Density functional theory and enzyme studies support interactions between angiotensin receptor blockers and angiotensin converting enzyme-2: Relevance to coronavirus 2019.

The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.

Adaptation of complex interventions for people with long-term conditions: a scoping review.

Adaptation seeks to transfer and implement healthcare interventions developed and evaluated in one context to another. The aim of this scoping review was to understand current approaches to the adaptation of complex interventions for people with long-term conditions (LTCs) and to identify issues for studies performed in low- and middle-income countries (LMICs). Bibliographic databases were searched from 2000 to October 2022. This review involved five stages: (i) definition of the research question(s); (ii) identifying relevant studies; (iii) study selection; (iv) data charting; and (v) data synthesis. Extraction included an assessment of the: rationale for adaptation; stages and levels of adaptation; use of theoretical frameworks, and quality of reporting using a checklist based on the 2021 ADAPT guidance. Twenty-five studies were included from across 21 LTCs and a range of complex interventions. The majority (16 studies) focused on macro (national or international) level interventions. The rationale for adaptation included intervention transfer across geographical settings [high-income country (HIC) to LMIC: six studies, one HIC to another: eight studies, one LMIC to another: two studies], or transfer across socio-economic/racial groups (five studies), or transfer between different health settings within a single country (one study). Overall, studies were judged to be of moderate reporting quality (median score 23, maximum 46), and typically focused on early stages of adaptation (identification and development) with limited outcome evaluation or implementation assessment of the adapted version of the intervention. Improved reporting of the adaptation for complex interventions targeted at LTCs is needed. Development of future adaptation methods guidance needs to consider the needs and priorities of the LMIC context.

Limited finance and human capacity may reduce access to new treatments for people with long-term conditions. This is especially true in low- and middle-income countries. One solution is to transfer treatments developed in one place for use in other areas. This paper provides a current summary of international research on adapting treatments. We used a checklist to assess study reporting quality, based on published advice. Our findings showed the need for better conduct and reporting of adaptation. Future guidance should consider the specific needs of low- and middle-income countries.

Structural Features Influencing the Bioactive Conformation of Angiotensin II and Angiotensin A: Relationship between Receptor Desensitization, Addiction, and the Blood-Brain Barrier.

The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT1R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (<5%) in bioactivity, implicating a specialized function for this cluster. In contrast, angiotensin A (ARVYIHPF; AngA) has reduced bioactivity at AT1R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood-brain barrier more readily than bisartans, are the preferred drug candidates.

Development of a school-based programme for mental health promotion and prevention among adolescents in Nepal and South Africa.

Introduction: Adolescence is a critical time for mental health promotion and prevention and establishing healthy behaviours. Implementing universal, school-based psychosocial interventions can improve short- and long-term health trajectories for adolescents. While these interventions may offer important opportunities for fostering skills and relationships, few school-based interventions have been developed for and tested in low- and middle-income countries (LMICs) where adolescent mental health needs may be significant and under-served. This manuscript details the development of a multi-component, universal school-based intervention, Health Action in ScHools for a Thriving Adolescent Generation (HASHTAG), for adolescents aged 12-15 years in Nepal and South Africa. Methods and results: We describe HASHTAG's development over four phases, combining methods and results as each phase was iteratively conducted between 2018 and 2021. Phase 1 included a systematic review and components analysis, building from WHO guidelines for adolescent mental health. Seven components were strongly supported by the evidence: emotional regulation, stress management, mindfulness, problem-solving, interpersonal skills, assertiveness training, and alcohol and drug education. Phase 2 encompassed site selection, theory of change development, and formative research engagements; research teams in each site engaged adolescents and key adult stakeholders to identify priorities for intervention. Stakeholders voiced preferences for external facilitators and key content and delivery for intervention sessions. These findings informed Phase 3, a draft manual of HASHTAG, including a whole-school component, called Thriving Environment in Schools, and a classroom-based, six-session component, Thrive Together. In Phase 4, participants engaged in consultative workshops to review and contextualise content by country, preparing HASHTAG for implementation in a feasibility trial. Minor adaptations were made in Nepal, including using school nurses and adjusting take-home materials; both country's workshops identified practical considerations for implementing activities. Conclusions: HASHTAG was designed around core evidence-based components to increase translatability across LMICs, while enabling country-specific tailoring to enhance feasibility. Future research will test whether this multi-component, whole-school approach can improve adolescent mental health.

