Chronic Obstructive Pulmonary Disease Self-Management in Three Low- and Middle-Income Countries: A Pilot Randomized Trial.

Objectives: Chronic obstructive pulmonary disease (COPD) disproportionately affects low- and middle-income countries. Health systems are ill prepared to manage the increase in COPD cases. Methods: We performed a pilot effectiveness-implementation randomized field trial of a community health worker (CHW)-supported, 1-year self-management intervention in individuals with COPD grades B-D. The study took place in low-resource settings of Nepal, Peru, and Uganda. The primary outcome was the St. George's Respiratory Questionnaire (SGRQ) score at 1 year. We evaluated differences in moderate to severe exacerbations, all-cause hospitalizations, and the EuroQol score (EQ-5D-3 L) at 12 months. Measurements and Main Results: We randomly assigned 239 participants (119 control arm, 120 intervention arm) with grades B-D COPD to a multicomponent, CHW-supported intervention or standard of care and COPD education. Twenty-five participants (21%) died or were lost to follow-up in the control arm compared with 11 (9%) in the intervention arm. At 12 months, there was no difference in mean total SGRQ score between the intervention and control arms (34.7 vs. 34.0 points; adjusted mean difference, 1.0; 95% confidence interval, -4.2, 6.1; P = 0.71). The intervention arm had a higher proportion of hospitalizations than the control arm (10% vs. 5.2%; adjusted odds ratio, 2.2; 95% confidence interval, 0.8, 7.5; P = 0.15) at 12 months. Conclusions: A CHW-based intervention to support self-management of acute exacerbations of COPD in three resource-poor settings did not result in differences in SGRQ scores at 1 year. Fidelity was high, and intervention engagement was moderate. Although these results cannot differentiate between a failed intervention or implementation, they nonetheless suggest that we need to revisit our strategy. Clinical trial registered with www.clinicaltrials.gov (NCT03359915).

Unmet Diagnostic and Therapeutic Opportunities for Chronic Obstructive Pulmonary Disease in Low- and Middle-Income Countries.

Rationale: Chronic obstructive pulmonary disease (COPD) is a prevalent and burdensome condition in low- and middle-income countries (LMICs). Challenges to better care include more effective diagnosis and access to affordable interventions. There are no previous reports describing therapeutic needs of populations with COPD in LMICs who were identified through screening. Objectives: To describe unmet therapeutic need in screening-detected COPD in LMIC settings. Methods: We compared interventions recommended by the international Global Initiative for Chronic Obstructive Lung Disease COPD strategy document, with that received in 1,000 people with COPD identified by population screening at three LMIC sites in Nepal, Peru, and Uganda. We calculated costs using data on the availability and affordability of medicines. Measurement and Main Results: The greatest unmet need for nonpharmacological interventions was for education and vaccinations (applicable to all), pulmonary rehabilitation (49%), smoking cessation (30%), and advice on biomass smoke exposure (26%). Ninety-five percent of the cases were previously undiagnosed, and few were receiving therapy (4.5% had short-acting ß-agonists). Only three of 47 people (6%) with a previous COPD diagnosis had access to drugs consistent with recommendations. None of those with more severe COPD were accessing appropriate maintenance inhalers. Even when available, maintenance treatments were unaffordable, with 30 days of treatment costing more than a low-skilled worker's daily average wage. Conclusions: We found a significant missed opportunity to reduce the burden of COPD in LMIC settings, with most cases undiagnosed. Although there is unmet need in developing novel therapies, in LMICs where the burden is greatest, better diagnosis combined with access to affordable interventions could translate to immediate benefit.

Multicentre evaluation of two multiplex PCR platforms for the rapid microbiological investigation of nosocomial pneumonia in UK ICUs: the INHALE WP1 study.

