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Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Jean-Pierre Moreau is an employee of Recherche Continuum Research and was contracted by Milestone Pharmaceuticals to design and monitor the study. Charles River Laboratories was contracted by Milestone Pharmaceuticals to perform this study. Douglas Wight was an employee of Milestone Pharmaceuticals at the time of this study. Veronique Boulanger was an employee of Milestone Pharmaceuticals at the time of this study.

Background: Stronger social and emotional well-being during primary school is positively associated with the health and educational outcomes of young people. However, there is little evidence on which programmes are the most effective for improving social and emotional well-being., Objective: The objective was to rigorously evaluate the Social and Emotional Education and Development (SEED) intervention process for improving pupils' social and emotional well-being., Design: This was a stratified cluster randomised controlled trial with embedded process and economic evaluations. Thirty-eight primary schools were randomly assigned to the SEED intervention or to the control group. Hierarchical regression analysis allowing for clustering at school learning community level was conducted in R (statistical package)., Setting: The SEED intervention is a whole-school intervention; it involved all school staff and two cohorts of pupils, one starting at 4 or 5 years of age and the second starting at 8 or 9 years of age, across all 38 schools., Participants: A total of 2639 pupils in Scotland., Intervention: The SEED intervention used an iterative process that involved three components to facilitate selection and implementation of school-based actions: (1) questionnaire completion, (2) benchmarked feedback to all staff and (3) reflective discussions (all staff and an educational psychologist)., Main Outcome Measure: The primary outcome was pupils' Strengths and Difficulties Questionnaire-Total Difficulties Score when pupils were 4 years older than at baseline., Results: The primary outcome, pupils' Strengths and Difficulties Questionnaire-Total Difficulties Score at follow-up 3, showed improvements for intervention arm pupils, compared with those in the control arm [relative risk -1.30 (95% confidence interval -1.87 to -0.73), standardised effect size -0.27 (95% confidence interval -0.39 to -0.15)]. There was no evidence of intervention effects according to deprivation: the results were significant for both affluent and deprived pupils. Subgroup analysis showed that all effect sizes were larger for the older cohort, particularly boys [relative risk -2.36 (95% confidence interval -3.62 to -1.11), standardised effect size -0.42 (95% confidence interval -0.64 to -0.20)]. Although there was no statistically significant difference in incremental cost and quality-adjusted life-years, the probability that the intervention is cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year was high, at 88%. Particularly valued mechanisms of the SEED intervention were its provision of time to reflect on and discuss social and emotional well-being and its contribution to a culture of evaluating practice., Limitations: It was a challenge to retain schools over five waves of data collection., Conclusions: This trial demonstrated that the SEED intervention is an acceptable, cost-effective way to modestly improve pupil well-being and improve school climate, particularly for older boys and those with greater levels of psychological difficulties. It was beneficial during the transition from primary to secondary school, but this diminished after 6 years. The SEED intervention can be implemented alongside existing systems for addressing pupil well-being and can be complementary to other interventions., Future Work: Assess whether or not the SEED intervention has a beneficial impact on academic attainment, is transferable to other countries and other organisational settings, would be strengthened by adding core training elements to the intervention process and is transferable to secondary schools. Understand the gender differences illustrated by the outcomes of this trial. Conduct further statistical research on how to handle missing data in longitudinal studies of complex social interventions., Trial Registration: This trial is registered as ISRCTN51707384., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 10/3006/13) and is published in full in Public Health Research ; Vol. 12, No. 6. See the NIHR Funding and Awards website for further award information.

