Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial.

Importance: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. ß-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. Design, Setting, and Participants: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 µg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, -1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

Reducing Opioid Use for Chronic Pain With a Group-Based Intervention: A Randomized Clinical Trial.

Importance: Opioid use for chronic nonmalignant pain can be harmful. Objective: To test whether a multicomponent, group-based, self-management intervention reduced opioid use and improved pain-related disability compared with usual care. Design, Setting, and Participants: Multicentered, randomized clinical trial of 608 adults taking strong opioids (buprenorphine, dipipanone, morphine, diamorphine, fentanyl, hydromorphone, methadone, oxycodone, papaveretum, pentazocine, pethidine, tapentadol, and tramadol) to treat chronic nonmalignant pain. The study was conducted in 191 primary care centers in England between May 17, 2017, and January 30, 2019. Final follow-up occurred March 18, 2020. Intervention: Participants were randomized 1:1 to either usual care or 3-day-long group sessions that emphasized skill-based learning and education, supplemented by 1-on-1 support delivered by a nurse and lay person for 12 months. Main Outcomes and Measures: The 2 primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS-PI-SF-8a) score (T-score range, 40.7-77; 77 indicates worst pain interference; minimal clinically important difference, 3.5) and the proportion of participants who discontinued opioids at 12 months, measured by self-report. Results: Of 608 participants randomized (mean age, 61 years; 362 female [60%]; median daily morphine equivalent dose, 46 mg [IQR, 25 to 79]), 440 (72%) completed 12-month follow-up. There was no statistically significant difference in PROMIS-PI-SF-8a scores between the 2 groups at 12-month follow-up (-4.1 in the intervention and -3.17 in the usual care groups; between-group difference: mean difference, -0.52 [95% CI, -1.94 to 0.89]; P = .15). At 12 months, opioid discontinuation occurred in 65 of 225 participants (29%) in the intervention group and 15 of 208 participants (7%) in the usual care group (odds ratio, 5.55 [95% CI, 2.80 to 10.99]; absolute difference, 21.7% [95% CI, 14.8% to 28.6%]; P < .001). Serious adverse events occurred in 8% (25/305) of the participants in the intervention group and 5% (16/303) of the participants in the usual care group. The most common serious adverse events were gastrointestinal (2% in the intervention group and 0% in the usual care group) and locomotor/musculoskeletal (2% in the intervention group and 1% in the usual care group). Four people (1%) in the intervention group received additional medical care for possible or probable symptoms of opioid withdrawal (shortness of breath, hot flushes, fever and pain, small intestinal bleed, and an overdose suicide attempt). Conclusions and Relevance: In people with chronic pain due to nonmalignant causes, compared with usual care, a group-based educational intervention that included group and individual support and skill-based learning significantly reduced patient-reported use of opioids, but had no effect on perceived pain interference with daily life activities. Trial Registration: isrctn.org Identifier: ISRCTN49470934.

Effects of early extubation followed by noninvasive ventilation versus standard extubation on the duration of invasive mechanical ventilation in hypoxemic non-hypercapnic patients: a systematic review and individual patient data meta-analysis of randomized controlled trials.

BACKGROUND: Usefulness of noninvasive ventilation (NIV) in weaning patients with non-hypercapnic hypoxemic acute respiratory failure (hARF) is unclear. The study aims to assess in patients with non-hypercapnic hARF, the efficacy of NIV after early extubation, compared to standard weaning. METHODS: In this individual patient data meta-analysis, we searched EMBASE, Medline and Cochrane Central Register of Controlled Trials to identify potentially eligible randomized controlled trials published from database inception to October 2020. To be eligible, studies had to include patients treated with NIV after early extubation and compared to conventional weaning in adult non-hypercapnic hARF patients. Anonymized individual patient data from eligible studies were provided by study investigators. Using one-step and two-step meta-analysis models we tested the difference in total days spent on invasive ventilation. RESULTS: We screened 1605 records. Six studies were included in quantitative synthesis. Overall, 459 participants (mean [SD] age, 62 [15] years; 269 [59%] males) recovering from hARF were included in the analysis (233 in the intervention group and 226 controls). Participants receiving NIV had a shorter duration of invasive mechanical ventilation compared to control group (mean difference, - 3.43; 95% CI - 5.17 to - 1.69 days, p < 0.001), a shorter duration of total days spent on mechanical ventilation (mean difference, - 2.04; 95% CI - 3.82 to - 0.27 days, p = 0.024), a reduced risk of ventilatory associated pneumonia (odds ratio, 0.24; 95% CI 0.08 to 0.71, p = 0.014), a reduction of time spent in ICU (time ratio, 0.81; 95% CI 0.68 to 0.96, p = 0.015) and in-hospital (time ratio, 0.81; 95% CI 0.69 to 0.95, p = 0.010), with no difference in ICU mortality. CONCLUSIONS: Although primary studies are limited, using an individual patient data metanalysis approach, NIV after early extubation appears useful in reducing total days spent on invasive mechanical ventilation. TRIAL REGISTRATION: The protocol was registered to PROSPERO database on 12/06/2019 and available at PROSPERO website inserting the study code i.e., CRD42019133837.

