The effect of frailty on mortality and hospital admission in patients with benign pleural disease in Wales: a cohort study.

BACKGROUND: Pleural disease is common, representing 5% of the acute medical workload, and its incidence is rising, partly due to the ageing population. Frailty is an important feature and little is known about disease progression in patients with frailty and pleural disease. We aimed to examine the effect of frailty on mortality and other relevant outcomes in patients diagnosed with pleural disease. METHODS: In this cohort study in Wales, the national Secure Anonymised Information Linkage databank was used to identify a cohort of individuals diagnosed with non-malignant pleural disease between Jan 1, 2005, and March 1, 2023, who were not known to have left Wales. Frailty was assessed at diagnosis of pleural disease using an electronic Frailty Index. The primary outcome was time from diagnosis to all-cause mortality for all patients. Data were analysed using multilevel mixed-effects Cox proportional hazards regression adjusting for the prespecified covariates of age, sex, Welsh Index of Multiple Deprivation quintile, smoking status, comorbidity, and subtype of pleural disease. FINDINGS: 54 566 individuals were included in the final sample (median age 66 years [IQR 47-77]; 26 477 [48·5%] were female and 28 089 [51·5%] were male). By the end of the study period, 25 698 (47·1%) participants had died, with a median follow-up of 1·0 years (IQR 0·2-3·6). There was an association between frailty and all-cause mortality, which increased as frailty worsened. Compared with fit individuals, there was increasing mortality for those with mild frailty (adjusted hazard ratio 1·11 [95% CI 1·08-1·15]; p<0·0001), moderate frailty (1·25 [1·20-1·31]; p<0·0001), and severe frailty (1·36 [1·28-1·44]; p<0·0001). INTERPRETATION: Independent of age and comorbidities, frailty status at diagnosis of pleural disease appeared to be useful as a prognostic indicator. Patients with moderate or severe frailty had a rapid decline in health. Future patients should be assessed for frailty at the time of diagnosis of pleural disease and might benefit from optimised care and advance care planning. FUNDING: Cardiff University's Wellcome Trust iTPA funding award.

Childhood Health and Educational outcomes afteR perinatal Brain injury (CHERuB): protocol for a population-matched cohort study.

INTRODUCTION: Over 3000 infants suffer a brain injury around the time of birth every year in England. Although these injuries can have important implications for children and their families, our understanding of how these injuries affect children's lives is limited. METHODS AND ANALYSIS: The aim of the CHERuB study (Childhood Health and Educational outcomes afteR perinatal Brain injury) is to investigate longitudinal childhood health and educational outcomes after perinatal brain injury through the creation of a population-matched cohort study. This study will use the Department of Health and Social Care definition of perinatal brain injury which includes infants with intracranial haemorrhage, preterm white matter injury, hypoxic ischaemic encephalopathy, perinatal stroke, central nervous system infections, seizures and kernicterus. All children born with a perinatal brain injury in England between 2008 and 2019 will be included (n=54 176) and two matched comparator groups of infants without brain injury will be created: a preterm control group identified from the National Neonatal Research Data Set and a term/late preterm control group identified using birth records. The national health, education and social care records of these infants will be linked to ascertain their longitudinal childhood outcomes between 2008 and 2023. This cohort will include approximately 170 000 children. The associations between perinatal brain injuries and survival without neurosensory impairment, neurodevelopmental impairments, chronic health conditions and mental health conditions throughout childhood will be examined using regression methods and time-to-event analyses. ETHICS AND DISSEMINATION: This study has West London Research Ethics Committee and Confidential Advisory Group approval (20/LO/1023 and 22/CAG/0068 issued 20/10/2022). Findings will be published in open-access journals and publicised via the CHERuB study website, social media accounts and our charity partners.

Why do young men not seek help for affective mental health issues? A systematic review of perceived barriers and facilitators among adolescent boys and young men.

