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Rashmi Mehta,1 Joseph Piscitelli,2 Allen Wolstenholme,3 Caifeng Fu,4 Herta Crauwels,5 Brian Wynne,6 Kimberly Adkison7 1GlaxoSmithKline, Research Triangle Park, NC, USA; 2UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA; 3GlaxoSmithKline, Collegeville, PA, USA; 4PAREXEL International, Durham, NC, USA; 5Janssen Pharmaceutical Companies, Beerse, Belgium; 6ViiV Healthcare, Collegeville, PA, USA; 7ViiV Healthcare, Research Triangle Park, NC, USACorrespondence: Kimberly AdkisonViiV Healthcare, 5 Moore Drive, Research Triangle Park, NC 27709, USATel +1 919 483-5867Email kim.k.adkison@viivhealthcare.comAbstract: Dolutegravir 50 mg (DTG) and rilpivirine 25 mg (RPV) are a newly approved 2-drug regimen for the treatment of HIV in virally suppressed patients. A 2-part study evaluated the relative bioavailability and food effect of five experimental fixed-dose combination (FDC) tablet formulations of DTG/RPV. When given with a moderate- or high-fat meal, the absorption of both DTG and RPV was increased, resulting in higher exposures. As per product labelling, DTG/RPV FDC should be taken with a meal.Keywords: food effect, pharmacokinetics, dolutegravir, rilpivirine

Abstract Background Societal changes have led to greater isolation and higher levels of loneliness particularly for older generations. Loneliness is a significant public health challenge leading to increased levels of poor mental health. Depression and anxiety are also increasing in prevalence amongst children and young people. Intergenerational activities are interventions designed to bring together older and younger generations with the purpose of allowing participants to utilise their experiences and skills, and to give participants a chance to experience the pleasure and excitement that occurs with the transmission of knowledge and skills from one generation to another. Intergenerational activities are therefore potential interventions that can address the growing problems associated with loneliness and lack of wellbeing. Objectives This systematic review aims to examine the impact of intergenerational interventions on the wellbeing and mental health in children and adolescents, and potential harmful effects. It also aims to identify areas for future research as well as key messages for service commissioners. Search Methods We searched an evidence and gap map published in 2022 (comprehensive searches conducted July 2021 and updated June 2023) to identify randomised controlled trials of intergenerational interventions that report mental health and wellbeing outcomes for children and young people. Selection Criteria Randomised controlled trials of intergenerational interventions that involved unrelated younger and older people with at least one skipped generation between them and reported mental health or wellbeing outcomes for children and young people were included in this review. Data Collection and Analysis We used standard methodological procedures expected by The Campbell Collaboration. We conducted data extraction and Cochrane risk of bias assessments in EPPI reviewer. Main Results While we identified 500 evaluations of intergenerational interventions, where the impact on participating children and/or young people was evaluated this was most often limited to assessing their impact on attitudes to aging. We identified five studies evaluating five different types of intergenerational interventions which included one‐off sessions to ones that spanned a year measuring their impact on the mental health and wellbeing of children and/or young people. The purposes of the interventions differed, which included promoting social skills, preventing harmful behaviour and promoting learning. The ages of children also varied across the five studies, with one targeting younger children, two targeting younger teenagers and two targeting older teenagers. One study included socioeconomically disadvantaged children, and in the other studies the socioeconomic backgrounds of the children and young people were not described. The outcome measures used to evaluate the interventions varied with none of the studies measuring the same outcomes. One study showed improvements in wellbeing measures, and this was an intervention delivered to children in deprived neighbourhoods, where the intervention duration was for a year allowing the development of a greater depth of relationship between the younger and older participants. Four studies found no……. The included studies were at high risk of bias therefore raising uncertainty in the reliability of the findings. Underpinning theories that supported the development of the interventions and explained the mechanisms of effect were poorly described. Authors' Conclusions The evidence for the effectiveness of intergenerational interventions on the mental health and wellbeing of children and young people is limited and inconclusive. Few evaluations have sought to measure how intergenerational interventions impact children and young people and where this impact is measured the focus is usually limited to attitudes to aging. The evidence that has been collected is too heterogenous to allow synthesis of the findings. The underpinning theories to support their development are poorly described with no follow‐up data to ascertain if benefits are maintained. Intergenerational interventions show promise but researchers have failed to measure how they impact on the mental health and wellbeing of children and young people. This is a serious limitation of the evidence base that needs to be addressed in robust and rigorous evaluations.

