Single Randomized Controlled Trials Research Articles

Non-surgical interventions for preventing contralateral tissue loss and amputation in dysvascular patients with a primary major lower limb amputation.

Major lower limb amputation (LLA, above the ankle) is performed for people with intractable pain, life-threatening infections, or non-functional limbs. Of 7500 LLAs carried out in England between 2015 and 2018, the majority of these were performed in dysvascular patients. Dysvascularity is the absence of adequate blood supply to maintain a limb's usual function (ischaemia, usually caused by peripheral arterial disease or diabetes mellitus), ultimately leading to pain and tissue injury (ulcers, gangrene, sometimes referred to as tissue loss). Among those who undergo dysvascular LLA, 5.7% and 11.5% will likely undergo contralateral LLA at one and five years respectively, which is associated with greater disability and lower likelihood of returning to work, increasing the psychological burden to the patient and socioeconomic cost to the patient and health service. While extensive research has been carried out in the management of peripheral arterial disease and the care of diabetic feet, there are no guidelines for practice on prevention of contralateral amputation. To assess the effects of non-surgical interventions versus placebo, no intervention, or other non-surgical interventions on contralateral limb (CLL) tissue loss and amputation in dysvascular patients with a primary major LLA. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and PEDro databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers until 20 March 2023. We also checked the references of identified studies and contacted study authors and manufacturers of relevant products. We aimed to include all randomised controlled trials (RCTs) and quasi-RCTs (e.g. randomised by birthdate) comparing the effectiveness of a non-surgical intervention with placebo, no intervention, or other non-surgical intervention, in adults with a primary major LLA due to dysvascularity. Interventions could be physical, pharmacological, educational, behavioural, or organisational, and delivered by a healthcare professional or carer. Our critical and important outcomes of interest were as follows. Critical outcomes • Incidence of new localised tissue injury or ulceration (tissue loss) of the CLL, regardless of stage or classification at given time points. • Time to the development of any localised tissue injury or ulceration (tissue loss) of the CLL, regardless of stage or classification. • Incidence of new minor amputation (through the ankle, foot, or toe(s)) of the CLL at given time points. • Time to new minor amputation (through the ankle, foot, or toe(s)) of the CLL. • Incidence of new major amputation (whole limb or partial limb, above the ankle) of the CLL at given time points. • Time to new major amputation (whole limb or partial limb, above the ankle) of the CLL. Important outcomes • Survival (time to death from all causes) at 12 months. • Patient-reported outcome measures of health-related quality of life (HRQoL) using validated scales such as the 12-item Short Form Health Survey (SF-12) and EQ-5D. • Adverse events (e.g. infections in the CLL). • Hospital readmission. We used Cochrane's RoB 1 tool to assess risk of bias in the included study. We were only able to perform a narrative review due to lack of data. We reported risk ratios (RR) with 95% CIs for dichotomous outcomes. We used GRADE to assess the certainty of evidence for each outcome. We found one eligible study, which compared electrostimulation of the gastrocnemius muscle and standard rehabilitation against standard rehabilitation in 50 dysvascular amputees. There was no new incidence of tissue loss reported. The following outcomes were not reported: time to new tissue loss; time to and incidence of minor amputation; HRQoL outcomes; adverse events; and hospital readmissions. Electrostimulation was associated with a three-fold reduction in the incidence of new major amputation of the CLL (RR 0.33, 95% CI 0.04 to 2.99), although time to new major amputation was not reported. There was no difference between groups in 12-month survival (RR 1.0, 95% CI 0.85 to 1.18). We judged the overall certainty of the evidence (GRADE) as very low across all outcomes, with unclear risk of selection and detection bias and high risk of performance bias. Despite the care of the CLL being identified as a key research priority by two separate consensus papers, there is insufficient high-quality evidence to address this priority to date. We found only a single RCT suitable for inclusion, and this study was subject to risk of bias. Contralateral limb outcomes should be recorded in future research on dysvascular amputees. Until better evidence and clearer recommendations are available, this topic is likely to remain a research priority. This Cochrane review had no dedicated funding. Protocol available via DOI 10.1002/14651858.CD013857.

Non-Ergot Dopamine Agonists and the Risk of Heart Failure and Other Adverse Cardiovascular Reactions in Parkinson's Disease.

Reports suggest possible risks of adverse cardiovascular reactions, including heart failure, associated with non-ergot dopamine agonist (DA) use in Parkinson's disease (PD). The objectives of our review were to evaluate the risk of heart failure and other adverse cardiovascular reactions in PD patients who received a non-ergot DA compared with other anti-PD pharmacological interventions, placebo, or no intervention. Studies were identified via searches of six bibliographic databases. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were eligible for study inclusion. Random-effect meta-analyses were performed to estimate adverse cardiovascular reaction risks. Quality of evidence was assessed using GRADE. In total, forty-four studies (thirty-six RCTs and eight NRS) satisfied our inclusion criteria. A single RCT found no significant difference in the risk of heart failure with ropinirole compared with bromocriptine (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.07 to 2.04; low certainty). Conversely, three case-control studies reported a risk of heart failure with non-ergot DA treatment. The quality of evidence for the risk of heart failure was judged as low or very low. Findings suggest that non-ergot DA use may be associated with adverse cardiovascular outcomes, including heart failure. Studies are needed to better understand cardiovascular risks associated with PD treatment.

Strength of statistical evidence for the efficacy of cancer drugs: a Bayesian reanalysis of randomized trials supporting Food and Drug Administration approval

ObjectivesTo quantify the strength of statistical evidence of randomized controlled trials (RCTs) for novel cancer drugs approved by the Food and Drug Administration in the last 2 decades. Study Design and SettingWe used data on overall survival (OS), progression-free survival, and tumor response for novel cancer drugs approved for the first time by the Food and Drug Administration between January 2000 and December 2020. We assessed strength of statistical evidence by calculating Bayes factors (BFs) for all available endpoints, and we pooled evidence using Bayesian fixed-effect meta-analysis for indications approved based on 2 RCTs. Strength of statistical evidence was compared among endpoints, approval pathways, lines of treatment, and types of cancer. ResultsWe analysed the available data from 82 RCTs corresponding to 68 indications supported by a single RCT and 7 indications supported by 2 RCTs. Median strength of statistical evidence was ambiguous for OS (BF = 1.9; interquartile range [IQR] 0.5–14.5), and strong for progression-free survival (BF = 24,767.8; IQR 109.0–7.3 × 106) and tumor response (BF = 113.9; IQR 3.0–547,100). Overall, 44 indications (58.7%) were approved without clear statistical evidence for OS improvements and 7 indications (9.3%) were approved without statistical evidence for improvements on any endpoint. Strength of statistical evidence was lower for accelerated approval compared to nonaccelerated approval across all 3 endpoints. No meaningful differences were observed for line of treatment and cancer type. This analysis is limited to statistical evidence. We did not consider nonstatistical factors (eg, risk of bias, quality of the evidence). ConclusionBFs offer novel insights into the strength of statistical evidence underlying cancer drug approvals. Most novel cancer drugs lack strong statistical evidence that they improve OS, and a few lack statistical evidence for efficacy altogether. These cases require a transparent and clear explanation. When evidence is ambiguous, additional postmarketing trials could reduce uncertainty.

Psychological and social interventions for the promotion of mental health in people living in low- and middle-income countries affected by humanitarian crises.

Because of wars, conflicts, persecutions, human rights violations, and humanitarian crises, about 84 million people are forcibly displaced around the world; the great majority of them live in low- and middle-income countries (LMICs). People living in humanitarian settings are affected by a constellation of stressors that threaten their mental health. Psychosocial interventions for people affected by humanitarian crises may be helpful to promote positive aspects of mental health, such as mental well-being, psychosocial functioning, coping, and quality of life. Previous reviews have focused on treatment and mixed promotion and prevention interventions. In this review, we focused on promotion of positive aspects of mental health. To assess the effects of psychosocial interventions aimed at promoting mental health versus control conditions (no intervention, intervention as usual, or waiting list) in people living in LMICs affected by humanitarian crises. We searched CENTRAL, MEDLINE, Embase, and seven other databases to January 2023. We also searched the World Health Organization's (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov to identify unpublished or ongoing studies, and checked the reference lists of relevant studies and reviews. Randomised controlled trials (RCTs) comparing psychosocial interventions versus control conditions (no intervention, intervention as usual, or waiting list) to promote positive aspects of mental health in adults and children living in LMICs affected by humanitarian crises. We excluded studies that enrolled participants based on a positive diagnosis of mental disorder (or based on a proxy of scoring above a cut-off score on a screening measure). We used standard Cochrane methods. Our primary outcomes were mental well-being, functioning, quality of life, resilience, coping, hope, and prosocial behaviour. The secondary outcome was acceptability, defined as the number of participants who dropped out of the trial for any reason. We used GRADE to assess the certainty of evidence for the outcomes of mental well-being, functioning, and prosocial behaviour. We included 13 RCTs with 7917 participants. Nine RCTs were conducted on children/adolescents, and four on adults. All included interventions were delivered to groups of participants, mainly by paraprofessionals. Paraprofessional is defined as an individual who is not a mental or behavioural health service professional, but works at the first stage of contact with people who are seeking mental health care. Four RCTs were carried out in Lebanon; two in India; and single RCTs in the Democratic Republic of the Congo, Jordan, Haiti, Bosnia and Herzegovina, the occupied Palestinian Territories (oPT), Nepal, and Tanzania. The mean study duration was 18 weeks (minimum 10, maximum 32 weeks). Trials were generally funded by grants from academic institutions or non-governmental organisations. For children and adolescents, there was no clear difference between psychosocial interventions and control conditions in improving mental well-being and prosocial behaviour at study endpoint (mental well-being: standardised mean difference (SMD) 0.06, 95% confidence interval (CI) -0.17 to 0.29; 3 RCTs, 3378 participants; very low-certainty evidence; prosocial behaviour: SMD -0.25, 95% CI -0.60 to 0.10; 5 RCTs, 1633 participants; low-certainty evidence), or at medium-term follow-up (mental well-being: mean difference (MD) -0.70, 95% CI -2.39 to 0.99; 1 RCT, 258 participants; prosocial behaviour: SMD -0.48, 95% CI -1.80 to 0.83; 2 RCT, 483 participants; both very low-certainty evidence). Interventions may improve functioning (MD -2.18, 95% CI -3.86 to -0.50; 1 RCT, 183 participants), with sustained effects at follow-up (MD -3.33, 95% CI -5.03 to -1.63; 1 RCT, 183 participants), but evidence is very uncertain as the data came from one RCT (both very low-certainty evidence). Psychosocial interventions may improve mental well-being slightly in adults at study endpoint (SMD -0.29, 95% CI -0.44 to -0.14; 3 RCTs, 674 participants; low-certainty evidence), but they may have little to no effect at follow-up, as the evidence is uncertain and future RCTs might either confirm or disprove this finding. No RCTs measured the outcomes of functioning and prosocial behaviour in adults. To date, there is scant and inconclusive randomised evidence on the potential benefits of psychological and social interventions to promote mental health in people living in LMICs affected by humanitarian crises. Confidence in the findings is hampered by the scarcity of studies included in the review, the small number of participants analysed, the risk of bias in the studies, and the substantial level of heterogeneity. Evidence on the efficacy of interventions on positive mental health outcomes is too scant to determine firm practice and policy implications. This review has identified a large gap between what is known and what still needs to be addressed in the research area of mental health promotion in humanitarian settings.

Home versus in-centre haemodialysis for people with kidney failure.

Home versus in-centre haemodialysis for people with kidney failure.

Enhanced recovery protocols after surgery: A systematic review and meta-analysis of randomized trials in cardiac surgery.

Previous meta-analyses combining randomized and observational evidence in cardiac surgery have shown positive impact of enhanced recovery protocols after surgery (ERAS) on postoperative outcomes. However, definitive data based on randomized studies are missing, and the entirety of the ERAS measures and pathway, as recently systematized in guidelines and consensus statements, have not been captured in the published studies. The available literature actually focuses on "ERAS-like" protocols or only limited number of ERAS measures. This study aims at analyzing all randomized studies applying ERAS-like protocols in cardiac surgery for perioperative outcomes. A meta-analysis of randomized controlled trials (RCTs) comparing ERAS-like with standard protocols of perioperative care was performed (PROSPERO registration CRD42021283765). PRISMA guidelines were used for abstracting and assessing data. Thirteen single center RCTs (N=1704, 850 in ERAS-like protocol and 854 in the standard care group) were selected. The most common procedures were surgical revascularization (66.3%) and valvular surgery (24.9%). No difference was found in the incidence of inhospital mortality between the ERAS and standard treatment group (risk ratio [RR] 0.61 [0.31; 1.20], p=0.15). ERAS was associated with reduced intensive care unit (standardized mean difference [SMD] -0.57, p<0.01) and hospital stay (SMD -0.23, p<0.01) and reduced rates of overall complications when compared to the standard protocol (RR 0.60, p<0.01) driven by the reduction in stroke (RR 0.29 [0.13; 0.62], p<0.01). A significant heterogeneity in terms of the elements of the ERAS protocol included in the studies was observed. ERAS-like protocols have no impact on short-term survival after cardiac surgery but allows for a faster hospital discharge while potentially reducing surgical complications. However, this study highlights a significant nonadherence and heterogeneity to the entirety of ERAS protocols warranting further RCTs in this field including a greater number of elements of the framework.

Frailty in acute coronary syndromes. A systematic review and narrative synthesis of frailty assessment tools and interventions from randomised controlled trials

AimWe aimed to review all randomised controlled trial (RCT) data to explore optimal identification and treatment strategies of frail patients with Acute Coronary Syndromes (ACS). MethodsThe protocol was preregistered (PROSPERO - CRD42021250235). We performed a systematic review including RCT's that 1; used at least one frailty assessment tool to assess frailty and its impact on outcomes in patients diagnosed with ACS and 2; used at least one intervention where change in frailty was measured in patients diagnosed with ACS. The Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE were searched on the 1st April 2021 and updated on 4th July 2023. Owing to low search output results are presented as a narrative synthesis of available evidence. ResultsA single RCT used a frailty assessment tool. A single RCT specifically targeted frailty with their intervention. This precluded further quantitative analysis. There was indication of selection bias against frail participants, and a signal of value for physical activity measurement in frail ACS patients. There was a high level of uncertainty and low level of robustness of this evidence. ConclusionsData from RCT's alone is inadequate in answering the reviews question. Future RCT's need to address ways to incorporate frail participants, whilst mitigating selection biases. Physical performance aspects of the frailty syndrome appear to be high yield modifiable targets that improve outcomes. Intervention trials should consider using change in frailty status as an outcome measure. Any trials that include frail participants should present data specifically attributable to this group.

Treatment strategies to prevent or mitigate the outcome of post-pancreatectomy hemorrhage (PPH): a review of randomized trials.

Post-pancreatectomy hemorrhage (PPH) is a leading cause for surgical mortality after pancreatic surgery. Several strategies for the prevention and management of PPH have been studied in randomized controlled trials (RCTs) but a systematic review is lacking. We systematically reviewed RCTs regarding the impact of treatment strategies on the incidence and outcome of PPH. Eligible RCTs reporting on impact of treatment on the rate of PPH were identified through a systematic literature search using the Evidence Map of Pancreatic Surgery (2012-2022). Methodological quality was assessed using the Cochrane Risk of Bias 2 (RoB-2) tool for RCTs. Various definitions of PPH were accepted and outcome reported separately for the International Study Group for Pancreatic Surgery (ISGPS) definition. Overall, 99 RCTs fulfilled the eligibility criteria with a pooled 6.1% rate of PPH (range 1%-32%). The pooled rate of PPH defined as ISGPS grade B/C was 8.1% (range 0-24.9%). Five RCTs reported five strategies that significantly reduced the rate of PPH. Three concerned surgical technique: pancreatic anastomosis with small jejunal incision, falciform ligament wrap around the gastroduodenal artery stump, and pancreaticojejunostomy (vs pancreaticogastrostomy). Two concerned perioperative management: perioperative pasireotide administration, and algorithm-based postoperative patient management. No single RCT specifically focused on the treatment of patients with PPH. This systematic review of RCTs identified five strategies which reduce the rate of PPH; three concerning intraoperative surgical technique and two concerning peri-operative patient management. Future studies should focus on the treatment of patients with PPH as RCTs are currently lacking.

Abstract 18858: At Heart , a Progressive Web App for Women With Heart Disease: A Pilot Randomized Controlled Trial

Introduction/Background: At heart ’s novel core feature set includes a Heart Check, Wellness Check, and a Library, with an interactive Chatbot to manage its content and conversations. at heart is the first of its kind; there are no previous trials of an intervention rigorously developed and tested. Goals/Aims: The overall goal of this study was to develop and evaluate a digital health intervention for women with heart disease. Specific aims of the pilot randomized controlled trial (RCT) were to examine: 1) the feasibility of randomization, recruitment, and retention, 2) acceptability and barriers to implementation (including the symptom triage algorithms), and 3) engagement with the intervention. Methods/Approach: This was a two-group parallel single blind pilot RCT. Women greater than 18 years of age with heart disease were recruited, all women spoke and read English. Following completion of baseline measures, participants were randomized to either an intervention or a usual care group. Participants randomized to the intervention group used at heart for 3 months. Recruitment, retention, and adverse events were tracked and engagement was assessed using Google Analytics . Acceptability was assessed with a six-item modified Acceptability e-Scale (AES), yielding a total acceptability score of 6-30. Results/Data: A total of 98 women were assessed for eligibility, 18 were excluded. Eighty women were randomized, 40 allocated to usual care and 40 to receive the intervention. Attrition was low. Mean age was 57 years (SD 13), 32% (n=27) were employed full time, and 48% (n=41) had a post-secondary diploma/certificate. There were 226 heart checks; 1-15 per participant, most symptoms were triaged as low risk (n=176, 78%). There were 198 wellness checks, 1-12 per participant. The mean number of articles accessed in the library was 8 per participant. The mean acceptability score was 23.46 (SD 4.87), there were no barriers to implementation, and no adverse events were reported. Conclusion(s): The at heart intervention is feasible; women were engaged and reported high acceptability scores. A larger, powered RCT is necessary.

POSTOPERATIVE USE OF GAME READYTM CRYOCOMPRESSION SYSTEM FOLLOWING TOTAL KNEE ARTHROPLASTY: A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL

Cryocompression therapy is a non-invasive and non-pharmacological modality used in managing acute post-operative inflammation and pain. A prospective, randomised controlled trial (RCT) was undertaken to evaluate the effectiveness of a post-operative cryocompression protocol using the Game ReadyTM (GR) device versus usual care on recovery following total knee arthroplasty (TKA).A single centre RCT was conducted with 70 TKAs (68 patients) randomised to a 2-week intervention period consisting of treatment with GR cryocompression (n=33, 33.3% males) or a usual care protocol of ice with static compression using tubigrip (n=35, 54.3% males). Knee range of movement (ROM) (flexion and extension), a visual analogue pain score (VAS) and limb circumference were documented at day 1, 2 and 14, as well as 6 and 12 weeks post-surgery. ROM was also recorded at day 90, while medication use and length of hospital stay were documented. Patient reported outcome measures (PROMs) including the KOOS and patient satisfaction questionnaire were employed.The GR group demonstrated 2.3° more (p=0.05) knee extension ROM overall, as well as 2. 8° more at day 1 (p=0.048), 3.8° at day 14 (p=0.007) and 5.4° at 3 months (p=0.017). There were no group differences (p&gt;0.05) observed in pain (VAS), flexion ROM, limb circumference, opioid use or other PROMs. Across the full cohort, higher pain levels resulted in increased opioid intake (p=0.002), older patients used significantly less opioids (p&lt;0.001) and males reported significantly less pain (VAS) than females (p=0.048).Using GR following TKA is a safe, non-invasive tool that can be used to aid in the post-operative recovery period.Patients using the GR cryocompression device gained significantly more extension ROM compared to the conventional ice with compression group, despite no other group differences.

Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data.

Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: (1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), (2) a single RCT, and (3) a hybrid randomized-external data study. The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis. In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of -1.53%-points (95% CI -2.75%-points to -0.30%-points). The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of the superiority of oral semaglutide versus standard-of-care for cardiovascular risk reduction.

Dysphagia treatments in Parkinson's disease: A systematic review and meta-analysis.

The majority of patients with Parkinson's disease (PD) develop oropharyngeal dysphagia during the course of their disease. However, the efficacy of dysphagia treatments for these patients remains controversial. Therefore, we conducted this systematic review and meta-analysis to evaluate treatment efficacy based on the evidence from randomized controlled trials (RCTs). Five electronic databases were systematically searched from inception date to April 2022. Two reviewers independently extracted and analyzed the data. The outcome measures were changes in swallowing-related characteristics based on instrumental swallowing assessments. An initial search identified 187 RCT studies of relevance. After screening, nine studies with a total sample size of 286 were included in the meta-analysis. The pooled effect size for all dysphagia treatments compared with control comparators was significant and medium (SMD [95% CI]=0.58 [0.22, 0.94], p=0.001; I2 = 50%). Subgroup analysis revealed a significant and medium pooled effect size for stimulation treatments (brain stimulation, peripheral neurostimulation and acupuncture) (SMD [95% CI]=0.54 [0.15, 0.92]; p=0.006; I2 = 22%). Specifically, the effect sizes for the single RCTs on neuromuscular stimulation (SMD [95% CI]=1.58 [0.49, 2.86]; p=0.005) and acupuncture (SMD [95% CI]=0.82 [0.27, 1.37]; p=0.003) were significant and large. Our results showed that overall, dysphagia treatments, particularly stimulation treatments, can potentially benefit PD patients. However, given the limited number of small RCTs for each type of treatment, the evidence remains weak and uncertain. Further large-scale, multicenter RCTs are warranted to fully explore their clinical efficacy in the PD population.

Early vitrectomy for exogenous endophthalmitis following surgery.

Endophthalmitis is a sight-threatening emergency that requires prompt diagnosis and treatment. The condition is characterised by purulent inflammation of the intraocular fluids caused by an infective agent. In exogenous endophthalmitis, the infective agent is foreign and typically introduced into the eye through intraocular surgery or open globe trauma. To assess the potential role of combined pars plana vitrectomy and intravitreal antibiotics in the acute management of exogenous endophthalmitis, versus the standard of care, defined as vitreous tap and intravitreal antibiotics. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5); Ovid MEDLINE; Ovid Embase; the International Standard Randomised Controlled Trial Number registry; ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. There were no restrictions to language or year of publication. The date of the search was 5 May 2022. We included randomised controlled trials (RCTs) that compared pars plana vitrectomy and intravitreal injection of antibiotics versus intravitreal injection of antibiotics alone, for the immediate management of exogenous endophthalmitis. We used standard methods expected by Cochrane. Two review authors independently screened search results and extracted data. We considered the following outcomes: visual acuity improvement and change in visual acuity at three and six months; additional surgical procedures, including vitrectomy and cataract surgery, at any time during follow-up; quality of life and adverse effects. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We identified a single RCT that met our inclusion criteria. The included RCT enrolled a total of 420 participants with clinical evidence of endophthalmitis, within six weeks of cataract surgery or secondary intraocular lens implantation. Participants were randomly assigned according to a 2 x 2 factorial design to either treatment with vitrectomy (VIT) or vitreous tap biopsy (TAP) and to treatment with or without systemic antibiotics. Twenty-four participants did not have a final follow-up: 12 died, five withdrew consent to be followed up, and seven were not willing to return for the visit. The study did not report visual acuity according to the review's predefined outcomes. At three months, 41% of all participants achieved 20/40 or better visual acuity and 69% had 20/100 or better acuity. The study authors reported that there was no statistically significant difference in visual acuity between treatment groups (very low-certainty evidence). There was low-certainty evidence of a similar requirement for additional surgical procedures (risk ratio RR 0.90, 95% confidence interval 0.66 to 1.21). Adverse effects included: VIT group: dislocated intraocular lens (n = 2), macular infarction (n = 1). TAP group: expulsive haemorrhage (n = 1). Quality of life and mean change in visual acuity were not reported. AUTHORS' CONCLUSIONS: We identified a single RCT (published 27 years ago) for the role of early vitrectomy in exogenous endophthalmitis, which suggests that there may be no difference between groups (VIT vs TAP) for visual acuity at three or nine months' follow-up. We are of the opinion that there is a clear need for more randomised studies comparing the role of primary vitrectomy in exogenous endophthalmitis. Moreover, since the original RCT study, there have been incremental changes in the surgical techniques with which vitrectomy is performed. Such advances are likely to influence the outcome of early vitrectomy in exogenous endophthalmitis.

Surgery for the treatment of obesity in children and adolescents.

