What predicts response to sertraline for people with depression in primary care? a secondary data analysis of moderators in the PANDA trial.

PURPOSE: Antidepressants are a first-line treatment for depression, yet many patients do not respond. There is a need to understand which patients have greater treatment response but there is little research on patient characteristics that moderate the effectiveness of antidepressants. This study examined potential moderators of response to antidepressant treatment. METHODS: The PANDA trial investigated the clinical effectiveness of sertraline (n = 326) compared with placebo (n = 329) in primary care patients with depressive symptoms. We investigated 11 potential moderators of treatment effect (age, employment, suicidal ideation, marital status, financial difficulty, education, social support, family history of depression, life events, health and past antidepressant use). Using multiple linear regression, we investigated the appropriate interaction term for each of these potential moderators with treatment as allocated. RESULTS: Family history of depression was the only variable with weak evidence of effect modification (p-value for interaction = 0.048), such that those with no family history of depression may have greater benefit from antidepressant treatment. We found no evidence of effect modification (p-value for interactions≥0.29) by any of the other ten variables. CONCLUSION: Evidence for treatment moderators was extremely limited, supporting an approach of continuing discuss antidepressant treatment with all patients presenting with moderate to severe depressive symptoms.

'Does it matter how old I feel?' The role of subjective age in a psychosocial intervention for improving depressive symptomatology among older adults in Brazil (PROACTIVE).

OBJECTIVES: Depression is a prevalent mental health condition that also often affects older adults. The PROACTIVE psychosocial intervention was developed to reduce depressive symptomatology among older adults within primary care settings in Brazil. An important psychological marker that affects individuals' aging experience relates to how old people feel. Known as subjective age, this marker has been shown to be a risk factor for experiencing greater depressive symptoms if individuals report feeling older than their (chronological) age. In this study, we perform secondary analyses of the PROACTIVE cluster-randomized controlled trial to examine the role of subjective age. METHOD: The sample included 715 Brazilian older adults (74% female, Mage 68.6, SD = 6.9, age range: 60-94 years) randomized to intervention (n = 360, 74% female, Mage 68.4, SD = 6.6, age range: 60-89 years) or control (n = 355, 74% female, Mage 68.9, SD = 7.2, age range: 60-94 years) arms. Here our primary outcome was depressive symptoms at the 8-month follow-up assessed with the 9-item Patient Health Questionnaire (PHQ-9) as a continuous variable. Our previous analyses demonstrated improved recovery from depression at follow-up in the intervention compared with the control arm. RESULTS: Relevant main effects and interactions in regression models for PHQ-9 presented here found that those reporting older subjective age had worse depressive symptoms at follow-up but that they benefitted more from the intervention when initial levels of depression were high. For participants who reported younger subjective ages the intervention showed positive effects that were independent of initial levels of depression. CONCLUSION: Our findings emphasize the importance of investigating possible underlying mechanisms that can help clarify the impact of mental health interventions.

Randomised pilot and feasibility trial of a group intervention for men who perpetrate intimate partner violence against women.

BACKGROUND: There is a need for robust evidence on the effectiveness and cost-effectiveness of domestic abuse perpetrator programmes in reducing abusive behaviour and improving wellbeing for victim/survivors. While any randomised controlled trial can present difficulties in terms of recruitment and retention, conducting such a trial with domestic abuse perpetrators is particularly challenging. This paper reports the pilot and feasibility trial of a voluntary domestic abuse perpetrator group programme in the United Kingdom. METHODS: This was a pragmatic individually randomised pilot and feasibility trial with an integrated qualitative study in one site (covering three local-authority areas) in England. Male perpetrators were randomised to either the intervention or usual care. The intervention was a 23-week group programme for male perpetrators in heterosexual relationships, with an average of three one-to-one sessions, and one-to-one support for female current- or ex-partners delivered by third sector organisations. There was no active control treatment for men, and partners of control men were signposted towards domestic abuse support services. Data were collected at three-monthly intervals for nine months from male and female participants. The main objectives assessed were recruitment, randomisation, retention, data completeness, fidelity to the intervention model, and acceptability of the trial design. RESULTS: This study recruited 36 men (22 randomly allocated to attend the intervention group programme, 14 to usual care), and 15 current- or ex-partners (39% of eligible partners). Retention and completeness of data were high: 67% of male (24/36), and 80% (12/15) of female participants completed the self-reported questionnaire at nine months. A framework for assessing fidelity to the intervention was developed. In interviews, men who completed all or most of the intervention gave positive feedback and reported changes in their own behaviour. Partners were also largely supportive of the trial and were positive about the intervention. Participants who were not allocated to the intervention group reported feeling disappointed but understood the rationale for the trial. CONCLUSIONS: It was feasible to recruit, randomise and retain male perpetrators and female victim/survivors of abuse and collect self-reported outcome data. Participants were engaged in the intervention and reported positive benefits. The trial design was seen as acceptable. TRIAL REGISTRATION: ISRCTN71797549, submitted 03/08/2017, retrospectively registered 27/05/2022.

