Efficacy and safety of selegiline for the treatment of Parkinson's disease: A systematic review and meta-analysis.

Background: Drug efficacy generally varies with different durations. There is no systematic review analyzing the effect of selegiline for Parkinson's disease (PD) on different treatment duration. This study aims to analyze how the efficacy and safety of selegiline changes for PD over time. Methods: PubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure and Wanfang Database were systematically retrieved for randomized controlled trials (RCTs) and observational studies of selegiline for PD. The search period was from inception to January 18th, 2022. The efficacy outcomes were measured by the mean change from baseline in the total and sub Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD) and Webster Rating Scale (WRS) scores. The safety outcomes were measured by the proportion of participants having any adverse events overall and that in different system organ classes. Results: Among the 3,786 studies obtained, 27 RCTs and 11 observational studies met the inclusion criteria. Twenty-three studies reported an outcome which was also reported in at least one other study, and were included in meta-analyses. Compared with placebo, selegiline was found with a stronger reduction of total UPDRS score with increasing treatment duration [mean difference and 95% CIs in 1 month: -3.56 (-6.67, -0.45); 3 months: -3.32 (-3.75, -2.89); 6 months: -7.46 (-12.60, -2.32); 12 months: -5.07 (-6.74, -3.41); 48 months: -8.78 (-13.75, -3.80); 60 months: -11.06 (-16.19, -5.94)]. A similar trend was also found from the point estimates in UPDRS I, II, III, HAMD and WRS score. The results of observational studies on efficacy were not entirely consistent. As for safety, compared with placebo, selegiline had higher risk of incurring any adverse events [rate: 54.7% vs. 62.1%; odd ratio and 95% CIs: 1.58 (1.02, 2.44)], with the excess adverse events mainly manifested as neuropsychiatric disorders [26.7% vs. 31.6%; 1.36 (1.06, 1.75)] and no significant change over time. The statistically difference in overall adverse event between selegiline and active controls was not found. Conclusion: Selegiline was effective in improving total UPDRS score with increasing treatment duration, and had a higher risk of incurring adverse events, especially the adverse events in the neuropsychiatric system. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: PROSPERO CRD42021233145.

Exploring the Influence of Dysphagia and Tracheostomy on Pneumonia in Patients with Stroke: A Retrospective Cohort Study.

Background: Pneumonia is common in patients with tracheostomy and dysphagia. However, the influence of dysphagia and tracheostomy on pneumonia in patients with stroke remains unclear. The aim of this study was to explore the risk factors related to pneumonia, and the association between dysphagia, tracheostomy and pneumonia in patients with stroke was investigated. Methods: Patients with stroke who experienced tracheostomy and dysphagia were included and divided into two groups based on record of pneumonia at discharge. Clinical manifestations and physical examination were used to diagnose pneumonia, whereas clinical swallowing examination, and videofluoroscopy swallowing studies (VFSS) were used to evaluate swallowing function. Results: There were significant differences between the pneumonia group and the no pneumonia group in total tracheostomy time (6.3 ± 5.9 vs. 4.3 ± 1.7 months, p = 0.003), number of instances of ventilator support (0.41 ± 0.49 vs. 0.18 ± 0.38, p = 0.007), PAS score (5.2 ± 1.92 vs. 4.3 ± 1.79, p = 0.039), impaired or absent cough reflex (76.4 vs. 55.6%, p = 0.035), oropharyngeal phase dysfunction (60.6 vs. 40.8%, p = 0.047), length of hospital stay (36.0 ± 7.2 vs. 30.5 ± 11.7 days, p = 0.025) and direct medical costs (15,702.21 ± 14,244.61 vs. 10,923.99 ± 7250.14 United States dollar [USD], p = 0.042). Multivariate logistic regression showed that the total tracheostomy time (95% confidence interval [CI], 1.966−12.922, p = 0.001), impaired or absent cough reflex (95% CI, 0.084−0.695, p = 0.008), and oropharyngeal phase dysfunction (95% CI, 1.087−8.148, p = 0.034) were risk factors for pneumonia. Spearman's correlation analysis demonstrated that PAS scores were significantly correlated with cough reflex dysfunction (r = 0.277, p = 0.03), oropharyngeal phase dysfunction (r = 0.318, p < 0.01) and total tracheostomy time (r = 0.178, p = 0.045). The oropharyngeal phase dysfunction was significantly correlated with cough reflex (r = 0.549, p < 0.001) and UES opening (r = 0.643, p < 0.01). Conclusions: Tracheostomy and dysphagia increased the risk of pneumonia in patients with stroke. Total tracheostomy time, duration of ventilator support, degree of penetration and aspiration, and oropharyngeal phase dysfunction are risk factors. Given this, we also found that there may be a correlation between tracheostomy and dysphagia.