Novel benzimidazole angiotensin receptor blockers with anti-SARS-CoV-2 activity equipotent to that of nirmatrelvir: computational and enzymatic studies.

BACKGROUND: Hypertension worsens outcomes in SARS-CoV-2 patients. Sartans, a type of antihypertensive angiotensin receptor blocker-(ARB), reduce COVID-19 morbidity and mortality by targeting angiotensin-converting enzyme-2 (ACE2). This study aimed to evaluate the antiviral and antihypertensive effects of nirmatrelvir, commercial sartans (candesartan, losartan, and losartan carboxylic (Exp3174)), and newly synthesized sartans (benzimidazole-N-biphenyl carboxyl (ACC519C) and benzimidazole-N-biphenyl tetrazole (ACC519T)), compared to nirmatrelvir, the antiviral component of Paxlovid. RESEARCH DESIGN AND METHODS: Surface plasmon resonance (SPR) and enzymatic studies assessed drug effects on ACE2. Antiviral abilities were tested with SARS-CoV-2-infected Vero E6 cells, and antihypertensive effects were evaluated using angiotensin II-contracted rabbit iliac arteries. RESULTS: Benzimidazole-based candesartan and ACC519C showed antiviral activity comparable to nirmatrelvir (95% inhibition). Imidazole-based losartan, Exp3174, and ACC519T were less potent (75%-80% and 50%, respectively), with Exp3174 being the least effective. SPR analysis indicated high sartans-ACE2 binding affinity. Candesartan and nirmatrelvir combined had greater inhibitory and cytopathic effects (3.96%) than individually (6.10% and 5.08%). ACE2 enzymatic assays showed varying effects of novel sartans on ACE2. ACC519T significantly reduced angiotensin II-mediated contraction, unlike nirmatrelvir and ACC519T(2). CONCLUSION: This study reports the discovery of a new class of benzimidazole-based sartans that significantly inhibit SARS-CoV-2, likely due to their interaction with ACE2.

Participatory translational science of neurodivergence: model for attention-deficit/hyperactivity disorder and autism research.

BACKGROUND: There are increasing calls for neurodivergent peoples' involvement in research into neurodevelopmental conditions. So far, however, this has tended to be achieved only through membership of external patient and public involvement (PPI) panels. The Regulating Emotions - Strengthening Adolescent Resilience (RE-STAR) programme is building a new participatory model of translational research that places young people with diagnoses of attention-deficit hyperactivity disorder (ADHD) and autism at the heart of the research team so that they can contribute to shaping and delivering its research plan. AIMS: To outline the principles on which the RE-STAR participatory model is based and describe its practical implementation and benefits, especially concerning the central role of members of the Youth Researcher Panel (Y-RPers). METHOD: The model presented is a culmination of a 24-month process during which Y-RPers moved from advisors to co-researchers integrated within RE-STAR. It is shaped by the principles of co-intentionality. The account here was agreed following multiple iterative cycles of collaborative discussion between academic researchers, Y-RPers and other stakeholders. RESULTS: Based on our collective reflections we offer general guidance on how to effectively integrate young people with diagnoses of ADHD and/or autism into the core of the translational research process. We also describe the specific theoretical, methodological and analytical benefits of Y-RPer involvement in RE-STAR. CONCLUSIONS: Although in its infancy, RE-STAR has demonstrated the model's potential to enrich translational science in a way that can change our understanding of the relationship between autism, ADHD and mental health. When appropriately adapted we believe the model can be applied to other types of neurodivergence and/or mental health conditions.

Process evaluation of an integrated community-based intervention for promoting health equity in children in a new residential development area.