Background: There is a growing need for interventions that reduce both violence against children and intimate partner violence in low- and middle-income countries. However, few parenting interventions deliberately address this link. We tested the feasibility of a 16-session group-based parenting programme, Parenting for Respectability, in semi-rural Ugandan communities., Methods: This was a pre-post study with parents and their children (N = 484 parents; 212 children)., Results: Pre-post comparisons found large effects for parent-reported reduced harsh parenting (Cohen's f2 = 0.41 overall; f2 = 0.47 (among session attendees); with an overall reduction of 26% for harsh parenting. Session attendees reported higher reductions than non-attendees (p = 0.014), and male caregivers reported higher reductions than female caregivers (p<0.001). Children also reported reduced harsh parenting by attending fathers (f2 = 0.64 overall; f2 = 0.60) and attending mothers (f2 = 0.56 overall; f2 = 0.51); with reduction in harsh parenting ranging between 27% to 29% in the various categories. Overall, spousal violence reduced by 27% (f2 = 0.19 overall; f2 = 0.26 (among session attendees). Both parents and children reported reduced dysfunctional parent relationships; parents: f2 = 0.19 overall; f2 = 0.26 (among session attendees); and children: f2 = 0.35 overall; f2 = 0.32 (for attending parents); with reductions ranging between 22% to 28%. Parents who attended more than 50% of the program reported greater effects on reduced dysfunctional relationships than those who attended less than half of the program (B = -0.74, p = 0.013). All secondary outcomes were improved with f2 ranging between 0.08 and 0.39; and improvements ranging between 6% and 28%., Conclusion: Results suggest the importance of more rigorous testing to determine program effectiveness., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Siu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Etripamil, a fast-acting nondihydropyridine L-type calcium channel blocker, is under investigation for potential self-administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double-blind studies: Study MSP-2017-1096 (sequential dose-escalation, crossover study design, n = 64) and NODE-102 (single dose, 4-way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5-8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4-7 minutes of doses of 60 mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60 mg or greater. The mean terminal half-life ranged from about 1.5 hours with 60 mg to about 2.5-3 hours for the 70- and 105-mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60 mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers., (© 2024 Milestone Pharma. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Having a good start in life during pregnancy and infancy has been shown to be important for living both a healthy life and a longer life. Despite the introduction of many policies for the early-years age group, including voucher schemes, with the aim of improving nutrition, there is limited evidence of their impact on health., Objectives: To assess the effectiveness of the Healthy Start voucher scheme on infant, child and maternal outcomes, and to capture the lived experiences of the Healthy Start voucher scheme for low-income women., Design: This was a natural experiment study using existing data sets, linked to routinely collected health data sets, with a nested qualitative study of low-income women and an assessment of the health economics., Setting: Representative sample of Scottish children and UK children., Participants: Growing Up in Scotland cohort 2 ( n = 2240), respondents to the 2015 Infant Feeding Study ( n = 8067) and a sample of 40 participants in the qualitative study., Interventions: The Health Start voucher, a means-tested scheme that provides vouchers worth £3.10 per week to spend on liquid milk, formula milk, fruit and vegetables., Main Outcome Measures: Infant and child outcomes - breastfeeding initiation and duration; maternal outcomes - vitamin use pre and during pregnancy., Results: The exposed group were women receiving the Healthy Start voucher (R), with two control groups: eligible and not claiming the Healthy Start voucher (E) and nearly eligible. There was no difference in vitamin use during pregnancy for either comparison (receiving the Healthy Start voucher, 82%; eligible and not claiming the Healthy Start voucher, 86%; p = 0.10 vs. receiving the Healthy Start voucher, 87%; nearly eligible, 88%; p = 0.43) in the Growing Up in Scotland cohort. Proportions were similar for the Infant Feeding Study cohort (receiving the Healthy Start voucher, 89%; eligible and not claiming the Healthy Start voucher, 86%; p = 0.01 vs. receiving the Healthy Start voucher, 89%; nearly eligible, 87%; p = 0.01); although results were statistically significantly different, these were small effect sizes. There was no difference for either comparison in breastfeeding initiation or breastfeeding duration in months in Growing Up in Scotland, but there was a negative effect of the Healthy Start voucher in the Infant Feeding Survey. This contrast between data sets indicates that results are inconclusive for breastfeeding. The qualitative study found that despite the low monetary value the women valued the Healthy Start voucher scheme. However, the broader lives of low-income women are crucial to understand the constraints to offer a healthy diet., Limitations: Owing to the policy being in place, it was difficult to identify appropriate control groups using existing data sources, especially in the Infant Feeding Study., Conclusions: As the Healthy Start voucher scheme attempts to influence health behaviour, this evaluation can inform other policies aiming to change behaviour and use voucher incentives. The null effect of Healthy Start vouchers on the primary outcomes may be due to the value of the vouchers being insufficient to change the broader lives of low-income women to offer a healthy diet., Future Work: The methods developed to undertake an economic evaluation alongside a natural experiment using existing data can be used to explore the cost-effectiveness of the Healthy Start voucher scheme., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research ; Vol. 11, No. 11. See the NIHR Journals Library website for further project information.