Evaluating the direct medical cost, drug utilization and expenditure for managing Parkinson's disease: a costing study at a medical center in China.

Background: With long-term pharmacotherapy, Parkinson's disease (PD) is expectedly to incur a significant healthcare burden. However, drug utilization and costing study is limited, so is the cost composition and its impact on resource allocation. This study took a healthcare provider's perspective to quantify medical and drug expenses and the utilization of drugs for managing PD and its complications. Methods: Medical resources use and associated cost of outpatient visits and inpatient admission episodes for PD patients were extracted from electronic medical records at a tertiary hospital in China from 1 January 2016 to 15 August 2018. Total and average direct medical (costs of outpatient visits and inpatient admission episodes) and drug costs were calculated during the study period and each calendar year. Drug cost was quantified by defined daily dose cost (DDDc) and levodopa equivalent dose cost (LEDc) per outpatient visit or inpatient admission episode for PD in Chinese yuan (¥), stratified by medication categories, and presented in descriptive statistics. Results: Overall, 18,158 outpatient visits and 366 inpatient admissions were incurred by 2,640 outpatients and 330 inpatients, with a median age of 71.0 and 73.5 years, respectively. Drug cost accounted for 97.82% and 23.33% of outpatient and inpatient medical expenditure. The average cost of drugs for managing PD accounted for 60.48% (¥952.50) and 2.70% (¥564.90) of cost per outpatient visit and inpatient episode, while drugs for managing PD complications was 11.38% and 0.70%, respectively. The highest DDDc and LEDc of drugs for managing PD per outpatient visit or inpatient episode were incurred by pramipexole (¥56.90-72.70 and ¥227.48-290.67) and entacapone (¥37.70-45.70 and ¥228.64-276.77). The DDDc and LEDc of pramipexole is more than 10 times that of levodopa/benserazide (DDDc: ¥4.90-5.70; LEDc: ¥10.14-11.98) and carbidopa/levodopa (DDDc: ¥4.00-5.00; LEDc: ¥11.02-13.95). Conclusions: The outpatient direct medical cost for patients with PD was predominantly attributed to drug cost for managing PD, but drug cost weighed less of the inpatient cost. After adjusting the dose and number of patients, drugs with indirect dopamine effects had an excessively higher cost than dopamine precursors. Their long-term cost-effectiveness in real-world settings warrants further studies.

The implementation of a FIP guidance for COVID-19: insights from a nationwide survey.

BACKGROUND: The International Pharmaceutical Federation (FIP) has established an interim guidance of coronavirus disease 2019 (COVID-19) for pharmacists worldwide. The aim of this study was to identify the implementation of FIP guidance in China and provide applicable strategies for further actions. METHODS: A nationwide cross-sectional survey on Chinese pharmacists was distributed electronically through groups of WeChat between 9 December 2020 and 18 December 2020. The 29-item questionnaire for the survey was designed based on the FIP guidance and knowledge, attitudes, and practices (KAP) framework. RESULTS: A total of 237 responses from 237 pharmacists (69.20% females) were received. Most pharmacists (81.86%) participated in work related to COVID-19. Respondents referred to other guidelines or consensus more than they did to FIP guidance. Most participants were qualified for the knowledge-based questions regarding COVID-19 (67.51%), had positive attitudes towards pharmacists' roles and actions (61.18%), and were qualified in the practices of prevention measures, infection risk monitoring, and pharmacists' advice (50.63%). Several factors were revealed as having impact on pharmacists' KAP, such as the relevance of participating in work related to COVID-19, work entailments, and information source. CONCLUSIONS: The FIP guidance has a certain degree of dissemination and implementation in China, which can be improved through effective actions directed towards impact factors.

Preoperative plasma biomarkers associated with atrial fibrillation after coronary artery bypass surgery.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is a common complication in coronary artery bypass grafting (CABG) procedures. This prospective study aimed to investigate predisposition of proteins and metabolites correlated to POAF after CABG and related cellular pathways. METHODS: Preoperative plasma samples from patients undergoing CABG procedures were prospectively collected. After CABG, the patients were grouped to POAF or sinus rhythm (N = 170; n = 90 in the discovery set and n = 80 in the validation set). The plasma samples were analyzed using proteomics, metabolomics, and bioinformatics to identify the differential proteins and differential metabolites. The correlation between differential proteins and POAF was also investigated by multivariable regression analysis and receiver operator characteristic analysis. RESULTS: In the POAF(+) group, 29 differential proteins and 61 differential metabolites were identified compared with the POAF(-) group. The analysis of integrated omics revealed that preoperative alteration of peroxisome proliferators-activated receptor α and glutathione metabolism pathways increased the susceptibility of POAF after CABG. There was a correlation between plasma levels of apolipoprotein-C3, phospholipid transfer protein, glutathione peroxidase 3, cholesteryl ester transfer protein, and POAF. CONCLUSIONS: The present study for first time at multi-omics levels explored the mechanism of POAF and validated the results in a new cohort of patients, suggesting preexisting differential proteins and differential metabolites in the plasma of patients prone to POAF after CABG. Dysregulation of peroxisome proliferators-activated receptor α and glutathione metabolism pathways related to metabolic remodeling and redox imbalance-associated electrical remodeling may play a key role in the pathogenesis of POAF. Lower plasma phospholipid transfer protein, apolipoprotein-C3, higher cholesteryl ester transfer protein and glutathione peroxidase 3 levels are linked with POAF. These proteins/metabolites may be developed as biomarkers to predict POAF.

Guideline for Quality Control of Powered Polymerisation Activators for Chairside Use.

The irradiance of powered polymerisation activators for chairside use affects composite resin adhesive curing during the restorative process, whereas radiant accumulated temperature rise relates to clinical safety. Irradiance reduction and high radiant accumulated temperature will compromise the treatment results as there is a lack of curing output efficacy and safety awareness for powered polymerisation activators. Insufficient attention has been paid to the activator's quality control, irradiance attenuation and radiant accumulated temperature excessive temperature rise during its lifetime. The present manuscript has been drafted by the Society of Dental Equipment, Chinese Stomatological Association to fill the quality control gap and guide the quality control process, following tested steps, using a metered radiometer and a thermometer to record the irradiance and radiant accumulated temperature separately. The testing result may indicate the equipment's situation in service and provide information about the irradiance values and performance of the powered polymerisation activator for its usage and maintenance.

Derivation and Validation of a Nomogram to Predict In-Hospital Complications in Children with Tetralogy of Fallot Repaired at an Older Age.

Background We aimed to develop and validate a prediction model for in-hospital complications in children with tetralogy of Fallot repaired at an older age. Methods and Results A total of 513 pediatric patients from the Tianjin data set formed a derivation cohort, and 158 pediatric patients from the Hefei and Xiamen data sets formed validation cohorts. We applied least absolute shrinkage and selection operator analysis for variable selection and logistic regression coefficients for risk scoring. We classified patients into different risk categorizations by threshold analysis and investigated the association with in-hospital complications using logistic regression. In-hospital complications were defined as death, need for extensive pharmacologic support (vasoactive-inotrope score of ≥20), and need for mechanical circulatory support. We developed a nomogram based on risk classifier and independent baseline variables using a multivariable logistic model. Based on risk scores weighted by 11 preoperative and 4 intraoperative selected variables, we classified patients as low, intermediate, and high risk in the derivation cohort. With reference to the low-risk group, the intermediate- and high-risk groups conferred significantly higher in-hospital complication risks (adjusted odds ratio: 2.721 [95% CI, 1.267-5.841], P=0.0102; 9.297 [95% CI, 4.601-18.786], P<0.0001). A nomogram integrating the ARIAR-Risk classifier (absolute and relative low risk, intermediate risk, and aggressive and refractory high risk) with age and mean blood pressure showed good discrimination and goodness-of-fit for derivation (area under the receiver operating characteristic curve: 0.785 [95% CI, 0.731-0.839]; Hosmer-Lemeshow test, P=0.544) and external validation (area under the receiver operating characteristic curve: 0.759 [95% CI, 0.636-0.881]; Hosmer-Lemeshow test, P=0.508). Conclusions A risk-classifier-oriented nomogram is a reliable prediction model for in-hospital complications in children with tetralogy of Fallot repaired at an older age, and strengthens risk/benefit-based decision-making.

SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes.

Previous studies have shown that sirtuin 1 (SIRT1) reduces the production of neuronal amyloid beta (Aß) and inhibits the inflammatory response of glial cells, thereby generating a neuroprotective effect against Aß neurotoxicity in animal models of Alzheimer's disease. However, the protective effect of SIRT1 on astrocytes is still under investigation. This study established a time point model for the clearance of Aß in primary astrocytes. Results showed that 12 hours of culture was sufficient for endocytosis of oligomeric Aß, and 36 hours sufficient for effective degradation. Immunofluorescence demonstrated that Aß degradation in primary astrocytes relies on lysosome function. Enzymatic agonists or SIRT1 inhibitors were used to stimulate cells over a concentration gradient. Aß was co-cultured for 36 hours in medium. Western blot assay results under different conditions revealed that SIRT1 relies on its deacetylase activity to promote intracellular Aß degradation. The experiment further screened SIRT1 using quantitative proteomics to investigate downstream, differentially expressed proteins in the Aß degradation pathway and selected the ones related to enzyme activity of SIRT1. Most of the differentially expressed proteins detected are close to the primary astrocyte lysosomal pathway. Immunofluorescence staining demonstrated that SIRT1 relies on its deacetylase activity to upregulate lysosome number in primary astrocytes. Taken together, these findings confirm that SIRT1 relies on its deacetylase activity to upregulate lysosome number, thereby facilitating oligomeric Aß degradation in primary astrocytes.

Increased circulating levels of tumor necrosis factor-like cytokine 1A and decoy receptor 3 correlate with SYNTAX score in patients undergoing coronary surgery.

OBJECTIVE: Chronic inflammation of the arteries is a critical mechanism responsible for coronary atherosclerosis. We aimed to determine if tumor necrosis factor (TNF)-like cytokine 1A (TL1A) and decoy receptor 3 (DcR3) were involved in promoting atherosclerosis. METHODS: We compared plasma levels of TL1A and DcR3 in patients with coronary artery disease (CAD) undergoing coronary artery bypass grafting (n=40) and patients without CAD group (n=37, normal coronary artery angiogram) by enzyme-linked immunosorbent assay. We also analyzed the correlation between CAD and SYNTAX scores. RESULTS: Plasma levels of TL1A and DcR3 were significantly higher in the CAD compared with the no-CAD group. Multivariate analysis showed that TL1A and DcR3 were significantly correlated with the presence of CAD, and receiver operating characteristic curve analysis indicated that both TL1A and DcR3 showed high sensitivity and specificity for diagnosing CAD. Furthermore, TL1A was positively and significantly correlated with SYNTAX score in CAD patients. CONCLUSIONS: CAD patients requiring coronary artery bypass grafting have high circulating levels of both TL1A and DcR3, which may thus be useful biomarkers for diagnosing severe CAD. Furthermore, plasma levels of TL1A correlate with SYNTAX score, supporting its potential use as an indicator of the severity of CAD.

Minimally invasive perventricular versus open surgical ventricular septal defect closure in infants and children: a randomised clinical trial.