Psychiatric hospital reform in low- and middle-income countries: a systematic review of literature.

PURPOSE: Psychiatric hospitals or mental asylums grew across the world in the colonial era. Despite concerns over quality of care and human rights violations, these hospitals continue to provide the majority of mental health care in most low- and middle-income countries (LMICs). We sought to review the evidence of reform of mental hospitals and associated patient outcomes. METHODS: We adopted an integrative review methodology by including experimental and non-experimental research. The review protocol was registered on PROSPERO (CRD42019130399). A range of databases and systematic hand searches were conducted by two independent reviewers. Research conducted between 1980 and May 2019, that focused on any aspect of reform in mental hospitals for adults (age 18 and upwards) with severe mental illness and published in English, were considered. RESULTS: 16 studies were included in the review. 12 studies met inclusion criteria, and four additional reports emerged from the hand search. Studies covered-India, China, South Africa, Grenada, Georgia, Sri Lanka, Argentina and Brazil. Key findings emphasise the role of judicial intervention as a critical trigger of reform. Structural reform composed of optimisation of resources and renovations of colonial structures to cater to diverse patient needs. Process reforms include changes in medical management, admission processes and a move from closed to open wards. Staff engagement and capacity building have also been used as a modality of reform in mental hospital settings. CONCLUSION: There is some documentation of reform in psychiatric hospitals. However, poor methodological quality and variation in approach and outcomes measured, make it challenging to extrapolate specific findings on process or outcomes of reform. Despite being integral service providers, psychiatric hospitals still do not adopt patient centric, recovery-oriented processes. Hence, there is an urgent need to generate robust evidence on psychiatric reform and its effect on patient outcomes.

Identification of subgroup effect with an individual participant data meta-analysis of randomised controlled trials of three different types of therapist-delivered care in low back pain.

BACKGROUND: Proven treatments for low back pain, at best, only provide modest overall benefits. Matching people to treatments that are likely to be most effective for them may improve clinical outcomes and makes better use of health care resources. METHODS: We conducted an individual participant data meta-analysis of randomised controlled trials of three types of therapist delivered interventions for low back pain (active physical, passive physical and psychological treatments). We applied two statistical methods (recursive partitioning and adaptive risk group refinement) to identify potential subgroups who might gain greater benefits from different treatments from our individual participant data meta-analysis. RESULTS: We pooled data from 19 randomised controlled trials, totalling 9328 participants. There were 5349 (57%) females with similar ratios of females in control and intervention arms. The average age was 49 years (standard deviation, SD, 14). Participants with greater psychological distress and physical disability gained most benefit in improving on the mental component scale (MCS) of SF-12/36 from passive physical treatment than non-active usual care (treatment effects, 4.3; 95% confidence interval, CI, 3.39 to 5.15). Recursive partitioning method found that participants with worse disability at baseline gained most benefit in improving the disability (Roland Morris Disability Questionnaire) outcome from psychological treatment than non-active usual care (treatment effects, 1.7; 95% CI, 1.1 to 2.31). Adaptive risk group refinement did not find any subgroup that would gain much treatment effect between psychological and non-active usual care. Neither statistical method identified any subgroups who would gain an additional benefit from active physical treatment compared to non-active usual care. CONCLUSIONS: Our methodological approaches worked well and may have applicability in other clinical areas. Passive physical treatments were most likely to help people who were younger with higher levels of disability and low levels of psychological distress. Psychological treatments were more likely to help those with severe disability. Despite this, the clinical importance of identifying these subgroups is limited. The sizes of sub-groups more likely to benefit and the additional effect sizes observed are small. Our analyses provide no evidence to support the use of sub-grouping for people with low back pain.

