Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: PROSPERO CRD42023391562.

High Dosage Omega-3 Fatty Acids Outperform Existing Pharmacological Options for Migraine Prophylaxis: A Network Meta-Analysis.

Migraine is a highly prevalent neurologic disorder with prevalence rates ranging from 9% to 18% worldwide. Current pharmacologic prophylactic strategies for migraine have limited efficacy and acceptability, with relatively low response rates of 40% to 50% and limited safety profiles. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered promising therapeutic agents for migraine prophylaxis. The aim of this network meta-analysis (NMA) was to compare the efficacy and acceptability of various dosages of EPA/DHA and other current Food and Drug Administration-approved or guideline-recommended prophylactic pharmacologic interventions for migraine. Randomized controlled trials (RCTs) were eligible for inclusion if they enrolled participants with a diagnosis of either episodic or chronic migraine. All NMA procedures were conducted under the frequentist model. The primary outcomes assessed were 1) changes in migraine frequency and 2) acceptability (i.e., dropout for any reason). Secondary outcomes included response rates, changes in migraine severity, changes in the frequency of using rescue medications, and frequency of any adverse events. Forty RCTs were included (N = 6616; mean age = 35.0 y; 78.9% women). Our analysis showed that supplementation with high dosage EPA/DHA yields the highest decrease in migraine frequency [standardized mean difference (SMD): -1.36; 95% confidence interval (CI): -2.32, -0.39 compared with placebo] and the largest decrease in migraine severity (SMD: -2.23; 95% CI: -3.17, -1.30 compared with placebo) in all studied interventions. Furthermore, supplementation with high dosage EPA/DHA showed the most favorable acceptability rates (odds ratio: 1.00; 95% CI: 0.06, 17.41 compared with placebo) of all examined prophylactic treatments. This study provides compelling evidence that high dosage EPA/DHA supplementation can be considered a first-choice treatment of migraine prophylaxis because this treatment displayed the highest efficacy and highest acceptability of all studied treatments. This study was registered in PROSPERO as CRD42022319577.

Network Meta-analysis of Different Treatments for Vestibular Migraine.

INTRODUCTION: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The current study provides evidence that only valproic acid, propranolol, and venlafaxine might be associated with beneficial efficacy in vestibular migraine treatment. TRIAL REGISTRATION: CRD42023388343.

Omega-3 polyunsaturated fatty acids in sarcopenia management: A network meta-analysis of randomized controlled trials.

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).

Efficacy and acceptability of anti-inflammatory eicosapentaenoic acid for cognitive function in Alzheimer's dementia: A network meta-analysis of randomized, placebo-controlled trials with omega-3 fatty acids and FDA-approved pharmacotherapy.

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.

Black cohosh extracts in women with menopausal symptoms: an updated pairwise meta-analysis.

OBJECTIVE: Menopausal symptoms are common in midlife women and have broad impacts on their daily functioning and quality of life. Black cohosh extracts have been widely used to relieve menopausal symptoms. However, the comparative benefits of different combined black cohosh regimens remain inconclusive. The aim of the current updated meta-analysis is to address the comparative efficacies of different black cohosh regimens in improving menopausal symptoms. METHODS: Random-effect model pairwise meta-analysis of randomized controlled trials was conducted to investigate the treatment effect on menopausal symptoms by the black cohosh extract both alone or combined with other related active ingredients. The outcomes studied were changes in menopausal symptoms after treatment with black cohosh extracts in menopausal women. RESULTS: Twenty-two articles including information on 2,310 menopausal women were included in the analyses. Black cohosh extracts were associated with significant improvements in overall menopausal symptoms (Hedges' g = 0.575, 95% CI = 0.283 to 0.867, P < 0.001), as well as in hot flashes (Hedges' g = 0.315, 95% CIs = 0.107 to 0.524, P = 0.003), and somatic symptoms (Hedges' g = 0.418, 95% CI = 0.165 to 0.670, P = 0.001), compared with placebo. However, black cohosh did not significantly improve anxiety (Hedges' g = 0.194, 95% CI = -0.296 to 0.684, P = 0.438) or depressive symptoms (Hedges' g = 0.406, 95% CI = -0.121 to 0.932, P = 0.131). The dropout rate for black cohosh products was similar to that for placebo (odds ratio = 0.911, 95% CI = 0.660 to 1.256, P = 0.568). CONCLUSIONS: This study provides updated evidence regarding the potentially beneficial effects of black cohosh extracts for relieving menopausal symptoms in menopausal women.