Child and adolescent overweight and obesity have increased globally and are associated with significant short- and long-term health consequences. To assess the effects of surgery for treating obesity in childhood and adolescence. For this update, we searched Cochrane Central Register of Controlled Trials, MEDLINE, Latin American and Caribbean Health Science Information database (LILACS), World Health Organization International Clinical Trials Registry Platform (ICTRP)and ClinicalTrials.gov on 20 August 2021 (date of the last search for all databases). We did not apply language restrictions. We checked references of identified studies and systematic reviews. We selected randomised controlled trials (RCTs) of surgical interventions for treating obesity in children and adolescents (age < 18 years) with a minimum of six months of follow-up. We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or which included participants with a secondary or syndromic cause of obesity, or who were pregnant. We used standard methodological procedures expected by Cochrane. Two review authors independently extracted data and assessed the risk of bias using the Cochrane Risk of Bias 2.0 tool. Where necessary, we contacted authors for additional information. With this update, we did not find any new RCTs. Therefore, this updated review still includes a single RCT (a total of 50 participants, 25 in both the intervention and comparator groups). The intervention focused on laparoscopic adjustable gastric banding surgery, which was compared to a control group receiving a multi-component lifestyle programme. The participating population consisted of Australian adolescents (a higher proportion of girls than boys) aged 14 to 18 years, with a mean age of 16.5 and 16.6 years in the gastric banding and lifestyle groups, respectively. The trial was conducted in a private hospital, receiving funding from the gastric banding manufacturer. For most of the outcomes, we identified a high risk of bias, mainly due to bias due to missing outcome data. Laparoscopic gastric banding surgery may reduce BMI by a mean difference (MD) of -11.40 kg/m2 (95% CI -13.22 to -9.58) and weight by -31.60 kg (95% CI -36.66 to -26.54) compared to a multi-component lifestyle programme at two years follow-up. The evidence is very uncertain due to serious imprecision and a high risk of bias. Adverse events were reported in 12/25 (48%) participants in the intervention group compared to 11/25 (44%) in the control group. A total of 28% of the adolescents undergoing gastric banding required revisional surgery. The evidence is very uncertain due to serious imprecision and a high risk of bias. At two years of follow-up, laparoscopic gastric banding surgery may increase health-related quality of life in the physical functioning scores by an MD of 16.30 (95% CI 4.90 to 27.70) and change in health scores by an MD of 0.82 (95% CI 0.18 to 1.46) compared to the lifestyle group. The evidence is very uncertain due to serious imprecision and a high risk of bias. No data were reported for all-cause mortality, behaviour change, participants' views of the intervention and socioeconomic effects. Finally, we have identified three ongoing RCTs that are evaluating the efficacy and safety of metabolic and bariatric surgery in children and adolescents. Laparoscopic gastric banding led to greater body weight loss compared to a multi-component lifestyle program in one small study with 50 participants. These results have very limited application, primarily due to more recent recommendations derived from observation studies to avoid the use of banding in youth due to long-term reoperation rates. This systematic review update still highlights the lack of RCTs in this field. The authors are concerned that there may be ethical barriers to RTCs in this field, despite the lack of other effective therapies for severe obesity in children and adolescents and the significant morbidity and premature mortality caused by childhood obesity. Nevertheless, future studies, whether pre-registered and planned non-randomised or pragmatic randomised trials, should assess the impact of the surgical procedure and post-operative care to minimise adverse events, including the need for post-operative adjustments and revisional surgery. Long-term follow-up is also critical to comprehensively assess the impact of surgery as participants enter adulthood.

Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction.

Olfactory dysfunction is a common consequence of COVID-19 infection and persistent symptoms can have a profound impact on quality of life. At present there is little guidance on how best to treat this condition. A variety of interventions have been suggested to promote recovery, including medication and olfactory training. However, it is uncertain whether any intervention is of benefit. This is an update of the 2021 review with one additional study added. OBJECTIVES: 1) To evaluate the benefits and harms of any intervention versus no treatment for people with persisting olfactory dysfunction due to COVID-19 infection. 2) Tokeep the evidence up-to-date, using a living systematic review approach. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the latest search was 20 October 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in people with COVID-19 related olfactory disturbance that had persisted for at least four weeks. We included any intervention compared to no treatment or placebo. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were the recovery of sense of smell, disease-related quality of life andserious adverse effects. Secondary outcomes were the change in sense of smell, general quality of life,prevalence of parosmiaand other adverse effects (including nosebleeds/bloody discharge). We used GRADE to assess the certainty of the evidence for each outcome. We included two studies with 30 participants. The studies evaluated the following interventions: systemic corticosteroids plus intranasal corticosteroid/mucolytic/decongestant and palmitoylethanolamide plus luteolin. Systemic corticosteroids plus intranasal corticosteroid/mucolytic/decongestant compared to no intervention We included a single RCT with 18 participants who had anosmia for at least 30 days following COVID-19 infection. Participants received a 15-day course of oral corticosteroids combined with nasal irrigation (consisting of an intranasal corticosteroid/mucolytic/decongestant solution) or no intervention. Psychophysical testing was used to assess olfactory function at 40 days. This is a single, small study and for all outcomes the certainty of evidence was very low. We are unable to draw meaningful conclusions from the numerical results. Palmitoylethanolamide plus luteolin compared to no intervention We included a single RCT with 12 participants who had anosmia or hyposmia for at least 90 days following COVID-19 infection. Participants received a 30-day course of palmitoylethanolamide and luteolin or no intervention. Psychophysical testing was used to assess olfactory function at 30 days. This is a single, small study and for all outcomes the certainty of evidence was very low. We are unable to draw meaningful conclusions from the numerical results. There is very limited evidence available on the efficacy and harms of treatments for persistent olfactory dysfunction following COVID-19 infection. However, we have identified a number of ongoing trials in this area. As this is a living systematic review we will update the data regularly, as new results become available.

