[Correspondence] In response to the letter by Howard JF and colleagues (eclinm-D-24-00922)

We would like to thank James Howard et al. for their insightful comments on our paper titled “Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee.”1 We appreciate their interest in the approach developed by the EBMT to standardize Good Clinical Practice (GCP), as outlined in detail on the EBMT webpage (https://www.ebmt.org/practice-harmonisation-and-guidelines-committee).

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Novembre 2024

Protocol for a randomised, double-blinded, controlled trial of youth with childhood-onset obesity treated with semaglutide 2.4 mg/week: the RESETTLE trial

Introduction
Childhood-onset obesity poses significant health risks, including early-onset type 2 diabetes, cardiovascular disease, and reduced quality of life. Hospital-based non-pharmacological obesity care can reduce childhood obesity, but 25% of children do not respond. Therefore, this study investigates the effect of the glucagon-like peptide-1 receptor agonist, semaglutide, as an add-on to hospital-based obesity care in youth who still have obesity following hospital-based obesity care as children. Furthermore, biomedical and psychosocial factors linked to treatment response will be investigated, alongside an exercise-based strategy to prevent weight regain and maintain a healthy body composition after semaglutide treatment.

Methods and analysis
This is an investigator-initiated, randomised, placebo-controlled, double-blind trial. We will enrol expectedly 180–270 young adults aged 18–28 years based on their previous response to a paediatric obesity management programme and their current body mass index (BMI). Participants are categorised into four groups: low treatment response (BMI SD score (SDS) reduction 0.25; BMI ≥30 kg/m2); high treatment response (BMI SDS reduction >0.50; BMI

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Novembre 2024

Abstract 4139117: Epidemiology of Patients Undergoing a Rapid Response within the First 24 Hours of Admission at an Urban Academic Center

Circulation, Volume 150, Issue Suppl_1, Page A4139117-A4139117, November 12, 2024. Introduction:A Rapid Response Team (RRT) is an inpatient team that aims to resuscitate deteriorating patients in non-critical care settings and reduce inpatient morbidity and mortality. It is not well understood which patients are likely to deteriorate and need a rapid response (RR) within the first 24 hours of admission.Research Question:We sought to identify the most common characteristics for patients who had a RR within 24 hours of admission.Methods:We performed a descriptive analysis evaluating 176 patients who had a RR called within 24 hours of admission to North Shore University Hospital from February 2022 to August 2023. Demographic and clinical variables were assessed, including medical history, admitting diagnosis, and indication for RR.Results:The median age of the population was 73 years; 92 (52.3%) were male, and 91 (51.7%) were white. The most common comorbidities were hypertension (119, 67.6%), coronary artery disease (51, 28.9%), and heart failure (34, 19.3%). Amongst these patients, acute hypoxic respiratory failure (11.6%) was the most common admission diagnosis followed by sepsis (9.7%) (Table 1). The most common reason for the RR was acute mental status change (26.1%) followed by hypotension (25.0%). Average time spent in the ED prior to admission was 6 hours 41 mins. Intensive care unit (ICU) consultation prior to the RRT occurred in 36 patients (20.5%) and 52 patients (29.5%) were transferred to an ICU while 124 (70.5%) remained on the medicine floors. Regarding hospital utilization, 98 (55.7%) patients were admitted within the last year and 47 (26.7%) patients were hospitalized within the last month. 14 (7.9%) patients had an ICU admission in the past year. 38 (21.5%) patients died during the admission post RR.Conclusion:In our cohort of RRs within 24 hours of admission, we observed a high prevalence of cardiac comorbidities and recent hospitalizations, a low prevalence of ICU consults prior to RR, and discordance between admitting diagnoses and reasons for RR. Further studies involving a larger cohort are needed to develop a prediction model for determining patients most at risk of deteriorating after admission and requiring RRs.