BACKGROUND: Robust evidence is lacking regarding the clinical efficacy, safety and cardiopulmonary performance of perventricular closure. This study investigated the perioperative efficacy, safety and cardiorespiratory performance of perventricular closure of perimembranous ventricular septal defects (pmVSDs). METHODS: Operation-naïve infants and young children aged 5-60 months with isolated pmVSDs were randomised to receive either standard open surgical or minimally invasive perventricular closure via direct entry into the ventricle with a catheter from a subxiphoid incision. The primary outcomes included complete closure at discharge, major and minor adverse events and the changes in perioperative cardiorespiratory performance from baseline. Complete closure was mainly analysed in the modified intention-to-treat (mITT) population, with sensitivity analyses for the ITT, per-protocol (PP) and as-treated (AT) populations (non-inferiority margin -5.0%). RESULTS: We recruited 200 patients with pmVSDs for this study (mean age 24.38 months, range 7-58 months, 104 girls), of whom 100 were randomly allocated to one of the study groups. The non-inferiority of perventricular to surgical closure regarding complete closure at discharge was not shown in the ITT (absolute difference -0.010 (95% CI -0.078 to 0.058)) and mITT populations (-0.010 (95% CI -0.069 to 0.048)), but was shown in the PP (0.010 (95% CI -0.043 to 0.062)) and AT populations (0.048 (95% CI -0.009 to 0.106)). Perventricular closure reduced the rate of compromising cardiac haemodynamics, electrophysiological responses, cardiomyocyte viability, respiratory mechanics, ventilatory and gas exchange function and oxygenation and tissue perfusion compared with surgical closure (all between-group P<0.05). CONCLUSIONS: For infants and young children with pmVSD, perventricular closure reduced the rate of postoperative cardiorespiratory compromise compared with surgical closure, but the non-inferiority regarding complete closure should be interpreted in the context of the specific population. TRIAL REGISTRATION NUMBER: NCT02794584 ;Results.

[Militarine alleviates white matter damage and cognitive impairment in rats with chronic cerebral hypoperfusion].

Chronic cerebral hypoperfusion is a model for white matter lesions (WMLs) and cognitive impairment. In this study, we used the model in testing the protective effect of (-)-(2R)-1-[（4-ß-D-glucopyranosyloxy)benzyl]-4-[4-(ß-D-glucopyranosyloxy)benzyl]-2-isobutyl malate (militarine) on the white matter damaged. The model was established by bilateral common carotid ligation. Militarine (10 and 20 mg·kg(-1)·d(-1)) or saline was intragastrically administered daily for 30 days following the operation. Militarine (20 mg·kg-1·d-1)-treated rats exhibited significantly shorter escape latency, latency of the first time crossing and more numbers of platform crossings in Morris water maze task. Luxol fast blue (LFB) staining and Western blot analysis indicated that militarine promoted rehabilitation of white matter and increased levels of myelin basic protein (MBP) in the rats. Immunohistochemical staining for 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) revealed that militarine (20 mg·kg(-1)·d(-1)) markedly suppressed loss of CNPase-positive oligodendrocytes in the rat model. In conclusion, militarine can improve WMLs and cognitive impairment in the rat chronic hypoperfusion model.

The antidepressant effect of Cynanchum auriculatum in mice.

CONTEXT: Antidepressant effects of various plants are generally attributed to their anti-inflammation and antioxidant activities. Cynanchum auriculatum Royle ex Wight (Asclepiadaceae) is a traditional medicinal plant in China and India used for immunological regulation, anti-inflammation, and antioxidant purposes. However knowledge about its antidepressant activity has been poorly investigated. OBJECTIVE: To investigate the antidepressant activities of the total glycosides of C. auriculatum (TGC) and its CHCl3/MeOH (10:1) fractions (TGC-D and TGC-E) in mice. MATERIALS AND METHODS: TGC, TGC-D and TGC-E (20, 40 and 80 mg/kg) were intragastrically administered to mice twice a day for 5 days. The tail suspension test, forced swimming test, and locomotor activity test in mice were used to evaluate the effect of C. auriculatum. The inhibition of [³H]-serotonin reuptake in rat brain synaptosomes was detected to investigate their mechanism. RESULTS: TGC, TGC-D and TGC-E (80 mg/kg) decreased the immobility time by 61.7, 64.5, and 61.9% in tail suspension test. TGC (80 mg/kg), TGC-D (80 mg/kg) and TGC-E (20 mg/kg) decreased the immobility time by 32.6, 47.3, and 48.7% in forced swimming test. TGC (80 mg/kg) and TGC-E (20 and 40 mg/kg) decreased the crossing distances by 28.8, 29.5, and 36.2% in locomotor activity test. TGC, TGC-D and TGC-E (10 mg/L) inhibited serotonin reuptake by 7.4, 4.5, and 71.1% in rat brain synaptosomes, and IC50 value of TGC-E was 5.2 mg/L. DISCUSSION AND CONCLUSION: TGC, TGC-D and TGC-E have potential antidepressant activities. The antidepressive effect of TGC-E maybe attributed partly by the inhibiting effect on serotonin reuptake.