs in relation to user characteristics, we performed ² tests and calculated percentages and CIs.

Results
The proportions of both people who currently use and people who ever used HTPs have increased from 2018 (current user: 0.1% [95%CI:

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How Machine Learning Could Help Target Nudges

This Medical News article is an interview with Stanford University economist Susan Athey, PhD, about the clinical practice implications of her recent research on machine learning and causal vs predictive targeting for student financial aid renewal.

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Campaign messages to support pictorial health warning labels for little cigars and cigarillos: an online survey-based experiment

Objectives
Campaigns to support pictorial health warning labels (HWLs) for cigarettes have enhanced their effectiveness, but little to no research on campaign messages to support little cigars and cigarillos (LCC) pictorial HWLs exists. The goal of this study was to examine the effectiveness of messages to augment pictorial HWLs on LCCs among priority populations.

Design
Online survey-based experiment.

Setting
Qualtrics research panel online of US adults, recruited between January and February 2023.

Participants
Adults ages 21–29 who reported current cigar use and reside in the USA.

Interventions
Participants (n=315) were randomly assigned to one of three conditions: (1) messages designed to elaborate pictorial HWLs, (2) pictorial HWLs alone and (3) messages and pictorial HWLs paired together.

Procedures and outcome measures
Within conditions, participants were shown six negative health effects of LCCs and answered questions about perceived message effectiveness (PME), negative affect, thinking about risks (TAR) and self-reported learning (SRL) as well as questions on quit intention, concern about their health and reactance. Using mixed-effects models and ANOVA, we evaluated for differences across conditions.

Results
Most participants identified as male (60%) and either Black (45%) or White (45%). PME was very high across all three conditions (≥ 3.85) but no difference between conditions in a statistically significant manner (p=0.18). Mixed-effects models indicated that negative affect varied across conditions, highest in condition 2 (3.76; 95% CI 3.58, 3.94) and lowest in condition 3 (3.44; 95% CI 3.27, 3.61) (p=0.01), and showed no statistically significant difference between conditions for SRL (p=0.31) or TAR (p=0.43). No statistically significant difference was noted for quit intentions (p=0.16), health concern (p=0.28) or reactance (p=0.84).

Conclusions
Pictorial HWLs, campaign messages and the combination of the conditions were all perceived as very effective, with little differences in PME. Such findings indicate that pictorial HWLs on LCCs and communication messages about LCCs both appear as promising approaches to reducing LCC use among target populations. Longitudinal studies with ongoing exposure may identify factors that can enhance the effectiveness of campaign messages to enhance pictorial HWLs for LCCs.

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Inactivation of RhoA for Hypertension Treatment Through the TRPV4–RhoA–RhoGDI1 Axis

Circulation, Ahead of Print. BACKGROUND:The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the RhoA signaling pathway are limited in hypertension treatment, suffering from poor efficacy, insufficient specificity, and developmental challenges.METHODS:Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation. VSMC, hypertensive animal models,Trpv4-/-andArhgdiaf/fMyh11-CREERT2(smooth muscle–specific RhoGDI1 knockout) mice were used to investigate the role of the TRPV4 (transient receptor potential cation channel subfamily V member 4)–RhoA–RhoGDI1 (Rho GDP dissociation inhibitor 1) axis in hypertension.RESULTS:AH001 ((R)-1-(3-ethylphenyl) ethane-1,2-diol) was identified as a novel inhibitor of the RhoA signaling pathway. It targets the TRPV4–RhoA–RhoGDI1 axis to effectively sequester inactive RhoA–GDP in the plasma membrane and cytoplasm, which is distinct from typical RhoA inhibition modes. The cryo-EM structure of the TRPV4AH001–RhoA complex showed that AH001-bound TRPV4 adopts a closed state with RhoA in an inactive GDP-bound state. Functional studies further revealed that AH001 reduced the pool of active RhoA by enhancing TRPV4–RhoA binding and facilitating RhoGDI1–RhoA interaction in VSMC. This inhibition notably decreased both acute and long-term blood pressure and prevented vascular remodeling in Ang II–induced hypertensive mice and spontaneously hypertensive rats. However, these antihypertensive effects were weakened inTrpv4-/-andArhgdiaf/fMyh11-CREERT2mice. Additionally, AH001 effectively inhibited VSMC contraction via the RhoA/ROCK (Rho-associated protein kinase)/MYPT1 (myosin phosphatase target subunit 1)/MLC (myosin light chain 2) signaling pathway and suppressed VSMC phenotype switching to myofibroblasts through the RhoA/ROCK/LIMK1 (LIM domain kinase)/cofilin/MRTF-A (myocardin-related transcription factor A)/SRF (serum response factor) signaling cascade. TRPV4 and RhoGDI1 knockdown attenuated AH001’s inhibition of VSMC contraction and phenotypic switching to myofibroblasts.CONCLUSIONS:This study revealed a novel mode of RhoA signaling inhibition targeting the TRPV4–RhoA–RhoGDI1 axis, offering new insights for future antihypertensive drug development and proposing innovative strategies for targeting challenging Rho GTPases.