Men are less likely to seek help for their mental health than women, but less is known about the specific patterns of help-seeking in adolescent boys and young men. This is concerning as adolescent boys and young men have high suicide rates but a low take-up of services. It is therefore of particular importance that the access needs of this group are understood. This review sought to identify the barriers and facilitators faced by adolescent boys and young men in help-seeking for affective mental health disorders. A search of the PubMed, APA PsycInfo, and Cochrane databases identified 3961 articles, of which 12 met the inclusion criteria. Six of the studies were qualitative, five were quantitative and one used mixed methods. Two authors independently extracted data and assessed the quality of the articles. Five key themes were identified, including the impact of social norms, with the subthemes of conformity to masculine norms and self-stigma, limited availability of information about mental health, and 'male-friendly' mental health literacy campaigns. Other themes referred to the help-seeking preferences of adolescent boys and young men, in terms of informal or formal and online or offline help-seeking. Some of the factors were well-researched (e.g., conformity to masculine norms as a barrier) whereas other factors (e.g., self-compassion as a facilitator) were less researched. These barriers and facilitators need to be considered in the development of future strategies to improve the help-seeking behaviour of adolescent boys and young men.

A multi-school study in England, to assess problematic smartphone usage and anxiety and depression.

AIM: To assess the association between problematic smartphone usage and anxiety and depression in adolescents. METHODS: A cross-sectional study in five schools in the UK were included. The primary outcome was moderate anxiety (GAD-7 ≥10) symptoms and secondary outcomes were moderate depression symptoms (PHQ-9 ≥10) and insomnia. Problematic smartphone usage was assessed using screentime and the Smartphone Addiction Scale. A multi-level logistic regression was fitted and adjusted Odds Ratio (aOR) with 95% confidence intervals (95% CI) reported. A mediation analysis was conducted. RESULTS: Of the five included schools, 657 adolescents aged 16-18 years were enrolled. The median age was 17.5 years (17-18 [IQR]) and 508 (77.3%) were female. Of these 188 (28.6%) exhibited moderate anxiety and 226 (34.4%) moderate depression symptoms. Almost two thirds (421, 64.1%) have tried to cut down their smartphone use and 81 (12.5%) wanted help to reduce use. Problematic smartphone use was associated with increased anxiety (aOR = 2.03, 95% CI 1.28-3.23); depression (aOR = 2.96, 95% CI 1.80-4.86); and insomnia (aOR = 1.64, 95% CI 1.08-2.50). Screentime was not associated with anxiety (ß = 0.99, 95% CI 0.91-1.08); or depression (ß = 0.98, 95% CI 0.89-1.07). Problematic smartphone use had a significant direct, indirect and total effect on both anxiety and depression. CONCLUSION: Problematic smartphone usage was associated with anxiety and depression, independent of screentime. Interventions are needed to reduce problematic use.

'There's more to life than staring at a small screen': a mixed methods cohort study of problematic smartphone use and the relationship to anxiety, depression and sleep in students aged 13-16 years old in the UK.

BACKGROUND: Depression and anxiety are common in adolescents and have increased over the last decade. During that period, smartphone usage has become ubiquitous. OBJECTIVES: The study aim was to assess the association between problematic smartphone usage (PSU) and anxiety. METHODS: Using a prospective mixed methods cohort study design, students aged 13-16 year old from two schools were enrolled regarding their smartphone use, mood and sleep via a semistructured questionnaire at baseline and week 4. The primary outcome was symptoms of anxiety (Generalised Anxiety Disorder Questionnaire, GAD-7) and exposure was PSU (Smartphone Addiction Scale Short Version). A linear regression was fitted to assess the change in anxiety. Thematic analysis of free-text responses was conducted. FINDINGS: The sample included 69 participants that were enrolled and followed up between 28 March and 3 June 2022. Of those with PSU, 44.4% exhibited symptoms of moderate to severe anxiety compared with 26.4% of those without PSU. There was a linear association between change in symptoms of anxiety and PSU ß=0.18 (95% CI 0.04 to 0.32, p=0.013). Several themes were found: both positive and negative effects of smartphones on relationships; negative effects on school performance and productivity; mixed effects on mood; a desire to reduce the amount of time spent on smartphones. CONCLUSIONS: Increased anxiety, depression and inability to sleep were seen in participants as their PSU score increased over time. Participants reported both positive and negative effects of smartphones and almost all used strategies to reduce use. CLINICAL IMPLICATIONS: Interventions need to be developed and evaluated for those seeking support.

