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Introduction Current international guidelines recommend aerobic, resistance, and combined exercises for the management of type 2 diabetes mellitus (T2DM). In our study, we conducted a network meta-analysis to assess the comparative impact of different exercise training modalities on glycemic control, cardiovascular risk factors, and weight loss in patients with T2DM. Methods We searched five electronic databases to identify randomized controlled trials (RCTs) that compared the differences between different exercise training modalities for patients with T2DM. The risk of bias in the included RCTs was evaluated according to the Cochrane tool. Network meta-analysis was performed to calculate mean difference the ratio of the mean and absolute risk differences. Data were analyzed using R-3.4.0. Results A total of 37 studies with 2208 patients with T2DM were included in our study. Both supervised aerobic and supervised resistance exercises showed a significant reduction in HbA1c compared to no exercise (0.30% lower, 0.30% lower, respectively), however, there was a less reduction when compared to combined exercise (0.17% higher, 0.23% higher). Supervised aerobic also presented more significant improvement than no exercise in fasting plasma glucose (9.38 mg/dl lower), total cholesterol (20.24 mg/dl lower), triacylglycerol (19.34 mg/dl lower), and low-density lipoprotein cholesterol (11.88 mg/dl lower). Supervised resistance showed more benefit than no exercise in improving systolic blood pressure (3.90 mmHg lower]) and total cholesterol (22.08 mg/dl lower]. In addition, supervised aerobic exercise was more powerful in improving HbA1c and weight loss than unsupervised aerobic (HbA1c: 0.60% lower; weight loss: 5.02 kg lower) and unsupervised resistance (HbA1c: 0.53% lower) exercises. Conclusion Compared with either supervised aerobic or supervised resistance exercise alone, combined exercise showed more pronounced improvement in HbA1c levels; however, there was a less marked improvement in some cardiovascular risk factors. In terms of weight loss, there were no significant differences among the combined, supervised aerobic, and supervised resistance exercises. Trial registration Our study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO); registration number: CRD42017067518 .

Introduction The second most prevalent cause of dementia is vascular dementia (VaD). Furthermore, acupuncture is a relatively safe and effective traditional therapy. We performed a network meta-analysis to assess the effectiveness and safety of various acupuncture therapies for VaD based on the existing research. Methods To screen for randomized controlled trials (RCTs) comparing different acupuncture treatments in VaD patients, we searched seven electronic databases. The Cochrane tool (Review Manager 5.3) was used to evaluate the risk of bias of the included RCTs. Based on the Grading of Recommendations Assessment, Development and Evaluation framework, we assessed the confidence in the evidence using the Confidence In the results from Network Meta-Analysis approach. We used the frequency approach to perform the network meta-analysis. Data were analyzed using R-4.1.1. Results In total, we included 47 eligible studies. The results of the network analysis showed that the combined interventions of moxibustion (MB) with body acupuncture (BA) (MB + BA) and electroacupuncture (EA) with scalp acupuncture (SA) with BA (EA + SA + BA) were more effective in improving cognitive functions and ability of daily life as compared to SA or BA alone. However, in the subgroup analysis, EA + SA + BA showed better efficacy in short- and mid-term acupuncture as compared with other acupuncture therapies. Conclusion Combined acupuncture therapy may be a safe and effective intervention for individuals with VaD, and MB + BA and EA+SA+BA appear to be the most effective interventions. However, because this study’s analysis was based on low-to-moderate evidence, there remains no strong supporting evidence. High-quality, large-scale, and long-term studies should be conducted in the future to assess the effectiveness and safety of acupuncture in VaD.