Chronic Headache Education and Self-management Study (CHESS) - a mixed method feasibility study to inform the design of a randomised controlled trial.

BACKGROUND: Self-management support programmes are effective in a range of chronic conditions however there is limited evidence for their use in the treatment of chronic headaches. The aim of this study was to test the feasibility of four key aspects of a planned, future evaluative trial of a new education and self-management intervention for people with chronic headache: 1) recruiting people with chronic headache from primary care; 2) a telephone interview for the classification of chronic headaches; 3) the education and self-management intervention itself; and 4) the most appropriate patient reported outcomes (PROMS). METHODS: Participants were identified and recruited from general practices in the West Midlands of the UK. We developed a nurse-led chronic headache classification interview and assessed agreement with an interview with headache specialists. We developed and tested a group based education and self-management intervention to assess training and delivery receipt using observation, facilitator, and participant feedback. We explored the acceptability and relevance of PROMs using postal questionnaires, interviews and a smartphone app. RESULTS: Fourteen practices took part in the study and participant recruitment equated to 1.0/1000 registered patients. Challenges to recruitment were identified. We did 107 paired headache classification interviews. The level of agreement between nurse and doctor interviews was very good. We piloted the intervention in four groups with 18 participants. Qualitative feedback from participants and facilitators helped refine the intervention including shortening the overall intervention and increasing the facilitator training time. Participants completed 131 baseline questionnaires, measurement data quality, reliability and validity for headache-specific and generic measures was acceptable. CONCLUSION: This study indicated that recruiting people with chronic headache from primary care is feasible but challenging, our headache classification interview is fit for purpose, our study intervention is viable, and that our choice of outcome measures is acceptable to participants in a future randomised controlled trial (RCT). TRIAL REGISTRATION: ISRCTN, ISRCTN79708100. Registered 16th December 2015, http://www.isrctn.com/ISRCTN79708100.

A recursive partitioning approach for subgroup identification in individual patient data meta-analysis.

BACKGROUND: Motivated by the setting of clinical trials in low back pain, this work investigated statistical methods to identify patient subgroups for which there is a large treatment effect (treatment by subgroup interaction). Statistical tests for interaction are often underpowered. Individual patient data (IPD) meta-analyses provide a framework with improved statistical power to investigate subgroups. However, conventional approaches to subgroup analyses applied in both a single trial setting and an IPD setting have a number of issues, one of them being that factors used to define subgroups are investigated one at a time. As individuals have multiple characteristics that may be related to response to treatment, alternative exploratory statistical methods are required. METHODS: Tree-based methods are a promising alternative that systematically searches the covariate space to identify subgroups defined by multiple characteristics. A tree method in particular, SIDES, is described and extended for application in an IPD meta-analyses setting by incorporating fixed-effects and random-effects models to account for between-trial variation. The performance of the proposed extension was assessed using simulation studies. The proposed method was then applied to an IPD low back pain dataset. RESULTS: The simulation studies found that the extended IPD-SIDES method performed well in detecting subgroups especially in the presence of large between-trial variation. The IPD-SIDES method identified subgroups with enhanced treatment effect when applied to the low back pain data. CONCLUSIONS: This work proposes an exploratory statistical approach for subgroup analyses applicable in any research discipline where subgroup analyses in an IPD meta-analysis setting are of interest.

Effect of Protocolized Weaning With Early Extubation to Noninvasive Ventilation vs Invasive Weaning on Time to Liberation From Mechanical Ventilation Among Patients With Respiratory Failure: The Breathe Randomized Clinical Trial.

