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.

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.

Receipt of social services intervention in childhood, educational attainment and emergency hospital admissions: longitudinal analyses of national administrative health, social care, and education data in Wales, UK.

BACKGROUND: Research consistently finds poorer health and educational outcomes for children who have experienced out-of-home care relative to the general population. Few studies have explored differences between those in care and those in receipt of intervention from social services but not in care. Children receiving social services interventions often experience Adverse Childhood Experiences (ACEs), and deprivation, which are known to negatively impact outcomes. We aimed to estimate the association of different social services interventions with educational outcomes and hospital admissions, while adjusting for ACEs and deprivation. METHODS: We linked retrospective, routinely collected administrative records from health, education, and social care to create a cohort via the Secure Anonymised Information Linkage (SAIL) databank in Wales, UK. We analysed data for children and household members (N = 30,439) across four different groups: [1] no social care intervention; [2] children in need but not in care (CIN); [3] children on the Child Protection Register but not in care (CPR); [4] children in care - i.e. removed from the family home and looked after by the local authority (CLA). Our primary outcome was education outcomes at age 16 years. Secondary outcomes were all cause emergency hospital admissions, and emergency admissions for external causes/injuries. RESULTS: Children in receipt of social services intervention were more likely to not attain the expected level upon leaving statutory education at age 16 after adjusting for ACEs and other characteristics (for children who had been in out-of-home care (conditional OR: 1·76, (95%CI) 1·25 - 2·48), in need (2·51, 2·00-3·15) and those at risk (i.e., on the child protection register) (4·04, 2·44 - 6·68). For all-cause emergency admissions, all social care groups were at greater risk compared to children in the general population (children in care (conditional HR: 1·31, 1·01-1·68), children in need (1·62, 1·38 - 1·90), and children at risk (1·51, 1·11 - 2·04). CONCLUSIONS: All groups receiving social service intervention experience poorer educational and health outcomes than peers in the general population. Children who remain with their home parents or caregivers but are identified as 'in need' or 'at risk' by social care practitioners require further research. Integrated support is needed from multiple sectors, including health, educational and social care.

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.

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.

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.

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.

Self-harm, in-person bullying and cyberbullying in secondary school-aged children: A data linkage study in Wales.

INTRODUCTION: Although the evidence base on bullying victimization and self-harm in young people has been growing, most studies were cross-sectional, relied on self-reported non-validated measures of self-harm, and did not separate effects of in-person and cyberbullying. This study aimed to assess associations of self-harm following in-person bullying at school and cyberbullying victimization controlling for covariates. METHODS: School survey data from 11 to 16 years pupils collected in 2017 from 39 Welsh secondary schools were linked to routinely collected data. Inverse probability weighting was performed to circumvent selection bias. Survival analyses for recurrent events were conducted to evaluate relative risks (adjusted hazard ratios [AHR]) of self-harm among bullying groups within 2 years following survey completion. RESULTS: A total of 35.0% (weighted N = 6813) of pupils reported being bullied, with 18.1%, 6.4% and 10.5% being victims of in-person bullying at school only, cyberbullying only and both in-person bullying at school and cyberbullying respectively. Adjusting for covariates, effect sizes for self-harm were significant after being in-person bullied at school only (AHR = 2.2 [1.1-4.3]) and being both in-person bullied at school and cyberbullied (AHR = 2.2 [1.0-4.7]) but not being cyberbullied only (AHR = 1.2 [0.4-3.3]). Feeling lonely during recent summer holidays was also a robust predictor (AHR = 2.2 [1.2-4.0]). CONCLUSIONS: We reaffirm the role of in-person bullying victimization on self-harm. Pupils were twice as likely to self-harm following in-person bullying as their nonvictimised peers. Interventions for young people that minimize the potential impacts of bullying on self-harm should also include strategies to prevent loneliness.

Adversity profiles of children receiving care and support from social services: A latent-class analysis of school-aged children in Wales.