Influence of frailty on cardiovascular events and mortality in patients with Chronic Obstructive Pulmonary Disease (COPD): Study protocol for a multicentre European observational study.

BACKGROUND: Frailty is a clinical state that increases susceptibility to minor stressor events. The risk of frailty is higher in chronic conditions, such as Chronic Obstructive Pulmonary Disease (COPD). Recent studies on COPD have shown that patients living with frailty have an increased risk of mortality. The presence of cardiovascular diseases or conditions are common in COPD and may increase the risk of death. METHODS: This protocol describes a European prospective cohort study of community-based people, in a stable condition with diagnosis of COPD (as defined by GOLD guidelines) across hospitals in Italy and UK. Frailty prevalence will be assessed using the Clinical Frailty Scale. At 1- and 2-year follow up, primary outcome will be the impact of frailty on the number of cardiovascular events; secondary outcomes: the influence of frailty on cardiovascular mortality, all-cause mortality, and deaths due to COPD. For the primary outcome a zero-inflated Poisson regression will compare the number of cardiovascular events at 1 year. Secondary outcomes will be analysed using the time to mortality. DISCUSSION: This multicentre study will assess the association between frailty and cardiovascular events and mortality in population with COPD. Data collection is prospective and includes routine clinical data. This research will have important implications for the management of patients with COPD to improve their quality of care, and potentially prognosis. TRIAL REGISTRATION NUMBER: NCT05922202 (www.clinicaltrials.gov).

Evaluation of system based psychological first aid training on the mental health proficiency of emergency medical first responders to natural disasters in China: a cluster randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of a system based psychological first aid (PFA) training programme for emergency medical first responders in China. DESIGN: Parallel-group, assessor-blinded, cluster randomised controlled trial. SETTING: 42 clusters of health workers from various health facilities in China. PARTICIPANTS: 1399 health workers who provide emergency service for survivors of disasters. INTERVENTIONS: One-day system based PFA training programme (PFA) or training as usual (TAU). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the PFA skills, knowledge and attitude (SKA-PFA) score at 2 months postintervention. Secondary outcomes included post-traumatic growth, self-efficacy and professional quality of life. RESULTS: The intervention group (n=690) had significantly higher SKA-PFA scores than the control group (n=709) at 2 months postintervention (adjusted mean difference=4.44; 95% CI 1.17 to 7.52; p=0.007; Cohen's d=0.35). The intervention group also had higher scores on post-traumatic growth (p=0.113, d=0.24), self-efficacy (p=0.032, d=0.20) and professional quality of life (p=0.281, d=0.04). CONCLUSIONS: The system based PFA training programme was more effective than the TAU in enhancing the PFA knowledge and skills of the emergency medical first responders and in increasing their competence to provide emergency service for survivors in China. TRIAL REGISTRATION NUMBER: ChiCTR2200060464.

Cohort profile: The Social media, smartphone use and Self-harm in Young People (3S-YP) study-A prospective, observational cohort study of young people in contact with mental health services.

OBJECTIVES: The Social media, Smartphone use and Self-Harm (3S-YP) study is a prospective observational cohort study to investigate the mechanisms underpinning associations between social media and smartphone use and self-harm in a clinical youth sample. We present here a comprehensive description of the cohort from baseline data and an overview of data available from baseline and follow-up assessments. METHODS: Young people aged 13-25 years were recruited from a mental health trust in England and followed up for 6 months. Self-report data was collected at baseline and monthly during follow-up and linked with electronic health records (EHR) and user-generated data. FINDINGS: A total of 362 young people enrolled and provided baseline questionnaire data. Most participants had a history of self-harm according to clinical (n = 295, 81.5%) and broader definitions (n = 296, 81.8%). At baseline, there were high levels of current moderate/severe anxiety (n = 244; 67.4%), depression (n = 255; 70.4%) and sleep disturbance (n = 171; 47.2%). Over half used social media and smartphones after midnight on weekdays (n = 197, 54.4%; n = 215, 59.4%) and weekends (n = 241, 66.6%; n = 263, 72.7%), and half met the cut-off for problematic smartphone use (n = 177; 48.9%). Of the cohort, we have questionnaire data at month 6 from 230 (63.5%), EHR data from 345 (95.3%), social media data from 110 (30.4%) and smartphone data from 48 (13.3%). CONCLUSION: The 3S-YP study is the first prospective study with a clinical youth sample, for whom to investigate the impact of digital technology on youth mental health using novel data linkages. Baseline findings indicate self-harm, anxiety, depression, sleep disturbance and digital technology overuse are prevalent among clinical youth. Future analyses will explore associations between outcomes and exposures over time and compare self-report with user-generated data in this cohort.

