Clinical and cost-effectiveness of nurse-delivered sleep restriction therapy for insomnia in primary care (HABIT): a pragmatic, superiority, open-label, randomised controlled trial.

BACKGROUND: Insomnia is prevalent and distressing but access to the first-line treatment, cognitive behavioural therapy (CBT), is extremely limited. We aimed to assess the clinical and cost-effectiveness of sleep restriction therapy, a key component of CBT, which has the potential to be widely implemented. METHODS: We did a pragmatic, superiority, open-label, randomised controlled trial of sleep restriction therapy versus sleep hygiene. Adults with insomnia disorder were recruited from 35 general practices across England and randomly assigned (1:1) using a web-based randomisation programme to either four sessions of nurse-delivered sleep restriction therapy plus a sleep hygiene booklet or a sleep hygiene booklet only. There was no restriction on usual care for either group. Outcomes were assessed at 3 months, 6 months, and 12 months. The primary endpoint was self-reported insomnia severity at 6 months measured with the insomnia severity index (ISI). The primary analysis included participants according to their allocated group and who contributed at least one outcome measurement. Cost-effectiveness was evaluated from the UK National Health Service and personal social services perspective and expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. The trial was prospectively registered (ISRCTN42499563). FINDINGS: Between Aug 29, 2018, and March 23, 2020 we randomly assigned 642 participants to sleep restriction therapy (n=321) or sleep hygiene (n=321). Mean age was 55·4 years (range 19-88), with 489 (76·2%) participants being female and 153 (23·8%) being male. 580 (90·3%) participants provided data for at least one outcome measurement. At 6 months, mean ISI score was 10·9 (SD 5·5) for sleep restriction therapy and 13·9 (5·2) for sleep hygiene (adjusted mean difference -3·05, 95% CI -3·83 to -2·28; p<0·0001; Cohen's d -0·74), indicating that participants in the sleep restriction therapy group reported lower insomnia severity than the sleep hygiene group. The incremental cost per QALY gained was £2076, giving a 95·3% probability that treatment was cost-effective at a cost-effectiveness threshold of £20 000. Eight participants in each group had serious adverse events, none of which were judged to be related to intervention. INTERPRETATION: Brief nurse-delivered sleep restriction therapy in primary care reduces insomnia symptoms, is likely to be cost-effective, and has the potential to be widely implemented as a first-line treatment for insomnia disorder. FUNDING: The National Institute for Health and Care Research Health Technology Assessment Programme.

Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial.

BACKGROUND: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. METHODS: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing. FINDINGS: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). INTERPRETATION: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. FUNDING: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

Research Review: Harnessing the power of individual participant data in a meta-analysis of the benefits and harms of the Incredible Years parenting program.

BACKGROUND: Parenting programs aim to reduce children's conduct problems through improvement of family dynamics. To date, research on the precise benefits and possible harms of parenting programs on family well-being has been unsystematic and likely to be subject to selective outcome reporting and publication bias. Better understanding of program benefits and harms requires full disclosure by researchers of all included measures, and large enough numbers of participants to be able to detect small effects and estimate them precisely. METHODS: We obtained individual participant data for 14 of 15 randomized controlled trials on the Incredible Years parenting program in Europe (total N = 1,799). We used multilevel modeling to estimate program effects on 13 parent-reported outcomes, including parenting practices, children's mental health, and parental mental health. RESULTS: Parental use of praise, corporal punishment, threats, and shouting improved, while parental use of tangible rewards, monitoring, or laxness did not. Children's conduct problems and attention deficit hyperactivity disorder (ADHD) symptoms improved, while emotional problems did not. Parental mental health (depressive symptoms, self-efficacy, and stress) did not improve. There was no evidence of harmful effects. CONCLUSIONS: The Incredible Years parenting program improves the aspects of family well-being that it is primarily designed to improve: parenting and children's conduct problems. It also improves parent-reported ADHD symptoms in children. Wider benefits are limited: the program does not improve children's emotional problems or parental mental health. There are no signs of harm on any of the target outcomes.

Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial.

