The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

Association of latent class analysis-derived multimorbidity clusters with adverse health outcomes in patients with multiple long-term conditions: comparative results across three UK cohorts.

Background: It remains unclear how to meaningfully classify people living with multimorbidity (multiple long-term conditions (MLTCs)), beyond counting the number of conditions. This paper aims to identify clusters of MLTCs in different age groups and associated risks of adverse health outcomes and service use. Methods: Latent class analysis was used to identify MLTCs clusters in different age groups in three cohorts: Secure Anonymised Information Linkage Databank (SAIL) (n = 1,825,289), UK Biobank (n = 502,363), and the UK Household Longitudinal Study (UKHLS) (n = 49,186). Incidence rate ratios (IRR) for MLTC clusters were computed for: all-cause mortality, hospitalisations, and general practice (GP) use over 10 years, using <2 MLTCs as reference. Information on health outcomes and service use were extracted for a ten year follow up period (between 01st Jan 2010 and 31st Dec 2019 for UK Biobank and UKHLS, and between 01st Jan 2011 and 31st Dec 2020 for SAIL). Findings: Clustering MLTCs produced largely similar results across different age groups and cohorts. MLTC clusters had distinct associations with health outcomes and service use after accounting for LTC counts, in fully adjusted models. The largest associations with mortality, hospitalisations and GP use in SAIL were observed for the "Pain+" cluster in the age-group 18-36 years (mortality IRR = 4.47, hospitalisation IRR = 1.84; GP use IRR = 2.87) and the "Hypertension, Diabetes & Heart disease" cluster in the age-group 37-54 years (mortality IRR = 4.52, hospitalisation IRR = 1.53, GP use IRR = 2.36). In UK Biobank, the "Cancer, Thyroid disease & Rheumatoid arthritis" cluster in the age group 37-54 years had the largest association with mortality (IRR = 2.47). Cardiometabolic clusters across all age groups, pain/mental health clusters in younger groups, and cancer and pulmonary related clusters in older age groups had higher risk for all outcomes. In UKHLS, MLTC clusters were not significantly associated with higher risk of adverse outcomes, except for the hospitalisation in the age-group 18-36 years. Interpretation: Personalising care around MLTC clusters that have higher risk of adverse outcomes may have important implications for practice (in relation to secondary prevention), policy (with allocation of health care resources), and research (intervention development and targeting), for people living with MLTCs. Funding: This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)-NIHR202020).

Alcohol attention bias modulates neural engagement during moral processing.

The neurobiology of typical moral cognition involves the interaction of frontal, limbic, and temporoparietal networks. There is still much to be understood mechanistically about how moral processing is disrupted; such understanding is key to combating antisociality. Neuroscientific models suggest a key role for attention mechanisms in atypical moral processing. We hypothesized that attention-bias toward alcohol cues in alcohol use disorder (AUD) leads to a failure to properly engage with morally relevant stimuli, reducing moral processing. We recruited patients with AUD (n = 30) and controls (n = 30). During functional magnetic resonance imaging, participants viewed pairs of images consisting of a moral or neutral cue and an alcohol or neutral distractor. When viewing moral cues paired with alcohol distractors, individuals with AUD had lower medial prefrontal cortex engagement; this pattern was also seen for left amygdala in younger iAUDs. Across groups, individuals had less engagement of middle/superior temporal gyri. These findings provide initial support for AUD-related attention bias interference in sociomoral processing. If supported in future longitudinal and causal study designs, this finding carries potential societal and clinical benefits by suggesting a novel, leverageable mechanism and in providing a cognitive explanation that may help combat persistent stigma.

Development of a group-based behaviour change intervention for people with severe obesity informed by the social identity approach to health.

INTRODUCTION: Interventions to support behaviour change in people living with chronic health conditions increasingly use patient groups as the mode of delivery, but these are often designed without consideration of the group processes that can shape intervention outcomes. This article outlines a new approach to designing group-based behaviour change interventions that prioritizes recipients' shared social identity as group members in facilitating the adoption of established behaviour change techniques (BCTs). The approach is illustrated through an example drawn from research focused on people living with severe obesity. METHODS: A prioritization process was undertaken in collaboration with stakeholders, including behaviour change experts, clinicians, and a former patient to develop an evidence-based, group intervention informed by the social identity approach to health. Three phases of development are reported: (1) identification of the health problem; (2) delineation of intervention mechanisms and operationalization of BCTs for group delivery and (3) intervention manualization. The fourth phase, intervention testing and optimization, is reported elsewhere. RESULTS: A group-based behaviour change intervention was developed, consisting of 12 group sessions and 3 one-to-one consultations. The intervention aimed to support the development of shared social identity among recipients, alongside the delivery of evidence-based BCTs, to improve the likelihood of successful intervention and health outcomes among people living with severe obesity. CONCLUSIONS: A manualized intervention, informed by the social identity approach to health, was systematically designed with input from stakeholders. The development approach employed can inform the design of behavioural interventions in other health contexts where group-based delivery is planned.