Clinical effectiveness and cost-effectiveness of a brief accessible cognitive behavioural therapy programme for stress in school-aged adolescents (BESST): a cluster randomised controlled trial in the UK.

BACKGROUND: Depression and anxiety are increasingly prevalent in adolescents. The Brief Educational Workshops in Secondary Schools Trial investigated the effectiveness of a brief accessible stress workshop programme for 16-18-year-olds. We aimed to investigate the clinical effectiveness and cost-effectiveness of the DISCOVER cognitive behavioural therapy (CBT) workshop on symptoms of depression in 16-18-year-olds at 6 months compared with treatment-as-usual. METHODS: We conducted a multicentre, cluster randomised controlled trial in UK schools or colleges with sixth forms to evaluate clinical effectiveness and cost-effectiveness of a brief CBT workshop (DISCOVER) compared with treatment-as-usual. We planned to enrol 60 schools and 900 adolescents, using a self-referral system to recruit participants. Schools were randomised in a 1:1 ratio for participants to receive either the DISCOVER workshop or treatment-as-usual, stratified by site and balanced on school size and index of multiple deprivation. Participants were included if they were 16-18 years old, attending for the full school year, seeking help for stress, and fluent in English and able to provide written informed consent. The outcome assessors, senior health economist, senior statistician, and chief investigator were masked. People with lived experience were involved in the study. The primary outcome was depression symptoms measured with the Mood and Feelings Questionnaire (MFQ) at 6-month follow-up, in the intention-to-treat population of all participants with full covariate data. The trial was registered with the ISRCTN registry (ISRCTN90912799). FINDINGS: 111 schools were invited to participate in the study, seven were deemed ineligible, and 47 did not provide consent. Between Oct 4, 2021, and Nov 10, 2022, 933 students at 57 schools were screened for eligibility, seven were not eligible for inclusion, and 26 did not attend the baseline meeting and assessment, resulting in 900 adolescents participating in the study. The DISCOVER group included 443 participants (295 [67%] female and 136 [31%] male) and the treatment-as-usual group included 457 participants (346 [76%] female and 92 [20%] male). 468 (52%) of the 900 participants were White, and the overall age of the participants was 17·2 years (SD 0·6). 873 (97%) adolescents were followed up in the intention-to-treat population. The primary intention-to-treat analysis (n=854) found an adjusted mean difference in MFQ of -2·06 (95% CI -3·35 to -0·76; Cohen's d=-0·17; p=0·0019) at the 6-month follow-up, indicating a clinical improvement in the DISCOVER group. The probability that DISCOVER is cost- effective compared with treatment-as-usual ranged from 61% to 78% at a £20 000 to £30 000 per quality-adjusted life-year threshold. Nine adverse events (two of which were classified as serious) were reported in the DISCOVER group and 14 (two of which were classified as serious) were reported in the treatment-as-usual group. INTERPRETATION: Our findings indicate that the DISCOVER intervention is modestly clinically effective and economically viable and could be a promising early intervention in schools. Given the importance of addressing mental health needs early in this adolescent population, additional research is warranted to explore this intervention. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Brief Educational Workshops in Secondary Schools Trial (BESST trial), a school-based cluster randomised controlled trial of the DISCOVER workshop for 16-18-year-olds: recruitment and baseline characteristics.