Self-help mobile messaging intervention for depression among older adults in resource-limited settings: a randomized controlled trial.

Scalable solutions to treat depression in older adults in low-resourced settings are urgently needed. The PRODIGITAL-D pragmatic, single-blind, two-arm, individually randomized controlled trial assessed the effectiveness of a mobile messaging psychosocial intervention in improving depressive symptomatology among older adults in socioeconomically deprived areas of Guarulhos, Brazil. Older adults (aged 60+ years) registered with 24 primary care clinics and identified with depressive symptomatology (9-item Patient Health Questionnaire (PHQ-9) scores ≥ 10) received the 6-week Viva Vida intervention based on psychoeducation and behavioral activation (n = 298) or a single message (n = 305). No health professional support was offered. The primary outcome was improvement from depressive symptomatology (PHQ-9 < 10) at 3 months. Of the 603 participants enrolled (mean age = 65.1 years; 451 (74.8%) women), 527 (87.4%) completed the follow-up assessment. In the intervention arm, 109 of 257 (42.4%) participants had an improved depressive symptomatology, compared with 87 of 270 (32.2%) participants in the control arm (adjusted odds ratio = 1.57; 95% confidence interval = 1.07-2.29; P = 0.019). No severe adverse events related to trial participation were observed. These results demonstrate the usefulness of a digital messaging psychosocial intervention in the short-term improvement from depressive symptomatology that can potentially be integrated into primary care programs for treating older adults with depression. Brazilian Registry of Clinical Trials registration: ReBEC ( RBR-4c94dtn ).

Do baseline characteristics affect depressive symptoms treatment success? Posthoc subgroup analysis from the CONEMO.

OBJECTIVE: As a secondary trial plan analysis, we aim to examine whether participant characteristics, measured before randomization, modified the effect of a digital intervention designed to improve depressive symptoms (CONEMO - Emotional Control) on recovery from depression that has presented a substantive impact on previous research. METHOD: Mixed logistic regression was used to explore interactions between the treatment arm and subgroups of interest, including suicidal ideation, race/color, age, gender, income, type of mobile phone, alcohol misuse, tobacco use, and diabetes/hypertension). We estimated interaction effects between the treatment group and these subgroup factors for the secondary outcomes using linear mixed regression models. RESULTS: Increased effects of the CONEMO intervention on the primary outcome (reduction of the scores of depressive symptoms in at least 50% at three-month follow-up) were observed amongst older and wealthier participants in Lima (p-values 0.030 and 0.001, respectively). At the same time, there was no evidence of such differential effects in São Paulo or any other secondary outcomes level in both countries. CONCLUSIONS: Digital intervention used in primary care settings needs to be accessible. We conclude that the technological intervention CONEMO has no heterogeneity effects on most subgroups studied, except income and age in the Lima trial.

An online clinical decision tool to screen for vertebral fragility fractures (Vfrac) in older women presenting with back pain in general practice: protocol for a feasibility study in preparation for a future cluster randomised controlled trial.