BACKGROUND: Culture-based microbiological investigation of hospital-acquired or ventilator-associated pneumonia (HAP or VAP) is insensitive, with aetiological agents often unidentified. This can lead to excess antimicrobial treatment of patients with susceptible pathogens, while those with resistant bacteria are treated inadequately for prolonged periods. Using PCR to seek pathogens and their resistance genes directly from clinical samples may improve therapy and stewardship. METHODS: Surplus routine lower respiratory tract samples were collected from intensive care unit patients about to receive new or changed antibiotics for hospital-onset lower respiratory tract infections at 15 UK hospitals. Testing was performed using the BioFire FilmArray Pneumonia Panel (bioMérieux) and Unyvero Pneumonia Panel (Curetis). Concordance analysis compared machine and routine microbiology results, while Bayesian latent class (BLC) analysis estimated the sensitivity and specificity of each test, incorporating information from both PCR panels and routine microbiology. FINDINGS: In 652 eligible samples; PCR identified pathogens in considerably more samples compared with routine microbiology: 60.4% and 74.2% for Unyvero and FilmArray respectively vs 44.2% by routine microbiology. PCR tests also detected more pathogens per sample than routine microbiology. For common HAP/VAP pathogens, FilmArray had sensitivity of 91.7%-100.0% and specificity of 87.5%-99.5%; Unyvero had sensitivity of 50.0%-100.0%%, and specificity of 89.4%-99.0%. BLC analysis indicated that, compared with PCR, routine microbiology had low sensitivity, ranging from 27.0% to 69.4%. INTERPRETATION: Conventional and BLC analysis demonstrated that both platforms performed similarly and were considerably more sensitive than routine microbiology, detecting potential pathogens in patient samples reported as culture negative. The increased sensitivity of detection realised by PCR offers potential for improved antimicrobial prescribing.

Negative interaction between nitrates and remote ischemic preconditioning in patients undergoing cardiac surgery: the ERIC-GTN and ERICCA studies.

Remote ischaemic preconditioning (RIPC) using transient limb ischaemia failed to improve clinical outcomes following cardiac surgery and the reasons for this remain unclear. In the ERIC-GTN study, we evaluated whether concomitant nitrate therapy abrogated RIPC cardioprotection. We also undertook a post-hoc analysis of the ERICCA study, to investigate a potential negative interaction between RIPC and nitrates on clinical outcomes following cardiac surgery. In ERIC-GTN, 185 patients undergoing cardiac surgery were randomized to: (1) Control (no RIPC or nitrates); (2) RIPC alone; (3); Nitrates alone; and (4) RIPC + Nitrates. An intravenous infusion of nitrates (glyceryl trinitrate 1 mg/mL solution) was commenced on arrival at the operating theatre at a rate of 2-5 mL/h to maintain a mean arterial pressure between 60 and 70 mmHg and was stopped when the patient was taken off cardiopulmonary bypass. The primary endpoint was peri-operative myocardial injury (PMI) quantified by a 48-h area-under-the-curve high-sensitivity Troponin-T (48 h-AUC-hs-cTnT). In ERICCA, we analysed data for 1502 patients undergoing cardiac surgery to investigate for a potential negative interaction between RIPC and nitrates on clinical outcomes at 12-months. In ERIC-GTN, RIPC alone reduced 48 h-AUC-hs-cTnT by 37.1%, when compared to control (ratio of AUC 0.629 [95% CI 0.413-0.957], p = 0.031), and this cardioprotective effect was abrogated in the presence of nitrates. Treatment with nitrates alone did not reduce 48 h-AUC-hs-cTnT, when compared to control. In ERICCA there was a negative interaction between nitrate use and RIPC for all-cause and cardiovascular mortality at 12-months, and for risk of peri-operative myocardial infarction. RIPC alone reduced the risk of peri-operative myocardial infarction, compared to control, but no significant effect of RIPC was demonstrated for the other outcomes. When RIPC and nitrates were used together they had an adverse impact in patients undergoing cardiac surgery with the presence of nitrates abrogating RIPC-induced cardioprotection and increasing the risk of mortality at 12-months post-cardiac surgery in patients receiving RIPC.

Discriminative Accuracy of Chronic Obstructive Pulmonary Disease Screening Instruments in 3 Low- and Middle-Income Country Settings.