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Novembre 2024

Abstract 4136905: EF-24, a curcumin analog, reverses interleukin-18-induced miR-30b or miR-342-dependent TRAF3IP2 expression, RECK suppression, and the proinflammatory phenotype of human aortic smooth muscle cells

Circulation, Volume 150, Issue Suppl_1, Page A4136905-A4136905, November 12, 2024. Curcumin, a polyphenolic compound derived from the widely used spiceCurcuma longa,has shown anti-atherosclerotic effects in cultured vascular cells and animal models. We previously reported that the induction of the proinflammatory molecule TRAF3IP2 (TRAF3 Interacting protein 2) or inhibition of the matrix metalloproteinase (MMP) regulator RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs) contributes to agonist-induced proinflammatory, pro-oxidant, pro-mitogenic and pro-migratory effects in vascular smooth muscle cells. Here we hypothesized that, EF-24 ((3E,5E)-3,5-bis[2-fluorophenyl (methylene]-4piperidinone), a curcumin analog with better bioavailability and potency, reverses interleukin (IL)-18-induced TRAF3IP2 induction, RECK suppression and the proinflammatory phenotype of primary human aortic smooth muscle cells (ASMC). Exposure to recombinant human IL-18 (10 ng/ml) induced TRAF3IP2 mRNA and protein expression, but markedly suppressed RECK in a time-dependent manner. Further investigations revealed that IL-18 induced miR-30b, but suppressed miR-342, in a p38 MAPK and JNK-dependent manner. While miR-30b inhibitor blunted IL-18-induced TRAF3IP2 expression, miR-30b inhibitor and miR-342 mimic each restored RECK expression. Further, IL-18 induced ASMC migration (Boyden chamber assay) and proliferation (CyQUANT Cell Proliferation assay), and these effects were reversed by TRAF3IP2 knockdown or RECK overexpression. Our results also show that IL-18 induced MMP2 and MMP9 expression and activity, and targeting their expression inhibited IL-18-induced ASMC migration. TRAF3IP2 knockdown or RECK overexpression also reversed IL-18-induced ASMC proinflammatory phenotype switching as evidenced by the enhanced expression of the SMC markers ACTA2 and MYH11, and reduced expression of the proinflammatory markers Galectin 3, Olr1, VCAM, CCL2, IL-6, IL-8, and TNF-α. Importantly, preincubation with EF-24 markedly suppressed IL-18-induced SMC proliferation, MMP expression, migration and the proinflammatory phenotype switching. Together, these results suggest that the curcumin analog EF-24 has therapeutic potential in vascular inflammatory and proliferative diseases, including atherosclerosis, by differentially regulating TRAF3IP2 and RECK in vascular SMC.

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Novembre 2024

Abstract 4141280: Machine Learning Predicts 24-Hour Change in Decongestion Biomarkers in Hospitalized Heart Failure Patients

Circulation, Volume 150, Issue Suppl_1, Page A4141280-A4141280, November 12, 2024. Background:Despite recent advances, patients with heart failure (HF) often experience repeat hospitalizations and worsening clinical trajectories from inadequate decongestion. Evidence-based approaches for optimizing interventions in the acute hospital setting for patients with decompensated HF are needed. We evaluated whether machine learning (ML) models can accurately predict next-day levels for decongestion surrogates in hospitalized HF patients.Hypothesis:ML can accurately predict body weight, hematocrit, creatinine, and potassium values in the next 24 hours in hospitalized HF patients.Methods:We utilized national Veterans Affairs (VA) databases to study all patients admitted with HF from January 2014 to July 2022. Records including at least one value for at least one biomarker of interest (body weight, hematocrit, creatinine, and potassium) were included. Patients were randomly split into training (80%), validation (10%), and test (10%) datasets. We trained a recurrent neural network to predict each biomarker’s value on admission day n+1 using data until day n, simulating a scenario where a clinician monitors response to treatment (e.g., diuresis) over a 24-hour cycle. The model that performed best on the validation set was evaluated on the test set. The R2, mean absolute error (MAE), and feature importance were determined.Results:We identified 589,114 admissions involving 124,163 unique patients. The mean (SD) age on admission was 72 (10) years; 98% were male, 69% were white, and 25% were Black. The performance (R2, MAE) for each biomarker model was as follows: body weight (0.94, 6.15 lb.), creatinine (0.92, 0.21 mg/dL), hematocrit (0.86, 1.7%), and potassium (0.53, 0.27 mmol/L). The top predictive features across all models were intravenous or oral diuretic use, patient age, and diastolic blood pressure. The predicted 24-hour change in each biomarker based on total daily diuretic dose for five representative patients is demonstrated in the Figure.Conclusions:ML can accurately predict the 24-hour body weight, hematocrit, creatinine, and potassium values in hospitalized HF patients, suggesting the potential for AI to guide acute in-hospital management.