BACKGROUND: The Brief Educational Workshops in Secondary Schools Trial (BESST) is an England-wide school-based cluster randomised controlled trial assessing the clinical and cost-effectiveness of an open-access psychological workshop programme (DISCOVER) for 16-18-year-olds. This baseline paper describes the self-referral and other recruitment processes used in this study and the baseline characteristics of the enrolled schools and participants. METHOD: We enrolled 900 participants from 57 Secondary schools across England from 4th October 2021 to 10th November 2022. Schools were randomised to receive either the DISCOVER day-long Stress workshop or treatment as usual which included signposting information. Participants will be followed up for 6 months with outcome data collection at baseline, 3-month, and 6-month post randomisation. RESULTS: Schools were recruited from a geographically and ethnically diverse sample across England. To reduce stigma, students were invited to self-refer into the study if they wanted help for stress. Their mean age was 17.2 (SD = 0.6), 641 (71%) were female and 411 (45.6%) were from ethnic minority groups. The general wellbeing of our sample measured using the Mood and Feelings Questionnaire (MFQ) found 314 (35%) of students exhibited symptoms of depression at baseline. Eighty percent of students reported low wellbeing on the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) suggesting that although the overall sample mean is below the cut-off for depression, the self-referral approach used in this study supports distressed students in coming forward. CONCLUSION: The BESST study will continue to follow up participants to collect outcome data and results will be analysed once all the data have been collected. TRIAL REGISTRATION: ISRCTN registry ISRCTN90912799. Registered on 28 May 2020.

Serum Albumin and Post-Stroke Outcomes: Analysis of UK Regional Registry Data, Systematic Review, and Meta-Analysis.

Hypoalbuminemia associates with poor acute ischemic stroke (AIS) outcomes. We hypothesised a non-linear relationship and aimed to systematically assess this association using prospective stroke data from the Norfolk and Norwich Stroke and TIA Register. Consecutive AIS patients aged ≥40 years admitted December 2003-December 2016 were included. Outcomes: In-hospital mortality, poor discharge, functional outcome (modified Rankin score 3-6), prolonged length of stay (PLoS) > 4 days, and long-term mortality. Restricted cubic spline regressions investigated the albumin-outcome relationship. We updated a systematic review (PubMed, Scopus, and Embase databases, January 2020-June 2023) and undertook a meta-analysis. A total of 9979 patients were included; mean age (standard deviation) = 78.3 (11.2) years; mean serum albumin 36.69 g/L (5.38). Compared to the cohort median, albumin < 37 g/L associated with up to two-fold higher long-term mortality (HRmax; 95% CI = 2.01; 1.61-2.49) and in-hospital mortality (RRmax; 95% CI = 1.48; 1.21-1.80). Albumin > 44 g/L associated with up to 12% higher long-term mortality (HRmax1.12; 1.06-1.19). Nine studies met our inclusion criteria totalling 23,597 patients. Low albumin associated with increased risk of long-term mortality (two studies; relative risk 1.57 (95% CI 1.11-2.22; I2 = 81.28)), as did low-normal albumin (RR 1.10 (95% CI 1.01-1.20; I2 = 0.00)). Strong evidence indicates increased long-term mortality in AIS patients with low or low-normal albumin on admission.

Antidepressant treatment in inflammatory bowel disease: a systematic review and meta-analysis.

Around 25% of patients with inflammatory bowel disease (IBD) have depressive symptoms, yet antidepressants have been poorly studied in IBD. We systematically searched IBD studies testing antidepressants in four databases. Outcomes were depressive symptoms, anxiety, IBD disease activity, quality of life (QoL) and adverse events. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in posttreatment scores between antidepressant and placebo groups. Risk of bias was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group tool (clinical trials) and Newcastle-Ottawa scale (cohort studies). We included 11 studies ( n  = 327): three placebo-controlled RCTs, two nonrandomized trials, and six other study types. In the pooled analysis, antidepressants improved depressive symptoms [SMD = -0.71 (95% confidence interval (CI) -1.32 to -0.10), P  = 0.02, I2  = 51%] and QoL [SMD = 0.88 (95% CI 0.30-1.45), P  = 0.003, I2  = 44%] more than placebo. Serotonin and noradrenaline reuptake inhibitors (SNRIs) alone improved depressive symptoms [SMD = -0.95 (95% CI -1.45 to -0.45, P  < 0.001, I2  = 11%], anxiety [SMD = -0.92 (95% CI 1.72 to -0.13), P  = 0.023, I2  = 65%] and QoL [SMD = 1.14 (95% CI 0.66-1.62), P  < 0.001, I2  = 0%]. The three RCTs were of good quality. In conclusion, based on three small but good-quality studies, antidepressants improve depressive symptoms and QoL compared to placebo in IBD. SNRI antidepressants may also improve anxiety. A fully powered study of antidepressants in IBD is needed.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). METHODS/DESIGN: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. DISCUSSION: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. ETHICS AND DISSEMINATION: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS).