Importance: Most of the global morbidity and mortality in chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries (LMICs), with significant economic effects. Objective: To assess the discriminative accuracy of 3 instruments using questionnaires and peak expiratory flow (PEF) to screen for COPD in 3 LMIC settings. Design, Setting, and Participants: A cross-sectional analysis of discriminative accuracy, conducted between January 2018 and March 2020 in semiurban Bhaktapur, Nepal; urban Lima, Peru; and rural Nakaseke, Uganda, using a random age- and sex-stratified sample of the population 40 years or older. Exposures: Three screening tools, the COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE; range, 0-6; high risk indicated by a score of 5 or more or score 2-5 with low PEF [<250 L/min for females and <350 L/min for males]), the COPD in LMICs Assessment questionnaire (COLA-6; range, 0-5; high risk indicated by a score of 4 or more), and the Lung Function Questionnaire (LFQ; range, 0-25; high risk indicated by a score of 18 or less) were assessed against a reference standard diagnosis of COPD using quality-assured postbronchodilator spirometry. CAPTURE and COLA-6 include a measure of PEF. Main Outcomes and Measures: The primary outcome was discriminative accuracy of the tools in identifying COPD as measured by area under receiver operating characteristic curves (AUCs) with 95% CIs. Secondary outcomes included sensitivity, specificity, positive predictive value, and negative predictive value. Results: Among 10 709 adults who consented to participate in the study (mean age, 56.3 years (SD, 11.7); 50% female), 35% had ever smoked, and 30% were currently exposed to biomass smoke. The unweighted prevalence of COPD at the 3 sites was 18.2% (642/3534 participants) in Nepal, 2.7% (97/3550) in Peru, and 7.4% (264/3580) in Uganda. Among 1000 COPD cases, 49.3% had clinically important disease (Global Initiative for Chronic Obstructive Lung Disease classification B-D), 16.4% had severe or very severe airflow obstruction (forced expiratory volume in 1 second <50% predicted), and 95.3% of cases were previously undiagnosed. The AUC for the screening instruments ranged from 0.717 (95% CI, 0.677-0.774) for LFQ in Peru to 0.791 (95% CI, 0.770-0.809) for COLA-6 in Nepal. The sensitivity ranged from 34.8% (95% CI, 25.3%-45.2%) for COLA-6 in Nepal to 64.2% (95% CI, 60.3%-67.9%) for CAPTURE in Nepal. The mean time to administer the instruments was 7.6 minutes (SD 1.11), and data completeness was 99.5%. Conclusions and Relevance: This study demonstrated that screening instruments for COPD were feasible to administer in 3 low- and middle-income settings. Further research is needed to assess instrument performance in other low- and middle-income settings and to determine whether implementation is associated with improved clinical outcomes.

Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial.

Importance: Robot-assisted radical cystectomy is being performed with increasing frequency, but it is unclear whether total intracorporeal surgery improves recovery compared with open radical cystectomy for bladder cancer. Objectives: To compare recovery and morbidity after robot-assisted radical cystectomy with intracorporeal reconstruction vs open radical cystectomy. Design, Setting, and Participants: Randomized clinical trial of patients with nonmetastatic bladder cancer recruited at 9 sites in the UK, from March 2017-March 2020. Follow-up was conducted at 90 days, 6 months, and 12 months, with final follow-up on September 23, 2021. Interventions: Participants were randomized to receive robot-assisted radical cystectomy with intracorporeal reconstruction (n = 169) or open radical cystectomy (n = 169). Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital within 90 days of surgery. There were 20 secondary outcomes, including complications, quality of life, disability, stamina, activity levels, and survival. Analyses were adjusted for the type of diversion and center. Results: Among 338 randomized participants, 317 underwent radical cystectomy (mean age, 69 years; 67 women [21%]; 107 [34%] received neoadjuvant chemotherapy; 282 [89%] underwent ileal conduit reconstruction); the primary outcome was analyzed in 305 (96%). The median number of days alive and out of the hospital within 90 days of surgery was 82 (IQR, 76-84) for patients undergoing robotic surgery vs 80 (IQR, 72-83) for open surgery (adjusted difference, 2.2 days [95% CI, 0.50-3.85]; P = .01). Thromboembolic complications (1.9% vs 8.3%; difference, -6.5% [95% CI, -11.4% to -1.4%]) and wound complications (5.6% vs 16.0%; difference, -11.7% [95% CI, -18.6% to -4.6%]) were less common with robotic surgery than open surgery. Participants undergoing open surgery reported worse quality of life vs robotic surgery at 5 weeks (difference in mean European Quality of Life 5-Dimension, 5-Level instrument scores, -0.07 [95% CI, -0.11 to -0.03]; P = .003) and greater disability at 5 weeks (difference in World Health Organization Disability Assessment Schedule 2.0 scores, 0.48 [95% CI, 0.15-0.73]; P = .003) and at 12 weeks (difference in WHODAS 2.0 scores, 0.38 [95% CI, 0.09-0.68]; P = .01); the differences were not significant after 12 weeks. There were no statistically significant differences in cancer recurrence (29/161 [18%] vs 25/156 [16%] after robotic and open surgery, respectively) and overall mortality (23/161 [14.3%] vs 23/156 [14.7%]), respectively) at median follow-up of 18.4 months (IQR, 12.8-21.1). Conclusions and Relevance: Among patients with nonmetastatic bladder cancer undergoing radical cystectomy, treatment with robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy resulted in a statistically significant increase in days alive and out of the hospital over 90 days. However, the clinical importance of these findings remains uncertain. Trial Registration: ISRCTN Identifier: ISRCTN13680280; ClinicalTrials.gov Identifier: NCT03049410.