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Novembre 2024

Abstract 4136654: Urine Output Response to a Furosemide Infusion is Associated with Acute Kidney Injury in Infants Following Cardiac Surgery

Circulation, Volume 150, Issue Suppl_1, Page A4136654-A4136654, November 12, 2024. Background:Acute kidney injury (AKI) following cardiac surgery in infants is common and associated with longer mechanical ventilation times and length of stay. Prior studies have shown that a lack of responsiveness to bolus dose furosemide has been associated with increased incidence of AKI. However, these studies have excluded patients on continuous furosemide infusions who are often younger, more hemodynamically unstable, and at higher risk for AKI.Hypothesis:Decreased urine output after initiation of a furosemide infusion predicts development of AKI.Methods:A retrospective cohort study of infants (

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Novembre 2024

Abstract 4143839: Irregular Sleep Duration is Associated with Altered 24-Hour Heart Rate Profile in Patients Enrolled in Cardiac Rehabilitation

Circulation, Volume 150, Issue Suppl_1, Page A4143839-A4143839, November 12, 2024. Introduction:Sleep duration is now recognized as an important determinant of cardiovascular (CV) health. Recently, the CV implications of day-to-day variability in sleep duration have become apparent, with irregular sleep duration associated with increased risk of CV disease, including hypertension. However, the relationship between sleep duration variability and ambulatory blood pressure (BP) patterns in the general population or in patients with CV disease is unknown.Research Questions:We sought to investigate whether irregular sleep duration is associated with aberrant ambulatory BP or heart rate (HR) profiles in patients undergoing cardiac rehabilitation (CR).Methods:We recruited a sample of 42 patients with coronary artery disease enrolled in CR at Mayo Clinic Rochester. Participants underwent 24-hour ambulatory BP monitoring and sleep assessment including one week of wrist actigraphy and sleep diary prior to entering CR. Twenty-four hour, awake, and asleep averages were calculated for systolic BP, diastolic BP, and HR. Nocturnal dipping and morning surge were also computed for BP and HR. Sleep regularity was quantified by SD of actigraphy-derived sleep duration and irregular sleep duration was defined as SD >1 hour. Chi-square tests and Mann-Whitney U tests were used to compare groups.Results:Thirty-six participants (22% females, median age [25th,75thIQR] 66.5 [61,75.8] years, body mass index 31.7 [26.9,35.1] kg/m2) had valid actigraphy and ambulatory BP recordings. We found sleep duration SD >1 hour in 36% of them. Demographics and average sleep duration were similar between those with irregular and regular sleep duration (all Ps >0.11). Twenty-four-hour, awake and asleep HR values were comparable between groups (all Ps >0.26). Participants with irregular sleep duration exhibited lower nocturnal HR dipping (9.2 [3.1,11.6] % vs 12.9 [8.9,18.2] %, P=0.019) than their counterparts with regular sleep. Morning HR surge was also attenuated in patients with irregular sleep duration (3 [-1,9] bpm vs 10 [7,14] bpm, P=0.006). Ambulatory SBP and DBP measures did not differ significantly between groups (all Ps >0.17).Conclusions:High day-to-day variability in sleep duration is linked to blunted nocturnal dipping and morning surge in HR in patients with coronary artery disease enrolled in CR. Because altered ambulatory HR profile predicts unfavorable CV outcomes, evaluation of sleep patterns in the CR setting may yield important prognostic information.

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Novembre 2024

Abstract 4119908: Outcomes for heart failure patients with reduced ejection fraction attending emergency department and discharged within 24 hours versus those admitted patients in heart failure unit.