BACKGROUND: Reducing health inequities for children from a disadvantaged background is an important task in public health. While intersectoral partnerships are a promising way to achieve this, few studies have examined the factors influencing the success of these interventions. In this study, we conducted a process evaluation of the integrated community-based intervention Präventionskette Freiham that the city of Munich, Germany, has implemented in a new residential development area. The aim was to investigate the implementation process as well as barriers and facilitators. METHODS: Following a mixed methods approach, we collected data from different core groups making up Präventionskette Freiham from April 2020 to August 2022, exploring their perspective on the implementation process. We conducted repeated qualitative interviews with the network coordinators and eleven local professionals from institutions engaged with or relevant for the intervention. We also undertook a focus group with four members of the advisory group representing the three municipal departments guiding the intervention. Ego-centered network maps were drawn by the network coordinators to chart the development of the network. Subsequently, we also conducted an online survey with local network members. RESULTS: At the early stage of the implementation process, the intervention was able to integrate actors from different sectors, serving as a platform for mutual exchange. However, the network produced limited output. According to the interviews, this may be mainly attributable to the early development status of the area. We identified seven topics that may act as facilitators or barriers to implementation of Präventionskette Freiham: (1) availability of resources, (2) political and administrative support, (3) the network coordinators, (4) network-internal processes, (5) trans-institutional cooperation, (6) perceived benefits of engagement, and (7) the output of the network. CONCLUSIONS: The early development status of the area was a challenge for the intervention. This emphasizes the need to carefully consider context when planning and implementing integrated community-based public health interventions in new residential development areas.

Satisfaction with remote consultations in primary care during COVID-19: a population survey of UK adults.

BACKGROUND: Mode of access to primary care changed during the COVID-19 pandemic; remote consultations became more widespread. With remote consultations likely to continue in UK primary care, it is important to understand people's perceptions of remote consultations and identify potential resulting inequalities. AIM: To assess satisfaction with remote GP consultations in the UK during the COVID-19 pandemic and identify demographic variation in satisfaction levels. DESIGN AND SETTING: A cross-sectional survey from the second phase of a large UK-based study, which was conducted during the COVID-19 pandemic. METHOD: In total, 1426 adults who self-reported having sought help from their doctor in the past 6 months completed an online questionnaire (February to March 2021). Items included satisfaction with remote consultations and demographic variables. Associations were analysed using multivariable regression. RESULTS: A novel six-item scale of satisfaction with remote GP consultations had good psychometric properties. Participants with higher levels of education had significantly greater satisfaction with remote consultations than participants with mid-level qualifications (B = -0.82, 95% confidence interval [CI] = -1.41 to -0.23) or those with low or no qualifications (B = -1.65, 95% CI = -2.29 to -1.02). People living in Wales reported significantly higher satisfaction compared with those living in Scotland (B = -1.94, 95% CI = -3.11 to -0.78), although caution is warranted due to small group numbers. CONCLUSION: These findings can inform the use and adaptation of remote consultations in primary care. Adults with lower educational levels may need additional support to improve their experience and ensure equitable care via remote consultations.

Family-focused intervention to promote adolescent mental health and well-being in Moldova and North Macedonia (FLOURISH): feasibility study protocol.

INTRODUCTION: Family-Focused Adolescent & Lifelong Health Promotion (FLOURISH) project will adapt, implement and evaluate a programme to support adolescent mental health and well-being through strategies, such as strengthening parenting practices, adolescent-caregiver relationships, adolescent and parent socioemotional skills, and social support. METHODS AND ANALYSIS: The project will focus on adolescents aged 10-14 years and their caregivers in North Macedonia and Moldova. The countries were selected based on implementation readiness of two organisations and a need for accessible evidence-informed services to help mitigate health risks due to economic, social and political challenges. Parenting for Lifelong Health (PLH) for Parents and Teens is a family-based programme developed for low-resource settings. PLH has been adapted with input from advisory groups. The programme includes additional components to strengthen impacts on adolescents: adolescent mental health tools, based on UNICEF's Helping Adolescents Thrive, adolescent peer support and participation booster. This pilot is first of three study phases. The pilot will be a feasibility testing of the adapted intervention and the assessment and implementation procedures to determine further refinements. The pilot will examine if the adapted programme is acceptable for adolescents, their families and providers, explore contextual factors relevant to embedding this programme into longer-term scale-up and investigate whether the programme can be delivered with fidelity and participation; whether the participants report changes in adolescent emotional and behavioural problems, well-being and other outcomes; and whether the study tools are feasible and appropriate. Pre-post adolescent and caregiver questionnaires will provide outcome data. Process evaluation will include attendance and fidelity data, and focus groups. We will examine delivery cost and resource requirements. ETHICS AND DISSEMINATION: The study was approved at the University of Klagenfurt (Austria), Medical Faculty at St. Cyril and Methodius University (North Macedonia) and National Committee of Ethical Expertise for Clinical Trials (Moldova). Through stakeholder engagement and dissemination, FLOURISH will advance scale-up of open-source family interventions. TRIAL REGISTRATION NUMBER: Trial registration: ID101095528; project page: https://www.flourish-study.org/about.html; https://www.linkedin.com/company/flourish-study/.