BACKGROUND: Anxiety problems are common in children, yet few affected children access evidence-based treatment. Digitally augmented psychological therapies bring potential to increase availability of effective help for children with mental health problems. This study aimed to establish whether therapist-supported, digitally augmented, parent-led cognitive behavioural therapy (CBT) could increase the efficiency of treatment without compromising clinical effectiveness and acceptability. METHODS: We conducted a pragmatic, unblinded, two-arm, multisite, randomised controlled non-inferiority trial to evaluate the clinical effectiveness and cost-effectiveness of therapist-supported, parent-led CBT using the Online Support and Intervention (OSI) for child anxiety platform compared with treatment as usual for child (aged 5-12 years) anxiety problems in 34 Child and Adolescent Mental Health Services in England and Northern Ireland. We examined acceptability of OSI plus therapist support via qualitative interviews. Participants were randomly assigned (1:1) to OSI plus therapist support or treatment as usual, minimised by child age, gender, service type, and baseline child anxiety interference. Outcomes were assessed at week 14 and week 26 after randomisation. The primary clinical outcome was parent-reported interference caused by child anxiety at week 26 assessment, using the Child Anxiety Impact Scale-parent report (CAIS-P). The primary measure of health economic effect was quality-adjusted life-years (QALYs). Outcome analyses were conducted blind in the intention-to-treat (ITT) population with a standardised non-inferiority margin of 0·33 for clinical analyses. The trial was registered with ISRCTN, 12890382. FINDINGS: Between Dec 5, 2020, and Aug 3, 2022, 706 families (706 children and their parents or carers) were referred to the study information. 444 families were enrolled. Parents reported 255 (58%) child participants' gender to be female, 184 (41%) male, three (<1%) other, and one (<1%) preferred not to report their child's gender. 400 (90%) children were White and the mean age was 9·20 years (SD 1·79). 85% of families for whom clinicians provided information in the treatment as usual group received CBT. OSI plus therapist support was non-inferior for parent-reported anxiety interference on the CAIS-P (SMD 0·01, 95% CI -0·15 to 0·17; p<0·0001) and all secondary outcomes. The mean difference in QALYs across trial arms approximated to zero, and OSI plus therapist support was associated with lower costs than treatment as usual. OSI plus therapist support was likely to be cost effective under certain scenarios, but uncertainty was high. OSI plus therapist support acceptability was good. No serious adverse events were reported. INTERPRETATION: Digitally augmented intervention brought promising savings without compromising outcomes and as such presents a valuable tool for increasing access to psychological therapies and meeting the demand for treatment of child anxiety problems. FUNDING: Department for Health and Social Care and United Kingdom Research and Innovation Research Grant, National Institute for Health and Care (NIHR) Research Policy Research Programme, Oxford and Thames Valley NIHR Applied Research Collaboration, Oxford Health NIHR Biomedical Research Centre.

Toxic Epidermal Necrolysis and Steven-Johnson Syndrome: A Comprehensive Review.

Significance: Toxic epidermal necrolysis (TEN) and Steven-Johnson syndrome (SJS) are potentially fatal acute mucocutaneous vesiculobullous disorders. Evidence to date suggests that outcomes for patients with both TEN and SJS are largely dependent on stopping the causative agent, followed by supportive care and appropriate wound management in a specialized burns unit. These are life-threatening conditions characterized by widespread full-thickness cutaneous and mucosal necrosis. This article outlines the approach to holistic management of such patients, in a specialized unit, highlighting various practical aspects of wound care to prevent complications such as infection, mucosal and adhesions, and ocular scaring. Recent Advances: There is improved understanding of pain and morbidity with regard to the type and frequency of dressing changes. More modern dressings, such as nanocrystalline, are currently favored as they may be kept in situ for longer periods. The most recent evidence on systemic agents, such as corticosteroids and cyclosporine, and novel treatments, are also discussed. Critical Issues: Following cessation of the culprit trigger, management in a specialized burns unit is the most important management step. It is now understood that a multidisciplinary team is essential in the care of these patients. Following admission of such patients, dermatology, ear, nose, and throat surgery, ophthalmology, urology, colorectal surgery, and gynecology should all be consulted to prevent disease sequelae. Future Directions: Looking forward, research is aimed at achieving prospective data on the efficacy of systemic immunomodulating agents and dressing types. Tertiary centers with burns units should develop policies for such patients to ensure that the relevant teams are consulted promptly to avoid mucocutaneous complications.

Prescriber Commitment Posters to Increase Prudent Antibiotic Prescribing in English General Practice: A Cluster Randomized Controlled Trial.

Unnecessary antibiotic prescribing contributes to Antimicrobial Resistance posing a major public health risk. Estimates suggest as many as half of antibiotics prescribed for respiratory infections may be unnecessary. We conducted a three-armed unblinded cluster randomized controlled trial (ISRCTN trial registry 83322985). Interventions were a commitment poster (CP) advocating safe antibiotic prescribing or a CP plus an antimicrobial stewardship message (AM) on telephone appointment booking lines, tested against a usual care control group. The primary outcome measure was antibiotic item dispensing rates per 1000 population adjusted for practice demographics. The outcome measures for post-hoc analysis were dispensing rates of antibiotics usually prescribed for upper respiratory tract infections and broad spectrum antibiotics. In total, 196 practice units were randomized to usual care (n = 60), CP (n = 66), and CP&AM (n = 70). There was no effect on the overall dispensing rates for either interventions compared to usual care (CP 5.673, 95%CI -9.768 to 21.113, p = 0.458; CP&AM, -12.575, 95%CI -30.726 to 5.576, p = 0.167). Secondary analysis, which included pooling the data into one model, showed a significant effect of the AM (-18.444, 95%CI -32.596 to -4.292, p = 0.012). Fewer penicillins and macrolides were prescribed in the CP&AM intervention compared to usual care (-12.996, 95% CI -34.585 to -4.913, p = 0.018). Commitment posters did not reduce antibiotic prescribing. An automated patient antimicrobial stewardship message showed effects and requires further testing.

Individual Participant Data Meta-analysis: Impact of Conduct Problem Severity, Comorbid Attention-Deficit/Hyperactivity Disorder and Emotional Problems, and Maternal Depression on Parenting Program Effects.

OBJECTIVE: There is concern whether established parenting programs for children's conduct problems meet the needs of families with severe and complex mental health problems. For example, many children with conduct problems show comorbid attention-deficit/hyperactivity disorder (ADHD) or emotional problems, or have parents who are depressed, but families with such complex mental health problems typically seen in real life are often underrepresented in evaluation trials. We tested whether children with more severe conduct problems, and those with more complex mental health problems, benefit less from the Incredible Years parenting program, using individual participant data meta-analysis of randomized trials in Europe. METHOD: In 1,696 families from 13 children aged (child age 2-11 years; 37% girls; 58% low income; 30% ethnic minority; 98% mothers), we used moderator analysis within a multilevel model to test whether initial conduct problem severity, comorbid ADHD or emotional problems, and maternal depression would diminish intervention effects for children's conduct problems. RESULTS: The Incredible Years program reduced children's conduct problems overall (Cohen's d = -0.35), but more so in children with more severe conduct problems. There was no evidence that children's comorbid ADHD and emotional problems changed the intervention benefits. Children of mothers with more depressive symptoms benefited more. CONCLUSION: Children with more severe conduct problems derive greater, rather than lesser, benefits from a high-quality group parenting program, and comorbid ADHD and emotional problems do not reduce effects; maternal depression, rather than being linked to less child change, was associated with greater reductions in children's conduct problems.

Opportunities and challenges in Improving Access to Psychological Therapies for people with Severe Mental Illness (IAPT-SMI): evaluating the first operational year of the South London and Maudsley (SLaM) demonstration site for psychosis.

Despite its demonstrated clinical and economic effectiveness, access to Cognitive Behavioural Therapy for psychosis (CBTp) in routine practice remains low. The UK National Health Service (NHS England) Improving Access to Psychological Therapies for people with Severe Mental Illness (IAPT-SMI) initiative aims to address this problem. We report 14-month outcomes for our psychosis demonstration site. Primary and secondary care and self-referrals were screened to check the suitability of the service for the person. Psychotic symptoms, distress, service use, functioning and satisfaction were measured before and after therapy, by trained assessors. User-defined wellbeing and goal-attainment were rated sessionally. Access to CBTp increased almost threefold (2011/12 accepted referrals/year n = 106; 2012/13, n = 300). The IAPT-SMI assessment protocol proved feasible and acceptable to service users, with paired primary outcomes for 97% of closed cases. Therapy completion (≥5 sessions) was high (83%) irrespective of ethnicity, age and gender. Preliminary pre-post outcomes showed clinical improvement and reduced service use, with medium/high effect sizes. User-rated satisfaction was high. We conclude that individual psychological interventions for people with psychosis can be successfully delivered in routine services using an IAPT approach. High completion rates for paired outcomes demonstrate good user experience, clinical improvement, and potential future cost savings.