Circulation, Volume 150, Issue Suppl_1, Page A4119908-A4119908, November 12, 2024. Introduction:Heart failure (HF) is a clinical syndrome with increasing prevalence. Currently, there are extensive evidence-based therapies targeted at managing patients with heart failure and reduced ejection fraction (HFrEF) to improve outcomes. The National Heart Failure Audit shows the quality of inpatient care (specialist review, discharge medication etc) is related to outcome. This study aimed to evaluate the current practice at a London tertiary centre hospital in managing patients with heart failure and compared outcomes in patients who had a short course of admission (less than 1 day) with those who had a more prolonged course of admission.Method:Retrospective data was collected from a London tertiary centre hospital database for consecutive patients from Sep/2022 till Sep/2023. Statistical analysis was performed using Chi-Square test. The eligibility criteria included a new or previous diagnosis of HF with left ventricular ejection fraction (LVEF) < 40%. Patients were divided into two groups: Group A included 40 eligible patients who were admitted and discharged from the emergency department (ED) within 24 hours. Group B included 37 eligible patients who were admitted and discharged from the dedicated heart failure unit after 10-15 days of hospital admission.Results:In Group A, prescribing guideline-directed medical therapy (GDMT) was lower compared to Group B; Renin-Angiotensin-Aldosterone Inhibitors (47.50% vs. 94.59%), beta blockers (55% vs. 91.89%), mineralocorticoid receptor antagonists (12.50 %vs. 94.59%), and sodium-glucose co-transporter 2 inhibitors (15% vs. 89.19%). More patients in Group B received all four pillars of GDMT (86.49%) compared to Group A (5%). At 6-month follow-up,18.75% were on 4 GDMT in Group A versus 92% in group Group B. Re-admission within 6 months was higher in Group A (30%) compared to Group B (16.22%); however, the difference was not statistically significant (P value: 0.153). Higher mortality rates were observed in Group A (mortality rate: 20%) compared to Group B (mortality rate: 2.70%), with statistical significance (P value: 0.018).Conclusion:This study showed that HFrEF patients admitted to a specialist heart failure unit achieve higher rates of GDMT and have significantly improved outcomes compared to those who had a shorter inpatient stay and discharged from the emergency department. These findings underscore the high risks associated with rapid discharge from hospital on incomplete medical therapy.

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Novembre 2024

Randomised clinical trial of a 16 mg vs 24 mg maintenance daily dose of buprenorphine to increase retention in treatment among people with an opioid use disorder in Rhode Island: study protocol paper

Introduction
Buprenorphine is a highly effective treatment for opioid use disorder (OUD). However, provider observations and preliminary research suggest that the current standard maintenance dose may be insufficient for suppressing withdrawal and preventing cravings among people who use or have used fentanyl. Buprenorphine dosing guidelines were based on studies among people who use heroin and have not been formally re-evaluated since fentanyl became predominant in the unregulated drug supply. We aim to compare the effectiveness of a high (24 mg) vs standard (16 mg) maintenance daily dose of buprenorphine for improving retention in treatment, decreasing the use of non-prescribed opioids, preventing cravings and reducing opioid overdose risk in patients.

Methods and analysis
Adults who are initiating or continuing buprenorphine for moderate to severe OUD and have a recent history of fentanyl use (n=250) will be recruited at four outpatient substance use treatment clinics in Rhode Island. Patients continuing buprenorphine must be on doses of 16 mg or less and have ongoing fentanyl use to be eligible. Participants will be randomly assigned 1:1 to receive either a high (24 mg) or standard (16 mg) maintenance daily dose, each with usual care, and followed for 12 months to evaluate outcomes. Providers will determine the buprenorphine initiation strategy, with the requirement that participants reach the study maintenance dose within 7 days of randomisation. Providers may adjust the maintenance dose, if clinically needed, for participant safety. The primary study outcome is retention in buprenorphine treatment at 6 months postrandomisation, measured using clinical and statewide administrative data. Other outcomes include non-prescribed opioid use and opioid cravings (secondary), as well as non-fatal or fatal opioid overdose (exploratory).

Ethics and dissemination
This protocol was approved by the Brown Institutional Review Board (STUDY00000075). Results will be presented at conferences and published in peer-reviewed journals.

Trial registration number
NCT06316830.

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Novembre 2024

Device-Measured 24-Hour Movement Behaviors and Blood Pressure: A 6-Part Compositional Individual Participant Data Analysis in the ProPASS Consortium

Circulation, Ahead of Print. BACKGROUND:Blood pressure (BP)–lowering effects of structured exercise are well-established. Effects of 24-hour movement behaviors captured in free-living settings have received less attention. This cross-sectional study investigated associations between a 24-hour behavior composition comprising 6 parts (sleeping, sedentary behavior, standing, slow walking, fast walking, and combined exercise-like activity [eg, running and cycling]) and systolic BP (SBP) and diastolic BP (DBP).METHODS:Data from thigh-worn accelerometers and BP measurements were collected from 6 cohorts in the Prospective Physical Activity, Sitting and Sleep consortium (ProPASS) (n=14 761; mean±SD, 54.2±9.6 years). Individual participant analysis using compositional data analysis was conducted with adjustments for relevant harmonized covariates. Based on the average sample composition, reallocation plots examined estimated BP reductions through behavioral replacement; the theoretical benefits of optimal (ie, clinically meaningful improvement in SBP [2 mm Hg] or DBP [1 mm Hg]) and minimal (ie, 5-minute reallocation) behavioral replacements were identified.RESULTS:The average 24-hour composition consisted of sleeping (7.13±1.19 hours), sedentary behavior (10.7±1.9 hours), standing (3.2±1.1 hours), slow walking (1.6±0.6 hours), fast walking (1.1±0.5 hours), and exercise-like activity (16.0±16.3 minutes). More time spent exercising or sleeping, relative to other behaviors, was associated with lower BP. An additional 5 minutes of exercise-like activity was associated with estimated reductions of –0.68 mm Hg (95% CI, –0.15, –1.21) SBP and –0.54 mm Hg (95% CI, –0.19, 0.89) DBP. Clinically meaningful improvements in SBP and DBP were estimated after 20 to 27 minutes and 10 to 15 minutes of reallocation of time in other behaviors into additional exercise. Although more time spent being sedentary was adversely associated with SBP and DBP, there was minimal impact of standing or walking.CONCLUSIONS:Study findings reiterate the importance of exercise for BP control, suggesting that small additional amounts of exercise are associated with lower BP in a free-living setting.

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Novembre 2024

24-hour movement behaviours in the early years, potential behavioural determinants and prospective associations with growth, motor and social-emotional development: the My Little Moves study protocol

Introduction
The early years are a critical period for establishing healthy 24-hour movement behaviours (physical activity, sedentary behaviour and sleep), yet studies examining prospective associations between all 24-hour movement behaviours and young children’s growth and development are lacking. The My Little Moves study aims to (1) examine the prospective association between 24-hour movement behaviours of young children (ie, 0–4 years) and their growth, motor and social–emotional development; and (2) explore potential determinants of young children’s 24-hour movement behaviours from an ecological perspective, to inform public health strategies aimed at promoting healthy behaviours and development.

Methods and analysis
My Little Moves is a longitudinal observational cohort study, with data collection at baseline, and after 9 and 18 months follow-up. Data are collected in three subcohorts. In all subcohorts, 24-hour movement behaviours are assessed by parent-report. Additionally in subcohort 1, data on potential determinants are collected by parental questionnaires, including child, parental and environmental factors. In subcohort 2, social–emotional development is assessed using the Dutch version of the Bayley Scales of Infant and Toddler Development-third edition (Bayley-III-NL) Social Emotional Scale. In subcohort 3, data on height and weight, gross motor development, using the Bayley-III-NL Gross Motor Scale, and 7 consecutive days of 24-hour accelerometer data are collected. Hybrid model analyses are used to assess the prospective associations of 24-hour movement behaviours with young children’s growth and development. Potential determinants of young children’s 24-hour movement behaviours are explored using regression analysis.

Ethics and dissemination
The Medical Ethics Committee of the VU University Medical Center approved the protocol for the My Little Moves study (2022.0020). The results of this study will be disseminated through the network of all authors, to inform public health strategies for promoting healthy 24-hour movement behaviours and contribute to the evidence-base of recommendations for ideal 24-hour movement behaviours in young children.

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Ottobre 2024

CT-Guided Thrombectomy for Large Core Stroke Up to 24 Hours

Prevailing dogma in the treatment of acute ischemic stroke has long dictated that endovascular reperfusion of large infarcted areas distal to an occluded large intracranial artery is detrimental to patient outcomes. These concerns were rooted in the presumed deleterious effects of reperfusion, most notably symptomatic intracranial hemorrhage, and in the constrained opportunity to improve outcome due to the substantial infarction already present. Indeed, the initial waves of positive randomized endovascular stroke trials addressing thrombectomy in the early time window (0-6 hours) and with imaging selection in the late time window (6-24 hours) generally excluded from enrollment patients with a large baseline infarct (core). However, among the relatively small number of patients with large core infarcts inadvertently enrolled in these trials, analyses suggested an acceptable safety profile and potential benefit of thrombectomy. These rather unexpected findings led to the launch of several randomized trials prospectively assessing the efficacy and safety of thrombectomy in patients with acute ischemic stroke presenting with a large core and proximal large vessel occlusion in the anterior circulation. Across these trials, characterization of the infarcted brain has occurred with different imaging modalities using different definitions for what constitutes a large core, but common to all trials has been a requirement that infarction already be present on computed tomography (CT) or magnetic resonance imaging (MRI) in at least 5 of the 10 regions of the Alberta Stroke Program Early CT Score (ASPECTS) scale.

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Ottobre 2024