This feasibility study for a future definitive randomized trial assesses the use and acceptability of a new clinical decision tool to identify risk of a vertebral fracture and those who should be referred for spinal radiography in women aged 65 or over presenting to primary care with back pain. PURPOSE: Approximately 12% of older adults have vertebral fragility fractures, but currently fewer than one-third are diagnosed, potentially limiting access to bone protection treatment. Vfrac is a vertebral fracture screening tool which classifies individuals into high or low risk of having a vertebral fracture, allowing targeting of spinal radiographs to high-risk individuals. The objective of this study was to investigate the feasibility of conducting a cluster randomized controlled trial to evaluate the use of an online version of Vfrac in primary care. METHODS: The study will run in six general practices, with three given the Vfrac tool for use on older women (> 65 years) consulting with back pain and three using standard clinical processes for managing such back pain. Anonymised data covering a 12-month period will be collected from all sites on consultations by older women with back pain. Focus groups will be undertaken with healthcare professionals and patients on whom the tool was used to understand the acceptability of Vfrac and identify factors that impact its use. These patients will be sent a paper version of the Vfrac questionnaire to self-complete at home. Outputs of the self-completion Vfrac (high versus low risk) will be compared with the face-to-face Vfrac (high versus low risk), and agreement assessed using Cohen's kappa. RESULTS: This study will evaluate the use and acceptability of Vfrac within primary care and determine if data on resource use can be collected accurately and comprehensively. CONCLUSIONS: This article describes the protocol of the Vfrac feasibility study. TRIAL REGISTRATION: ISRCTN18000119 (registered 01/03/2022) and ISRCTN12150779 (registered 10/01/2022).

Is well-becoming important for children and young people? Evidence from in-depth interviews with children and young people and their parents.

PURPOSE: This study explores how important well-becoming factors appear to be to children during childhood. We define well-becoming as the indicators which predict children and young people's future wellbeing and opportunities. The priority for this work was to explore whether well-becoming might be an important factor to include in outcome measures for children and young people. The inclusion of well-becoming indicators could ensure that opportunities to invest in promoting wellbeing in children's futures are not missed. METHODS: In-depth, qualitative interviews (N = 70) were undertaken with children and young people aged 6-15 years and their parents. Analysis used constant comparison and framework methods to investigate whether well-becoming factors were considered important by informants to children and young people's current wellbeing. RESULTS: The findings of the interviews suggested that children and young people and their parents are concerned with future well-becoming now, as factors such as future achievement, financial security, health, independence, identity, and relationships were identified as key to future quality of life. Informants suggested that they considered it important during childhood to aspire towards positive outcomes in children and young people's futures. CONCLUSION: The study findings, taken alongside relevant literature, have generated evidence to support the notion that future well-becoming is important to current wellbeing. We have drawn on our own work in capability wellbeing measure development to demonstrate how we have incorporated a well-becoming attribute into our measures. The inclusion of well-becoming indicators in measures could aid investment in interventions which more directly improve well-becoming outcomes for children and young people.

Quality improvement interventions to increase the uptake of magnesium sulphate in preterm deliveries for the prevention of cerebral palsy (PReCePT study): a cluster randomised controlled trial.

OBJECTIVE: To compare two quality improvement (QI) interventions to improve antenatal magnesium sulphate (MgSO4 ) uptake in preterm births for the prevention of cerebral palsy. DESIGN: Unblinded cluster randomised controlled trial. SETTING: Academic Health Sciences Network, England, 2018. SAMPLE: Maternity units with ≥10 preterm deliveries annually and MgSO4 uptake of ≤70%; 40 (27 NPP, 13 enhanced support) were included (randomisation stratified by MgSO4 uptake). METHODS: The National PReCePT Programme (NPP) gave maternity units QI materials (clinical guidance, training), regional support, and midwife backfill funding. Enhanced support units received this plus extra backfill funding and unit-level QI coaching. MAIN OUTCOME MEASURES: MgSO4 uptake was compared using routine data and multivariable linear regression. Net monetary benefit was estimated, based on implementation costs, lifetime quality-adjusted life-years and societal costs. The implementation process was assessed through qualitative interviews. RESULTS: MgSO4 uptake increased in all units, with no evidence of any difference between groups (0.84 percentage points lower uptake in the enhanced group, 95% CI -5.03 to 3.35). The probability of enhanced support being cost-effective was <30%. NPP midwives gave more than their funded hours for implementation. Units varied in their support needs. Enhanced support units reported better understanding, engagement and perinatal teamwork. CONCLUSIONS: PReCePT improved MgSO4 uptake in all maternity units. Enhanced support did not further improve uptake but may improve teamwork, and more accurately represented the time needed for implementation. Targeted enhanced support, sustainability of improvements and the possible indirect benefits of stronger teamwork associated with enhanced support should be explored further.

