The findings concerning the association between endocannabinoid system (ECS) and Alzheimer\'s disease (AD) exhibited inconsistencies when examining the expression levels of endocannabinoids. This study aimed to provide a comprehensive summary of the studies regarding alterations of the ECS in AD. Six databases were thoroughly searched for literature to select relevant studies investigating the ECS in AD, including changes in cannabinoid receptors (CB1R and CB2R), endocannabinoids (2-AG and AEA), and their associated enzymes (FAAH and MAGL). Traditional meta-analysis evaluated the expression levels of the ECS in AD, and the results showed no significant differences in ECS components between healthy controls and AD patients. However, subgroup analysis revealed significantly lower expression levels of CB1R in AD than in controls, particularly in studies using western blot (SMD = -0.88, p < 0.01) and in studies testing CB1R of frontal cortex (SMD = -1.09, p < 0.01). For studies using HPLC, the subgroup analysis indicated significantly higher 2-AG levels in AD than in controls (SMD = 0.46, p = 0.02). Network meta-analysis examined the rank of ECS alterations in AD compared to controls, and the findings revealed that 2-AG and MAGL exhibited the largest increase and CB1R showed the largest decrease relative to the control group. Based on the findings of traditional meta-analysis and network meta-analysis, we proposed that AD patients may present decreased expression levels of CB1R and increased expression levels of 2-AG and its degrading enzyme MAGL. Our results may contribute to the growing body of research supporting the therapeutic potential of ECS modulation in the management of AD.

BACKGROUND: Influenza vaccines are available to help protect persons aged ≥65 years, who experience thousands of influenza hospitalizations annually. Because some influenza vaccines may work better than others, we sought to assess benefit of high-dose (HD), adjuvanted (ADJ), and recombinant (RIV) influenza vaccines (\"enhanced influenza vaccines\") compared with standard-dose unadjuvanted influenza vaccines (SD) and with one another for prevention of influenza-associated hospitalizations among persons aged ≥65 years.
METHODS: We searched MEDLINE, Embase, CINAHL, Scopus, and Cochrane Library to identify randomized or observational studies published between January 1990 and October 2023 and reporting relative vaccine effectiveness (rVE) of HD, ADJ, or RIV for prevention of influenza-associated hospitalizations among adults aged ≥65 years. We extracted study data, assessed risk of bias, and conducted random-effects network meta-analysis and meta-regression.
RESULTS: We identified 32 studies with 90 rVE estimates from five randomized and 27 observational studies (71,459,918 vaccinated participants). rVE estimates varied across studies and influenza seasons. Pooled rVE from randomized studies was 20% (95% CI -54 to 59) and 25% (95% CI -19 to 53) for ADJ and HD compared with SD, respectively; rVE was 6% (95% CI -109 to 58) for HD compared with ADJ; these differences were not statistically significant. In observational studies, ADJ, HD, and RIV conferred modestly increased protection compared with SD (rVE ranging from 10% to 19%), with no significant differences between HD, ADJ, and RIV. With enhanced vaccines combined, rVE versus SD was 18% (95% CI 3 to 32) from randomized and 11% (95% CI 8 to 14) from observational evidence. Meta-regression of observational studies suggested that those requiring laboratory confirmation of influenza reported greater benefit of enhanced vaccines.
CONCLUSIONS: HD, ADJ, and RIV provided stronger protection than SD against influenza hospitalizations among older adults. No differences in benefit were observed in comparisons of enhanced influenza vaccines with one another.

BACKGROUND: Cancer cachexia affects more than half of all cancer patients, reducing survival rates. Evidence-based approaches are urgently needed to optimize treatment.
METHODS: A systematic review and network meta-analysis were conducted to assess the effectiveness and safety of different pharmacotherapies for cancer cachexia. Three databases (PubMed, Cochrane Library, and Web of Science) were searched for the period from January 1, 2000, to March 20, 2024. The netmeta package in R software was used to calculate the pooled effect, employing a random effects model.
RESULTS: Seven placebo-controlled randomized trials involving 1421 patients were analyzed. Pairwise analysis showed that body weight increases were 4.6 kg (95% confidence interval [CI] 0.83-8.37 kg) for olanzapine, 3.82 kg (95% CI 0.73-6.91 kg) for espindolol (20 mg), 2.36 kg (95% CI 1.84-2.89 kg) for anamorelin (100 mg), and 1.31 kg (95% CI 0.42-2.19 kg) for anamorelin (50 mg). In terms of safety profiles, olanzapine demonstrated the lowest odds ratio when compared to placebo, at 0.26 (95% CI 0.07-0.94), followed by anamorelin (50 mg) at 0.86 (95% CI 0.30-2.48), and anamorelin (100 mg) at 0.89 (95% CI 0.42-1.88). However, network meta-analysis could not confirm the superiority of olanzapine over anamorelin in terms of efficacy and safety.
CONCLUSIONS: Both olanzapine and anamorelin are useful in improving body weight in patients with cancer cachexia. Personalization may be helpful for different patients.

OBJECTIVE: Eczema is the most burdensome skin condition worldwide and topical anti-inflammatory treatments are commonly used to control symptoms. The relative effectiveness and safety of different topical anti-inflammatory treatments is uncertain.
METHODS: Network meta-analysis performed within a Cochrane systematic review to compare and statistically rank efficacy and safety of topical anti-inflammatory eczema treatments.
METHODS: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to June 2023.
UNASSIGNED: Included trials were within-participant or between-participant randomised controlled trials. Participants had eczema that was not clinically infected and was not contact dermatitis, seborrheic eczema or hand eczema. Interventions were topical anti-inflammatory treatments but not complementary treatments, antibiotics alone, wet wraps, phototherapy or systemic treatments. Comparators were no treatment/vehicle or another topical anti-inflammatory.
RESULTS: We identified 291 trials (45,846 participants), mainly in high-income countries. Most were industry-funded with median 3 weeks treatment duration. Risk of bias assessed using the Cochrane Risk of Bias 2.0 tool was high in 89% of trials, mainly due to risk of selective reporting. Network meta-analysis of binary outcomes ranked potent and/or very potent topical steroids, tacrolimus 0.1% and ruxolitinib 1.5% among the most effective treatments for improving patient-reported symptoms (40 trials, all low confidence) and clinician-reported signs (32 trials, all moderate confidence). For investigator global assessment, the Janus kinas inhibitors ruxolitinib 1.5%, delgocitinib 0.5% or 0.25%, very potent/potent topical steroids and tacrolimus 0.1% were ranked as most effective (140 trials, all moderate confidence). Continuous outcome data were mixed. Local application site reactions were most common with tacrolimus 0.1% (moderate confidence) and crisaborole 2% (high confidence) and least common with topical steroids (moderate confidence). Skin thinning was not increased with short-term use of any topical steroid potency (low confidence) but skin thinning was reported in 6/2044 (0.3%) participants treated with longer-term (6-60 months) topical steroids.
CONCLUSIONS: Potent topical steroids, Janus kinase inhibitors and tacrolimus 0.1% were consistently ranked as among the most effective topical anti-inflammatory treatments for eczema.

OBJECTIVE: To compare the efficacy and safety of different vasodilators in the treatment of persistent pulmonary hypertension of the newborn (PPHN) by a Bayesian network meta-analysis.
METHODS: We searched databases (Cochrane, PubMed, Embase, and Web of Science) from January, 1990 up to December, 2023. Randomized controlled trials on the use of vasodilators in the treatment of PPHN. We extracted details of population, intervention, and outcome indicators. R and STATA software were used for data analysis. Sixteen articles were included, encompassing 776 neonates with PPHN. Among them, 12 articles were included in the quantitative analysis. The vasodilators included Sildenafil, Bosentan, Milrinone, Magnesium, Adenosine, and Tadalafil.
RESULTS: The Bayesian network meta-analysis results suggested that compared to placebo, Milrinone [OR = 0.125, 95% CI (0.0261, 0.562)], Sildenafil [OR = 0.144, 95% CI (0.0428, 0.420)], and Sildenafil_Milrinone [OR = 0.0575, 95% CI (0.00736, 0.364)] reduced the mortality, but the difference among the three was not significant. There was also no significant difference in the incidence of hypotension, the duration of mechanical ventilation, and the use of extracorporeal membrane oxygenation among the vasodilators. Compared to Bosentan, Adenosine was more effective in reducing the oxygenation index [MD = -12.78, 95% CI (-25.56, -0.03)], and Magnesium was less effective in reducing the oxygenation index than Sildenafil [MD = 5.19, 95% CI (1.23, 9.2)].
CONCLUSIONS: Milrinone, Sildenafil, and Sildenafil_Milrinone reduced the mortality of neonates with PPHN. More clinical trials are needed to verify the efficacy and safety of vasodilators in the treatment of PPHN.

Lymph node metastases (LNM) play a central role in the tumour-node-metastasis (TNM) classification for colorectal cancer (CRC), with extranodal extension (ENE) as an adverse feature. ENE has never been directly compared to tumour deposits (TD). The aim of this study was to perform an up-to-date systematic review, including a network meta-analysis to compare their prognostic value. A comprehensive search was conducted on PubMed, Embase, Web of Science and Cochrane databases to identify all prognostic studies on ENE and TD. A total of 20 studies were included, with 7719 cases. The primary outcome was 5-year disease-free survival (DFS); secondary outcomes were overall survival (OS) and disease-specific survival (DSS). Frequentist paired and network meta-analyses were performed using the netmeta package in R. For univariable DFS analysis, LNM + TD+ cases had a significantly worse outcome compared with LNM + ENE+ cases [hazard ratio (HR) = 1.27, 95% confidence interval (CI) = 1.06-1.53], which was no longer significant for multivariable DFS analysis (HR = 1.13, 95% CI = 0.87-1.46). All OS and multivariable DSS analyses showed a significantly worse outcome for LNM + TD+ cases compared with LNM + ENE cases. For all outcomes, both LNM + TD+ and LNM + ENE+ had a significantly increased hazard compared with LNM+ cases. This study shows that there is a trend towards worse outcome for LNM + TD+ than LNM + ENE+, not statistically significant in multivariable DFS analysis. Both groups perform significantly worse than cases with LNM only. To improve the accuracy of CRC staging, we recommend to put more emphasis on both ENE and TD in the TNM classification, with the most prominent role for TD.

BACKGROUND: Growing evidence suggests that immunotherapy has a positive effect on non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). However, it remains unclear which type of immunotherapy is more efficient. The aim of this network meta-analysis (NMA) was to compare the efficacy and safety of different immunotherapy types and determine the optimal option.
METHODS: Four databases (PubMed, Cochrane Library databases, Embase, and Web of Science) and ClinicalTrial.gov were searched from inception until January 26, 2023. Randomized controlled trials (RCTs), prospective nonrandomized trials, or observational studies investigating NSCLC patients with BMs treated by immunotherapy were included. The quality of the included studies was evaluated using the Cochrane risk of bias (ROB) tool and the Newcastle-Ottawa Scale (NOS). The efficacy of immunotherapy on NSCLC patients with BMs was evaluated using frequentist random-effects NMA.
RESULTS: Eleven studies from 1560 citations, encompassing 1437 participants, were included in this NMA. Statistical analysis showed that pembrolizumab (SMD = 4.35, 95% CI [2.21, 6.60]) and nivolumab+ipilimumab (SMD = 3.81, 95% CI [1.21, 6.40]) could improve overall survival (OS). Pembrolizumab (SMD = 3.32, 95% CI [2.75, 3.90]) demonstrated better effects in improving the overall response rate (ORR). No significant difference in adverse event (AE) was observed between immunotherapy and chemotherapy.
CONCLUSIONS: Our findings indicated that pembrolizumab was the most promising immunotherapy for NSCLC patients with BMs. Nivolumab+ipilimumab might be an alternative choice to improve OS.
CONCLUSIONS: Inconsistency tests were not performed because of the scarcity of direct comparison. Besides, high heterogeneity was observed in our NMA.

There has been a transition from broad to more specific research questions in the practice of network meta-analysis (NMA). Such convergence is also taking place in the context of individual registrational trials, following the recent introduction of the estimand framework, which is impacting the design, data collection strategy, analysis and interpretation of clinical trials. The language of estimands has much to offer to NMA, particularly given the \"narrow\" perspective of treatments and target populations taken in health technology assessment.

BACKGROUND: Recent advancements in advanced non-small-cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first-line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first-line treatment for KRAS-mutant NSCLC.
METHODS: We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression-free survival (PFS) and overall survival (OS). A random-effects network meta-analysis was conducted to perform direct and indirect comparisons among treatment groups.
RESULTS: Six RCTs were eligible for inclusion. In the network meta-analysis for KRAS-mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22-0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47-0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49-0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34-0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48-0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56-0.92). Regarding OS in wild-type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50-1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63-0.99).
CONCLUSIONS: The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS-mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first-line treatment.

Recently, Ades and colleagues discussed the controversies and advancements in network meta-analysis (NMA) over the past two decades, discussing its reliability, assumptions, novel approaches, and provided some useful recommendations for the conduction of NMAs. The present discussion paper builds on the insights by Ades and colleagues, providing a roadmap for NMA applications, advancements in software and tools, and approaches designed to facilitate the assessment and interpretation of NMA findings. It also discusses the impact of NMA across disciplines, particularly for policymakers and guideline developers. Despite 20 years of NMA history, challenges remain in understanding and assessing assumptions, communicating and interpreting findings, and applying common approaches like network meta-regression and NMA involving non-randomized studies in readily available software. NMA has proven particularly valuable in clinical decision-making, which highlights the need for additional training and interdisciplinary collaboration of knowledge users, including patient engagement, to enhance its adoption and address real-world problems.