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action. METHODS: A confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment. DISCUSSION: This multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD. TRIAL REGISTRATION: ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .

Toward the right treatment at the right time: Modeling the trajectory of cognitive decline to identify the earliest age of change in people with Alzheimer's disease.

Introduction: Age is the greatest risk factor for Alzheimer's disease (AD). A limitation of randomized control trials in AD is a lack of specificity in the age ranges of participants who are enrolled in studies of disease-modifying therapies. We aimed to apply Emax (i.e., maximum effect) modeling as a novel approach to identity ideal treatment windows. Methods: Emax curves were fitted to longitudinal cognitive data of 101 participants with AD and 1392 healthy controls. We included the Mini-Mental State Examination (MMSE) and tests of verbal fluency and executive functioning. Results: In people with AD, the earliest decline in the MMSE could be detected in the 67-71 age band while verbal fluency declined from the 41-45 age band. In healthy controls, changes in cognition showed a later trajectory of decline. Discussion: Emax modeling could be used to design more efficient trials which has implications for randomized control trials targeting the earlier stages of AD.

Mediators of change in psychological interventions for adult offenders with personality disorders: A scoping review of the literature.

Offenders with personality disorder cause disproportionate harm to society and pose significant challenges for those responsible for their care and rehabilitation. Personality disorders are heterogeneous in terms of symptoms, as well as their pathways to offending behaviour. Thus, there is limited evidence regarding effective interventions. One solution might be to focus on how interventions are delivered as well as what is delivered. Within the non-offender personality disorder literature, the identification of potential mediators of change has enabled interventions to focus on 'how' they are delivered (e.g., therapeutic alliance) rather than the intervention itself. We explore the evidence and present a scoping review of the available literature on the mechanisms of change in psychological treatments for offenders with personality disorder. Only one study was found in the scoping review, highlighting a significant gap in the evidence base. We discuss the implications of this finding and potential future directions.

Olanzapine for young PEople with aNorexia nervosa (OPEN): A protocol for an open-label feasibility study.

INTRODUCTION: Antipsychotics are routinely prescribed off-label for anorexia nervosa (AN) despite limited evidence. This article presents a protocol of a study aiming to assess the feasibility of a future definitive trial on olanzapine in young people with AN. METHODS AND ANALYSIS: In an open-label, one-armed feasibility study, 55 patients with AN or atypical AN, aged 12-24, receiving outpatient, inpatient or day-care treatment who are considered for olanzapine treatment will be recruited from NHS sites based in England. Assessments will be conducted at screening, baseline and at 8-, 16 weeks, 6- and 12 months. Primary feasibility parameters will be proportions of patients who agree to take olanzapine and who adhere to treatment and complete study assessments. Qualitative methods will be used to explore acceptability of the intervention and study design. Secondary feasibility parameters will be changes in body mass index, psychopathology, side effects, health-related quality of life, carer burden and proportion of participants who would enrol in a future randomised controlled trial. The study is funded by the National Institute for Health Research via Health Technology Assessment programme. DISCUSSION: Olanzapine for young PEople with aNorexia nervosa will inform a future randomised controlled trial on the efficacy and safety of prescribing olanzapine in young people with AN.