Importance: In adults in whom weaning from invasive mechanical ventilation is difficult, noninvasive ventilation may facilitate early liberation, but there is uncertainty about its effectiveness in a general intensive care patient population. Objective: To investigate among patients with difficulty weaning the effects of protocolized weaning with early extubation to noninvasive ventilation on time to liberation from ventilation compared with protocolized invasive weaning. Design, Setting, and Participants: Randomized, allocation-concealed, open-label, multicenter clinical trial enrolling patients between March 2013 and October 2016 from 41 intensive care units in the UK National Health Service. Follow-up continued until April 2017. Adults who received invasive mechanical ventilation for more than 48 hours and in whom a spontaneous breathing trial failed were enrolled. Interventions: Patients were randomized to receive either protocolized weaning via early extubation to noninvasive ventilation (n = 182) or protocolized standard weaning (continued invasive ventilation until successful spontaneous breathing trial, followed by extubation) (n = 182). Main Outcomes and Measures: Primary outcome was time from randomization to successful liberation from all forms of mechanical ventilation among survivors, measured in days, with the minimal clinically important difference defined as 1 day. Secondary outcomes were duration of invasive and total ventilation (days), reintubation or tracheostomy rates, and survival. Results: Among 364 randomized patients (mean age, 63.1 [SD, 14.8] years; 50.5% male), 319 were evaluable for the primary effectiveness outcome (41 died before liberation, 2 withdrew, and 2 were discharged with ongoing ventilation). The median time to liberation was 4.3 days in the noninvasive group vs 4.5 days in the invasive group (adjusted hazard ratio, 1.1; 95% CI, 0.89-1.40). Competing risk analysis accounting for deaths had a similar result (adjusted hazard ratio, 1.1; 95% CI, 0.86-1.34). The noninvasive group received less invasive ventilation (median, 1 day vs 4 days; incidence rate ratio, 0.6; 95% CI, 0.47-0.87) and fewer total ventilator days (median, 3 days vs 4 days; incidence rate ratio, 0.8; 95% CI, 0.62-1.0). There was no significant difference in reintubation, tracheostomy rates, or survival. Adverse events occurred in 45 patients (24.7%) in the noninvasive group compared with 47 (25.8%) in the invasive group. Conclusions and Relevance: Among patients requiring mechanical ventilation in whom a spontaneous breathing trial had failed, early extubation to noninvasive ventilation did not shorten time to liberation from any ventilation. Trial Registration: ISRCTN Identifier: ISRCTN15635197.

Close Contact Casting vs Surgery for Initial Treatment of Unstable Ankle Fractures in Older Adults: A Randomized Clinical Trial.

Importance: Ankle fractures cause substantial morbidity in older persons. Surgical fixation is the contemporary intervention but is associated with infection and other healing complications. Objective: To determine whether initial fracture treatment with close contact casting, a molded below-knee cast with minimal padding, offers outcome equivalent to that with immediate surgery, with fewer complications and less health resource use. Design, Setting, and Participants: This was a pragmatic, equivalence, randomized clinical trial with blinded outcome assessors. A pilot study commenced in May 2004, followed by multicenter recruitment from July 2010 to November 2013; follow-up was completed May 2014. Recruitment was from 24 UK major trauma centers and general hospitals. Participants were 620 adults older than 60 years with acute, overtly unstable ankle fracture. Exclusions were serious limb or concomitant disease or substantial cognitive impairment. Interventions: Participants were randomly assigned to surgery (n = 309) or casting (n = 311). Casts were applied in the operating room under general or spinal anesthesia by a trained surgeon. Main Outcomes and Measures: The primary 6-month, per-protocol outcome was the Olerud-Molander Ankle Score at 6 months (OMAS; range, 0-100; higher scores indicate better outcomes and fewer symptoms), equivalence prespecified as ±6 points. Secondary outcomes were quality of life, pain, ankle motion, mobility, complications, health resource use, and patient satisfaction. Results: Among 620 adults (mean age, 71 years; 460 [74%] women) who were randomized, 593 (96%) completed the study. Nearly all participants (579/620; 93%) received allocated treatment; 52 of 275 (19%) who initially received casting later converted to surgery, which was allowable in the casting treatment pathway to manage early loss of fracture reduction. At 6 months, casting resulted in ankle function equivalent to that with surgery (OMAS score, 66.0 [95% CI, 63.6-68.5] for surgery vs 64.5 [95% CI, 61.8-67.2] for casting; mean difference, -0.6 [95% CI, -3.9 to 2.6]; P for equivalence = .001). Infection and wound breakdown were more common with surgery (29/298 [10%] vs 4/275 [1%]; odds ratio [OR], 7.3 [95% CI, 2.6-20.2]), as were additional operating room procedures (18/298 [6%] for surgery and 3/275 [1%] for casting; OR, 5.8 [95% CI, 1.8-18.7]). Radiologic malunion was more common in the casting group (38/249 [15%] vs 8/274 [3%] for surgery; OR, 6.0 [95% CI, 2.8-12.9]). Casting required less operating room time compared with surgery (mean difference [minutes/participant], -54 [95% CI, -58 to -50]). There were no significant differences in other secondary outcomes: quality of life, pain, ankle motion, mobility, and patient satisfaction. Conclusions and Relevance: Among older adults with unstable ankle fracture, the use of close contact casting compared with surgery resulted in similar functional outcomes at 6 months. Close contact casting may be an appropriate treatment for such patients. Trial Registration: isrctn.com Identifier: ISRCTN04180738.

