The effect of single nucleotide polymorphisms on depression in combination with coronary diseases: a systematic review and meta-analysis.

Background: Depression and coronary heart disease (CHD) have common risk mechanisms. Common single nucleotide polymorphisms (SNPs) may be associated with the risk of depression combined with coronary heart disease. Methods: This study was designed according to the PRISMA-P guidelines. We will include case-control studies and cohort studies investigating the relationship between gene SNPs and depression and coronary heart disease comorbidities. The Newcastle-Ottawa Scale (NOS) will be used to assess the risk of bias. When measuring dichotomous outcomes, we will use the odds ratio (OR) and 95% confidence interval (95%CIs) in a case-control study. Five genetic models (allele model, homozygous model, co-dominant model, dominant model, and recessive model) will be evaluated for each included study. Subgroup analysis by ethnicity will be performed. If necessary, post hoc analysis will be made according to different types. Results: A total of 13 studies were included in this study, and the types of genes included are FKBP5 and SGK1 genes that act on glucocorticoid; miR-146a, IL-4-589, IL-6-174, TNF-α-308, CRP-717 genes that act on inflammatory mechanisms; eNOS genes from endothelial cells; HSP70 genes that act on the autoimmune response; ACE2 and MAS1 genes that act to mediate Ang(1-7) in the RAS system; 5-HTTLPR gene responsible for the transport of serotonin 5-HT and neurotrophic factor BDNF gene. There were three studies on 5-HTTLPR and BDNF genes, respectively, while there was only one study targeting FKBP5, SGK1, miR-146a, IL-4-589, IL-6-174, TNF-alpha-308, CRP-717, eNOS, HSP70, ACE2, and MAS1 genes. We did not perform a meta-analysis for genes reported in a single study, and meta-analysis was performed separately for studies exploring the 5-HTTLPR and BDNF genes. The results showed that for the 5-HTTLPR gene, there was a statistically significant association between 5-HTTLPR gene polymorphisms and depression in combination with coronary diseases (CHD-D) under the co-dominant model (LS vs LL: OR 1.76, 95%CI 1.20-2.59; SS vs LL: OR 2.80, 95%CI 1.45 to 5.41), the dominant model (LS+SS vs LL: OR 2.06, 95%CI 1.44 to 2.96), and the homozygous model (SS vs LL: OR 2.80 95%CI 1.45 to 5.5.41) were statistically significant for CHD-D, demonstrating that polymorphisms in the 5-HTTLPR gene are associated with the development of CHD-D and that the S allele in the 5-HTTLPR gene is likely to be a risk factor for CHD-D. For the BDNF gene, there were no significant differences between one of the co-dominant gene models (AA vs GG: OR 6.63, 95%CI 1.44 to 30.64), the homozygous gene model (AA vs GG: OR 6.63,95% CI 1.44 to 30.64), the dominant gene model (GA+AA vs GG: OR4.29, 95%CI 1.05 to 17.45), recessive gene model (AA vs GG+GA: OR 2.71, 95%CI 1.16 to 6.31), and allele model (A vs G: OR 2.59, 95%CI 1.18 to 5.67) were statistically significant for CHD-D, demonstrating that BDNFrs6265 gene polymorphisms are associated with the CHD-D development and that the A allele in the BDNFrs6265 gene is likely to be a risk factor for CHD-D. We analyzed the allele frequencies of SNPs reported in a single study and found that the SNPs in the microRNA146a gene rs2910164, the SNPs in the ACE2 gene rs2285666 and the SNPs in the SGK1 gene rs1743963 and rs1763509 were risk factors for the development of CHD-D. We performed a subgroup analysis of three studies involving the BDNFrs6265 gene. The results showed that European populations were more at risk of developing CHD-D than Asian populations in both dominant model (GA+AA vs GG: OR 10.47, 95%CI 3.53 to 31.08) and co-dominant model (GA vs GG: OR 6.40, 95%CI 1.98 to 20.73), with statistically significant differences. In contrast, the studies involving the 5-HTTLPR gene were all Asian populations, so subgroup analyses were not performed. We performed sensitivity analyses of studies exploring the 5-HTTLPR and BDNF rs6265 genes. The results showed that the results of the allele model, the dominant model, the recessive model, the homozygous model and the co-dominant model for both 5-HTTLPR and BDNF rs6265 genes were stable. Due to the limited number of studies of the 5-HTTLPR and BDNF genes, it was not possible to determine the symmetry of the funnel plot using Begg's funnel plot and Egger's test. Therefore, we did not assess publication bias. Discussion: SNPs of the microRNA146a gene at rs2910164, the ACE2 gene at the rs2285666 and the SGK1 gene at rs1743963 and rs1763509, and the SNPs at the 5-HTTLPR and BDNF gene loci are associated with the onset of comorbid depression in coronary heart disease. We recommend that future research focus on studying SNPs' impact on comorbid depression in coronary heart disease, specifically targeting the 5-HTTLPR and BDNF gene at rs6265. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021229371.