Barriers and facilitators to engaging in smoking cessation support among lung screening participants.

INTRODUCTION: Embedded smoking cessation support within lung cancer screening is recommended in the UK; however, little is known about why individuals decline smoking cessation support in this setting. This study identified psychosocial factors that influence smoking cessation and quit motivation among those who declined support for quitting smoking alongside lung cancer screening. METHODS: Qualitative interviews conducted between August 2019 - April 2021 with thirty adults with a smoking history, recruited from the Yorkshire Lung Screening Trial. Participants had declined smoking cessation support. Verbatim interview transcripts were thematically analysed. RESULTS: Fifty percent of participants were male and the majority were from the most deprived groups. Participants reported low motivation and a variety of barriers to stopping smoking. Participants described modifiable behavioural factors that influenced their quit motivation including self-efficacy, perceived effectiveness of stop-smoking services including smoking cessation aids, risk-minimising beliefs, lack of social support, absence of positive influences on smoking and beliefs about smoking/smoking cessation. Broader contextual factors included social isolation and stigma, COVID-19 and comorbid mental and physical health conditions that deterred smoking cessation. CONCLUSIONS: To encourage engagement in smoking cessation support during lung cancer screening, interventions should seek to encourage positive beliefs about the effectiveness of smoking cessation aids and increase confidence in quitting as part of supportive, person-centred care. Interventions should also acknowledge the wider social determinants of health among the lung screening-eligible population. IMPLICATIONS: This study provides an in-depth understanding of the beliefs surrounding smoking and smoking cessation and further potential psychosocial factors that influence those attending lung cancer screening. Many of the barriers to smoking cessation found in the present study are similar to those outside of a lung screening setting however this work offers an understanding of potential facilitators that should be considered in future lung screening programmes.

Trends in adolescent emotional problems in Wales between 2013 and 2019: the contribution of peer relationships.

BACKGROUND: Epidemiological evidence shows a substantial increase in adolescent emotional problems in many countries, but reasons for this increase remain poorly understood. We tested change in emotional problems in a national sample of young people in Wales in 2013, 2017 and 2019 using identical symptom screens, and examined whether trends were accounted for by changes in youth friendship quality and bullying. METHODS: The present study of 230,735 11-16-year olds draws on repeat cross-sectional data obtained on three occasions (2013, 2017 and 2019) in national school-based surveys in Wales (conducted by the School Health Research Network). Emotional problems were assessed with a brief validated symptom screen (the SCL-4). RESULTS: There was a significant increase in emotional problem scores between 2013 and 2019 (b[95% CI] = 1.573 [1.380, 1.765]). This increase was observed for all ages and was more pronounced for girls than boys (interaction b [95% CI] = 0.229 [0.004, 0.462]) and for young people from less affluent families (interaction b [95% CI] = -0.564[-0.809, -0.319]). Of the total sample, 14.2% and 5.7% reported frequent face-to-face and cyberbullying respectively. There were modest decreases in friendship quality and increases in rates of bullying between 2013 and 2019, but accounting for these changes did not attenuate estimates of the population-level increase in emotional problems. CONCLUSIONS: This study provides evidence of a substantial increase in emotional problems among young people in Wales, particularly for young people from less affluent backgrounds. Changes in bullying or friendship quality did not explain this increase.

Existence of Quantum Pharmacology in Sartans: Evidence in Isolated Rabbit Iliac Arteries.

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N'-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K+)2), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K+)2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K+)2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K+)2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.

Hospital-based violence prevention programmes in South Wales Emergency Departments: A process evaluation protocol.