Evidence for exercise-based interventions across 45 different long-term conditions: an overview of systematic reviews.

Background: Almost half of the global population face significant challenges from long-term conditions (LTCs) resulting in substantive health and socioeconomic burden. Exercise is a potentially key intervention in effective LTC management. Methods: In this overview of systematic reviews (SRs), we searched six electronic databases from January 2000 to October 2023 for SRs assessing health outcomes (mortality, hospitalisation, exercise capacity, disability, frailty, health-related quality of life (HRQoL), and physical activity) related to exercise-based interventions in adults (aged >18 years) diagnosed with one of 45 LTCs. Methodological quality was assessed using AMSTAR-2. International Prospective Resister of Systematic Reviews (PROSPERO) ID: CRD42022319214. Findings: Forty-two SRs plus three supplementary RCTs were included, providing 990 RCTs in 936,825 people across 39 LTCs. No evidence was identified for six LTCs. Predominant outcome domains were HRQoL (82% of SRs/RCTs) and exercise capacity (66%); whereas disability, mortality, physical activity, and hospitalisation were less frequently reported (≤25%). Evidence supporting exercise-based interventions was identified in 25 LTCs, was unclear for 13 LTCs, and for one LTC suggested no effect. No SRs considered multimorbidity in the delivery of exercise. Methodological quality varied: critically-low (33%), low (26%), moderate (26%), and high (12%). Interpretation: Exercise-based interventions improve HRQoL and exercise capacity across numerous LTCs. Key evidence gaps included limited mortality and hospitalisation data and consideration of multimorbidity impact on exercise-based interventions. Funding: This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)-NIHR202020).

An online training resource for clinicians to optimise exercise prescription for persistent low back pain: Design, development and usability testing.

BACKGROUND: Low back pain (LBP) is the leading cause of disability worldwide. A recent realist review identified the behavioural mechanisms of trust, motivation, and confidence as key to optimising exercise prescription for persistent LBP. OBJECTIVES: Our objectives were to (1) design and develop an online training programme, and (2) gain end-user feedback on the useability, usefulness, informativeness and confidence in using the online training programme using a mixed-methods, pre-post study design. PARTICIPANTS AND INTERVENTION: The online training programme was designed and developed using the results from a realist review, and input from a multi-disciplinary stakeholder group. A five-module online training programme was piloted by the first 10 respondents who provided feedback on the course. Further modifications were made prior to additional piloting. The satisfaction, usefulness, ease of use, and confidence of clinicians in applying the learned principles were assessed on completion. RESULTS: The online programme was advertised to clinicians using social media. Forty-four respondents expressed initial interest, of which 22 enrolled and 18 completed the course. Of the participants, most were physiotherapists (n = 16/18, 88.9%), aged between 30 and 49 (n = 11/18, 61.1%). All participants were satisfied with the course content, rated the course platform as easy to use and useful, and reported that they were very confident to apply the learning. Most (n = 10/14, 71.4%) reported that their manner of prescribing exercise had changed after completion of the course. CONCLUSIONS: An online training programme to optimise exercise prescription for persistent LBP appears to be easy to use, informative and improves confidence to apply the learning.

Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (PERFORM): protocol for a randomised feasibility trial.