Procedural Complications During Early Versus Late Endovascular Treatment in Acute Stroke: Frequency and Clinical Impact.

BACKGROUND AND PURPOSE: Endovascular treatment (EVT) in acute ischemic stroke is effective in the late time window in selected patients. However, the frequency and clinical impact of procedural complications in the early versus late time window has received little attention. METHODS: We retrospectively studied all acute ischemic strokes from 2015 to 2019 receiving EVT in the Acute Stroke Registry and Analysis of Lausanne. We compared the procedural EVT complications in the early (<6 hours) versus late (6-24 hours) window and correlated them with short-term clinical outcome. RESULTS: Among 695 acute ischemic strokes receiving EVT (of which 202 were in the late window), 113 (16.3%) had at least one procedural complication. The frequency of each single, and for overall procedural complications was similar for early versus late EVT (16.2% versus 16.3%, Padj=0.90). Procedural complications lead to a significantly less favorable short-term outcome, reflected by the absence of National Institutes of Health Stroke Scale improvement in late EVT (delta-National Institutes of Health Stroke Scale-24 hours, -2.5 versus 2, Padj=0.01). CONCLUSIONS: In this retrospective analysis of consecutive EVT, the frequency of procedural complications was similar for early and late EVT patients but very short-term outcome seemed less favorable in late EVT patients with complications.

Clinical and cost effectiveness of a parent mediated intervention to reduce challenging behaviour in pre-schoolers with moderate to severe intellectual disability (EPICC-ID) study protocol: a multi-centre, parallel-group randomised controlled trial.

BACKGROUND: Children with intellectual disabilities are likely to present with challenging behaviour. Parent mediated interventions have shown utility in influencing child behaviour, although there is a paucity of UK research into challenging behaviour interventions in this population. NICE guidelines favour Stepping Stones Triple P (SSTP) as a challenging behaviour intervention and this trial aims to evaluate its clinical and cost effectiveness in preschool children with moderate to severe intellectual disabilities. METHODS: This trial launched in 2017 at four sites across England, with the aim of recruiting 258 participants (aged 30-59 months). The Intervention Group receive nine weeks of SSTP parenting therapy (six group sessions and three individualised face to face or telephone sessions) in addition to Treatment as Usual, whilst the Treatment as Usual only group receive other available services in each location. Both study groups undergo the study measurements at baseline and at four and twelve months. Outcome measures include parent reports and structured observations of behaviour. Service use and health related quality of life data will also be collected to carry out a cost effectiveness and utility evaluation. DISCUSSION: Findings from this study will inform policy regarding interventions for challenging behaviour in young children with moderate to severe intellectual disabilities. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, NCT03086876. Registered 22nd March 2017, https://clinicaltrials.gov/ct2/show/NCT03086876.

Online training improves medical students' ability to recognise when a person is dying: The ORaClES randomised controlled trial.

BACKGROUND: Recognising dying is a key clinical skill for doctors, yet there is little training. AIM: To assess the effectiveness of an online training resource designed to enhance medical students' ability to recognise dying. DESIGN: Online multicentre double-blind randomised controlled trial (NCT03360812). The training resource for the intervention group was developed from a group of expert palliative care doctors' weightings of various signs/symptoms to recognise dying. The control group received no training. SETTING/PARTICIPANTS: Participants were senior UK medical students. They reviewed 92 patient summaries and provided a probability of death within 72 hours (0% certain survival - 100% certain death) pre, post, and 2 weeks after the training. Primary outcome: (1) Mean Absolute Difference (MAD) score between participants' and the experts' scores, immediately post intervention. Secondary outcomes: (2) weight attributed to each factor, (3) learning effect and (4) level of expertise (Cochran-Weiss-Shanteau (CWS)). RESULTS: Out of 168 participants, 135 completed the trial (80%); 66 received the intervention (49%). After using the training resource, the intervention group had better agreement with the experts in their survival estimates (δMAD = -3.43, 95% CI -0.11 to -0.34, p = <0.001) and weighting of clinical factors. There was no learning effect of the MAD scores at the 2-week time point (δMAD = 1.50, 95% CI -0.87 to 3.86, p = 0.21). At the 2-week time point, the intervention group was statistically more expert in their decision-making versus controls (intervention CWS = 146.04 (SD 140.21), control CWS = 110.75 (SD 104.05); p = 0.01). CONCLUSION: The online training resource proved effective in altering the decision-making of medical students to agree more with expert decision-making.

Exploring the costs, consequences and efficiency of three types of palliative care day services in the UK: a pragmatic before-and-after descriptive cohort study.

BACKGROUND: Palliative Care Day Services (PCDS) offer supportive care to people with advanced, progressive illness who may be approaching the end of life. Despite the growth of PCDS in recent years, evidence of their costs and effects is scarce. It is important to establish the value of such services so that health and care decision-makers can make evidence-based resource allocation decisions. This study examines and estimates the costs and effects of PCDS with different service configurations in three centres across the UK in England, Scotland and Northern Ireland. METHODS: People who had been referred to PCDS were recruited between June 2017 and September 2018. A pragmatic before-and-after descriptive cohort study design analysed data on costs and outcomes. Data on costs were collected on health and care use in the 4 weeks preceding PCDS attendance using adapted versions of the Client Service Receipt Inventory (CSRI). Outcomes, cost per attendee/day and volunteer contribution to PCDS were also estimated. Outcomes included quality of life (MQOL-E), health status (EQ-5D-5L) and capability wellbeing (ICECAP-SCM). RESULTS: Thirty-eight attendees were recruited and provided data at baseline and 4 weeks (centre 1: n = 8; centre 2: n = 8, centre 3: n = 22). The cost per attendee/day ranged from £121-£190 (excluding volunteer contribution) to £172-£264 (including volunteer contribution) across the three sites. Volunteering constituted between 28 and 38% of the total cost of PCDS provision. There was no significant mean change at 4 week follow-up from baseline for health and care costs (centre 1: £570, centre 2: -£1127, centre 3: £65), or outcomes: MQOL-E (centre 1: - 0.48, centre 2: 0.01, centre 3: 0.24); EQ-5D-5L (centre 1: 0.05, centre 2: 0.03, centre 3: - 0.03) and ICECAP-SCM (centre 1:0.00, centre 2: - 0.01, centre 3: 0.03). Centre costs variation is almost double per attendee when attendance rates are held constant in scenario analysis. CONCLUSIONS: This study highlights the contribution made by volunteers to PCDS provision. There is insufficient evidence on whether outcomes improved, or costs were reduced, in the three different service configurations for PCDS. We suggest how future research may overcome some of the challenges we encountered, to better address questions of cost-effectiveness in PCDS.

How good are the outcomes of instrumented debulking operations for symptomatic spinal metastases and how long do they stand? A subgroup analysis in the global spine tumor study group database.

BACKGROUND: The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as cancer treatments improve and overall survival lengths increase, the incidence of recurrent spinal cord compression after debulking may increase. The aim of the current paper is to document the postoperative evolution of neurological function, pain, and quality of life following debulking and instrumentation in the Global Spine Tumor Study Group (GSTSG) database. METHODS: The GSTSG database is a prospective multicenter data repository of consecutive patients that underwent surgery for a symptomatic spinal metastasis. For the present analysis, patients were selected from the database that underwent decompressive debulking surgery with instrumentation. Preoperative tumor type, Tomita and Tokuhashi scores, EQ-5D, Frankel, Karnofsky, and postoperative complications, survival, EQ-5D, Frankel, Karnofsky, and pain numeric rating scores (NRS) at 3, 6, 12, and 24 months were analyzed. RESULTS: A total of 914 patients underwent decompressive debulking surgery with instrumentation and had documented follow-up until death or until 2 years post surgery. Median preoperative Karnofsky performance index was 70. A total of 656 patients (71.8%) had visceral metastases and 490 (53.6%) had extraspinal bone metastases. Tomita scores were evenly distributed above (49.1%) and below or equal to 5 (50.9%), and Tokuhashi scores almost evenly distributed below or equal to 8 (46.3%) and above 8 (53.7%). Overall, 12-month survival after surgery was 56.3%. The surgery resulted in EQ-5D health status improvement and NRS pain reduction that was maintained throughout follow-up. Frankel scores improved at first follow-up in 25.0% of patients, but by 12 months neurological deterioration was observed in 18.8%. CONCLUSION: We found that palliative debulking and instrumentation surgeries were performed throughout all Tomita and Tokuhashi categories. These surgeries reduced pain scores and improved quality of life up to 2 years after surgery. After initial improvement, a proportion of patients experienced neurological deterioration by 1 year, but the majority of patients remained stable.

Health promotion interventions for community-dwelling older people with mild or pre-frailty: a systematic review and meta-analysis.

BACKGROUND: Mild or pre-frailty is common and associated with increased risks of hospitalisation, functional decline, moves to long-term care, and death. Little is known about the effectiveness of health promotion in reducing these risks. This systematic review aimed to synthesise randomised controlled trials (RCTs) evaluating home and community-based health promotion interventions for older people with mild/pre-frailty. METHODS: We searched 20 bibliographic databases and 3 trials registers (January 1990 - May 2016) using mild/pre-frailty and associated terms. We included randomised controlled and crossover trials of health promotion interventions for community-dwelling older people (65+ years) with mild/pre-frailty and excluded studies focussing on populations in hospital, long term care facilities or with a specific condition. Risk of bias was assessed by two reviewers using the Cochrane Risk of Bias tool. We pooled study results using standardised mean differences (SMD) where possible and used narrative synthesis where insufficient outcome data were available. RESULTS: We included 10 articles reporting on seven trials (total n = 506 participants) and included five trials in a meta-analysis. Studies were predominantly small, of limited quality and six studies tested group exercise alone. One study additionally investigated a nutrition and exercise intervention and one evaluated telemonitoring. Interventions of exercise in groups showed mixed effects on functioning (no effects on self-reported functioning SMD 0.19 (95% CI -0.57 to 0.95) n = 3 studies; positive effects on performance-based functioning SMD 0.37 (95% CI 0.07 to 0.68) n = 3 studies). No studies assessed moves to long-term care or hospitalisations. CONCLUSIONS: Currently the evidence base is of insufficient size, quality and breadth to recommend specific health promotion interventions for older people with mild or pre- frailty. High quality studies of rigorously developed interventions are needed. PROSPERO REGISTRATION: CRD42014010370 (Review 2).

Crossover randomized controlled trial of bumetanide to rescue an attack of exercise induced hand weakness in hypokalaemic periodic paralysis.

The aim of this study was to establish whether bumetanide can abort an acute attack of weakness in patients with HypoPP. This was a randomised, double-blind, cross-over, placebo-controlled phase II clinical trial. Focal attack of weakness was induced by isometric exercise of ADM followed by rest (McManis protocol). Participants had two study visits and received either placebo or 2 mg bumetanide at attack onset (defined as 40 % decrement in the abductor digiti minimi CMAP amplitude from peak). CMAP measurements assessed attack severity and duration. Nine participants completed both visits. CMAP percentage of peak amplitudes in the bumetanide (40.6 %) versus placebo (34.9 %) group at 1hr following treatment did not differ significantly (estimated effect difference 5.9 % (95 % CI: (-5.7 %; 17.5 %), p = 0.27, primary outcome). CMAP amplitudes assessed by the area under the curve for early (0-2hr post-treatment) and late (2-4 h post-treatment) efficacy were not statistically different between bumetanide and placebo (early effect estimate 0.043, p = 0.3; late effect estimate 0.085, p = 0.1). Two participants recovered from the attack following bumetanide intake; none recovered following placebo. Bumetanide was well tolerated but not efficacious to rescue a focal attack in an immobilised hand in the majority of patients, although data supports further studies of this agent.

