Risk Of Non-serious Adverse Events Research Articles

Benefits and Harms of Digital Health Interventions Promoting Physical Activity in People With Chronic Conditions: Systematic Review and Meta-Analysis.

Digital health interventions for managing chronic conditions have great potential. However, the benefits and harms are still unclear. This systematic review and meta-analysis aimed to investigate the benefits and harms of digital health interventions in promoting physical activity in people with chronic conditions. We searched the MEDLINE, Embase, CINAHL, and Cochrane Central Register of Controlled Trials databases from inception to October 2022. Eligible randomized controlled trials were included if they used a digital component in physical activity promotion in adults with ≥1 of the following conditions: depression or anxiety, ischemic heart disease or heart failure, chronic obstructive pulmonary disease, knee or hip osteoarthritis, hypertension, or type 2 diabetes. The primary outcomes were objectively measured physical activity and physical function (eg, walk or step tests). We used a random effects model (restricted maximum likelihood) for meta-analyses and meta-regression analyses to assess the impact of study-level covariates. The risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Of 14,078 hits, 130 randomized controlled trials were included. Compared with usual care or minimal intervention, digital health interventions increased objectively measured physical activity (end of intervention: standardized mean difference [SMD] 0.29, 95% CI 0.21-0.37; follow-up: SMD 0.17, 95% CI 0.04-0.31) and physical function (end of intervention: SMD 0.36, 95% CI 0.12-0.59; follow-up: SMD 0.29, 95% CI 0.01-0.57). The secondary outcomes also favored the digital health interventions for subjectively measured physical activity and physical function, depression, anxiety, and health-related quality of life at the end of the intervention but only subjectively measured physical activity at follow-up. The risk of nonserious adverse events, but not serious adverse events, was higher in the digital health interventions at the end of the intervention, but no difference was seen at follow-up. Digital health interventions improved physical activity and physical function across various chronic conditions. Effects on depression, anxiety, and health-related quality of life were only observed at the end of the intervention. The risk of nonserious adverse events is present during the intervention, which should be addressed. Future studies should focus on better reporting, comparing the effects of different digital health solutions, and investigating how intervention effects are sustained beyond the end of the intervention. PROSPERO CRD42020189028; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=189028.

Cannabinoids versus placebo for pain: A systematic review with meta-analysis and Trial Sequential Analysis.

To assess the benefits and harms of cannabinoids in participants with pain. Systematic review of randomised clinical trials with meta-analysis, Trial Sequential Analysis, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The Cochrane Library, MEDLINE, Embase, Science Citation Index, and BIOSIS. Published and unpublished randomised clinical trials comparing cannabinoids versus placebo in participants with any type of pain. All-cause mortality, pain, adverse events, quality of life, cannabinoid dependence, psychosis, and quality of sleep. We included 65 randomised placebo-controlled clinical trials enrolling 7017 participants. Fifty-nine of the trials and all outcome results were at high risk of bias. Meta-analysis and Trial Sequential Analysis showed no evidence of a difference between cannabinoids versus placebo on all-cause mortality (RR 1.20; 98% CI 0.85 to 1.67; P = 0.22). Meta-analyses and Trial Sequential Analysis showed that cannabinoids neither reduced acute pain (mean difference numerical rating scale (NRS) 0.52; 98% CI -0.40 to 1.43; P = 0.19) or cancer pain (mean difference NRS -0.13; 98% CI -0.33 to 0.06; P = 0.1) nor improved quality of life (mean difference -1.38; 98% CI -11.81 to 9.04; P = 0.33). Meta-analyses and Trial Sequential Analysis showed that cannabinoids reduced chronic pain (mean difference NRS -0.43; 98% CI -0.72 to -0.15; P = 0.0004) and improved quality of sleep (mean difference -0.42; 95% CI -0.65 to -0.20; P = 0.0003). However, both effect sizes were below our predefined minimal important differences. Meta-analysis and Trial Sequential Analysis indicated that cannabinoids increased the risk of non-serious adverse events (RR 1.20; 95% CI 1.15 to 1.25; P < 0.001) but not serious adverse events (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07). None of the included trials reported on cannabinoid dependence or psychosis. Cannabinoids reduced chronic pain and improved quality of sleep, but the effect sizes are of questionable importance. Cannabinoids had no effects on acute pain or cancer pain and increased the risks of non-serious adverse events. The harmful effects of cannabinoids for pain seem to outweigh the potential benefits.