Supportive Self-Management Program for People With Chronic Headaches and Migraine: A Randomized Controlled Trial and Economic Evaluation.

BACKGROUND AND OBJECTIVES: Chronic headache disorders are a major cause of pain and disability. Education and supportive self-management approaches could reduce the burden of headache disability. We tested the effectiveness of a group educational and supportive self-management program for people living with chronic headaches. METHODS: This was a pragmatic randomized controlled trial. Participants were aged 18 years or older with chronic migraine or chronic tension-type headache, with or without medication overuse headache. We primarily recruited from general practices. Participants were assigned to either a 2-day group education and self-management program, a one-to-one nurse interview, and telephone support or to usual care plus relaxation material. The primary outcome was headache related-quality of life using the Headache Impact Test (HIT)-6 at 12 months. The primary analysis used intention-to-treat principles for participants with migraine and both baseline and 12-month HIT-6 data. RESULTS: Between April 2017 and March 2019, we randomized 736 participants. Because only 9 participants just had tension-type headache, our main analyses were on the 727 participants with migraine. Of them, 376 were allocated to the self-management intervention and 351 to usual care. Data from 586 (81%) participants were analyzed for primary outcome. There was no between-group difference in HIT-6 (adjusted mean difference = -0.3, 95% CI -1.23 to 0.67) or headache days (0.9, 95% CI -0.29 to 2.05) at 12 months. The Chronic Headache Education and Self-management Study intervention generated incremental adjusted costs of £268 (95% CI, £176-£377) (USD383 [95% CI USD252-USD539]) and incremental adjusted quality-adjusted life years (QALYs) of 0.031 (95% CI -0.005 to 0.063). The incremental cost-effectiveness ratio was £8,617 (USD12,322) per QALY gained. DISCUSSION: These findings conclusively show a lack of benefit for quality of life or monthly headache days from a brief group education and supportive self-management program for people living with chronic migraine or chronic tension-type headache with episodic migraine. TRIAL REGISTRATION INFORMATION: Registered on the International Standard Randomized Controlled Trial Number registry, ISRCTN79708100 16th December 2015 doi.org/10.1186/ISRCTN79708100. The first enrollment was April 24, 2017. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a brief group education and self-management program does not increase the probability of improvement in headache-related quality of life in people with chronic migraine.

biomArker-guided Duration of Antibiotic treatment in hospitalised Patients with suspecTed Sepsis (ADAPT-Sepsis): A protocol for a multicentre randomised controlled trial.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis. Design: Multicentre three-arm randomised controlled trial. Setting: UK NHS hospitals. Target population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis. Health technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed. Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice.

The effects of supported employment interventions in populations of people with conditions other than severe mental health: a systematic review.

