Metabolic regulation of the immune system in health and diseases: mechanisms and interventions.

Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.

miRNAs in patients with alcoholic liver disease: a systematic review and meta-analysis.

INTRODUCTION: Alcoholic liver disease (ALD) encompasses a spectrum of liver conditions, including liver steatosis, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). microRNAs (miRNAs) have garnered significant interest as potential biomarkers for ALD. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) systemically from inception to June 2024. All extracted data was stratified according to the stages of ALD. The vote-counting strategy performed a meta-analysis on miRNA expression profiles. RESULTS: We included 40 studies. In serum of individuals with alcohol-use vs. no alcohol-use, miRNA-122 and miRNA-155 were upregulated, and miRNA-146a was downregulated. In patients with ALD vs. healthy controls, miRNA-122 and miRNA-155 were also upregulated, and miRNA-146a was downregulated. However, in patients with AH vs. healthy individuals, only the serum miRNA-122 level was upregulated. Due to insufficient data on diagnostic accuracy, we failed to conclude the ability of miRNAs to distinguish between different stages of ALD-related liver fibrosis. The results for ALD-related HCC were also insufficient and controversial. CONCLUSIONS: Circulating miRNA-122 was the most promising biomarker to manage individuals with ALD. More studies were needed for the diagnostic accuracy of miRNAs in ALD. REGISTRATION: This protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (www.crd.york.ac.uk/prospero/) with registration number CRD42023391931.

Early discontinuation and results reporting of robot-assisted surgery studies registered on ClinicalTrials.gov: a research on research study.

OBJECTIVES: In this study, we aimed to investigate the characteristics of robot-assisted surgery studies registered on ClinicalTrials.gov and identify factors associated with early trial discontinuation and timely results reporting. DESIGN: We searched ClinicalTrials.gov to identify interventional studies on robot-assisted surgery on 24 May 2021. All structured information of the potential studies was downloaded and reviewed. A descriptive analysis was performed. Logistic and Cox regression analyses were respectively performed to determine the significance of the association of study characteristics with results reporting and early discontinuation. RESULTS: A total of 529 interventional studies on robot-assisted surgery were included, with 45 studies reporting results and 54 studies being stopped early. Of the 289 due studies, only 45 (16%) had submitted their results, and only 6 (2%) had submitted their results within the 1-year deadline. Funding source was associated with results reporting: academic funded were 63% less likely than industry to report results (OR=0.37, 95% CI: 0.16 to 0.83, p=0.02). Studies related to device feasibility were associated with greater risk of early discontinuation compared to treatment-related studies (HR=2.30, 95% CI: 1.08 to 4.89, p=0.03). Surprisingly, National Institutes of Health-funded studies were at greater hazard of discontinuation compared to industry-funded studies (HR=3.30, 95% CI: 1.09 to 10.00, p=0.04). CONCLUSIONS: There was poor compliance with results reporting requirements for robot-assisted surgical studies. It is important that investigators remain informed about the regulatory requirements, and should be helped to develop a sense of responsibility for reporting results. Also, they need to ensure the careful design of the study protocol and adequate resources to reduce the risk of early discontinuation.

The Underappreciated Placebo Effects and Responses in Randomized Controlled Trials on Neck Pain: A Systematic Review With Meta-analysis.

OBJECTIVE: To quantify placebo effects and responses in randomized controlled trials (RCTs) on neck pain and explore how they would influence the treatment of neck pain. DATA SOURCES: We searched MEDLINE (PubMed), EMBASE (Ovid), CINAHL (EBSCO), Physiotherapy Evidence Database (PEDro), and World Health Organization International Clinical Trials Registry Platform from the inception of August 15, 2021, to identify relevant RCTs. STUDY SELECTION AND DATA EXTRACTION: The abstracts and full texts of potential studies were independently screened, and data extraction was also independently performed by 2 researchers. Scales of the score measuring neck pain and the scores both at baseline and the endpoint were extracted. DATA SYNTHESIS: A total of 60 RCTs were included. The mean improvement in the pain score after placebo treatment was 15.65 (mean difference [MD]=-15.65, 95% confidence interval; CI [-19.19, -12.12]; P<.05), which we defined as the placebo response. In the active groups, it was 25.91 (MD=-25.91, 95% CI [-29.15, -22.68]; P<.05), and in the no-treatment groups, it was 5.80 (MD=-5.80, 95% CI [13.28, 1.69]; P=.13). Using the 3 MDs from the 3 groups, the placebo effect was calculated to account for 38.0% of the pain score improvement in the active group. CONCLUSIONS: The pain scores of patients with neck pain were reduced after treatment with placebos, but the magnitude of pain score reduction was not clinically significant enough. The 38.0% amount of pain score reduction in patients treated with active interventions was caused by placebo. Interventions with considerable clinically significance for neck pain were still required.

Core outcomes were rarely reported overall in systematic reviews on acupuncture for osteoarthritis: a cross-sectional meta-epidemiological study.

OBJECTIVE: To identify a comprehensive list of outcomes and explore the reporting rate of core outcome sets (COS) and related factors in systematic reviews (SRs) of acupuncture for osteoarthritis (OA). STUDY DESIGN AND SETTING: Databases were searched for the relative SRs. Descriptive statistics were calculated as frequencies and percentages. Binary logistic regression was used to explore the factors affecting the reporting rate of COS. RESULTS: We included 59 SRs. Outcome measures reported in the SRs were classified into 11 domains and 67 unique outcomes. No SR completely reported COS. In COS released in 2016, 75% of outcomes (6/8) were only reported by ⩽5% SRs. In COS released in 2019, the reporting rate was very low (from 0% to 17%) for 73.3% of outcomes (11/15). SRs published in the most recent 5 years had a significantly greater possibility of reporting COS (odds ratio (OR) = 4.74, 95% confidence interval (CI) = 1.33 to 16.88, p = 0.016). CONCLUSION: Core outcomes were rarely reported in systematic reviews of acupuncture for OA, with considerable heterogeneity in the use of outcomes. The publication of COS in the COMET (Core Outcome Measures in Effectiveness Trials) database may help promote the reporting of COS. We encourage systematic reviewers to use relevant COS.

Endoplasmic Reticulum Stress in Hepatitis B Virus and Hepatitis C Virus Infection.

Endoplasmic reticulum (ER) stress, a type of cellular stress, always occurs when unfolded or misfolded proteins accumulating in the ER exceed the protein folding capacity. Because of the demand for rapid viral protein synthesis after viral infection, viral infections become a risk factor for ER stress. The hepatocyte is a cell with large and well-developed ER, and hepatitis virus infection is widespread in the population, indicating the interaction between hepatitis viruses and ER stress may have significance for managing liver diseases. In this paper, we review the process that is initiated by the hepatocyte through ER stress against HBV and HCV infection and explain how this information can be helpful in the treatment of HBV/HCV-related diseases.

Is the CyberKnife© radiosurgery system effective and safe for patients? An umbrella review of the evidence.

Background: The CyberKnife© system combines real-time image guidance and a dynamic tracking system to implement frameless radiotherapy. This umbrella review is aimed to evaluate the effectiveness and safety of CyberKnife. Methods: A comprehensive search of health technology assessments and systematic reviews was performed among the Embase, PubMed and other grey databases until July 2020. Treatment outcomes were extracted, and the quality of included studies were assessed using AMSTAR-2. Results: Nineteen studies were eligible. CyberKnife not only had a wide range of applications, long overall survival and great local control, but also had a limited toxicity and good cost-effectiveness compared with other radiotherapy equipment. Conclusion: Despite the relatively low quality of the evidence, our findings can still provide a decision reference for policymakers.

An umbrella review on the effectiveness and safety of the CyberKnife^© system was performed by comprehensively searching for all related publications. The CyberKnife system had excellent effect on treatment of cancer and some noncancer diseases, with limited toxicity. Additionally, it was a cost-effective treatment compared with other types of radiotherapy. Despite the relatively low quality of the included evidence, our findings can still provide a comprehensive decision reference for policymakers of patients, government and hospitals.

Characteristic and Early Discontinuation of Obsessive-Compulsive Disorder Trials Registered on ClinicalTrials.gov.

Objective: This study aimed to analyze the characteristics and reasons of early discontinuation of obsessive-compulsive disorder (OCD) trials registered on ClinicalTrials.gov. Methods: OCD trials and relevant publications were searched on ClinicalTrials.gov and PubMed, respectively. The characteristics and details regarding the timely publication of trials were recorded. Cox regression analysis was used to explore factors associated with the early discontinuation of OCD trials. Results: The analysis included 298 OCD therapy trials. Most investigations recruited <100 patients and were more likely to involve adults. Of all OCD studies identified, 67.8% were randomized and 61.4% were blind (single- or double-blind). Universities and hospitals were recorded as the two primary locations in the majority of trials. A total of 155 trials (52%) were completed; however, only 29% of those were published. Of the published trials, >70% were published at least 1 year after completion. Behavioral therapy trials were the most common type of major treatment-aimed OCD trials (39%), followed by drug trials (35.1%) and device/procedure trials (24.7%). The univariate Cox regression analysis indicated that drug trials [hazard ratio (HR) = 2.56, 95% confidence interval (CI): 1.21-5.43], absence of collaborators (HR = 3.87, 95% CI: 1.62-9.26), and sponsorship by industry (HR = 3.97, 95% CI: 1.49-10.53) were risk factors for early discontinuation of OCD trials. Further multivariate Cox regression showed that drug trials (HR = 3.93, 95% CI: 1.71-9.08) and absence of collaborators (HR = 5.17, 95% CI: 1.97-13.54) were independent risk factors for early trial discontinuation of OCD trials. The sensitivity analysis confirmed these results. Non-drug trials (OR = 3.32, 95% CI: 1.21-9.11), absence of collaborators (OR = 3.25, 95% CI: 1.10-9.60), and non-blinded trials (OR = 5.23, 95% CI: 1.05-26.2) were independent risk factors for unreported results in registry. Conclusion: The diagnosis and prevention of OCD are rarely investigated in trials. Underreporting and delayed reporting remain major problems. The type of intervention and participation of collaborators are associated with early discontinuation of OCD trials.

Serum Bilirubin Is Correlated With the Progression of IgA Vasculitis With Nephritis.

Background: Bilirubin has been identified as an endogenous antioxidant and cellular protectant. The present study was performed to clarify the potential influence of serum bilirubin on IgA vasculitis with nephritis (IgAV-N). Methods: One hundred and eighty-nine IgAV-N patients over 14 years old were enrolled. The patients were divided into two groups by the optimum cut-off value calculated by ROC curve. The composite endpoints were defined as a 60% decline in estimate glomerular filtration rate (e-GFR), end-stage renal disease (ESRD) and/or death. Kaplan-Meier (K-M) analysis and multivariate Cox analysis were carried out to determine the predictors for renal outcomes. In order to eliminate the influence of different baseline data, a 1:2 propensity score (PS) match was performed to make the results comparable and convictive. Results: The baseline data suggested that patients in low serum bilirubin group had significantly higher levels of systolic blood pressure, proteinuria, serum creatinine and crescent formation ratio and lower levels of serum albumin and hemoglobin. Renal survival analysis indicated that lower serum bilirubin levels were significantly correlated with a poorer prognosis. Multivariate Cox analysis demonstrated that the higher level of serum bilirubin was an independent protective factor for renal survival (HR, 0.172; 95% CI, 0.030-0.991; P = 0.049). After PS matching, the baseline characters of two groups had no statistical differences. Similar outcomes were demonstrated in K-M curve and the multivariate Cox analysis. Conclusion: Elevated bilirubin levels might be related to the favorable renal outcomes.

Agreement of Risk-of -Bias varied in systematic reviews on acupuncture and was associated with methodological quality.

OBJECTIVES: The objective of the study was to evaluate the consistency of risk of bias assessments for overlapping randomized controlled trials (RCTs) included in systematic reviews (SRs) on acupuncture. STUDY DESIGN AND SETTING: Databases were searched for acupuncture SRs. A weighted kappa (κ) statistic was calculated, and logistic regression was used to explore the factors of disagreements. RESULTS: We included 241 RCTs from 109 SRs on acupuncture. The percentage disagreements ranged from 25% to 44%, with moderate agreement for random sequence generation (κ = 0.57), allocation concealment (κ = 0.50), and incomplete outcome data (κ = 0.50), besides fair agreement for blinding of participants and personnel (κ = 0.44), blinding of outcome assessment (κ = 0.31), and selective reporting (κ = 0.39). Only 19% RCTs were evaluated completely consistent. Methodological quality (random sequence generation, odds ratio (OR) = 3.46), international cooperation (allocation concealment, OR = 0.14; incomplete outcome data, OR = 0.14; selective reporting, OR = 0.05), and risk of bias reporting completeness score (selective reporting, OR = 0.53) significantly affected the relative odds of disagreements. CONCLUSION: The level of agreement varied from fair to moderate agreement depending on the risk of bias domain. Methodological quality appears to be an overarching factor to account for disagreements.

The efficacy and safety of immunosuppressive therapies in the treatment of IgA nephropathy: A network meta-analysis.

Immunoglobulin A nephropathy (IgAN) is a common autoimmune glomerulonephritis that can result in end-stage renal disease (ESRD). Whether immunosuppressants are superior or equivalent to supportive care is still controversial. A network meta-analysis was conducted to compare the efficacy and safety of immunosuppressive treatment for IgAN. Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and EMBASE were searched on December 30, 2018. We used a random-effects model with a Bayesian approach to appraise both renal outcomes and serious adverse effects. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated to present the relative effects. The ranking probabilities were calculated by the surface under the cumulative ranking curve (SUCRA). In total, 24 RCTs comprising 6 interventions were analyzed. Steroids significantly delayed the progression of renal deterioration with acceptable serious adverse effects, compared with supportive care (RR = 0.28, 95% CI = 0.13-0.51, SUCRA = 48.7%). AZA combined with steroids might be an alternative immunosuppressive therapy. Tacrolimus might decrease the proteinuria level (RR = 3.1, 95% CI = 1.2-9.4, SUCRA = 66.5%) but cannot improve renal function, and the side effects of tacrolimus should not be neglected. MMF and CYC showed no superiority in the treatment of IgAN. In summary, steroids might be recommended as the first-line immunosuppressive therapy for IgAN.

Effectiveness of N95 respirators versus surgical masks against influenza: A systematic review and meta-analysis.

OBJECTIVE: Previous meta-analyses concluded that there was insufficient evidence to determine the effect of N95 respirators. We aimed to assess the effectiveness of N95 respirators versus surgical masks for prevention of influenza by collecting randomized controlled trials (RCTs). METHODS: We searched PubMed, EMbase and The Cochrane Library from the inception to January 27, 2020 to identify relevant systematic reviews. The RCTs included in systematic reviews were identified. Then we searched the latest published RCTs from the above three databases and searched ClinicalTrials.gov for unpublished RCTs. Two reviewers independently extracted the data and assessed risk of bias. Meta-analyses were conducted to calculate pooled estimates by using RevMan 5.3 software. RESULTS: A total of six RCTs involving 9 171 participants were included. There were no statistically significant differences in preventing laboratory-confirmed influenza (RR = 1.09, 95% CI 0.92-1.28, P > .05), laboratory-confirmed respiratory viral infections (RR = 0.89, 95% CI 0.70-1.11), laboratory-confirmed respiratory infection (RR = 0.74, 95% CI 0.42-1.29) and influenzalike illness (RR = 0.61, 95% CI 0.33-1.14) using N95 respirators and surgical masks. Meta-analysis indicated a protective effect of N95 respirators against laboratory-confirmed bacterial colonization (RR = 0.58, 95% CI 0.43-0.78). CONCLUSION: The use of N95 respirators compared with surgical masks is not associated with a lower risk of laboratory-confirmed influenza. It suggests that N95 respirators should not be recommended for general public and nonhigh-risk medical staff those are not in close contact with influenza patients or suspected patients.