The STAR care pathway for patients with chronic pain after total knee replacement: four-year follow-up of a randomised controlled trial.

BACKGROUND: The Support and Treatment After Replacement (STAR) care pathway is a clinically important and cost-effective intervention found to improve pain outcomes over one year for people with chronic pain three months after total knee replacement (TKR). We followed up STAR trial participants to evaluate the longer-term clinical- and cost-effectiveness of this care pathway. METHODS: Participants who remained enrolled on the trial at one year were contacted by post at a median of four years after randomisation and invited to complete a questionnaire comprising the same outcomes collected during the trial. We captured pain (co-primary outcome using the Brief Pain Inventory (BPI) pain severity and interference scales; scored 0-10, best to worst), function, neuropathic characteristics, emotional aspects of pain, health-related quality of life, and satisfaction. Electronic hospital informatics data on hospital resource use for the period of one to four years post-randomisation were collected from participating hospital sites. The economic evaluation took an National Health Service (NHS) secondary care perspective, with a four-year time horizon. RESULTS: Overall, 226/337 (67%) of participants returned completed follow-up questionnaires, yielding adjusted between-group differences in BPI means of -0.42 (95% confidence interval, CI (-1.07, 0.23); p = 0.20) for pain severity and - 0.64 (95% CI -1.41, 0.12); p = 0.10) for pain interference. Analysis using a multiple imputed data set (n = 337) showed an incremental net monetary benefit in favour of the STAR care pathway of £3,525 (95% CI -£990 to £8,039) at a £20,000/QALY willingness-to-pay threshold, leading to a probability that the intervention was cost-effective of 0.94. CONCLUSIONS: The magnitude of the longer-term benefits of the STAR care pathway are uncertain due to attrition of trial participants; however, there is a suggestion of some degree of sustained clinical benefit at four years. The care pathway remained cost-effective at four years. TRIAL REGISTRATION: ISRCTN: 92,545,361.

Patient Health Questionnaire-9 Item Pairing Predictiveness for Prescreening Depressive Symptomatology: Machine Learning Analysis.

BACKGROUND: Anhedonia and depressed mood are considered the cardinal symptoms of major depressive disorder. These are the first 2 items of the Patient Health Questionnaire (PHQ)-9 and comprise the ultrabrief PHQ-2 used for prescreening depressive symptomatology. The prescreening performance of alternative PHQ-9 item pairings is rarely compared with that of the PHQ-2. OBJECTIVE: This study aims to use machine learning (ML) with the PHQ-9 items to identify and validate the most predictive 2-item depressive symptomatology ultrabrief questionnaire and to test the generalizability of the best pairings found on the primary data set, with 6 external data sets from different populations to validate their use as prescreening instruments. METHODS: All 36 possible PHQ-9 item pairings (each yielding scores of 0-6) were investigated using ML-based methods with logistic regression models. Their performances were evaluated based on the classification of depressive symptomatology, defined as PHQ-9 scores ≥10. This gave each pairing an equal opportunity and avoided any bias in item pairing selection. RESULTS: The ML-based PHQ-9 items 2 and 4 (phq2&4), the depressed mood and low-energy item pairing, and PHQ-9 items 2 and 8 (phq2&8), the depressed mood and psychomotor retardation or agitation item pairing, were found to be the best on the primary data set training split. They generalized well on the primary data set test split with area under the curves (AUCs) of 0.954 and 0.946, respectively, compared with an AUC of 0.942 for the PHQ-2. The phq2&4 had a higher AUC than the PHQ-2 on all 6 external data sets, and the phq2&8 had a higher AUC than the PHQ-2 on 3 data sets. The phq2&4 had the highest Youden index (an unweighted average of sensitivity and specificity) on 2 external data sets, and the phq2&8 had the highest Youden index on another 2. The PHQ-2≥2 cutoff also had the highest Youden index on 2 external data sets, joint highest with the phq2&4 on 1, but its performance fluctuated the most. The PHQ-2≥3 cutoff had the highest Youden index on 1 external data set. The sensitivity and specificity achieved by the phq2&4 and phq2&8 were more evenly balanced than the PHQ-2≥2 and ≥3 cutoffs. CONCLUSIONS: The PHQ-2 did not prove to be a more effective prescreening instrument when compared with other PHQ-9 item pairings. Evaluating all item pairings showed that, compared with alternative partner items, the anhedonia item underperformed alongside the depressed mood item. This suggests that the inclusion of anhedonia as a core symptom of depression and its presence in ultrabrief questionnaires may be incompatible with the empirical evidence. The use of the PHQ-2 to prescreen for depressive symptomatology could result in a greater number of misclassifications than alternative item pairings.