Background: Pharmacologic termination of paroxysmal supraventricular tachycardia (PSVT) often requires medically supervised intervention. Intranasal etripamil, is an investigational fast-acting, nondihydropyridine, L-type calcium channel blocker, designed for unsupervised self-administration to terminate atrioventricular nodal-dependent PSVT. Phase 2 results showed potential safety and efficacy of etripamil in 104 patients with PSVT., Methods: NODE-301, a phase 3, multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of etripamil nasal spray administered, unsupervised in patients with symptomatic sustained PSVT. After a medically supervised etripamil test dose while in sinus rhythm, patients were randomized 2:1 to receive etripamil 70 mg or placebo. When PSVT symptoms developed, patients applied a cardiac monitor and attempted a vagal maneuver; if symptoms persisted, they self-administered blinded treatment. An independent Adjudication Committee reviewed continuous electrocardiogram recordings. The primary efficacy endpoint was termination of adjudicated PSVT within 5 hours after study drug administration., Results: NODE-301 accrued 156 positively adjudicated PSVT events treated with etripamil (n=107) or placebo (n=49). The hazard ratio for the primary endpoint, time-to-conversion to sinus rhythm during the 5-hour observation period, was 1.086 (95% CI, 0.726-1.623; P =0.12). In predefined sensitivity analyses, etripamil effects (compared with placebo) occurred at 3, 5, 10, 20, and 30 minutes ( P <0.05). For example, at 30 minutes, there was a 53.7% of SVT conversion in the treatment arm compared to 34.7% in the placebo arm (hazard ratio, 1.87 [95% CI, 1.09-3.22]; P =0.02). Etripamil was well tolerated; adverse events were mainly related to transient nasal discomfort and congestion (19.6% and 8.0%, respectively, of randomized treatment-emergent adverse events., Conclusions: Although the primary 5-hour efficacy endpoint was not met, analyses at earlier time points indicated an etripamil treatment effect in terminating PSVT. Etripamil self-administration during PSVT was safe and well tolerated. These results support continued clinical development of etripamil nasal spray for self-administration during PSVT in a medically unsupervised setting., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03464019.

Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT., (Copyright © 2022. Published by Elsevier Inc.)

Purpose : To develop a culturally-sensitive intervention for the early prevention of gender-based violence (GBV) in Uganda. Methods : Programme design followed the 6SQuID model of intervention development and multi-sectorial advice. A formative evaluation was conducted in two communities with six groups and 138 participants. Findings : Four familial predictors of GBV were identified as potentially malleable: poor parent-child attachment, harsh parenting, inequitable gendered socialization and parental conflict. A community-based parenting programme was developed to address them. Its programme theory incorporates Attachment Theory, the concept that positive behavioural control develops emotional control, and Social Learning Theory. Its rationale, structure and content are presented using the TIDieR checklist. A formative evaluation showed the programme to be widely acceptable, culturally appropriate, and perceived to be effective, but also identified challenges. Conclusion : The careful development of this community-based parenting programme shows promise for the early prevention of GBV., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)