Background: The associations between 1-carbon metabolism (OCM) nutrients (methionine, folate, vitamin B-6, and vitamin B-12) and Alzheimer disease (AD) remains inconclusive. Objectives: This study aimed to investigate the association of dietary OCM nutrients with subsequent risk of AD and further assess whether participants with high genetic risk for AD might benefit from dietary OCM nutrients. Methods: We analyzed data from 192,214 participants who completed at least one 24-h dietary questionnaire and had no previous history of AD based on the UK Biobank. Nutrients intake was calculated using McCance and Widdowson's The Composition of Food and USDA's Food and Nutrient Database for Dietary Studies. Cox proportional models with restricted cubic splines were applied to explore the associations. Results: Over a median follow-up of 13.35 y, 959 cases of AD (41 early-onset cases and 918 late-onset cases) were identified. Compared with those in the low-intake OCM group (quartile 1), participants in the high-intake OCM group (quartile 4) had reduced risk of developing AD. The corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for methionine, folate, vitamin B-6, and vitamin B-12 intake were 0.66 (0.54, 0.80), 0.71 (0.58, 0.87), 0.71 (0.59, 0.87), and 0.77 (0.64, 0.93), respectively. Similar associations were observed in late-onset AD. In early-onset AD, high methionine and vitamin B-12 intake were associated with 70% (HR: 0.30; 95% CI: 0.10, 0.86) and 71% (HR: 0.29; 95% CI: 0.09, 0.96) reduction in risk, respectively. Participants with low genetic risk and high OCM nutrients intake had >75% reduced AD risk compared with high-risk, low-intake participants. Conclusions: In this prospective cohort study, we found that higher intake of OCM nutrients is associated with reduced risk of AD. Participants with high genetic risk of AD are more likely to benefit from dietary OCM nutrients intake.

ObjectiveTo compare the outcomes associated with the use of probiotics, prebiotics, and synbiotics for the treatment of chronic constipation in adults.MethodsWe searched eight electronic databases from database inception to July 11, 2023, to identify randomized controlled trials (RCTs) that report efficacy and safety for the treatment of chronic constipation. The risk of bias in the included RCTs was evaluated according to the Cochrane tool, and the certainty of the evidence was assessed using the Confidence in Network Meta-Analysis framework. The analysis was conducted using R version 4.3.0.ResultsOut of the 37 RCTs, a total of 21 different types of interventions were reported, involving 3,903 patients. This NMA demonstrated that both prebiotics and synbiotics resulted in an increase in frequency of stool movements per week. Compared to placebo, lactulose (Mean difference [MD] = 3.39, 95% Confdence interval [CI] [1.13, 5.65], moderate certainty), mix2 (consisting of Lactulose and Bacillus coagulans) (MD = 3.63, 95% CI [1.37, 5.89], moderate certainty), mix6 (consisting of Lactulose and Bifidobacterium coagulans) (MD = 4.30, 95% CI [1.04, 7.54], low certainty), and mix7 (consisting of Lactulose, Bifidobacterium subtilis, and Enterococcus faecium) (MD = 4.58, 95% CI [1.35, 7.78], moderate certainty) exhibited a significant effect. Notably, mix7 demonstrated the highest probability of being the most effective intervention (94.8%). Furthermore, when compared to L. plantarum, four probiotics and two synbiotics showed significant advantages in the Patient Assessment of Constipation Symptoms (PAC-SYM) score. L. reuteri (MD = -13.74, 95% CI [-22.20, -4.66], very low certainty) exhibited a significant effect in improving the Patient Assessment of Constipation Quality of Life (PAC-QoL) score. In terms of safety, there were no statistically significant differences between the intervention and control groups in all adverse event analyses.ConclusionsModerate to very low evidence supports the use of lactulose and synbiotics to increase the number of weekly stool movements in patients, particularly highlighting the significant impact of synbiotics in increasing the number of weekly stool movements in patients with constipation. The use of L. paracasei showed improvements in PAC-SYM scores, while L. reuteri demonstrated enhancements in PAC-QoL scores.