AIM: To assess the effectiveness of supported employment interventions for improving competitive employment in populations of people with conditions other than only severe mental illness. BACKGROUND: Supported employment interventions have been extensively tested in severe mental illness populations. These approaches may be beneficial outside of these populations. METHODS: We searched PubMed, Embase, CINAHL, PsycInfo, Web of Science, Scopus, JSTOR, PEDro, OTSeeker, and NIOSHTIC for trials including unemployed people with any condition and including severe mental illness if combined with other co-morbidities or other specific circumstances (e.g., homelessness). We excluded trials where inclusion was based on severe mental illness alone. Two reviewers independently assessed risk of bias (RoB v2.0) and four reviewers extracted data. We assessed rates of competitive employment as compared to traditional vocational rehabilitation or waiting list/services as usual. FINDINGS: Ten randomised controlled trials (913 participants) were included. Supported employment was more effective than control interventions for improving competitive employment in seven trials: in people with affective disorders [risk ratio (RR) 10.61 (1.49, 75.38)]; mental disorders and justice involvement [RR 4.44 (1.36,14.46)]; veterans with posttraumatic stress disorder (PTSD) [RR 2.73 (1.64, 4.54)]; formerly incarcerated veterans [RR 2.17 (1.09, 4.33)]; people receiving methadone treatment [RR 11.5 (1.62, 81.8)]; veterans with spinal cord injury at 12 months [RR 2.46 (1.16, 5.22)] and at 24 months [RR 2.81 (1.98, 7.37)]; and young people not in employment, education, or training [RR 5.90 (1.91-18.19)]. Three trials did not show significant benefits from supported employment: populations of workers with musculoskeletal injuries [RR 1.38 (1.00, 1.89)]; substance abuse [RR 1.85 (0.65, 5.41)]; and formerly homeless people with mental illness [RR 1.55 (0.76, 3.15)]. Supported employment interventions may be beneficial to people from more diverse populations than those with severe mental illness alone. Defining competitive employment and increasing (and standardising) measurement of non-vocational outcomes may help to improve research in this area.

Study into the reversal of septic shock with landiolol (beta blockade): STRESS-L Study protocol for a randomised trial.

INTRODUCTION: In 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; p<0.001). Beta blockers are one of the most studied groups of drugs but their effect in septic shock is poorly understood; proposed mechanisms include not only the modulation of cardiac function but also immunomodulation. METHODS AND ANALYSIS: STRESS-L is a randomised, open-label, non-blinded clinical trial which is enrolling a total of 340 patients with septic shock as defined by Sepsis-3 consensus definition and a tachycardia (heart rate ≥95 beats per minute (bpm)) after vasopressor treatment of at least 24 hours. Standard randomisation (1:1 ratio) allocates patients to receive usual care (according to international standards) versus usual care and a continuous landiolol infusion to reduce the heart rate between 80 and 94 bpm. The primary endpoint is the mean Sequential Organ Failure Assessment score over 14 days from entry into the trial and while in intensive care unit. Results will inform current clinical practice guidelines. ETHICS AND DISSEMINATION: This trial has clinical trial authorisation from the UK competent authority, the Medicines and Healthcare products Regulatory Agency, and has been approved by the East of England-Essex Research Ethics Committee (reference: 17/EE/0368).The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial coordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration. REGISTRATION: The trial is funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) (Project Number: EME-14/150/85) and registered ISRCTN12600919 and EudraCT: 2017-001785-14.

Psychiatric hospital reform in low-income and middle-income countries Structured Individualised inTervention And Recovery (SITAR): a two-arm pragmatic randomised controlled trial study protocol.

