The role of immunoglobulin in cerebrospinal fluid on the differential diagnosis of autoimmune encephalitis and viral encephalitis in children.

BACKGROUND: A case-control study was conducted to analyze the role of cerebrospinal fluid immunoglobulin in the differential diagnosis of autoimmune encephalitis and viral encephalitis in children. METHODS: One hundred and twenty patients with autoimmune encephalitis (AE) treated in our hospital from February 2021 to February 2022 were included as the observation group (AE group). 100 patients with viral encephalitis (VE group) were selected as the control group. The clinical data of all patients were collected and analyzed retrospectively. Immunoglobulin G (IgG) and immunoglobulin A (IgA)in cerebrospinal fluid of the two patients were measured by immune turbidimetry. Immunoglobulin M (IgM), and the diagnostic value of immunoglobulin in cerebrospinal fluid (CSF) in patients with AE was analyzed by receiver working curve (ROC). RESULTS: The level of IgG in the cerebrospinal fluid of the AE group was higher than that of the VE group, and the level of IgM was lower than that of the VE group, and the difference was statistically significant (P < 0.05). There was no significant difference in IgA levels between the two groups (P > 0.05). In terms of Magnetic Resonance (MR) features, the paraventricular, hippocampal, occipital and parietal lobes were more involved in AE patients, frontal and temporal lobes were more involved in VE patients, and paraventricular and occipital lobes were involved in MS. The proportion of bilateral extensive lesions in both groups was significantly higher than 50%. The proportions of patients in the AE group involving the lateral ventricle, insula, and parietal lobes were significantly higher than those in the VE group, and the proportions involving the basal ganglia, temporal lobes, and frontal lobes were significantly lower than those in the VE group, and the differences were statistically significant (All P < 0.05). The Area Under Curve (AUC) of IgG, IgA and IgM alone in the diagnosis of AE were 0.795(0.587-0.762), 0.602(0.502-0.631) and 0.627(0.534-0.708), respectively with the sensitivity values of 81.24% and 65.608, respectively and the specificity values of 65.08%, 57.54% and 75.01% respectively. The AUC of IgA + IgM in the diagnosis of AE was 0.733(0.617-0.849), and the sensitivity and specificity are 62.58% and 75.07% respectively. The AUC of IgA + IgG in the diagnosis of AE was 0.823(0.730-0.917), and the sensitivity and specificity were 81.24% and 67.54% respectively. The AUC of IgG + IgM in the diagnosis of AE was 0.886(0.814 ~ 0.958), and the sensitivity and specificity were 84.48% and 77.59% respectively. The AUC of IgA + IgM + IgG in the diagnosis of AE was 0.924 (0.868-0.981) with the sensitivity of 93.82%, and the specificity of 77.56%. CONCLUSION: The level of immunoglobulin in cerebrospinal fluid can be used as an effective reference index for the diagnosis of AE. The combined detection of IgA, IgM and IgG can improve the accuracy, sensitivity and specificity of AE.

Associations between whole grains intake and new-onset hypertension: a prospective cohort study.

IMPORTANCE: Epidemiological evidences regarding the association between whole grain intake and the risk of new-onset hypertension are still controversial. OBJECTIVE: We aimed to investigate the relationship between whole grain intake and new-onset hypertension and examine possible effect modifiers in the general population. METHODS: A total of 10,973 participants without hypertension from the China Health and Nutrition Survey were enrolled, with follow-up beginning in 1997 and ending in 2015. Whole grain intake was assessed by 3 consecutive 24-h dietary recalls combined with a household food inventory. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression model after adjusting for potential risk factors. RESULTS: During a median follow-up of 7.0 years, 3,733 participants developed new-onset hypertension. The adjusted HRs (95% CIs) were as follows: for quartile 2 (HR: 0.52; 95% CI: 0.47-0.57), quartile 3 (HR: 0.46; 95% CI: 0.42-0.51), and quartile 4 (HR: 0.35; 95% CI: 0.31-0.38), compared with quartile 1. Different types of whole grain types, including wheat (adjusted HR, 0.35; 95% CI, 0.32-0.39), maize (adjusted HR, 0.50; 95% CI, 0.42-0.59), and millet (adjusted HR, 0.38; 95% CI, 0.30-0.48), showed significant associations with a reduced risk of hypertension. The association between whole grain intake and new-onset hypertension was stronger in individuals with older age (P for interaction < 0.001) and higher BMI (P for interaction < 0.001). CONCLUSION: Higher consumption of whole grains was significantly associated with a lower risk of new-onset hypertension. This study provides further evidence supporting the importance of increasing whole grain intake for hypertension prevention among Chinese adults.

