Synthesizing Evidence on Adverse Events of Perioperative Clonidine: An Umbrella Review

Shift work is commonly increasing, and some physiological changes occur as workers sleep less and their circadian rhythms are disrupted. This umbrella review not only summarizes the evidence but also evaluates the validity of the associations of shift work with different health outcomes. We searched the MEDLINE, Web of Science, and Embase databases from their inception to April 25, 2020. For each systematic review and/or meta-analysis, we estimated the summary effect size, the 95% confidence interval, the 95% prediction interval, the between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. Eight eligible systematic reviews and meta-analyses were identified, providing data on 16 associations. We observed highly suggestive evidence for associations between shift work and myocardial infarction (having ever vs having never done shift work) and diabetes mellitus incidence (per 5-year increment in shift work). Furthermore, we observed suggestive evidence for an association between shift work and diabetes mellitus incidence (having ever vs having never done shift work). Two health outcomes, including prostate cancer incidence (having ever vs having never done shift work and rotating night shift work vs daytime work) and colorectal cancer incidence (longest vs shortest shift work time), were only supported by weak evidence. This umbrella review found that shift work was associated with several health outcomes with different levels of evidence. Associations for myocardial infarction and diabetes mellitus incidence were supported by highly suggestive evidence. Registry: PROSPERO; Identifier: CRD42020188537. Wu Q-J, Sun H, Wen Z-Y, etal. Shift work and health outcomes: an umbrella review of systematic reviews and meta-analyses of epidemiological studies. J Clin Sleep Med. 2022;18(2):653-662.

A reappraisal of corticosteroids use for COVID-19

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

Multiple meta-analyses (MAs) have demonstrated that six pharmacotherapies, including orlistat, liraglutide, phentermine/topiramate, naltrexone/bupropion, semaglutide, and tirzepatide, improve weight loss and weight maintenance. However, few studies have synthesized and evaluated the quality of this evidence. To identify the relevant MAs of randomized clinical trials (RCTs) that explored the association between the six pharmacotherapies and obesity-related health outcomes and adverse events (AEs). A comprehensive search was conducted across PubMed, Embase, Cochrane Library, and Web of Science from database inception up to January 2024. We calculated the effect size as the mean difference and risk ratio using the random-effects model. The quality of MAs was evaluated using "A Measurement Tool to Assess Systematic Reviews 2". Sixteen MAs comprising 235 RCTs that described 115 unique associations between the six pharmacotherapies and various health outcomes were included. Overall, 101 statistically significant associations (88%) had beneficial outcomes on body weight, weight loss, waist circumference, body mass index, total cholesterol, triglycerides, both low-density and high-density lipoprotein cholesterol, blood pressure, and glycemic profile. The pharmacotherapies were associated with significant weight loss and partial improvements in the lipid profile, blood pressure, and glycemic control among individuals with overweight or obesity. Notable AEs were associated with liraglutide, naltrexone/bupropion, semaglutide, and orlistat. The methodological quality of the included MAs requires improvement. This umbrella review identified significant beneficial associations between pharmacotherapies and anthropometric measures, lipid profile, blood pressure, glycemic profile, and quality-of-life outcomes in individuals with overweight or obesity. In addition, the umbrella review highlighted safety considerations. The findings affirm the efficacy of the six pharmacotherapies in promoting weight loss in this demographic. Further clinical trials with long-term follow-up are essential to evaluate the effects of these pharmacotherapies on clinical outcomes, including cancer, cardiovascular events, and mortality.