BACKGROUND Several systematic reviews (SRs) have investigated the association between ultra -processed foods (UPFs) and the risk of hypertension in various populations. However, the quality of the evidence remains unclear. This umbrella review was thus conducted to fill this gap. METHODS We searched for SRs with and without meta -analyses comparing high UPF versus low UPF consumption on the risk of hypertension in the Cochrane Library, Embase, PubMed, and Web of Science from inception to August 2022. This study was registered in PROSPERO (No. CRD42022352934). The A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR -2) tool and the Preferred Reporting Item for Systematic Review and Meta -analysis 2009 (PRISMA 2009) statement were used to evaluate the methodological and reporting quality of the included SRs. Stata 15/SE was used to reanalyse the data using the random -effects model, and the risk of bias of observational studies from included SRs was reassessed using the Newcastle -Ottawa Scale (NOS) tool. The certainty of the evidence body was assessed using the GRADE recommendation. RESULTS Seven SRs were included in the umbrella review. Among them, nine observational studies (5 cross-sectional and 4 cohort studies), whose available data were resynthesised using meta -analysis. The methodological and reporting quality of the included SRs were relatively poor. The meta -analysis results revealed suggestive evidence of an association between high UPF consumption and the incidence of hypertension (odds ratio: 1.23, 95% con fidence interval: 1.11 to 1.37, p < 0.001, 95% prediction interval: 0.92 to 1.64, critically low certainty) compared to low UPF consumption. CONCLUSION High UPF consumption is associated with an increased risk of hypertension. However, well-conducted SRs, including high -quality prospective cohort studies, are needed to further verify these findings.

Consumption of ultra-processed foods (UPFs) is associated with various adverse health outcomes, which significantly influence the global disease burden. This umbrella review aimed to fill the knowledge gap and guide public health practices by summarizing the association between UPFs and multiple health outcomes. A total of four databases were systematically searched from inception to December 2022, and 14 eligible systematic re-views (SRs) with meta-analyses (MAs) were identified. The SRs were published in 10 journals from 2020 to 2023, with 54,147-5,750,133 participants and 5-61 studies. The overall corrected covered area (CCA) was corresponded to a slight overlap. The results showed that an increased UPFs consumption is associated with multiple health outcomes (e.g., obesity, diabetes, hypertension, mortality). Only two SRs were "Moderate" regarding the overall methodological quality, while the other twelve were "Low" or "Critically low". Therefore, well-conducted SRs with high-quality prospective cohorts with a particular focus on special populations are needed to verify these findings further.

ObjectiveTo compare the outcomes associated with the use of lasmiditan, rimegepant, ubrogepant, and zavegepant for the acute management of migraine headaches.MethodsWe searched four electronic databases from database inception to August 31, 2023, to identify randomized controlled trials (RCTs) that report efficacy and safety for the acute treatment of migraine. The risk of bias in the included RCTs was evaluated according to the Cochrane tool, and the certainty of evidence using the CINeMA approach. We conducted frequentist network meta-analyses (NMA) to summarise the evidence. Data were analyzed using R-4.3.1.ResultsA total of 18 eligible studies including 10 different types of interventions with 22,429 migraine patients were included. NMA results showed that compared to ubrogepant (25 mg and 50 mg) and zavegepant, lasmiditan (100 mg and 200 mg) exhibits an elevated probability of achieving pain relief within a 2-hour interval. Similarly, relative to zavegepant, rimegepant (75 mg) and ubrogepant (50 mg and 100 mg) demonstrate an enhanced likelihood of sustaining pain relief over a 24-hour period. Furthermore, in contrast to ubrogepant (25 mg) and lasmiditan (50 mg), rimegepant (75 mg) presents a heightened probability of achieving freedom from photophobia within 2 h. Regarding safety, lasmiditan carries the highest risk of adverse events, which are associated with an increased incidence of adverse effects, including dizziness, somnolence, asthenia, paresthesia, and fatigue.ConclusionsIn this NMA, a spectrum of evidence ranging from very low to high levels underscores the favorable efficacy and tolerability of rimegepant 75 mg and ubrogepant 100 mg, positioning them as potential candidates for the acute management of migraine. Concurrently, lasmiditan (100 mg and 200 mg) exhibits notable efficacy, albeit accompanied by an increased susceptibility to adverse events. These findings should still be approached with caution, primarily due to the intrinsic limitations associated with indirect comparisons.