Long-term air pollutants exposure and respiratory mortality: A large prospective cohort study.

Ambient air pollution is a major global health concern. Yet, no study has thoroughly assessed its link to respiratory mortality. Our research evaluated the combined and individual effects of air pollutants on respiratory mortality risks based on the UK Biobank. A total of 366,478 participants were studied. A Cox proportional hazards model was used to estimate the respiratory mortality risk from combined long-term exposure to five pollutants, summarized as a weighted air pollution score. During a median of 13.6 years of follow-up, 6113 deaths due to respiratory diseases were recorded. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of respiratory diseases were 2.64 (2.05-3.39), 1.62 (1.23-2.12), 2.06 (1.73-2.45), 1.20 (1.16-1.25), and 1.07 (1.05-1.08) per 10 µg/m3 increase in PM2.5, PM2.5-10, PM10, NO2, and NOx, respectively. The air pollution score showed a dose-response association with an elevated respiratory mortality risk. The highest versus lowest quartile air pollution score was linked to a 44% increase in respiratory mortality risk (HR 1.44, 95% CI: 1.33-1.57), with consistent findings in subgroup and sensitivity analyses. Long-term individual and joint air-pollutant exposure showed a dose-response association with an increased respiratory mortality risk, highlighting the importance of a comprehensive air-pollutant assessment to protect public health.

Association between Whole Grain Intake and Chronic Kidney Disease.

BACKGROUND: The relationship between whole grain intake and chronic kidney disease (CKD) remains uncertain. OBJECTIVE: This study aimed to evaluate the association between whole grain intake and risk of CKD in Chinese adults. METHODS: The present cross-sectional study used data from the China Health and Nutrition Survey conducted in 2009. Whole grain intake was measured using 3 consecutive 24-h dietary recalls and a household food inventory. A multivariable logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of CKD. In addition, a restricted cubic spline was used to investigate the dose‒response relationship between whole grain and risk of CKD. RESULTS: A total of 6747 participants were included, 728 of whom had CKD. Compared with those in the lowest whole grain intake group, those in the higher grain intake group had an inverse association with risk of CKD (Q2: adjusted OR 0.70, 95% CI: 0.54, 0.89; Q3: adjusted OR 0.54, 95% CI: 0.42, 0.69; and Q4: adjusted OR 0.29, 95% CI: 0.21, 0.41). The association between whole grain intake and CKD seems to be stronger for individuals who were male (P for interaction = 0.008) or smokers (P for interaction = 0.013). In addition, the restricted cubic spline suggested an obvious L-shaped correlation. CONCLUSIONS: Increased whole grain intake was associated with a decreased risk of CKD in Chinese adults.

In vitro and in vivo study of andrographolide nanoparticles for the treatment of Mycoplasma pneumoniae pneumonia.