BACKGROUND: Addressing violence related harm is a global public health priority. While violence is primarily managed in the criminal justice system, healthcare supports and manages those injured by violence. Emergency Departments (EDs), the primary destination for those seriously injured, have emerged as a candidate location for violence prevention initiatives. There is limited evaluation of ED-based violence prevention, and a lack of guidance for the implementation and delivery of them. Nurse-led Violence Prevention Teams (VPTs) have been developed and implemented in two EDs in Wales, UK. This protocol describes methods used in the process evaluation of these VPTs. AIM: To understand how VPTs function, how they were implemented, and mechanisms of impact, as well as the exploration of wider contextual factors influencing their function. METHODS: Adopting a critical realist approach and informed by the Medical Research Council (MRC) guidance for process evaluations, the process evaluation will employ qualitative methods to collect and analyse data: a scoping review of evidence of effectiveness that considers the causal mechanisms underpinning violence; a documentary analysis to determine operational considerations concerning the development, implementation and delivery of the VPTs; a descriptive analysis of routine ED data to characterise the prevalence of violence-related attendances in each ED; interviews with professional stakeholders (N = 60) from the violence prevention ecologies in which the VPTs are embedded. DISCUSSION: This protocol outlines a process evaluation of a novel, nurse led violence prevention intervention. Findings will be used to inform policy makers' decision making on whether and how VPTs should be used in practice in other EDs across the UK, and the extent that a single operational model should be adjusted to address the local characteristic of violence. To the authors knowledge, this is the first process evaluation of a UK-based, nurse led Emergency Department Violence Prevention Team. TRIAL REGISTRATION: Protocol registration ISRCTN: 15286575. Registered 13th March, 2023.

W254 in furin functions as a molecular gate promoting anti-viral drug binding: Elucidation of putative drug tunneling and docking by non-equilibrium molecular dynamics.

Furins are serine endoproteases that process precursor proteins into their biologically active forms, and they play essential roles in normal metabolism and disease presentation, including promoting expression of bacterial virulence factors and viral pathogenesis. Thus, furins represent vital targets for development of antimicrobial and antiviral therapeutics. Recent experimental evidence indicated that dichlorophenyl (DCP)-pyridine "BOS" drugs (e.g., BOS-318) competitively inhibit human furin by an induced-fit mechanism in which tryptophan W254 in the furin catalytic cleft (FCC) functions as a molecular gate, rotating nearly 180o through a steep energy barrier about its chi-1 dihedral to an "open" orientation, exposing a buried (i.e., cryptic) hydrophobic pocket 1. Once exposed, the non-polar DCP group of BOS-318, and similar halo-phenyl groups of analogs, enter the cryptic pocket, stabilizing drug binding. Here, we demonstrate flexible-receptor docking of BOS-318 (and various analogs) was unable to emulate the induced-fit motif, even when tryptophan was replaced with less bulky phenylalanine or glycine. While either substitution allowed access to the hydrophobic pocket for most ligands tested, optimal binding was observed only for W254, inferring a stabilizing effect of the indole sidechain. Furthermore, non-equilibrium steered molecular dynamics (sMD) in which the bound drugs (or their fragments) were extracted from the FCC did not cause closure of the open W254 gate, consistent with the thermodynamic stability of the open or closed W254 orientations. Finally, interactive molecular dynamics (iMD) revealed two putative conduits of drug entry and binding into the FCC, each coupled with W254 dihedral rotation and opening of the cryptic pocket. The iMD simulations further revealed ligand entry and binding in the FCC is likely driven in part by energy fluxes stemming from disruption and re-formation of ligand and protein solvation shells during drug migration from the solution phase into the FCC.

A mixed-methods process evaluation of the feasibility and acceptability of involving community and peer role models within a physical activity intervention for primary-school-aged girls (the CHARMING study).