The effect of various exercise modalities on people with sleep disorders remains unclear. This network meta analysis aims to explore the effects of various exercise modalities in improving sleep quality in people with sleep disorders. Four electronic databases were searched from inception to April 8, 2023. We conducted pairwise meta-analyses and frequentist network meta-analyses with random effects models. A total of 17 randomized controlled trials enrolled 1090 participants were included. Compared with passive control, with moderate-to-low certainty of evidence, mind-body exercise combined with treatment as usual [standard mean difference (SMD) =-2.26, 95% confidence interval (CI) (-3.29,-1,24)], moderate aerobic exercise combined with light strength exercise [SMD =-1.26, 95% CI (-2.22,-0.31)], mind-body exercise [SMD =-0.81, 95% CI (-1.37,-0.25)] and moderate aerobic exercise [SMD =-0.75, 95% CI (-1.38,-0.13)] were more effect in improving sleep disorders. Various exercise modalities have favorable effects on sleep quality for people with sleep disorders compared with passive control. However, due to the low quality of evidence, well-designed trials should be conducted to elucidate these promising findings in the future.

ObjectiveTo investigate the most effective and best-tolerated drugs for treating diseased smokers.MethodsEight databases were searched for randomized controlled trials (RCTs) involving different pharmacological interventions for smoking cessation in disease patients (January 2023). Network meta-analysis was performed using STATA 15.1 software. The Cochrane Risk of Bias Tool assessed the risk of bias, and confidence in evidence was assessed using CINeMA.ResultsA total of 60 RCTs involving 13,009 patients of 12 disease categories were included. All trials reported 13 interventions, resulting in 78 comparisons. Network meta-analysis showed that varenicline (OR = 2.30, 95% CI (1.77, 3.00)) and bupropion (OR = 1.65, 95% CI (1.29, 2.11)) showed favorable abstinence effects compared to placebo in the cardiovascular disease population. Nicotine replacement therapy (NRT) had better withdrawal advantages than placebo (OR = 11.18, 95% CI (2.25, 55.54)) in the chronic obstructive pulmonary disease (COPD) population. Some combination treatments showed better results than monotherapy, such as bupropion + NRT was superior to bupropion (OR = 8.45, 95% CI (1.84, 38.89)) and NRT (OR = 4.98, 95% CI (1.25, 19.78)) in mental illness population. The final surface under the cumulative ranking curve indicated that bupropion + NRT achieved the best smoking cessation effect. Overall confidence in the evidence was low. In a comparison of drugs, the results showed that bupropion + NRT had the best safety.ConclusionsMost interventions show the benefit of quitting smoking compared with placebo, including monotherapy and combination therapy. Moreover, varenicline or bupropion combined with NRT is superior to some monotherapies.

This is the protocol for a Campbell systematic review. The objectives are as follows. The objectives of the present study are to answer the following questions: (1) What types of home-based interventions are currently being studied to prevent child neglect? (2) How effective are the different home-based interventions for preventing child neglect? (3) What are the causes of heterogeneity among included studies and their impact on study effects?

ObjectiveInternet-based cognitive behavior therapy (ICBT) may provide an accessible alternative to face-to-face treatment, but the evidence base in adolescents is limited. This systematic review and meta-analysis aims to comprehensively assess the efficacy of ICBT in addressing depression among adolescents.MethodsFour electronic databases were searched on June 8, 2023. Randomized controlled trials (RCTs) evaluating the efficacy of ICBT for depression in adolescents were included. The quality of the studies was assessed using the risk of bias tool recommended by the Cochrane Handbook. Furthermore, the GRADE approach was employed to gauge the certainty of the obtained evidence. Meta-analysis was conducted using RevMan 5.4, and Egger's test was implemented through Stata for assessment of potential publication bias.ResultsA total of 18 RCTs involving 1683 patients were included. In comparison to control groups like attention control, waiting list, and treatment as usual, our meta-analysis findings elucidate a significant reduction in depression scores (SMD = −0.42, 95 % CI: [−0.74, −0.11], p .05).ConclusionResults provide evidence of the efficacy of ICBT to reduce depressive and anxiety symptoms in adolescents. These research findings are of vital significance for the establishment of evidence-based treatment guidelines in the digital era.Trial registrationPROSPERO registration: CRD42021277562