The effectiveness and cost-effectiveness of a group domestic abuse perpetrator programme: protocol for a randomised controlled trial.

BACKGROUND: In contrast to evidence for interventions supporting victim/survivors of domestic violence and abuse (DVA), the effectiveness of perpetrator programmes for reduction of abuse is uncertain. This study aims to estimate the effectiveness and cost-effectiveness of a perpetrator programme for men. METHODS: Pragmatic two-group individually randomised controlled trial (RCT) with embedded process and economic evaluation. Five centres in southwest England and South Wales aim to recruit 316 (reduced from original target of 366) male domestic abuse perpetrators. These will be randomised 2:1 to a community-based domestic abuse perpetrator programme (DAPP) or usual care comparator with 12-month follow-up. Female partners/ex-partners will be invited to join the study. The intervention for men comprises 23 weekly sessions of a group programme delivered in voluntary sector domestic abuse services. The intervention for female partners/ex-partners is one-to-one support from a safety worker. Men allocated to usual care receive no intervention; however, they are free to access other services. Their partners/ex-partners will be signposted to support services. Data is collected at baseline, and 4, 8 and 12 months' follow-up. The primary outcome is men's self-reported abusive behaviour measured by the Abusive Behaviour Inventory (ABI-29) at 12 months. Secondary measures include physical and mental health status and resource use alongside the abuse measure ABI (ABI-R) for partners/ex-partners and criminal justice contact for men. A mixed methods process evaluation and qualitative study will explore mechanisms of effectiveness, judge fidelity to the intervention model using interviews and group observations. The economic evaluation, over a 1-year time horizon from three perspectives (health and social care, public sector and society), will employ a cost-consequences framework reporting costs alongside economic outcomes (Quality-Adjusted Life Years derived from EQ-5D-5L, SF-12 and CHU-9D, and ICECAP-A) as well as the primary and other secondary outcomes. DISCUSSION: This trial will provide evidence of the (cost)effectiveness of a DAPP. The embedded process evaluation will further insights in the experiences and contexts of participants and their journey through a perpetrator programme, and the study will seek to address the omission in other studies of economic evaluations. TRIAL REGISTRATION: ISRCTN15804282, April 1, 2019.

Social, emotional and behavioural difficulties associated with persistent speech disorder in children: A prospective population study.

Purpose: Social, emotional and behavioural difficulties (SEBD) in childhood are associated with negative consequences across the life course. Children with developmental language disorder have been identified as being at risk of developing SEBD but it is unclear whether a similar risk exists for children with speech sound disorder, a condition which impacts on children's ability to make themselves understood and has been shown to be associated with poor educational outcomes. Methods: Participants were children who attended the 8-year-old clinic in the Avon Longitudinal Study of Parents and Children (N = 7390). Children with speech sound disorder that had persisted beyond the period of typical speech acquisition (persistent speech disorder [PSD]) at age 8 were identified from recordings and transcriptions of speech samples (N = 263). Parent-, teacher- and child-reported questionnaires and interviews including the Strengths and Difficulties Questionnaire, Short Moods and Feelings Questionnaire and measures for antisocial and risk-taking behaviour were used to provide outcome scores for SEBD at 10-14 years in a series of regression analyses. Results: Following adjustment for biological sex, socio-economic status and Intelligence Quotient, children with PSD at age 8 were more likely to show peer problems at age 10-11 years compared with their peers, as reported by teachers and parents. Teachers were more likely to report problems with emotionality. Children with PSD were no more likely to report symptoms of depression than their peers. No associations were observed between PSD, risk of antisocial behaviour, trying alcohol at age 10 or smoking cigarettes at age 14. Conclusions: Children with PSD may be at risk in terms of their peer relationships. This could impact on their wellbeing and, while not observed at this age, may lead to depressive symptoms in older childhood and adolescence. There is also the potential that these symptoms may impact on educational outcomes.

Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1.

Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy. METHODS: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes). RESULTS: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis. CONCLUSIONS: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.).

National PReCePT Programme: a before-and-after evaluation of the implementation of a national quality improvement programme to increase the uptake of magnesium sulfate in preterm deliveries.

OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of the National PReCePT Programme (NPP) in increasing use of magnesium sulfate (MgSO4) in preterm births. DESIGN: Before-and-after study. SETTING: Maternity units (N=137) within NHS England and the Academic Health Science Network (AHSN) in 2018. PARTICIPANTS: Babies born ≤30 weeks' gestation admitted to neonatal units in England. INTERVENTIONS: The NPP was a quality improvement (QI) intervention including the PReCePT (Preventing Cerebral Palsy in Pre Term labour) QI toolkit and materials (preterm labour proforma, staff training presentations, parent leaflet, posters for the unit and learning log), regional AHSN-level support, and up to 90 hours funded backfill for a midwife 'champion' to lead implementation. MAIN OUTCOME MEASURES: MgSO4 uptake post implementation was compared with pre-NPP implementation uptake. Implementation and lifetime costs were estimated. RESULTS: Compared with pre-implementation estimates, the average MgSO4 uptake for babies born ≤30 weeks' gestation, in 137 maternity units in England, increased by 6.3 percentage points (95% CI 2.6 to 10.0 percentage points) to 83.1% post implementation, accounting for unit size, maternal, baby and maternity unit factors, time trends, and AHSN. Further adjustment for early/late initiation of NPP activities increased the estimate to 9.5 percentage points (95% CI 4.3 to 14.7 percentage points). From a societal and lifetime perspective, the health gains and cost savings associated with the NPP effectiveness generated a net monetary benefit of £866 per preterm baby and the probability of the NPP being cost-effective was greater than 95%. CONCLUSION: This national QI programme was effective and cost-effective. National programmes delivered via coordinated regional clinical networks can accelerate uptake of evidence-based therapies in perinatal care.

Patient-Reported Outcomes 12 Years after Localized Prostate Cancer Treatment.

Outcomes after Localized Prostate Cancer TreatmentDonovan et al. present the long-term patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial. Functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring are described. Over the trial period from 7 to 12 years, generic quality-of-life scores were similar among all groups, with varying degrees of impact on urinary leakage, sexual function, and fecal leakage depending on the treatment group.

A task-shared, collaborative care psychosocial intervention for improving depressive symptomatology among older adults in a socioeconomically deprived area of Brazil (PROACTIVE): a pragmatic, two-arm, parallel-group, cluster-randomised controlled trial.