To optimize patient outcomes, healthcare decisions should be based on the most up-to-date high-quality evidence. Randomized controlled trials (RCTs) are vital for demonstrating the efficacy of interventions; however, information on how an intervention compares to already available treatments and/or fits into treatment algorithms is sometimes limited. Although different therapeutic classes are available for the treatment of chronic obstructive pulmonary disease (COPD), assessing the relative efficacy of these treatments is challenging. Synthesizing evidence from multiple RCTs via meta-analysis can help provide a comprehensive assessment of all available evidence and a “global summary” of findings. Pairwise meta-analysis is a well-established method that can be used if two treatments have previously been examined in head-to-head clinical trials. However, for some comparisons, no head-to-head studies are available, for example the efficacy of single-inhaler triple therapies for the treatment of COPD. In such cases, network meta-analysis (NMA) can be used, to indirectly compare treatments by assessing their effects relative to a common comparator using data from multiple studies. However, incorrect choice or application of methods can hinder interpretation of findings or lead to invalid summary estimates. As such, the use of the GRADE reporting framework is an essential step to assess the certainty of the evidence. With an increasing reliance on NMAs to inform clinical decisions, it is now particularly important that healthcare professionals understand the appropriate usage of different methods of NMA and critically appraise published evidence when informing their clinical decisions. This review provides an overview of NMA as a method for evidence synthesis within the field of COPD pharmacotherapy. We discuss key considerations when conducting an NMA and interpreting NMA outputs, and provide guidance on the most appropriate methodology for the data available and potential implications of the incorrect application of methods. We conclude with a simple illustrative example of NMA methodologies using simulated data, demonstrating that when applied correctly, the outcome of the analysis should be similar regardless of the methodology chosen. Plain Language Summary There are several different treatments available for chronic obstructive pulmonary disease (COPD). Finding out which of these treatments is the most effective is difficult, especially if conflicting results from clinical trials have been reported, or if treatments have never been directly compared to each other. Meta-analysis allows the results from multiple studies to be combined together to give a single summary of findings. This can be useful in cases where previous trials have shown contradictory findings. However, this method can only be used if there is more than one study looking at the same two treatments (e.g., several studies that compared treatment A to treatment B). For treatments that have never been compared in clinical trials, network meta-analysis (NMA) can be used. This method allows several treatments to be compared at the same time using the results from trials comparing different treatments. This method creates ‘indirect evidence’. Indirect evidence refers to cases where two treatments have never been directly compared to each other in a clinical study, but both have been separately compared to a common treatment (e.g., treatment A and treatment C have never been directly compared to each other, but both have been separately compared to treatment B in a clinical study). NMA can be carried out using different methods. However, if the correct method is not chosen, this can lead to inaccurate results. It is becoming more common for NMA findings to be used to help make clinical decisions. Therefore, it is important that healthcare professionals are able to assess the results of published NMAs, including the methods used, to find the most appropriate results to support their clinical decisions. This tutorial provides an overview of different NMA methods, with a focus on the use of these methods within the context of COPD treatments. We also present an example where we use various NMA methods on the same data set to show that different methods should lead to similar results if the methods are used correctly.

ObjectivesTo compare the effectiveness of remineralizing agents in the prevention and reversal of white spot lesions (WSLs), which occur during fixed orthodontic treatment, through a systematic review and network meta-analysis.Materials and methodsWe reviewed controlled randomized clinical trial (RCT) data querying nine databases combined with a manual search (last search date: March 10, 2020). Of 2273 identified studies, 36 RCTs were finally included. After study selection and data extraction, pair-wise and network meta-analyses were performed to analyze the effectiveness of remineralizing agents in the prevention and reversal of WSLs in the short term (≤ 3 months) and long term (> 3 months). The risk of bias was assessed based on the Cochrane guidelines. Statistical heterogeneity, inconsistencies, and cumulative ranking were also evaluated.ResultsIn terms of WSL prevention, sodium fluoride (NaF) varnish had the highest cumulative ranking for the short-term decalcification index (99.3%); acidulated phosphate fluoride (APF) foam ranked first for long-term incidence (96.9%), followed by difluorosilane (Dfs) varnish and high-concentration fluoride toothpaste (HFT) (79.4% and 77.4%, respectively). In the reversal of WSLs, no significant difference was found among different agents or their combinations for the two available outcomes (short-term integrated fluorescence loss and short-term percentage of fluorescence loss).ConclusionsIn the prevention of WSLs, APF foam showed the best remineralizing effectiveness in the long term (after debonding), followed by Dfs varnish and HFT. It is unclear whether remineralizing agents can effectively reverse WSLs based on the existing evidence.Clinical RelevanceAPF foam may be recommended as a remineralizing agent for preventing orthodontically induced WSLs.PROSPERO registration numberCRD42019116852.