Aluminium adjuvants versus placebo or no intervention in vaccine randomised clinical trials: a systematic review with meta-analysis and Trial Sequential Analysis.

OBJECTIVES: To assess the benefits and harms of aluminium adjuvants versus placebo or no intervention in randomised clinical trials in relation to human vaccine development. DESIGN: Systematic review with meta-analysis and trial sequential analysis assessing the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SOURCES: We searched CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Science Citation Index Expanded and Conference Proceedings Citation Index-Science until 29 June 2021, and Chinese databases until September 2021. ELIGIBILITY CRITERIA: Randomised clinical trials irrespective of type, status and language of publication, with trial participants of any sex, age, ethnicity, diagnosis, comorbidity and country of residence. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias with Cochrane's RoB tool 1. Dichotomous data were analysed as risk ratios (RRs) and continuous data as mean differences. We explored both fixed-effect and random-effects models, with 95% CI. Heterogeneity was quantified with I2 statistic. We GRADE assessed the certainty of the evidence. RESULTS: We included 102 randomised clinical trials (26 457 participants). Aluminium adjuvants versus placebo or no intervention may have no effect on serious adverse events (RR 1.18, 95% CI 0.97 to 1.43; very low certainty) and on all-cause mortality (RR 1.02, 95% CI 0.74 to 1.41; very low certainty). No trial reported on quality of life. Aluminium adjuvants versus placebo or no intervention may increase adverse events (RR 1.13, 95% CI 1.07 to 1.20; very low certainty). We found no or little evidence of a difference between aluminium adjuvants versus placebo or no intervention when assessing serology with geometric mean titres or concentrations or participants' seroprotection. CONCLUSIONS: Based on evidence at very low certainty, we were unable to identify benefits of aluminium adjuvants, which may be associated with adverse events considered non-serious.

A new tool to assess Clinical Diversity In Meta-analyses (CDIM) of interventions.

OBJECTIVE: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions. STUDY DESIGN AND SETTING: The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups. RESULTS: CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters. CONCLUSION: CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis.

Xiao Chai Hu Tang, a herbal medicine, for chronic hepatitis B.

BACKGROUND: Chronic hepatitis B is associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming at reduction of the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, and improving health-related quality of life. The Chinese herbal medicine formula Xiao Chai Hu Tang has been used to decrease discomfort and replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Xiao Chai Hu Tang formula have never been established with rigorous review methodology. OBJECTIVES: To assess the benefits and harms of Xiao Chai Hu Tang formula versus placebo or no intervention in people with chronic hepatitis B. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, and seven other databases to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry for ongoing or unpublished trials to 1 March 2019. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing Xiao Chai Hu Tang formula versus no intervention or placebo in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B according to guidelines or as defined by the trialists. We allowed co-interventions when the co-interventions were administered equally to all the intervention groups. DATA COLLECTION AND ANALYSIS: Review authors independently retrieved data from reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risks of bias using risk of bias domains with predefined definitions. We used GRADE methodology to evaluate our certainty in the evidence. MAIN RESULTS: We included 10 randomised clinical trials with 934 participants, but only five trials with 490 participants provided data for analysis. All the trials compared Xiao Chai Hu Tang formula with no intervention. All trials appeared to have been conducted and published only in China. The included trials assessed heterogeneous forms of Xiao Chai Hu Tang formula, administered for three to eight months. One trial included participants with hepatitis B and comorbid tuberculosis, and one trial included participants with hepatitis B and liver cirrhosis. The remaining trials included participants with hepatitis B only. All the trials were at high risk of bias, and the certainty of evidence for all outcomes that provided data for analyses was very low. We downgraded the evidence by one or two levels because of outcome risk of bias, inconsistency or heterogeneity of results (opposite direction of effect), indirectness of evidence (use of surrogate outcomes instead of clinically relevant outcomes), imprecision of results (the CIs were wide), and publication bias (small sample size of the trials). Additionally, 47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review. None of the included trials aimed to assess clinically relevant outcomes such as all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, or hepatitis B-related morbidity. The effects of Xiao Chai Hu Tang formula on the proportion of participants with adverse events considered 'not to be serious' is uncertain (RR 0.43, 95% CI 0.02 to 11.98; I2 = 69%; very low-certainty evidence). Only three trials with 222 participants reported the proportion of people with detectable hepatitis B virus DNA (HBV-DNA), but the evidence that Xiao Chai Hu Tang formula reduces the presence of HBV-DNA in the blood (a surrogate outcome) is uncertain (RR 0.62, 95% CI 0.45 to 0.85; I2 = 0%; very low-certainty evidence). Only two trials with 160 participants reported the proportion of people with detectable hepatitis B virus e-antigen (HBeAg; a surrogate outcome) (RR 0.72, 95% CI 0.50 to 1.02; I2 = 38%; very low-certainty evidence) and the evidence is uncertain. The evidence is also uncertain for separately reported adverse events considered 'not to be serious'. FUNDING: two of the 10 included trials received academic funding from government or hospital. None of the remaining eight trials reported information on funding. AUTHORS' CONCLUSIONS: The clinical effects of Xiao Chai Hu Tang formula for chronic hepatitis B remain unclear. The included trials were small and of low methodological quality. Despite the wide use of Xiao Chai Hu Tang formula, we lack data on all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The evidence in this systematic review comes from data obtained from a maximum three trials. We graded the certainty of evidence as very low for adverse events considered not to be serious and the surrogate outcomes HBeAg and HBV-DNA. We found a large number of trials which lacked clear description of their design and conduct, and hence, these trials are not included in the present review. As all identified trials were conducted in China, there might be a concern about the applicability of this review outside China. Large-sized, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding are lacking.

Acupuncture for chronic hepatitis B.

BACKGROUND: Chronic hepatitis B is a liver disease associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming to reduce the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, as well as to improve health-related quality of life. Acupuncture is being used to decrease discomfort and improve immune function in people with chronic hepatitis B. However, the benefits and harms of acupuncture still need to be established in a rigorous way. OBJECTIVES: To assess the benefits and harms of acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. SEARCH METHODS: We undertook electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry (ChiCTR) for ongoing or unpublished trials until 1 March 2019. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B as defined by the trialists or according to guidelines. We allowed co-interventions when the co-interventions were administered equally to all intervention groups. DATA COLLECTION AND ANALYSIS: Review authors in pairs individually retrieved data from reports and through correspondence with investigators. Primary outcomes were all-cause mortality, proportion of participants with one or more serious adverse events, and health-related quality of life. Secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered not to be serious. We presented the pooled results as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed the risks of bias using risk of bias domains with predefined definitions. We put more weight on the estimate closest to zero effect when results with fixed-effect and random-effects models differed. We evaluated the certainty of evidence using GRADE. MAIN RESULTS: We included eight randomised clinical trials with 555 randomised participants. All included trials compared acupuncture versus no intervention. These trials assessed heterogeneous acupuncture interventions. All trials used heterogeneous co-interventions applied equally in the compared groups. Seven trials included participants with chronic hepatitis B, and one trial included participants with chronic hepatitis B with comorbid tuberculosis. All trials were assessed at overall high risk of bias, and the certainty of evidence for all outcomes was very low due to high risk of bias for each outcome, imprecision of results (the confidence intervals were wide), and publication bias (small sample size of the trials, and all trials were conducted in China). Additionally, 79 trials lacked the necessary methodological information to ensure their inclusion in our review.None of the included trials aim to assess all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. We are uncertain whether acupuncture, compared with no intervention, has an effect regarding adverse events considered not to be serious (RR 0.67, 95% CI 0.43 to 1.06; I² = 0%; 3 trials; 203 participants; very low-certainty evidence) or detectable hepatitis B e-antigen (HBeAg) (RR 0.64, 95% CI 0.11 to 3.68; I² = 98%; 2 trials; 158 participants; very low-certainty evidence). Acupuncture showed a reduction in detectable hepatitis B virus (HBV) DNA (a non-validated surrogate outcome; RR 0.45, 95% CI 0.27 to 0.74; 1 trial, 58 participants; very low-certainty evidence). We are uncertain whether acupuncture has an effect regarding the remaining separately reported adverse events considered not to be serious.Three of the eight included trials received academic funding from government or hospital. None of the remaining five trials reported information on funding. AUTHORS' CONCLUSIONS: The clinical effects of acupuncture for chronic hepatitis B remain unknown. The included trials lacked data on all-cause mortality, health-related quality of life, serious adverse events, hepatitis-B related mortality, and hepatitis-B related morbidity. The vast number of excluded trials lacked clear descriptions of their design and conduct. Whether acupuncture influences adverse events considered not to be serious is uncertain. It remains unclear if acupuncture affects HBeAg, and if it is associated with reduction in detectable HBV DNA. Based on available data from only one or two small trials on adverse events considered not to be serious and on the surrogate outcomes HBeAg and HBV DNA, the certainty of evidence is very low. In view of the wide usage of acupuncture, any conclusion that one might try to draw in the future should be based on data on patient and clinically relevant outcomes, assessed in large, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding.

Radix Sophorae flavescentis versus other drugs or herbs for chronic hepatitis B.

BACKGROUND: Hepatitis B virus (HBV) infection is a liver disease caused by hepatitis B virus, which may lead to serious complications such as cirrhosis and hepatocellular carcinoma. People with HBV infection may also have coinfections including HIV and other hepatitis viruses (hepatitis C or D), and coinfections may increase the risk of all-cause mortality. Chronic HBV infection increases morbidity, psychological stress, and it is an economic burden on people with chronic hepatitis B and their families. Radix Sophorae flavescentis, a herbal medicine, is administered mostly in combination with other drugs or herbs. It is believed that it decreases discomfort and prevents the replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Radix Sophorae flavescentis on patient-centred outcomes are unknown, and its wide usage has never been established with rigorous review methodology. OBJECTIVES: To assess the benefits and harms of Radix Sophorae flavescentis versus other drugs or herbs in people with chronic hepatitis B. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and seven other databases to December 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry for ongoing or unpublished trials to December 2018. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, or blinding, comparing Radix Sophorae flavescentis versus other drugs or herbs for people with chronic hepatitis B. In addition to chronic hepatitis B, participants could also have had cirrhosis, hepatocellular carcinoma, or any other concomitant disease. We excluded polyherbal blends containing Radix Sophorae flavescentis. We allowed cointerventions when the cointerventions were administered equally to all intervention groups. DATA COLLECTION AND ANALYSIS: Review authors in pairs individually retrieved data from published reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risk of bias using domains with predefined definitions. We conducted Trial Sequential Analyses to control the risks of random errors. We used GRADE methodology to evaluate our certainty in the evidence (i.e. "the extent of our confidence that the estimates of the effect are correct or are adequate to support a particular decision or recommendation"). MAIN RESULTS: We included 10 randomised clinical trials with 898 participants. We judged all trials at high risk of bias. The trials covered oral capsules, intravenous infusion, intramuscular injection, and acupoint (a specifically chosen site of acupuncture) injection of Radix Sophorae flavescentis with a follow-up period from 1 to 12 months. The drugs being used as a comparator were lamivudine, adefovir, interferon, tiopronin, thymosin, or other Chinese herbs. Two trials included children up to 14 years old. Participants in one trial had cirrhosis in chronic hepatitis B. None of the trials reported all-cause mortality, health-related quality of life, serious adverse events, hepatitis B-related mortality, or morbidity. We are uncertain as to whether Radix Sophorae flavescentis has a beneficial or harmful effect on adverse events considered 'not to be serious' (RR 0.86, 95% CI 0.42 to 1.75; I2 = 0%; 2 trials, 163 participants; very low-certainty evidence), as well as if it decreases or increases the proportion of participants with detectable HBV-DNA (RR 1.14, 95% CI 0.81 to 1.63; I2 = 92%; 8 trials, 719 participants; very low-certainty evidence). Radix Sophorae flavescentis showed a reduction in the proportion of participants with detectable hepatitis B virus e-antigen (HBeAg) (RR 0.86, 95% CI 0.75 to 0.98; I2 = 43%; 7 trials, 588 participants; very low-certainty evidence).Two of the 10 trials were not funded, and one received academic funding. The remaining seven trials provided no information on funding.The randomisation process in another 109 trials was insufficiently reported to ensure the inclusion of any of these studies in our review. AUTHORS' CONCLUSIONS: The included trials lacked data on all-cause mortality, health-related quality of life, serious adverse events, hepatitis-B related mortality, and hepatitis-B related morbidity. The evidence on the effect of Radix Sophorae flavescentis on the proportion of participants with adverse events considered 'not to be serious' and on the proportion of participants with detectable HBV-DNA is still unclear. We advise caution regarding the results of Radix Sophorae flavescentis showing a reduction in the proportion of people with detectable HBeAg because the trials were at high risk of bias, because it is a non-validated surrogate outcome, and because of the very low certainty in the evidence. As we were unable to obtain information on a large number of studies regarding their trial design, we were deterred from including them in our review. Undisclosed funding may have influence on trial results and lead to poor design of the trial. In view of the wide usage of Radix Sophorae flavescentis, we need large, unbiased, high-quality placebo-controlled randomised trials assessing patient-centred outcomes.

Radix Sophorae flavescentis versus no intervention or placebo for chronic hepatitis B.

BACKGROUND: Hepatitis B virus (HBV) infection, a liver disease caused by hepatitis B virus, may lead to serious complications such as cirrhosis and hepatocellular carcinoma. People with HBV infection may have co-infections including HIV and other hepatitis viruses (hepatitis C or D), and co-infection may increase the risk of all-cause mortality. Chronic HBV infection increases morbidity and psychological stress and is an economic burden on people with chronic hepatitis B and their families. Radix Sophorae flavescentis, an herbal medicine, is administered most often in combination with other drugs or herbs. It is believed that it decreases discomfort and prevents replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Radix Sophorae flavescentis for patient-centred outcomes are not known, and its wide usage has never been established with rigorous review methodology. OBJECTIVES: To assess the benefits and harms of Radix Sophorae flavescentis versus placebo or no intervention in people with chronic hepatitis B. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry for ongoing or unpublished trials. We conducted the last search in December 2018. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, or blinding, comparing Radix Sophorae flavescentis versus no intervention or placebo in people with chronic hepatitis B. We excluded polyherbal blends containing Radix Sophorae flavescentis. We allowed co-interventions when the co-interventions were administered equally to all intervention groups. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Review authors in pairs retrieved data from individual published reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented meta-analysed results as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed risk of bias using domains with pre-defined definitions. We conducted Trial Sequential Analyses to control the risk of random errors. We used GRADE methodology to evaluate our certainty in the evidence (i.e. "the extent of our confidence that the estimates of the effect are correct or are adequate to support a particular decision or recommendation"). MAIN RESULTS: We included 35 randomised clinical trials with 3556 participants. One trial compared Radix Sophorae flavescentis with placebo; the remaining 34 trials compared effects of Radix Sophorae flavescentis in addition to a co-intervention versus the same co-intervention. The included trials assessed heterogenous forms and ways of administering Radix Sophorae flavescentis (e.g. oral capsules, oral tablets, intravenous infusion, intramuscular injection, acupoint (a specifically chosen site of acupuncture) injection) with treatment duration of 1 to 24 months. Two of the trials included children up to 14 years old. Participants in two trials had cirrhosis in addition to chronic hepatitis B. All trials were assessed at high risk of bias, and certainty of the evidence for all outcomes was very low.Only one of the 35 trials assessed mortality; no deaths occurred. Ten trials assessed serious adverse events; no serious adverse events occurred. None of the trials reported health-related quality of life, hepatitis B-related mortality, or morbidity. Adverse events considered 'not to be serious' was an outcome in 19 trials; nine of these trials had zero events in both groups. Radix Sophorae flavescentis versus placebo or no intervention showed no difference in effects on adverse events considered 'not to be serious' (RR 1.10, 95% CI 0.76 to 1.59; I² = 49%; 10 trials, 1050 participants). Radix Sophorae flavescentis showed a reduction in the proportion of participants with detectable HBV-DNA (RR 0.61, 95% CI 0.55 to 0.68; I² = 56%; 29 trials, 2914 participants) and in the proportion of participants with detectable HBeAg (hepatitis B e-antigen) (RR 0.71, 95% CI 0.66 to 0.76; I² = 19%; 20 trials, 2129 participants).Seven of the 35 randomised clinical trials received academic funding from government or hospital. Four trials received no funding. The remaining 24 trials provided no information on funding.Additionally, 432 trials lacked the methodological information needed to ensure inclusion of these trials in our review. AUTHORS' CONCLUSIONS: The included trials lacked data on health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The effects of Radix Sophorae flavescentis on all-cause mortality and on the proportion of participants with serious adverse events and adverse events considered 'not to be serious' remain unclear. We advise caution in interpreting results showing that Radix Sophorae flavescentis reduced the proportion of people with detectable HBV-DNA and detectable HBeAg because the trials reporting on these outcomes are at high risk of bias and both outcomes are non-validated surrogate outcomes. We were unable to obtain information on the design and conduct of a large number of trials; therefore, we were deterred from including them in our review. Undisclosed funding may influence trial results and may lead to poor trial design. Given the wide usage of Radix Sophorae flavescentis, we need large, unbiased, high-quality placebo-controlled randomised trials in which patient-centred outcomes are assessed.

Error Matrix Tool to Overview the Validity of Evidence on Radix Sophorae flavescentis for Chronic Hepatitis B.

Objectives: To introduce a conceptualized visual error matrix tool to overview the validity of evidence by taking Radix Sophorae flavescentis for chronic hepatitis B as an example and to propose recommendations for improving clinical trial design and evidence quality. Methods: The randomized clinical trials and reviews were collected during the conduct of a Cochrane systematic review. The authors used a visual error matrix tool to overview the evidence validity by looking at systematic, random, and design error risks. Systematic errors were measured by the type of evidence. Random errors were expressed by the standard error (SE). Design errors were assessed on the priority of outcome measures and the adequacy of nine design components. Three-dimensional error matrix on benefits and harms were then constructed. Results: The authors included 6 meta-analyses and 28 randomized clinical trials. In terms of systematic errors, all reviews were at critically low quality, and all included randomized trials were assessed at high risk of bias. On this systematic error level, they found that there was substantial risk of random errors regarding all-cause mortality (SE 0.36), moderate risk regarding serious adverse events (SE 0.22), substantial risk regarding nonserious adverse events (SE 0.35), and small to moderate risk regarding surrogate outcomes such as detectable hepatitis B e-antigen (HBeAg) and detectable hepatitis B virus (HBV)-DNA (SE 0.16 and 0.21). No study reported results on quality of life, hepatitis B-related mortality, and morbidity. The design error risks were mainly misuse of outcomes (14/34), inadequate selection of participants (5/34), inadequate description of intervention (11/34) and control (9/34), single-center setting (33/34), and unclear study objective regarding superiority, equivalence, or noninferiority. Conclusion: The current evidence on Radix S. flavescentis for chronic hepatitis B showed high risks of systematic errors, moderate or high risks of random errors, and high risks of design errors. These findings suggest that more randomized trials at minimum risks of all three errors are needed to assess the benefits and harms of Radix S. flavescentis for chronic hepatitis B. The visual error matrix tool provides an overview of the reliability of evidence and may assist in design and conduct of future randomized trials.