OBJECTIVE(S): The emergence of antibiotic resistance has led to suboptimal treatment outcomes for Mycoplasma pneumoniae pneumonia (MPP). Exploring naturally occurring drug components that are both effective against MPP and non-toxic may be a promising choice. This study aimed to investigate the therapeutic effect of andrographolide nanoparticles on pneumonia caused by Mycoplasma pneumoniae infection. METHODS: Andrographolide alginate-poloxamer nanoparticles (AND-ALG-POL/NPs) were obtained by wet medium grinding, and the characterization and in vitro release of the prepared andrographolide nanoparticles were examined by high performance liquid chromatography, particle size analyzer, zeta potential meter and transmission electron microscopy. The cytotoxicity and anti-inflammatory effects of AND-ALG-POL/NPs were evaluated in vitro by MP-infected lung epithelial cells BEAS-2B. Symptoms of pneumonia, total cell count, total protein content and inflammatory factor levels in BALF were assessed by MP-induced pneumonia in BALB/c mice treated with AND-ALG-POL/NPs, and histopathological studies were performed on lung tissues from experimental animals. RESULTS: The results showed that the prepared AND-ALG-POL/NPs were homogeneous spherical with a diameter of 180 ± 23 nm, a zeta potential of (-14.4 ± 2.1) mV, an average encapsulation rate of 87.74 ± 0.87 %, and an average drug loading of 13.17 ± 0.54 %. AND-ALG-POL/NPs were capable of slow release in vitro and showed significant inhibitory ability against MP (P < 0.001). However, AND-ALG-POL/NPs were not cytotoxic to normal cells and alleviated MP infection-induced apoptosis and elevated inflammatory factors. In the in vivo experiments, AND-ALG-POL/NPs alleviated the symptoms of pneumonia in MPP mice, reduced the abnormally elevated total cell count, total protein content and inflammatory factor levels in BALF, and alleviated lung tissue edema, inflammatory cell infiltration and apoptosis (P < 0.001). Meanwhile, the therapeutic effects of AND-ALG-POL/NPs on MPP were similar to those of azithromycin (AZM) and higher than those of andrographolide (AND) free monotherapy (P < 0.001). CONCLUSION: In summary, the prepared AND-ALG-POL/NPs can effectively inhibit MPP in vitro and in vivo, and the effect is similar to that of AZM. Therefore, AND- ALG - POL/NPs have the potential to replace AZM as a potential drug for the treatment of MPP.

Effect of Gouteng Jiangya Jieyu Perscription on Polarization of Hippocampal Microglia in Hypertensive Rats Complicated with Depression by Inhibiting TLR4/NF-кB Signaling Pathway / 中药新药与临床药理

Objective To investigate the effect of Gouteng Jiangya Jieyu Perscription(Uncariae Ramulus cum Uncis,Gastrodiae Rhizoma,Pheretima,Puerariae Lobatae Radix,etc.)modulating the TLR4/NF-кB signaling pathway on the polarization of hippocampal microglia in rats with hypertension complicated with depression(HD)Methods Forty primary hypertensive rats were randomly divided into five groups:the model group,the positive drug group,and the high-,medium-,and low-dose groups of Gouteng Jiangya Jieyu Perscription,with 8 rats in each group;and another 8 SD rats were taken as the control group.The HD model was replicated using 42 days of continuous chronic unpredictable mild stress(CUMS)combined with solitary rearing.The modeling was accompanied by the administration of drugs,including 29.61,14.81,and 7.40 g·kg-1 of Gouteng Jiangya Jieyu Perscription in the high-,medium-,and low-dose groups of Chinese herbal medicine,respectively,and 0.45 mg·kg-1 of Levamlodipine Besylate+1.8 mg·kg-1 of Fluoxetine in the positive group;the volume of the gavage was 10 mL·kg-1,once a day,for 42 consecutive days.The systolic blood pressure of rat tail artery was measured by non-invasive sphygmomanometer before drug administration and in the morning of the last day of each week;the behavioural test of Sucrose Preference Test(SPT)was carried out once in the second week and once in the last week after the start of the modelling;the water maze experiment was carried out after the end of the modelling;the levels of serum inflammatory factor tumor necrosis factor-α(TNF-α),interleukin(IL)1β and IL-10 were determined by ELISA;the pathological changes of rat hippocampal tissue neurons were observed by HE staining and Nissl stain were used to observe the neuronal pathological changes in rat hippocampal tissue;immunofluorescence double staining was used to detect the expressions of microglia M1(CD16)and M2(CD206)types in the hippocampal region;and Western Blot was used to detect the protein expressions of TLR4 and NF-кB p65 in the hippocampal tissue.Results Compared with the control group,the systolic blood pressure in the tail artery of rats in the model group from week 1 to week 6 were all significantly increased(P＜0.01);sucrose preference rate was significantly decreased(P＜0.01);evasion latency was significantly prolonged(P＜0.05,P＜0.01),the number of times of traversing the plateau and the percentage of time spent in the target quadrant were significantly decreased(P＜0.01);the contents of serum TNF-α and IL-1β were significantly increased(P＜0.01),IL-10 content was significantly decreased(P＜0.01);cytosolic nuclei were deeply stained,cytoplasmic solidification and apoptosis were obvious;the fluorescence intensity ratio of CD206/CD16 in hippocampal microglial cells were significantly decreased(P＜0.05);the protein expressions of TLR4 and NF-кB p65 in hippocampal tissues were significantly up-regulated(P＜0.01).Compared with the model group,the systolic blood pressure in the tail artery of rats in the first to sixth weeks of the drug administration group were all significantly reduced(P＜0.01);the sucrose preference rates were all significantly increased(P＜0.05);the contents of serum TNF-α and IL-1β were significantly decreased(P＜0.01),and the content of IL-10 was significantly increased(P＜0.01);the Nissl substances are abundant and apoptosis is significantly reduced,and apoptosis were significantly reduced.The escape latency of rats in the positive drug group and the high-dose group of Gouteng Jiangya Jieyu Perscription was significantly shortened(P＜0.05,P＜0.01),and the number of times of crossing the plateau and the percentage of time spent in the target quadrant were significantly increased(P＜0.05);the ratio of fluorescence intensity of hippocampal microglial cells,CD206/CD16 was significantly increased(P＜0.05,P＜0.01);and the hippocampal tissues,protein expressions of TLR4 and NF-κB p65 were significantly down-regulated(P＜0.05,P＜0.01).Conclusion Gouteng Jiangya Jieyu Perscription may regulate the polarisation state of hippocampal microglial cells,modulate the secretion of inflammatory factors,and attenuate the damage of hippocampal neurons in HD rats by inhibiting the TLR4/NF-кB pathway.