BACKGROUND: Role models have been identified as a potential means to tackle the persisting low levels of physical activity among young girls. The aim of this research was to explore the involvement of community- and peer role models within the CHARMING (CHoosing Active Role Models to INspire Girls) intervention, an intervention which aims to increase and sustain physical activity among 9-10-year-old girls. The research questions were, is it feasible and acceptable to recruit role models? and what are the perceived barriers and facilitators to the inclusion of peer role models within the intervention? METHODS: A mixed methods process evaluation was embedded within a larger feasibility study, involving three secondary schools and four adjoining primary schools in South Wales, United Kingdom. One-to-one interviews were conducted with teachers (N = 10) across the seven schools and community role models (N = 10). Focus groups were conducted with 18 peer role models (older girls from adjoining secondary schools) and 18 girls aged 9-10-years who had participated in the intervention. Primary school teachers kept observation logs of each intervention session. A researcher completed observation logs of two random sessions per school. Qualitative data were analysed using thematic analysis with a combined deductive and inductive coding approach. Observation data were analysed using descriptive statistics. Data were triangulated and comparative analyses conducted across schools. RESULTS: Twenty-three peer role models (aged 12-16-years) and 16 community role models participated in intervention delivery. Overall, the inclusion of both types of role models was shown as acceptable and feasible within the CHARMING intervention. Observation data highlighted key areas (i.e., intervention components delivered inconsistently) for further qualitative exploration. Six themes were identified during analyses; reach and access, communication, logistics, existing systems, interpersonal relationships, and perceived impacts. Themes were intertwined across the barriers and facilitators of recruitment and implementation. Areas for future improvement were highlighted. CONCLUSIONS: Findings can be used to optimise the CHARMING intervention and inform wider interventions or policies employing several role models across settings to promote physical activity among children.

Alcohol and smoking brief interventions by socioeconomic position: a population-based, cross-sectional study in Great Britain.

BACKGROUND: Alcohol and smoking brief interventions (BIs) in general practice have been shown to be effective in lowering alcohol and smoking-related harm. AIM: To assess prevalence of self-reported BI receipt among increasing or higher-risk drinkers and past-year smokers in England, Scotland, and Wales, and associations between intervention receipt and socioeconomic position. DESIGN & SETTING: Cross-sectional study using data from a monthly population-based survey in England, Scotland, and Wales. METHOD: The study comprised 47 799 participants (15 573 increasing or higher-risk drinkers [alcohol use disorders identification test consumption score ≥5] and 7791 past-year smokers) surveyed via telephone in 2020-2022 (during the COVID-19 pandemic). All data were self-reported. Prevalence of self-reported BI receipt was assessed descriptively; associations between receipt and socioeconomic position were analysed using logistic regression. RESULTS: Among adults in England, Scotland, and Wales, 32.2% (95% confidence interval [CI] = 31.8 to 32.7) reported increasing or higher-risk drinking and 17.7% (95% CI = 17.3 to 18.1) past-year smoking. Among increasing or higher-risk drinkers, 58.0% (95% CI = 57.1 to 58.9) consulted with a GP in the past year, and of these, 4.1% (95% CI = 3.6 to 4.6) reported receiving BIs. Among past-year smokers, 55.8% (95% CI = 54.5 to 57.1) attended general practice in the past year; of these, 41.0% (95% CI = 39.4 to 42.7) stated receiving BIs. There was a tendency for patients from socioeconomically disadvantaged backgrounds to receive more alcohol (adjusted odds ratio [aOR] 1.38, 95% CI = 1.10 to 1.73) or smoking BIs (aOR 1.11, 95% CI = 0.98 to 1.26), but for the latter the results were statistically non-significant. Results did not differ notably by nation within Great Britain. CONCLUSION: BIs in general practice are more common for smoking than for alcohol. A greater proportion of BIs for alcohol were found to be delivered to people who were from socioeconomically disadvantaged backgrounds and who were increasing or higher-risk drinkers.

DMC1 stabilizes crossovers at high and low temperatures during wheat meiosis.