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Unpacking the black box of interprofessional collaboration within healthcare networks: a scoping review

Introduction
Health systems are facing increasingly complex healthcare challenges, including system fragmentation, silos culture, lack of accountability, budgetary constraints and epidemiological transitions. Many governments adopted healthcare networks as a new strategy to address the complex healthcare challenges (eg, multidisciplinary care) by fostering effective clinical and interprofessional collaboration (IPC) across clinical pathways. Yet, limited evidence exists on how IPC is fostered within healthcare networks (ie, happening inside the structure of the network—including processes, systems, communication and practices).

Objectives
This review aims to identify the underlying processes and drivers for effective IPC within healthcare networks, as well as facilitators and barriers.

Design
We followed the scoping review guidance developed by the Joanna Briggs Institute and Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Reviews reporting guidelines.

Data sources
We searched five databases (PubMed (Medline), Scopus, Web of Science, Research4Life and BDSP).

Eligibility criteria
We included peer-reviewed articles published between 2010–2024 in French or English that addressed IPC within healthcare networks.

Data extractions and synthesis
Data charting included the general characteristics of included studies, IPC characteristics, barriers and facilitators and implications for policy and practice. Thematic analysis was guided by the levels of IPC at individual, professional, interactional and organisational levels.

Results
29 studies were included in this review. Most scholars from the included studies indicated that IPC is a complex, socially stratified process that includes four levels: individual, interactional, professional role and organisational characteristics. The main barriers were poor communication, lack of shared knowledge and decision-making, hierarchy and power imbalances. Key facilitators included clarifying roles, building formal structures for IPC, enhancing communication and promoting interprofessional education and training.

Conclusion
Promoting IPC necessitates systemic interventions that target multiple levels, including the individual, interactional, professional and organisational dimensions. Additional research is needed to understand how to foster effective IPC and develop strategies to ensure high-quality patient care.

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Carer administration of as-needed subcutaneous medication for breakthrough symptoms in people dying at home: the CARiAD feasibility RCT

Objectives
To determine if carer administration of as-needed subcutaneous medication for common breakthrough symptoms in people dying at home is feasible and acceptable in the UK, and if it would be feasible to test this intervention in a future definitive randomised controlled trial.

Design
We conducted a two-arm, parallel-group, individually randomised, open pilot trial of the intervention versus usual care, with a 1:1 allocation ratio, using convergent mixed methods.

Setting
Home-based care without 24/7 paid care provision, in three UK sites.

Participants
Participants were dyads of adult patients and carers: patients in the last weeks of their life who wished to die at home and lay carers who were willing to be trained to give subcutaneous medication. Strict risk assessment criteria needed to be met before the approach, including a known history of substance abuse or carer ability to be trained to competency.

Intervention
Intervention-group carers received training by local nurses using a manualised training package.

Primary outcome measures
Quantitative data were collected at baseline and 6–8 weeks post-bereavement and via carer diaries. Interviews with carers and healthcare professionals explored attitudes to, experiences of and preferences for giving subcutaneous medication and experience of trial processes. The main outcomes of interest were feasibility, acceptability, recruitment rates, attrition and selection of the most appropriate outcome measures.

Secondary outcome measures
The secondary outcome measure was time to symptom relief, calculated using data items from the carer diary, after the patient had died.

Results
In total, 40 out of 101 eligible dyads were recruited (39.6%), which met the feasibility criterion of recruiting >30% of eligible dyads. The expected recruitment target (50 dyads) was not reached, as fewer than expected participants were identified. Although the overall retention rate was 55% (22/40), this was substantially unbalanced (30% (6/20) usual care and 80% (16/20) intervention). The feasibility criterion of >40% retention was, therefore, considered not met. A total of 12 carers (intervention, n=10; usual care, n=2) and 20 healthcare professionals were interviewed. The intervention was considered acceptable, feasible and safe in the small study population. The intervention group had a considerably shorter time to medication administration than the usual-care group (median time to administer medication in intervention=5 min, usual-care=105 min). Intervention group carers felt confident in administering medication. Healthcare professional support was sought by intervention group carers in 24 out of 147 (16.3%) medication administration entries. The context of the feasibility study was not ideal, as district nurses were overstretched, unfamiliar with research methods and possibly not in equipoise. A disparity in readiness to consider the intervention was demonstrated between carers, who were uniformly enthusiastic, and healthcare professionals who were not. Findings confirmed methodological and ethics issues pertaining to researching the last days of life care.

Conclusion
The success of a future definitive trial is uncertain because of equivocal results in the progression criteria, particularly poor recruitment overall and a low retention rate in the usual-care group. Future work regarding the intervention should include understanding the context of UK areas where this has been adopted, ascertaining wider public views and exploring healthcare professional views on burden and risk in the NHS context. There should be consideration of the need for national policy and the most appropriate quantitative outcome measures to use. This will help to ascertain if there are unanswered questions to be studied in a trial.

Trial registration number
ISRCTN11211024.

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Gender and age disparities in cardiac immune-related adverse events associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FAERS database

Objectives
The cardiotoxicity of immune checkpoint inhibitors (ICIs) has garnered significant clinical attention due to its high mortality rate. However, limited clinical research and inconsistent results have hindered a comprehensive understanding of this issue. This study seeks to elucidate gender and age differences in cardiac-related adverse reactions, aiming to offer scientific evidence to inform clinical practice.

Design
A retrospective pharmacovigilance study.

Setting
Based on the reports of ICIs in the FDA Adverse Event Reporting System database from 2003–2023, we conducted a disproportionality analysis to identify cardiac immune-related adverse events (irAEs) and explored the correlation of age and gender with these adverse events.

Main outcome measures
The main cardiac irAEs were defined by four preferred terms: myocarditis, atrial fibrillation, cardiac failure and pericardial effusion. Both the proportional reporting ratio (PRR) and reporting odds ratio (ROR) are frequency methods. Data mining was performed using the PRR method, which assesses the relative risk of adverse drug reactions by comparing the frequency of reports associating a specific drug with a particular adverse reaction to the frequency of reports linking any drug to the same reaction. A higher PRR indicates a more robust adverse event signal, suggesting a stronger statistical association between the drug of interest and the target adverse event. In the research process, we primarily used the ROR and PRR from disproportionality analysis to screen for cardiac irAEs, while also elucidating the correlation between these reactions and factors such as age and gender.

Results
A total of 2033 adverse events were retrieved, and myocarditis was the most common cardiac irAEs. Gender disparities exist in the incidence of various adverse reactions to the same medication. Female patients need to be particularly vigilant for cardiac adverse events when taking atezolizumab, and male patients should be especially cautious for cardiac adverse events when using ipilimumab. Furthermore, ipilimumab produced a positive signal for pericardial effusion in the elderly group but not in the younger group, suggesting that elderly patients may be more susceptible to adverse reactions. Therefore, increased vigilance and careful monitoring are warranted during clinical administration of this medication to elderly patients.

Conclusion
Our study highlights the gender and age differences in cardiac adverse events with ICIs, providing valuable insights for clinical application.

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Rare Variant Association Analysis Uncovers Involvement of VNN2 in Stroke Outcome

Stroke, Ahead of Print. BACKGROUND:A stroke’s functional outcome presents vast variability among patients, which is influenced by age, sex, characteristics of the lesion, and genetic factors. However, there is little knowledge about stroke recovery genetics. Recently, some GWAS (Genome-Wide Association Studies) have highlighted the involvement of common or low-frequency variants near or withinPATJ,PPP1R21,PTCH1,NTN4, andTEK genes, whereas the role of rare variants is still unclear. This study aims to identify the genetic contributions to differences in stroke outcomes by analyzing the effect of rare variants.METHODS:We performed a pilot study analyzing 90 exomes of extreme good and bad recovery (modified Rankin Scale score at 3 months, 0–1 versus 4–5) to select target genes involved in stroke recovery. To expand this study, 702 additional samples were sequenced by targeted next-generation sequencing capturing loci selected from the pilot study, GWASs, and literature input. Here, we performed continuous (modified Rankin Scale score, 0–6) and dichotomous (modified Rankin Scale score, 0–1 versus 3–6) analyses, yielding 1 candidate gene. All samples were selected by a retrospective cohort study from incidental stroke cases collected at Spanish Hospitals between 2000 and 2018. The identifiedVNN2variants were assessed for protein structure and stability analysis, and an analysis of their effect on basal inflammation levels was performed using UK Biobank data.RESULTS:Our work identified rare coding variants inVNN2associated with patients with better stroke recovery (∆ deviance information criterion >10, equivalent toP1.6 kcal/mol); meanwhile, another variant, located in the active site, could affect the electrostatic surface.CONCLUSIONS:We propose thatVNN2might play a role in stroke outcomes by modulating poststroke inflammation. A potentially affected function would be neutrophil cell adhesion and migration.

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