OBJECTIVES: To evaluate the benefits and harms of any type of endoscopic sphincterotomy compared with a placebo drug, sham operation, or any pharmaceutical treatment, administered orally or endoscopically, alone or in combination, or a different type of endoscopic sphincterotomy in adults with biliary sphincter of Oddi dysfunction.

SEARCH METHODS: We used extensive Cochrane search methods. The latest search date was 16 May 2023.

SELECTION CRITERIA: We included randomised clinical trials assessing any type of endoscopic sphincterotomy versus placebo drug, sham operation, or any pharmaceutical treatment, alone or in combination, or a different type of endoscopic sphincterotomy in adults diagnosed with sphincter of Oddi dysfunction, irrespective of year, language of publication, format, or outcomes reported.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods and Review Manager to prepare the review. Our primary outcomes were: proportion of participants without successful treatment; proportion of participants with one or more serious adverse events; and health-related quality of life. Our secondary outcomes were: all-cause mortality; proportion of participants with one or more non-serious adverse events; length of hospital stay; and proportion of participants without improvement in liver function tests. We used the outcome data at the longest follow-up and the random-effects model for our primary analyses. We assessed the risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We planned to present the results of time-to-event outcomes as hazard ratios (HR). We presented dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI).

MAIN RESULTS: We included four randomised clinical trials, including 433 participants. Trials were published between 1989 and 2015. The trial participants had sphincter of Oddi dysfunction. Two trials were conducted in the USA, one in Australia, and one in Japan. One was a multicentre trial conducted in seven US centres, and the remaining three were single-centre trials. One trial used a two-stage randomisation, resulting in two comparisons. The number of participants in the four trials ranged from 47 to 214 (median 86), with a median age of 45 years, and the mean proportion of males was 49%. The follow-up duration ranged from one year to four years after the end of treatment. All trials assessed one or more outcomes of interest to our review. The trials provided data for the comparisons and outcomes below, in conformity with our review protocol. The certainty of evidence for all the outcomes was very low. Endoscopic sphincterotomy versus sham Endoscopic sphincterotomy versus sham may have little to no effect on treatment success (RR 1.05, 95% CI 0.66 to 1.66; 3 trials, 340 participants; follow-up range 1 to 4 years); serious adverse events (RR 0.71, 95% CI 0.34 to 1.46; 1 trial, 214 participants; follow-up 1 year), health-related quality of life (Physical scale) (MD -1.00, 95% CI -3.84 to 1.84; 1 trial, 214 participants; follow-up 1 year), health-related quality of life (Mental scale) (MD -1.00, 95% CI -4.16 to 2.16; 1 trial, 214 participants; follow-up 1 year), and no improvement in liver function test (RR 0.89, 95% CI 0.35 to 2.26; 1 trial, 47 participants; follow-up 1 year), but the evidence is very uncertain. Endoscopic sphincterotomy versus endoscopic papillary balloon dilation Endoscopic sphincterotomy versus endoscopic papillary balloon dilationmay have little to no effect on serious adverse events (RR 0.34, 95% CI 0.04 to 3.15; 1 trial, 91 participants; follow-up 1 year), but the evidence is very uncertain. Endoscopic sphincterotomy versus dual endoscopic sphincterotomy Endoscopic sphincterotomy versus dual endoscopic sphincterotomy may have little to no effect on treatment success (RR 0.65, 95% CI 0.32 to 1.31; 1 trial, 99 participants; follow-up 1 year), but the evidence is very uncertain. Funding One trial did not provide any information on sponsorship; one trial was funded by a foundation (the National Institutes of Diabetes and Digestive and Kidney Diseases, NIDDK), and two trials seemed to be funded by the local health institutes or universities where the investigators worked. We did not identify any ongoing randomised clinical trials.

DATA SOURCES: MEDLINE, Embase, CINAHL, and Cochrane Central were searched from inception to February 10, 2023.

STUDY SELECTION: RCTs evaluating the effect of enteral or IV glutamine supplementation alone in severe adult burn patients were included.

DATA EXTRACTION: Two reviewers independently extracted data on study characteristics, burn injury characteristics, description of the intervention between groups, adverse events, and clinical outcomes.

DATA SYNTHESIS: Random effects meta-analyses were performed to estimate the pooled risk ratio (RR). Trial sequential analyses (TSA) for mortality and infectious complications were performed. Ten RCTs (1,577 patients) were included. We observed no significant effect of glutamine supplementation on overall mortality (RR, 0.65, 95% CI, 0.33-1.28; p = 0.21), infectious complications (RR, 0.83; 95% CI, 0.63-1.09; p = 0.18), or other secondary outcomes. In subgroup analyses, we observed no significant effects based on administration route or burn severity. We did observe a significant subgroup effect between single and multicenter RCTs in which glutamine significantly reduced mortality and infectious complications in singe-center RCTs but not in multicenter RCTs. However, TSA showed that the pooled results of single-center RCTs were type 1 errors and further trials would be futile.