Hypertriglyceridemia and hypercholesterolemia are well-known risk factors for atherosclerotic cardiovascular disease (ASCVD), especially in patients already at elevated cardiovascular risk. Despite current treatment approaches, including lifestyle changes and medication, many individuals do not reach ideal lipid levels, emphasizing the need for new therapeutic options. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (ApoC-III) synthesis, has emerged as a promising candidate to reduce residual cardiovascular risk in these patients. This systematic review and meta-analysis aimed to assess the effectiveness and safety of different dosages of Olezarsen in patients with high-risk hypertriglyceridemia. Additionally, it explored whether varying dosage regimens impacted lipid outcomes and adverse events. Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library for randomized controlled trials (RCTs) published in English. The studies included compared different doses of Olezarsen with placebo in high-risk hypertriglyceridemia patients. Primary outcomes were changes in triglycerides (TG), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and treatment-emergent adverse events (TEAE). Secondary outcomes included changes in non-HDL-C and total cholesterol (TC). The data were analyzed as mean differences (MD) or odds ratios (OR) using a random-effects model. Four RCTs (309 participants) were included. The pooled analysis demonstrated significant reductions in TG (MD = -76.11), VLDL-C (MD = -54.95 mg/dL), ApoB (MD = -12.40 mg/dL), non-HDL-C (MD = -18.03 mg/dL), and LDL-C (MD = -10.09 mg/dL) with Olezarsen treatment compared to placebo. Olezarsen also significantly increased HDL-C levels (MD = + 22.60 mg/dL), while total cholesterol remained unchanged. No significant differences in overall adverse events or drug-related adverse events were observed compared to placebo. Subgroup analysis revealed a dose-dependent effect on several lipid parameters without an increase in adverse events with higher doses. Olezarsen effectively improves key lipid parameters, including TG, VLDL-C, ApoB, non-HDL-C, and LDL-C, while also safely raising HDL-C in patients with high-risk hypertriglyceridemia. Total cholesterol remained stable, and no increase in adverse events was noted. Further studies are needed to determine optimal dosing and long-term cardiovascular benefits.

Efficacy and safety of fitusiran prophylaxis in people with haemophilia a or haemophilia B: A systematic review and meta-analysis

There is insufficient evidence to support AT III substitution in any category of critically ill participants including the subset of patients with sepsis and DIC. We did not find a statistically significant effect of AT III on mortality, but AT III increased the risk of bleeding events. Subgroup analyses performed according to duration of intervention, length of follow-up, different patient groups, and use of adjuvant heparin did not show differences in the estimates of intervention effects. The majority of included trials were at high risk of bias (GRADE; very low quality of evidence for most of the analyses). Hence a large RCT of AT III is needed, without adjuvant heparin among critically ill patients such as those with severe sepsis and DIC, with prespecified inclusion criteria and good bias protection.

There is some evidence that case management is beneficial at improving some outcomes at certain time points, both in the person with dementia and in their carer. However, there was considerable heterogeneity between the interventions, outcomes measured and time points across the 13 included RCTs. There was some evidence from good-quality studies to suggest that admissions to care homes and overall healthcare costs are reduced in the medium term; however, the results at longer points of follow-up were uncertain. There was not enough evidence to clearly assess whether case management could delay institutionalisation in care homes. There were uncertain results in patient depression, functional abilities and cognition. Further work should be undertaken to investigate what components of case management are associated with improvement in outcomes. Increased consistency in measures of outcome would support future meta-analysis.

In adult women with PCOS, metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m² to 30 kg/m² but we are uncertain if there was a difference between metformin and the OCP in subgroups BMI < 25 kg/m² and BMI > 30kg/m². Compared to the OCP, metformin may increase the incidence of severe gastro-intestinal adverse events and decrease the incidence of severe other adverse events with no trials reporting on minor adverse events. Either metformin alone or the OCP alone may be less effective in improving hirsutism compared to metformin combined with the OCP. We are uncertain whether there is a difference between the OCP alone and metformin alone compared to metformin combined with the OCP for severe or minor adverse events except for the OCP versus metformin combined with the OCP where the OCP may decrease the incidence of severe and minor gastro-intestinal adverse events. In adolescent women with PCOS, we are uncertain whether there is a difference between any of the comparisons for hirsutism and adverse events due to either no evidence or very low-quality evidence. Further large well-designed RCTs that stratify for BMI are needed to evaluate metformin versus the OCP and combinations in women with PCOS, in particular adolescent women.