Clinical Practice Guidelines for the Therapeutic Use of Repetitive Transcranial Magnetic Stimulation in Neuropsychiatric Disorders.

Clinical Practice Guidelines for the Therapeutic Use of Repetitive Transcranial Magnetic Stimulation in Neuropsychiatric Disorders.

Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses

ObjectiveTo investigate the effects of fever therapy compared with no fever therapy in a wide population of febrile adults.DesignSystematic review with meta-analyses and trial sequential analyses of randomised clinical trials.Data...

Vaccines to prevent COVID-19: A living systematic review with Trial Sequential Analysis and network meta-analysis of randomized clinical trials.

COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

Recent Clinical Trials Insights into the Treatment of Primary Membranous Nephropathy.

Immunosuppressive therapy is mandatory for primary membranous nephropathy with persistent nephrotic proteinuria or anti-phospholipase A2 receptor antibodies, reduced kidney function, or another risk factor for progression. Rituximab has demonstrated efficacy for proteinuria remission compared with renin-angiotensin system blockade or cyclosporine in two well-powered randomized controlled trials. More recently, STARMEN showed that alternating glucocorticoid-cyclophosphamide is superior to sequential tacrolimus-rituximab for proteinuria remission, although it was associated with a higher risk of non-serious adverse events. However, sequential tacrolimus-rituximab involved delayed lower dose rituximab and was the worst-performing rituximab regimen among those tested in randomized clinical trials. The RI-CYCLO pilot study did not demonstrate superiority of glucocorticoid-cyclophosphamide over rituximab and found no difference in adverse events. Overall, STARMEN and RI-CYCLO confirmed the efficacy of glucocorticoid-cyclophosphamide in patients with high-risk membranous nephropathy and the role of rituximab as a valid alternative. However, none of the trials tested an optimized rituximab protocol involving a second rituximab cycle before declaring treatment failure. Calcineurin inhibitors should be considered third-line drugs and sequential use of calcineurin inhibitor rituximab did not add over rituximab-only regimens. We critically review recent randomized controlled trials, propose a research agenda, and call for multinational pragmatic trials that enroll patients at referral centers to address unmet research needs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-021-01656-1.

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

Minimally Invasive Interventions for Pulmonary Nodule Biopsy - Systematic Review

Background: In the diagnosis of lung cancer, a biopsy should be recommended to confirm malignancy. This study was designed to compare diagnostic yield and safety of different techniques used for pulmonary nodule biopsies. Methods: Systematic review of randomized controlled trials that evaluated minimally invasive methods for lung nodule biopsies, comparing tomography-guided percutaneous biopsy (PERCUT), and transbronchial biopsies guided by fluoroscopy (FLUOR), endobronchial ultrasound with radial probe (EBUSR) or electromagnetic navigation (NAVIG). The certainty of evidence was assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Findings: Seven RCTs (randomized controlled trials) were included (total of 913 participants, 39·1% female, mean age 59·28 years). All RCTs were classified as high risk of bias. The certainty of evidence was considered low or very low according to GRADE system. For PERCUT versus FLUOR, PERCUT versus EBUSR, FLUOR versus NAVIG, and EBUSR versus NAVIG comparisons, there was no difference regarding diagnostic yield and need of approach by another technique. There were similar findings for the safety outcomes, however in the comparison between PERCUT versus EBUSR, there was greater risk of non-serious adverse events with PERCUT. In the comparison between FLUOR versus EBUSR, there was clinically relevant benefit in favor of EBUSR in diagnostic yield, need for another technique approach and risk of serious adverse events. Interpretation: In this review, there was no significant difference in the comparison between the diagnostic yield and safety in most of the interventions. There is insufficient current evidence to recommend one method over another, and therefore the potential risks and benefits must be presented to patients for a shared decision on the method. Clinical Trial Registration Details: The protocol was prospectively registered in the PROSPERO database (CRD42018092367, available from https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=92367). Funding Information: None. Declaration of Interests: None.

Vaccines to Prevent COVID-19:&amp;nbsp;A Living Systematic Review With Trial Sequential Analysis and Network Meta-Analysis of Randomised Controlled Trials

Background: COVID-19 is a rapidly spreading disease that is causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. Several vaccines have been accepted by regulatory authorities, but their individual and relative efficacy and adverse effects remain unclear.Methods: We conducted a systematic review of randomised clinical trials with network meta-analysis and Trial Sequential Analysis (TSA). Searches were made in CENTRAL, MEDLINE, Embase, and other sources from inception to May 12, 2021 for randomised clinical trials, assessing vaccines for COVID-19 . At least two independent reviewers screened studies, extracted data, and assessed the risk of bias. Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events.Findings We identified 22 trials; 19 trials randomising 144 434 participants were included in our analyses. mRNA vaccines (efficacy 95%, 95% confidence interval (CI) 92% to 97%; 69 285 participants; 2 trials; GRADE: moderate certainty) and viral vector vaccines (efficacy 68%, 95% CI 61% to 74%; 71 401 participants; 5 trials; GRADE: low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio (RR) 0·25, 95% CI 0·09 to 0·67; 67 563 participants; 3 trials, GRADE: low certainty), but data on mRNA vaccines are still imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence indicated rare serious adverse events. mRNA and viral vector vaccines increased the risk of non-serious adverse events. Interpretation The evidence suggests that mRNA vaccines and viral vector vaccines are effective in preventing COVID-19. mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. mRNA vaccines and viral vector vaccines increase the risks of rare serious adverse events according to observational evidence. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines. Registration Information: PROSPERO CRD42020196492. Funding Information: The Copenhagen Trial Unit funded the wages for the authors affiliated with the Copenhagen Trial Unit. None of the authors received any specific funding related to the review. Declaration of Interests: The authors declare that they have no known competing interests.

90 Intranasal Ketamine for Acute Pain Management in Children: A Systematic Review and Meta-analysis

We conducted a systematic review and meta-analysis to assess the efficacy and safety of intranasal (IN) analgesic-dose ketamine as compared to IN fentanyl for pediatric acute pain management in the emergency department (ED). We searched PubMed, Embase, and Scopus for randomized controlled trials from inception to December 2019 without language restrictions. Reference lists of articles were hand searched. We conducted a meta-analysis and random-effects models to evaluate efficacy (pain reduction and rescue analgesia) and safety outcomes (rates of adverse events and sedation). We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method to evaluate the quality of evidence for each outcome. A total of 546 studies were screened and 56 selected for full-text review. A total of 4 randomized controlled trials were included. In the meta-analysis of 4 studies, IN ketamine had similar reductions in pain scores from baseline to all post-intervention times (10 to 15 minutes: weighted mean difference [WMD] -1.42, 95% confidence interval [CI] -9.95 to 7.10; 30 minutes: WMD 0.40, CI -6.29 to 7.10; 60 minutes: WMD 0.64, CI -6.76 to 5.47). The use of IN ketamine was associated with similar rates of rescue analgesia when compared to fentanyl (RR 0.74, CI 0.44 to 1.25). IN ketamine had a higher risk of non-serious adverse events (RR 2.00, CI 1.43 to 2.79), and no patients receiving ketamine had a serious adverse event. There was one serious adverse event (hypotension) in the fentanyl group that self-resolved. No patients receiving either IN fentanyl or ketamine had significant sedation (University of Michigan Sedation Score > 2). The certainty in the pooled estimates was deemed to be “High” for all outcomes except for the outcome of rescue analgesia, which was downgraded because of imprecision given its wide confidence interval. Intranasal analgesic-dose ketamine was found to be as efficacious as IN fentanyl in regards to pain reduction at all time points. Ketamine was associated with higher rates of non-serious adverse events. Intranasal analgesic-dose ketamine may be considered as an opioid alternative for acute pain management in children.

Effects of adding ivabradine to usual care in patients with angina pectoris: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis

ObjectiveTo determine the impact of ivabradine on outcomes important to patients with angina pectoris caused by coronary artery disease.MethodsWe conducted a systematic review. We included randomised clinical trials comparing ivabradine...

Acetyl-L-carnitine for patients with hepatic encephalopathy.

Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. Ammonia content in the blood seems to play a role in the development of hepatic encephalopathy. Treatment for hepatic encephalopathy is complex. Acetyl-L-carnitine is a substance that may reduce ammonia toxicity. This review assessed the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. To assess the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, and Science Citation Index Expanded for randomised clinical trials. We sought additional randomised clinical trials from the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. We performed all electronic searches until 10 September 2018. We looked through the reference lists of retrieved publications and review articles, and we searched the FDA and EMA websites. We searched for randomised clinical trials in any setting, recruiting people with hepatic encephalopathy. Trials were eligible for inclusion if they compared acetyl-L-carnitine plus standard care (e.g. antibiotics, lactulose) versus placebo or no acetyl-L-carnitine plus standard care. We are well aware that by selecting randomised clinical trials, we placed greater focus on potential benefits than on potential harms. We selected randomised clinical trials, assessed risk of bias in eight domains, and extracted data in a duplicate and independent fashion. We estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We measured statistical heterogeneity using I² and D² statistics. We subjected our analyses to fixed-effect and random-effects model meta-analyses. We assessed bias risk domains to control systematic errors. We assessed overall quality of the data for each individual outcome by using the GRADE approach. We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry.None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated. This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements.

Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.

Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.

Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices.

Non-selective beta-blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non-selective beta-blocker with additional intrinsic alpha1-blocking effects, which may be superior to traditional, non-selective beta-blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. To assess the beneficial and harmful effects of carvedilol compared with traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. We combined searches in the Cochrane Hepato-Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. We included randomised clinical trials comparing carvedilol versus traditional, non-selective beta-blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the quality of the evidence with GRADE. Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low-quality evidence). There appeared to be no differences between carvedilol versus traditional, non-selective beta-blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low-quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low-quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long-term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non-selective beta-blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non-serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low-quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non-selective beta-blockers both in absolute (MD -1.75 mmHg, 95% CI -2.60 to -0.89; 368 participants; 6 trials; I2 = 0%; low-quality evidence) and percentage terms (MD -8.02%, 95% CI -11.49% to -4.55%; 368 participants; 6 trials; I2 = 0%; low-quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low-quality evidence) or in clinical outcomes. We found no clear beneficial or harmful effects of carvedilol versus traditional, non-selective beta-blockers on mortality, upper gastrointestinal bleeding, serious or non-serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

Anabolic steroids for treating pressure ulcers.

Pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localised injury to the skin or underlying tissue, or both. The ulcers usually arise over a bony prominence, and are recognised as a common medical problem affecting people confined to a bed or wheelchair for long periods of time. Anabolic steroids are used as off-label drugs (drugs which are used without regulatory approval) and have been used as adjuvants to usual treatment with dressings, debridement, nutritional supplements, systemic antibiotics and antiseptics, which are considered to be supportive in healing of pressure ulcers. Anabolic steroids are considered because of their ability to stimulate protein synthesis and build muscle mass. Comprehensive evidence is required to facilitate decision making, regarding the benefits and harms of using anabolic steroids. To assess the effects of anabolic steroids for treating pressure ulcers. In March 2017 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. Published or unpublished randomised controlled trials (RCTs) comparing the effects of anabolic steroids with alternative treatments or different types of anabolic steroids in the treatment of pressure ulcers. Two review authors independently carried out study selection, data extraction and risk of bias assessment. The review contains only one trial with a total of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV. The participants were mainly male (98.2%, 106/108) with a mean age of 58.4 (standard deviation 10.4) years in the oxandrolone group and were all male (100%, 104/104) with a mean age of 57.3 (standard deviation 11.6) years in the placebo group. This trial compared oxandrolone (20 mg/day, administered orally) with a dose of placebo (an inactive substance consisting of 98% starch and 2% magnesium stearate) and reported data on complete healing of ulcers and adverse events. There was very low-certainty evidence on the relative effect of oxandrolone on complete ulcer healing at the end of a 24-week treatment period (risk ratio RR) 0.81, 95% confidence interval (CI) 0.52 to 1.26) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, we are uncertain whether oxandrolone improves or reduces the complete healing of pressure ulcers, as we assessed the certainty of the evidence as very low.There was low-certainty evidence on the risk of non-serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 3.85, 95% CI 1.12 to 13.26) (downgraded once for imprecision and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, the treatment with oxandrolone may increase the risk of non-serious adverse events reported in participants.There was very low-certainty evidence on the risk of serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 0.54, 95% CI 0.25 to 1.17) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Of the five serious adverse events reported in the oxandrolone-treated group, none were classed by the trial teams as being related to treatment. We are uncertain whether oxandrolone increases or decreases the risk of serious adverse events as we assessed the certainty of the evidence as very low.Secondary outcomes such as pain, length of hospital stay, change in wound size or wound surface area, incidence of different type of infection, cost of treatment and quality of life were not reported in the included trial.Overall the evidence in this study was of very low quality (downgraded for imprecision and indirectness). This trial stopped early when the futility analysis (interim analysis) in the opinion of the study authors showed that oxandrolone had no benefit over placebo for improving ulcer healing. There is no high quality evidence to support the use of anabolic steroids in treating pressure ulcers.Further well-designed, multicenter trials, at low risk of bias, are necessary to assess the effect of anabolic steroids on treating pressure ulcers, but careful consideration of the current trial and its early termination are required when planning future research.

Ranolazine for stable angina pectoris.

Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin. Ranolazine is a second-line anti-anginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance. To assess the effects of ranolazine on cardiovascular and non-cardiovascular mortality, all-cause mortality, quality of life, acute myocardial infarction incidence, angina episodes frequency and adverse events incidence in stable angina patients, used either as monotherapy or as add-on therapy, and compared to placebo or any other anti-anginal agent. We searched CENTRAL, MEDLINE, Embase and the Conference Proceedings Citation Index - Science in February 2016, as well as regional databases and trials registers. We also screened reference lists. Randomised controlled trials (RCTs) which directly compared the effects of ranolazine versus placebo or other anti-anginals in people with stable angina pectoris were eligible for inclusion. Two authors independently selected studies, extracted data and assessed risk of bias. Estimates of treatment effects were calculated using risk ratios (RR), mean differences (MD) and standardised mean differences (SMD) with 95% confidence intervals (CI) using a fixed-effect model. Where we found statistically significant heterogeneity (Chi² P < 0.10), we used a random-effects model for pooling estimates. Meta-analysis was not performed where we found considerable heterogeneity (I² ≥ 75%). We used GRADE criteria to assess evidence quality and the GRADE profiler (GRADEpro GDT) to import data from Review Manager 5.3 to create 'Summary of findings' tables. We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear.For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence).For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence). We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.

Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children.