Impact of Frailty on Symptom Burden in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), the sixth leading cause of death in the United States in 2022 and the third leading cause of death in England and Wales in 2022, is associated with high symptom burden, particularly dyspnoea. Frailty is a complex clinical syndrome associated with an increased vulnerability to adverse health outcomes. The aim of this review was to explore the current evidence of the influence of frailty on symptoms in patients with a confirmed diagnosis of COPD according to GOLD guidelines. Fourteen studies report a positive association between frailty and symptoms, including dyspnoea, assessed with the COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) scale. Data were analysed in a pooled a random-effects meta-analysis of mean differences (MDs). There was an association between COPD patients living with frailty and increased CAT score versus COPD patients without frailty [pooled SMD, 1.79 (95% CI 0.72-2.87); I2 = 99%]. A lower association was found between frailty and dyspnoea measured by the mMRC scale versus COPD patients without frailty [pooled SMD, 1.91 (95% CI 1.15-2.66); I2 = 98%]. The prevalence of frailty ranged from 8.8% to 82% and that of pre-frailty from 30.4% to 73.7% in people living with COPD. The available evidence supports the role of frailty in worsening symptom burden in COPD patients living with frailty. The review shows that frailty is common in patients with COPD. Future research is needed to have further details related to the data from CAT to improve our knowledge of the frailty impact in this population.

The impact of psychiatric comorbidity on Parkinson's disease outcomes: a systematic review and meta-analysis.

Background: The burden of psychiatric symptoms in Parkinson's disease includes depression, anxiety, apathy, psychosis, and impulse control disorders. However, the relationship between psychiatric comorbidities and subsequent prognosis and neurological outcomes is not yet well understood. In this systematic review and meta-analysis, in individuals with Parkinson's disease, we aimed to characterise the association between specific psychiatric comorbidities and subsequent prognosis and neurological outcomes: cognitive impairment, death, disability, disease progression, falls or fractures and care home admission. Methods: We searched MEDLINE, Embase, PsycINFO and AMED up to 13th November 2023 for longitudinal observational studies which measured disease outcomes in people with Parkinson's disease, with and without specific psychiatric comorbidities, and a minimum of two authors extracted summary data. Studies of individuals with other parkinsonian conditions and those with outcome measures that had high overlap with psychiatric symptoms were excluded to ensure face validity. For each exposure-outcome pair, a random-effects meta-analysis was conducted based on standardised mean difference, using adjusted effect sizes-where available-in preference to unadjusted effect sizes. Study quality was assessed using the Newcastle-Ottawa Scale. Between-study heterogeneity was assessed using the I2 statistic and publication bias was assessed using funnel plots. PROSPERO Study registration number: CRD42022373072. Findings: There were 55 eligible studies for inclusion in meta-analysis (n = 165,828). Data on participants' sex was available for 164,514, of whom 99,182 (60.3%) were male and 65,460 (39.7%) female. Study quality was mostly high (84%). Significant positive associations were found between psychosis and cognitive impairment (standardised mean difference [SMD] 0.44, [95% confidence interval [CI] 0.23-0.66], I2 30.9), psychosis and disease progression (SMD 0.46, [95% CI 0.12-0.80], I2 70.3%), depression and cognitive impairment (SMD 0.37 [95% CI 0.10-0.65], I2 27.1%), depression and disease progression (SMD 0.46 [95% CI 0.18-0.74], I2 52.2), depression and disability (SMD 0.42 [95% CI 0.25-0.60], I2 7.9%), and apathy and cognitive impairment (SMD 0.60 [95% CI 0.02-1.19], I2 27.9%). Between-study heterogeneity was moderately high. Interpretation: Psychosis, depression, and apathy in Parkinson's disease are all associated with at least one adverse outcome, including cognitive impairment, disease progression and disability. Whether this relationship is causal is not clear, but the mechanisms underlying these associations require exploration. Clinicians should consider these psychiatric comorbidities to be markers of a poorer prognosis in people with Parkinson's disease. Future studies should investigate the underlying mechanisms and which treatments for these comorbidities may affect Parkinson's disease outcomes. Funding: Wellcome Trust, UK National Institute for Health Research (NIHR), National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospitals NHS Foundation Trust, National Brain Appeal.