Objective To compare the efficacy and safety of different cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer. Methods Randomized controlled trials (RCTs) on CDK4/6i for the treatment of HR+/HER2− metastatic or advanced breast cancer were retrieved from databases including PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, Wanfang, VIP, and SinoMed, with the search period ranging from database inception to August 2023. Bayesian network meta-analysis was conducted using R 4.2.0 software. Results A total of 18 RCTs from 25 articles, involving 8 031 patients and 11 treatment regimens, were included. There was no significant difference in progression-free survival (PFS) or overall survival (OS) among different CDK4/6i+ET combinations. The highest cumulative probability for PFS was observed with dalpiciclib (DAL)+fulvestrant (FUL), while ribociclib (RIB)+FUL ranked first for OS. In terms of efficacy, abemaciclib (ABE)+aromatase inhibitors (AI) and ABE+FUL ranked first in objective response rate and clinical benefit rate, respectively. Regarding safety, statistically significant difference in grade 3-4 adverse events was observed among certain types of CDK4/6i (P<0.05). Conclusion Current evidence suggests that CDK4/6i+ET is superior to ET alone for the treatment of HR+/HER2− advanced/metastatic breast cancer. Different CDK4/6i+ET combinations demonstrate comparable or similar efficacy; however, the incidence of adverse reactions is higher with combination therapy. Treatment regimens should be selected based on individual conditions.

OBJECTIVE: To identify F7 gene mutations in one pedigree with congenital coagulation factor VII (FVII) deficiency and explore the effect of F7 gene mutations on the structure and function of FVII. METHODS: Prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured based on the one-stage assay, and PT-based one stage assay was used to detect the activity of FII, V, VII and X. Genomic DNA was extracted from the peripheral blood of family members. The sequences of all the exons and exon-intron boundaries of F7 were amplified by polymerase chain reaction (PCR) using specific primers followed by Sanger sequencing. PolyPhen-2, PROVEAN and Swiss-Pdb Viewer software were used to analyze the effect of mutations on the structure and function of FVII. RESULTS: The proband had a prolonged PT (33.8 s) due to low FVII activity (6.6%) and normal APTT, and had a history of epistaxis. The proband's mother and father displayed a slightly prolonged PT (13.2 and 13.9 s, respectively), and their FVII activity was 40.3% and 38.3%, respectively. The compound heterozygous c.722C>A (p.Thr241Asn) in exon 7 and c.1165T>G (p.Cys389Gly) in exon 8 of F7 gene were identified in the proband, and inherited from his father and mother, respectively. The p.Thr241Asn and p.Cys389Gly missense change were likely to have a damaging effect predicted by polyphen-2 and PROVEAN software. In silico modeling analysis showed that there was one hydrogen bond formed between wild-type Thr241 and Val249, two hydrogen bonds formed between mutant Asn241 and Val249 and between mutant Asn241 and Leu242, as well as one hydrogen bond and one disulfide bond formed between wild-type Cys389 and Leu370 and between wild-type Cys389 and Cys375, respectively. The hydrogen bond formed between mutant Gly389 and Leu370 and disulfide bond formed between mutant Gly389 and Cys375 both broke. CONCLUSIONS FVII deficiency in this family is caused by p.Thr241Asn and p.Cys389Gly mutation. In silico modeling may be a valuable tool for understanding amino acid residues from variants leading to congenital FVII deficiency.
Humans ; Factor VII/genetics* ; Mutation ; Pedigree ; Factor VII Deficiency/genetics* ; Prothrombin Time ; Partial Thromboplastin Time ; Male ; Female

OBJECTIVE: To evaluate the clinical efficacy and safety of Yangxue Qingnao Pills (YXQNP) combined with amlodipine in treating patients with grade 1 hypertension. METHODS: This is a multicenter, randomized, double-blind, and placebo-controlled study. Adult patients with grade 1 hypertension of blood deficiency and Gan (Liver)-yang hyperactivity syndrome were randomly divided into the treatment or the control groups at a 1:1 ratio. The treatment group received YXQNP and amlodipine besylate, while the control group received YXQNP's placebo and amlodipine besylate. The treatment duration lasted for 180 days. Outcomes assessed included changes in blood pressure, Chinese medicine (CM) syndrome scores, symptoms and target organ functions before and after treatment in both groups. Additionally, adverse events, such as nausea, vomiting, rash, itching, and diarrhea, were recorded in both groups. RESULTS: A total of 662 subjects were enrolled, of whom 608 (91.8%) completed the trial (306 in the treatment and 302 in the control groups). After 180 days of treatment, the standard deviations and coefficients of variation of systolic and diastolic blood pressure levels were lower in the treatment group compared with the control group. The improvement rates of dizziness, headache, insomnia, and waist soreness were significantly higher in the treatment group compared with the control group (P<0.05). After 30 days of treatment, the overall therapeutic effects on CM clinical syndromes were significantly increased in the treatment group as compared with the control group (P<0.05). After 180 days of treatment, brachial-ankle pulse wave velocity, ankle brachial index and albumin-to-creatinine ratio were improved in both groups, with no statistically significant differences (P>0.05). No serious treatment-related adverse events occurred during the study period. CONCLUSIONS Combination therapy of YXQNP with amlodipine significantly improved symptoms such as dizziness and headache, reduced blood pressure variability, and showed a trend toward lowering urinary microalbumin in hypertensive patients. These findings suggest that this regimen has good clinical efficacy and safety. (Registration No. ChiCTR1900022470).
Humans ; Amlodipine/adverse effects* ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Hypertension/complications* ; Middle Aged ; Treatment Outcome ; Drug Therapy, Combination ; Adult ; Blood Pressure/drug effects* ; Double-Blind Method ; Aged ; Antihypertensive Agents/adverse effects*

