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Social learning through friendships is important in child development. Autistic children often initiate and engage in social interactions differently than neurotypical peers. LEGO® based therapy is a group intervention which facilitates social interactions with peers using collaborative LEGO® play. A 1:1 cluster randomised controlled trial with autistic children aged 7-15 comparing 12 weeks' LEGO® based therapy and usual support to usual support alone in 98 mainstream schools (2017-2019) was carried out. The primary outcome was social skills (Social Skills Improvement System) completed by unblinded teachers (not intervention deliverers) at 20 weeks. Analysis used intention-to-treat. Fifty intervention schools (127 participants) and 48 control schools (123 participants) were allocated. Primary analysis included 45 intervention schools (116 participants) and 42 control schools (101 participants). The between-arms difference was 3.74 (p = 0.06, 95% confidence interval: -0.16, 7.63) and 1.68 (p = 0.43, 95% confidence interval: -2.51, 5.87) at 20 and 52 weeks (0.18 and 0.08 standardised effect sizes). Twenty-week outcomes for those receiving per protocol intervention were 4.23 (95% confidence interval 0.27, 8.19) with a standardised effect size of 0.21. Sensitivity estimates were between 3.10 and 4.37 (0.15-0.21 standardised effect sizes). Three unrelated serious adverse events were reported. LEGO® based therapy has a small positive non-significant benefit for social skills at 20 weeks but not 52 weeks.

Abstract Background Alcohol dependence is a significant and costly problem in the UK yet only 6% of people a year receive treatment. Current service provision based on the treatment of acute episodes of illness and emphasising personal choice and motivation results in a small proportion of these patients engaging with alcohol treatment. There is a need for interventions targeted at the population of alcohol dependent patients who are hard to engage in conventional treatment. Assertive Community Treatment (ACT), a model of care based on assertive outreach, has been used for treating patients with severe mental illnesses and presents a promising avenue for engaging patients with primary alcohol dependence. So far there has been little research on this. Methods/Design In this single blind exploratory randomised controlled trial, a total of 90 alcohol dependent participants will be recruited from community addiction services. After completing a baseline assessment, they will be assigned to one of two conditions: (1) ACT plus care as usual, or (2) care as usual. Those allocated to the ACT plus care as usual will receive the same treatment that is routinely provided by services, plus a trained key worker who will provide ACT. ACT comprises intensive and assertive contact at least once a week, over 50% of contacts in the participant's home or local community, and comprehensive case management across social and health care, for a period of one year. All participants will be followed up at 6 months and 12 months to assess outcome post randomisation. The primary outcome measures will be alcohol consumption: mean drinks per drinking day and percentage of days abstinent measured by the Time Line Follow Back interview. Secondary outcome measures will include severity of alcohol dependence, alcohol related problems, motivation to change, social network involvement, quality of life, therapeutic relationship and service use. Other outcome variables are treatment engagement including completion of assessment, detoxification and aftercare. Discussion Results of this trial will help clarify the potential beneficial effects of ACT for people with alcohol dependence and provide information to design a definitive trial. Trial registration number ISRCTN: ISRCTN22775534

Abstract Background Depression accounts for the greatest burden of disease among all mental health problems, and is expected to become the second-highest amongst all general health problems by 2020. By the age of 75, 1 in 7 older people meet formal diagnostic criteria for depression. Efforts to ameliorate the burden of illness and personal suffering associated with depression in older people have focussed on those with more severe depressive syndromes. Less attention has been paid to those with mild disorders/sub-threshold depressive syndromes but these patients also suffer impairments in their quality of life and level of functioning. Methods/Design The CASPER study has been designed to assemble an epidemiological cohort of people over 75 years of age (the CASPER cohort), from which we will identify those eligible to participate in a trial of collaborative care for sub-threshold depression (the CASPER trial). We aim to undertake a pragmatic randomised controlled multi-centre trial evaluating the effectiveness and cost-effectiveness of collaborative care; a low intensity psychological intervention in addition to usual general practitioner care versus usual general practitioner care alone. General practitioners from practices based in the North of England will be asked to identify potentially eligible patients over the age of 75 years. Patients will be sent a letter inviting them to participate in the study. We aim to recruit approximately 540 participants for the CASPER trial. A diagnostic interview will be carried out to ascertain trial eligibility with the major depressive episode module of the Mini International Neuropsychiatric Interview (M.I.N.I.), eligible participants randomised to either the intervention or usual care. The primary outcome will be measured with the Patient Health Questionnaire-9 (PHQ-9) and additional quality of life measures will be collected. Data will be collected at baseline, 4 and 12 months for both trial and cohort participants. Trial Registration ISRCTN: ISRCTN02202951

Abstract Background A large number of randomised controlled trials in health settings have consistently reported positive effects of brief intervention in terms of reductions in alcohol use. However, although alcohol misuse is common amongst offenders, there is limited evidence of alcohol brief interventions in the criminal justice field. This factorial pragmatic cluster randomised controlled trial with Offender Managers (OMs) as the unit of randomisation will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in probation and different intensities of brief intervention to reduce excessive drinking in probation clients. Methods and design Ninety-six OMs from 9 probation areas across 3 English regions (the North East Region (n = 4) and London and the South East Regions (n = 5)) will be recruited. OMs will be randomly allocated to one of three intervention conditions: a client information leaflet control condition (n = 32 OMs); 5-minute simple structured advice (n = 32 OMs) and 20-minute brief lifestyle counselling delivered by an Alcohol Health Worker (n = 32 OMs). Randomisation will be stratified by probation area. To test the relative effectiveness of different screening methods all OMs will be randomised to either the Modified Single Item Screening Questionnaire (M-SASQ) or the Fast Alcohol Screening Test (FAST). There will be a minimum of 480 clients recruited into the trial. There will be an intention to treat analysis of study outcomes at 6 and 12 months post intervention. Analysis will include client measures (screening result, weekly alcohol consumption, alcohol-related problems, re-offending, public service use and quality of life) and implementation measures from OMs (the extent of screening and brief intervention beyond the minimum recruitment threshold will provide data on acceptability and feasibility of different models of brief intervention). We will also examine the practitioner and organisational factors associated with successful implementation. Discussion The trial will evaluate the impact of screening and brief alcohol intervention in routine probation work and therefore its findings will be highly relevant to probation teams and thus the criminal justice system in the UK. Ethical approval was given by Northern & Yorkshire REC Trial Registration number ISRCTN 19160244

Abstract Background There have been many randomized controlled trials of screening and brief alcohol intervention in primary care. Most trials have reported positive effects of brief intervention, in terms of reduced alcohol consumption in excessive drinkers. Despite this considerable evidence-base, key questions remain unanswered including: the applicability of the evidence to routine practice; the most efficient strategy for screening patients; and the required intensity of brief intervention in primary care. This pragmatic factorial trial, with cluster randomization of practices, will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in primary care and different intensities of brief intervention to reduce excessive drinking in primary care patients. Methods and design GPs and nurses from 24 practices across the North East (n = 12), London and South East (n = 12) of England will be recruited. Practices will be randomly allocated to one of three intervention conditions: a leaflet-only control group (n = 8); brief structured advice (n = 8); and brief lifestyle counselling (n = 8). To test the relative effectiveness of different screening methods all practices will also be randomised to either a universal or targeted screening approach and to use either a modified single item (M-SASQ) or FAST screening tool. Screening randomisation will incorporate stratification by geographical area and intervention condition. During the intervention stage of the trial, practices in each of the three arms will recruit at least 31 hazardous or harmful drinkers who will receive a short baseline assessment followed by brief intervention. Thus there will be a minimum of 744 patients recruited into the trial. Discussion The trial will evaluate the impact of screening and brief alcohol intervention in routine practice; thus its findings will be highly relevant to clinicians working in primary care in the UK. There will be an intention to treat analysis of study outcomes at 6 and 12 months after intervention. Analyses will include patient measures (screening result, weekly alcohol consumption, alcohol-related problems, public service use and quality of life) and implementation measures from practice staff (the acceptability and feasibility of different models of brief intervention.) We will also examine organisational factors associated with successful implementation. Trial registration Current Controlled Trials ISRCTN06145674.

Abstract Background There is a wealth of evidence regarding the detrimental impact of excessive alcohol consumption on the physical, psychological and social health of the population. There also exists a substantial evidence base for the efficacy of brief interventions aimed at reducing alcohol consumption across a range of healthcare settings. Primary research conducted in emergency departments has reinforced the current evidence regarding the potential effectiveness and cost-effectiveness. Within this body of evidence there is marked variation in the intensity of brief intervention delivered, from very minimal interventions to more intensive behavioural or lifestyle counselling approaches. Further the majority of primary research has been conducted in single centre and there is little evidence of the wider issues of generalisability and implementation of brief interventions across emergency departments. Methods/design The study design is a prospective pragmatic factorial cluster randomised controlled trial. Individual Emergency Departments (ED) (n = 9) are randomised with equal probability to a combination of screening tool (M-SASQ vs FAST vs SIPS-PAT) and an intervention (Minimal intervention vs Brief advice vs Brief lifestyle counselling). The primary hypothesis is that brief lifestyle counselling delivered by an Alcohol Health Worker (AHW) is more effective than Brief Advice or a minimal intervention delivered by ED staff. Secondary hypotheses address whether short screening instruments are more acceptable and as efficient as longer screening instruments and the cost-effectiveness of screening and brief interventions in ED. Individual participants will be followed up at 6 and 12 months after consent. The primary outcome measure is performance using a gold-standard screening test (AUDIT). Secondary outcomes include; quantity and frequency of alcohol consumed, alcohol-related problems, motivation to change, health related quality of life and service utilisation. Discussion This paper presents a protocol for a large multi-centre pragmatic factorial cluster randomised trial to evaluate the effectiveness and cost-effectiveness of screening and brief interventions for hazardous alcohol users attending emergency departments. Trial Registration ISRCTN 93681536

Abstract Background There is a wealth of evidence regarding the detrimental impact of excessive alcohol consumption. In older populations excessive alcohol consumption is associated with increased risk of coronary heart disease, hypertension, stroke and a range of cancers. Alcohol consumption is also associated with an increased risk of falls, early onset of dementia and other cognitive deficits. Physiological changes that occur as part of the ageing process mean that older people experience alcohol related problems at lower consumption levels. There is a strong evidence base for the effectiveness of brief psychosocial interventions in reducing alcohol consumption in populations identified opportunistically in primary care settings. Stepped care interventions involve the delivery of more intensive interventions only to those in the population who fail to respond to less intensive interventions and provide a potentially resource efficient means of meeting the needs of this population. Methods/design The study design is a pragmatic prospective multi-centre two arm randomised controlled trial. The primary hypothesis is that stepped care interventions for older hazardous alcohol users reduce alcohol consumption compared with a minimal intervention at 12 months post randomisation. Potential participants are identified using the AUDIT questionnaire. Eligible and consenting participants are randomised with equal probability to either a minimal intervention or a three step treatment approach. The step treatment approach incorporates as step 1 behavioural change counselling, step 2 three sessions of motivational enhancement therapy and step 3 referral to specialist services. The primary outcome is measured using average standard drinks per day and secondary outcome measures include the Drinking Problems Index, health related quality of life and health utility. The study incorporates a comprehensive economic analysis to assess the relative cost-effectiveness of the interventions. Discussion The paper presents a protocol for the first pragmatic randomised controlled trial evaluating the effectiveness and cost-effectiveness of stepped care interventions for older hazardous alcohol users in primary care. Trial registration ISRCTN52557360

Background: Globally alcohol consumption is a leading risk factor for premature death and disability and is associated with crime, social and economic consequences. Local communities may be able to play a role in addressing alcohol-related issues in their area. Objectives: To evaluate the effectiveness and cost–benefit of an asset-based community development approach to reducing alcohol-related harm and understand the context and factors that enable or hinder its implementation. Design: A mixed-methods evaluation. Area-level quasi-experimental trial analysed using four different evaluation methods (a stepped-wedge design where each area was a control until it entered the intervention, comparison to matched local/national controls and comparison to synthetic controls), alongside process and economic evaluations. Setting: Ten local authorities in Greater Manchester, England. Participants: The outcomes evaluation was analysed at an area level. Ninety-three lay persons representing nineareas completed questionnaires, with 12 follow-up interviews in five areas; 20 stakeholders representing ten areas were interviewed at baseline, with 17 follow-up interviews in eight areas and 26 members of the public from two areas attended focus groups. Interventions: Professionals in a co-ordinator role recruited and supported lay volunteers who were trained to become alcohol health champions. The champion's role was to provide informal, brief alcohol advice to the local population and take action to strengthen restrictions on alcohol availability. Main outcome measures: Numbers of alcohol-related hospital admissions, accident and emergency attendances, ambulance call-outs, street-level crime and antisocial behaviour in the intervention areas (area size: 1600–5500 residents). Set-up and running costs were collected alongside process evaluation data exploring barriers and facilitators. Data sources: Routinely collected quantitative data on outcome measures aggregated at the intervention area and matched control and synthetic control areas. Data from policy documents, licensing registers, meeting notes, invoices, time/cost diaries, training registers, questionnaires, interviews, reflective diaries and focus groups. Results: The intervention rolled out in nine out of ten areas, seven of which ran for a full 12 months. Areas with better-established infrastructure at baseline were able to train more champions. In total, 123 alcohol health champions were trained (95 lay volunteers and 28 professionals): lay volunteers self-reported positive impact. Champions engaged in brief advice conversations more readily than taking action on alcohol availability. There were no consistent differences in the health and crime area-level indicators between intervention areas and controls, as confirmed by using three different analysis methods for evaluating natural experiments. The intervention was not found to be cost-beneficial. Limitations: Although the sequential roll-out order of the intervention was randomised, the selection of the intervention areas was not. Self-reported impact may have been subject to social desirability bias due to the project's high profile. Conclusions: There was no measurable impact on health and crime outcomes. Possible explanations include too few volunteers trained, volunteers being unwilling to get involved in licensing decisions, or that the intervention has no direct impact on the selected outcomes. Future work: Future similar interventions should use a coproduced community outcomes framework. Other natural experiment evaluations should use methodological triangulation to strengthen inferences about effectiveness. Trial registration: This trial is registered as ISRCTN81942890. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/129/03) and is published in full in Public Health Research; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary: What was the question?: Alcohol consumption puts an individual's health and social relationships at risk of harm. The more a person drinks, the more harmful it is. The harmful effects can place a burden on emergency services and hospitals. We wanted to find out whether community members can make a difference by taking action to address alcohol harm in their local area. What did we do?: Local councils in Greater Manchester developed a project called Communities in Charge of Alcohol, where volunteers in targeted local areas were trained to become 'alcohol health champions'. Alcohol health champions gave alcohol-related brief advice to people to help them drink less. They had a say about when, where and how alcohol is sold by reporting issues to their local council. We compared numbers of alcohol-related hospital admissions, accident and emergency attendances, ambulance call-outs and reports of crime and antisocial behaviour between areas that had alcohol health champions with other similar areas in England that did not. We calculated how much it costs to run and whether Communities in Charge of Alcohol could save society money. What did we find?: Not as many volunteers came forward to become an alcohol health champion as hoped for. Those who did give alcohol-related brief advice to people. They preferred not to report issues about alcohol sales to their local council, either because it was too complicated or because they did not want to be called a 'grass'. We did not find levels of alcohol harm changed in the Communities in Charge of Alcohol areas. Because of this, we could not demonstrate that Communities in Charge of Alcohol could save society money. What does this mean?: Getting involved in alcohol licensing decisions needs to be made easier for communities, with more anonymity, through the support of professionals. More work needs to be done to understand whether giving brief advice can reduce alcohol harm in whole communities. Scientific summary: Background: The availability of, and access to, alcohol is a key determinant of alcohol harm, and powers exist within the Licensing Act 2003 of England and Wales that enable the public to influence the local sale and supply of alcohol. At an individual level, implementing programmes to promote early risk identification and brief advice have the potential to reduce alcohol consumption and prevent alcohol-related harm, but there is a dearth of evidence to determine the feasibility and effectiveness of lay people having a role. The Greater Manchester (GM) Combined Authority (GMCA) and Greater Manchester Health and Social Care Partnership (GMHSCP) designed a new programme, 'Communities in Charge of Alcohol' (CICA) in 2017 to train lay volunteers to become alcohol health champions (AHCs), who would be able to (1) give alcohol-related brief advice to individuals and (2) help communities influence alcohol availability and strengthen restrictions in alcohol risk environments. Overall aims: To evaluate the effectiveness and cost–benefit of implementing a locally delivered AHC intervention and understand the context and factors that enable or hinder the intervention. Objectives: Relating to the outcome evaluation: to determine the effect on area-level key health performance indicators: alcohol-related hospital admissions (narrow measure), weekend accident and emergency (A&E) attendances (Friday 3 p.m.–Sunday 3 p.m.), weekday A&E attendances (Monday–Friday 9 a.m.–5 p.m. each day), weekend ambulance call-outs (Friday 3 p.m.–Sunday 3 p.m.), weekday ambulance call-outs (Monday–Friday 9 a.m.–5 p.m. each day) to determine the effect on key crime indicators (street-level crime data) at the weekend (Friday 3 p.m.–Sunday 3 p.m.) and weekday (Monday–Friday 9 a.m.–5 p.m. each day) to determine the effect on key antisocial behaviour (ASB) indicators (police recorded calls for service were classified as ASB according to the National Standard for Incident Recording). Relating to the process evaluation: to explore policy context and variation in licensing practice, including any impact of devolution in GM to explore barriers and facilitators at key stages of the implementation of the intervention: recruitment of AHCs to initial training and cascade training, delivery of initial training and cascade training, use of skills beyond the training in AHC activity, retention of AHCs to explore responses to AHC training, modelling of health behaviours, perceptions of community cohesion and development to determine numbers of brief interventions applied and community awareness events organised/participated in to examine and quantify the amount and success of community involvement in licensing issues to determine whether there was a change in composite measures of alcohol availability. Relating to the economic evaluation: to identify set-up and running costs using a standardised costing exercise to resolve costs by sector (health, ambulance and police) before, during and after set-up to quantify benefits due to reduced hospital admissions, ambulance call-outs, A&E use, crime and ASB. Methods: Communities in Charge of Alcohol was a complex intervention already planned by the GMCA in 10 small local authority areas (~1600–5500 residents each) and was outside direct researcher control. Intervention areas were chosen by each local authority public health team as having high levels of alcohol harm in comparison to the rest of the local authority. All intervention areas were at the bottom of the deprivation index, in deprivation decile 1 or 2. Using a stepped-wedge design, researchers were able to randomise the order of roll-out of intervention areas to bring a quasi-experimental approach to the evaluation. Two additional evaluation designs were used in order to triangulate findings, namely comparison to matched controls and comparison to synthetic controls. Ethical approval was received from the University of Salford Research Ethics Committee on 17 May 2017 (reference number: HSR1617–135) and obtained from the University of Bristol on 16 May 2019 (reference number: 82762). Outcome evaluation data sources: Routinely collected data at the lower-layer super output area (LSOA) level for intervention areas was compared with control areas. Data sources were as follows: alcohol-related hospital admissions data – Public Health England (now Office for Health Improvement and Disparities) accident and emergency department attendance data – NHS Digital ambulance call-out data – North West Ambulance Service reported crime and ASB data – GM Police. Analysis spanned a 10-year period (7 years pre intervention and a maximum of 3 years post implementation), ending in January 2020. Data were analysed using log-rate growth models and time series analyses to quantify the effect of the CICA programme on key performance indicators. Process evaluation data sources: Pre-implementation phase document review of local Statements of Licensing Policy (n = 9), alcohol availability composite score of on- and off-licensed premises (n = 9 areas), roll-out preparatory meeting notes. Train-the-Trainer attendance registers by area (n = 5, representing 9 areas, attended by 48 lay participants and 25 professional participants). Cascade training attendance registers by area (n = 11, representing 7 areas, attended by 47 lay participants and 3 professional participants). Pre- and post-training questionnaires (n = 93 lay people, 98% response rate). Baseline interviews with stakeholders (n = 20) (initial implementation phase); interviews with lay volunteer AHCs (n = 5, representing 3 areas) within 3–6 months of initial training (implementation phase). Follow-up interviews (12 months) with stakeholders (n = 11, representing eight areas), licensing officers (n = 6, representing six areas) and lay volunteer AHCs (n = 7, representing four areas); follow-up questionnaires with AHCs (n = 11); focus groups with local residents (n = 3 groups, representing two areas, with a total of 26 participants). Economic evaluation data sources: Time and transportation costs incurred during project meetings aggregated from meeting minutes and stakeholder time/cost diaries. Invoices for the design, development and delivery of training packages and accreditation fees. Invoices for the qualification and assessment fees, time and miscellaneous (transportation, room hire, catering, printing costs). AHC time and costs aggregated from volunteer diaries and stakeholder time/cost diaries. Invoices for engagement materials (AUDIT-C scratchcards). Greater Manchester Combined Authority research team's (formerly New Economy) cost–benefit analysis (CBA) tool was populated using aggregated outcome evaluation data to resolve costs for each key performance indicator before, during and after CICA setup. Results: Nine out of 10 local authorities rolled out the CICA intervention on their given start date: seven areas completed a full year, carrying out cascade training in the first 12 months, two areas withdrew at 6 and 9 months and one area withdrew in the pre-implementation phase. There were 118 [interquartile range (IQR): 60–205] alcohol-related hospital admissions per month per pre-intervention LSOA , rising to 134 (IQR : 67–203) post intervention. Some outcomes had very small counts at the LSOA level; notably, there were only 2 (IQR : 1–3) weekend crimes per month pre-intervention and 4 (IQR : 2–6) post intervention. The primary, stepped-wedge analyses provide weak evidence of an average increase in alcohol-related hospital admissions following the implementation of CICA of about 13%, corresponding to about 20 admissions weekly, although the confidence interval was wide, −1.98 to 31.39, and not statistically significant (p~0.09), while the analysis that made use of local controls suggested a bigger effect, at 16.4% (7.33–26.16, p < 0.001). However, the other methods of analysis (national controls and counterfactuals) indicated much smaller effect sizes and confidence intervals, including unity: 3.42% (−4.56 to 12.07; p = 0.41) and 7.14% (−9.76 to 24.04; p = 0.41), respectively. The other quantitative outcomes (A&E admissions, or ambulance call-outs to the area, nor to reported crimes or reported ASB incidents) showed some were individual statistically significant effects (with some methods and some indicators), but these were more often not in favour of the intervention. Triangulation of three methods of analysis did not indicate any consistent differences between control and intervention areas. The pre-implementation phase was defined as the period leading up to the roll-out of the first Train-the-Trainer event. Several facilitating contextual factors were identified a priori. The total number of these factors in place at baseline correlated with numbers trained in the first year (Rs = 0.77, p = 0.01). Specifically, areas with a healthcare provider to co-ordinate the intervention (p = 0.02); a pool of other volunteers to recruit from (p = 0.02); a contract in place with a commissioned service (p = 0.02); and formal volunteer arrangements (p = 0.03) trained more AHCs. Across all nine areas, fewer volunteers were recruited than the anticipated target of 35 per area. In total, 123 AHCs were trained and gained a Royal Society for Public Health Level 2 qualification. Of these, 95 were lay volunteers from the intervention areas. The majority identified as white (70%), with ages ranging from 18 to 65+, and almost half aged between 41 and 60 (48%). Slightly more women volunteered compared to men (61%). Most AHCs self-reported being in the lower-risk drinking category (66% scored 0–4 on AUDIT-C). Post-training questionnaires suggested that volunteers felt more confident to talk about the harms associated with alcohol and give alcohol-related brief advice than they did pre training (91.4% compared with 79.6%, p < 0.001) and that they felt more confident to raise issues about venues selling alcohol (90.3% compared with 74.2% pre training, p < 0.001). Intervention areas that recorded AHC activity (n = 5) captured 1100 conversations, 251 AUDIT-Cs completed and 65 community events attended. Time/cost diaries suggested that AHCs spent on average 11 minutes having an informal brief advice conversation. Interviews with AHCs on self-reported activity were consistent with time/cost and reflective diaries: AHCs put into practice brief advice conversations more than community action to influence licensing. Interviews with stakeholders indicated several enabling factors to consider when rolling out and embedding an AHC intervention: a clear understanding of the place-based focus; commissioned provider services needing a clear understanding of own roles and the anticipated outcomes; and co-ordinators having the skills and capacity to support inexperienced volunteer groups. The importance of infrastructure was reflected in interviews, recognising that preparing the ground at a hyperlocal level takes time, needing to be well in advance of the formal implementation period. Recruitment strategies need to be multipronged, and stakeholders need to be prepared to provide a sustained period of support for new and existing champions. In the follow-up phase, 12 months post intervention, interviews with stakeholders revealed how the local co-ordinators' ability to operationalise and sustain CICA was significantly impacted by their lack of capacity to sustain the levels of support, as well as the complexity of skills required of the role. After 12 months, there was strong consistency in findings from follow-up interviews with stakeholders, AHCs and focus groups with members of the public. Communities in Charge of Alcohol's intended mechanism of action was to reduce alcohol-related harm through secondary prevention interventions; however perceptions of those most in need of an AHC conversation were 'problem drinkers' to signpost into tertiary interventions. Quality of local alcohol treatment services was considered to be poor, with multiple barriers to help and information seeking. Conclusions: To our knowledge, CICA is the first alcohol-focused champion role of its kind to be investigated and across multiple intervention sites. It is also the first evaluation of a health champion programme that uses methodological triangulation to strengthen inferences about effectiveness. There was evidence that lay people trained as AHCs were able to have conversations with members of their communities who were consuming alcohol at higher risk levels, demonstrating a level of skill and confidence that can sometimes be absent in health professionals. AHCs, their co-ordinators and the public valued the role. However, significant infrastructure is needed to support an intervention such as CICA , and time is needed to develop and embed a group of volunteers. Despite evidence (from the process evaluation) of the planned activity taking place at local level, we were not able to show that CICA was effective, nor was it cost-effective. There are likely to be two main reasons for this. Firstly, the number of champions trained was too small to have a sufficient number of brief advice conversations to generate any measurable effect at the area level of analysis. Moreover, brief interventions may not directly impact on primary health and crime outcomes at a population level. Secondly, the AHCs were less willing (and had less opportunity) to get involved with alcohol licensing decisions. Since licensing policies theoretically have an impact at an area level, this theoretically would have been more likely to generate a significant area-level effect. The evidence from this study is that communities continue to struggle to influence statutory processes that affect alcohol availability where they live, and further consideration of how to enable increased community engagement is necessary. Recommendations for future research (numbered in priority order): natural experiment evaluations should include methodological triangulation to guard against overinterpretation of spurious results investigate coproducing a community outcomes framework to measure reductions in alcohol harm evaluate whether rebalancing local licensing policy to be community-centred might increase community engagement in the local licensing decision-making process investigate the effectiveness of CICA in areas where indicators of alcohol harm are increasing but are not at the highest level of harm within the local authority a wider range of external contextual factors could be tested in the pre-implementation phase of a complex intervention, incorporating methods to combine factors into mean scores, to test relationships between process indicators and outcomes. Trial registration: This trial is registered as ISRCTN81942890. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/129/03) and is published in full in Public Health Research; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. Methods: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. Results: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10–39; OR = 4.73, p = 2 × 10–10; OR = 2.3, p = 7.49 × 10–9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10–7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10–16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10–6). Conclusions: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2. [ABSTRACT FROM AUTHOR]

Background and Aim: Drinking alcohol may cause harm to an individual's health and social relationships, while a drinking culture may harm societies as it may increase crime rates and make an area feel less safe. Local councils in Greater Manchester, UK, developed the Communities in Charge of Alcohol (CICA) intervention, in which volunteers were trained to give alcohol‐related advice to the public and taught how to influence policies to restrict when, where and how alcohol is sold. As part of a larger study, the aim of the current project is to measure the impact of CICA on health and crime outcomes at the lower super output (LSOA) geographical aggregation. Design: Quantitative evaluation using four time series analytic methods (stepped‐wedge design, and comparisons to local controls, national controls and synthetic controls) with findings triangulated across these methods. A cost–benefit analysis was carried out alongside the effectiveness analysis. Setting and Participants: The general public in Greater Manchester, UK, between 2010 and 2020. Measurements: The primary outcome of interest was alcohol‐related hospital admissions. Secondary outcomes were accident and emergency (A&E) attendances, ambulance callouts, recorded crimes and anti‐social behaviour incidents. Findings Triangulation of the results did not indicate any consistent effect on area‐level alcohol‐related hospital admissions, A&E attendances, ambulance callouts, reported crimes or anti‐social behaviour associated with the implementation of CICA. The primary stepped‐wedge analysis indicated an increase in alcohol‐related hospital admissions following the implementation of CICA of 13.4% (95% confidence interval −3.3%, +30.1%), which was consistent with analyses based on other methods with point estimates ranging from +3.4% to 16.4%. Conclusion: There is no evidence of a measurable impact of the Communities in Charge of Alcohol (CICA) programme on area‐level health and crime outcomes in Greater Manchester, UK, within 3 years of the programme start. The increase in alcohol‐related hospital admissions was likely the result of other temporal trends rather than the CICA programme. Possible explanations include insufficient follow‐up time, too few volunteers trained, volunteers being unwilling to get involved in licensing decisions or that the intervention has no direct impact on the selected outcomes. [ABSTRACT FROM AUTHOR]

Social learning through friendships is important in child development. Autistic children often initiate and engage in social interactions differently than neurotypical peers. LEGO® based therapy is a group intervention which facilitates social interactions with peers using collaborative LEGO® play. A 1:1 cluster randomised controlled trial with autistic children aged 7–15 comparing 12 weeks' LEGO® based therapy and usual support to usual support alone in 98 mainstream schools (2017–2019) was carried out. The primary outcome was social skills (Social Skills Improvement System) completed by unblinded teachers (not intervention deliverers) at 20 weeks. Analysis used intention-to-treat. Fifty intervention schools (127 participants) and 48 control schools (123 participants) were allocated. Primary analysis included 45 intervention schools (116 participants) and 42 control schools (101 participants). The between-arms difference was 3.74 (p = 0.06, 95% confidence interval: −0.16, 7.63) and 1.68 (p = 0.43, 95% confidence interval: −2.51, 5.87) at 20 and 52 weeks (0.18 and 0.08 standardised effect sizes). Twenty-week outcomes for those receiving per protocol intervention were 4.23 (95% confidence interval 0.27, 8.19) with a standardised effect size of 0.21. Sensitivity estimates were between 3.10 and 4.37 (0.15–0.21 standardised effect sizes). Three unrelated serious adverse events were reported. LEGO® based therapy has a small positive non-significant benefit for social skills at 20 weeks but not 52 weeks. Autism is characterised by keen interests and differences in social interactions and communication. Activities that help autistic children and young people with social skills are commonly used in UK schools. LEGO® based therapy is a new activity that provides interesting and fun social opportunities for children and young people and involves building LEGO® models together. This study looked at LEGO® based therapy for the social skills of autistic children and young people in schools. It was a randomised controlled trial, meaning each school was randomly chosen (like flipping a coin) to either run LEGO® based therapy groups in school over 12 weeks and have usual support from school or other professionals, or only have usual support from school or other professionals. The effect of the LEGO® based therapy groups was measured by asking children and young people, their parents/guardians, and a teacher at school in both arms of the study to complete some questionnaires. The main objective was to see if the teacher's questionnaire answers about the children and young people's social skills changed between their first and second completions. The social skills of participants in the LEGO® based therapy groups were found to have improved in a small way when compared to usual support only. The study also found that LEGO® based therapy was not very costly for schools to run and parents/guardians and teachers said they thought it was good for their children and young people. We suggest further research into different potential benefits of LEGO® based therapy. [ABSTRACT FROM AUTHOR]