A review of clinical efficacy data supporting emergency use authorization for COVID-19 therapeutics and lessons for future pandemics.

Emergency Use Authorization (EUA) allows the US Food and Drug Administration (FDA) to expedite the availability of therapeutics in the context of a public health emergency. To date, an evidentiary standard for clinical efficacy to support an EUA has not yet been established. This review examines the clinical data submitted in support of EUA for antiviral and anti‐inflammatory therapeutics for coronavirus disease 2019 (COVID‐19) through December of 2021 and the resilience of the authorization as new clinical data arose subsequent to the authorization. In the vast majority of cases, EUA was supported by at least one well‐powered randomized controlled trial (RCT) where statistically significant efficacy was demonstrated. This included branded medications already approved for use outside of the context of COVID‐19. When used, the standard of a single RCT seemed to provide adequate evidence of clinical efficacy, such that subsequent clinical studies generally supported or expanded the EUA of the therapeutic in question. The lone generic agent that was granted EUA (chloroquine/hydroxychloroquine) was not supported by a well‐controlled RCT, and the EUA was withdrawn within 3 months time. This highlighted not only the ambiguity of the EUA standard, but also the need to provide avenues through which high quality clinical evidence for the efficacy of a generic medication could be obtained. Therefore, maintaining the clinical trial networks assembled during the COVID‐19 pandemic could be a critical component of our preparation for future pandemics. Consideration could also be given to establishing a single successful RCT as regulatory guidance for obtaining an EUA.

Systematic review and Meta-analysis of Lianhua Qingwen preparations combined with Oseltamivir in treatment of influenza

This study aims to explore the efficacy and safety of Lianhua Qingwen preparations combined with Oseltamivir in the treatment of influenza patients. PubMed, Cochrane Library, EMbase, SinoMed, CNKI, Wanfang, and VIP were searched for the randomized controlled trials(RCTs) involving the comparison between the influenza patients treated with Lianhua Qingwen preparations combined with Oseltamivir and those treated with Oseltamivir alone. Fever clearance time was taken as the primary outcome indicator. Clinical effective rate(markedly effective and effective), time to muscle pain relief, time to sore throat relief, time to cough relief, time to nasal congestion and runny nose relief, time to negative result of viral nucleic acid test, and adverse reactions were taken as the secondary outcome indicators. The data were extracted based on the outcome indicators and then combined. The Cochrane collaboration's tool for assessing risk of bias was used to evaluate the quality of a single RCT, and the grading of recommendations assessment, development and evaluations(GRADE) system to assess the quality of a single outcome indicator. RevMan 5.3 was employed to analyze data and test heterogeneity. Finally, 16 RCTs involving 1 629 patients were included for analysis. The Meta-analysis showed that Lianhua Qingwen preparations combined with Oseltamivir was superior to Oseltamivir alone in the treatment of influenza in terms of clinical effective rate(RR=1.16, 95%CI [1.12, 1.20], P&lt;0.000 01), fever clearance time(SMD=-2.02, 95%CI [-2.62,-1.41], P&lt;0.000 01), time to muscle pain relief(SMD=-2.50, 95%CI [-3.84,-1.16], P=0.000 2), time to sore throat relief(SMD=-1.40, 95%CI [-1.93,-0.85], P&lt;0.000 01), time to cough relief(SMD=-1.81, 95%CI [-2.44,-1.19], P&lt;0.000 01), time to nasal congestion and runny nose(SMD=-2.31, 95%CI [-3.61,-1.01], P=0.000 5), and time to negative result of viral nucleic acid test(SMD=-0.68, 95%CI [-1.19,-0.16], P=0.01). However, due to the low quality of the trials, the above conclusions need to be proved by more high-quality clinical studies. In addition, we still need to attach importance to the adverse reactions of the integrated application of Chinese and western medicines.

Colchicine for cardiovascular medicine: a systematic review and meta-analysis.

Aim: Colchicine, a microtubule-disassembling (antitubulin) agent used for centuries for the treatment of gout and autoimmune diseases, is a drug of growing interest in the cardiovascular field. While in the last decades it has become cornerstone of pericarditis treatment, it has also emerged in the last few years as a promising drug in the management of coronary artery disease, atrial fibrillation and heart failure. This systematic review and meta-analysis aimed to assess the efficacy of colchicine in patients with cardiovascular diseases. Methods: Systematic search in electronic databases (MEDLINE/PubMed, Scopus, BioMed Central, the Cochrane Collaboration Database of Randomized Trials, ClinicalTrials.gov, EMBASE, Google Scholar) was performed to identify randomized controlled trials (RCTs) up to February 2021. Random-effects meta-analysis was performed to assess the risk of cardiovascular events, defined according to clinical setting. Results: Among 15,569 pooled patients from 21 RCTs, colchicine was superior to placebo in the reduction of cardiovascular events. In the setting of pericardial diseases, it was associated with a lower risk of recurrent pericarditis (17 vs 34%, RR=0.50, 95% CI: 0.42-0.60, I2=10%). In other studies assessing coronary artery disease patients, colchicine was associated with a reduced risk of major adverse cardiovascular events (MACE) such as myocardial infarction, stroke, cardiovascular death, coronary revascularisation and hospitalization (6.3 vs 9%, RR=0.67, 95% CI: 0.54-0.84, I2=55). Among patients with atrial fibrillation, it was associated with lower rates of recurrence (20 vs 30%, RR=0.68, 95% CI: 0.58-0.81, I2=0). In the single RCT on heart failure, colchicine was not associated with improved NYHA class. Conclusion: Colchicine is a valuable anti-inflammatory agent for the prevention of cardiovascular events in patients with inflammatory cardiac conditions such as pericardial diseases, coronary artery disease and atrial fibrillation.

The evidence behind the use of LASER for genitourinary syndrome of menopause, vulvovaginal atrophy, urinary incontinence and lichen sclerosus: A state-of-the-art review.

In recent years, LASER has been introduced as a minimally invasive treatment for a broad range of vaginal and vulvar symptoms and diseases. However, the efficacy and safety of vaginal and vulvar LASER has continuously been questioned. The aim of this study is to create an overview of the current literature and discuss the controversies within the use of LASER for genitourinary syndrome of menopause, vulvovaginal atrophy, urinary incontinence and lichen sclerosus. A search string was built in PubMed. The search was commenced on August 25, 2021 and closed on October 27, 2021. Two authors screened the studies in Covidence for inclusion according to the eligibility criteria in the protocol. The data were extracted from the studies and are reported in both text and tables. This review included 114 papers, of which 15 were randomized controlled trials (RCTs). The effect of LASER as a vaginal treatment was investigated for genitourinary syndrome of menopause in 36 studies (six RCTs), vulvovaginal atrophy in 34 studies (four RCTs) and urinary incontinence in 30 studies (two RCTs). Ten studies (three RCTs) investigated the effect of vulvar treatment for lichen sclerosus. Half of the included RCTs, irrespective of indication, did not find a significant difference in improvement in women treated with vaginal CO2 or Er:YAG LASER compared with their respective controls. However, most non-comparative studies reported significant improvement after exposure to vaginal or vulvar LASER across all indications. Included studies generally had a short follow-up period and only a single RCT followed their participants for more than 6 months post treatment. Adverse events were reported as mild and transient and 99 studies including 51 094 patients provided information of no serious adverse events. In conclusion, this review found that the effect of vaginal and vulvar LASER decreases with higher study quality where potential biases have been eliminated. We therefore stress that all patients who are treated with vaginal or vulvar LASER should be carefully monitored and that LASER for those indications as a treatment should be kept on a research level until further high-quality evidence is available.

Efficacy, tolerability and safety of perampanel in population with pharmacoresistant focal seizures: A systematic review and meta-analysis

BackgroundFocal seizures are associated with various co-morbidities. Seizure disorders also affect the quality of life of the patients. A huge proportion of patients continue to have uncontrolled seizures despite the availability of numerous antiepileptic drugs. Novel therapeutic targets too, have failed to overcome this problem. Therefore, drugs acting on conventional targets are being explored. Perampanel is one such drug. The present study aimed to assess its efficacy, safety, and effect on quality of life and cognition in patients aged 12 years and above. MethodsDatabase search was conducted using keywords perampanel, partial seizures and randomized controlled trials (RCTs). Single and double blinded RCTs were included in the analysis. The primary outcomes assessed were 50% responder rate and seizure freedom rates. Secondary outcomes assessed were Improvement in Clinical Global Improvement for Change (CGI-C), number of patients who experienced adverse events, number of patients who withdrew from trials, adverse drug reaction (ADR) profile from Vigibase, long term safety, quality of Life (QoL) assessment and cognitive assessment, especially in adolescents. The Risk ratios (RR) were calculated for these parameters. Results24 full text articles were obtained out of a total 421 studies. From these seven double blind randomized controlled trials were included in the meta-analysis. Perampanel treated patients showed higher 50% responder rates than those treated with placebo. The Risk Ratios (RRs) were 1.39 [95% confidence interval (CI) 1.08–1.79], 1.83 [95% CI 1.51 – 2.22] and 1.81 [95% CI 1.45–2.27] for the 4 mg per day, 8 mg once daily and 12 mg once daily subgroups of perampanel respectively. The RRs for the seizure freedom rates were 4.52 [95% CI 1.30–15.73], 3.65 [95% CI 1.40–9.52] and 2.14 [95% CI 1.11–4.11] for 4 mg per day, 8 mg once daily and 12 mg once daily subgroups of perampanel respectively. There was a significantly higher risk of TEAEs with the 8 mg and 12 mg doses of perampanel as compared to that with placebo. Number of patients who withdrew from the trials due to adverse events was statistically significant in only the 12 mg subgroup of perampanel in comparison to that with placebo group. ConclusionPerampanel was observed to be an effective add on drug for treating pharmacoresistant focal seizures. The patients achieved higher 50% response rates and freedom from seizures with its use. Tolerability of perampanel was more at lower doses.