People with asthma may experience exacerbations or "attacks" during which their symptoms worsen and additional treatment is required. Written action plans may advocate doubling the dose of inhaled steroids in the early stages of an asthma exacerbation to reduce the severity of the attack and to prevent the need for oral steroids or hospital admission. To compare the clinical effectiveness and safety of increased versus stable doses of inhaled corticosteroids (ICS) as part of a patient-initiated action plan for home management of exacerbations in children and adults with persistent asthma. We searched the Cochrane Airways Group Specialised Register, which is derived from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) to March 2016. We handsearched respiratory journals and meeting abstracts. We included randomised controlled trials (RCTs) that compared increased versus stable doses of ICS for home management of asthma exacerbations. We included studies of children or adults with persistent asthma who were receiving daily maintenance ICS. Two review authors independently selected trials, assessed quality and extracted data. We contacted authors of RCTs for additional information. This review update added three new studies including 419 participants to the review. In total, we identified eight RCTs, most of which were at low risk of bias, involving 1669 participants with mild to moderate asthma. We included three paediatric (n = 422) and five adult (n = 1247) studies; six were parallel-group trials and two had a cross-over design. All but one study followed participants for six months to one year. Allowed maintenance doses of ICS varied in adult and paediatric studies, as did use of concomitant medications and doses of ICS initiated during exacerbations. Investigators gave participants a study inhaler containing additional ICS or placebo to be started as part of an action plan for treatment of exacerbations.The odds of treatment failure, defined as the need for oral corticosteroids, were not significantly reduced among those randomised to increased ICS compared with those taking their usual stable maintenance dose (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.68 to 1.18; participants = 1520; studies = 7). When we analysed only people who actually took their study inhaler for an exacerbation, we found much variation between study results but the evidence did not show a significant benefit of increasing ICS dose (OR 0.84, 95% CI 0.54 to 1.30; participants = 766; studies = 7). The odds of having an unscheduled physician visit (OR 0.96, 95% CI 0.66 to 1.41; participants = 931; studies = 3) or acute visit (Peto OR 0.98, 95% CI 0.24 to 3.98; participants = 450; studies = 3) were not significantly reduced by an increased versus stable dose of ICS, and evidence was insufficient to permit assessment of impact on the duration of exacerbation; our ability to draw conclusions from these outcomes was limited by the number of studies reporting these events and by the number of events included in the analyses. The odds of serious events (OR 1.69, 95% CI 0.77 to 3.71; participants = 394; studies = 2) and non-serious events, such as oral irritation, headaches and changes in appetite (OR 2.15, 95% CI 0.68 to 6.73; participants = 142; studies = 2), were neither increased nor decreased significantly by increased versus stable doses of ICS during an exacerbation. Too few studies are available to allow firm conclusions on the basis of subgroup analyses conducted to investigate the impact of age, time to treatment initiation, doses used, smoking history and the fold increase of ICS on the magnitude of effect; yet, effect size appears similar in children and adults. Current evidence does not support increasing the dose of ICS as part of a self initiated action plan to treat exacerbations in adults and children with mild to moderate asthma. Increased ICS dose is not associated with a statistically significant reduction in the odds of requiring rescue oral corticosteroids for the exacerbation, or of having adverse events, compared with a stable ICS dose. Wide confidence intervals for several outcomes mean we cannot rule out possible benefits of this approach.

Methylphenidate for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.

Is treatment with methylphenidate associated with benefits or harms for children and adolescents with attention-deficit/hyperactivity disorder (ADHD)? Methylphenidate is associated with improvement in ADHD symptoms, general behavior, and quality of life; however, due to the very low quality of the evidence, the magnitude of the associated improvement is uncertain. Methylphenidate was associated with an increased risk of nonserious adverse events. There are too few data to assess the association with serious adverse events.

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials

Study question Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents?Methods Electronic databases were searched up to February 2015 for parallel and crossover...