The beneficial effect on cognition of noninvasive brain stimulation intervention in patients with dementia: a network meta-analysis of randomized controlled trials.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: 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).

The efficacy of exogenous melatonin supplement in ameliorating irritable bowel syndrome severity: A meta-analysis of randomized controlled trials.

BACKGROUND: Irritable bowel syndrome (IBS) was found in 11% of the general population worldwide. The current pharmacologic management of IBS was unsatisfactory, and it was accompanied by a number of adverse events. Melatonin was found to play an important role in gastrointestinal smooth muscle motility. Dysregulation of endogenous melatonin secretion has been found in IBS patients. Exogenous melatonin supplement has become one alternative treatment for IBS, but the evidence is inconclusive. The current meta-analysis sought to determine the efficacy of exogenous melatonin supplement in improving IBS severity in IBS patients. METHODS: We included randomized controlled trials (RCTs) that investigated the efficacy of exogenous melatonin supplement in ameliorating IBS severity in IBS patients. This meta-analysis was conducted using a random effects model. The primary target outcomes were changes in IBS severity associated with melatonin or placebo. RESULTS: This meta-analysis of 4 RCTs and 115 participants revealed that exogenous melatonin supplement was associated with significantly better improvement in overall IBS severity than placebo (k = 4, Hedges' g = 0.746, 95% confidence intervals = 0.401-1.091, p < 0.001). The subgroup without concurrent medication had the same result (p < 0.001). In addition, exogenous melatonin supplement was also associated with significantly better improvement in IBS pain severity (p < 0.001) and quality of life (p = 0.007) than placebo, but not in abdominal distension (p = 0.111) or sleep quality (p = 0.142). Finally, melatonin was associated with similar safety profiles with placebo. CONCLUSION: This meta-analysis provides evidence for the use of exogenous melatonin in IBS patients to ameliorate overall IBS severity, IBS pain severity, and quality of life. TRIAL REGISTRATION: PROSPERO CRD42021269451.

Cancer related fatigue-light therapy: updated meta-analysis of randomised controlled trials.

BACKGROUND: Moderate-to-severe cancer related fatigue occurs in 45% of patients with cancer and interferes with many aspects of quality of life. Although physical exercise has level 1 evidence for improvement of cancer related fatigue, it has a relatively high behavioural demand compared with other non-pharmacological interventions. The aim of this updated meta-analysis was to address the efficacy of light therapy in improving cancer related fatigue in patients with cancer. METHODS: We included randomised controlled trials investigating the efficacy of bright white light (BWL) therapy in ameliorating cancer related fatigue in patients with cancer. This meta-analysis was conducted using a random-effects model. The target outcomes were changes in cancer related fatigue associated with BWL or dim red light (DRL). RESULTS: There were 9 articles with 231 participants included. The main results revealed that daily morning BWL for 30 min was associated with significantly better improvement in fatigue severity compared with DRL (k=5, Hedges' g=-0.414, 95% CI -0.740 to -0.087, p=0.013). The subgroup without psychiatric comorbidities (k=4, Hedges' g=-0.479, 95% CI -0.801 to -0.156, p=0.004) was associated with significantly better improvement in fatigue severity with BWL than with DRL. In contrary, BWL was not associated with significantly different changes in depression severity or quality of life compared with DRL. Finally, BWL was associated with similar acceptability (ie, dropout rate) and safety profile (ie, any discomfort) as those of DRL. CONCLUSIONS: This meta-analysis provides an updated evidence on the rationale for application of BWL in ameliorating cancer related fatigue in patients with different types of cancer. TRIAL REGISTRATION NUMBER: INPLASY202140090.

Comparative efficacy of omega-3 polyunsaturated fatty acids on major cardiovascular events: A network meta-analysis of randomized controlled trials.

The role of omega-3 polyunsaturated fatty acids (PUFAs) in primary and secondary prevention on major cardiovascular events (MCE) is inconclusive due to the potential heterogeneity in study designs of formulas, dosages, and ratios of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the findings of previous randomized controlled trials (RCTs). Here we conducted a comprehensive narrative review of pre-clinical studies and updated a network meta-analysis (NMA) to determine the comparative efficacy against MCE with different EPA/DHA dosages and formulas. We found that pure EPA was ranked the best option in the secondary prevention (hazard ratio: 0.72, 95% confidence interval: 0.65 to 0.81) from the NMA of 39 RCTs with 88,359 participants. There was no evidence of omega-3 PUFAs' efficacy in primary prevention. The mechanisms of omega-3 PUFAs' cardiovascular protection might link to the effects of anti-inflammation and stabilization of endothelial function from PUFA's derivatives including eicosanoids and the special pre-resolving mediators (SPMs).

Effects of modern technology (exergame and virtual reality) assisted rehabilitation vs conventional rehabilitation in patients with Parkinson's disease: a network meta-analysis of randomised controlled trials.

BACKGROUND: Modern technological applications, including exergames and virtual technology-assisted rehabilitation (VTAR) programmes, are promising for Parkinson's disease (PD) rehabilitation. However, evidence regarding their efficacy for rehabilitation is inconclusive. OBJECTIVES: This network meta-analysis (NMA) investigated the efficacy of exergames and VTAR on gait and balance outcomes and acceptability for patients with PD. DATA SOURCES: ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, Web of Science and ClinicalTrials.gov. STUDY SELECTION: Randomised controlled trials (RCTs) investigating changes in gait or balance parameters were included in this study. STUDY APPRAISAL AND SYNTHESIS METHODS: In the NMA, standardised mean differences with 95% confidence intervals were calculated using a frequentist model. GRADE ratings were used to evaluate the quality of evidence in this study. RESULTS: Twenty-three RCTs with 949 participants were included. Exergames and VTAR were associated with significantly better improvements in balance and gait outcomes than usual treatment and other active control interventions. However, exergames were not associated with changes in depressive symptoms. The evaluation of acceptability results indicated that all exergames and VTAR were adequately tolerated, as indicated by the low drop-out rates. LIMITATIONS: Small sample sizes and heterogeneity were the key limitations of this study. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: This NMA confirmed that exergames are associated with more favourable gait and balance outcomes in patients with PD compared with usual treatment and other active control interventions. GRADE ratings revealed that most direct, indirect and overall network evidence was of low to medium quality. Larger-scale studies with longer follow-up periods are warranted.

Multiple comparison of different noninvasive brain stimulation and pharmacologic interventions in patients with methamphetamine use disorders: A network meta-analysis of randomized controlled trials.

AIM: In recent decades, the prevalence of amphetamine and methamphetamine use disorders has at least doubled in some regions/countries, with accompanying high risks of drug overdose-associated mortality. Noninvasive brain stimulation (NIBS) methods may be effective treatments. However, the comparative efficacy of the NIBS protocol for amphetamine/methamphetamine use disorder (AUD/MUD) remains unknown to date. The aim of this network meta-analysis (NMA) was to compare the efficacy and acceptability of various NIBS methods/protocols for AUD/MUD management. METHODS: A frequentist model-based NMA was conducted. We included randomized controlled trials (RCTs) that investigated the efficacy of NIBS and guideline-recommended pharmacologic treatments to reduce craving severity in patients with either AUD or MUD. RESULTS: Twenty-two RCTs including 1888 participants met the eligibility criteria. Compared with the sham/placebo group (study = 19, subjects = 891), a combination of intermittent theta burst stimulation over the left dorsolateral prefrontal cortex (DLPFC) and continuous TBS over the left ventromedial prefrontal cortex (study = 1, subjects = 19) was associated with the largest decreases in craving severity [standardized mean difference (SMD) = -1.50; 95% confidence intervals (95%CIs) = -2.70 to -0.31]. High-frequency repetitive transcranial magnetic stimulation over the left DLPFC was associated with the largest improvements in depression and quality of sleep (study = 3, subjects = 86) (SMD = -2.48; 95%CIs = -3.25 to -1.71 and SMD = -2.43; 95%CIs = -3.38 to -1.48, respectively). The drop-out rate of most investigated treatments did not significantly differ between groups. CONCLUSION: The combined TBS protocol over the prefrontal cortex was associated with the greatest improvement in craving severity. Since few studies were available for inclusion, additional large-scale randomized controlled trials are warranted.