INTRODUCTION: Low-income and middle-income settings like India have large treatment gaps in mental healthcare. People with severe mental disorders face impediments to their clinical and functional recovery, and have large unmet needs. The infrastructure and standards of care are poor in colonial period psychiatric hospitals, with no clear pathways to discharge and successfully integrate recovered individuals into the community. Our aim is to study the impact of psychiatric hospital reform on individual patient outcomes in a psychiatric hospital in India. METHODS AND ANALYSIS: Structured Individualised inTervention And Recovery (SITAR) is a two-arm pragmatic randomised controlled trial, focusing on patients aged 18-60 years with a hospital stay of 12-120 months and a primary diagnosis of psychosis. It tests the effectiveness of structural and process reform with and without an individually tailored recovery plan on patient outcomes of disability (primary outcome WHO Disability Assessment Scale), symptom severity, social and occupational functioning and quality of life. A computer-generated permuted block randomisation schedule will allocate recruited subjects to the two study arms. We aim to recruit 100 people into each trial arm. Baseline and outcome measures will be undertaken by trained researchers independent to the case managers providing the individual intervention. A health economic analysis will determine the costing of implementing the individually tailored recovery plan. ETHICS AND DISSEMINATION: The study will provide answers to important questions around the nature and process of reforms in institutional care that promote recovery while being cognizant of protecting human rights, and dignity. Ethical approval for SITAR was obtained from a registered ethics committee in India (Institutional Ethics Committee VikasAnvesh Foundation, VAF/2018-19/012 dated 6 December 2018) and the University of Warwick's Biomedical and Scientific Research Ethics Committee (REGO-2019-2332, dated 21 March 2019), and registered on the Central Trial Registry of India (CTRI/2019/01/017267). Trial results will be published in accordance to CONSORT guidelines.

Moderators of Cognitive Outcomes from an Exercise Program in People with Mild to Moderate Dementia.

BACKGROUND/OBJECTIVES: Our aim was to estimate whether baseline participant variables were able to moderate the effect of an exercise intervention on cognition in patients with mild to moderate dementia. DESIGN: Subgroup analysis of a multicenter pragmatic randomized controlled trial. SETTING: Community-based gym/rehabilitation centers. PARTICIPANTS: A total of 494 community-dwelling participants with mild to moderate dementia. INTERVENTION: Participants were randomized to a moderate- to high-intensity aerobic and strength exercise program or a usual care control group. Experimental group participants attended twice weekly 60- to 90-minute gym sessions for 4 months. Participants were prescribed home exercises for an additional hour per week during the supervised period and 150 minutes each week after the supervised period. MEASUREMENTS: Multilevel regression model analyses were undertaken to identify individual moderators of cognitive function measured through the Alzheimer Disease Assessment Scale-Cognitive Subscale score at 12 months. RESULTS: When tested for a formal interaction effect, only cognitive function assessed by the baseline number cancellation test demonstrated a statistically significant interaction effect (-2.7 points; 95% confidence interval = -5.14 to -0.21). CONCLUSION: People with worse number cancellation test scores may experience greater progression of cognitive decline in response to a moderate- to high-intensity exercise program. Further analyses to examine whether these findings can be replicated in planned sufficiently powered analyses are indicated.

Is Protocolised Weaning that Includes Early Extubation Onto Non-Invasive Ventilation More Cost Effective Than Protocolised Weaning Without Non-Invasive Ventilation? Findings from the Breathe Study.

BACKGROUND: Optimising techniques to wean patients from invasive mechanical ventilation (IMV) remains a key goal of intensive care practice. The use of non-invasive ventilation (NIV) as a weaning strategy (transitioning patients who are difficult to wean to early NIV) may reduce mortality, ventilator-associated pneumonia and intensive care unit (ICU) length of stay. OBJECTIVES: Our objectives were to determine the cost effectiveness of protocolised weaning, including early extubation onto NIV, compared with weaning without NIV in a UK National Health Service setting. METHODS: We conducted an economic evaluation alongside a multicentre randomised controlled trial. Patients were randomised to either protocol-directed weaning from mechanical ventilation or ongoing IMV with daily spontaneous breathing trials. The primary efficacy outcome was time to liberation from ventilation. Bivariate regression of costs and quality-adjusted life-years (QALYs) provided estimates of the incremental cost per QALY and incremental net monetary benefit (INMB) overall and for subgroups [presence/absence of chronic obstructive pulmonary disease (COPD) and operative status]. Long-term cost effectiveness was determined through extrapolation of survival curves using flexible parametric modelling. RESULTS: NIV was associated with a mean INMB of £620 ($US885) (cost-effectiveness threshold of £20,000 per QALY) with a corresponding probability of 58% that NIV is cost effective. The probability that NIV is cost effective was higher for those with COPD (84%). NIV was cost effective over 5 years, with an estimated incremental cost-effectiveness ratio of £4618 ($US6594 per QALY gained). CONCLUSIONS: The probability of NIV being cost effective relative to weaning without NIV ranged between 57 and 59% overall and between 82 and 87% for the COPD subgroup.