METHODS: VALID is a prospective, multi-center, multinational validation study that will assess the accuracy and feasibility of measuring VA function, defined as the need for interventions to enable and maintain the use of a VA for HD. The primary objective is to determine whether VA function can be measured accurately by clinical staff as part of routine clinical practice (Assessor 1) compared to the reference standard of documented VA procedures collected by a VA expert (Assessor 2) during a 6-month follow-up period. Secondary outcomes include feasibility and acceptability of measuring VA function and the time to, rate of, and type of VA interventions. An estimated 612 participants will be recruited from approximately 10 dialysis units of different size, type (home-, in-center and satellite), governance (private versus public), and location (rural versus urban) across Australia, Canada, Europe, and Malaysia. Validity will be measured by the sensitivity and specificity of the data acquisition process. The sensitivity corresponds to the proportion of correctly identified interventions by Assessor 1, among the interventions identified by Assessor 2 (reference standard). The feasibility of measuring VA function will be assessed by the average data collection time, data completeness, feasibility questionnaires and semi-structured interviews on key feasibility aspects with the assessors.

DISCUSSION: Accuracy, acceptability, and feasibility of measuring VA function as part of routine clinical practice are required to facilitate global implementation of this core outcome across all HD trials. Global use of a standardized, patient-centered outcome measure for VA function in HD research will enhance the consistency and relevance of trial evidence to guide patient-centered care.

METHODS: From personal files, citation searching, and three databases searched up to 29-5-2023, we included randomized controlled trials (RCTs) of adult critically ill patients that compared higher vs lower protein delivery with similar energy delivery between groups and reported clinical and/or patient-centred outcomes. We conducted random-effect meta-analyses and subsequently trial sequential analyses (TSA) to control for type-1 and type-2 errors. The main subgroup analysis investigated studies with and without combined early physical rehabilitation intervention. A subgroup analysis of AKI vs no/not known AKI was also conducted.

RESULTS: Twenty-three RCTs (n = 3303) with protein delivery of 1.49 ± 0.48 vs 0.92 ± 0.30 g/kg/d were included. Higher protein delivery was not associated with overall mortality (risk ratio [RR]: 0.99, 95% confidence interval [CI] 0.88-1.11; I2 = 0%; 21 studies; low certainty) and other clinical outcomes. In 2 small studies, higher protein combined with early physical rehabilitation showed a trend towards improved self-reported quality-of-life physical function measurements at day-90 (standardized mean difference 0.40, 95% CI - 0.04 to 0.84; I2 = 30%). In the AKI subgroup, higher protein delivery significantly increased mortality (RR 1.42, 95% CI 1.11-1.82; I2 = 0%; 3 studies; confirmed by TSA with high certainty, and the number needed to harm is 7). Higher protein delivery also significantly increased serum urea (mean difference 2.31 mmol/L, 95% CI 1.64-2.97; I2 = 0%; 7 studies).

CONCLUSION: Higher, compared with lower protein delivery, does not appear to affect clinical outcomes in general critically ill patients but may increase mortality rates in patients with AKI. Further investigation of the combined early physical rehabilitation intervention in non-AKI patients is warranted.

METHODS AND ANALYSIS: This study is an international, multicentre, randomised controlled study at five institutions with a total of 150 patients with subacute stroke. Participants will be randomised into two groups (75 patients in the robot-assisted gait training (RAGT) group and 75 patients in the control group). The gait training will be performed with a total of 20 sessions (60 min/session); 5 sessions a week for 4 weeks. The RAGT group will receive 30 min of gait training using an exoskeleton (ANGEL LEGS M20, Angel Robotics) and 30 min of conventional gait training, while the control group will receive 60 min conventional gait training. In all the patients, the functional assessments such as ambulation, motor and balance will be evaluated before and after the intervention. Follow-up monitoring will be performed to verify whether the patient can walk without physical assistance for 3 months. The primary outcome is the improvement of the Functional Ambulatory Category after the gait training. The functional assessments will also be evaluated immediately after the last training session in the RAGT group to assess the assistive effects of an exoskeletal wearable robot. This trial will provide evidence on the effects of an exoskeleton to improve and assist ambulatory function in patients with subacute stroke.

ETHICS AND DISSEMINATION: This protocol has been approved by the Institutional Review Board of each hospital and conforms to the Declaration of Helsinki. The results will be disseminated through publication.

METHODS AND ANALYSIS: We are undertaking an international multicentre, double-blind, placebo-RCT to evaluate whether 12 months of erdosteine is beneficial for children and adults with bronchiectasis. We will recruit 194 children and adults with bronchiectasis to a parallel, superiority RCT at eight sites across Australia, Malaysia and Philippines. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, exacerbation duration, time-to-next exacerbation, hospitalisations and lung function.

ETHICS AND DISSEMINATION: The Human Research Ethics Committees (HREC) of Children's Health Queensland (for all Australian sites), University of Malaya Medical Centre (Malaysia) and St. Luke's Medical Centre (Philippines) approved the study. We will publish the results and share the outcomes with the academic and medical community, funding and relevant patient organisations.