Dirichlet process mixture models for regression discontinuity designs.

The regression discontinuity design is a quasi-experimental design that estimates the causal effect of a treatment when its assignment is defined by a threshold for a continuous variable. The regression discontinuity design assumes that subjects with measurements within a bandwidth around the threshold belong to a common population, so that the threshold can be seen as a randomising device assigning treatment to those falling just above the threshold and withholding it from those who fall below. Bandwidth selection represents a compelling decision for the regression discontinuity design analysis as results may be highly sensitive to its choice. A few methods to select the optimal bandwidth, mainly from the econometric literature, have been proposed. However, their use in practice is limited. We propose a methodology that, tackling the problem from an applied point of view, considers units' exchangeability, that is, their similarity with respect to measured covariates, as the main criteria to select subjects for the analysis, irrespectively of their distance from the threshold. We cluster the sample using a Dirichlet process mixture model to identify balanced and homogeneous clusters. Our proposal exploits the posterior similarity matrix, which contains the pairwise probabilities that two observations are allocated to the same cluster in the Markov chain Monte Carlo sample. Thus we include in the regression discontinuity design analysis only those clusters for which we have stronger evidence of exchangeability. We illustrate the validity of our methodology with both a simulated experiment and a motivating example on the effect of statins on cholesterol levels.

COVID-19 and the Physio4FMD trial: Impact, mitigating strategies and analysis plans.

Introduction: Functional motor disorder (FMD) is a common cause of disabling neurological symptoms such as weakness and tremor. Physio4FMD is a pragmatic, multicentre single blind randomised controlled trial to evaluate effectiveness and cost effectiveness of specialist physiotherapy for FMD. Like many other studies this trial was affected by the COVID-19 pandemic. Methods: The planned statistical and health economics analyses for this trial are described, as well as the sensitivity analyses designed to assess the disruption caused by COVID-19. The trial treatment of at least 89 participants (33%) was disrupted due to the pandemic. To account for this, we have extended the trial to increase the sample size. We have identified four groups based on how participants' involvement in Physio4FMD was affected; A: 25 were unaffected; B: 134 received their trial treatment before the start of the COVID-19 pandemic and were followed up during the pandemic; C: 89 were recruited in early 2020 and had not received any randomised treatment before clinical services closed because of COVID-19; D: 88 participants were recruited after the trial was restarted in July 2021. The primary analysis will involve groups A, B and D. Regression analysis will be used to assess treatment effectiveness. We will conduct descriptive analyses for each of the groups identified and sensitivity regression analyses with participants from all groups, including group C, separately. Discussion: The COVID-19 mitigation strategy and analysis plans are designed to maintain the integrity of the trial while providing meaningful results. Trial registration: ISRCTN56136713.

Exogenous Volatile Organic Compound (EVOC®) Breath Testing Maximizes Classification Performance for Subjects with Cirrhosis and Reveals Signs of Portal Hypertension.

Background: Cirrhosis detection in primary care relies on low-performing biomarkers. Consequently, up to 75% of subjects with cirrhosis receive their first diagnosis with decompensation when causal treatments are less effective at preserving liver function. We investigated an unprecedented approach to cirrhosis detection based on dynamic breath testing. Methods: We enrolled 29 subjects with cirrhosis (Child-Pugh A and B), and 29 controls. All subjects fasted overnight. Breath samples were taken using Breath Biopsy® before and at different time points after the administration of 100 mg limonene. Absolute limonene breath levels were measured using gas chromatography-mass spectrometry. Results: All subjects showed a >100-fold limonene spike in breath after administration compared to baseline. Limonene breath kinetics showed first-order decay in >90% of the participants, with higher bioavailability in the cirrhosis group. At the Youden index, baseline limonene levels showed classification performance with an area under the roc curve (AUROC) of 0.83 ± 0.012, sensitivity of 0.66 ± 0.09, and specificity of 0.83 ± 0.07. The best performing timepoint post-administration was 60 min, with an AUROC of 0.91, sensitivity of 0.83 ± 0.07, and specificity of 0.9 ± 0.06. In the cirrhosis group, limonene bioavailability showed a correlation with MELD and fibrosis indicators, and was associated with signs of portal hypertension. Conclusions: Dynamic limonene breath testing enhances diagnostic performance for cirrhosis compared to static testing. The correlation with disease severity suggests potential for monitoring therapeutic interventions. Given the non-invasive nature of breath collection, a dynamic limonene breath test could be implemented in primary care.

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Evaluation of blood pressure trajectories and outcome in critically ill children with initial hypertension on admission to Paediatric Intensive Care.

OBJECTIVE: Hypertension on paediatric intensive care (PICU) is associated with adverse outcomes. Management is complex; hypertension often represents a physiological adaptive response and exposure to hypertension could lead to altered pressure-flow autoregulation. International treatment consensus is to avoid rapid blood pressure (BP) reduction. Our aim was to examine if the rate and magnitude of BP reduction in hypertensive patients was correlated with harm. PATIENTS AND METHODS: We performed a single centre, retrospective, observational study in a quaternary PICU analysing the first 24 h post admission high resolution BP profiles of children with admission BP above the 95th centile. Individual BP profiles were analysed regarding both time spent and magnitude below a threshold; 75% of the admission BP in the first 24 h. Outcomes were organ support-free days at day 28, change in serum creatinine and PICU mortality. MAIN FINDINGS: Of 3069 admissions in a 36-month period (2016-2018), 21.7% had initial hypertension on admission to PICU. A total of 3,259,111 BP measurements (99.4% invasive) were available. Pre-existing hypertension was documented in 4.9% of patients. Both time spent and magnitude below threshold BP was poorly correlated with duration of required organ support and risk of death after adjusting for PIM score, pre-existing hypertension and raised intracranial pressure. We did find an association with a rise in serum creatinine on both uni- and multivariable analysis. CONCLUSIONS: The risk of harm due to early and significant reduction of raised blood pressure in critically ill children appears to be limited.

ASPECTS-based selection for late endovascular treatment: a retrospective two-site cohort study.

INTRODUCTION: The DAWN trial demonstrated the effectiveness of late endovascular treatment in acute ischemic stroke patients selected on the basis of a clinical-core mismatch. We explored in a real-world sample of endovascular treatment patients if a clinical-ASPECTS (Alberta Stroke Program Early CT Score) mismatch was associated with an outcome benefit after late endovascular treatment. METHODS: We retrospectively analyzed all consecutive acute ischemic stroke patients admitted 6-24 h after last proof of good health in two stroke centers, with initial National Institutes of Health Stroke Scale (NIHSS) ≥10 and an internal carotid artery or M1 occlusion. We defined clinical-ASPECTS mismatch as NIHSS ≥ 10 and ASPECTS ≥ 7, or NIHSS ≥ 20 and ASPECTS ≥ 5. We assessed the interaction between the presence of the clinical-ASPECTS mismatch and late endovascular treatment using ordinal shift analysis of the three-month modified Rankin Scale and adjusting for multiple confounders. RESULTS: The included 337 patients had a median age of 73 years (IQR = 61-82), admission NIHSS of 18 (15-22), and baseline ASPECTS of 7 (5-9). Out of 196 (58.2%) patients showing clinical-ASPECTS mismatch, 146 (74.5%) underwent late endovascular treatment. Among 141 (41.8%) mismatch negative patients, late endovascular treatment was performed in 72 (51.1%) patients. In the adjusted analysis, late endovascular treatment was significantly associated with a better outcome in the presence of clinical-ASPECTS mismatch (adjusted odd ratio, aOR = 2.83; 95% confidence interval, CI: 1.48-5.58) but not in its absence (aOR = 1.32; 95%CI: 0.61-2.84). The p-value for the interaction term between clinical-ASPECTS mismatch and late endovascular treatment was 0.073. CONCLUSIONS: In our retrospective two-site analysis, late endovascular treatment seemed effective in the presence of a clinical-ASPECTS mismatch, but not in its absence. If confirmed in randomized trials, this finding could support the use of an ASPECTS-based selection for late endovascular treatment decisions, obviating the need for advanced imaging.