INTRODUCTION: Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (PERFORM) is a research programme that seeks to develop and evaluate a comprehensive exercise-based rehabilitation intervention designed for people with multimorbidity, the presence of multiple long-term conditions (MLTCs). This paper describes the protocol for a randomised trial to assess the feasibility and acceptability of the PERFORM intervention, study design and processes. METHODS AND ANALYSIS: A multicentre, parallel two-group randomised trial with individual 2:1 allocation to the PERFORM exercise-based intervention plus usual care (intervention) or usual care alone (control). The primary outcome of this feasibility trial will be to assess whether prespecified progression criteria (recruitment, retention, intervention adherence) are met to progress to the full randomised trial. The trial will be conducted across three UK sites and 60 people with MLTCs, defined as two or more LTCs, with at least one having evidence of the beneficial effect of exercise. The PERFORM intervention comprises an 8-week (twice a week for 6 weeks and once a week for 2 weeks) supervised rehabilitation programme of personalised exercise training and self-management education delivered by trained healthcare professionals followed by two maintenance sessions. Trial participants will be recruited over a 4.5-month period, and outcomes assessed at baseline (prerandomisation) and 3 months postrandomisation and include health-related quality of life, psychological well-being, symptom burden, frailty, exercise capacity, physical activity, sleep, cognition and serious adverse events. A mixed-methods process evaluation will assess acceptability, feasibility and fidelity of intervention delivery and feasibility of trial processes. An economic evaluation will assess the feasibility of data collection and estimate the costs of the PERFORM intervention. ETHICS AND DISSEMINATION: The trial has been given favourable opinion by the West Midlands, Edgbaston Research Ethics Service (Ref: 23/WM/0057). Participants will be asked to give full, written consent to take part by trained researchers. Findings will be disseminated via journals, presentations and targeted communications to clinicians, commissioners, service users and patients and the public. TRIAL REGISTRATION NUMBER: ISRCTN68786622. PROTOCOL VERSION: 2.0 (16 May 2023).

Deep learning to predict rapid progression of Alzheimer's disease from pooled clinical trials: A retrospective study.

The rate of progression of Alzheimer's disease (AD) differs dramatically between patients. Identifying the most is critical because when their numbers differ between treated and control groups, it distorts the outcome, making it impossible to tell whether the treatment was beneficial. Much recent effort, then, has gone into identifying RPs. We pooled de-identified placebo-arm data of three randomized controlled trials (RCTs), EXPEDITION, EXPEDITION 2, and EXPEDITION 3, provided by Eli Lilly and Company. After processing, the data included 1603 mild-to-moderate AD patients with 80 weeks of longitudinal observations on neurocognitive health, brain volumes, and amyloid-beta (Aß) levels. RPs were defined by changes in four neurocognitive/functional health measures. We built deep learning models using recurrent neural networks with attention mechanisms to predict RPs by week 80 based on varying observation periods from baseline (e.g., 12, 28 weeks). Feature importance scores for RP prediction were computed and temporal feature trajectories were compared between RPs and non-RPs. Our evaluation and analysis focused on models trained with 28 weeks of observation. The models achieved robust internal validation area under the receiver operating characteristic (AUROCs) ranging from 0.80 (95% CI 0.79-0.82) to 0.82 (0.81-0.83), and the area under the precision-recall curve (AUPRCs) from 0.34 (0.32-0.36) to 0.46 (0.44-0.49). External validation AUROCs ranged from 0.75 (0.70-0.81) to 0.83 (0.82-0.84) and AUPRCs from 0.27 (0.25-0.29) to 0.45 (0.43-0.48). Aß plasma levels, regional brain volumetry, and neurocognitive health emerged as important factors for the model prediction. In addition, the trajectories were stratified between predicted RPs and non-RPs based on factors such as ventricular volumes and neurocognitive domains. Our findings will greatly aid clinical trialists in designing tests for new medications, representing a key step toward identifying effective new AD therapies.

Inflammation, endothelial injury, and the acute respiratory distress syndrome after out-of-hospital cardiac arrest.

Background: Acute respiratory distress syndrome (ARDS) is often seen in patients resuscitated from out-of-hospital cardiac arrest (OHCA). We aim to test whether inflammatory or endothelial injury markers are associated with the development of ARDS in patients hospitalized after OHCA. Methods: We conducted a prospective, cohort, pilot study at an urban academic medical center in 2019 that included a convenience sample of adults with non-traumatic OHCA. Blood and pulmonary edema fluid (PEF) were collected within 12 hours of hospital arrival. Samples were assayed for cytokines (interleukin [IL]-1, tumor necrosis factor-α [TNF-α], tumor necrosis factor receptor1 [TNFR1], IL-6), epithelial injury markers (pulmonary surfactant-associated protein D), endothelial injury markers (Angiopoietin-2 [Ang-2] and glycocalyx degradation products), and other proteins (matrix metallopeptidase-9 and myeloperoxidase). Patients were followed for 7 days for development of ARDS, as adjudicated by 3 blinded reviewers, and through hospital discharge for mortality and neurological outcome. We examined associations between biomarker concentrations and ARDS, hospital mortality, and neurological outcome using multivariable logistic regression. Latent phase analysis was used to identify distinct biological classes associated with outcomes. Results: 41 patients were enrolled. Mean age was 58 years, 29% were female, and 22% had a respiratory etiology for cardiac arrest. Seven patients (17%) developed ARDS within 7 days. There were no significant associations between individual biomarkers and development of ARDS in adjusted analyses, nor survival or neurologic status after adjusting for use of targeted temperature management (TTM) and initial cardiac arrest rhythm. Elevated Ang-2 and TNFR-1 were associated with decreased survival (RR = 0.6, 95% CI = 0.3-1.0; RR = 0.5, 95% CI = 0.3-0.9; respectively), and poor neurologic status at discharge (RR = 0.4, 95% CI = 0.2-0.8; RR = 0.4, 95% CI = 0.2-0.9) in unadjusted associations. Conclusion: OHCA patients have markedly elevated plasma and pulmonary edema fluid biomarker concentrations, indicating widespread inflammation, epithelial injury, and endothelial activation. Biomarker concentrations were not associated with ARDS development, though several distinct biological phenotypes warrant further exploration. Latent phase analysis demonstrated that patients with low biomarker levels aside from TNF-α and TNFR-1 (Class 2) fared worse than other patients. Future research may benefit from considering other tools to predict and prevent development of ARDS in this population.

Understanding how therapeutic exercise prescription changes outcomes important to patients with persistent non-specific low back pain: a realist review protocol.

INTRODUCTION: Persistent low back pain (LBP) is the leading cause of disability worldwide, and therapeutic exercise is recommended as a first-line treatment in international guidelines. The effects of exercise on clinical outcomes of pain and physical function are small to moderate, despite broader impacts on cardiovascular systems, biological health, mood, and emotional well-being. Therapeutic exercise prescription is defined as exercise that is prescribed by a clinician for a health-related treatment. It is unknown how therapeutic exercise prescription creates effects on outcomes of importance. Realist reviews explore how underlying mechanisms (M) may be active in the context (C) of certain situations, settings, or populations to create an intended or unintended outcome (O). Our objective is to explore and understand the mechanisms by which therapeutic exercise prescription changes outcomes for people with persistent LBP. METHODS: We will develop initial programme theories based on preliminary data from a previous systematic review and consensus workshop. These theories will be modified with input from a steering group (experts), a stakeholder group (people with lived experience of exercise for persistent LBP and clinicians), and a scoping search of the published literature. An information specialist will design and undertake an iterative search strategy. These will be used to create CMO configurations, which will be refined and tested using the literature. The realist review will be reported following RAMESES guidance. DISCUSSION: Realist reviews are uncommon in LBP research to date, yet those offer an opportunity to contrast with traditional methods of randomised controlled trials and systematic reviews and provide additional information regarding the contexts and mechanisms that may trigger certain outcomes. This can aid our understanding of the contextual features that may influence exercise prescription, such as for whom they are most effective, in what setting, how they are implemented and why. This realist synthesis will enhance our understanding of therapeutic exercise prescription to improve adherence and engagement and ultimately will provide clinically relevant recommendations regarding exercise prescription for those with persistent LBP. SYSTEMATIC REVIEW REGISTRATION: The review has been registered with PROSPERO (CRD42017072023).

"So that's why I found PrEP to be safest way to protect yourself": exploring IPV experiences and impact on HIV prevention among pregnant and postpartum women in Cape Town, South Africa.

Intimate partner violence (IPV) occurs at alarmingly high rates towards pregnant women in South Africa. Experiences of emotional, physical, and sexual IPV in pregnancy can adversely impact the health and safety of mother and fetus. Furthermore, IPV is associated with increased risk of HIV, exacerbating the public health impact of violence among pregnant women in this HIV endemic setting. In-depth understanding of cultural and contextual drivers of experiences of IPV is a critical precursor to development of interventions effectively addressing this issue among pregnant women in South Africa. The present study examines factors contributing to IPV among pregnant women to identify potential points of intervention. We conducted twenty in-depth interviews with postpartum women who used oral pre-exposure prophylaxis (PrEP) in pregnancy and reported recent experiences of IPV and/or ongoing alcohol use in a township near Cape Town, South Africa that experiences a heavy burden of both HIV and IPV. Interpretive thematic analysis was used. Several patterns of IPV during pregnancy were identified and violence was frequently described as co-occurring with male partner alcohol use. A majority of women referenced oral PrEP as their preferred method for HIV prevention, highlighting the agency and discretion it provided as beneficial attributes for women experiencing IPV. Fear of judgement from peers for remaining with an abusive partner and a lack of clear community messaging around IPV were identified as barriers to disclosure and support-seeking. Addressing the lack of social support received by women experiencing IPV during pregnancy in South Africa is essential to comprehensive IPV programming.

Contexts, behavioural mechanisms and outcomes to optimise therapeutic exercise prescription for persistent low back pain: a realist review.

OBJECTIVE: Therapeutic exercises are a core treatment for low back pain (LBP), but it is uncertain how rehabilitative exercise facilitates change in outcomes. Realist reviews explore how the context (C) of certain settings or populations and underlying mechanisms (M) create intended or unintended outcomes (O). Our objective was to explore and understand the behavioural mechanisms by which therapeutic exercise creates change in outcomes of adherence, engagement and clinical outcomes for patients with LBP. METHODS: This was a realist review reported following the Realist and Meta-narrative Evidence Syntheses: Evolving Standards guidance. We developed initial programme theories, modified with input from a steering group (experts, n=5), stakeholder group (patients and clinicians, n=10) and a scoping search of the published literature (n=37). Subsequently, an information specialist designed and undertook an iterative search strategy, and we refined and tested CMO configurations. RESULTS: Of 522 initial papers identified, 75 papers were included to modify and test CMO configurations. We found that the patient-clinician therapeutic consultation builds a foundation of trust and was associated with improved adherence, engagement and clinical outcomes, and that individualised exercise prescription increases motivation to adhere to exercise and thus also impacts clinical outcomes. Provision of support such as timely follow-up and supervision can further facilitate motivation and confidence to improve adherence to therapeutic exercises for LBP. CONCLUSIONS: Engagement in and adherence to therapeutic exercises for LBP, as well as clinical outcomes, may be optimised using mechanisms of trust, motivation and confidence. These CMO configurations provide a deeper understanding of ways to optimise exercise prescription for patients with LBP.

Pregnancy outcomes following self-reported and objective-measured exposure to oral preexposure prophylaxis in South Africa.

OBJECTIVE: To compare pregnancy outcomes using self-reported and objective levels of intracellular tenofovir diphosphate (TFV-DP) in pregnant women using preexposure prophylaxis (PrEP). DESIGN: We enrolled pregnant women >15 years without HIV at first antenatal care visit in an observational cohort study to compare pregnancy outcomes by PrEP use. METHODS: Exposure defined as: any PrEP use [tenofovir disoproxil and emtricitabine (TDF/FTC]) prescription + reported taking PrEP], or objectively-measured TFV-DP in dried blood spots in PrEP-using pregnant women. The primary outcome was a composite of pregnancy loss, preterm birth (<37weeks), low birthweight (<2500 g), small for gestational age ([SGA] ≤ tenth percentile), or neonatal death. Multivariable logistic regression models evaluated individual and composite adverse outcomes by self-reported or objectively measured PrEP use adjusting for age, gestational age, gravidity and socio-economic status. RESULTS: Between August 19 and February 23, we followed 1195 pregnant women and ascertained 1145 pregnancy outcomes (96%); 72% ( n  = 826) reported taking PrEP while pregnant, 16% did not take PrEP ( n  = 178), 12% were unconfirmed ( n  = 141). Overall, 94.5% ( n  = 1082) had singleton live births with a median birthweight of 3.2 kg [interquartile range (IQR) = 2.9-3.5], with no difference in pregnancy loss between self-reported PrEP exposed vs. unexposed [4.0 vs. 5.6%; adjusted odds ratio (aOR) = 0.65, 95% confidence interval (CI) = 0.32-1.47]. Composite adverse outcomes did not differ by reported PrEP use (20% for both groups; aOR = 1.07, 95% CI = 0.71-1.63). Comparing objective PrEP use (any TFV-DP vs. no TFV-DP or not on PrEP), adverse outcomes did not differ (aOR = 0.64, 95% CI = 0.39-1.04), nor did other outcomes including preterm birth nor SGA. CONCLUSIONS: Pregnancy outcomes did not differ by PrEP exposure (self-reported or objective), suggesting real-world efficacy that TDF/FTC as PrEP is safe in pregnancy.

Integration of HIV pre-exposure prophylaxis (PrEP) services for pregnant and breastfeeding women in eight primary care clinics: results of an implementation science study.

Background: Although HIV vertical transmission (VT) has declined significantly in sub-Saharan Africa, incident HIV infection in pregnant and postpartum women is estimated to account for roughly one-third of VT. Oral pre-exposure prophylaxis (PrEP) for pregnant and breastfeeding women (PBFW) is part of the recommended guidelines in South Africa since 2021; however, integration of PrEP services within antenatal (ANC) and postnatal care (PNC) remains limited. Methods: Between March 2022 and September 2023, we evaluated the acceptability, feasibility and sustainability of integrating PrEP for PBFW in high-HIV prevalence clinics after training and mentoring health care providers (HCP). We used the Reach Effectiveness-Adoption Implementation Maintenance (RE-AIM) framework to evaluate the intervention. Acceptability and maintenance were defined as the proportion of PBFW without HIV who initiated PrEP and the proportion of women continuing PrEP at 3 months in ANC or PNC services. Feasibility was defined as the proportion of trained HCPs (HIV lay counsellors and nurses/ midwives) who provided PrEP according to national guidelines, measured through post-training surveys and in-service assessments. Sustainability was defined as number of facilities and providers that continued to provide PrEP for PBFW past the mentoring period. Results: In 8 facilities providing ANC and PNC, we trained 224 HCP (127 nurses and 37 counsellors). Of those, we mentored 60 nurses, midwives and HIV counsellors working with PBFW, with 72% of nurse/midwives and 65% of counsellors scoring over 8/10 on the final mentoring assessment Overall, 12% (1493/12,614) of HIV-negative pregnant women started PrEP and 41% of those continued PrEP at 3-months. Among the HIV-negative breastfeeding women in postnatal care, 179/1315 (14%) initiated PrEP and 25% continued PrEP at 3-months. All 8 facilities continued providing PrEP 3-months after handover of the clinics. Conclusion: Integration of PrEP services in ANC and services for breastfeeding women was feasible, acceptable and sustainable. Acceptability and PrEP continuation showed improvement over time. Barriers to the PrEP integration were observed including the lack of regular HIV testing of breastfeeding mothers and need for ART-trained nurses to prescribe PrEP. Enablers included motivated and dedicated staff.

Home-based versus centre-based cardiac rehabilitation.

BACKGROUND: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based and technology-supported cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation, especially during the SARS-CoV-2 pandemic. This is an update of a review previously published in 2009, 2015, and 2017. OBJECTIVES: To compare the effect of home-based (which may include digital/telehealth interventions) and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 16 September 2022. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials that compared centre-based cardiac rehabilitation (e.g. hospital, sports/community centre) with home-based programmes (± digital/telehealth platforms) in adults with myocardial infarction, angina, heart failure, or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references for inclusion based on predefined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Certainty of evidence was assessed using GRADE. MAIN RESULTS: We included three new trials in this update, bringing a total of 24 trials that have randomised a total of 3046 participants undergoing cardiac rehabilitation. A further nine studies were identified and are awaiting classification. Manual searching of trial registers until 16 September 2022 revealed a further 14 clinical trial registrations - these are ongoing. Participants had a history of acute myocardial infarction, revascularisation, or heart failure. Although there was little evidence of high risk of bias, a number of studies provided insufficient detail to enable assessment of potential risk of bias; in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported. No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in our primary outcomes up to 12 months of follow-up: total mortality (risk ratio [RR] = 1.19, 95% confidence interval [CI] 0.65 to 2.16; participants = 1647; studies = 12/comparisons = 14; low-certainty evidence) or exercise capacity (standardised mean difference (SMD) = -0.10, 95% CI -0.24 to 0.04; participants = 2343; studies = 24/comparisons = 28; low-certainty evidence). The majority of evidence (N=71 / 77 comparisons of either total or domain scores) showed no significant difference in health-related quality of life up to 24 months follow-up between home- and centre-based cardiac rehabilitation. Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate-certainty evidence). There was a similar level of trial completion (RR 1.03, 95% CI 0.99 to 1.08; participants = 2638; studies = 22/comparisons = 26; low-certainty evidence) between home-based and centre-based participants. The cost per patient of centre- and home-based programmes was similar. AUTHORS' CONCLUSIONS: This update supports previous conclusions that home- (± digital/telehealth platforms) and centre-based forms of cardiac rehabilitation formally supported by healthcare staff seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction, or revascularisation, or with heart failure. This finding supports the continued expansion of healthcare professional supervised home-based cardiac rehabilitation programmes (± digital/telehealth platforms), especially important in the context of the ongoing global SARS-CoV-2 pandemic that has much limited patients in face-to-face access of hospital and community health services. Where settings are able to provide both supervised centre- and home-based programmes, consideration of the preference of the individual patient would seem appropriate. Although not included in the scope of this review, there is an increasing evidence base supporting the use of hybrid models that combine elements of both centre-based and home-based cardiac rehabilitation delivery. Further data are needed to determine: (1) whether the short-term effects of home/digital-telehealth and centre-based cardiac rehabilitation models of delivery can be confirmed in the longer term; (2) the relative clinical effectiveness and safety of home-based programmes for other heart patients, e.g. post-valve surgery and atrial fibrillation.

A Qualitative Exploration of Patient and Staff Experiences of the Receipt and Delivery of Specialist Weight Management Services in the UK.

BACKGROUND: Addressing the increasing prevalence of obesity is a global public health priority. Severe obesity (body mass index > 40) reduces life expectancy, due to its association with people developing complications (e.g. diabetes, cancer, cardiovascular disease), and greatly impairs quality of life. The National Health Service (NHS) in the UK provides specialist weight management services (SWMS) for people with severe obesity, but key uncertainties remain around patient access to and engagement with weight management services, as well as pathways beyond the service. METHODS: In this multiple methods study, using online forum data and semi-structured interviews, stakeholders' experiences of delivering and receiving SWMS were explored. Using the web search engine Google with keywords and web address (URL) identifiers, relevant public online platforms were sourced with snowball sampling and search strings used to identify threads related to people's experiences of accessing SWMS (n = 57). Interviews were conducted with 24 participants (nine patients, 15 staff), and data from all sources were analysed thematically using the framework approach. RESULTS: Six themes related to access to and engagement with SWMS emerged during data analysis: (1) making the first move, (2) uncertainty and confusion, (3) resource issues, (4) respect and understanding, (5) mode of delivery, and (6) desire for ongoing support. CONCLUSION: There is a mixed and varied picture of SWMS provision across the UK. The service offered is based on local clinical decision making and available resources, resulting in a range of patient experiences and perspectives. Whilst service capacity issues and patient anxiety were seen as barriers to accessing care, peer support and positive clinical and group interactions (connectedness between individuals) were considered to increase engagement.

Selecting an optimal real-time fMRI neurofeedback method for alcohol craving control training.

Real-time fMRI neurofeedback (rt-fMRI-NF) is a technique in which information about an individual's neural state is given back to them, typically to enable and reinforce neuromodulation. Its clinical potential has been demonstrated in several applications, but lack of evidence on optimal parameters limits clinical utility of the technique. This study aimed to identify optimal parameters for rt-fMRI-NF-aided craving regulation training in alcohol use disorder (AUD). Adults with AUD (n = 30) participated in a single-session study of four runs of rt-fMRI-NF where they downregulated "craving-related" brain activity. They received one of three types of neurofeedback: multi-region of interest (ROI), support vector machine with continuous feedback (cSVM), and support vector machine with intermittent feedback (iSVM). Performance was assessed on the success rate, change in neural downregulation, and change in self-reported craving for alcohol. Participants had more successful trials in run 4 versus 1, as well as improved downregulation of the insula, anterior cingulate, and dorsolateral prefrontal cortex (dlPFC). Greater downregulation of the latter two regions predicted greater reduction in craving. iSVM performed significantly worse than the other two methods. Downregulation of the striatum and dlPFC, enabled by ROI but not cSVM neurofeedback, was correlated with a greater reduction in craving. rt-fMRI-NF training for downregulation of alcohol craving in individuals with AUD shows potential for clinical use, though this pilot study should be followed with a larger randomized-control trial before clinical meaningfulness can be established. Preliminary results suggest an advantage of multi-ROI over SVM and intermittent feedback approaches.

Reducing the burden of knee osteoarthritis through community pharmacy: Protocol for a randomised controlled trial of the Knee Care for Arthritis through Pharmacy Service.

INTRODUCTION: Knee osteoarthritis (OA) negatively impacts the health outcomes and equity, social and employment participation, and socio-economic wellbeing of those affected. Little community-based support is offered to people with knee OA in Aotearoa New Zealand. Identifying Maori and non-Maori with knee OA in community pharmacy and providing co-ordinated, evidence- and community-based care may be a scalable, sustainable, equitable, effective and cost-effective approach to improve health and wellbeing. AIM: Assess whether the Knee Care for Arthritis through Pharmacy Service (KneeCAPS) intervention improves knee-related physical function and pain (co-primary outcomes). Secondary aims assess impacts on health-related quality of life, employment participation, medication use, secondary health care utilisation, and relative effectiveness for Maori. METHODS AND ANALYSIS: A pragmatic randomised controlled trial will compare the KneeCAPS intervention to the Pharmaceutical Society of New Zealand Arthritis Fact Sheet and usual care (active control) at 12 months for Maori and non-Maori who have knee OA. Participants will be recruited in community pharmacies. Knee-related physical function will be measured using the function subscale of the Short Form of the Western Ontario and McMaster Universities Osteoarthritis Index. Knee-related pain will be measured using an 11-point numeric pain rating scale. Primary outcome analyses will be conducted on an intention-to-treat basis using linear mixed models. Parallel within-trial health economic analysis and process evaluation will also be conducted. ETHICS AND TRIAL DISSEMINATION: Ethical approval was obtained from the Central Health and Ethics Committee (2022-EXP-11725). The trial is registered with ANZCTR (ACTRN12622000469718). Findings will be submitted for publication and shared with participants.

"Kind of empowered": Perceptions of socio-emotional development in children driving ride-on cars.

PURPOSE/OBJECTIVE: Early powered mobility (PM) experiences can be essential facilitators of self-initiated mobility, socialization, and exploration for young children with disabilities. Cerebral palsy (CP) and developmental delay are two of the most common diagnoses associated with motor disability in young children with 1 in 345 children diagnosed with CP and 1 in 6 with developmental delay in the US. The purpose of this study was to explore the longitudinal experiences and caregiver perceptions of socio-emotional development in particular, in young children with disabilities during modified ride-on car (ROC) use. RESEARCH METHOD/DESIGN: A qualitative, grounded theory approach was used. Semi-structured interviews were conducted with 15 families (children ages 1-4 with CP or developmental delay) at baseline, 6 months (as able due to COVID), and 1 year following ROC introduction. Data were coded independently by three researchers using constant comparison until data saturation occurred and themes emerged. RESULTS: Four themes emerged from the data: "Leveling the Playing Field," "Breaking Down Barriers," "Fun and Work: ROC as Toy and Therapy Device," and "Mobility is a Pathway to Autonomy." Conclusions/Implication: Children and caregivers viewed ROCs as both fun and therapeutic, consistently identifying perceived benefits for children's socio-emotional development. This qualitative study provides a better understanding of the complexities and impact of ROCs on children and their families in the socio-emotional domain and may help facilitate clinical decision-making when introducing PM to young children with disabilities as part of a multimodal approach to early intervention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Protocol for a pragmatic cluster randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of Electronic RIsk-assessment for CAncer for patients in general practice (ERICA).

INTRODUCTION: The UK has worse cancer outcomes than most comparable countries, with a large contribution attributed to diagnostic delay. Electronic risk assessment tools (eRATs) have been developed to identify primary care patients with a ≥2% risk of cancer using features recorded in the electronic record. METHODS AND ANALYSIS: This is a pragmatic cluster randomised controlled trial in English primary care. Individual general practices will be randomised in a 1:1 ratio to intervention (provision of eRATs for six common cancer sites) or to usual care. The primary outcome is cancer stage at diagnosis, dichotomised to stage 1 or 2 (early) or stage 3 or 4 (advanced) for these six cancers, assessed from National Cancer Registry data. Secondary outcomes include stage at diagnosis for a further six cancers without eRATs, use of urgent referral cancer pathways, total practice cancer diagnoses, routes to cancer diagnosis and 30-day and 1-year cancer survival. Economic and process evaluations will be performed along with service delivery modelling. The primary analysis explores the proportion of patients with early-stage cancer at diagnosis. The sample size calculation used an OR of 0.8 for a cancer being diagnosed at an advanced stage in the intervention arm compared with the control arm, equating to an absolute reduction of 4.8% as an incidence-weighted figure across the six cancers. This requires 530 practices overall, with the intervention active from April 2022 for 2 years. ETHICS AND DISSEMINATION: The trial has approval from London City and East Research Ethics Committee, reference number 19/LO/0615; protocol version 5.0, 9 May 2022. It is sponsored by the University of Exeter. Dissemination will be by journal publication, conferences, use of appropriate social media and direct sharing with cancer policymakers. TRIAL REGISTRATION NUMBER: ISRCTN22560297.