Association between regular proton pump inhibitors use and cardiovascular outcomes: A large prospective cohort study.

BACKGROUND: Proton pump inhibitors (PPIs) are widely prescribed for gastroesophageal reflux disease and peptic ulcer disease. However, the association between the regular PPIs use and the risk of cardiovascular disease (CVD) outcomes remains unclear. We aimed to determine whether regular proton pump inhibitors (PPIs) use is associated with an altered incidence of cardiovascular disease (CVD) in the general population. METHODS: This prospective cohort study included 459,207 participants (mean [SD] age, 56.2 [8.1] years) from the UK Biobank study without prevalent CVD who enrolled between 2006 and 2010 and were followed until 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CVD and its components (coronary heart disease [CHD], stroke, heart failure, atrial fibrillation, and venous thromboembolism) were obtained using Cox proportional hazards models with adjustment for potential confounding factors, including demographic factors, lifestyle behaviors, prevalent comorbidities, and clinical indicators for PPIs use. RESULTS: During the follow-up period, we recorded 26,346 incident CVD events (including 13,749 CHD events, 4144 stroke events, 5812 atrial fibrillation events, 1159 heart failure events, and 4206 venous thromboembolism events). The fully adjusted HRs (and 95% CIs) associated with PPIs users compared to nonusers were 1.44 (95% CI 1.39-1.50) for incident CVD, 1.65 (95% CI 1.57-1.74) for CHD, 1.21 (95% CI 1.09-1.33) for stroke, 1.17 (95% CI 1.08-1.28) for atrial fibrillation, 1.61 (95% CI 1.37-1.89) for heart failure, and 1.36 (95% CI 1.24-1.50) for venous thromboembolism. CONCLUSIONS: Regular PPIs use was associated with higher risk of CVD outcomes. Clinicians should therefore exercise caution when prescribing PPIs.

Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Atomoxetine (ATX) is a non-stimulant used to treat attention-deficit/hyperactivity disorder (ADHD) and systemic exposure is highly variable due to polymorphic cytochrome P450 2D6 (CYP2D6) activity. The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine (4-OH); N-desmethylatomoxetine (NDA); and 2-carboxymethylatomoxetine (2-COOH)) exposure following oral ATX dosing in children with ADHD to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from children with ADHD (n = 23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic modeling approach was used in which a model for ATX, 4-OH, and NDA in plasma and urine, and 2-COOH in urine was developed. Plasma ATX, 4-OH, and NDA were modeled using two-compartment models with first-order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4-OH, and systemic exposure of NDA. CL/F of ATX varied almost 7-fold across the CYP2D6 AS groups: AS 2: 20.02 L/hour; AS 1: 19.00 L/hour; AS 0.5: 7.47 L/hour; and AS 0: 3.10 L/hour. The developed model closely captures observed ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles. Application of the model shows the potential for AS-based dosing recommendations for improved individualized dosing.

Long-term air pollution exposure, habitual physical activity, and incident chronic kidney disease.

Both air pollution and physical inactivity contribute to the increased risk of incident chronic kidney disease (CKD). However, the detrimental effects of air pollution exposure could be augmented by an elevated intake of air pollutants during exercise. In the present study, we analyzed 367,978 participants who were CKD-free at baseline (2006-2010) based on the UK Biobank. Air pollutants included fine particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOX). Physical activity (PA) was obtained by the self-reported questionnaire. Using Cox proportional hazards models, hazard ratios (HRs) for incident CKD related to air pollution, PA, and incident CKD were evaluated. During a median of 12.4 years of follow-up, 14,191 incident CKD events were documented. High PM2.5, PM10, NO2, and NOX increased CKD risks by 11 %, 15 %, 14 %, and 12 %, respectively, while moderate and high PA reduced CKD risks by 18 % and 22 %, respectively. Participants with high PA and low air pollution exposure had 29 %, 31 %, 30 %, and 30 % risks of incident CKD than those with low PA and high air pollution exposure for the four air pollutants, with multivariable-adjusted HRs of 0.71 (95 % confidence intervals [CI]: 0.65-0.76) for PM2.5, 0.69 (95 % CI: 0.64-0.75) for PM10, 0.70 (95 % CI: 0.64-0.75) for NO2, and 0.70 (95 % CI: 0.64-0.75) for NOX. No clear interactions were observed between each air pollutant exposure and PA (all P for interaction > 0.05). The findings that reducing air pollution exposure and increasing PA were both independently correlated with a diminished risk of incident CKD suggest that PA could be targeted to prevent CKD generally regardless of air pollution levels. Further research is needed in areas polluted moderately and severely to examine our findings.

Associations of long-term joint exposure to various ambient air pollutants with all-cause and cause-specific mortality: evidence from a large population-based cohort study.

The association between long-term joint exposure to all kinds of ambient air pollutants and the risk of mortality is not known. Our study prospectively assessed the joint associations of various air pollutants with cause-specific and all-cause mortality risk and identified potential modifying factors affecting these associations. A total of 400,259 individuals aged 40-70 years were included in this study. Information on PM10, PM2.5-10, PM2.5, NO2, and NOx was collected. A weighted air pollution score was calculated to assess joint exposure to the above air pollutants. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. During a median of 12.0 years (4,733,495 person-years) of follow-up, 21,612 deaths were recorded, including 7097 deaths from cardiovascular disease and 11,557 deaths from cancer. The adjusted HRs of all-cause mortality were 1.39 (95% CI: 1.29-1.50), 1.86 (95% CI: 1.63-2.13), 1.12 (95% CI: 1.10-1.14), and 1.04 (95% CI: 1.03-1.05) for every 10-ug/m3 increase in PM10, PM2.5, NO2, and NOx, respectively. The adjusted HRs associated with the air pollution score (the highest quintile versus the lowest quintile) were 1.24 (95% CI: 1.19-1.30) for all-cause mortality, 1.33 (95% CI: 1.23-1.43) for cardiovascular mortality, and 1.16 (95% CI: 1.09-1.23) for cancer mortality. Furthermore, we found that the air pollution score was associated with a linear dose-response increase in mortality risk (all P for linearity < 0.001). The findings highlight the importance of a comprehensive assessment of various air pollutants.

Matching Bidentate Ligand Anchoring: an Accurate Control Strategy for Stable Single-Atom/ZIF Nanocatalysts.