Objective: An overview, meta-analysis, and trial sequential analysis were conducted to evaluate the efficacy and safety of varenicline for smoking cessation. Methods: Systematic reviews (SRs) and randomized controlled trials evaluating varenicline versus placebo for smoking cessation were included. A forest plot was used to summarize the effect size of the included SRs. Traditional meta-analysis and trial sequential analysis (TSA) were performed using Stata software and TSA 0.9 software, respectively. Finally, the Grades of Recommendation, Assessment, Development, and Evaluation approach was used to assess the quality of evidence for the abstinence effect. Results: A total of 13 SRs and 46 randomized controlled trials were included. Twelve review studies showed that varenicline was superior to placebo for smoking cessation. The meta-analysis results showed that, compared with the placebo, varenicline significantly increased the odds of smoking cessation (odds ratio = 2.54, 95% confidence interval = 2.20-2.94, P < 0.05, moderate quality). Subgroup analysis showed that there were significant differences in smokers with disease and general smokers (P < 0.05). Differences were also found in the follow-up time at 12, 24, and 52 weeks (P < 0.05). The common adverse events were nausea, vomit, abnormal dreams, sleep disturbances, headache, depression, irritability, indigestion, and nasopharyngitis (P < 0.05). The TSA results confirmed the evidence for the effect of varenicline on smoking cessation. Conclusions: Existing evidence supports the superiority of varenicline over a placebo for smoking cessation. Varenicline had mild to moderate adverse events but was well tolerated. Future trials should investigate varenicline in combination with other smoking cessation approaches and compare it with other interventions.

Background: Although non-pharmacological smoking cessation measures have been widely used among smokers, current research evidence on the effects of smoking cessation is inconsistent and of mixed quality. Moreover, there is a lack of comprehensive evidence synthesis. This study seeks to systematically identify, describe, and evaluate the available evidence for non-pharmacological interventions in smoking populations through evidence mapping (EM), and to search for best-practice smoking cessation programs. Methods: A comprehensive search for relevant studies published from the establishment of the library to January 8, 2023, was conducted in PubMed, Web of Science, Embase, the Cochrane Library, CNKI, CBM, Wan Fang, and VIP. Two authors independently assessed eligibility and extracted data. The PRISMA statement and AMSTAR 2 tool were used to evaluate the report quality and methodology quality of systematic reviews/meta-analyses (SRs/MAs), respectively. Bubble plots were utilized to display information, such as the study population, intervention type, evidence quality, and original study sample size. Results: A total of 145 SRs/MAs regarding non-pharmacological interventions for smoking cessation were investigated, with 20 types of interventions identified. The most commonly used interventions were cognitive behaviour education (n = 32, 22.07%), professional counselling (n = 20, 13.79%), and non-nicotine electronic cigarettes (e-cigarettes) (n = 13, 8.97%). Among them, counselling and behavioural support can improve smoking cessation rates, but the effect varies depending on the characteristics of the support provided. These findings are consistent with previous SRs/MAs. The general population (n = 108, 74.48%) was the main cohort included in the SRs/MAs. The total score of PRISMA for the quality of the reports ranged from 8 to 27, and 13 studies (8.97%) were rated as high confidence, and nine studies (6.21%) as moderate confidence, in the AMSTAR 2 confidence rating. Conclusions: The abstinence effect of cognitive behaviour education and money incentive intervention has advantages, and non-nicotine e-cigarettes appear to help some smokers transition to less harmful replacement tools. However, the methodological shortcomings of SRs/MAs should be considered. Therefore, to better guide future practice in the field of non-pharmacological smoking cessation, it is essential to improve the methodological quality of SRs and carry out high-quality randomized controlled trials (RCTs).

This is the protocol for an evidence and gap map. The objectives are as follows: To map available randomized control trials, economic evaluations, and systematic reviews that assess the effectiveness and cost-effectiveness of non-pharmacological interventions for older people with a diagnosis of depression and identify any existing gaps in the evidence that can inform future research.

None

Objective: The available evidence on selenium supplementation in the treatment of autoimmune thyroiditis (AIT) was inconclusive. This research serves to assess the effects of selenium supplementation in the treatment of AIT. Methods: Online databases including PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to 10 June 2022. The AMSTAR-2 tool was used to assess the methodological quality of included studies. The information on the randomized controlled trials of the included studies was extracted and synthesized. The GRADE system was used to assess the certainty of evidence. Results: A total of 6 systematic reviews with 75 RCTs were included. Only one study was rated as high quality. The meta-analysis showed that in the levothyroxine (LT4)-treated population, thyroid peroxidase antibody (TPO-Ab) levels decreased significantly in the selenium group at 3 months (SMD = -0.53, 95% CI: [-0.89, -0.17], p < 0.05, very low certainty) and 6 months (SMD = -1.95, 95% CI: [-3.17, -0.74], p < 0.05, very low certainty) and that thyroglobulin antibody (Tg-Ab) levels were not decreased. In the non-LT4-treated population, TPO-Ab levels decreased significantly in the selenium group at 3 and 6 months and did not decrease at 12 months. Tg-Ab levels decreased significantly in the selenium group at 3 and 6 months and did not decrease at 12 months. The adverse effects reported in the selenium group were not significantly different from those in the control group, and the certainty of evidence was low. Conclusion: Although selenium supplementation might reduce TPO-Ab levels at 3 and 6 months and Tg-Ab levels at 3 and 6 months in the non-LT4-treated population, this was based on a low certainty of evidence.

Introduction: Smoking is a risk factor for most chronic diseases and premature death, with a global prevalence of more than 1 billion people who smoke. This network meta-analysis aimed to investigate the impact of different behavioral interventions on smoking cessation.Methods: Four electronic databases were searched for RCTs from inception to August 29, 2022. The risk of bias for the included RCTs was evaluated using the revised version of Cochrane tool for assessing risk of bias and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The network meta-analysis was performed using Stata 16SE and R 4.1.3 software.Results: A total of 119 included RCTs enrolled 118,935 participants. For the 7-day-point prevalence abstinence rate, video counseling had a best intervention effect than brief advice, followed by financial incentives, self-help materials plus telephone counseling, motivational interview, health education, telephone counseling, and text messages. For the 30-day-point prevalence abstinence rate, face-to-face cognitive education and financial incentives were superior to brief advice. For the continuous abstinence rate, motivational interview and financial incentives were more effective than brief advice. The certainty of evidence was very low to moderate for these studies.Discussion: From the results of the network meta-analysis, different behavioral interventions resulted in positive impacts on smoking cessation compared with that of brief advice, especially video counseling, face-to-face cognitive education, and motivational interviews. Owing to the poor quality of evidence, high-quality trials should be conducted in the future to provide more robust evidence. Am J Prev Med 2023;65(2):327-336.& COPY; 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

To evaluate the effectiveness, safety and tolerability of antidepressants in helping smokers quit tobacco dependence, five databases were searched for randomized controlled trials (RCTS ) on different antidepressant interventions involving smoking cessation in populations (September 2022). The STATA 15.1 software was used to perform network meta-analysis. The Cochrane bias risk tool was used to assess the risk of bias, and CINeMA was used to evaluate the evidence credibility for the effect of different interventions on smoking cessation. In all, 107 RCTs involving 42 744 patients were included. Seven studies were rated as having a low risk of bias. All trials reported 18 interventions and 153 pairwise comparisons were generated. The network meta-analysis showed that compared with placebo, varenicline + bupropion (OR = 3.53, 95% CI [2.34, 5.34]), selegiline + nicotine replacement therapy (NRT) (OR = 3.78, 95% CI [1.20, 11.92]), nortriptyline + NRT (OR = 2.33, 95% CI [1.21, 4.47), nortriptyline (OR = 1.58, 95% CI [1.11,2.26]), naltrexone + bupropion (OR = 3.84, 95% CI [1.39, 10.61]), bupropion + NRT (OR = 2.29, 95% CI [1.87, 2.81]) and bupropion (OR = 1.70, 95% CI [1.53, 1.89]) showed benefits with respect to smoking cessation. In addition, bupropion + NRT showed better effects than bupropion (OR = 1.35, 95% CI [1.12, 1.64]) and NRT (OR = 1.38, 95% CI [1.13, 1.69]) alone. The final cumulative ranking curve showed that varenicline + bupropion was the most likely to be the best intervention. There was moderate- to very-low-certainty evidence that most interventions showed benefits for smoking cessation compared with placebo, including monotherapy and combination therapies. Varenicline + bupropion had a higher probability of being the best intervention for smoking cessation.

Background: Sedentary time in workplaces has been linked to increased risks of chronic occupational diseases, obesity, and overall mortality. Currently, there is a burgeoning research interest in the implementation of multicomponent interventions aimed at decreasing sedentary time among office workers, which encompass a comprehensive amalgamation of individual, organizational, and environmental strategies. Objective: This meta-analysis aims at evaluating the effectiveness of multicomponent interventions to mitigate occupational sedentary behavior at work compared with no intervention. Methods: PubMed, Web of Science, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from database inception until March 2023 to obtain randomized controlled trials (RCTs) assessing the efficacy of multicomponent interventions on occupational sedentary behavior among office-based workers. Two reviewers independently extracted the data and assessed the risk of bias by using the Cochrane Collaboration's risk of bias tool. The average intervention effect on sedentary time was calculated using Stata 15.1. Mean differences (MDs) with 95% CIs were used to calculate the continuous variables. Subgroup analyses were performed to determine whether sit-stand workstation, feedback, and prompt elements played an important role in multicomponent interventions. Further, the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system was used to evaluate the certainty of evidence. Results: A total of 11 RCTs involving 1894 patients were included in the analysis. Five studies were rated as low risk of bias, 2 as unclear risk of bias, and 4 as high risk. The meta-analysis results showed that compared with no intervention, multicomponent interventions significantly reduced occupational sitting time (MD=-52.25 min/8-h workday, 95% CI -73.06 to -31.44; P<.001) and occupational prolonged sitting time (MD=-32.63 min/8-h workday, 95% CI -51.93 to -13.33; P=.001) and increased occupational standing time (MD=44.30 min/8-h workday, 95% CI 23.11-65.48; P<.001), whereas no significant differences were found in occupational stepping time (P=.06). The results of subgroup analysis showed that compared with multicomponent interventions without installment of sit-stand workstations, multicomponent interventions with sit-stand workstation installment showed better effects for reducing occupational sitting time (MD=-71.95 min/8-h workday, 95% CI -92.94 to -51.15), increasing occupational standing time (MD=66.56 min/8-h workday, 95% CI 43.45-89.67), and reducing occupational prolonged sitting time (MD=-47.05 min/8-h workday, 95% CI -73.66 to -20.43). The GRADE evidence summary showed that all 4 outcomes were rated as moderate certainty. Conclusions: Multicomponent interventions, particularly those incorporating sit-stand workstations for all participants, are effective at reducing workplace sedentary time. However, given their cost, further research is needed to understand the effectiveness of low-cost/no-cost multicomponent interventions.

Background Village doctors, as gatekeepers of the health system for rural residents in China, are often confronted with adversity in providing the basic public healthcare services. Objective We sought to summarize the training contents, training method, training location, and training costs most preferred by village doctors in China and hope to provide evidence and support for the government to deliver better training in the future. Methods Eight databases were searched to include studies that reported on the training needs of village doctors in China. We undertook a systematic review and a narrative synthesis of data. Results A total of 38 cross-sectional studies including 35,545 participants were included. In China, village doctors have extensive training needs. “Clinical knowledge and skill” and “diagnosis and treatment of common disease” were the most preferred training content; “continuing medical education” was the most preferred delivery method; above county- and county-level hospitals were the most desirable training locations, and the training costs were expected to be low or even free. Conclusion Village doctors in various regions of China have similar preferences for training. Thus, future training should focus more on the training needs and preferences of village doctors.

BackgroundPharmacological treatment is common in practice and widely used for the management of insomnia. However, evidence comparing the relative effectiveness, safety, and certainty of evidence among drug classes and individual drugs for insomnia are still lacking. This study aimed to determine the relative effectiveness, safety, and tolerability of drugs for insomnia.MethodsIn this systematic review and network meta-analysis we systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and ClinicalTrials.gov, from inception to January 10, 2022 to identify randomized controlled trials that compared insomnia drugs with placebo or an active comparator in adults with insomnia. We conducted random-effects frequentist network meta-analyses to summarize the evidence, and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty, categorize interventionsand present the findings.ResultsA total of 148 articles met our eligibility criteria; these included 153 trials which enrolled 46,412 participants and assessed 36 individual drugs from eight drug classes. Compared with placebo, both subjectively and objectively measured total sleep time were significantly improved with non-benzodiazepine (subjective: mean difference [MD] 25.07, 95% confidence interval [CI] 15.49-34.64, low certainty; objective: MD 22.34, 95% CI 7.64-37.05, high certainty), antidepressants (subjective: MD 54.40, 95% CI 34.96-75.83, low certainty; objective: MD 35.64, 95% CI 13.05-58.24, high certainty), and orexin receptor antagonists (subjective: MD 21.62, 95% CI 0.84-42.40, high certainty; objective: MD 31.81, 95% CI 2.66-60.95, high certainty); of which doxepin, almorexant, suvorexant, and lemborexant were among the relatively effective drugs with relatively good tolerability and lower risks of any adverse events (AEs). Both subjectively and objectively measured sleep onset latency were significantly shortened with non-benzodiazepines (subjective: MD - 10.12, 95% CI - 13.84 to - 6.40, moderate certainty; objective: MD - 12.11, 95% CI - 19.31 to - 4.90, moderate certainty) and melatonin receptor agonists (subjective: MD - 7.73, 95% CI - 15.21 to - 0.26, high certainty; objective: MD - 7.04, 95% CI - 12.12 to - 1.95, moderate certainty); in particular, zopiclone was among the most effective drugs with a lower risk of any AEs but worse tolerability. Non-benzodiazepines could significantly decrease both subjective and objective measured wake time after sleep onset (subjective: MD - 16.67, 95% CI - 21.79 to - 11.56, moderate certainty; objective: MD - 13.92, 95% CI - 22.71 to - 5.14, moderate certainty).ConclusionsNon-benzodiazepines probably improve total sleep time, sleep onset latency, and wake time after sleep onset. Other insomnia drug classes and individual drugs also showed potential benefits in improving insomnia symptoms. However, the choice of insomnia drugs should be based on the phenotype of insomnia presented, as well as each drug's safety and tolerability.Protocol registration PROSPERO (CRD42019138790).

Background and ObjectiveConsidering that physicians and patients widely use acupuncture, it is necessary to explore its adverse effects during treatment. Herein, an evidence map was generated based on published studies to identify acupuncture-induced adverse effects and assess their severity, with the overarching goal of providing references for safe and effective implementation.MethodsA comprehensive literature search was performed in four public databases (PubMed, Embase, Web of science, and the Cochrane Library) to identify relevant studies published up to 15(th) June 2022. In addition, relevant studies were explored in the Epistemonikos database and reference lists were retrieved as a supplement. A MeaSurement Tool to Assess systematic Reviews, Version 2 (AMSTAR-2) quality assessment tool was applied to determine the methodological quality of included systematic reviews (SRs) and/or meta-analysis (MAs), whereas Microsoft Excel 2019 tool was used for data extraction and coding. Heatmaps were generated to display disease type, countries of origin for the first authors, and the sample sizes of original studies. Moreover, bubble charts comprehensively presented intervention categories, adverse reaction types, and evidence levels.ResultsA total of 535 SRs involving 33 adverse reactions were included. Among them, 22 studies were rated as high quality, 28 as moderate, 106 as low, and the rest were of critically-low quality. Numerous adverse effects were described in the studies, including syncope (86 SRs), organ or tissue injury (233 SRs), systemic reactions (113 SRs), infection (19 SRs), and other adverse events (373 SRs). Importantly, these adverse reactions were mainly associated with 19 acupuncture techniques, including electroacupuncture (n = 67), manual acupuncture (n = 47) and acupoint catgut embedding (n = 41). Furthermore, the 535 SRs described 23 diseases, among which symptoms, signs or clinical findings (83 SRs), mental, behavioral or neurodevelopmental disorders (67 SRs), and diseases of the nervous system (66 SRs) had the highest incidence.ConclusionThis evidence mapping explores the adverse effects of acupuncture, showing that there are multiple types of adverse reactions to acupuncture, with milder symptoms. The methodological assessment revealed that most of the included studies were of low- or critically low-quality. Therefore, there is a need for future randomized controlled trials and SRs to comprehensively analyze acupuncture-related adverse events in order to provide reliable and credible evidence.