Background: Migraine is known to be the most prevalent primary headache in pediatric and adolescent patients, affecting around 28% of teenagers. Besides this, only a limited number of prophylactic treatments have proven effective for these age groups. Melatonin, a hormone primarily produced by the pineal gland, plays an important role in the modulation of the circadian rhythm and has shown effectiveness in preventing migraines in adults in previous studies. However, its efficacy in younger patients remains uncertain. Objective: To assess the safety and efficacy of melatonin for migraine prophylaxis among children and adolescents. Methods: Pubmed, Scopus, Web of Science, and Cochrane databases were systematically searched for randomized controlled trials (RCTs) testing melatonin for migraine prevention in pediatric or adolescent populations. A random-effects model was used to calculate the mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was determined using I² statistics. Efficacy was assessed based on headache frequency, while safety was evaluated by adverse events (AEs), including daily sleepiness, nausea, vomiting, worsened headache, worsened movement sensitivity, elevated heart rate, flu-like symptoms, constipation, fatigue, malaise, and fever. Statistical analysis was conducted using R, version 4.4.0. Results: We included 4 RCTs with 238 patients. The mean age ranged from 9.28 to 15.00 years, with a majority of female patients (55.9%). Compared with the control group, melatonin use was associated with a significant reduction in monthly headache days (MD 2.93 days; 95% CI 0.72-5.14; p=0.009310; I²=65%). Additionally, the meta-analysis showed that the incidence of adverse events in the intervention group was comparable with control, hence, not associated with melatonin use (17.3% vs 24.24%; MD 0.69; 95% CI 0.22-2.12; p=0.518081; I²=37%). Conclusion: This systematic review and meta-analysis suggest that the use of melatonin in younger patients with migraine leads to a reduction in monthly headache frequency. While AEs were reported, their incidence was comparable to the control group, indicating a favorable safety profile.

BACKGROUNDCotadutide (MEDI0382) is a twincretin that acts as an agonist for both the glucagon-like peptide-1 and glucagon receptors. Several randomized controlled trials (RCTs) have been published evaluating the use of cotadutide in individuals with type 2 diabetes (T2D), showing promising results. However, the efficacy and safety of the drug use have been inadequately explored by systematic reviews and meta-analyses.AIMTo assess the clinical efficacy and safety of cotadutide in individuals with T2D having overweight or obesity.METHODSThe systematic reviews and meta-analyses have been registered with International Prospective Register of Systematic Reviews (CRD42024511703), and the protocol summary can be accessed online. Several databases and registries, including MEDLINE (via PubMed), Scopus, Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, were systematically searched using related terms from their inception to May 15, 2025, for RCTs involving individuals with T2D receiving cotadutide in the intervention group. Review Manager web was used to conduct meta-analysis using random-effects models. The co-primary outcomes of interest were the changes in glycated hemoglobin (HbA1c) and the percent changes in body weight from baseline. The results of the outcomes were expressed as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). The analysis of outcomes was stratified according to whether the control group received a placebo, denoted as the placebo control group (PCG), or an active comparator, referred to as the active control group (ACG).RESULTSNine RCTs (mostly phase 2 RCTs, n = 1525) with study durations varying from 28 days to 54 weeks that met all the inclusion criteria were analyzed; five studies had a low overall risk of bias, while the other four had some concerns. Compared to the PCG, greater reductions in HbA1c were achieved with cotadutide 100 μg (MD -0.77%, 95%CI: -1.06 to -0.47), 200 μg (MD -0.68%, 95%CI: -1.12 to -0.23), 300 μg (MD -0.67%, 95%CI: -0.79 to -0.56), and 600 μg (MD -0.69%, 95%CI: -0.97 to -0.41). Cotadutide 100 μg (MD -1.74%, 95%CI: -3.23 to -0.25), 200 μg (MD -2.56%, 95%CI: -3.37 to -1.75), 300 μg (MD -3.49%, 95%CI: -4.14 to -2.84), and 600 μg (MD -5.45%, 95%CI: -7.17 to -3.73) achieved greater percent reductions in body weight from baseline. However, the certainty of evidence for HbA1c and percent body weight reductions was very low to low. Cotadutide, at all doses, also outperformed PCG in reducing fasting plasma glucose and absolute body weight. The changes in HbA1c, percent body weight, fasting plasma glucose, and absolute body weight were similar between the cotadutide group and the ACG. Compared to PCG, pooled doses of cotadutide increased the risks of treatment-emergent adverse events (AEs), treatment-related AEs, and discontinuation of the study drug due to AEs, but not for serious AEs. More subjects experienced overall gastrointestinal AEs, dyspepsia, nausea, vomiting, constipation, and decreased appetite with cotadutide than with PCG. Compared to the ACG, none of the AEs showed increased risk in the cotadutide group.CONCLUSIONCotadutide demonstrated glycemic control and weight-loss benefits in short-term, small RCTs (mostly phase 2). However, small sample sizes, very low to low certainty of evidence, and the absence of data on long-term cardiovascular and renal outcomes highlight substantial uncertainties, warranting cautious interpretation and further investigation in larger, longer-term trials to establish its safety and efficacy profile.

The efficacy and safety of glucagon-like peptide-1 receptor agonists in non-diabetic adults with overweight/obesity: An umbrella review of systematic reviews and meta-analyses.

Renal Denervation for Resistant Hypertension

Role of Antimuscarinics Combined With Alpha-blockers in the Management of Urinary Storage Symptoms in Patients With Benign Prostatic Hyperplasia: An Updated Systematic Review and Meta-analysis.

Background Despite its modest efficacy, guidelines consistently recommend paracetamol as a first-line analgesic for osteoarthritis (OA) based on its perceived safety. However, there is growing controversy, highlighted in the National Institute for Health and Care Excellence OA (NICE) 2014 guidance on OA, that paracetamol is not as safe as previously thought, especially at the highest therapeutic dose of 4gm/day. Objectives To investigate the association between paracetamol and gastrointestinal, liver, renal and cardiovascular adverse events both in randomised controlled trials (RCTs) and observational studies. Methods We systematically searched MEDLINE, EMBASE, PUBMED, AHMED, CINAHL, Web of Science, and Google Scholar for published literature in any language to the end of November 2018 for (1) RCTs of paracetamol in symptomatic OA, and (2) observational studies irrespective of any underlying condition, to determine the risk of gastrointestinal, liver, renal and cardiovascular adverse events. We included studies assessing oral paracetamol in people aged ≥18 years and reporting on clinically relevant adverse effects. Risk ratio (RR) and 95% confidence interval (CI) were estimated for RCT and cohort studies, whereas odds ratio (OR) and 95% CI were used for case-control studies. Results were pooled as appropriate using random effects model. The risk of bias was assessed using modified Cochrane tool for RCTS and Newcastle Ottawa scale for observational studies. Results We reviewed titles and abstracts of 3,622 records in the systematic search (1,997 RCTs and 1,635 observational studies). After examining full papers 23 RCTs (7,863 participants), 15 cohort studies (2,262,517 participants) and 34 case-control studies (441,638 participants) met inclusion criteria. Compared to placebo, paracetamol was associated with increased incidence of treatment-related adverse events (RR 1.35, 95% CI 1.04 to 1.75), especially diarrhoea (RR 2.14, 95% CI 1.35 to 3.37) and abnormal liver function (RR 3.99, 95% CI 2.05 to 7.77). The pooled OR from twelve age and gender matched case-control studies (7894 participants) was 1.36 (95% CI 1.13 to 1.64) for upper gastrointestinal bleeding. In addition, a dose response relationship was observed in a cohort study (382,404 participants) for this outcome. The RR was 1.11 (95% CI 1.04 to 1.21) with low dose paracetamol (measured as medication possession rate) and 1.49 (95% CI 1.29 to 1.71) with high dose paracetamol. Paracetamol was not associated with cardiovascular events in two RCTs (775 participants) (RR 1.27, 95% CI 0.06 to 27.77) and three case-control studies (42,180 participants) (OR 0.97, 95% CI 0.77 to 1.21), but in three cohort studies (208,926 participants) (RR 1.35, 95% CI 1.14 to 1.59). There were insufficient data in RCTs and case-control studies for renal adverse events. However, three cohort studies (7,360 participants) demonstrated a dose response relationship between paracetamol and renal function impairment (defined as ≥30 percentage decrease in estimated glomerular filtration rate). The data of these three cohort studies could not be pooled due to different doses of paracetamol. One cohort study (1697 participants) reported RR of 1.40 (95% CI 0.79 to 2.48) for renal impairment for paracetamol 100-499g, and 2.19 (95% CI 1.4 to 3.43) for paracetamol >3000g. Conclusion Paracetamol is associated with diarrhoea and abnormal liver function in short-term trial data, and with upper GI bleeding and renal impairment in long-term observational data. Methodological limitations of observational data, such as channelling bias, may confound the results. Large-scale well-designed prospective studies are needed to ascertain the long-term safety of paracetamol. Disclosure of Interests Jaspreet Kaur: None declared, Burak Kundaki: None declared, Georgina Nakafero: None declared, Abhishek Abhishek Grant/research support from: AstraZeneca and OxfordImmunotech, Grant/research support from: AstraZeneca and Oxford Immunotech, Speakers bureau: Menarini pharmaceuticals, Speakers bureau: Menarini pharmaceuticals, Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Consultant for: Advisory Boards on Grunenthal and Mallinckrodt, Weiya Zhang Consultant for: Grunenthal for advice on gout management, Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium