Identification and Validation of Glomeruli Cellular Senescence-Related Genes in Diabetic Nephropathy by Multiomics.

Accumulating evidence indicates that cellular premature senescence of the glomerulus, including endothelial cells, mesangial cells, and podocytes leads to diabetic nephropathy (DN), and DN is regarded as a clinical model of premature senescence. However, the role of cellular senescence-associated genes in the glomerulus in DN progression remains unclear. Therefore, this work aims to identify and validate potential cellular aging-related genes in the glomerulus in DN to provide novel clues for DN treatment based on anti-aging. The microarray GSE96804 dataset, including 41 diabetic glomeruli and 20 control glomeruli, is retrieved from the Gene Expression Omnibus (GEO) database and cellular senescence-related genes (CSRGs) are obtained from the GeneCards database and literature reports. Subsequently, PPI, GO, and KEGG enrichment are analyzed by screening the intersection between differentially expressed genes (DEGs) and CSRGs. scRNA-seq dataset GSE127235 is used to verify core genes expression in glomerulocytes of mice. Finally, db/db mice are utilized to validate the hub gene expression in the glomeruli, and high glucose-induced mesangial cells are used to confirm key gene expression. This study reveals that FOS and ZFP36 may play an anti-aging role in DN to ameliorate cell intracellular premature aging in mesangial cells of glomeruli.

The guideline for therapeutic drug monitoring guidelines development.

AIM: The guideline is meant to standardize the principles, procedures, and methods for developing therapeutic drug monitoring (TDM) guidelines and promoting open, transparent, scientific, and credible TDM guidelines. METHODS: Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society established guideline working groups, declared and managed conflicts of interest. The guideline working groups used the Delphi method to formulate the purpose and scope of the guidelines and questions in the PICO format, searched and synthesized evidence, and integrated with the current situation in China and TDM characteristics to preliminarily develop recommendations for the guideline for TDM guideline development in China. Through internal discussions of the guideline working groups and external peer review, the content was improved, and we eventually formulated a guideline suitable for guiding TDM-related guidelines. RESULTS: The guideline provides suggestions for problems to be identified and solved in the planning, development, publishing, and updating stages of TDM guidelines, including forming guideline working groups, planning guidelines, declaration and management of interests, formulating questions and selecting outcomes, preparing the planning proposal, evidence retrieval and synthesis, evidence assessment, developing recommendations, drafting guidelines, external review guidelines, publishing and disseminating guidelines, postevaluation of guidelines, and updating guidelines. CONCLUSIONS: This guideline can provide methodological guidance and reference for the development of TDM guidelines.

The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: A systematic review and meta-analysis.

BACKGROUND: Intolerance to gastric feeding tubes is common among critically ill adults and may increase morbidity. Administration of prokinetics in the ICU is common. However, the efficacy and safety of prokinetics are unclear in critically ill adults with gastric feeding tubes. We conducted a systematic review to determine the efficacy and safety of prokinetics for improving gastric feeding tube tolerance in critically ill adults. METHODS: Randomized controlled trials (RCTs) were identified by systematically searching the Medline, Cochrane and Embase databases. Two independent reviewers extracted the relevant data and assessed the quality of the studies. We calculated pooled relative risks (RRs) for dichotomous outcomes and the mean differences (MDs) for continuous outcomes with the corresponding 95% confidence intervals (CIs). We assessed the risk of bias using the Cochrane risk-of-bias tool and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to rate the quality of the evidence. RESULTS: Fifteen RCTs met the inclusion criteria. A total of 10 RCTs involving 846 participants were eligible for the quantitative analysis. Most studies (10 of 13, 76.92%) showed that prokinetics had beneficial effects on feeding intolerance in critically ill adults. In critically ill adults receiving gastric feeding, prokinetic agents may reduce the ICU length of stay (MD -2.03, 95% CI -3.96, -0.10; P = 0.04; low certainty) and the hospital length of stay (MD -3.21, 95% CI -5.35, -1.06; P = 0.003; low certainty). However, prokinetics failed to improve the outcomes of reported adverse events and all-cause mortality. CONCLUSION: As a class of drugs, prokinetics may improve tolerance to gastric feeding to some extent in critically ill adults. However, the certainty of the evidence suggesting that prokinetics reduce the ICU or hospital length of stay is low. Prokinetics did not significantly decrease the risks of reported adverse events or all-cause mortality among critically ill adults.

Improving the Applicability and Feasibility of Clinical Practice Guidelines in Primary Care: Recommendations for Guideline Development and Implementation.