Changes in Periodic Limb Movements of Sleep After the Use of Continuous Positive Airway Pressure Therapy: A Meta-Analysis.

Background: Both obstructive sleep apnea (OSA) and periodic limb movements of sleep (PLMS) are common in the sleep laboratory. The severity of OSA can be improved by using continuous positive airway pressure (CPAP). However, increasing evidence has shown an elevated periodic limb movement index (PLMI) in patients with OSA who use CPAP, although the pathophysiology is still unknown. This meta-analysis aimed to investigate changes in PLMS after using CPAP and the potential pathophysiology of these changes. Methods: Clinical trials in adult humans investigating the comorbidity between PLMS and CPAP were identified and analyzed using random-effects model meta-analysis. Results: This meta-analysis included 14 studies comprising 2,938 patients with OSA. The PLMI was significantly increased after using CPAP with a difference in means of 1.894 (95% confidence interval = 0.651-3.138, p = 0.003). Subgroup analysis showed that CPAP was only significantly associated with an increase in PLMI in the patients without PLMS at baseline (p = 0.045) and in those with a baseline body-mass index <30 kg/m2 (p = 0.045). The use of CPAP, apnea-hypopnea index, and arousal index were positively correlated with changes in PLMI. Conclusion: These characteristics may serve as qualitative predictive indicators of changes in PLMI after CPAP usage. Further analysis of the quantitative relationships between PLMI and the predictive indicators may be warranted. Trial Registration: PROSPERO (registration number: CRD42021252635).

The efficacy and tolerability of antibiotics in scrub typhus: an updated network meta-analysis of randomized controlled trials.

OBJECTIVES: Inadequate treatment of scrub typhus results in severe complications such as septic shock and is also associated with a high median mortality rate of 6%. However, there has been no conclusive evidence about the superiority of different antibiotics in managing scrub typhus in terms of efficacy and tolerability. METHODS: We conducted a network meta-analysis (NMA) using the frequentist method. The included participants were pediatric and adult patients infected with scrub typhus. The primary outcome was the cure rate in the patients included. The subgroup analysis was done according to pediatric or adult patients. RESULTS: Overall, 14 randomized controlled trials (RCTs) with 1264 participants were included in this study. The NMA revealed that all the investigated antibiotics were associated with cure rates similar to those of doxycycline. The chloramphenicol and minocycline were ranked to be associated with the highest cure rate in the pediatric subgroup and adult subgroup, respectively. Second-generation quinolones, including ofloxacin, ciprofloxacin, and chloramphenicol, were associated with significantly lower adverse event rates than doxycycline. CONCLUSION: The current updated NMA provides evidence for the efficacy of chloramphenicol and minocycline in scrub typhus management. However, future large-scale RCTs with longer follow-up times are warranted.

The Dose and Duration-dependent Association between Melatonin Treatment and Overall Cognition in Alzheimer's Dementia: A Network Meta- Analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: 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. OBJECTIVE: 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). METHODS: 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). RESULTS: 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. CONCLUSION: The current NMA provides evidence for the potential benefits of exogenous melatonin supplementation, especially medium-term low-dose melatonin, in participants with AD.

Pharmacologic interventions for Kawasaki disease in children: A network meta-analysis of 56 randomized controlled trials.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: None.