Ethanol’s anxiolytic actions contribute to increased consumption and the development of Alcohol Use Disorder (AUD). Our laboratory previously identified genetic loci contributing to the anxiolytic-like properties of ethanol in BXD recombinant inbred mice, derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. That work identified Ninein (Nin) as a candidate gene underlying ethanol’s acute anxiolytic-like properties in BXD mice. Nin has a complex exonic content with known alternative splicing events that alter cellular distribution of the NIN protein. We hypothesize that strain-specific differences in Nin alternative splicing contribute to changes in Nin gene expression and B6/D2 strain differences in ethanol anxiolysis. Using quantitative reverse-transcriptase PCR to target specific Nin splice variants, we identified isoform-specific exon expression differences between B6 and D2 mice in prefrontal cortex, nucleus accumbens and amygdala. We extended this analysis using deep RNA sequencing in B6 and D2 nucleus accumbens samples and found that total Nin expression was significantly higher in D2 mice. Furthermore, exon utilization and alternative splicing analyses identified eight differentially utilized exons and significant exon-skipping events between the strains, including three novel splicing events in the 3′ end of the Nin gene that were specific to the D2 strain. Additionally, we document multiple single nucleotide polymorphisms in D2 Nin exons that are predicted to have deleterious effects on protein function. Our studies provide the first in-depth analysis of Nin alternative splicing in brain and identify a potential genetic mechanism altering Nin expression and function between B6 and D2 mice, thus possibly contributing to differences in the anxiolytic-like properties of ethanol between these strains. This work adds novel information to our understanding of genetic differences modulating ethanol actions on anxiety that may contribute to the risk for alcohol use disorder.

IntroductionBinge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the susceptibility of these changes. Animal models to understand ethanol’s actions on myelin and white matter show that adolescent binge ethanol can alter the developmental trajectory of oligodendrocytes, myelin structure, and myelin fiber density. Oligodendrocyte differentiation is epigenetically regulated by H3K9 trimethylation (H3K9me3). Prior studies have shown that adolescent binge ethanol dysregulates H3K9 methylation and decreases H3K9-related gene expression in the PFC.MethodsHere, we assessed ethanol-induced changes to H3K9me3 occupancy at genomic loci in the developing adolescent PFC. We further assessed ethanol-induced changes at the transcription level with qPCR time course approaches in oligodendrocyte-enriched cells to assess changes in oligodendrocyte progenitor and oligodendrocytes specifically.ResultsAdolescent binge ethanol altered H3K9me3 regulation of synaptic-related genes and genes specific for glutamate and potassium channels in a sex-specific manner. In PFC tissue, we found an early change in gene expression in transcription factors associated with oligodendrocyte differentiation that may lead to the later significant decrease in myelin-related gene expression. This effect appeared stronger in males.ConclusionFurther exploration in oligodendrocyte cell enrichment time course and dose response studies could suggest lasting dysregulation of oligodendrocyte maturation at the transcriptional level. Overall, these studies suggest that binge ethanol may impede oligodendrocyte differentiation required for ongoing myelin development in the PFC by altering H3K9me3 occupancy at synaptic-related genes. We identify potential genes that may be contributing to adolescent binge ethanol-related myelin loss.

Abstract Historically, the NHS did not routinely collect cost data, unlike many countries with private insurance markets. In 1998, for the first time the government mandated NHS trusts to submit estimates of their costs of service, known as reference costs. These have informed a wide range of health economic evaluations and important functions in the health service, such as setting prices. Reference costs are collected by progressively disaggregating budgets top-down into disease and treatment groups. Despite ongoing improvements to methods and guidance, these submissions continued to suffer a lack of accuracy and comparability, fundamentally undermining their credibility for critical functions. To overcome these issues, there was a long-held ambition to collect “patient-level” cost data. Patient-level costs are estimated with a combination of disaggregating budgets but also capturing the patient-level “causality of costs” bottom-up in the allocation of resources to patient episodes. These not only aim to capture more of the drivers of costs, but also improve consistency of reporting between providers. The change in methods may confer improvements to data quality, though judgement is still required and achieving consistency between trusts will take further work. Estimated costs may also change in important ways that may take many years to fully understand. We end on a cautionary note that patient-level cost methods may unlock potential, they alone contribute little to our understanding of the complexities involved with service quality or need, while that potential will require substantial investment to realise. Many healthcare resources cannot be attributed to individual patients so the very notion of “patient-level” costs may be misplaced. High hopes have been put in these new data, though much more work is now necessary to understand their quality, what they show and how their use will impact the system.

Abstract Increased extreme heat events draw attention to the potential of urban nature as a heat adaptation strategy for cities. This is reflected in multiple scientific perspective pieces, policy documents and science media publications advocating for urban greening as a cooling approach. Although attention to the dangers of heat and the benefits of urban nature is welcomed, it is vital that nature-based approaches to cooling are underpinned by diverse knowledge and a sound understanding of what nature in cities can and cannot do. We explain why an evidence-driven and cautious approach to heat adaptation through urban greening is so important, and propose three actions that urban actors can take towards effective and equitable long-term cooling through urban nature: enabling dialogue between different sectors with multiple remits; including diverse knowledge systems in planning and governance processes; and investing in long-term stewardship for the climatological and societal conditions of the coming decades. Policy and practice recommendation • Create fora for dialogue between governments, residents, civil society and developers from planning stage for green cooling; • Cooling through nature must be driven by expertise spanning diverse knowledge systems, combined with local knowledge and community needs; • Consider future climates and stewardship when planning urban cooling via nature. Science highlights • Understanding link between urban thermal environment and nature is an inter- and transdisciplinary task; • Critical need for evidence of how greening reduces heat impacts across different social and cultural contexts; • Evidence of how species perform under future climates required for stewardship of urban nature.

Abstract Educational Leadership in Teaching Excellence (EnLITE) is an 11-month faculty development program at the University of Guelph, Ontario. Created and led by faculty members and educational developers, EnLITE is designed to engage participants in the principles, practice and theory of teaching and learning in higher education and to promote a learner-centred approach to teaching. Participants critically examine and discuss scholarly topics on teaching and learning and in their own disciplines; collaborate with one or more teaching mentors; engage in peer classroom observation; and participate in other teaching-related activities informed by their individual learning plans. Our objective was to determine the perceived impact of EnLITE on participants' teaching-related practices and experiences. We collected pre-, post- and one-year post-program quantitative and qualitative survey responses from each of the 2014-2015, 2015-2016 and 2016-2017 EnLITE cohorts (N = 17 participants representing a variety of disciplines; 71% female). There were significant improvements in participants' perceived teaching practices related to critical self-reflection (13% increase from pre- to one-year post-program), student engagement (+28.2%), collaborative learning (+31%) and learner-centred pedagogy (+22.9%, all p < 0.05). There was little to no change in use of technology, student assessment, leadership, participation in communities of practice, or dissemination of teaching-related scholarship. These results provide empirical evidence of the effectiveness of a peer-driven faculty development program in promoting a learning-centred approach to teaching. Future research should determine whether these changes translate into improved student learning, and whether such programs demonstrate longer term improvements in engagement in teaching-related leadership, communities of practice and dissemination.

Abstract While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors.

Aims and method Factors influencing trainees’ decisions about choosing and remaining in higher training subspecialties have not been widely researched. We administered telephone questionnaires to higher specialist trainees in the north-east of England to ascertain what influences these decisions. Thematic analysis was employed to develop overall constructs. Results Twenty-seven trainees were interviewed, resulting in six overall constructs. These were: supervisory experiences; perceived work–life balance; career prospects; training and working environments; interest in the chosen subspecialty; and previous experience within the chosen subspecialty. Most trainees interviewed felt they had made the right specialty choice. Clinical implications This study demonstrates the particular importance of exposure to a specialty and perceptions of the supervisory experience in determining trainees’ choices of, and decisions to remain in, a particular psychiatric specialty. Factors highlighted in this study must inform training, recruitment and workforce planning in order to bolster the recruitment and retention of trainees into higher specialty training.

IntroductionAdolescence is a critical period in cognitive and emotional development, characterized by high levels of social interaction and increases in risk-taking behavior including binge drinking. Adolescent exposure to social stress and binge ethanol have individually been associated with the development of social, emotional, and cognitive deficits, as well as increased risk for alcohol use disorder. Disruption of cortical development by early life social stress and/or binge drinking may partly underlie these enduring emotional, cognitive, and behavioral effects. The study goal is to implement a novel neighbor housing environment to identify the effects of adolescent neighbor housing and/or binge ethanol drinking on (1) a battery of emotional and cognitive tasks (2) adult ethanol drinking behavior, and (3) the nucleus accumbens and prefrontal cortex transcriptome.MethodsAdolescent male and female C57BL/6J mice were single or neighbor housed with or without access to intermittent ethanol. One cohort underwent behavioral testing during adulthood to determine social preference, expression of anxiety-like behavior, cognitive performance, and patterns of ethanol intake. The second cohort was sacrificed in late adolescence and brain tissue was used for transcriptomics analysis.ResultsAs adults, single housed mice displayed decreased social interaction, deficits in the novel object recognition task, and increased anxiety-like behavior, relative to neighbor-housed mice. There was no effect of housing condition on adolescent or adult ethanol consumption. Adolescent ethanol exposure did not alter adult ethanol intake. Transcriptomics analysis revealed that adolescent housing condition and ethanol exposure resulted in differential expression of genes related to synaptic plasticity in the nucleus accumbens and genes related to methylation, the extracellular matrix and inflammation in the prefrontal cortex.DiscussionThe behavioral results indicate that social interaction during adolescence via the neighbor housing model may protect against emotional, social, and cognitive deficits. In addition, the transcriptomics results suggest that these behavioral alterations may be mediated in part by dysregulation of transcription in the frontal cortex or the nucleus accumbens.

There is an urgent need to engage with deep leverage points in sustainability transformations—fundamental myths, paradigms, and systems of meaning making—to open new collective horizons for action. Art and creative practice are uniquely suited to help facilitate change in these deeper transformational leverage points. However, understandings of how creative practices contribute to sustainability transformations are lacking in practice and fragmented across theory and research. This lack of understanding shapes how creative practices are evaluated and therefore funded and supported, limiting their potential for transformative impact. This paper presents the 9 Dimensions tool, created to support reflective and evaluative dialogues about links between creative practice and sustainability transformations. It was developed in a transdisciplinary process between the potential users of this tool: researchers, creative practitioners, policy makers, and funders. It also brings disciplinary perspectives on societal change from evaluation theory, sociology, anthropology, psychology, and more in connection with each other and with sustainability transformations, opening new possibilities for research. The framework consists of three categories of change, and nine dimensions: changing meanings (embodying, learning, and imagining); changing connections (caring, organizing, and inspiring); and changing power (co-creating, empowering, and subverting). We describe how the 9 Dimensions tool was developed, and describe each dimension and the structure of the tool. We report on an application of the 9 Dimensions tool to 20 creative practice projects across the European project Creative Practices for Transformational Futures (CreaTures). We discuss user reflections on the potential and challenges of the tool, and discuss insights gained from the analysis of the 20 projects. Finally, we discuss how the 9 Dimensions can effectively act as a transdisciplinary research agenda bringing creative practice further in contact with transformation research.

'Mastery' is central to current policy in mathematics education in England, influenced by East Asian success in transnational assessments. We scrutinise the prospects for mastery pedagogies to improve pupil attainment in English primary schools. The Mathematics Teacher Exchange (MTE)--an element of the mastery innovation--involves teachers visiting Shanghai and then hosting Shanghai teachers in their schools. Informed by programme evaluation, core component practices are analysed, which were implemented by schools belonging to the first cohort of MTE schools. These consist of: varied and interactive teaching; meaningful and coherent mathematical activity; and full curriculum access for all. These elements are supported, optimally, by collaborative, embedded, and mathematically focused professional development. Details of the implemented pedagogy and forms of professional development are reported. Differences from prevailing practice in primary mathematics in England are highlighted. Evidence is reviewed from quasi-experimental trials, reviews and meta-analyses, and rigorous observational studies of the efficacy of practices similar to the MTE mastery pedagogy components in order to assess the prospects for increases in pupil attainment. The analysis suggests that many of the specific practices, if considered individually, have the potential to improve attainment, though overall policy ambitions may not be realised. Based on the review, component practices are identified for which existing evidence justifies immediate implementation by schools and teachers. In addition, practices that would benefit from further testing and evaluation are highlighted.

Abstract This is the protocol for a Campbell systematic review. The objectives are as follows: this systematic review will examine the impact of intergenerational interventions on the wellbeing and mental health in children and young people and will identify areas for future research as well as key messages for service commissioners.

Abstract Background Despite growing enthusiasm for co-production in healthcare services and research, research on co-production practices is lacking. Multiple frameworks, guidelines and principles are available but little empirical research is conducted on ‘how to do’ co-production of research to improve healthcare services. This paper brings together insights from UK-based collaborative research partnerships on leading co-production. Its aim is to inform practical guidance for new partnerships planning to facilitate the co-production of applied health research in the future. Methods Using an auto-ethnographic approach, experiential evidence was elicited through collective sense making from recorded conversations between the research team and senior leaders of five UK-based collaborative research partnerships. This approach applies a cultural analysis and interpretation of the leaders’ behaviours, thoughts and experiences of co-production taking place in 2008–2018 and involving academics, health practitioners, policy makers and representatives of third sector organisations. Results The findings highlight a variety of practices across CLAHRCs, whereby the intersection between the senior leaders’ vision and local organisational context in which co-production occurs largely determines the nature of co-production process and outcomes. We identified four tensions in doing co-production: (1) idealistic, tokenistic vs realistic narratives, (2) power differences and (lack of) reciprocity, (3) excluding vs including language and communication, (4) individual motivation vs structural issues. Conclusions The tensions were productive in helping collaborative research partnerships to tailor co-production practices to their local needs and opportunities. Resulting variation in co-production practices across partnerships can therefore be seen as highly advantageous creative adaptation, which makes us question the utility of seeking a unified ‘gold standard’ of co-production. Strategic leadership is an important starting point for finding context-tailored solutions; however, development of more distributed forms of leadership over time is needed to facilitate co-production practices between partners. Facilitating structures for co-production can enable power sharing and boost capacity and capability building, resulting in more inclusive language and communication and, ultimately, more credible practices of co-production in research. We provide recommendations for creating more realistic narratives around co-production and facilitating power sharing between partners.

Abstract Plantation forests constitute a significant amount of the wooded area in many parts of the globe. However, the extent of biological provision conferred by plantation forest depends on regional conservation priorities and biogeographical context. Here, we evaluate the arthropod biodiversity in a chronosequence of pine plantation (clear‐felled, 1, 3, 5, 7, 9, 13, 21‐years) in the largest lowland conifer forest in the UK. We compare the assemblage within 37 plantation stands and eight important open habitat remnants in a formerly heathland dominated region. We also assess the configuration and potential isolation of ephemeral open early growth stage habitat across a 60‐year plantation rotation. Carabid and spider assemblages changed throughout the sampled chronosequence. In the early growth stages (1–7 years) before canopy closure, arthropod assemblages contained many individuals and species associated with dry‐open habitats, greater numbers of rare species than closed canopy plantation and had similar composition (non‐metric multidimensional scaling) to heathland samples. Early growth stages and heathlands primarily differed in the additional presence of generalist species in the plantation. Species associated with woodland increased in abundance as the plantation aged, but remained far less numerous than dry‐open or generalist species. The spatial distribution of young growth stages across the rotation cycle was significantly clustered in the early and late rotation phases. Plantation landscapes often support high species richness but we highlight their value for vulnerable heathland biodiversity early in the rotation cycle. To increase plantation value regional conservation priorities should be supported with appropriate consideration of growth stage configuration across the full rotation.

Background Implementation of national multiprofessional training for managing the obstetric emergency of impacted fetal head (IFH) at caesarean birth has potential to improve quality and safety in maternity care, but is currently lacking in the UK.Objectives To evaluate a training package for managing IFH at caesarean birth with multiprofessional maternity teams.Methods The training included an evidence-based lecture supported by an animated video showing management of IFH, followed by hands-on workshops and real-time simulations with use of a birth simulation trainer, augmented reality and management algorithms. Guided by the Kirkpatrick framework, we conducted a multimethod evaluation of the training with multiprofessional maternity teams. Participants rated post-training statements about relevance and helpfulness of the training and pre-training and post-training confidence in their knowledge and skills relating to IFH (7-point Likert scales, strongly disagree to strongly agree). An ethnographer recorded sociotechnical observations during the training. Participants provided feedback in post-training focus groups.Results Participants (N=57) included 21 midwives, 25 obstetricians, 7 anaesthetists and 4 other professionals from five maternity units. Over 95% of participants agreed that the training was relevant and helpful for their clinical practice and improving outcomes following IFH. Confidence in technical and non-technical skills relating to managing IFH was variable before the training (5%–92% agreement with the pre-training statements), but improved in nearly all participants after the training (71%–100% agreement with the post-training statements). Participants and ethnographers reported that the training helped to: (i) better understand the complexity of IFH, (ii) recognise the need for multiprofessional training and management and (iii) optimise communication with those in labour and their birth partners.Conclusions The evaluated training package can improve self-reported knowledge, skills and confidence of multiprofessional teams involved in management of IFH at caesarean birth. A larger-scale evaluation is required to validate these findings and establish how best to scale and implement the training.

Abstract Aberrant protein aggregation leads to various human diseases, but little is known about the physical chemical properties of these aggregated proteins in cells. Herein, we developed a boron‐dipyrromethene (BODIPY)‐based HaloTag probe, whose conjugation to HaloTag‐fused proteins allows us to study protein aggregates using both fluorescence intensity and lifetime. Modulation of BODIPY fluorophore reveals key structural features to attain the dual function. The optimized probe exhibits increased fluorescence intensity and elongated fluorescence lifetime in protein aggregates. Fluorescence lifetime imaging using this probe indicates that protein aggregates afford different viscosity in the forms of soluble oligomers and insoluble aggregates in live cells. The strategy presented in this work can be extended to enable a wide class of HaloTag probes that can be used to study a variety of physical properties of protein aggregates, thus helping unravel the pathogenic mechanism and develop therapeutic strategy.

Background Influenza and influenza-like illness place significant burden on the NHS. Children with underlying health conditions are vulnerable to developing bacterial complications. Objective To strengthen the evidence base underlying antibiotic use in at-risk children with influenza-like illness. Design This programme comprised five separate work packages. Work package A investigated published and unpublished data from previously published literature and work package B explored attitudes of parents and general practitioners to influenza-like illness and antibiotics in at-risk children. This was followed by a clinical trial to assess the effectiveness of early co-amoxiclav (Augmentin®, GlaxoSmithKline UK) use at reducing reconsultation due to clinical deterioration (work package C), a nested sub-study to examine bacterial carriage indicators of antibiotic resistance (work package D) and a within-trial economic evaluation and clinical risk prediction analysis (work package E). Setting Interviews were conducted by telephone with general practitioners across the UK and parents/guardians in England (work package B). We conducted the clinical trial (work package C and nested work packages D and E) in general practices and ambulatory care services in England and Wales. Participants General practitioners and parents/guardians of at-risk children who previously had influenza-like illness participated in work package B. At-risk children with influenza-like illness aged 6 months to 12 years participated in work packages C and E and optionally in work package D. Interventions The intervention for the clinical trial was a 5-day course of co-amoxiclav 400/57 with dosing regimens based on British National Formulary guidance. Main outcome measures Hospital admission (work package A); findings from semi-structured interviews with patients and health-care professionals (work package B); proportion of patients who reconsulted owing to clinical deterioration (work package C); respiratory bacterial carriage and antibiotic resistance of potentially pathogenic respiratory tract bacteria at 3, 6, 9 and 12 months (work package D); and risk factors for reconsultation owing to clinical deterioration, quality of life (EuroQol-5 Dimensions, three-level youth version), symptoms (Canadian Acute Respiratory Infection and Flu Scale), health-care use and costs (work package E). Review methods For work package A, we searched the MEDLINE, MEDLINE In-Process, EMBASE, Science Citation Index and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases until 3 April 2013 with no language restrictions and requested unpublished data from authors of studies which had collected but not published relevant data. We included studies involving children up to 18 years of age with influenza or influenza-like illness from primary or ambulatory care settings. We used univariable meta-analysis methods to calculate odds ratios with 95% confidence intervals for individual risk factors. We reported our systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2009 statement. Results Work package A analysed data from 28 articles reporting data from 27 studies. Neurological disorders, sickle cell disease, immunosuppression, diabetes and an age of

Abstract Background Opportunities for social connection between generations in the UK have diminished over the last few decades because of changes in the way that we live and work. The decline in communal spaces such as libraries, youth clubs and community centres mean that there are fewer opportunities to meet and mix socially with other generations outside our own families. Increased working hours, improved technology, changes in family patterns, relationship breakdowns within families and migration are also believed to be contributory factors to generation segregation. There are many potential economic, social and political impacts of generations living separate and parallel lives, for example, higher health and social care costs, an undermining of trust between generations reduced social capital, a reliance on the media to form understanding of others’ viewpoints and higher levels of anxiety and loneliness. Intergenerational programmes and activities can take many forms and are delivered in many settings. Evidence suggests that intergenerational activity can have a positive impact on participants, for example, in reducing loneliness and exclusion for both older people and children and young people, improving mental health, increasing mutual understanding and addressing important issues such as ageism, housing and care. There are currently no other EGMs that exist that address this type of intervention; however, it would complement existing EGMs addressing child welfare. Objectives To identify, appraise and bring together the evidence on the use of intergenerational practice, to answer the following specific research questions: What is the volume, nature and diversity of research on, and evaluation of, intergenerational practice and learning? What approaches have been used to deliver intergenerational activities and programmes that may be relevant to providing such services during and in the subsequent recovery from the COVID‐19 pandemic? What promising intergenerational activities and programmes have been developed and are being used but have not yet been subject to formal evaluation? Search Methods We searched MEDLINE (via OvidSp), EMBASE (via OvidSp), PsycINFO (via OvidSp), CINAHL (via EBSCOHost), Social Policy and Practice (via OvidSp), Health Management Information Consortium (via OvidSp), Ageline (via EBSCOhost), ASSIA (via ProQuest), Social Science Citations Index (via Web of Science), ERIC (via EBSCOhost), Community Care Inform Children, Research in Practice for Children, ChildData (via Social Policy and Practice), the Campbell Library, the Cochrane Database of Systematic Reviews and the CENTRAL database between 22 and 30 July 2021. We searched for additional grey literature via the Conference Proceedings Citation Index (via Web of Science) and ProQuest Dissertation & Theses Global and via relevant organisation websites, for example, Age UK, Age International, the Centre for Ageing Better, Barnado's, Children's Commission, UNICEF, Generations Working Together, the Intergenerational Foundation, Linking Generations and The Beth Johnson Foundation) and the Ottawa initiative called Older Adults and Students for Intergenerational support. Selection Criteria Any intervention that brings older and younger people together with the purpose of interacting to achieve positive health and/or social and/or educational outcomes from any study design including systematic reviews, randomised controlled studies, observational studies, surveys and qualitative studies are included. The titles and abstracts, and later full texts, of records identified by the search methods were screened against inclusion criteria by two independent reviewers. Data Collection and Analysis Data extraction was undertaken by one reviewer and checked by a second with any inconsistencies identified and resolved through discussion. The data extraction tool was developed on EPPI reviewer and was modified and tested through stakeholder and advisor consultation, and piloting of the process. The tool was informed by the research question and the structure of the map. We did not undertake quality appraisal of the included studies. Main Results Our searches identified 12,056 references, after screening 500 research articles were included in the evidence gap map conducted across 27 countries. We identified 26 systematic reviews, 236 quantitative comparative studies (of which 38 were randomised controlled trials), 227 were qualitative studies (or had a qualitative element), 105 were observational studies (or had elements of observational methods) and 82 used a mixed methods approach. The outcomes reported in the research cover mental health (n = 73), physical health (n = 62), attainment and knowledge (n = 165), agency (n = 174), mental wellbeing (n = 224), loneliness and social isolation (n = 54), attitudes towards the other generation (n = 283), intergenerational interactions (n = 196), peer interactions (n = 30) and health promotion (n = 23) and including mutual outcomes such as the impact on community (n = 37) and perceptions on the sense of community (n = 43). Gaps in the evidence that were identified include: research that reports on mutual, societal and community outcomes of intergenerational interventions; more research on interventions classified as levels 1–4 and level 7 on the Intergenerational Engagement Scale, mental health, loneliness, social isolation, peer interactions, physical health and health promotion outcomes in children and young people; health promotion in older people; outcomes centred on care giver wellbeing, mental health and attitudes; economic outcomes; process outcomes and adverse or unexpected outcomes. Authors’ Conclusions Whilst a substantional amount of research on intergenerational interventions has been identified in this EGM, as well as the gaps identified above, there is a need to explore promising interventions not yet formally evaluated. Research on this topic is gradually increasing, and systematic reviews will be important to determine how and why interventions are or are not beneficial. However, the primary research needs to build more cohesively so that the findings can be comparable and avoid research waste. The EGM presented here will nevertheless be a useful resource for decision‐makers allowing them to explore the evidence with regard to the different interventions that may be relevant to their population needs and the settings or resources available to them.

Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4 g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA-and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis – a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.