Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired motility of cilia and flagella. Mutations in cilia- and flagella-associated protein 300 ( CFAP300 ) are associated with human PCD and male infertility; however, the underlying pathogenic mechanisms remain poorly understood. In a consanguineous Chinese family, we identified a homozygous CFAP300 loss-of-function variant (c.304delC) in a proband presenting with classical PCD symptoms and severe sperm abnormalities, including dynein arm deficiency and acrosomal malformation, as confirmed by transmission electron microscopy (TEM). Histological analysis revealed multiple morphological abnormalities of the sperm flagella in CFAP300 -mutant individual, whereas immunofluorescence demonstrated markedly reduced CFAP300 expression in the spermatozoa of the proband. Furthermore, tandem mass tag (TMT)-based quantitative proteomics showed that the CFAP300 mutation reduced key spermatogenesis proteins (e.g., sperm flagellar 2 [SPEF2], solute carrier family 25 member 31 [SLC25A31], and A-kinase anchoring protein 3 [AKAP3]) and mitochondrial ATP synthesis factors (e.g., SLC25A31, cation channel sperm-associated 3 [CATSPER3]). It also triggered abnormal increases in autophagy-related proteins and signaling mediator phosphorylation. These molecular alterations are likely to contribute to progressive deterioration of sperm ultrastructure and function. Notably, successful pregnancy was achieved via intracytoplasmic sperm injection (ICSI) using the proband's sperm. Overall, this study expands the known CFAP300 mutational spectrum and offers novel mechanistic insights into its role in spermatogenesis.
Humans ; Male ; Infertility, Male/pathology* ; Acrosome/pathology* ; Sperm Tail/pathology* ; Pedigree ; Spermatozoa ; Adult ; Loss of Function Mutation ; Ciliary Motility Disorders/genetics* ; Spermatogenesis/genetics* ; Female

BACKGROUND: The association of systemic inflammatory response index (SIRI) with prognosis of coronary artery disease (CAD) patients has never been investigated in a large sample with long-term follow-up. This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States. METHODS: A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Cox proportional hazards model, restricted cubic spline (RCS), and receiver operating characteristic curve (ROC) were performed to investigate the association of SIRI with all-cause and cause-specific mortality. Piece-wise linear regression and sensitivity analyses were also performed. RESULTS: During a median follow-up of 7.7 years, 1454 all-cause mortality occurred. After adjusting for confounding factors, higher lnSIRI was significantly associated with higher risk of all-cause (HR = 1.16, 95% CI: 1.09-1.23) and CVD mortality (HR = 1.17, 95% CI: 1.05-1.30) but not cancer mortality (HR = 1.17, 95% CI: 0.99-1.38). The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI, respectively. ROC curves showed that lnSIRI had robust predictive effect both in short and long terms. CONCLUSIONS SIRI was independently associated with all-cause and CVD mortality, and the dose-response relationship was J-shaped. SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

This paper aims to evaluate the pharmacodynamic effect and mechanism of Zhifuxin in the prevention and treatment of vascular dementia(VD), providing a theoretical basis for later development. Bilateral common carotid artery ligation in male Wistar rats was conducted to replicate the long-term hypoperfused VD model, and the drug was given to groups after one month. The rats were fed daily with nimodipine of 20 mg·kg~(-1), Zhifuxin of 50, 100, and 200 mg·kg~(-1), or the same volume of solvent for four weeks. 24 hours after the last dose, Morris water maze experiments were performed to detect the learning and memory abilities of rats. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the brain tissue of rats; the immunohistochemical method was used to detect the expression of muscarinic acetylcholine receptors M1 and M4 in rats and determine the content of acetyl choline(Ach), acetylcholin esterase(AchE), malondialdehyde(MDA), choline acetyl transferase(ChAT), and dimethyl arginine hydrolase 1(DDAH1) in the cerebral cortex of rats. Western blot was employed to detect protein expression of endothelial nitric oxide synthase(eNOS), caveolin-1, monoamine oxidase A(MAO-A), and monoamine oxidase B(MAO-B). RT-qPCR was utilized to detect mRNA expression of eNOS, caveolin-1, MAO-A, and MAO-B. The results showed that compared with the model group, the different doses of Zhifuxin were able to shorten the latency of VD rats in the water maze positioning navigation test, increase the number of crossing platforms in the space exploration test, and alleviate cone cell contracture in the hippocampus of VD rats. The expression of biochemical indicators related to the cholinergic system in the cerebral cortex: M1 and M4 receptors increased, as well as ChAT activity, and AchE activity significantly decreased. The protein and mRNA expression of indicators related to the eNOS/NO pathway: DDAH1 content, eNOS, and caveolin-1 increased, and that of indicators related to monoamine oxidase(MAO): MAO-A and MAO-B significantly decreased. The results show that Zhifuxin can improve cognition ability in long-term hypoperfused VD rats, and its mechanism of action may be related to its ability to modulate the cholinergic system and the eNOS/NO pathway and inhibit MAO expression.
Animals ; Dementia, Vascular/metabolism* ; Male ; Rats, Wistar ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Maze Learning/drug effects* ; Nitric Oxide Synthase Type III/genetics* ; Acetylcholinesterase/metabolism* ; Humans ; Choline O-Acetyltransferase/genetics* ; Disease Models, Animal

The scaphoid bone is one of the important bone of hand,which is frequently injured and difficult to treat in clinical practice.Therefore,it is very important to deeply study the microstructure and biomechanical characteristics of the scaphoid bone for understanding its injury mechanism and optimizing treatment scheme.Microcomputed tomography(micro-CT)provides high-resolution imaging of bone tissue,while finite element analysis can help to simulate the stress distribution and behavioral patterns of the scaphoid bone under various physiological and pathological states.The high-resolution three-dimensional image of the scaphoid bone obtained by micro-CT technology can be used to construct finite element models of real anatomical structure of the scaphoid bone,thus achieving accurate simulation of the mechanical properties of the scaphoid bone.The fusion of these two advanced technologies provides a new perspective for revealing the structural and functional relationships and injury mechanism of the scaphoid bone.Therefore,this paper reviews the anatomical characteristics of the scaphoid bone and its biomechanical behavior in different states,emphasizing the specific applications and advantages of micro-CT and finite element analysis techniques in the study of the scaphoid bone.By summarizing the research findings in recent years,this paper provides novel scientific basis and methods for the diagnosis,treatment,and prevention of scaphoid bone-related disorders.

Bruton's tyrosine kinase inhibitors (BTKi) are a class of novel small-molecule targeted antitumor drugs used to treat B-cell malignancies. However, safety issues associated with BTKi may lead to treatment interruption, compromising their efficacy. To promote the standardized management of safety in BTKi treatment, Evidence-Based Pharmacy Professional Committee of the Chinese Pharmaceutical Association, Hospital Pharmacy Professional Committee of the Chinese Pharmaceutical Association, Division of Therapeutic Drug Monitoring of Chinese Pharmacological Society, Expert Committee on Lymphoma of Chinese Society of Clinical Oncology, Expert Committee on Leukemia of Chinese Society of Clinical Oncology, Integrated Cancer Cardiology Branch of China Anti-Cancer Association, Hematology Branch of the Chinese Medical Association, and Hospital Pharmacy Professional Committee of the Cross-Straits Medicine Exchange Association formulated the Evidence-based Expert Consensus on the Clinical Management of Safety of Bruton′s Tyrosine Kinase Inhibitors (2024), which was published in the Chinese Journal of Cancer Research in June 2024. It covered 9 clinical issues in the following 3 domains: (1) the management of common adverse reactions of BTKi such as bleeding, cardiovascular events, hematological toxicity, infections, rashes, diarrhea, and arthralgia; (2) the management of drug-drug interactions; (3) management guidance for special populations. This consensus provides evidence-based recommendations for the safety management of BTKi medication in clinical practice. This article provides an interpretation and evidence summary of the consensus in Chinese, aiming to facilitate its implementation in China, enhance the safety management of BTKi treatment, and improve patient outcomes.

Objective:To analyze the disease burden of colorectal cancer (CRC) among young and middle-aged people in China from 1990 to 2021, and to explore the influence of age, period and cohort on the incidence and mortality of CRC in young and middle-aged people of China.Methods:Data on CRC in patients aged 40-59 years in China from 1990 to 2021 were extracted from the Global Burden of Disease Study 2021 (GBD 2021) database. Statistics such as incidence rate, mortality rate, disability-adjusted life years (DALY), and their corresponding age-standardized rates were calculated to analyze the CRC incidence and mortality in different age and sex groups of young and middle-aged Chinese young people from 1990 to 2021. The Joinpoint regression model was used to analyze the CRC incidence, the mortality and the DALY rate, as well as to calculate the annual percentage change (APC) and the average annual percentage change (AAPC). The effects of three independent factors, namely age, period and cohort, on the incidence and mortality of CRC in young and middle-aged people of China were analyzed and evaluated through the age-period-cohort model.Results:From 1990 to 2021, there was a remarkable upward trend in the incidence, mortality, and DALY of CRC among Chinese young and middle-aged adults. In 2021, the number of incidence cases of CRC among young and middle-aged people in China reached 181 000, and the number of deaths reached 57 900, which were 236.80% and 75.48% higher than those in 1990 (53 800 and 33 000, respectively). During the same period, DALY increased by 62.59%, with the 55-59 age group having the largest increase at 83.35%. From 1990 to 2021, the age-standardized incidence rate (ASIR) increased by 49.04%, rising from 25.51/100 000 to 38.02/100 000, and the age-standardized mortality rate (ASMR) declined by 28.75%, decreasing from 17.01/100 000 to 12.12/100 000, respectively. The increase in ASIR was the greatest among the 40-44 age group, reaching 57.31%, while the decline in ASMR was the most significant among the 50-54 age group, amounting to 30.18%. However, the DALY rate declined by 26.66%, from 673.52/100 000 to 493.94/100 000. The decline in DALY was the greatest among the 50-54 age group, reaching 28.26%. Joinpoint regression model analysis showed that, from 1990 to 2021, the incidence of CRC in Chinese young and middle-aged adults rose on average by 1.32% annually, and the increase was higher in men (1.87%) than that in women (0.36%). The mortality rate showed a downward trend, with an average annual decline of 1.10%, with a higher decline in women than in men (-2.14% vs. -0.50%). The DALY rate showed a downward trend, with an average annual decline of 1.00%, and more decline in women than in men (-2.06% vs. -0.41%). All of these trends were statistically significant (all P<0.001). The age-period-cohort model analysis showed that, the net drift of CRC incidence was 1.21% (1.02%-1.41%) per year among Chinese young and middle-aged adults between 1990 and 2021, while the net drift in mortality was -1.40% (-1.59%--1.21%) per year. The impact of age on CRC incidence and mortality intensified with advancing age. Incidence attributable to age rose from 12.66% (11.90%- 13.46%) in the 40-44 age group to 56.68% (54.37%-59.08%) in the 55-59 age group. Similarly, mortality attributable to age increased from 6.47% (6.12%-6.85%) in the 40-44 age group to 25.74% (24.58%-26.96%) in the 55-59 age group. In all age groups, the role of CRC incidence and mortality attributable to age was higher in men than in women. Period effects on the RR value of CRC incidence showed a declining trend followed by an upward trend, with the highest risk during 2015-2019 ( RR=1.36, 95% CI: 1.28-1.43), using 2000-2004 as the reference. For mortality, period effects exhibited a declining trend, with the highest risk during 1990-1994 ( RR=1.23, 95% CI: 1.15-1.32), using 2000-2004 as the reference. Cohort effects indicated that later birth cohorts had higher incidence risks, with the highest incidence observed in the 1973-1977 birth cohort ( RR=1.30, 95% CI: 1.16-1.45), using the 1953-1957 birth cohort as the reference. Conversely, later birth cohorts had lower mortality risks, with the lowest mortality in the 1973-1977 birth cohort ( RR=0.78, 95% CI: 0.69-0.88), using the 1953-1957 birth cohort as the reference. Conclusions:From 1990 to 2021, the changes in the disease burden of CRC among young and middle-aged people in China are manifested as an increase in standardized incidence rate and a decrease in standardized mortality rate. Meanwhile, there are gender differences in the trend of temporal changes. Age, period and cohort all have a significant impact on the incidence and mortality trends of colorectal cancer in young and middle-aged people. Research on the etiology of CRC should be strengthened, and targeted prevention and control strategies should be formulated.

Objective To explore the therapeutic effect of precise disconnection of pargastric varices guided by endoscopic ultrasound in the treatment of esophagogastric variceal bleeding.Method A retrospective analysis was conducted on 20 patients with cirrhosis esophagogastric variceal bleeding treated with endoscopic ultrasound-guided precise disconnection of pargastric varices from January 1,2024 to December 31,2024.The efficacy was analyzed.Result All 20 patients successfully completed the precise disconnection of pargastric varices under the guidance of endoscopic ultrasound.The injection of tissue gel combined with the placement of spring coils(14 cases)and the injection of tissue gel alone(4 cases)successfully blocked the pargastric varices.All patients did not experience perforation,esophageal and cardia stenosis,massive bleeding,septicemia,or ectopic embolization.One patient who received tissue gel alone had slight bleeding from the pargastric varices after surgery and improved after 3 days of treatment to reduce portal vein pressure.Another one patient who received tissue gel alone had a low-grade fever and normal body temperature after 3 days of anti-infection treatment.Conclusion Precise disconnection of pargastric varices under the guidance of endoscopic ultrasound has a good therapeutic effect on esophagogastric variceal bleeding,with fewer complications such as ectopic embolization,massive bleeding,infection,and perforation.However,close follow-up observation is still needed to address the issue of pargastric varices.

AIM To investigate the protective effect of Sanfeng Tongqiao Dropping Pills against house dust mite(HDM)-induced allergic asthma in mice.METHODS Compared to the intact BALB/c mice in the blank control group,the BALB/c mice randomly assigned into the model group,the dexamethasone group(0.67 mg/kg),and the low-dose,medium-dose,and high-dose Sanfeng Tongqiao Dropping Pills groups(15,30 and 60 mg/kg),were induced into acute allergic asthma models via weekly intraperitoneal sensitization with 0.1 mL HDM solution(0.5 mg/mL)for three weeks followed by three consecutive daily intranasal challenges with 10 μL HDM solution(2.5 mg/mL)starting in the third week.The drug administered continuously 7 days after the last excitation.The mice had their airway reactive Penh value detected,their pulmonary pathological changes observed by HE staining,their blood eosinophils(EOS)counted,their Th2 cytokines in lung tissue and serum IgE levels detected by ELISA,and their number of peripheral blood mononuclear cells(PBMC)and pulmonary Th2 cells detected by flow cytometry.Chronic allergic asthma was induced in grouped BALB/c mice through repeated intranasal challenges with 10 μL HDM solution(2.5 mg/mL)administered five times weekly for five consecutive weeks.Drug treatment continued for 14 days following the final challenge.After the final treatment,the mice had their pulmonary pathological changes observed by HE staining,and their levels of Th2 cytokines in B ALF and lung tissue and serum IgE detected by ELISA.RESULTS Compared to the blank control group,the acute allergic asthma model group exhibited increases in Penh value,EOS count and IgE level in serum,IL-4 and IL-5 levels in lung tissue(P＜0.01);obvious pulmonary inflammatory cells infiltration,and thickened airway wall;and increase in pulmonary number of Th2 cells(P＜0.01).Compared to the model group,the groups intervened with Sanfeng Tongqiao Dropping Pills demonstrated decreased Penh value,serum EOS count,IgE level and IL-5 level in lung tissue(P＜0.05,P＜0.01);reduced pulmonary inflammatory infiltration and alleviated airway wall thickening;and decreased number of pulmonary Th2 cells.Compared to the blank group,the chronic allergic asthma model group showed obvious pulmonary inflammatory infiltration and airway wall thickening;and increased EOS count and IgE level in serum,IL-4 and IL-13 in lung tissue and IL-14 in BALF(P＜0.05,P＜0.01).Compared to the model group,the groups intervened with either medium-dose or high-dose Sanfeng Tongqiao Dropping Pills demonstrated reduced pulmonary inflammatory infiltration;and decreased serum EOS count,IgE level,IL-13 in lung tissue and IL-14 in BALF(P＜0.05,P＜0.01).CONCLUSION Sanfeng Tongqiao Dropping Pills reduce Th2 cells in peripheral blood and lung tissue,suppress type 2 inflammation,and thereby alleviate allergic asthma.

Objective:To evaluate the long-term efficacy and safety of recombinant coagulation factor Ⅷ (Octocog alfa) in Chinese patients with hemophilia A (HA) enrolled in the International Antihemophilic Factor Hemophilia A Outcome Database (AHEAD) study (NCT02078427) .Methods:Enrollment of Chinese patients in the AHEAD study was completed by January 2021, and data were collected up to July 15, 2022. This study primarily assessed patients in terms of the Gilbert score, global gait score within the Hemophilia Joint Health Score (HJHS), annualized bleeding rate (ABR), annualized joint bleeding rate, and adverse events.Results:A total of 168 male patients were included in this study, of which 113 received prophylactic treatment and 53 received on-demand treatment. The average age of the patients was 21.4±13.37 years. Compared with baseline, the global gait score within HJHS significantly decreased during the 1-year follow-up in patients with moderately severe HA in the prophylactic treatment group ( P=0.01) and on-demand treatment group ( P=0.008). The mean reduction in Gilbert score was greater in the prophylactic treatment group than in the on-demand treatment group (28.6% vs 8.2%). The average ABR decreased significantly during the 1-year follow-up (3.70 vs 7.78, P=0.01) in the prophylactic treatment group, particularly in patients with severe HA (2.14 vs 8.98, P=0.006) and pediatric patients (2.1 vs 4.73, P=0.03). The ABR score also decreased significantly in the moderate-dose prophylactic treatment group ( P=0.015). During the 1-year follow-up, 25 patients (14.9%) reported 39 adverse events, with only one patient developing treatment-related F Ⅷ inhibitor. Conclusion:Joint mobility improved in patients receiving either prophylactic or on-demand Octocog alfa. Bleeding episodes significantly reduced in patients receiving prophylactic treatment, particularly in pediatric patients and those with severe HA.