Improving metal loading and controlling the coordination environment is nontrivial and challenging for single-atom catalysts (SACs), which have the greatest atomic efficiency and largest number of interface sites. In this study, a matching bidentate ligand (MBL) anchoring strategy is designed for the construction of CuN4 SACs with tunable coordination environments (Cu loading range from 0.4 to15.4 wt.%). The obtained Cu SA/ZIF and Cu SA/ZIF* (0.4 wt.%) (ZIF and ZIF* = Zeolitic imidazolate framework with Matching bidentate N-ligands) nanocomposites exhibit superior performance in homo-coupling of phenyl acetylene under light irradiation (TON = 580, selectivity > 99%), which is 22 times higher than that of Cu SA/NC-800 (NC = N-doped porous carbon). Experiments and density functional theory calculations confirmed that the specific Cu five-membered ring formed using the MBL anchoring strategy is the key to the immobilization of isolated Cu atoms. This strategy provides a basis for the construction of M SA/MOF, which has the potential to narrow the gap between experimental and theoretical catalysis, as further confirmed by the successful preparation of Fe SA/ZIF and Ni SA/ZIF.

Gelsemine Exerts Neuroprotective Effects on Neonatal Mice with Hypoxic-Ischemic Brain Injury by Suppressing Inflammation and Oxidative Stress via Nrf2/HO-1 Pathway.

Given that the role of Gelsemine in neuroinflammation has been demonstrated, this research aimed to investigate the effect of Gelsemine on neonatal hypoxic-ischemic (HI) brain injury. An in vivo HI brain injury neonatal mouse model and an in vitro oxygen-glucose deprivation (OGD) cell model were established and pretreated with Gelsemine. The brain infarct volume, neuronal loss and apoptosis, as well as spatial learning and memory were examined by TTC staining, Nissl's staining, TUNEL staining and Morris water maze test. Immunohistochemical staining was applied to detect the microglia cells and astrocytes in the mouse brain tissue. The cell viability was analyzed by CCK-8 assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), TNF-α, IL-1ß, and IL-6 were determined via ELISA. The lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) level in OGD-treated cells were detected by colorimetry and DCFH-DA staining. Nrf2, HO-1, and inflammation-related factors were analyzed by immunofluorescence, qRT-PCR, or western blot. Gelsemine reduced the infarct volume and neuronal loss and apoptosis, yet improved spatial learning and memory impairment of HI-injured mice. Gelsemine inhibited the elevated MDA, TNF-α, IL-1ß, IL-6, LDH and ROS levels, promoted the reduced SOD level and viability, and strengthened the up-regulation of HO-1 and Nrf2 in brain tissues and OGD-treated cells. However, Nrf2 silencing reversed the effects of Gelsemine on the Nrf2/HO-1 pathway, inflammation, and oxidative stress in OGD-treated cells. Gelsemine produces neuroprotective effects on neonatal mice with HI brain injury by suppressing inflammation and oxidative stress via Nrf2/HO-1 pathway.

A Physiological-Based Pharmacokinetic Model Embedded with a Target-Mediated Drug Disposition Mechanism Can Characterize Single-Dose Warfarin Pharmacokinetic Profiles in Subjects with Various CYP2C9 Genotypes under Different Cotreatments.

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high interindividual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiology-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin that integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of a single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. SIGNIFICANCE STATEMENT: The present study found that a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

Application of CBL combined with clinical pathway in thoracic surgery practice teaching / 中华医学教育探索杂志