Commercial Chinese polyherbal preparations (CCPPs) are widely used in China to treat coronary microvascular dysfunction (CMD). However, the discussion on the best CCPPs continues. This network meta-analysis (NMA) aimed to evaluate and rank the relative efficacy of CCPPs for CMD and summarize the possible mechanisms according to experimental researches. From the time the database was established to 12 December 2024, We systematically searched eight databases and two registry systems, including Web of Science, Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang database, China Science and Technology Journal Database (VIP), Chinese Biomedical Literature database (CBM), Clinical Trials, and the China Clinical Trials Registry. Clinical randomized controlled trials (RCTs) of nine CCPPs in treating CMD, including Shexiangbaoxin Pill (SXBX), Tongxinluo Capsule (TXL), Shexiangtongxindi Pill (SXTXD), Yindanxinnaotong Capsule (YDXNT), Kedalin Tablet (KDL), Xinbao Pill (XB), Xinkeshu Tablet (XKS), Diaoxinxuekang Capsule (DAXXK), and Yixintongluo Capsule (YXTL), were retrieved. The primary outcomes were the Index of Microcirculatory Resistance (IMR) and Coronary Flow Reserve (CFR). Secondary outcomes included the Angina attack frequency, hypersensitive C-reactive protein (hs-CRP), Endothelin-1 (ET-1), Nitric oxide (NO), and Low-density lipoprotein cholesterol (LDL-C). Two researchers performed rigorous data extraction and quality assessment. The quality of the included RCTs was evaluated using the Cochrane Risk of Bias assessment tool, version 2.0 (RoB 2). We then conducted the NMA using a random-effects model under the frequentist framework with Stata version 15. Interventions were ranked based on the surface under the cumulative ranking curve (SUCRA) probability values. The risk of bias was detected using funnel plots and Egger's test. A total of 39 RCTs involving 3,240 patients were included in this study. NMA results showed that SXBX had the highest probability of being the best treatment on account of the reduction of IMR [MD = -5.93, 95% CI (-8.75, -3.11)] and LDL-C [[MD = -0.56, 95% CI (-0.99, -0.14)], XB showed better efficacy in improving CFR [MD = 0.71, 95% CI (0.53, 0.89)], TXL showed better efficacy in angina attack frequency [MD = -5.30, 95% CI (-7.08, -3.53)]; YXTL showed better efficacy in hs-CRP [MD = -5.04, 95% CI (-8.38, -1.7)]; XKS showed better efficacy in ET-1 [MD = -43.3, 95% CI (-59.71, -26.89)]; YDXNT showed better efficacy in NO [MD = 17.69, 95% CI (6.07, 29.32)]. In addition, the protective effect of CCPP on CMD may be achieved by altering multiple signalling pathways through anti-atherosclerosis, anti-vascular smooth muscle cell proliferation and migration, anti-inflammation, antioxidant stress, protection of vascular endothelium, improving energy metabolism, antiplatelet activation and aggregation, and promoting angiogenesis. CCPPs combined with conventional therapy led to a significant improvement in CFR and NO, as well as a reduction in IMR, angina attack frequency, hs-CRP, ET-1, and LDL-C levels. SXBX emerged as the optimal treatment regimen for lowering IMR and LDL-C levels. Additionally, XB demonstrated superiority in improving CFR. TXL demonstrated superiority in reducing angina attack frequency, YXTL in lowering hs-CRP levels, XKS in lowering ET-1 levels, and YDXNT in increasing NO levels. Nevertheless, the majority of the evidence was rated as low certainty according to the GRADE assessment. Conclusion should be framed as hypothesis-generating rather than definitive, and there is a need for large-scale, multicenter, and direct comparative RCTs of CCPPs treated for CMD to generate higher-quality evidence. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42025632143.

RationaleMitochondrial dysfunctions have emerged as new biological hypothesis and therapeutic target for bipolar disorder. This network meta-analysis has been done to evaluate the comparative efficacy of mitochondrial agents in bipolar depression.MethodsAfter a comprehensive literature search on PubMed/MEDLINE, Cochrane databases, and International Trials Registry Platform, efficacy data were extracted from 15 randomized controlled trials. Random-effects meta-analysis was done following both frequentist and Bayesian approaches to pool the effects across the interventions. A network graph was built, relative effects of interventions in respect to one another and placebo were calculated, and treatments were ranked as per P- and SUCRA scores. Change in depression rating score was the primary outcome. Data was entered in contrast level and arm level for frequentist and Bayesian approaches, respectively.ResultsAmongst mitochondrial agents, N-acetylcysteine (NAC) was shown to have the highest probability of being the best treatment, followed by coenzyme Q10 and combination therapy of alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) as depicted by P- and SUCRA scores. In the Bayesian approach, none of the treatments had better efficacy than placebo, but in the frequentist approach, NAC (effect estimate: − 1.18 (95% CI: − 2.05; − 0.31)) was significantly better than placebo.ConclusionMethodically, there may be a difference of magnitude in frequentist and Bayesian approaches, but the direction of effect and ranking probabilities do not differ. We conclude that none of the existing mitochondrial agents showed better efficacy than placebo in bipolar depression regarding depression rating scores.

To illustrate that bias associated with indirect treatment comparison and network meta-analyses can be reduced by adjusting for outcomes on common reference arms. Approaches to adjusting for reference-arm effects are presented within a causal inference framework. Bayesian and Frequentist approaches are applied to three real data examples. Reference-arm adjustment can significantly impact estimated treatment differences, improve model fit and align indirectly estimated treatment effects with those observed in randomized trials. Reference-arm adjustment can possibly reverse the direction of estimated treatment effects. Accumulating theoretical and empirical evidence underscores the importance of adjusting for reference-arm outcomes in indirect treatment comparison and network meta-analyses to make full use of data and reduce the risk of bias in estimated treatments effects. Indirect treatment comparisons (ITCs) and network meta-analyses (NMAs) can help decision makers compare therapies that lack head-to-head randomized trials. However, these estimates are vulnerable to biases due to cross-trial differences in patient characteristics and other factors. In this study, we outline methods to reduce biases associated with ITC/NMA and apply them to three real-world examples (antiretroviral therapy for human immunodeficiency virus, treatments for Type 2 diabetes and biological treatments for psoriasis). Our results show that reference-arm adjustment can have a significant impact on indirectly estimated treatment effects and can improve consistency between indirect evidence and gold-standard evidence from randomized trials. ITC and NMA without reference-arm adjustment present an avoidable risk of misleading or biased treatment effects. We argue that reference-arm adjustment should always be considered and reported when feasible in ITC and NMA.

In this systematic review and network meta-analysis (NMA), we aimed to assess the benefits and harms of third-line (L3) treatments in randomized controlled trials (RCTs) of patients with metastatic castration-resistant prostate cancer (mCRPC). Two reviewers searched for publications from 1 January 2006 to 30 June 2021. The review analyzed seven RCTs that included 3958 patients and eight treatments. Treatment with prostate-specific membrane antigen (PSMA)-based radioligand therapy (PRLT) resulted in a 1.3-times-higher rate of median PSA decline ≥50% than treatment with abiraterone, enzalutamide, mitoxantrone, or cabazitaxel (p = 0.00001). The likelihood was 97.6% for PRLT to bring about the best PSA response, out of the examined treatments. PRLT resulted in a 1.1-times-higher six-month rate of median radiographic progression-free survival. Treatment with PRLT in the VISION trial resulted in 1.05-times-higher twelve-month median overall survival than L3 treatment with cabazitaxel in other RCTs. PRLT more often resulted in severe thrombocytopenia and less often in severe leukopenia than did cabazitaxel. In conclusion, for patients with mCRPC, L3 treatment with PRLT is highly effective and safe.

Introduction No hierarchy of first-line treatments for anogenital warts (AGWs) is provided in international guidelines. This study aimed to determine the efficacy of topical treatments and ablative procedures for the management of AGWs. Methods Twelve electronic databases were systematically searched from inception to August 2018. All randomized controlled trials (RCTs) comparing immunocompetent adults with AGWs who received at least 1 provider-administered or patient-administered treatment in at least 1 parallel group were included. Risk of bias assessment followed the Cochrane Handbook. The study endpoint was complete lesion response after clearance and recurrence assessment. A network meta-analysis was performed. Results A network geometry was constructed based on 49 of the 70 RCTs included in our systematic review. All but 4 RCTs had a high risk of bias. The most efficacious treatments compared to placebo were surgery (RR 10.54; CI 95% 4.53–24.52), ablative therapy + imiquimod (RR 7.52; CI 95% 4.53–24.52), and electrosurgery (RR 7.10; CI 95% 3.47–14.53). SUCRA values confirmed the superiority of surgery (90.9%), ablative therapy + imiquimod (79.8%), and electrosurgery (77.1%). The most efficacious patient-administered treatments were podophyllotoxin 0.5% solution (63.5%) and podophyllotoxin 0.5% cream (62.2%). Conclusions With low-level evidence of most included RCTs, surgery and electrosurgery were superior to other treatments after clearance and recurrence assessment. Podophyllotoxin 0.5% was the most efficacious patient-administered treatment. Combined therapies should be evaluated in future RCTs in view of their identified effectiveness. The results of future RCTs should systematically include clinical type, number and location of AGWs, and sex of the patient, to refine therapeutic indications. Protocol Registration PROSPERO-CRD42015025827