Background The Inner Mongolia Autonomous Region is a vast area with a wide array of ecological environments, resulting in considerable regional variations in air pollution characteristics. Current research is limited by a scarcity of systematic, region-wide studies and risk assessments. Objective To assess the health risks associated with inhalation exposure to nine heavy metal and metalloid elements in atmospheric fine particulate matter (PM_2.5) for the population of the Inner Mongolia Autonomous Region. Methods From the 10th to the 16th of each month throughout 2023, atmospheric PM_2.5 samples were collected at designated monitoring sites in 12 leagues (cities) across the Inner Mongolia Autonomous Region to analyze the characteristics and trends in concentration. The health risk assessment model developed by the United States Environmental Protection Agency was employed to evaluate both the non-carcinogenic and carcinogenic risks associated with the heavy metal elements beryllium (Be), cadmium (Cd), chromium (Cr), hydrargyrum (Hg), plumbum (Pb), manganese (Mn), and nickel (Ni) and the metalloid elements stibium (Sb) and arsenic (As). Results In 2023, a total of 1206 valid PM_2.5 samples were analyzed from the Inner Mongolia Autonomous Region. The annual average PM_2.5 concentrations in Inner Mongolia, as well as in the cities of Ordos, Wuhai, and the Alxa League, all exceeded the national limit of 35 μg·m⁻³. The PM_2.5 concentrations across the leagues (cities) exhibited a clear seasonal variation, peaking in winter, followed by spring, and reaching a minimum in summer and autumn. The median PM_2.5 concentration in Ordos throughout the year was higher than that in the other leagues (cities) of the region. Concerning health risks, the non-carcinogenic risks associated with the 9 elements detected in each league (city) were all below 1, indicating acceptable levels. However, the non-carcinogenic risk values for Mn, Cr, and As were relatively high; specifically, Ordos City displayed the highest non-carcinogenic risk values for Mn (7.74×10⁻¹) and Cr (2.97×10⁻²), while Chifeng City recorded the highest value for As (2.34×10⁻³). The carcinogenic risk values for As, Cd, Cr, and Ni fell within the range of 1×10⁻⁹ to 1×10⁻⁵, representing an acceptable level. The health risks varied with age, and the elderly residents faced the highest non-carcinogenic and carcinogenic health risks. Conclusion While the carcinogenic and non-carcinogenic risks from heavy metals and metalloids within atmospheric PM_2.5 in the Inner Mongolia Autonomous Region are generally within acceptable limits, the potential risks that Mn, As, and Cr pose to the health of elderly people warrants particular attention, and Ordos and Chifeng cities exhibit notably higher health risks among other areas. It is recommended that regular, long-term monitoring be conducted, taking into account the specific conditions at monitoring sites across each league (city), and that targeted air quality management strategies be implemented to protect public health.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

COMPERA 2.0 risk stratification has been demonstrated to be useful in patients with precapillary pulmonary hypertension (PH). However, its suitability for patients at risk for post-capillary PH or PH associated with left heart disease (PH-LHD) is unclear. To investigate the use of COMPERA 2.0 in patients with severe aortic stenosis (SAS) undergoing transcatheter aortic valve replacement (TAVR), who are at risk for post-capillary PH, a total of 327 eligible SAS patients undergoing TAVR at our institution between September 2015 and November 2020 were included in the study. Patients were classified into four strata before and after TAVR using the COMPERA 2.0 risk score. The primary endpoint was all-cause mortality. Survival analysis was performed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression model. The study cohort had a median (interquartile range) age of 76 (70‒80) years and a pulmonary arterial systolic pressure of 33 (27‒43) mmHg (1 mmHg=0.133 kPa) before TAVR. The overall mortality was 11.9% during 26 (15‒47) months of follow-up. Before TAVR, cumulative mortality was higher with an increase in the risk stratum level (log-rank, both P<0.001); each increase in the risk stratum level resulted in an increased risk of death (hazard ratio (HR) 2.53, 95% confidential interval (CI) 1.54‒4.18, P<0.001), which was independent of age, sex, estimated glomerular filtration rate (eGFR), hemoglobin, albumin, and valve type (HR 1.76, 95% CI 1.01‒3.07, P=0.047). Similar results were observed at 30 d after TAVR. COMPERA 2.0 can serve as a useful tool for risk stratification in patients with SAS undergoing TAVR, indicating its potential application in the management of PH-LHD. Further validation is needed in patients with confirmed post-capillary PH by right heart catheterization.