METHODS: In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2-2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8-1.2 g/kg/day). The primary outcome is 90-day all-cause mortality; other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30 to 25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data.

CONCLUSION: Ethics approval was obtained from the institutional review board, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings.

AIMS: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI.

MATERIALS & METHODS: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option.

RESULTS: EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals.

DISCUSSION: EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD.

METHODS AND ANALYSIS: At least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated.

ETHICS AND DISSEMINATION: The study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation's Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal.

METHODS AND ANALYSIS: PRoVENT-iMIC (study of PRactice of VENTilation in Middle-Income Countries) is an international multicentre observational study to be undertaken in approximately 60 ICUs in 11 Asian countries. Consecutive patients aged 18 years or older who are receiving invasive ventilation in participating ICUs during a predefined 28-day period are to be enrolled, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cm H2O) during the first 3 days of mechanical ventilation-compared between patients at no risk for acute respiratory distress syndrome (ARDS), patients at risk for ARDS and in patients with ARDS (in case the diagnosis of ARDS can be made on admission). Secondary outcomes include occurrence of pulmonary complications and all-cause ICU mortality.

ETHICS AND DISSEMINATION: PRoVENT-iMIC will be the first international study that prospectively assesses ventilation practices, outcomes and epidemiology of invasively ventilated patients in ICUs in Asia. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance when designing trials of invasive ventilation in resource-limited ICUs. Access to source data will be made available through national or international anonymised datasets on request and after agreement of the PRoVENT-iMIC steering committee.

METHODS: RCTs that compared probiotics or synbiotics to usual care or placebo and reported clinical and diarrheal outcomes were searched in 4 electronic databases from inception to March 8, 2022 without language restriction. Four reviewers independently extracted data and assessed the study qualities using the Critical Care Nutrition (CCN) Methodological Quality Scoring System. Random-effect meta-analysis and trial sequential analysis (TSA) were used to synthesize the results. The primary outcome was ventilator-associated pneumonia (VAP). The main subgroup analysis compared the effects of higher versus lower quality studies (based on median CCN score).

RESULTS: Seventy-five studies with 71 unique trials (n = 8551) were included. In the overall analysis, probiotics significantly reduced VAP incidence (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.56-0.88; I2 = 65%; 16 studies). However, such benefits were demonstrated only in lower (RR 0.47, 95% CI 0.32, 0.69; I2 = 44%; 7 studies) but not higher quality studies (RR 0.89, 95% CI 0.73, 1.08; I2 = 43%; 9 studies), with significant test for subgroup differences (p = 0.004). Additionally, TSA showed that the VAP benefits of probiotics in the overall and subgroup analyses were type-1 errors. In higher quality trials, TSA found that future trials are unlikely to demonstrate any benefits of probiotics on infectious complications and diarrhea. Probiotics had higher adverse events than control (pooled risk difference: 0.01, 95% CI 0.01, 0.02; I2 = 0%; 22 studies).

CONCLUSION: High-quality RCTs did not support a beneficial effect of probiotics on clinical or diarrheal outcomes in critically ill patients. Given the lack of benefits and the increased incidence of adverse events, probiotics should not be routinely administered to critically ill patients.

METHODS: This protocol was drafted in agreement with the ROBUST-statement, and is submitted for publication before database lock and primary data analysis. The primary outcome is health-related quality of life as measured by the EQ-5D-5L health utility score and is longitudinally assessed. Secondary outcomes comprise the 6-min walking test and handgrip strength over the entire follow-up period (longitudinal analyses), and 60-day mortality, duration of mechanical ventilation, and EQ-5D-5L health utility scores at 30, 90 and 180 days (cross-sectional). All analyses will primarily be performed under weakly informative priors. When available, informative priors elicited from contemporary literature will also be incorporated under alternative scenarios. In all other cases, objectively formulated skeptical and enthusiastic priors will be defined to assess the robustness of our results. Relevant identified subgroups were: patients with acute kidney injury, severe multi-organ failure and patients with or without sepsis. Results will be presented as absolute risk differences, mean differences, and odds ratios, with accompanying 95% credible intervals. Posterior probabilities will be estimated for clinically important benefit and harm.

METHODS: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion.

RESULTS: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L.

CONCLUSIONS: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L.

METHODS AND ANALYSIS: Hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) is a multicentre, international, parallel-group randomised controlled trial (RCT). Patients who suffer a hip fracture are randomly allocated to either accelerated medical assessment and surgical repair with a goal of surgery within 6 hours of diagnosis or standard care where a repair typically occurs 24 to 48 hours after diagnosis. The primary outcome of this substudy is the development of AKI within 7 days of randomisation. We anticipate at least 1998 patients will participate in this substudy.

ETHICS AND DISSEMINATION: We obtained ethics approval for additional serum creatinine recordings in consecutive patients enrolled at 70 participating centres. All patients provide consent before randomisation. We anticipate reporting substudy results by 2021.