OBJECTIVE: To give recommendations for the development of primary care clinical practice guideline (CPG) to improve applicability and feasibility of primary care CPGs in China. DESIGN: A two-round Delphi survey. METHODS: A two-round Delphi survey including guideline development methodologists and clinical practitioners from six countries was conducted. In round one, participants were asked to raise special considerations for the development of primary care CPGs through open-ended questions. In round two, participants were asked to rate the level of agreement on each recommendation item generated by round one and to raise additional recommendations. Opinions from participants were reviewed by thematic analysis. Integrated results from the Delphi survey were validated by participants. RESULTS: The necessity of developing recommendations for the development of primary care CPGs were consistently recognized by participants. The main recommendations of guideline development were generated as follows: (1) considering the context of primary care institutions and the applicability of existing guidelines for primary care in planning guideline; (2) involving primary care practitioners and patients in guideline groups; (3) considering the variation of health-care resources between primary care settings when developing recommendations; (4) presenting the difference of recommendations between primary care CPG and general CPG; (5) implementing more active education and training; and (6) considering the changing of primary care medical resource when updating guideline. CONCLUSION: In this study, we present recommendations to inform the development of clinical practice guidelines in primary care settings. Next steps will include merging these recommendations with general guideline development methods to inform the development of guidelines for primary care.

Pharmacist-Led Intervention on the Inappropriate Use of Stress Ulcer Prophylaxis Pharmacotherapy in Intensive Care Units: A Systematic review.

Background: Pharmacist's direct intervention or participation in multidisciplinary management teams can improve the clinical outcome and quality of life of patients. We aimed to determine the effectiveness of pharmacist-led interventions on the inappropriate use of stress ulcer prophylaxis (SUP) pharmacotherapy in intensive care units (ICUs). Methods: A systematic review was performed for relevant studies using searched PubMed, EMBASE (Ovid), the Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), and four Chinese databases from the establishment of databases to 12 March 2020. We conducted a descriptive analysis of participants, the intervention content and delivery, and the effects on inappropriate medication rates. Results: From 529 records, 8 studies from 9 articles were included in the systematic review. The time of appropriateness judgment and the criteria of "appropriate" varied from included studies. Pharmacist interventions mainly included clarifying indications for SUP pharmacotherapy, education and awareness campaign, reviewed patients on SUP pharmacotherapy during rounds, and adjustments of drug use. Five (62.5%) studies found a significant intervention effect during hospitalization, while 2 (25%) studies at ICU transfer and 2 (25%) studies at hospital discharge. 4 (50%) studies identified the complications related to SUP pharmacotherapy and found no significant difference. 4 (50%) studies declared the pharmacist-led interventions were associated with cost savings. Conclusion: Pharmacist-led intervention is associated with a decrease in inappropriate use of SUP pharmacotherapy during hospitalization, at ICU transferred and hospital discharged, and a lot of medical cost savings. Further research is needed to determine whether pharmacist-led intervention is cost-effective.

Quality of therapeutic drug monitoring guidelines is suboptimal: an evaluation using the Appraisal of Guidelines for Research and Evaluation II instrument.

OBJECTIVES: Although therapeutic drug monitoring (TDM) guidelines are available, systematic evaluations of their methodological quality are scarce. This study aimed to assess the quality of current TDM guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. STUDY DESIGN AND SETTING: We performed a systematic search to identify the relevant TDM guidelines in PubMed, EMBASE, CNKI, Wan Fang Database, CBM, VIP, four main guideline databases (NICE, NGC, GIN, and WHO guideline databases), and official websites of the governments and societies associated with TDM from the inception date to May 2018. Four independent appraisers rated the quality of each TDM guideline using the AGREE II instrument, and the mean score of each AGREE II item was calculated. The overall agreement among the appraisers was evaluated using the intraclass correlation coefficient (ICC). RESULTS: Twenty-eight TDM guidelines satisfied the eligibility criteria from among 12,235 references. The overall agreement among the appraisers was substantial (0.700-0.880). The mean scores for the six AGREE II domains were scope and purpose, 67.7% (95% CI, 64.0-71.4%); stakeholder involvement, 39.8% (95% CI, 33.3-46.3%); rigor of development, 36.0% (95% CI, 28.1-43.9%); clarity and presentation, 61.6% (95% CI, 55.7-67.4%); applicability, 30.6% (95% CI, 26.4-34.8%); and editorial independence, 49.2% (95% CI, 40.0-58.6%). The reviewers recommended only four guidelines, and most of the TDM guidelines were rated as "recommended with modifications." CONCLUSION: Overall, the quality of TDM guidelines is suboptimal according to the evaluation using the AGREE II instrument. The domains of applicability, rigor of development, stakeholder involvement, and editorial independence of the guidelines need to be reported. In addition, guideline developers closely adhering to the AGREE II instrument and the Grading of Recommendations Assessment Development and Evaluation system are required to draft high-quality and reliable TDM guidelines.

Safety of aripiprazole for tics in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Aripiprazole is widely used in the management of tic disorders (TDs), we aimed to assess the safety of aripiprazole for TDs in children and adolescents. METHODS: A systematic literature review was performed in the databases of MEDLINE, Embase, the Cochrane Library and 4 Chinese databases, from inception to February 2019. All types of studies evaluating the safety of aripiprazole for TDs were included. The quality of studies was assessed using the Cochrane Risk of Bias tool, the Newcastle-Ottawa Scale tool, the National Institute of Clinical Excellence, the CARE (Case Report) guidelines according to types of studies. Risk ratio (RR) and incidence rate with a 95% confidence interval (CI) were used to summarize the results. RESULTS: A total 50 studies involving 2604 children met the inclusion criteria. The result of meta-analysis of randomized controlled trials showed that there was a significant difference between aripiprazole and haloperidol with respect to rate of somnolence (RR = 0.596, 95% CI: 0.394, 0.901), extrapyramidal symptoms (RR = 0.236, 95% CI: 0.111, 0.505), tremor (RR = 0.255, 95% CI: 0.114, 0.571), constipation (RR = 0.148, 95% CI: 0.040, 0.553), and dry mouth (RR = 0.141, 95% CI: 0.046, 0.425). There was a significant difference between aripiprazole and placebo in the incidence rate of adverse events (AEs) for somnolence (RR = 6.565, 95% CI: 1.270, 33.945). The meta-analysis of incidence of AEs related to aripiprazole for case series studies revealed that the incidence of sedation was 26.9% (95% CI: 16.3%, 44.4%), irritability 25% (95% CI: 9.4%, 66.6%), restlessness 31.3% (95% CI: 13%, 75.1%), nausea and vomiting 28.9% (95% CI: 21.1%, 39.5%), and weight gain 31.3% (95% CI: 10.7%, 91.3%). CONCLUSION: Aripiprazole was generally well tolerated in children and adolescents. Common AEs were somnolence, headache, sedation, nausea, and vomiting. Further high-quality studies are needed to confirm the safety of aripiprazole for children and adolescents with TDs.

Methodological quality of clinical practice guidelines for genetic testing in children: A systematic assessment using the appraisal of guidelines for research and evaluation II instrument.

Genetic testing of children is faced with numerous problems. High-quality clinical practice guidelines (CPGs) are needed to ensure its safe, and appropriate use. This study aimed to systematically identify the current CPGs for genetic testing in children, and to assess the methodological quality of these CPGs.We searched 6 databases, 3 guideline clearinghouses, and 9 web sites of relevant academic agencies from inception to February 2019. CPGs focused on genetic testing in children were included. Four reviewers independently appraised the quality of the eligible CPGs using the appraisal of guidelines for research, and evaluation (AGREE) II instrument.Seventeen CPGs meeting our inclusion criteria were included. Among them, 16 CPGs were focused on the genetic diagnosis/evaluation of diseases, while only 1 CPG was focused on pharmacogenetics. The median domain scores from highest to lowest were: scope and purpose 80.56% (range: 56.95%-87.50%), clarity of presentation 72.22% (range: 45.83%-88.89%), stakeholder involvement 45.83% (range: 27.78%-55.56%), applicability 31.25% (range: 19.79%-54.17%), rigor of development 21.88%, (range: 13.02%-71.88%), and editorial independence 18.75% (range: 0%-83.33%). According to the overall quality, 6 (35%) CPGs were "not recommended," 8 (47%) CPGs were "recommended with modifications," and only 3 (18%) CPGs were "recommended." The clinical topics of the "recommended" CPGs were warfarin, familial Mediterranean fever, and pediatric pulmonary arterial hypertension.The quality of CPGs for genetic testing in children was generally low, and variable across different CPGs and different AGREE II domains. In future guideline development, more attention should be paid to the aspects of stakeholder involvement, rigor of development, applicability, and editorial independence. Not only will guideline users benefit from our results when determining whether to adopt related CPGs to guide genetic testing in children, but guideline developers could also take into account our results to improve the quality of future CPGs.

Volatile anesthetics versus total intravenous anesthesia in patients undergoing coronary artery bypass grafting: An updated meta-analysis and trial sequential analysis of randomized controlled trials.

BACKGROUND: The benefits of volatile anesthetics in coronary artery bypass grafting (CABG) patients remain controversial. We aimed to conduct an updated meta-analysis to assess whether the use of volatile anesthetics during CABG could reduce mortality and other outcomes. METHODS: We searched eight databases from inception to June 2019 and included randomized controlled trials (RCTs) comparing the effects of volatile anesthetics versus total intravenous anesthesia (TIVA) in CABG patients. The primary outcomes were operative mortality and one-year mortality. The secondary outcomes included the length of stay in the intensive care unit (ICU) and hospital and postoperative safety outcomes (myocardial infarction, heart failure, arrhythmia, stroke, delirium, postoperative cognitive impairment, acute kidney injury, and the use of intra-aortic balloon pump (IABP) or other mechanical circulatory support). Trial sequential analysis (TSA) was performed to control for random errors. RESULTS: A total of 89 RCTs comprising 14,387 patients were included. There were no significant differences between the volatile anesthetics and TIVA groups in operative mortality (relative risk (RR) = 0.92, 95% confidence interval (CI): 0.68-1.24, p = 0.59, I2 = 0%), one-year mortality (RR = 0.64, 95% CI: 0.32-1.26, p = 0.19, I2 = 51%), or any of the postoperative safety outcomes. The lengths of stay in the ICU and hospital were shorter in the volatile anesthetics group than in the TIVA group. TSA revealed that the results for operative mortality, one-year mortality, length of stay in the ICU, heart failure, stroke, and the use of IABP were inconclusive. CONCLUSIONS: Conventional meta-analysis suggests that the use of volatile anesthetics during CABG is not associated with reduced risk of mortality or other postoperative safety outcomes when compared with TIVA. TSA shows that the current evidence is insufficient and inconclusive. Thus, future large RCTs are required to clarify this issue.

Pharmacotherapies to tics: a systematic review.

The efficacy of all pharmacotherapies for patients suffering from tics were unclear. Literatures were searched from Medline, Embase, The Cochrane Library, and four Chinese databases. The primary efficacy outcome scale was defined as the Yale Global Tic Severity Scale (YGTSS). Overall estimates of pooled weighted mean difference (WMD) with 95% confidence interval (CI) were calculated for each outcome measure. A total of 53 trials were included. Meta-analysis suggested that alpha-2 adrenergic agonist agents and atypical antipsychotic agents were effective in improving tics, which included the maximum number of trials. Typical antipsychotic agents were associated with severer side-effects than alpha-2 adrenergic agonist agents. Besides, Traditional Chinese Medicine showed positive effects in YGTSS (NingDong Granule: WMD=-7.100, 95% CI, -10.430- -3.770; 5-Ling Granule: WMD=-11.300, 95% CI, -14.208- -8.392), while glutamate modulators (D-serine, N-Acetylcysteine and riluzole) might not be working. In summary, alpha-2 adrenergic agonist agents were associated with the optimal weigh between efficacy and safety. However, the significant factor of limited trials and sample sizes discounted these findings. Further better studies are necessary to ascertain them.

Efficacy and Safety of Tacrolimus in Myasthenia Gravis: A Systematic Review and Meta-analysis.

AIMS: This study was designed to determine whether treatments with tacrolimus would provide benefit for patients with myasthenia gravis (MG). MATERIALS AND METHODS: The databases of Medline, EMBASE, the Cochrane Library, and four Chinese databases were searched for eligible studies. Weighted mean differences and standardized mean differences (SMD) with corresponding 95% confidence intervals (CIs) were used to summarize the primary outcome, namely, steroid-sparing effect of tacrolimus in maintaining minimal manifestations, and the secondary outcome, namely, the effect of tacrolimus in reducing the severity of MG, respectively. RESULTS: After systematic retrieval, 13 researches with two randomized controlled trials (RCTs) and 11 prospective open-label single-arm clinical trials were included in the study. For the primary outcome of two RCTs, one RCT which was followed up for 1 year showed a positive effect and the other RCT which was associated with treatment duration of 28 weeks showed a negative result. For the secondary outcome, meta-analyses of other 11 trials showed a benefit effect, overall. For the quantitative MG (QMG) score, there were significant differences with high heterogeneity (SMD: 2.93; 95% CI: 1.14-4.73; I2 = 86%). In contrast, for MG activities of daily living (MGADL) score, it was reduced by tacrolimus with significant SMD and less heterogeneity (SMD: 0.59; 95% CI: 0.33-0.85; I2 = 7%). Adverse effects were mentioned as mild. DISCUSSION: The opposite results of two RCTs showed that tacrolimus with enough treatment duration might have positive steroid-sparing effect. The most possible cause of heterogeneity in the outcome of QMG score between trials was the baseline severity of MG. CONCLUSION: The above finding suggests that there might be a potential beneficial role with no serious side effects of tacrolimus, and additional better RCTs including larger sample sizes and long-term study are needed to confirm or refute the results.