Humans ; Aortic Valve Stenosis/complications* ; Aged ; Hypertension, Pulmonary/mortality* ; Male ; Female ; Transcatheter Aortic Valve Replacement ; Aged, 80 and over ; Risk Assessment/methods* ; Proportional Hazards Models ; Kaplan-Meier Estimate ; Retrospective Studies

Objective:To analyze the clinical features and genetic etiology of 17 Chinese pedigrees affected with X-linked intellectual disability (XLID).Methods:Seventeen pedigrees affected with unexplained intellectual disability which had presented at Henan Provincial People′s Hospital from May 2021 to May 2023 were selected as the study subjects. Clinical data of the probands and their pedigree members were collected. Trio-whole exome sequencing (Trio-WES), Sanger sequencing and X chromosome inactivation (XCI) analysis were carried out. Pathogenicity of candidate variants was predicted based on the guidelines from the American College of Medical Genetics and Genomics and co-segregation analysis.Results:The 17 probands, including 9 males and 8 females with an age ranging from 0.6 to 8 years old, had all shown mental retardation and developmental delay. Fourteen variants were detected by genetic testing, which included 4 pathogenic variants ( MECP2: c. 502C>T, MECP2: c. 916C>T/c.806delG, IQSEC2: c.1417G>T), 4 likely pathogenic variants ( MECP2: c. 1157_1197del/c.925C>T, KDM5C: c. 2128A>T, SLC6A8: c. 1631C>T) and 6 variants of uncertain significance ( KLHL15: c. 26G>C, PAK3: c. 970A>G/c.1520G>A, GRIA3: c. 2153C>G, TAF1: c. 2233T>G, HUWE1: c. 10301T>A). The PAK3: c.970A>G, GRIA3: c. 2153C>G and TAF1: c. 2233T>G variants were considered as the genetic etiology for pedigrees 12, 14 and 15 by co-segregation analysis, respectively. The proband of pedigree 13 was found to have non-random XCI (81: 19). Therefore, the PAK3: c. 1520G>A variant may underlie its pathogenesis. Conclusion:Trio-WES has attained genetic diagnosis for the 17 XLID pedigrees. Sanger sequencing and XCI assay can provide auxiliary tests for the diagnosis of XLID.

Objective:To evaluate the epidemiological characteristics and explore the associated factors of breakthrough cases (BC) from Public Health Emergency Events (PHEEs) of varicella in Zhejiang Province from 2019 to 2022.Methods:Data on cases were obtained from the China Information System for Disease Control and Prevention and the PHEEs Reporting Information Database of Varicella in Zhejiang Province. History records were matched through the Zhejiang Provincial Immunization Information System. Descriptive analysis and multiple logistic regression model with a bidirectional stepwise selection method were performed to explore associated factors for BC during 2019-2022.Results:A total of 144 276 varicella cases were reported from 2019 to 2022, with the annual reported incidence of 47.35-82.80 cases per 100 000 population. Among these cases, 109 172 were non-breakthrough cases (NBC, accounting for 75.67%), 34 517 were BC (23.92%), and the rest 587 cases had unclear vaccination history on varicella (0.41%). A total of 214 PHEEs of varicella were reported, of which 99.07% occurred in school settings. The proportion of PHEEs that occurred in high school increased significantly as time went on ( χ2trend=5.742, P=0.017). Multiple logistic regression model which focused on "BC vs. NBC (as the reference)" indicated that the year of onset ( OR=1.585, 95% CI:1.343-1.878), the month of onset (taking January as the reference, OR=2.311-15.652), city (taking Hangzhou as the reference, Jiaxing OR=2.370, Jinhua OR=2.197, Lishui OR=0.134), age ( OR=0.887, 95% CI: 0.826-0.944), PHEEs setting (taking "primary school and below" as the reference, "high school and above" OR=0.516, 95% CI: 0.305-0.897), and the number of rashes ( OR=0.569, 95% CI: 0.458-0.703) were associated factors. Multiple logistic regression model which focused on "two-dose BC vs. one-dose BC (as the reference)" showed that the age of initial vaccination ( OR=0.045, 95% CI: 0.014-0.107), the time interval from onset to the last dose ( OR=0.037, 95% CI: 0.011-0.087) and the age of onset ( OR=20.724, 95% CI: 8.383-72.485) were associated factors. Conclusion:During 2019-2022, the reported high-risk group of varicella in Zhejiang Province has shifted to adolescents and young adults. Although vaccination could not completely prevent the onset of VZV, it could relieve clinical symptoms and delay the age of onset.

Objective:To evaluate the epidemiological characteristics and explore the associated factors of breakthrough cases (BC) from Public Health Emergency Events (PHEEs) of varicella in Zhejiang Province from 2019 to 2022.Methods:Data on cases were obtained from the China Information System for Disease Control and Prevention and the PHEEs Reporting Information Database of Varicella in Zhejiang Province. History records were matched through the Zhejiang Provincial Immunization Information System. Descriptive analysis and multiple logistic regression model with a bidirectional stepwise selection method were performed to explore associated factors for BC during 2019-2022.Results:A total of 144 276 varicella cases were reported from 2019 to 2022, with the annual reported incidence of 47.35-82.80 cases per 100 000 population. Among these cases, 109 172 were non-breakthrough cases (NBC, accounting for 75.67%), 34 517 were BC (23.92%), and the rest 587 cases had unclear vaccination history on varicella (0.41%). A total of 214 PHEEs of varicella were reported, of which 99.07% occurred in school settings. The proportion of PHEEs that occurred in high school increased significantly as time went on ( χ2trend=5.742, P=0.017). Multiple logistic regression model which focused on "BC vs. NBC (as the reference)" indicated that the year of onset ( OR=1.585, 95% CI:1.343-1.878), the month of onset (taking January as the reference, OR=2.311-15.652), city (taking Hangzhou as the reference, Jiaxing OR=2.370, Jinhua OR=2.197, Lishui OR=0.134), age ( OR=0.887, 95% CI: 0.826-0.944), PHEEs setting (taking "primary school and below" as the reference, "high school and above" OR=0.516, 95% CI: 0.305-0.897), and the number of rashes ( OR=0.569, 95% CI: 0.458-0.703) were associated factors. Multiple logistic regression model which focused on "two-dose BC vs. one-dose BC (as the reference)" showed that the age of initial vaccination ( OR=0.045, 95% CI: 0.014-0.107), the time interval from onset to the last dose ( OR=0.037, 95% CI: 0.011-0.087) and the age of onset ( OR=20.724, 95% CI: 8.383-72.485) were associated factors. Conclusion:During 2019-2022, the reported high-risk group of varicella in Zhejiang Province has shifted to adolescents and young adults. Although vaccination could not completely prevent the onset of VZV, it could relieve clinical symptoms and delay the age of onset.

Objective:To explore whether tryptophan metabolism is related to bone growth by comparing the differences in tryptophan metabolism after rotator cuff tear (RCT) repair between rats with normal bone remodeling capability and those with defective bone remodeling capability.Methods:Of the 50 adult female Sprague Dawley (SD) rats used for this study, 18 were randomly selected to undergo bilateral ovariectomy (OVX) (OVX group), and the remaining 32 underwent bilateral OVX sham surgery (sham surgery group). All rats were maintained in standard conditions. Three months after surgery, 4 rats were randomly selected from OVX group and the sham surgery group, respectively, for Micro CT identification of bone loss at the rat humeral head. The remaining rats in OVX group underwent RCT modeling and surgical repair of acute supraspinatus muscle transection (OVX+RCT group) ( n=14); the remaining rats in the sham surgery group were subjected to either surgical repair of acute supraspinatus muscle transection (RCT group, n=14) or RCT sham surgery (SO group, n=14). The grip power of the rats was tested 2 weeks after surgery. The supraspinatus tendon-bone complex was harvested for evaluation of new bone formation and growth through real-time fluorescence quantitative polymerase chain reaction (qPCR), hematoxylin eosin (HE) staining, and immunohistochemistry (IHC) staining. The tryptophan metabolism was analyzed using ultra high performance liquid chromatography (UPLC). Results:The grip power test showed that SO group had the greatest grip power, followed by RCT group and OVX+RCT group, with statistically significant differences between the 3 groups ( P<0.05). The qPCR showed that the relative expression of osteosclerosis in the tendon-bone complex in SO group was significantly higher than that in OVX+RCT group and RCT group; IHC staining showed that the relative expression of osteocalcin in RCT group was significantly higher than that in SO group and OVX+RCT group ( P<0.05). The UPLC showed that the content of tryptophan in the rotator cuff tendon-bone complex was similar among SO, RCT, and OVX+RCT groups, showing no significant difference ( P>0.05). The qPCR showed that the expression of indoleamine 2, 3-dioxygenase 2 in the Kynurenic acid metabolism pathway showed an increasing trend from SO group to RCT group to OVX+RCT group, with OVX+RCT group significantly higher than SO group ( P<0.05). The expression of 3-hydroxybenzoate 3, 4-dioxygenase in OVX+RCT group was significantly higher than that in RCT group and in SO group ( P<0.001). The subtypes A and B of monoamine oxidase in the 5-hydroxytryptamine metabolism pathway increased from SO group to RCT group to OVX+RCT group. The subtypes A and B of monoamine oxidase in the 5-hydroxytryptamine metabolism pathway increased among SO, RCT, and OVX+RCT groups( P<0.001). The expression of dopamine decarboxylase in the indole metabolism pathway in OVX+RCT group was significantly higher than that in SO group ( P<0.01). The expression of cytochrome P450 oxidoreductase increased from SO group to RCT group to OVX+RCT group ( P<0.001). Conclusions:The tryptophan metabolism in the supraspinatus tendon-bone complex after RCT in rats is mainly dominated by kynurenic acid metabolism, followed by 5-hydroxytryptamine metabolism. In RCT bone remodeling, the 5-hydroxytryptamine metabolic pathway changes the most, followed by the indole pathway. The contents of niacin and xanthurenic acid in the kynurenic acid metabolism pathway are related to bone growth; the 5-hydroxytryptamine, hydroxyindoleacetic acid, and melatonin in the 5-hydroxytryptophan metabolic pathway are related to bone growth; the tryptophan and indole lactate in the indole metabolism pathway are related to bone growth. Therefore, tryptophan metabolism is related to bone growth, providing potential therapeutic targets for RCT repair.

Inflammatory response is one of the key mechanisms of cerebral ischemia/reperfusion injury(CIRI),which seriously affects the prognosis of patients.In recent years,it has been found that long non-coding RNA(LncRNA)is closely related to the inflammatory response of cerebral ischemia/reperfusion injury,and can affect the development and prognosis of CIRI through multiple pathways.The article reviews and summarizes the LncRNAs and their action pathways affecting the inflammatory response in CIRI.The article preliminary explores the possible mechanisms by which LncRNAs affect CIRI,and also briefly summarizes the drugs related to LncRNA therapy.In order to provide new therapeutic targets and research ideas for the treatment of CIRI.

Objective:To investigate the value of systemic inflammatory response syndrome (SIRS), pediatric sequential organ failure assessment (pSOFA) and pediatric critical illness score (PCIS) in predicting mortality of pediatric sepsis in pediatric intensive care units (PICU) from Southwest China.Methods:This was a prospective multicenter observational study. A total of 447 children with sepsis admitted to 12 PICU in Southwest China from April 2022 to March 2023 were enrolled. Based on the prognosis, the patients were divided into survival group and non-survival group. The physiological parameters of SIRS, pSOFA and PCIS were recorded and scored within 24 h after PICU admission. The general clinical data and some laboratory results were recorded. The area under the curve (AUC) of the receiver operating characteristic curve was used to compare the predictive value of SIRS, pSOFA and PCIS in mortality of pediatric sepsis.Results:Amongst 447 children with sepsis, 260 patients were male and 187 patients were female, aged 2.5 (0.8, 7.0) years, 405 patients were in the survival group and 42 patients were in the non-survival group. 418 patients (93.5%) met the criteria of SIRS, and 440 patients (98.4%) met the criteria of pSOFA≥2. There was no significant difference in the number of items meeting the SIRS criteria between the survival group and the non-survival group (3(2, 4) vs. 3(3, 4) points, Z=1.30, P=0.192). The pSOFA score of the non-survival group was significantly higher than that of the survival group (9(6, 12) vs. 4(3, 7) points, Z=6.56, P<0.001), and the PCIS score was significantly lower than that of the survival group (72(68, 81) vs. 82(76, 88) points, Z=5.90, P<0.001). The predictive value of pSOFA (AUC=0.82) and PCIS (AUC=0.78) for sepsis mortality was significantly higher than that of SIRS (AUC=0.56) ( Z=6.59, 4.23, both P<0.001). There was no significant difference between pSOFA and PCIS ( Z=1.35, P=0.176). Platelet count, procalcitonin, lactic acid, albumin, creatinine, total bilirubin, activated partial thromboplastin time, prothrombin time and international normalized ratio were all able to predict mortality of sepsis to a certain degree (AUC=0.64, 0.68, 0.80, 0.64, 0.68, 0.60, 0.77, 0.75, 0.76, all P<0.05). Conclusion:Compared with SIRS, both pSOFA and PCIS had better predictive value in the mortality of pediatric sepsis in PICU.

Objective:To evaluate the nutritional status of patients with decompensated liver cirrhosis and explore the correlation with malnutrition and the risk factors of depressed mood.Methods:190 cirrhotic patients admitted to the Department of Gastroenterology of the First Hospital of Shanxi Medical University from June to September 2023 were selected according to the inclusion and exclusion criteria. Eligible patients were divided into subgroups based on the presence or absence of malnutrition as determined by subjective global assessment (SGA). The Center for Epidemiological Studies Depression (CES-D) scale was used to assess patients' propensity for depressed mood. Relevant clinical data were also collected and analyzed.Results:A total of 185 patients were included, of which 126 were in the non-malnutrition group and 59 malnutrition group. There were significant between-group differences in terms of CES-D results, age, body mass index, platelets, D-dimer, serum sodium, third lumbar skeletal muscle index, grip strength, triceps skinfold thickness, and upper arm muscle circumference (all P<0.05). Correlation analysis showed that grip strength, triceps skinfold thickness, upper arm muscle circumference, serum sodium, and depressed mood tendency status were correlated with the development of cirrhotic malnutrition ( P<0.05). The diagnostic model for malnutrition in cirrhosis using these five indicators showed the area under the curve of 81.9%. Conclusions:Depression is closely related to the development of malnutrition in patients with liver cirrhosis. Independent risk factors for malnutrition in cirrhosis include serum sodium≤135 mmol/L, grip strength, triceps skinfold thickness, lower-than-normal upper arm circumference , and the tendency of depression , which demonstrate the combined contribution to the diagnosis of malnutrition in cirrhosis.