BACKGROUND: There is an urgent need to reduce the burden of depression among older adults in low-income and middle-income countries (LMICs). We aimed to evaluate the efficacy of a task-shared, collaborative care psychosocial intervention for improving recovery from depression in older adults in Brazil. METHODS: PROACTIVE was a pragmatic, two-arm, parallel-group, cluster-randomised controlled trial conducted in Guarulhos, Brazil. Primary care clinics (clusters) were stratified by educational level and randomly allocated (1:1) to either enhanced usual care alone (control group) or to enhanced usual care plus the psychosocial intervention (intervention group), which involved a 17-week psychosocial programme based on psychoeducation and behavioural activation approaches. Individuals approached for the initial screening assessment were selected randomly from a list of individuals provided by the Health Secretariat of Guarulhos. Face-to-face baseline assessments were conducted among adults aged 60 years or older registered with one of the primary care clinics and identified with clinically significant depressive symptomatology (9-item Patient Health Questionnaire [PHQ-9] score ≥10). Community health workers delivered the programme through home sessions, supported by a dedicated tablet application. Masking of clinic staff and community health workers who delivered the intervention was not feasible; however, research assistants conducting recruitment and follow-up assessments were masked to trial allocation. The primary outcome was recovery from depression (PHQ-9 score <10) at 8-month follow-up. All primary analyses were performed by intention to treat with imputed data. Adaptations to the protocol were made due to the COVID-19 pandemic; recruitment and intervention home sessions were stopped, and follow-up assessments were conducted by telephone. This trial is registered with the ISRCTN registry, ISRCTN57805470. FINDINGS: We identified 24 primary care clinics in Guarulhos that were willing to participate, of which 20 were randomly allocated to either the control group (ten [50%] clusters) or to the intervention group (ten [50%] clusters). The four remaining eligible clusters were kept as reserves. Between May 23, 2019, and Feb 21, 2020, 8146 individuals were assessed for eligibility, of whom 715 (8·8%) participants were recruited: 355 (49·7%) in the control group and 360 (50·3%) in the intervention group. 284 (80·0%) participants in the control group and 253 (70·3%) in the intervention group completed follow-up at 8 months. At 8-month follow-up, 158 (62·5%) participants in the intervention group showed recovery from depression (PHQ-9 score <10) compared with 125 (44·0%) in the control group (adjusted odds ratio 2·16 [95% CI 1·47-3·18]; p<0·0001). These findings were maintained in the complete case analysis. No adverse events related to the intervention were observed. INTERPRETATION: Although the COVID-19 pandemic altered delivery of the intervention, the low-intensity psychosocial intervention delivered mainly by non-mental health professionals was highly efficacious in improving recovery from depression in older adults in Brazil. Our results support a low-resource intervention that could be useful to reduce the treatment gap for depression among older people in other LMICs. FUNDING: São Paulo Research Foundation and Joint Global Health Trials (UK Department for International Development, Medical Research Council, and the Wellcome Trust).

Digital psychosocial intervention for depression among older adults in socioeconomically deprived areas in Brazil (PRODIGITAL-D): protocol for an individually randomised controlled trial.

BACKGROUND: Depression in older adults is a challenge for health systems in most low- and middle-income countries (LMICs). Digital strategies for the management of this condition have been emerging worldwide, but the effectiveness of most of them is still unclear, especially among older adults. Thus, we aim to assess the effectiveness and cost-effectiveness of a digital psychosocial intervention to treat depression among older adults living in socioeconomically deprived areas in Guarulhos, Brazil. METHODS: We will conduct a two-arm individually randomised controlled trial with 1:1 allocation ratio. Five hundred older adults aged 60 years or over with depressive symptomatology (9-item Patient Health Questionnaire score, PHQ-9 ≥ 10) and registered with one of the primary care clinics will be recruited to participate in this study. A 6-week digital psychosocial programme, named Viva Vida, will be delivered via WhatsApp to participants allocated to the intervention arm. The Viva Vida will send psychoeducational and behavioural activation audio and visual messages 4 days a week for 6 weeks. The control arm will only receive a single message with general information about depression. The primary outcome will be the proportion of depression recovery (PHQ-9 < 10) assessed at 3 months. The cost-effectiveness of the intervention will be assessed at 5 months. A detailed process evaluation will be used to explore context and important implementation outcomes. DISCUSSION: This programme was based on the PROACTIVE intervention and designed to be delivered without face-to-face contact. If effective, it could be a simple treatment option, appropriate not only when social distancing is required, but it could also be included as a regular public health programme to initiate depression treatment, particularly in LMICs where resources allocated to mental health are scarce. TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clínicos (ReBEC), RBR-4c94dtn. Registered on 22 October 2021 (submitted on 03 August 2021).

Genetic and structural basis of the human anti-α-galactosyl antibody response.

Humans lack the capacity to produce the Galα1-3Galß1-4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development.

Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study).

OBJECTIVE: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. PATIENTS AND METHODS: Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. RESULTS: Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. CONCLUSION: Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes.