Background/Objectives: Emerging evidence suggests an association between glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors with altered risk of damage in the inner ear system. However, limited research exists on the relationship between these medications and subsequent irreversible hearing loss. We conducted this network meta-analysis (NMA) to evaluate the comparative risk of hearing loss associated with such medications. Methods: In this NMA, we used a confirmatory approach to specifically focus on particular adverse effects of interest (i.e., incidence of hearing loss here) based on the Cochrane recommendation. A Bayesian-based NMA of randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors was conducted. The primary outcome was the hearing loss events. Results: Our NMA of 29 RCTs with 145,895 participants found that only two exendin-4 derivatives-lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week)-showed increased hearing loss events compared to controls. No other GLP-1 receptor agonists or SGLT2 inhibitors demonstrated significantly elevated hearing loss risk. Lixisenatide ranked highest in risk among all investigated regimens. Conclusions: This comprehensive NMA identifies a significant association between exendin-4 derivatives (lixisenatide and efpeglenatide) and potential ototoxicity. Clinicians should carefully consider this potential ototoxicity when prescribing exendin-4 derivatives, particularly in patients with pre-existing hearing loss risk factors.

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies.

We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA.

Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.

This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease.

PROSPERO CRD42021252381.

Despite the high lifetime prevalence and elevated disability rates, treatments for obsessive-compulsive disorder (OCD) have limited efficacy. Considering the abnormal connectivity in the cortical-striatal-thalamic-cortical loop circuits in OCD, several randomized controlled trials (RCTs) have addressed the efficacy of different non-invasive brain stimulation (NIBS) modalities for the management of OCD. However, these RCTs yielded inconclusive results.

This network meta-analysis (NMA) included RCTs of NIBS interventions, such as transcranial direct current stimulation (tDCS) and various repetitive transcranial magnetic stimulation (rTMS), in OCD patients. The primary outcomes were changes in the overall severity of OCD and acceptability (i.e., dropout rates).

This NMA of 34 eligible RCTs (1089 participants) and 24 different NIBS interventions revealed that three NIBS interventions significantly improved overall OCD severity compared with sham controls, which were high-frequency rTMS over the dorsolateral prefrontal cortex (DLPFC) [mean difference (MD) = -10.81, 95% confidence intervals (95% CIs) = -20.80 to -0.82], high-frequency deep TMS over the dorsal medial prefrontal cortex/anterior cingulate cortex (dmPFC/ACC) (MD = -9.74, 95% CIs = -16.42 to -3.06), and low-frequency rTMS over the right DLPFC (MD = -4.70, 95% CIs = -8.84 to -0.57).

This study highlighted that excitatory stimulation over the dmPFC/ACC and bilateral DLPFC, or inhibitory stimulation over the right DLPFC, was associated with significant improvements in overall OCD severity. Further large-scale RCTs with longer follow-up periods are needed to investigate the true impact of NIBS-based intervention to manage OCD.

PROSPERO: CRD42023394953.

Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Alendronate belongs to the bisphosphonate class of drugs, which inhibit bone resorption by interfering with the activity of osteoclasts (bone cells that break down bone tissue). This is an update of a Cochrane review first published in 2008.

To assess the benefits and harms of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively.

We searched Evidence-Based Medicine Reviews (which includes CENTRAL), MEDLINE, Embase, two trial registers, drug approval agency websites, and the bibliographies of relevant systematic reviews to identify the studies included in this review. The latest search date was 01 February 2023. We imposed no restrictions on language, date, form of publication, or reported outcomes.

We included only randomized controlled trials that assessed the effects of alendronate on postmenopausal women. Targeted participants must have received at least one year of alendronate. We classified a study as secondary prevention if its population met one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (-2.5 or lower), and 75 years old or older. If a study population met none of those criteria, we classified it as a primary prevention study.

Our major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events.

We used the Cochrane risk of bias 1 tool.

We used standard methodological procedures expected by Cochrane. Based on the previous review experience, in which the clinical and methodological characteristics in the primary and secondary prevention studies were homogeneous, we used a fixed-effect model for meta-analysis and estimated effects using the risk ratio (RR) for dichotomous outcomes. Our base case analyses included all eligible placebo-controlled studies with usable data. We selected the data available for the longest treatment period. We consider a relative change exceeding 15% as clinically important.

We included 119 studies, of which 102 studies provided data for quantitative synthesis. Of these, we classified 34 studies (15,188 participants) as primary prevention and 68 studies (29,577 participants) as secondary prevention. We had concerns about risks of bias in most studies. Selection bias was the most frequently overlooked domain, with only 20 studies (19%) describing appropriate methods for both sequence generation and allocation concealment. Eight studies (8%) were at low risk of bias in all seven domains.

The base case analyses included 16 primary prevention studies (one to five years in length; 10,057 women) and 20 secondary prevention studies (one to three years in length; 7375 women) which compared alendronate 10 mg/day (or 70 mg/week) to placebo, no treatment, or both. Indirectness, imprecision, and risk of bias emerged as the main factors contributing to the downgrading of the certainty of the evidence. For primary prevention, alendronate may lead to a clinically important reduction in clinical vertebral fractures (16/1190 in the alendronate group versus 24/926 in the placebo group; RR 0.45, 95% confidence interval [CI] 0.25 to 0.84; absolute risk reduction [ARR] 1.4% fewer, 95% CI 1.9% fewer to 0.4% fewer; low-certainty evidence) and non-vertebral fractures (RR 0.83, 95% CI 0.72 to 0.97; ARR 1.6% fewer, 95% CI 2.6% fewer to 0.3% fewer; low-certainty evidence). However, clinically important differences were not observed for the following outcomes: hip fractures (RR 0.76, 95% CI 0.43 to 1.32; ARR 0.2% fewer, 95% CI 0.4% fewer to 0.2% more; low-certainty evidence); wrist fractures (RR 1.12, 95% CI 0.84 to 1.49; ARR 0.3% more, 95% CI 0.4% fewer to 1.1% more; low-certainty evidence); withdrawals due to adverse events (RR 1.03, 95% CI 0.89 to 1.18; ARR 0.2% more, 95% CI 0.9% fewer to 1.5% more; low-certainty evidence); and serious adverse events (RR 1.08, 95% CI 0.82 to 1.43; ARR 0.5% more, 95% CI 1.2% fewer to 2.8% more; low-certainty evidence). For secondary prevention, alendronate probably results in a clinically important reduction in clinical vertebral fractures (24/1114 in the alendronate group versus 51/1055 in the placebo group; RR 0.45, 95% CI 0.28 to 0.73; ARR 2.7% fewer, 95% CI 3.5% fewer to 1.3% fewer; moderate-certainty evidence). It may lead to a clinically important reduction in non-vertebral fractures (RR 0.80, 95% CI 0.64 to 0.99; ARR 2.8% fewer, 95% CI 5.1% fewer to 0.1% fewer; low-certainty evidence); hip fractures (RR 0.49, 95% CI 0.25 to 0.96; ARR 1.0% fewer, 95% CI 1.5% fewer to 0.1% fewer; low-certainty evidence); wrist fractures (RR 0.54, 95% CI 0.33 to 0.90; ARR 1.8% fewer, 95% CI 2.6% fewer to 0.4% fewer; low-certainty evidence); and serious adverse events (RR 0.75, 95% CI 0.59 to 0.96; ARR 3.5% fewer, 95% CI 5.8% fewer to 0.6% fewer; low-certainty evidence). However, the effects of alendronate for withdrawals due to adverse events are uncertain (RR 0.95, 95% CI 0.78 to 1.16; ARR 0.4% fewer, 95% CI 1.7% fewer to 1.3% more; very low-certainty evidence). Furthermore, the updated evidence for the safety risks of alendronate suggests that, irrespective of participants' risk of fracture, alendronate may lead to little or no difference for gastrointestinal adverse events. Zero incidents of osteonecrosis of the jaw and atypical femoral fracture were observed.

For primary prevention, compared to placebo, alendronate 10 mg/day may reduce clinical vertebral and non-vertebral fractures, but it might make little or no difference to hip and wrist fractures, withdrawals due to adverse events, and serious adverse events. For secondary prevention, alendronate probably reduces clinical vertebral fractures, and may reduce non-vertebral, hip, and wrist fractures, and serious adverse events, compared to placebo. The evidence is very uncertain about the effect of alendronate on withdrawals due to adverse events.

This Cochrane review had no dedicated funding.

This review is an update of the previous review (DOI: 10.1002/14651858.CD001155).

Meta-analyses examining dichotomous outcomes often include single-zero studies, where no events occur in intervention or control groups. These pose challenges, and several methods have been proposed to address them. A fixed continuity correction method has been shown to bias estimates, but it is frequently used because sometimes software (e.g., RevMan software in Cochrane reviews) uses it as a default. We aimed to empirically compare results using the continuity correction with those using alternative models that do not require correction. To this aim, we reanalyzed the original data from 885 meta-analyses in Cochrane reviews using the following methods: (i) Mantel-Haenszel model with a fixed continuity correction, (ii) random effects inverse variance model with a fixed continuity correction, (iii) Peto method (the three models available in RevMan), (iv) random effects inverse variance model with the treatment arm continuity correction, (v) Mantel-Haenszel model without correction, (vi) logistic regression, and (vii) a Bayesian random effects model with binominal likelihood. For each meta-analysis we calculated ratios of odds ratios between all methods, to assess how the choice of method may impact results. Ratios of odds ratios <0.8 or <1.25 were seen in ~30% of the existing meta-analyses when comparing results between Mantel-Haenszel model with a fixed continuity correction and either Mantel-Haenszel model without correction or logistic regression. We concluded that injudicious use of the fixed continuity correction in existing Cochrane reviews may have substantially influenced effect estimates in some cases. Future updates of RevMan should incorporate less biased statistical methods.

Lung cancer is a cancer of the elderly, with a median age at diagnosis of 71. More than one-third of people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) are special antibodies that target a pathway in the immune system called the programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway. These antibodies help the immune system fight cancer cells by blocking signals that cancer cells use to avoid being attacked by the immune system. ICIs have changed the treatment of people with lung cancer. In particular, for people with previously-untreated advanced non-small cell lung cancer (NSCLC), current first-line treatment now comprises ICIs plus platinum-based chemotherapy, rather than platinum-based chemotherapy alone, regardless of their PD-L1 expression status. However, as people age, their immune system changes, becoming less effective in its T cell responses. This raises questions about how well ICIs work in older adults.

To assess the effects of immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy compared to platinum-based chemotherapy (with or without bevacizumab) in treatment-naïve adults aged 65 years and older with advanced NSCLC.

We searched the Cochrane Lung Cancer Group Trial Register, CENTRAL, MEDLINE, Embase, two other trial registers, and the websites of drug regulators. The latest search date was 23 August 2023. We also checked references and searched abstracts from the meetings of seven cancer organisations from 2019 to August 2023.

We included randomised controlled trials (RCTs) that reported on the efficacy and safety of adding ICIs to platinum-based chemotherapy compared to platinum-based chemotherapy alone for people 65 years and older who had not previously been treated. All data emanated from international multicentre studies involving adults with histologically-confirmed advanced NSCLC who had not received any previous systemic anticancer therapy for their advanced disease.

We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival and treatment-related adverse events (grade 3 or higher). Our secondary outcomes were progression-free survival, objective response rate, time to response, duration of response, and health-related quality of life (HRQoL).

We included 17 primary studies, with a total of 4276 participants, in the review synthesis. We identified nine ongoing studies, and listed one study as 'awaiting classification'. Twelve of the 17 studies included people older than 75 years, accounting for 9% to 13% of their participants. We rated some studies as having 'some concerns' for risk of bias arising from the randomisation process, deviations from the intended interventions, or measurement of the outcome. The overall GRADE rating for the certainty of the evidence ranged from moderate to low because of the risk of bias, imprecision, or inconsistency. People aged 65 years and older The addition of ICIs to platinum-based chemotherapy probably increased overall survival compared to platinum-based chemotherapy alone (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.70 to 0.88; 8 studies, 2093 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events may not differ between the two treatment groups (risk ratio (RR) 1.09, 95% CI 0.89 to 1.32; 1 study, 127 participants; low-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improves progression-free survival (HR 0.61, 95% CI 0.54 to 0.68; 7 studies, 1885 participants; moderate-certainty evidence). People aged 65 to 75 years, inclusive The addition of ICIs to platinum-based chemotherapy probably improved overall survival compared to platinum-based chemotherapy alone (HR 0.75, 95% CI 0.65 to 0.87; 6 studies, 1406 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events probably increased in people treated with ICIs plus platinum-based chemotherapy compared to those treated with platinum-based chemotherapy alone (RR 1.47, 95% CI 1.02 to 2.13; 1 study, 97 participants; moderate-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improved progression-free survival (HR 0.64, 95% CI 0.57 to 0.73; 8 studies, 1466 participants; moderate-certainty evidence). People aged 75 years and older There may be no difference in overall survival in people treated with ICIs combined with platinum-based chemotherapy compared to platinum-based chemotherapy alone (HR 0.90, 95% CI 0.70 to 1.16; 4 studies, 297 participants; low-certainty evidence). No data on treatment-related adverse events were available in this age group. The effect of combination ICI and platinum-based chemotherapy on progression-free survival is uncertain (HR 0.83, 95% CI 0.51 to 1.36; 3 studies, 226 participants; very low-certainty evidence). Only three studies assessed the objective response rate. For time to response, duration of response, and health-related quality of life, we do not have any evidence yet.

Compared to platinum-based chemotherapy alone, adding ICIs to platinum-based chemotherapy probably leads to higher overall survival and progression-free survival, without an increase in treatment-related adverse events (grade 3 or higher), in people 65 years and older with advanced NSCLC. These data are based on results from studies dominated by participants between 65 and 75 years old. However, the analysis also suggests that the improvements reported in overall survival and progression-free survival may not be seen in people older than 75 years.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness and safety of immune checkpoint inhibitors (ICI) as monotherapy or in combination compared to standard of care for elderly people (≥ 65 years) with non-small cell lung cancer (NSCLC).

Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management.

We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason).

We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity.

This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms.

PROSPERO CRD42023391562.

Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts - bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate's effects on postmenopausal women stratified by fracture risk (low versus high).

To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively.

We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023.

We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention.

We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study.

Thirty studies met the review's eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies. We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain. The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here. For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies. For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate's effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies.

This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.

Sepsis is a critical medical condition associated with high mortality for patients. Current pharmacological strategies for sepsis management or prevention had not achieved satisfactory results. The omega-3 fatty acids, with anti-inflammatory benefits, are considered to be promising agents for sepsis management/prevention. The aim of this network meta-analysis (NMA) is to compare the efficacy of various dosages and formulations of fish oil supplements for sepsis management and sepsis prevention. The current NMA consisted of two parts: (1) sepsis management and (2) sepsis prevention. The PubMed, ClinicalKey, Embase, ProQuest, Cochrane CENTRAL, ScienceDirect, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of February 22nd, 2024 for relevant randomized controlled trials (RCTs). RCTs were eligible for inclusion if they enrolled participants with a diagnosis of sepsis or who with high risk for sepsis. All NMA procedures were conducted under the frequentist model. The primary outcomes assessed are (1) mortality rate in sepsis treatment or (2) incidence of sepsis in sepsis prevention. Our NMA, based on 28 RCTs and 1718 participants (mean age=51.6 years, mean female proportion=35.6 %), showed that (1) high dose parenteral fish oil supplement yield the lowest mortality rate in sepsis management in adult patients, and (2) high dose enteral fish oil supplement yield the lowest incidence of sepsis in pediatric patients. This study provides compelling evidence that high-dose fish oil supplements provide beneficial effects for both sepsis management and sepsis prevention. Our findings provide a preliminary rationale for future large-scale RCTs to investigate the role of fish oil supplementation in sepsis management or prevention.

Several observational studies have reported acute kidney injury from intravitreal anti-vascular endothelial growth factor (anti-VEGF) drugs for retinal diseases. However, systematic reviews and meta-analyses of randomized controlled trials on this critical topic are scant.

To evaluate acute kidney injury risk associated with intravitreal anti-VEGF drugs in patients with retinal diseases.

We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials on 12 July, 2023, and included randomized controlled trials reporting acute kidney injury between anti-VEGF drugs (e.g., aflibercept, bevacizumab, brolucizumab, and ranibizumab) and controls for retinal diseases (e.g., age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic retinopathy/diabetic macular edema, retinal vein occlusion, and myopic choroidal neovascularization). Data were synthesized by a fixed-effects model for pooling odds ratios (ORs) using the Peto method.

We included 13 randomized controlled trials (four and nine trials for aflibercept and ranibizumab, respectively) with a total of 4282 participants. The meta-analysis indicated intravitreal anti-VEGF drugs did not increase the acute kidney injury risk, compared with controls (odds ratio [OR]: 1.00, 95% confidence interval [CI] 0.49-2.04, I2: 0%), and no differences in the acute kidney injury risk were observed between different anti-VEGF drugs (OR: 1.10, 95% CI 0.27-4.43, I2: 0% for aflibercept; OR: 0.97, 95% CI 0.42-2.22, I2: 0% for ranibizumab) and between different retinal diseases (OR: 4.61, 95% CI 0.07-284.13, I2: not applicable for age-related macular degeneration; OR: 0.90, 95% CI 0.42-1.93, I2: 0% for diabetic retinopathy/diabetic macular edema; OR: 1.57, 95% CI 0.16-15.88, I2: 0% for retinal vein occlusion).

Intravitreal anti-VEGF drugs were not associated with an acute kidney injury risk, regardless of which anti-VEGF drugs (aflibercept or ranibizumab) or retinal diseases (age-related macular degeneration, diabetic retinopathy/diabetic macular edema, or retinal vein occlusion) were involved.

PROSPERO CRD42021267854.

Sarcopenia frequently occurs with aging and leads to major adverse impacts on activities of daily living and quality of life in elderly individuals. Omega-3 polyunsaturated fatty acid (omega-3 PUFAs) supplements are considered promising therapeutic agents for sarcopenia management; however, the evidence remains inconsistent. We reviewed randomized controlled trials (RCTs) about omega-3 PUFA supplementation in patients with sarcopenia or in those at high risk for sarcopenia. Network meta-analysis (NMA) procedures were conducted using a frequentist model. The primary outcomes were (1) upper-extremity muscle strength and (2) lower-extremity physical function. The NMA of 16 RCTs showed that the high-dose (more than 2.5 g/day omega-3 PUFAs) group yielded the greatest improvement in both upper-extremity muscle strength and lower-extremity physical function [compared to placebo/standard care groups, standardized mean difference (SMD)= 1.68, 95% confidence interval (95%CI)= 0.03-3.33, and SMD= 0.73, 95%CI= 0.16-1.30, respectively], and the effects were reaffirmed in subgroup analyses of placebo-controlled RCTs or those excluding concurrent resistance training programs. None of the investigated omega-3 PUFAs supplementation was associated with significantly increased skeletal muscle mass, fat mass, or overall body weight. Our findings provide a basis for future large-scale RCTs to investigate the dose effects and clinical application of omega-3 PUFA supplementation in sarcopenia management. TRIAL REGISTRATION: The current study was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (TSGHIRB No. B-109-29) and registered in PROSPERO (CRD42022347161).

Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories. However, in contrast to ordinary migraine, vestibular migraine patients have distinct characteristics, and the detailed treatment strategy for vestibular migraine is different and more challenging than ordinary migraine treatment. Currently, there is no conclusive evidence regarding its management, including vestibular migraine prophylaxis.

The objective of this current network meta-analysis (NMA) was to compare the efficacy and acceptability of individual treatment strategies in patients with vestibular migraine.

The PubMed, Embase, ScienceDirect, ProQuest, Web of Science, ClinicalKey, Cochrane Central, and ClinicalTrials.gov databases were systematically searched for randomized controlled trials (RCTs), with a final literature search date of 30 December 2022. Patients diagnosed with vestibular migraine were included. The PICO of the current study included (1) patients with vestibular migraine; (2) intervention: any active pharmacologic or non-pharmacologic intervention; (3) comparator: placebo-control, active control, or waiting list; and (4) outcome: changes in migraine frequency or severity. This NMA of RCTs of vestibular migraine treatment was conducted using a frequentist model. We arranged inconsistency and similarity tests to re-examine the assumption of NMA, and also conducted a subgroup analysis focusing on RCTs of pharmacological treatment for vestibular migraine management. The primary outcome was changes in the frequency of vestibular migraines, while the secondary outcomes were changes in vestibular migraine severity and acceptability. Acceptability was set as the dropout rate, which was defined as the participant leaving the study before the end of the trial for any reason. Two authors independently evaluated the risk of bias for each domain using the Cochrane risk-of-bias tool.

Seven randomized controlled trials (N = 828, mean age 37.6 years, 78.4% female) and seven active regimens were included. We determined that only valproic acid (standardized mean difference [SMD] -1.61, 95% confidence interval [CI] -2.69, -0.54), propranolol (SMD -1.36, 95% CI -2.55, -0.17), and venlafaxine (SMD -1.25, 95% CI -2.32, -0.18) were significantly associated with better improvement in vestibular migraine frequency than the placebo/control groups. Furthermore, among all the investigated pharmacologic/non-pharmacologic treatments, valproic acid yielded the greatest decrease in vestibular migraine frequency among all the interventions. In addition, most pharmacologic/non-pharmacologic treatments were associated with similar acceptability (i.e. dropout rate) as those of the placebo/control groups.

The current study provides evidence that only valproic acid, propranolol, and venlafaxine might be associated with beneficial efficacy in vestibular migraine treatment.

CRD42023388343.

Although significant portion of women experience depressive symptoms during or after menopausal transition, there has been considerable controversy over the benefits of hormone replacement therapy (HRT) and antidepressants due to insufficient evidence supporting the superiority of either treatment. This frequentist model based network meta-analysis (NMA) included randomized controlled trials (RCTs) of menopausal depression symptoms management in menopausal women. Seventy RCTs involving a total of 18,530 women (mean age 62.5) were analyzed. The results demonstrated that fluoxetine plus oral HRT [standardized mean difference (SMD)=-1.59, 95% confidence interval (95%CIs)=-2.69 to -0.50] were associated with the largest improvement in depressive symptoms than placebos in overall menopausal women. Similar findings were also noted in the subgroup of participants with a definite diagnosis of depression, while no pharmacological or hormone replacement therapy was better than placebo in the subgroup of post-menopausal women (amenorrhea > 1 year) or in patients without diagnosis of depression. This NMA presented evidence that fluoxetine plus HRT may be beneficial to menopausal women with a definite diagnosis of depression but not to those without depression or post-menopausal women. Trial registration: PROSPERO (CRD42020167459).

Alzheimer's dementia (AD) is a major contributor to global disability, and effective therapies to modify disease progression are currently lacking. The neuro-inflammatory theory is a potential etiology underlying this neurodegenerative disease. Previous randomized, controlled trials (RCTs) have provided inconclusive results regarding efficacy of omega-3 polyunsaturated fatty acids (PUFAs) regimens, which might provide anti-inflammatory benefits in the management of AD, in improving cognitive function among participants with AD. The objective of this frequentist-model based network meta-analysis (NMA) was to evaluate the potential advantages of omega-3 PUFAs and currently FDA-approved medications for AD on overall cognitive function in AD individuals. The primary outcomes were: (1) changes in cognitive function, and (2) acceptability, which refers to all-cause discontinuation. Additionally, secondary outcomes included quality of life, behavioral disturbances and safety/tolerability, which was assessed through the frequency of any reported adverse event. This NMA included 52 RCTs (6 with omega-3 PUFAs and 46 with FDA-approved medications) involving 21,111 participants. The results showed that long-term high-dose (1500-2000 mg/day) of eicosapentaenoic acid (EPA)-dominant omega-3 PUFAs augmented with anti-oxidants had the highest potential for cognitive improvement among all investigated treatments [standardized mean difference = 3.00, 95% confidence intervals (95 %CIs) = 1.84-4.16]. Compared to placebo, omega-3 PUFAs had similar acceptability [odds ratio (OR) = 0.46, 95 %CIs = 0.04 to 5.87] and safety profiles (OR = 1.24, 95 %CIs = 0.66 to 2.33)o. These findings support the potential neurotherapeutic effects of high dosage EPA-dominant omega-3 PUFAs for the amelioration of cognitive decline in patients with AD. Future large-scale, long-term RCTs should focus on different dosages of EPA-dominant omega-3 PUFAs regimens on improving cognitive dysfunction in patients with AD at different levels of inflammatory status and psychopathology.

Dementia [i.e., Alzheimer disease (AD)], the most common neurodegenerative disease, causes profound negative impacts on executive function and quality of life. Available pharmacological treatments often fail to achieve satisfactory outcomes. Noninvasive brain stimulation (NIBS) techniques, which focally modify cortical function and enhance synaptic long-term potentiation, are potentially beneficial for the cognition in patients with AD. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and safety of different NIBS interventions in patients with AD through NMA.

Only randomized controlled trials (RCTs) examining NIBS interventions in patients with AD had been included. All NMA procedures were performed under the frequentist model. The primary and secondary outcomes were changes in cognitive function and quality of life, respectively.

Nineteen RCTs (639 participants) were included. The mean treatment and follow-up durations were 5.7 and 10.5 weeks, respectively. The combination of cathodal tDCS of the left dorsolateral prefrontal cortex and anodal tDCS over the right supraorbital region (c-tDCS-F3 + a-tDCS-Fp2) was associated with a significant beneficial effect on cognition compared with sham controls (standardized mean difference=2.43, 95% confidence interval=0.61-4.26, n=12 and 11). It was also associated with the greatest beneficial effect on cognition among all the investigated NIBS approaches. All the methods were well tolerated with regard to the safety profile, as reflected in the rates of adverse events or local discomfort, as well as acceptability, as indicated by dropout rate.

The present findings provide evidence of the benefits of NIBS, especially tDCS, for beneficial effect on cognition in patients with AD. However, because of few studies included, this effect was not replicated yet in the other studies. Therefore, future larger-scale and longer follow-up duration RCTs should be warranted.

PROSPERO CRD42020209516. The current study had been approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).

Meta-analyses are used to summarise the results of several studies on a specific research question. Standard methods for meta-analyses, namely inverse variance random effects models, have unfavourable properties if only very few (2 - 4) studies are available. Therefore, alternative meta-analytic methods are needed. In the case of binary data, the "common-rho" beta-binomial model has shown good results in situations with sparse data or few studies. The major concern of this model is that it ignores the fact that each treatment arm is paired with a respective control arm from the same study. Thus, the randomisation to a study arm of a specific study is disrespected, which may lead to compromised estimates of the treatment effect. Therefore, we extended this model to a version that respects randomisation. The aim of this simulation study was to compare the "common-rho" beta-binomial model and several other beta-binomial models with standard meta-analyses models, including generalised linear mixed models and several inverse variance random effects models.

We conducted a simulation study comparing beta-binomial models and various standard meta-analysis methods. The design of the simulation aimed to consider meta-analytic situations occurring in practice.

No method performed well in scenarios with only 2 studies in the random effects scenario. In this situation, a fixed effect model or a qualitative summary of the study results may be preferable. In scenarios with 3 or 4 studies, most methods satisfied the nominal coverage probability. The "common-rho" beta-binomial model showed the highest power under the alternative hypothesis. The beta-binomial model respecting randomisation did not improve performance.

The "common-rho" beta-binomial appears to be a good option for meta-analyses of very few studies. As residual concerns about the consequences of disrespecting randomisation may still exist, we recommend a sensitivity analysis with a standard meta-analysis method that respects randomisation.

To perform a systematic review and meta-analysis of studies reporting data on atherosclerosis and inflammatory markers in familial Mediterranean fever (FMF).

EMBASE and PubMed databases were screened according to PRISMA guidelines from inception to January 2022 for articles reporting measurements of the intima media thickness (IMT) of carotid arteries and eventually carotid plaques; random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events were employed.

The screening and selection search strategy yielded 18 case controls studies (16 full papers and 2 abstracts); the IMT was greater in FMF (n = 1112) than in controls (n = 901) (p < 0.0001) with wide heterogeneity (I2 = 86.4%); a sensitivity analysis according to mean age of participants, male to female ratio, disease duration, C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen (FNG), atherogenic index of plasma (AIP), colchicine use and NOQAS revealed that the heterogeneity variance was partly explained by CRP (p = 0.01) and to a much lesser extent by the AIP (p = 0.10). The pooled prevalence of carotid plaques was greater in FMF (n = 137) than in controls (n = 156) (19% vs 8.3%, p = 0.02) with low heterogeneity.

FMF is characterised by premature atherosclerosis expressed as a thicker intima media and a greater prevalence of carotid plaques, partially related to the C-reactive protein, as expected by the autoinflammatory nature of FMF. Key Points • Familial Mediterranean fever is characterised by premature atherosclerosis. • C-reactive protein relates to intima media thickness in keeping with the autoinflammatory nature Familial Mediterranean fever. • Targeting the inter-critical low-grade inflammation may be relevant to minimise the additional cardiovascular risk posed by premature atherosclerosis.

Nicotine is a highly addictive substance in tobacco products that dysregulates several neurotransmitters in the brain and impairs executive function. Non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are promising treatments for nicotine dependence. We investigated the efficacy and acceptability of NIBS in managing smoking cessation through a systematic review and network meta-analysis (NMA).

We conducted a systematic review to identify randomized controlled trials (RCTs) that investigated the efficacy of NIBS for smoking cessation. All pairwise meta-analyses and NMA procedures were conducted using random-effects and frequentist models. The co-primary outcomes were (1) the change in number of cigarettes smoked per day (change in frequency of smoking) in patients with nicotine dependence after NIBS and (2) acceptability (the dropout rate). The effect sizes for co-primary outcomes of change in frequency of smoking and acceptability were assessed according to standardized mean difference (SMD) and odds ratio, respectively.

Twelve RCTs with 710 participants (mean age: 44.2 years, 31.2% female) were included. Compared with the sham control, 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) was associated with the largest changes in smoking frequency [SMD = -1.22, 95% confidence interval (95% CI) = -1.77 to -0.66]. The 2-mA bifrontal tDCS (SMD = -0.97, 95% CI = -1.32 to -0.62) and 10-Hz deep rTMS over the bilateral DLPFC with cue provocation (SMD = -0.77, 95% CI = -1.20 to -0.34) were associated with a significantly larger decrease in smoking frequency versus the sham. None of the investigated NIBSs was associated with dropout rates significantly different from those of the sham control groups.

Prefrontal non-invasive brain stimulation interventions appear to reduce the number of cigarettes smoked with good acceptability.

The prevalence of clinically significant endoscopic findings in people with dyspepsia and understanding how symptoms can predict endoscopic pathology can help inform dyspepsia guidelines. We evaluated this in an updated systematic review and meta-analysis.

We searched MEDLINE, EMBASE, Cochrane CENTRAL, and the Cochrane Database of Systematic Reviews from 2010 through to January 2022 to identify relevant articles. Eligible studies enrolled adults from the community, workplace, blood donation or screening clinics, family physician offices, or internal medicine clinics. Studies were required to report prevalence of dyspepsia and perform esophagogastroduodenoscopy (EGD). Prevalence of clinically significant endoscopic findings in subjects with and without dyspepsia was pooled for all studies and compared using odds ratios and 95% confidence intervals (CIs). The data were pooled with those of the 9 studies included in the prior review.

Of 511 papers evaluated, 184 reported prevalence of dyspepsia. Fifteen reported prevalence of endoscopic findings among 41,763 participants (40.4% with dyspepsia). Erosive esophagitis was the most common abnormality (pooled prevalence, 11.0%; 95% CI, 8.9%-13.2%) followed by peptic ulcer (pooled prevalence, 4.4%; 95% CI, 2.5%-6.7%). The only finding encountered more frequently in individuals with dyspepsia, compared with those without, was peptic ulcer (odds ratio, 1.61; 95% CI, 1.08-2.39). More than 85% of EGDs were completely normal. Gastroesophageal cancer was rare (<0.4%) and equally prevalent among those with and without dyspepsia.

Erosive esophagitis was the most common clinically significant finding at EGD, whereas gastroesophageal cancers were rare. Most pathology, including esophagitis and cancer, were found in similar proportions in both groups. These findings support noninvasive approaches to managing dyspepsia in the community, with EGD reserved for those at high risk of malignancy.

Although the current consensus recommends a standard treatment of high-dose intravenous immunoglobulin with high-dose aspirin to manage Kawasaki disease (KD), the use of different adjunctive therapies remains controversial. The aim of the current network meta-analysis (NMA) was to compare the efficacy and tolerability of different existing interventions for the initial and refractory stages of KD.

An NMA of randomised controlled trials (RCTs) was conducted using the frequentist model applied after electronic searches in PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, and Web of Science. The main outcomes were reduced fever duration/diminished severity of fever subsided. The initial stage of KD was defined as the first stage to treat patients with KD; the refractory stage of KD represents KD patients who failed to respond to standard KD treatment. The cut-off points for intravenous immunoglobulin (IVIG) were low (100-400 mg), medium (1 g), and high (at least 2 g).

A total of fifty-six RCTs with 6486 participants were included. NMA demonstrated that the medium-dosage IVIG + aspirin + infliximab [mean difference=-1.76 days (95% confidence intervals (95% CIs): -3.65 to 0.13 days) compared to high-dosage IVIG + aspirin] exhibited the shortest fever duration; likewise, the medium-dosage IVIG + aspirin + infliximab [odds ratio (OR)=0.50, 95% CIs: 0.18-1.37 compared to high-dosage IVIG + aspirin] exhibited the smallest incidence of coronary artery lesion (CAL) in the initial-stage KD. In the refractory-stage KD, the high-dosage IVIG + pulse steroid therapy (OR=0.04, 95% CIs: 0.00-0.43 compared to the high-dosage IVIG only) had the best rate of decline of fever; likewise, the high-dosage IVIG + ciclosporin [OR=0.05 (95% CIs: 0.00-1.21) compared to the high-dosage IVIG only] exhibited the smallest incidence of CAL. Infliximab significantly improved resolution compared to the high-dosage IVIG only group (OR=0.20, 95%CIs: 0.07-0.62) in refractory-stage KD.

The NMA demonstrated that the combination therapy with the standard therapy of IVIG and aspirin might have an additional effect on shortening the duration of fever and lowering the CAL incidence rate in patients with acute KD. Moreover, the combination therapy with high-dose IVIG and pulse steroid therapy or cyclosporine therapy might have an additional effect on improving the rate of decline of fever and lowering the incidence rate of CAL in children with refractory KD. Because some of the findings of this NMA should be considered hypothesis-generating rather than confirmatory, further evidence from de novo randomised trials is needed to support our results.

None.

Current pharmacologic prophylactic strategies for migraine have exhibited limited efficacy, with response rates as low as 40%-50%. In addition to the limited efficacy, the acceptability of those pharmacologic prophylactic strategies were unacceptable. Although noninvasive brain/nerve stimulation strategies may be effective, the evidence has been inconsistent. The aim of this network meta-analysis (NMA) was to compare strategies of noninvasive brain/nerve stimulation for migraine prophylaxis with respect to their effectiveness and acceptability.

The PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov , ClinicalKey, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of June 4th, 2021 for randomized controlled trials (RCTs). Patients with diagnosis of migraine, either episodic migraine or chronic migraine, were included. All NMA procedures were conducted under the frequentist model.

Nineteen RCTs were included (N = 1493; mean age = 38.2 years; 82.0% women). We determined that the high frequency repetitive transcranial magnetic stimulation (rTMS) over C3 yielded the most decreased monthly migraine days among all the interventions [mean difference = - 8.70 days, 95% confidence intervals (95%CIs): - 14.45 to - 2.95 compared to sham/control groups]. Only alternating frequency (2/100 Hz) transcutaneous occipital nerve stimulation (tONS) over the Oz (RR = 0.36, 95%CIs: 0.16 to 0.82) yielded a significantly lower drop-out rate than the sham/control groups did.

The current study provided a new direction for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on migraine prophylaxis in participants with migraine by different noninvasive brain/nerve stimulation, especially the application of rTMS and tONS.

CRD42021252638. The current study had been approval by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).

The meta-analysis of single proportions has become a popular application over the last two decades. Especially, systematic reviews of prevalence studies are conducted in various fields of science, including medicine, ecology, psychology, or social sciences. In this chapter, we illustrate meta-analysis methods to pool single proportions and to compare proportions from two groups. We introduce classic approaches based on the inverse variance method as well as generalized linear mixed models taking the binary structure of the data into account. The most common transformations of proportions and their back-transformations are described both for individual studies and in the meta-analysis setting.

While Alzheimer's dementia (AD) has a prevalence as high as 3-32% and is associated with cognitive dysfunction and the risk of institutionalization, no efficacious and acceptable treatments can modify the course of cognitive decline in AD. Potential benefits of exogenous melatonin for cognition have been divergent across trials.

The current network meta-analysis (NMA) was conducted under the frequentist model to evaluate the potential beneficial effects of exogenous melatonin supplementation on overall cognitive function in participants with AD in comparison to other FDA-approved medications (donepezil, galantamine, rivastigmine, memantine, and Namzaric).

The primary outcome was the changes in the cognitive function [measured by mini-mental state examination (MMSE)] after treatment in patients with Alzheimer's dementia. The secondary outcomes were changes in the quality of life, behavioral disturbance, and acceptability (i.e., drop-out due to any reason and rate of any adverse event reported).

The current NMA of 50 randomized placebo-controlled trials (RCTs) revealed the medium-term lowdose melatonin to be associated with the highest post-treatment MMSE (mean difference = 1.48 in MMSE score, 95% confidence intervals [95% CIs] = 0.51 to 2.46) and quality of life (standardized mean difference = -0.64, 95% CIs = -1.13 to -0.15) among all of the investigated medications in the participants with AD. Finally, all of the investigated exogenous melatonin supplements were associated with similar acceptability as was the placebo.

The current NMA provides evidence for the potential benefits of exogenous melatonin supplementation, especially medium-term low-dose melatonin, in participants with AD.

The purpose of this systematic review and meta-analysis was to estimate and compare rates of unplanned reoperation and complications after undergoing either fronto-orbital advancement (anterior cranial vault expansion) or posterior cranial vault expansion as an early surgery in the management of syndromic craniosynostosis.

A literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant articles were identified in 2 electronic databases (PubMed and EMBASE) from the time of electronic publication to November 2020. Quality assessment and risk of bias were appraised using the Grading of Recommendations Assessment, Development and Evaluation system. A meta-analysis was performed comparing rates of reoperation and complications between participants who underwent anterior or posterior cranial vault expansion as an early surgery.

Of 1,373 screened records, 7 met inclusion criteria. Six were included in the meta-analysis. The studies that met inclusion criteria reported on 103 patients treated with anterior techniques and 72 patients treated with a posterior approach. Anterior cranial vault expansion was associated with significantly higher rates of reoperation (Peto odds ratio = 2.83; 95% confidence interval = 1.19, 6.74, P = .02) and complications (Peto odds ratio = 2.61; 95% confidence interval = 1.12, 6.12, P = .03) than posterior cranial vault expansion.

Both anterior and posterior approaches are suitable options in the treatment of syndromic craniosynostosis depending on patient-specific factors. Anterior cranial vault expansion was associated with higher rates of unplanned reoperation and complications than posterior techniques in this analysis. Because of the paucity of literature which met inclusion criteria, this study was not able to assess critical outcome variables such as distance distracted/volumetric expansion, estimated blood loss, and cost. Larger studies evaluating both techniques under multiple institutions with long-term follow-up are indicated.

The Peto odds ratio is a well-known effect measure in meta-analysis of binary outcomes. For pairwise comparisons, the Peto odds ratio estimator can be severely biased in the situation of unbalanced sample sizes in the two treatment groups or large treatment effects. In this publication, we evaluate Peto odds ratio estimators in the setting of multi-arm studies and in network meta-analysis using illustrative examples. We observe that Peto odds ratio estimators in a multi-arm study are inconsistent if the observed event probabilities are different or the sample sizes of treatment groups are unbalanced. The same problem emerges in network meta-analysis including only two-arm studies and translates to indirect comparisons of pairwise meta-analyses. We conclude that the Peto odds ratio should not be used as effect measure in network meta-analysis or indirect comparisons of pairwise meta-analyses.

This updated network meta-analysis aims at exploring whether the concurrent use of midazolam or antiemetics may enhance the efficacy of other pharmacological regimens for delirium prophylaxis in pediatric population after general anesthesia (GA).

Network meta-analysis (PROSPERO registration: CRD42020179483).

Postoperative recovery area.

Pediatric patients undergoing GA with sevoflurane.

Pharmacological interventions applied during GA with sevoflurane.

This network meta-analysis of randomized controlled trials (RCTs) was conducted with a frequentist model. PubMed, Embase, ProQuest, ScienceDirect, Cochrane CENTRAL, ClinicalKey, Web of Science, and ClinicalTrials.gov were searched from their inception dates to April 12, 2020, for RCTs of either placebo-controlled or active-controlled design containing information on the incidence of emergence delirium in pediatric patients undergoing sevoflurane anesthesia.

Seventy studies comprising 6904 participants were included for the analysis of 30 pharmacological interventions. Based on surface under the cumulative ranking curve (SUCRA) analysis, midazolam was ranked the lowest in therapeutic effect (SUCRA: 20%), while antiemetics as a monotherapy had no effect on delirium prophylaxis. However, there was a trend that most combination therapies with midazolam or antiemetics were superior to monotherapies for delirium prophylaxis. Subgroup analyses based on age (i.e., ≤7 years) and a validated scoring system (i.e., the Pediatric Anesthesia Emergence Delirium scale) for delirium also suggested a better efficacy of combination therapies than monotherapies. Overall, combination therapies with midazolam or antiemetics did not have a negative impact on the incidence of postoperative nausea and vomiting, length of stay in the postanesthesia care unit, or time to extubation. The dexmedetomidine-midazolam-antiemetic combination was the most effective strategy for the prevention of emergence delirium.

This network meta-analysis suggested that the incorporation of midazolam or antiemetics as adjuncts for combination therapies may have synergistic effects against pediatric postoperative emergence delirium. Future large-scale placebo-controlled RCTs are warranted to validate our findings.

Although tinnitus has a prevalence between 20 and 42.8%, the currently recommended management for tinnitus, such as tinnitus support and psychologic therapies, are relatively time-consuming and expensive. Several new pharmacologic treatments designed for tinnitus patients without specific origin had been developed but their efficacy remains unclear.

The current Network Meta-Analysis (NMA) of randomised controlled trials (RCTs) was conducted to evaluate the efficacy of different pharmacologic treatments for tinnitus management in tinnitus patients without specific or treatable origin (i.e. primary tinnitus). Databases were searched from inception to April 5^th, 2021. All network meta-analytic procedures were conducted under the frequentist model. We calculated the effect size of outcomes with different rating scales with standardized mean difference. PROSPERO registration: CRD42020177742.

Overall, 36 RCTs were included with 2,761 participants. The main results revealed that pharmacologic interventions with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) and those with anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) were associated with superior improvement in tinnitus severity and response rate compared to placebo/control. Oral amitriptyline were associated with the highest improvement in tinnitus severity and the fourth highest response rate. None of the investigated interventions was associated with different changes in quality of life compared to placebo/control. All the investigated treatments were associated with similar drop-out rate to placebo/control.

The current NMA suggests a potential role for treatments with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) or anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) as the preferable effective treatments for tinnitus without specific or treatable origin.

none.