BACKGROUND: Children receive care and support from social services due to the risk of harm or impeded development or because of disability. This study aimed to identify typologies of adversity experienced by children receiving care and support from social services and to explore how typologies differ by sociodemographic characteristics. METHODS: This is a cross-sectional study of 'Children Receiving Care and Support' (N = 12 792) during 2017/2018 in Wales, UK. We sought to (1) examine the prevalence of household adversities experienced by children in receipt of care and support from social services; (2) identify typologies of household adversities; and (3) explore how typologies of household adversities differ by family characteristics (demographics, measures of social disadvantage, perinatal and care factors). RESULTS: We found evidence for multiple risk factor constellations. The four-class solution suggested four distinct classes of adversities: child disability (50.0%), low adversities (20.3%), family poor health (6.7%) and multiple risks (23.0%). Children in the 'multiple risk' class were significantly more likely to be younger, more deprived and 'looked after' by the local authority compared with those in the 'low adversities' class. CONCLUSIONS: Given the presence of different constellations of household adversities, policies and interventions that address multiple risk factors simultaneously may be more effective and have longer-lasting benefits.

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.

Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics.

This study is an extension of current research into a novel class of synthetic antihypertensive drugs referred to as "bisartans", which are bis-alkylated imidazole derivatives bearing two symmetric anionic biphenyltetrazoles. Research to date indicates that bisartans are superior to commercially available hypertension drugs, since the former undergo stronger docking to angiotensin-converting enzyme 2 (ACE2). ACE2 is the key receptor involved in SARS-CoV-2 entry, thus initiating COVID-19 infection and in regulating levels of vasoactive peptides such as angiotensin II and beneficial heptapeptides A(1-7) and Alamandine in the renin-angiotensin system (RAS). In previous studies using in vivo rabbit-iliac arterial models, we showed that Na+ or K+ salts of selected Bisartans initiate a potent dose-response inhibition of vasoconstriction. Furthermore, computational studies revealed that bisartans undergo stable binding to the vital interfacial region between ACE2 and the SARS-CoV-2 "receptor binding domain" (i.e., the viral RBD). Thus, bisartan homologs are expected to interfere with SARS-CoV-2 infection and/or suppress disease expression in humans. The primary goal of this study was to investigate the role of tetrazole in binding and the network of amino acids of SARS-CoV-2 Spike RBD-ACE2 complex involved in interactions with sartans. This study would, furthermore, allow the expansion of the synthetic space to create a diverse suite of new bisartans in conjunction with detailed computational and in vitro antiviral studies. A critical role for tetrazole was uncovered in this study, shedding light on the vital importance of this group in the binding of sartans and bisartans to the ACE2/Spike complex. The in silico data predicting an interaction of tetrazole-containing sartans with ACE2 were experimentally validated by the results of surface plasmon resonance (SPR) analyses performed with a recombinant human ACE2 protein.

Young people's online communication and its association with mental well-being: results from the 2019 student health and well-being survey.

BACKGROUND: Online communication has become an integral aspect of daily life for young people internationally. Very little research has examined whether the association between social media use and well-being depends on who young people engage with (i.e. real, or virtual friendships). METHODS: Data were drawn from a subsample of students (N = 38,736) who took part in the School Health Research Network (SHRN) 2019 Student Health and Well-being (SHW) survey. A series of multivariable regression models were used to assess the association between who adolescents were communicating with online and well-being, controlling for confounders: passive social media use; friendship quality; and cyberbullying. We also tested whether these associations were modified based on gender. RESULTS: Students are highly engaged on social networking sites, and these sites are used to communicate with existing friendship groups and develop virtual friendships. Frequent online communication with best friends (b = .340, p < .001) and bigger friendship groups (b = .397; p < .001) was associated with higher levels of well-being. However, the frequency of online contact with virtual friends made online was negatively and significantly associated with well-being (b = -.760; p < .001), with a larger negative association for girls than boys. CONCLUSIONS: Online communication with virtual friendship networks were associated with lower mental well-being, with stronger associations for girls than boys; however, frequent online communication with 'real' friends was associated with better well-being. Our results indicate the importance of considering the nature of adolescent online communication, rather than just its quantity, in developing interventions to improve adolescent well-being.

Prevalence of Menthol and Menthol Capsule Cigarette Use Among 11-16 Year Olds in Wales Prior to a Ban on Characterizing Flavors in Cigarettes: Findings From the 2019 Student Health and Wellbeing Survey.

INTRODUCTION: The use of flavored cigarettes has increased in many countries because of the inclusion of one or more frangible flavor-changing capsules in the filter. Research suggests that these "capsule" cigarettes appeal most to youth, but little is known about how prevalent their use is among children. METHODS: A cross-sectional school survey was conducted between September and December 2019 with 11-16 year-olds (N = 119 388) from 198 secondary schools across Wales; the sample represented approximately two-thirds of all 11-16 year-olds in the country. The sample was asked about smoking behavior, with a quarter (N = 26 950) also asked about awareness of menthol cigarettes, and use of menthol and menthol capsule cigarettes if a current smoker (N = 1447). RESULTS: Current smoking prevalence was 5.7% among the entire sample and 5.9% among the analytical sample (those also asked about menthol and menthol capsule cigarettes). For the analytical sample, almost all current smokers (93.2%) were aware of menthol cigarettes, with three-fifths (60.5%) reporting having used menthol cigarettes in the past 30 days (42.3% capsule cigarettes, 18.2% noncapsule cigarettes). In comparison to nonmenthol smokers, those using menthol cigarettes (capsule and noncapsule) were more likely to be frequent smokers, with those using menthol capsule cigarettes more likely to have smoked for longer. CONCLUSIONS: While past research suggests that flavored cigarettes appeal to youth, this study shows just how popular these products, and capsule cigarettes, in particular, were among young smokers in Wales. It also raises questions about why capsule cigarettes have received such limited public health attention. IMPLICATIONS: That three in five 11-16 year-old smokers reported using menthol cigarettes in the past 30 days highlights how appealing these products are to young people, particularly capsule cigarettes, used by seventy percent of menthol smokers. Capsule cigarettes are one of the most successful tobacco product innovations in decades, even in countries with comprehensive bans on tobacco marketing and standardized packaging. The dearth of research on capsule cigarettes is a failure of global public health. Evaluation of the ban on characterizing flavors in the United Kingdom and across the European Union is critical.

Inequalities in Smoking and Quitting-Related Outcomes Among Adults With and Without Children in the Household 2013-2019: A Population Survey in England.

INTRODUCTION: Smoking among those who live with children is an important influence on smoking initiation among children. This study assessed socioeconomic inequalities in smoking and quitting-related outcomes among all adults with and without children in the household. AIMS AND METHODS: Monthly repeat cross-sectional household survey of adults (16+) from 2013-2019 in England (N = 138 583). We assessed the association between cigarette smoking and quitting-related outcomes and having children in the household, and whether these relationships were moderated by occupational social grade (categories AB-E from most to least advantaged). Trends in smoking prevalence among adults with and without children in the household were explored. RESULTS: In adjusted analysis, the association of having children in the household with smoking prevalence depended on social grade: smoking prevalence was between 0.71 (95% confidence interval 0.66-0.77) and 0.93 (0.88-0.98) times lower among social grades AB-D with children in the household relative to those without. Conversely, it was 1.11 (1.05-1.16) times higher among social grade E. Yearly prevalence declined similarly among those with and without children (both prevalence ratio: 0.98, 95% confidence interval 0.97-0.99). Motivation to stop smoking was higher among those with children than those without, but lower among disadvantaged than more advantaged groups. Social grades D-E had greater heavy smoking, but higher prevalence of past-month quit attempts. CONCLUSIONS: Among the most disadvantaged social grade in England, smoking prevalence was higher in those with children in the household than without. To attenuate future smoking-related inequalities, there is an urgent need to target support and address barriers to quitting and promote longer-term quit success. IMPLICATIONS: In the most disadvantaged occupational social grade, having children in the household was associated with higher smoking prevalence compared with not having children. This contrasts with all other social grades in which there was lower comparative smoking prevalence among those with than without children in the household. Without attention this disparity could exacerbate existing and future health inequalities related to smoking.

Measurement invariance of the short Warwick-Edinburgh Mental Wellbeing Scale and latent mean differences (SWEMWBS) in young people by current care status.

PURPOSE: Studying mental wellbeing requires the use of reliable, valid, and practical assessment tools, such as the Short version of the Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS). Research on the mental wellbeing of children in care is sparse. The current study aims to: (1) examine the unidimensionality of SWEMWBS; (2) assess measurement invariance of SWEMWBS across children and young people in care compared to their peers not in care; and (3) investigate the latent factor mean differences between care status groups. METHODS: We used data from the 2017 School Health Research Network Student Health and Wellbeing (SHW) survey, completed by 103,971 students in years 7 to 11 from 193 secondary schools in Wales. The final data include a total of 2,795 participants (46% boys), which includes all children in care and a sub-sample of children not in care who completed the SWEMWBS scale fully and answered questions about their living situation. RESULTS: Confirmatory factor analysis supported the unidimensionality of SWEMWBS. The SWEMWBS is invariant across groups of young people in foster, residential and kinship care compared to children and young people not in care at configural, metric and scalar levels. Findings from latent mean comparisons showed that young people in care reported lower mental wellbeing than their peers, with those in residential care reporting the lowest scores. CONCLUSIONS: Findings suggest that SWEMWBS is a valid scale for measuring differences in mental wellbeing for young people in care similar to the population.

Assessing the profile of support for potential tobacco control policies targeting availability in Great Britain: a cross-sectional population survey.

AIM: To examine the level of support for tobacco availability policies across Great Britain (GB) and associations between support for policy and sociodemographic, smoking and quitting characteristics. METHODS: A cross-sectional representative survey (the Smoking Toolkit Study) of adults in GB (n=2197) during September 2021. Logistic regressions estimated the associations between support for each policy and sociodemographic and smoking characteristics. FINDINGS: There was majority support for requiring retailers to have a license which can be removed if they sell to those under-age (89.6%) and for restrictions on the sale of cigarettes and tobacco near schools (69.9%). More supported than opposed raising the legal age of sale of cigarettes and tobacco to 21 (49.2% supported; 30.7% opposed; 20.1% unsure) and reducing the number of retailers selling tobacco in neighbourhoods with a high density of tobacco retailers (46.5% supported; 23.3% opposed; 30.2% unsure). More opposed than supported a ban on the sale of cigarettes and tobacco to everyone born after a certain year from 2030 onward (a 'tobacco-free generation') (41.3% opposed; 34.5% supported; 24.2% unsure). Age was positively associated with support for raising the age of sale and inversely associated with requiring tobacco retailer licenses. Women were more likely to support raising the age of sale and reducing the number of retailers. CONCLUSIONS: Requiring tobacco retailer licensing and restrictions on sales near schools received majority support. Other tobacco availability policies received substantial support despite considerable opposition.

Police referrals for domestic abuse before and during the first COVID-19 lockdown: An analysis of routine data from one specialist service in South Wales.

BACKGROUND: COVID-19 lockdown measures may have led to more, and increasingly severe, domestic abuse. This study examines police referrals to a specialist domestic abuse service in Wales, UK before and during the first lockdown. METHODS: Routine data relating to 2292 police referrals for female adult victim-survivors from December 2019 until July 2020 were analysed and presented in the form of descriptive statistics to monitor changes in referral rates and the profile of those referrals. RESULTS: There was little increase in the overall volume of police referrals during lockdown, but the proportion assessed as high risk increased, and children became the primary source of third-party referrals, with a higher proportion of reports made by other third parties as restrictions eased. Police reports for cases of Child/Adolescent to Parent Violence (C/APV) occurred almost exclusively during lockdown. CONCLUSIONS: The increase in risk level despite less clear increase in volume may suggest unmet need, with victims less likely to seek help during lockdown other than for more severe instances. Increased reports by children suggest increased exposure of children to domestic abuse during school closure. Unmet need for women and children may have been made visible to services, and acquaintances, as measures began to ease.

Mental health and life satisfaction among 10-11-year-olds in Wales, before and one year after onset of the COVID-19 pandemic.

BACKGROUND: In many countries, including in the United Kingdom (UK), COVID-19 social distancing measures placed substantial restrictions on children's lives in 2020 and 2021, including closure of schools and limitations on play. Many children faced milestones such as transition to secondary school having missed several months of face-to-face schooling in the previous academic years. METHODS: This paper examines change in mental health difficulties, life satisfaction, school connectedness, and feelings about transition to secondary school among 10-11-year-olds in Wales, UK, using data from repeat cross-sectional surveys before and after the onset of the COVID-19 pandemic. Participants were 4032 10-11-year-old schoolchildren. The first cohort completed a school-based survey in 2019 (prior to introduction of social distancing measures), and the second in 2021 (following full return to school after two rounds of school closure). RESULTS: The percentage of children reporting elevated emotional difficulties rose from 17% in 2019 to 27% in 2021 (Odds Ratio = 1.65; 95%CI = 1.23 to 2.20). There was no evidence of increased behavioural difficulties (OR = 1.04; 95%CI = 0.73 to 1.46). There was a tendency toward declines in life satisfaction in all analyses, but this intersected the null (OR = 0.86; 95%CI = 0.70 to 1.07). Children reported a high degree of school connectedness before and after the pandemic, with no evidence of change in ratings of teacher relationships, pupil relationships or pupil involvement in school life. There was no evidence of impacts of the pandemic on children's feelings about the transition to secondary school, with feelings becoming more positive as transition neared. Most findings were robust to a range of sensitivity analyses. CONCLUSIONS: Supporting children's emotional recovery from the COVID-19 pandemic is a public health priority requiring urgent and effective action at multiple levels of society. Maintaining connectedness to school through the pandemic may have played a role in preventing a steeper increase in child mental health difficulties.

Health behaviour change among UK adults during the pandemic: findings from the COVID-19 cancer attitudes and behaviours study.

BACKGROUND: COVID-19 related lockdowns may have affected engagement in health behaviours among the UK adult population. This prospective observational study assessed socio-demographic patterning in attempts to change and maintain a range of health behaviours and changes between two time points during the pandemic. METHODS: Adults aged 18 years and over (n = 4,978) were recruited using Dynata (an online market research platform) and the HealthWise Wales platform, supplemented through social media advertising. Online surveys were conducted in August/September 2020 when lockdown restrictions eased in the UK following the first major UK lockdown (survey phase 1) and in February/March 2021 during a further national lockdown (survey phase 2). Measures derived from the Cancer Awareness Measure included self-reported attempts to reduce alcohol consumption, increase fruit/vegetable consumption, increase physical activity, lose weight and reduce/stop smoking. Multivariable logistic regressions were used to assess individual health behaviour change attempts over time, adjusted for age, sex, ethnicity, employment and education. RESULTS: Around half of participants in survey phase 1 reported trying to increase physical activity (n = 2607, 52.4%), increase fruit/vegetables (n = 2445, 49.1%) and lose weight (n = 2413, 48.5%), with 19.0% (n = 948) trying to reduce alcohol consumption among people who drink. Among the 738 participants who smoked, 51.5% (n = 380) were trying to reduce and 27.4% (n = 202) to stop smoking completely. Most behaviour change attempts were more common among women, younger adults and minority ethnic group participants. Efforts to reduce smoking (aOR: 0.98, 95% CI: 0.82-1.17) and stop smoking (aOR: 0.98, 95% CI: 0.80-1.20) did not differ significantly in phase 2 compared to phase 1. Similarly, changes over time in attempts to improve other health behaviours were not statistically significant: physical activity (aOR: 1.07; 95% CI: 0.99-1.16); weight loss (aOR: 0.95; 95% CI: 0.90-1.00); fruit/vegetable intake (aOR: 0.98, 95% CI: 0.91-1.06) and alcohol use (aOR: 1.32, 95% CI: 0.92-1.91). CONCLUSION: A substantial proportion of participants reported attempts to change health behaviours in the initial survey phase. However, the lack of change observed over time indicated that overall motivation to engage in healthy behaviours was sustained among the UK adult population, from a period shortly after the first lockdown toward the end of the second prolonged lockdown.

Actions of Novel Angiotensin Receptor Blocking Drugs, Bisartans, Relevant for COVID-19 Therapy: Biased Agonism at Angiotensin Receptors and the Beneficial Effects of Neprilysin in the Renin Angiotensin System.

Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin 'antipeptides'. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor 'switching' between an activated state invoking receptor dimerization/G protein coupling and an inverse agonist state mediated by an alternative/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans ('Bisartans') to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1-7). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells.