Factors influencing concentrations of risperidone and 9-hydroxyrisperidone in psychiatric outpatients taking immediate-release formulations of risperidone.

OBJECTIVES: To analyze the factors affecting the concentrations of the active moiety of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in psychiatric outpatients taking immediate-release formulations. METHODS: This is a retrospective study on the therapeutic drug monitoring (TDM) data regarding RIS and 9-OH-RIS in adult psychiatric outpatients. TDM data with simultaneous RIS and 9-OH-RIS monitoring from March 2018 to February 2020 and relevant medical records (including dosage, dosage form, sex, age, diagnosis, combined medication, and comorbid disease) from 399 adult psychiatric outpatients (223 males and 176 females) were included in this study. RESULTS: The daily dose of RIS was 5.56 ± 2.05 mg, the concentration of total active moiety was 42.35 ± 25.46 ng/mL, and the dose-adjusted plasma concentration (C/D) of active moiety was 7.83 ± 3.87 (ng/ml)/(mg/day). Dose, sex, and age were identified as important factors influencing concentrations of RIS and 9-OH-RIS in adult psychiatric outpatients. CONCLUSIONS: Individualized medication adjustments should be made according to the specific conditions of psychiatric outpatients. The findings strongly support the use of TDM to guide dosing decisions in psychiatric outpatients taking RIS.

Efficacy of acupuncture for cardiopulmonary cerebral resuscitation: A systematic review and meta-analysis.

Background: Cerebral resuscitation is one of the main therapeutic aims in the treatment of cardiac arrest (CA) patients who experience a return of spontaneous circulation (ROSC). However, the therapeutic effects of current treatments are not ideal. The purpose of this study was to evaluate the efficacy of neurological function of acupuncture combined with conventional cardiopulmonary cerebral resuscitationthe (CPCR) for patients after ROSC. Methods: Seven electronic databases and other related websites were searched to identify studies on acupuncture combined with conventional CPCR for patients after ROSC. R software was used to conduct a meta-analysis, and the outcomes that could not be pooled were analyzed using a descriptive analysis. Results: Seven RCTs involving 411 participants who had experienced ROSC were eligible for inclusion. The main acupoints were Neiguan (PC6), Shuigou (DU26), Baihui (DU20), Yongquan (KI1), and Sanyinjiao (SP6). Compared to conventional CPCR, acupuncture combined with conventional CPCR led to significantly higher Glasgow Coma Scale (GCS) scores on day 3 (mean difference (MD)=0.89, 95% CI: 0.43, 1.35, I2 = 0%), day 5 (MD = 1.21, 95% CI: 0.27, 2.15; I2 = 0%), and day 7 (MD = 1.92, 95% CI: 1.35, 2.50; I2 = 0%). Conclusion: Acupuncture-assisted conventional CPCR may have a potential role in improving neurological function in CA patients after ROSC, but the certainty of evidence is very low and more high-quality studies are required. Protocol registration: This review was registered at the International Prospective Registry of Systematic Reviews (PROSPERO): CRD42021262262.

The preliminary evidence on the association of the gut microbiota with stroke risk stratification in South Chinese population.

Aims: This study aimed to investigate the association between the gut microbiota and the risk of stroke. Methods: Faecal samples from 60 participants in South China, including 45 individuals with risk factors for stroke and 15 healthy controls, were collected and subjected to 16S rRNA sequencing. A bioinformatics analysis was performed to characterise the gut microbial diversity and taxonomic compositions at different risk levels (low, moderate, and high) of stroke. Functional prediction and correlation analyses between the microbiota and laboratory markers were performed to explore the potential mechanisms. Results: A significant difference in beta diversity was observed between the participants from the stroke risk and healthy control groups. Linear discriminant effect size analysis revealed a large number of vascular beneficial bacteria enriched in the participants from the healthy control and low-risk groups, but a few vascular harmful bacteria were more abundant in the participants from the high-risk group than in those from the other groups. In addition, Anaerostipes, Clostridium_XlVb, and Flavonifractor, all of which belonged to the Firmicutes phylum, were enriched in the participants from the low-risk group, and their relative abundances gradually decreased as the stroke risk increased. Spearman's analysis revealed that these outstanding microbiota correlated with the levels of triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, white blood cells, neutrophils, and carotid intima-media thickness. Conclusion: The preliminary evidence suggests that gut microbiota is associated with stroke risk. It potentially ameliorates atherosclerosis by targeting lipid metabolism and inflammation. This provides novel insights into the early screening of stroke risk and primary prevention.

Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication.

Introduction: Venlafaxine (VEN) is a widely used dual selective serotonin/noradrenaline reuptake inhibitor indicated for depression and anxiety. It undergoes first-pass metabolism to its active metabolite, O-desmethyl venlafaxine (ODV). The aim of the present study was to develop a joint population pharmacokinetic (PPK) model to characterize their pharmacokinetic characters simultaneously. Methods: Plasma concentrations with demographic and clinical data were derived from a bioequivalence study in 24 healthy subjects and a naturalistic TDM setting containing 127 psychiatric patients. A parent-metabolite PPK modeling was performed with NONMEM software using a non-linear mixed effect modeling approach. Goodness of fit plots and normalized prediction distribution error method were used for model validation. Results and conclusion: Concentrations of VEN and ODV were well described with a one-compartment model incorporating first-pass metabolism. The first-pass metabolism was modeled as a first-order conversion. The morbid state and concomitant amisulpride were identified as two significant covariates affecting the clearance of VEN and ODV, which may account for some of the variations in exposure. This model may contribute to the precision medication in clinical practice and may inspire other drugs with pre-system metabolism.

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients.

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine's pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine's PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population's apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients.

Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

Population pharmacokinetics model for escitalopram in Chinese psychiatric patients: effect of CYP2C19 and age.

Objective: To establish a population pharmacokinetic model in Chinese psychiatric patients to characterize escitalopram pharmacokinetic profile to identify factors influencing drug exposure, and through simulation to compare the results with the established therapeutic reference range. Methods: Demographic information, dosing regimen, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators were retrospectively collected for inpatients taking escitalopram with therapeutic drug monitoring from 2018 to 2021. Nonlinear mixed-effects modeling was used to model the pharmacokinetic characteristics of escitalopram. Goodness-of-fit plots, bootstrapping, and normalized prediction distribution errors were used to evaluate the model. Simulation for different dosing regimens was based on the final estimations. Results: The study comprised 106 patients and 337 measurements of serum sample. A structural model with one compartment with first-order absorption and elimination described the data adequately. The population-estimated apparent volume of distribution and apparent clearance were 815 and 16.3 L/h, respectively. Age and CYP2C19 phenotype had a significant effect on the apparent clearance (CL/F). CL/F of escitalopram decreased with increased age, and CL/F of poor metabolizer patients was significantly lower than in extensive and immediate metabolizer patients. The final model-based simulation showed that the daily dose of adolescents with poor metabolizer might be as high as 15 mg or 20 mg and referring to the therapeutic range for adults may result in overdose and a high risk of adverse effects in older patients. Conclusion: A population pharmacokinetics model of escitalopram was successfully created for the Chinese population. Depending on the age of the patients, CYP2C19 genotype and serum drug concentrations throughout treatment are required for adequate individualization of dosing regimens. When developing a regimen for older patients, especially those who are poor metabolizers, vigilance is required.

The role of acupuncture and moxibustion in the treatment, prevention, and rehabilitation of patients with COVID-19: A scoping review.

Introduction: This study aims to summarize the available evidence and guideline/consensus recommendations for acupuncture and moxibustion in the treatment, prevention and rehabilitation of patients with coronavirus disease 2019 (COVID-19). Methods: A scoping review was performed. Eight electronic databases and other related websites were searched. All studies related to acupuncture and moxibustion for COVID-19 were considered. Descriptive analysis was applied to analyze the all included studies and guideline recommendations. Results: We ultimately included 131 eligible studies. The main topics of the included studies were the treatment (82.4%) and prevention (38.9%) of COVID-19. The most included studies were literature reviews (65, 49.6%), protocols of systematic reviews (20, 15.3%), and guidelines and consensuses (18, 13.7%). The 18 (13.7%) COVID-19 guidelines and consensuses included 47 recommendations on acupuncture and moxibustion, which focused on the treatment (21/47, 44.7%), rehabilitation (17/47, 36.2%) and prevention (6, 12.8%) of COVID-19 patients. Zusanli (ST36), Feishu (BL13), Guanyuan (RN4) were recommended mostly for the treatment, rehabilitation and prevention respectively. Conclusion: Acupuncture and moxibustion are effective in the treatment of COVID-19 patients to some extent. However, more high-quality of clinical trials still needed to determine the feasibility of acupuncture and moxibustion in COVID-19 patients to better guide clinical practice. Study registration: Open Science Framework Registries (Registration DOI: 10.17605/OSF.IO/Z35WN; https://osf.io/z35wn).

Knowledge atlas of the involvement of glutamate and GABA in alcohol use disorder: A bibliometric and scientometric analysis.

Introduction: Abnormal neurotransmission of glutamate and γ-aminobutyric acid (GABA) is a key characteristic of alcohol-related disorders. To track research output, we conducted a bibliometric analysis to explore the current status and trends in this field over the past decades. Methods: Studies related to neurotransmitters and alcohol use disorder published in English from 2005-2021 were retrieved from the Web of Science Core Collection and Scopus databases. The R-bibliometrix package was used for a descriptive analysis of the publications. Citespace, WOSviewer, and R-bibliometrix were used to construct networks of countries/institutions/authors based on co-authorship, co-citation analysis of cited references and co-occurrence as well as burst detection of keywords. Results: A total of 4,250 unique articles and reviews were included in the final analysis. The annual growth rate of publications was 5.4%. The USA was the most productive country in this field, contributing nearly half of the total documents. The top ten most productive institutions were all located in the USA. The most frequent worldwide collaboration was between the USA and Italy. The most productive and influential institution was the University of California. The author contributing the most productions to this field was Marisa Roberto from the Scripps Research Institute. The top co-cited reference was a review titled "Neurocircuitry of addiction." The top journal in terms of the number of records and citations was Alcoholism: Clinical and Experimental Research. Comprehensive analyses have been conducted over past decades based on co-cited reference analysis, including modulators, transporters, receptor subtypes, and animal models. In recent years, the research frontiers have been shifting to the identification of risk factors/biomarkers, drug development for alcohol use disorder, and mechanisms related to alcoholic and non-alcoholic fatty liver. Conclusion: Our bibliometric analysis shows that glutamate and GABA continue to be of interest in alcohol use disorder. The focus has evolved from mechanisms and medications related to glutamate and GABA in alcohol use disorder, to novel drug development, risk factor/biomarker identification targeting neurotransmitters, and the mechanisms of related diseases.

Traditional Chinese Medicine for Post-stroke Sleep Disorders: The Evidence Mapping of Clinical Studies.

Background and Purpose: Recently, there are a number of clinical studies on traditional Chinese medicine (TCM) for post-stroke sleep disorders (PSSDs). This study aimed to map the current clinical studies and identify gaps to inform future study agendas. Methods: PubMed, Embase, Cochrane Library, and Chinese databases, including SinoMed, CNKI, and Wanfang, were searched for clinical studies on PSSDs treated with TCM from their inception to September 2021. Evidence sources, number of studies, types of PSSDs, intervention categories, effectiveness, and quality assessment were graphically displayed. Results: The evidence map involved 810 clinical studies, of which the earliest report was dated back to 1993, and an advanced growth of the whole evidence was observed in 2012. Randomized controlled trials (RCTs) were the most common type of study design (78.15%), and post-stroke insomnia was the most common type of sleep disorders (65.80%). The benefits of Chinese herbal medicine (CHM) and acupuncture therapies for post-stroke insomnia have been widely reported in RCTs (81.60% and 75.38%, respectively). However, the benefits of CHM interventions were assessed using a global approach rather than being based on a specific formula, and the highest level of evidence supporting the effectiveness of acupuncture therapies was of low methodological quality. In addition, evidence from primary studies was insufficient in the areas of TCM for post-stroke sleep-related breathing disorders (SBDs) and Chinese mind-body exercises for post-stroke insomnia. Conclusions: PSSDs treated with TCM have been widely assessed in clinical studies. For better evidence translation, clinical trials on specific CHM interventions and high-quality systematic reviews on acupuncture for post-stroke insomnia should be conducted. For a better solution to clinical questions, TCM on SBDs after stroke and the benefits of Chinese mind-body exercises for post-stroke insomnia should be explored in future clinical studies.

Risk of Stroke Among Different Metabolic Obesity Phenotypes: A Systematic Review and Meta-Analysis.

Background and Purpose: Overweight/obesity is a modified risk factor for stroke. This systematic review and meta-analysis aimed to assess the impact of different obesity phenotypes on stroke risk in adults. Methods: The PubMed, Embase, and Cochrane Library databases were searched from their inception to 7 March 2021 to identify the prospective cohort studies investigating stroke risk among different metabolic overweight/obesity phenotypes. The methodological quality of the included studies was evaluated using the Newcastle-Ottawa Scale. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Results: A total of eleven prospective cohorts (n = 5,609,945 participants) were included in the systematic review, nine of which were included in the meta-analysis. All metabolically unhealthy phenotypes had a higher risk of stroke than the metabolically healthy normal-weight phenotypes, including metabolically unhealthy normal weight (HR = 1.63, 95% CI: 1.41-1.89, I2 = 89.74%, n = 7 cohort studies, 1,042,542 participants), metabolically unhealthy overweight (HR = 1.94, 95% CI: 1.58-2.40, I2 = 91.17%, n = 4 cohort studies, 676,166 participants), and metabolically unhealthy obese (HR = 1.99, 95% CI: 1.66-2.40, I2 = 93.49%, n = 6 cohort studies, 1,035,420 participants) phenotypes. However, no risk of stroke was observed in the populations with metabolically healthy overweight (MHOW) (HR = 1.07, 95% CI: 1.00-1.14, I2 = 69.50%, n = 5 studies, 4,171,943 participants) and metabolically healthy obese (MHO) (HR = 1.07, 95% CI: 0.99-1.16, I2 = 54.82%, n = 8 studies, 5,333,485 participants) phenotypes. The subgroup analyses for the MHO studies suggested that the risk of stroke increased only when the MHO participants were mainly females, from North America, and when the World Health Organization standard was applied to define obesity. In the subgroup analysis of the risk of stroke in MHOW, a longer follow-up duration was also associated with a higher risk of stroke. Conclusion: The risk of stroke increase for all metabolically unhealthy phenotypes irrespective of the body mass index (BMI). The associated risk of stroke with metabolic health but high BMI shows substantial heterogeneity, which requires future research considering the impact of sex and transition of the metabolic status on the risk of stroke. Systematic Review Registration: The study protocol was prospectively registered in PROSPERO (No. CRD42021251021).

A Simple and Sensitive HPLC-MS/MS Assay for the Quantitation of Blonanserin and N-Desethyl Blonanserin in Rat Plasma and Its Application to Pharmacokinetic Study.

A high-performance liquid chromatographic method coupled with triple quadrupole mass spectrometry (LC-MS/MS) for the analysis of blonanserin and its active metabolite, N-desethyl blonanserin, in rat plasma has been developed and validated. The biological samples were treated by simple direct protein precipitation before separation on an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with a column temperature of 35°C at a flow rate of 0.5 mL/min. The mobile phase A is a mixture of methanol and water (75 : 25, v/v, 5 mM ammonium formate), and the mobile phase B is acetonitrile containing 0.1% formic acid. The ratio of mobile phase A to mobile phase B is 15 : 85. Electrospray ionization (ESI) multiple reaction monitoring modes are used for detection, which are m/z 368.10 ⟶ 296.90 (blonanserin), m/z 340.15 ⟶ 297.05(N-desethyl blonanserin), and m/z 348.15⟶ 302.05 (N-desethyl blonanserin-d8). The linear response range was 0.1-100.0 ng/mL for blonanserin and N-desethyl blonanserin. The lower limit of quantification (LLOQ), calibration curves, carryover, and matrix effects were sufficiently accurate and precise according to the National Medical Products Administration (NMPA) guidelines for bioanalytical method validation. This analytical method was successfully applied in a blonanserin-poloxamer thermosensitive gel pharmacokinetic study in rats.

Comparative effectiveness of multiple acupuncture therapies for primary insomnia: a systematic review and network meta-analysis of randomized trial.

BACKGROUND: Acupuncture has been widely practiced for primary insomnia (PI). However, the relative benefit and harm among acupuncture therapies remain uncertain. OBJECTIVES: To compare and evaluate the effect differences of multiple acupuncture therapies for patients with PI. METHODS: Systematic literature search for randomized controlled trials (RCTs). Pairs of reviewers independently conducted literature screening, data extraction, and risk of bias assessment. Meta-analysis was conducted using R and Stata software. The Grading of Recommendations Assessment, Development, and Evaluation system (GRADE) was used to assess certainty of evidence and interpret results. RESULTS: Fifty-seven RCTs with 4678 patients were included. Compared with usual treatment, multiple acupuncture therapies showed a better effect for Pittsburgh sleep quality index score. And acupoints catgut embedding (ACE) was proved to be the most effective with a moderate certainty of evidence; auricular acupressure or auricular acupuncture plus manual acupuncture (AP + MA), electroacupuncture plus acupoint application (EA + APA), and intradermal needle (IN) might be also the most effective with low certainty of evidence. ACE, ACE + MA, AP + MA, EA, EA + APA, HPN, MA and PBN + MA showed significantly improvement in effective rate when compared with usual treatment. Insufficient evidence reported on Epworth Sleepiness Scale, Athens Insomnia Scale, and recurrence rate. The most common slight adverse events mainly included hematoma, pain, headache, and bleeding. CONCLUSIONS: With moderate to low certainty of evidence, multiple acupuncture therapies showed impressive insomnia improvement, especially ACE, AP + MA, and EA + APA. Differences between therapies were small or insignificant and based-on low or very low certainty of evidence.

Clinical Evidence on the Use of Chinese Herbal Medicine for Acute Infectious Diseases: An Overview of Systematic Reviews.

Background: Acute infectious diseases constitute the most prevalent public health emergency (PHE) in China. Chinese herbal medicine (CHM) has long been used in the treatment of acute infections, but the overall evidence of its benefit and harm has not been comprehensively and systematically evaluated. Methods: We searched CBM, CNKI, Wanfang, PubMed, Cochrane Library, embase and preprint platforms to retrieve systematic reviews (SRs) on CHM for acute infectious. Participants with COVID-19, SARS, H1N1, tuberculosis, bacillary dysentery, mumps, herpangina, hand-foot-and-mouth disease (HFMD), and other acute infectious diseases were included. Interventional group consisting of patients treated with CHM combined with Western medicine or CHM alone. The AMSTAR 2 tool was used to assess the methodological quality of the retrieved studies. Information on interventions, control measures and outcomes of the included studies was extracted, and meta-analyses were qualitatively synthesized. Results: A total of 51 SRs and meta-analyses were eligible for this overview, including 19 for COVID-19, 11 for hand-foot-and-mouth disease, 8 for severe acute respiratory syndrome (SARS), 4 for tuberculosis, 3 for mumps, 2 for bacillary dysentery, 2 for H1N1 influenza and 2 for herpangina. Six systematic reviews were of high quality, all of which were on the use of CHM for COVID-19; 24 were of moderate quality; 10 were of low quality; and 11 were of very low quality. CHM appeared to have potential benefits in improving clinical symptoms and signs for most infections with an acceptable safety profile, and the clinical evidence of the benefits of CHM for acute respiratory infections such as COVID-19, SARS and H1N1 seems more sufficient than that for other acute infections. Conclusion: Overall, CHM, both decoction and Chinese patent medicine, used alone or in combination with conventional medicine may offer potential benefits to relieving symptoms of people with acute respiratory infections. Full reporting of disease typing, staging, and severity, and intervention details is further required for a better evidence translation to the responses for PHE. Future CHM research should focus mainly on the specific aspects of respiratory infections such as its single use for mild infections, and the adjunct administration for sever infections, and individual CHM prescriptions for well-selected outcomes should be prioritized.

Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal.

Background: Alcohol use disorder (AUD) is characterized by chronic excessive alcohol consumption, often alternating with periods of abstinence known as alcohol withdrawal syndrome (AWS). Diazepam is the preferred benzodiazepine for treatment of alcohol withdrawal syndrome under most circumstances, but the specific mechanism underlying the treatment needs further research. Methods: We constructed an animal model of two-bottle choices and chronic intermittent ethanol exposure. LC-MS/MS proteomic analysis based on the label-free and intensity-based quantification approach was used to detect the protein profile of the whole brain. Weighted gene correlated network analysis was applied for scale-free network topology analysis. We established a protein-protein interaction network based on the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software and identified hub proteins by CytoHubba and MCODE plugins of Cytoscape. The online tool Targetscan identified miRNA-mRNA pair interactions. Results: Seven hub proteins (Dlg3, Dlg4, Shank3, Grin2b, Camk2b, Camk2a and Syngap1) were implicated in alcohol withdrawal syndrome or diazepam treatment. In enrichment analysis, glutamatergic synapses were considered the most important pathway related to alcohol use disorder. Decreased glutamatergic synapses were observed in the late stage of withdrawal, as a protective mechanism that attenuated withdrawal-induced excitotoxicity. Diazepam treatment during withdrawal increased glutamatergic synapses, alleviating withdrawal-induced synapse inhibition. Conclusion: Glutamatergic synapses are considered the most important pathway related to alcohol use disorder that may be a potential molecular target for new interventional strategies.

Reporting quality evaluation of the stroke clinical practice guidelines: a systematic review.

OBJECTIVES: To analyze the effectiveness and quality of stroke clinical practice guidelines (CPGs) published in recent years in order to guide future guideline developers to develop better guidelines. PARTICIPANTS: No patient involved METHOD: PubMed, China Biology Medicine (CBM), Wanfang, CNKI, and CPG-relevant websites were searched from January 2015 to December 2019 by two researchers independently. The RIGHT (Reporting Items for Practice Guidelines in Healthcare) checklist was used to assess the reporting quality in terms of domains and items. Then, a subgroup analysis of the results was performed. PRIMARY AND SECONDARY OUTCOME MEASURES: RIGHT checklist reporting rate RESULTS: A total of 66 CPGs were included. Twice as many CPGs were published internationally as were published in China. More than half were updated. Most CPGs are published in journals, developed by societies or associations, and were evidence-based grading. The average reporting rate for all included CPGs was 47.6%. Basic information got the highest (71.7% ± 19.7%) reporting rate, while review and quality assurance got the lowest (22.0% ± 24.6%). Then, a cluster analysis between countries, publishing channels, and institutions was performed. There were no statistically significant differences in the reporting quality on the CPGs between publishing countries (China vs. international), publishing channels (journals vs. websites), and institutions (associations vs. non-associations). CONCLUSIONS: Current stroke CPGs reports are of low quality. We recommend that guideline developers improve the quality of reporting of key information and improve the management of conflicts of interest. We recommend that guideline developers consider the RIGHT checklist as an important tool for guideline development. TRIAL REGISTRATION: https://doi.org/10.17605/OSF.IO/PBWUX .

Comprehensive Bibliometric Analysis of the Kynurenine Pathway in Mood Disorders: Focus on Gut Microbiota Research.

Background: Emerging evidence implicates the dysregulated kynurenine pathway (KP), an immune-inflammatory pathway, in the pathophysiology of mood disorders (MD), including depression and bipolar disorder characterized by a low-grade chronic pro-inflammatory state. The metabolites of the KP, an important part of the microbiota-gut-brain axis, serve as immune system modulators linking the gut microbiota (GM) with the host central nervous system. Aim: This bibliometric analysis aimed to provide a first glimpse into the KP in MD, with a focus on GM research in this field, to guide future research and promote the development of this field. Methods: Publications relating to the KP in MD between the years 2000 and 2020 were retrieved from the Scopus and Web of Science Core Collection (WoSCC), and analyzed in CiteSpace (5.7 R5W), biblioshiny (using R-Studio), and VOSviewer (1.6.16). Results: In total, 1,064 and 948 documents were extracted from the Scopus and WoSCC databases, respectively. The publications have shown rapid growth since 2006, partly owing to the largest research hotspot appearing since then, "quinolinic acid." All the top five most relevant journals were in the neuropsychiatry field, such as Brain Behavior and Immunity. The United States and Innsbruck Medical University were the most influential country and institute, respectively. Journal co-citation analysis showed a strong tendency toward co-citation of research in the psychiatry field. Reference co-citation analysis revealed that the top four most important research focuses were "kynurenine pathway," "psychoneuroimmunology," "indoleamine 2,3-dioxygenase," and "proinflammatory cytokines," and the most recent focus was "gut-brain axis," thus indicating the role of the KP in bridging the GM and the host immune system, and together reflecting the field's research foundations. Overlap analysis between the thematic map of keywords and the keyword burst analysis revealed that the topics "Alzheimer's disease," "prefrontal cortex," and "acid," were research frontiers. Conclusion: This comprehensive bibliometric study provides an updated perspective on research associated with the KP in MD, with a focus on the current status of GM research in this field. This perspective may benefit researchers in choosing suitable journals and collaborators, and aid in the further understanding of the field's hotspots and frontiers, thus facilitating future research.

Calling for improved quality in the registration of traditional Chinese medicine during the public health emergency: a survey of trial registries for COVID-19, H1N1, and SARS.

OBJECTIVE: To assess the registration quality of traditional Chinese medicine (TCM) clinical trials for COVID-19, H1N1, and SARS. METHOD: We searched for clinical trial registrations of TCM in the WHO International Clinical Trials Registry Platform (ICTRP) and Chinese Clinical Trial Registry (ChiCTR) on April 30, 2020. The registration quality assessment is based on the WHO Trial Registration Data Set (Version 1.3.1) and extra items for TCM information, including TCM background, theoretical origin, specific diagnosis criteria, description of intervention, and outcomes. RESULTS: A total of 136 records were examined, including 129 severe acute respiratory syndrome coronavirus 2 (COVID-19) and 7 H1N1 influenza (H1N1) patients. The deficiencies in the registration of TCM clinical trials (CTs) mainly focus on a low percentage reporting detailed information about interventions (46.6%), primary outcome(s) (37.7%), and key secondary outcome(s) (18.4%) and a lack of summary result (0%). For the TCM items, none of the clinical trial registrations reported the TCM background and rationale; only 6.6% provided the TCM diagnosis criteria or a description of the TCM intervention; and 27.9% provided TCM outcome(s). CONCLUSION: Overall, although the number of registrations of TCM CTs increased, the registration quality was low. The registration quality of TCM CTs should be improved by more detailed reporting of interventions and outcomes, TCM-specific information, and sharing of the result data.

A machine learning approach to personalized dose adjustment of lamotrigine using noninvasive clinical parameters.

The pharmacokinetic variability of lamotrigine (LTG) plays a significant role in its dosing requirements. Our goal here was to use noninvasive clinical parameters to predict the dose-adjusted concentrations (C/D ratio) of LTG based on machine learning (ML) algorithms. A total of 1141 therapeutic drug-monitoring measurements were used, 80% of which were randomly selected as the "derivation cohort" to develop the prediction algorithm, and the remaining 20% constituted the "validation cohort" to test the finally selected model. Fifteen ML models were optimized and evaluated by tenfold cross-validation on the "derivation cohort," and were filtered by the mean absolute error (MAE). On the whole, the nonlinear models outperformed the linear models. The extra-trees' regression algorithm delivered good performance, and was chosen to establish the predictive model. The important features were then analyzed and parameters of the model adjusted to develop the best prediction model, which accurately described the C/D ratio of LTG, especially in the intermediate-to-high range (≥ 22.1 µg mL-1 g-1 day), as illustrated by a minimal bias (mean relative error (%) = + 3%), good precision (MAE = 8.7 µg mL-1 g-1 day), and a high percentage of predictions within ± 20% of the empirical values (60.47%). This is the first study, to the best of our knowledge, to use ML algorithms to predict the C/D ratio of LTG. The results here can help clinicians adjust doses of LTG administered to patients to minimize adverse reactions.