Effective chromosome synapsis and crossover formation during meiosis are essential for fertility, especially in grain crops such as wheat. These processes function most efficiently in wheat at temperatures between 17-23 °C, although the genetic mechanisms for such temperature dependence are unknown. In a previously identified mutant of the hexaploid wheat reference variety 'Chinese Spring' lacking the long arm of chromosome 5D, exposure to low temperatures during meiosis resulted in asynapsis and crossover failure. In a second mutant (ttmei1), containing a 4 Mb deletion in chromosome 5DL, exposure to 13 °C led to similarly high levels of asynapsis and univalence. Moreover, exposure to 30 °C led to a significant, but less extreme effect on crossovers. Previously, we proposed that, of 41 genes deleted in this 4 Mb region, the major meiotic gene TaDMC1-D1 was the most likely candidate for preservation of synapsis and crossovers at low (and possibly high) temperatures. In the current study, using RNA-guided Cas9, we developed a new Chinese Spring CRISPR mutant, containing a 39 bp deletion in the 5D copy of DMC1, representing the first reported CRISPR-Cas9 targeted mutagenesis in Chinese Spring, and the first CRISPR mutant for DMC1 in wheat. In controlled environment experiments, wild-type Chinese Spring, CRISPR dmc1-D1 and backcrossed ttmei1 mutants were exposed to either high or low temperatures during the temperature-sensitive period from premeiotic interphase to early meiosis I. After 6-7 days at 13 °C, crossovers decreased by over 95% in the dmc1-D1 mutants, when compared with wild-type plants grown under the same conditions. After 24 hours at 30 °C, dmc1-D1 mutants exhibited a reduced number of crossovers and increased univalence, although these differences were less marked than at 13 °C. Similar results were obtained for ttmei1 mutants, although their scores were more variable, possibly reflecting higher levels of background mutation. These experiments confirm our previous hypothesis that DMC1-D1 is responsible for preservation of normal crossover formation at low and, to a certain extent, high temperatures. Given that reductions in crossovers have significant effects on grain yield, these results have important implications for wheat breeding, particularly in the face of climate change.

Impacts of EU Tobacco Products Directive regulations on use of e-cigarettes in adolescents in Great Britain: a natural experiment evaluation.

Background: E-cigarettes are a popular smoking-cessation tool. Although less harmful than tobacco, use of e-cigarettes by non-smokers should be prevented. There is concern about the use of e-cigarettes by young people and that e-cigarettes may renormalise smoking. In May 2016, Tobacco Products Directive regulations aimed to reduce e-cigarettes' appeal to young people. Aims: To examine the effects of the Tobacco Products Directive regulations on young people's use of e-cigarettes, and the role of e-cigarettes in renormalising smoking. Design: A mixed-method natural experimental evaluation combining secondary analyses of survey data, with process evaluation, including interviews with young people, policy stakeholders, retailers and trading standards observers, and observations of retail settings. Settings: Wales, Scotland and England. Participants: Survey participants were aged 13-15 years, living in England, Scotland or Wales and participated in routinely conducted surveys from 1998 to 2019. Process evaluation participants included 14- to 15-year-olds in England, Scotland and Wales, policy stakeholders, trading standards offices and retailers. Intervention: Regulation of e-cigarettes, including bans on cross-border advertising, health warnings and restrictions on product strength. Comparison group: Interrupted time series design, with baseline trends as the comparator. Main outcome measures: The primary outcome was ever e-cigarette use. Secondary outcomes included regular use, ever and regular smoking, smoking attitudes, alcohol and cannabis use. Data capture and analysis: Our primary statistical analysis used data from Wales, including 91,687 young people from the 2013-19 Health Behaviour in School-aged Children and School Health Research Network surveys. In Scotland, we used the Scottish Schools Adolescent Lifestyle and Substance Use Survey and in England we used the Smoking Drinking and Drug Use surveys. The process evaluation included interviews with 73 young people in 2017 and 148 young people in 2018, 12 policy stakeholders, 13 trading standards officers and 27 retailers. We observed 30 retail premises before and after implementation. Data were integrated using the Medical Research Council's process evaluation framework. Results: Ever smoking continued to decline alongside the emergence of e-cigarettes, with a slight slowing in decline for regular use. Tobacco Products Directive regulations were described by stakeholders as well implemented, and observations indicated good compliance. Young people described e-cigarettes as a fad and indicated limited interaction with the components of the Tobacco Products Directive regulations. In primary statistical analyses in Wales [i.e. short (to 2017) and long term (to 2019)], growth in ever use of e-cigarettes prior to Tobacco Products Directive regulations did not continue after implementation. Change in trend was significant in long-term analysis, although of similar magnitude at both time points (odds ratio 0.96). Data from England and Scotland exhibited a similar pattern. Smoking followed the opposite pattern, declining prior to the Tobacco Products Directive regulations, but plateauing as growth in e-cigarette use stalled. Limitations: Alternative causal explanations for changes cannot be ruled out because of the observational design. Conclusions: Young people's ever and regular use of e-cigarettes appears to have peaked around the time of the Tobacco Products Directive regulations and may be declining. Although caution is needed in causal attributions, findings are consistent with an effect of regulations. Our analysis provides little evidence that e-cigarettes renormalise smoking. More recent data indicate that declines in smoking are plateauing. Future work: International comparative work to understand differences in use of e-cigarettes, and tobacco, within varying regulatory frameworks is a priority. Study registration: This study is registered as ResearchRegistry4336. 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. 5. See the NIHR Journals Library website for further project information.