Objective:To explore the feasibility and application value of case-based learning (CBL) combined with clinical pathway in thoracic surgery practice teaching.Methods:A total of 30 clinical undergraduate students who practiced from January 2018 to August 2018 were selected and randomly divided into the traditional group and the research group. The traditional group used traditional teaching mode, while the research group adopted the CBL combined with clinical pathway teaching. The scores of theoretical examination and practice skills assessment and the case analysis ability of the two groups were compared at the time of department. In addition, the evaluation of the teaching effect of the two groups of teachers and students was observed through anonymous questionnaires. SPSS 21.0 was used for t-test and Chi-square test. Results:The scores of the students in the research group were better than those in the traditional group, including score of theoretical examination [(88.20±4.02) vs. (80.76±4.62), P<0.001], score of practice skills assessment [(90.80±2.16) vs. (84.80±3.07), P<0.001] and case analysis ability [(89.80±3.34) vs. (81.86±4.31), P<0.001]. The differences were statistically significant. At the same time, the questionnaire showed that the research group was superior to the traditional group in improving students' learning interest, clinical skills, case analysis ability, clinical communication ability, theoretical knowledge understanding and clinical thinking ability, with a statistically significant difference ( P<0.05). While the two groups had no statistically significant difference in students' satisfaction with teachers ( P=0.083). Conclusion:The CBL method combined with clinical pathway teaching method can improve the teaching effect of thoracic surgery practice, which is worth popularizing.

MR-guided focused ultrasound surgery for localized prostate cancer: a preliminary investigation / 中华放射学杂志

Objective:To investigate the safety and efficacy of MR-guided focused ultrasound surgery (MRgFUS) in treating localized prostate cancer.Methods:Six patients with localized prostate cancer who underwent MRgFUS treatment from August 2020 to September 2021 in Beijing Hospital were prospectively enrolled in this study. The patients were all over 18 years old, with an average age of (68±10) years, and had not received any prior treatment for prostate cancer. Pretreatment pelvic MR and CT scans were performed to determine the region of treatment (ROT). Different urinary catheterization measures were given based on the location of the lesion. Under general anesthesia, the lesions were treated by MRgFUS using a specialized rectal ultrasound transducer on the treatment bed. The patients were followed up at 1, 3, and 6 months after treatment and annually thereafter. During follow-up, prostate-specific antigen (PSA) levels, pelvic MR scans, International Prostate Symptom Score (IPSS), International Index of Erectile Function-15 (IIEF-15) scores, and adverse events were assessed.Results:(1) All six patients underwent MRgFUS treatment for six lesions, with an average duration of (126±56) minutes, an average number of (7.3±3.2) focal ultrasound pulses per lesion, and an average non-perfusion volume of (3.8±1.1) cm 3, which covered the entire treatment target area. No treatment-related adverse events were reported. (2) The PSA levels at baseline, 1, 3, 6, and 12 months after treatment were (6.6±0.8), (3.6±1.3), (3.4±3.0), (2.5±1.7), and (2.3±1.8) ng/ml, respectively. PSA levels increased in 2 out of 6 patients during follow-up, and pelvic MR scan revealed recurrent lesions, while PSA levels continued to decrease in the remaining 4 patients, and pelvic MR scan were normal. (3) The IPSS scores at baseline, 1, and 3 months after treatment were 13.0 (4.0, 16.0), 10.0 (4.0, 12.0), and 5.0 (3.0, 6.0) points, respectively. For the three sexually active patients, the IIEF-15 scores at baseline were 40, 51, and 14 points, respectively, and IIEF-15 at 1 month after treatment were 9, 8, and 14 points, respectively, and at 3 months after treatment were 9, 66 and 26 points, respectively. (4) One patient was diagnosed with recurrence 10 months after treatment, and another patient was found to have a new lesion 6 months after treatment. Conclusions:MRgFUS might be a safe, non-invasive, and effective treatment for localized prostate cancer, but regular follow-up is vital for detecting tumor recurrence.

Long-term efficacy and influencing factors of extended thymectomy for myasthenia gravis with thymic atrophy / 中国胸心血管外科临床杂志

@#Objective    To analyze the surgical efficacy and influencing factors of myasthenia gravis (MG) patients with thymic atrophy after thymectomy. Methods    The clinical data of MG patients with thymic atrophy undergoing thymectomy between October 2014 and May 2018 in Daping Hospital of Army Medical University and Shijiazhuang People Hospital were retrospectively analyzed. Results    A total of 71 patients were collected, including 40 males and 31 females with a mean age of 45.17±12.42 years. All patients received the surgery successfully. After the surgery, 20 (28.17%) patients were stable remission, 12 (16.90%) patients were minimal manifestation status,19 (26.76%) patients were improved, 5 (7.04%) patients showed no change, 3 (4.23%) patients were worsened, 10 (14.08%) patients were exacerbated and 2 (2.82%) patients were dead. Multivariate logistic regression analysis showed that the preoperative illness duration (OR=4.61, 95%CI 1.13-18.85, P=0.03), and postoperative pyridostigmine combined with immunosuppressive (OR=0.12, 95%CI 0.03-0.45, P=0.00) were independent risk factors for long-term efficacy of thymectomy for MG patients with thymic atrophy. Conclusion    Early surgery after diagnosis of MG and postoperative pyridostigmine combined with immunosuppressive treatment is beneficial to the prognosis of MG patients with thymic atrophy.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor / 中西医结合学报

OBJECTIVE@#This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR).@*METHODS@#Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway.@*RESULTS@#Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon.@*CONCLUSION@#Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Right visual double lumen endotracheal tube versus common right double lumen endotracheal tube lung isolation technique: A randomized controlled study / 中国胸心血管外科临床杂志

@#Objective    To compare the clinical efficacy between right visual double lumen tube (VDLT) intubation and right common double lumen tube (DLT) intubation in lung isolation technique. Methods    A total of 57 patients undergoing thoracoscopic surgery with right DLT lung isolation technique in the First People's Hospital of Chenzhou City and West China Hospital from June 2020 to June 2021 were randomly divided into two groups: a DLT group (n=29, 16 males and 13 females, with a mean age of 54.3±13.2 years) and a VDLT group (n=28, 18 males and 10 females, with a mean age of 55.1±13.7 years) at 1 : 1 with random number table generated by the computer. The clinical data of the two groups were compared. Results    Compared with the DLT group, the catheter positioning time in the VDLT group was statistically shorter (74.9±47.5 s vs. 151.6±88.9 s, P<0.001), the right upper lung occlusion rate (21.4% vs. 51.7%) and the intraoperative re-adjustment catheterization rate (14.3% vs. 48.3%) were lower (P<0.05). The quality of lung collapses immediately after thoracotomy (67.9% vs. 24.1%) and 20 minutes after thoracotomy (100.0% vs. 75.9%) were improved (P<0.05). There was no significant difference in the rate of fiberoptic bronchoscope assistance for positioning, or the incidence of pharynx pain and hoarseness between the two groups (P>0.05). Conclusion    Compared  with common DLT, VDLT is more efficient, accurate and intuitive in the location of right bronchial intubation.

A study of the safety and efficacy of intravascular lithotripsy in the treatment of coronary artery calcification lesions / 中国介入心脏病学杂志

Objective To evaluate the safety and efficacy of intravascular lithotripsy(IVL)in the treatment of coronary artery calcification lesions.Methods A total of 53 patients who underwent endovascular imaging guided treatment of coronary artery calcified lesions with either IVL or cutting balloon(CB)at the Affiliated Hospital of Jining Medical College from January 2023 to July 2023 were retrospectively analysed(IVL:n=18,CB:n=35)were retrospectively analysed to compare the technique,clinical success rate,major adverse cardiovascular events(MACE)and readmission for cardiovascular events in patients followed during hospitalisation and 1 month after the procedure.Results Clinical success rates were identical in the IVL and CB groups(100.0％vs.100.0％,P＞0.999),the minimum lumen area of lesions was similar in the VL and CB groups[(1.7±0.4)mm2 vs.(1.7±0.5 mm2),P=0.628].And there was a statistically significant difference in the overall mean lesion length between the IVL and CB groups[(28.4±9.6)mm vs.(20.9±8.6)mm,P=0.008].During the procedure,there were no complications such as aneurysm,thrombus,or emergency vessel closure.There was a statistically significant difference in the overall mean value of residual stenosis between the IVL and CB groups[(1.7±1.7)％vs.(6.9±2.0)％,P=0.049].There were no MACE in either group during hospitalisation or at the one-month follow-up(0 vs.0,P＞0.999),and 3 patients in the CB group were readmitted for angina pectoris(0 vs.8.6％,P=0.543),with no significant difference in readmission rates between the two groups.Conclusions The technique of intravascular lithotripsy is safe and effective in the treatment of coronary artery calcification lesions.