Usual care and a self-management support programme versus usual care and a relaxation programme for people living with chronic headache disorders: a randomised controlled trial protocol (CHESS).

INTRODUCTION: Chronic headaches are poorly diagnosed and managed and can be exacerbated by medication overuse. There is insufficient evidence on the non-pharmacological approaches to helping people living with chronic headaches. METHODS AND ANALYSIS: Chronic Headache Education and Self-management Study is a pragmatic randomised controlled trial to test the effectiveness and cost-effectiveness of a self-management education support programme on top of usual care for patients with chronic headaches against a control of usual care and relaxation. The intervention is a 2-day group course based on education, personal reflection and a cognitive behavioural approach, plus a nurse-led one-to-one consultation and follow-up over 8 weeks. We aim to recruit 689 participants (356 to the intervention arm and 333 to the control) from primary care and self-referral in London and the Midlands. The trial is powered to show a difference of 2.0 points on the Headache Impact Test, a patient-reported outcome measure at 12 months post randomisation. Secondary outcomes include health related quality of life, self-efficacy, social activation and engagement, anxiety and depression and healthcare utilisation. Outcomes are being measured at 4, 8 and 12 months. Cost-effectiveness will be expressed in terms of incremental cost per quality-adjusted life year gained. ETHICS AND DISSEMINATION: This trial will provide data on effectiveness and cost-effectiveness of a self-management support programme for chronic headaches. The results will inform commissioning of services and clinical practice. North West - Greater Manchester East Research Ethics Committee have approved the trial. The current protocol version is 3.6 date 7 March 2019. TRIAL REGISTRATION NUMBER: ISRCTN79708100.

Does Structured Exercise Improve Cognitive Impairment in People with Mild to Moderate Dementia? A Cost-Effectiveness Analysis from a Confirmatory Randomised Controlled Trial: The Dementia and Physical Activity (DAPA) Trial.

BACKGROUND: Previous studies suggest that physical exercise could slow dementia progression. However, evidence for the cost effectiveness of structured exercise is conflicting and based on small trials. OBJECTIVES: The objective of this study was to compare the cost effectiveness of a tailored, structured, moderate- to high-intensity exercise programme versus usual care in people with mild to moderate dementia. METHODS: An economic evaluation was conducted from the UK National Health Service and personal social services perspective, based on data from a large randomised controlled trial. The primary clinical outcome was the participant reported ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive Subscale) at 12 months. Costs (£; 2014-2015 prices) were collected prospectively over a 12-month follow-up period. A bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, was conducted with the view to estimating the incremental cost per QALY gained and the incremental net monetary benefit (INMB) associated with the exercise programme plus usual care versus usual care. Sensitivity analyses were undertaken to assess the impact of uncertainty surrounding aspects of the economic evaluation, and pre-specified subgroup analyses explored heterogeneity in the cost-effectiveness results. RESULTS: Participants (n = 494) were randomised to exercise plus usual care or usual care only. By 12 months the mean ADAS-Cog score had worsened slightly to 25.2 (standard deviation [SD] 12.3) in the exercise arm and 23.8 (SD 10.4) in the usual care: difference - 1.4, 95% confidence interval (CI) - 2.6 to - 0.2 (p = 0.03). The mean (standard error [SE]) costs over 12 months for experimental versus control was £5945 (US$7856) versus £4597 (US$6574), respectively; (difference: £1347 [$1926]; p = 0.0426). Mean (SE) QALY estimates were 0.787 (0.012) versus 0.826 (0.019), respectively (p = 0.090). The probability that the exercise programme is cost effective was < 1% across cost-effectiveness thresholds. INMBs ranged between -£2601 (US$3719) and £2158 (US$3086) at cost-effectiveness thresholds between £15,000 (US$21,450) and £30,000 (US$42,900) per QALY. The cost-effectiveness results remained robust to several sensitivity and subgroup analyses. CONCLUSIONS: Building on the clinical results of the trial, which showed that the structured exercise programme evaluated does not slow cognitive impairment in people with mild to moderate dementia, this economic evaluation shows that the programme is not cost effective.