Much has been achieved in preventing young people smoking; however, e-cigarettes have emerged as a new issue. E-cigarettes can help smokers stop, but might also appeal to young people or make smoking look 'normal'. Until recently, In the United Kingdom, there were not many rules for e-cigarettes. In 2016, new rules came in as part of the European Union Tobacco Products Directive regulations. The Tobacco Products Directive regulations limited advertising and included rules about how e-cigarettes should be labelled. In our study, we wanted to know if (1) e-cigarettes make young people think smoking is 'normal' and (2) people's use of e-cigarettes changed after new rules. We included young people who took part in surveys in England, Scotland and Wales between 1998 and 2019. Overall, about 360,000 young people did one of the surveys and about 90,000 were included in our main analysis. We spoke with young people in 2017 and 2018. In addition, in 2018, we spoke with people involved in tobacco policy, trading standards officers and people who sold e-cigarettes. Young people held negative attitudes about smoking and said that friends disagreed with smoking. Young people approved of occasional social e-cigarette use, but not regular use. Stakeholders described a range of views on how e-cigarettes should be regulated. Retailers and trading standards officers said that some retailers did not get much information about Tobacco Products Directive regulations, but new rules were implemented well. The percentage of young people saying that they had tried e-cigarettes was growing, but the number had stopped growing after the new rules. Regular use remained low throughout. Our findings suggest that e-cigarettes are not making smoking look normal again and new rules may have helped stop growth in use of e-cigarettes by young people.

ZIP4 is required for normal progression of synapsis and for over 95% of crossovers in wheat meiosis.

Tetraploid (AABB) and hexaploid (AABBDD) wheat have multiple sets of similar chromosomes, with successful meiosis and preservation of fertility relying on synapsis and crossover (CO) formation only taking place between homologous chromosomes. In hexaploid wheat, the major meiotic gene TaZIP4-B2 (Ph1) on chromosome 5B, promotes CO formation between homologous chromosomes, whilst suppressing COs between homeologous (related) chromosomes. In other species, ZIP4 mutations eliminate approximately 85% of COs, consistent with loss of the class I CO pathway. Tetraploid wheat has three ZIP4 copies: TtZIP4-A1 on chromosome 3A, TtZIP4-B1 on 3B and TtZIP4-B2 on 5B. Here, we have developed single, double and triple zip4 TILLING mutants and a CRISPR Ttzip4-B2 mutant, to determine the effect of ZIP4 genes on synapsis and CO formation in the tetraploid wheat cultivar 'Kronos'. We show that disruption of two ZIP4 gene copies in Ttzip4-A1B1 double mutants, results in a 76-78% reduction in COs when compared to wild-type plants. Moreover, when all three copies are disrupted in Ttzip4-A1B1B2 triple mutants, COs are reduced by over 95%, suggesting that the TtZIP4-B2 copy may also affect class II COs. If this is the case, the class I and class II CO pathways may be interlinked in wheat. When ZIP4 duplicated and diverged from chromosome 3B on wheat polyploidization, the new 5B copy, TaZIP4-B2, could have acquired an additional function to stabilize both CO pathways. In tetraploid plants deficient in all three ZIP4 copies, synapsis is delayed and does not complete, consistent with our previous studies in hexaploid wheat, when a similar delay in synapsis was observed in a 59.3 Mb deletion mutant, ph1b, encompassing the TaZIP4-B2 gene on chromosome 5B. These findings confirm the requirement of ZIP4-B2 for efficient synapsis, and suggest that TtZIP4 genes have a stronger effect on synapsis than previously described in Arabidopsis and rice. Thus, ZIP4-B2 in wheat accounts for the two major phenotypes reported for Ph1, promotion of homologous synapsis and suppression of homeologous COs.