OBJECTIVE: To evaluate the effect and safety of Chinese medicine (CM) Fuzheng Huazhuo Decoction (FHD) in treating patients with coronavirus disease 2019 (COVID-19) who persistently tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: This retrospective cohort study was conducted at Shanghai New International Expo Center shelter hospital in China between April 1 and May 30, 2022. Patients diagnosed as COVID-19 with persistently positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test results for ⩾8 days after diagnosis were enrolled. Patients in the control group received conventional Western medicine (WM) treatment, while those in the FHD group received conventional WM plus FHD for at least 3 days. The primary outcome was viral clearance time. Secondary outcomes included negative conversion rate within 14 days, length of hospital stay, cycle threshold (Ct) values of the open reading frame 1ab (ORF1ab) and nucleocapsid protein (N) genes, and incidence of new-onset symptoms during hospitalization. Adverse events (AEs) that occurred during the study period were recorded. RESULTS: A total of 1,765 eligible patients were enrolled in this study (546 in the FHD group and 1,219 in the control group). Compared with the control group, patients receiving FHD treatment showed shorter viral clearance time for nucleic acids [hazard ratio (HR): 1.500, 95% confidence interval (CI): 1.353-1.664, P<0.001] and hospital stays (HR: 1.371, 95% CI: 1.238-1.519, P<0.001), and a higher negative conversion rate within 14 days (96.2% vs. 82.6%, P<0.001). The incidence of new-onset symptoms was 59.5% in the FHD group, similar to 57.8% in the control group (P>0.05). The Ct values of ORF1ab and N genes increased more rapidly over time in the FHD group than those in the control group post-randomization (ORF1ab gene: β =0.436±0.053, P<0.001; N gene: β =0.415 ±0.053, P<0.001). The incidence of AEs in the FHD group was lower than that in the control group (24.2% vs. 35.4%, P<0.001). No serious AEs were observed. CONCLUSION FHD was effective and safe for patients with persistently positive SARS-CoV-2 PCR tests. (Registration No. ChiCTR2200063956).
Humans ; Drugs, Chinese Herbal/adverse effects* ; Retrospective Studies ; Male ; Female ; Middle Aged ; COVID-19 Drug Treatment ; SARS-CoV-2/drug effects* ; COVID-19/virology* ; Adult ; Aged ; Treatment Outcome

Intervertebral disc degeneration (IDD) is largely attributed to impaired endogenous repair. Nucleus pulposus-derived stem cells (NPSCs) senescence leads to endogenous repair failure. Small extracellular vesicles/exosomes derived from mesenchymal stem cells (mExo) have shown great therapeutic potential in IDD, while whether mExo could alleviate NPSCs senescence and its mechanisms remained unknown. We established a compression-induced NPSCs senescence model and rat IDD models to evaluate the therapeutic efficiency of mExo and investigate the mechanisms. We found that mExo significantly alleviated NPSCs senescence and promoted disc regeneration while knocking down thioredoxin (TXN) impaired the protective effects of mExo. TXN was bound to various endosomal sorting complex required for transport (ESCRT) proteins. Autocrine motility factor receptor (AMFR) mediated TXN K63 ubiquitination to promote the binding of TXN on ESCRT proteins and sorting of TXN into mExo. Knocking down exosomal TXN inhibited the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2) and activator protein 1 (AP-1). NRF2 and AP-1 inhibition reduced endogenous TXN production that was promoted by exosomal TXN. Inhibition of NRF2 in vivo diminished the anti-senescence and regenerative effects of mExo. Conclusively, AMFR-mediated TXN ubiquitination promoted the sorting of TXN into mExo, allowing exosomal TXN to promote endogenous TXN production in NPSCs via TXN/NRF2/AP-1 feed-forward circuit to alleviate NPSCs senescence and disc degeneration.

Patients requiring extracorporeal membrane oxygenation (ECMO) often need concurrent continuous renal replacement therapy (CRRT). At present, there are various connection methods between ECMO and CRRT circuits, among which in-series integration is the most common. However, ECMO blood flow and catheter type, pressure changes at the pre-pump, post-pump pre-oxygenator, and post-oxygenator segments frequently result in circuit pressures that exceed the alarm threshold of the device. Excessive negative or positive pressures may compromise blood withdrawal and return within the CRRT circuit, leading to frequent system alarms, interruptions in therapy, filter occlusion, and an increased risk of thrombus formation. To address this issue, the critical care nursing team of Zhongda Hospital Affiliated to Southeast University, developed a novel pressure-regulating clamp for CRRT vascular access in ECMO patient, which has been granted a National Utility Model Patent of China (patent number: ZL 2021 2 1496610.7). The device comprises opposing left and right clamp arms joined at the top by a flexible plastic bridge, with dual internal compression surfaces designed to fit CRRT tubing of various calibers. A locking mechanism and serrated strip at the base enable precise adjustment of the compression distance, thereby modulating the tubing's cross-sectional area. This configuration allows real-time regulation of blood flow and stabilization of pressures at blood withdrawal and return sites within the CRRT circuit. By reducing pressure-related alarms and extending filter life, the device may enhance the safety and efficiency of CRRT delivery during ECMO. It is user-friendly, cost-effective, and well-suited for broad clinical implementation, with the potential to alleviate the overall treatment burden on patients and their families.
Extracorporeal Membrane Oxygenation/instrumentation* ; Humans ; Continuous Renal Replacement Therapy/instrumentation* ; Equipment Design ; Pressure

Objective To explore the deeper understanding of the pregnancy and delivery experience of three-child pregnant and matemal women,and to provide a basis for healthcare personnel to provide more systematic,safe,and targeted perinatal healthcare services and care measures for three-child pregnant and matemal women.Methods Purposive sampling method was used to select 17 cases of three-child pregnant and matemal women who were admitted and delivered in a tertiary level-A matemal and child healthcare hospital in Nanjing from August 2022 to June 2023 for semi-structured interviews,and Colaizzi 7-step process of analyzing,summarizing,and refining the themes was used.Results A total of 4 themes were extracted,including determination of willingness to become pregnant,perceived risks of childbirth,perceived benefits to themselves and their families,diversified support needs.Conclusion The establishment of pregnancy intention of three-child pregnant women is affected by many factors.Relevant departments should actively implement the supporting measures of the three-child birth policy;healthcare workers should strengthen perinatal healthcare services for three-child mothers to reduce the risk of giving birth,actively strengthen their sense of benefits related to pregnancy,and establish a whole process of support system to promote the health of mothers and infants.

AIM To investigate the effects of Wuzi Yanzong Pills on subacute aging-induced testicular trauma and AMPK/mTOR pathway in rats.METHODS Rat models of subacute aging were induced by 8-week subcutaneous injection of D-gal(200 mg/kg)into the rat neck,followed by their random assignment into the model group,the metformin group(0.3 g/kg)and the low-dose and high-dose Wuzi Yanzong Pills groups(0.54,2.16 g/kg),with 9 rats in each group,in contrast to the 8 intact rats of the normal group.And the corresponding drug was given by gavage for 4 weeks after modeling,after which the rats had their levels of serum T,FSH,SOD,LH,8-OHdG and MDA detected by ELISA;their pathological changes of testes observed by HE and β-galactosidase staining;and their expressions of aging-related proteins(p16,p21,p53),testicle secretory function-related proteins(CYP11A1,HSD17B3,STAR),autophagy-related proteins(p62,ATG5,Beclin-1,LC3B)and AMPK/mTOR pathway-related protein detected by Western blot and immunohistochemistry.RESULTS Compared with the normal group,the model group displayed morphologically smaller testes and body surface;dry hair;overall atrophic testicular tissue structure;increased testicular protein expressions of γ-H2AX,p16,p21 andβ-galactosidase(P＜0.05,P＜0.01);and decreased p53 protein expression(P＜0.05);suggesting the modeling success.Compared with the model group,the high-dose Wuzi Yanzong Pills group shared decreased levels of serum 8-OHdG,MDA,FSH and LH(P＜0.01);increased levels of SOD and T(P＜0.01);improved sperm damage and almost morphologically normal testicular tissue;decreased testicular protein expressions of p16,p21,p53,p62 and p-mTOR(P＜0.01);and increased protein expressions of CYP11A1,HSD17B3,STAR,ATG5,Beclin-1,LC3B and p-AMPK(P＜0.01).CONCLUSION Wuzi Yanzong Pills can improve the subacute aging-induced testicular injury and testicular function in rats by reducing their oxidative stress through improving their autophagy level and testicle antioxidant capacity.

Objective:To evaluate the survival benefit of surgical treatment for intrahepatic cholangiocarcinoma.Methods:This study is conducted based on the hepatobiliary tumor registry database. From May 2009 to December 2022,a total of 704 patients who were initially diagnosed with intrahepatic cholangiocarcinoma and underwent liver resection were consecutively enrolled at the Hepatobiliary Center of the First Affiliated Hospital of Nanjing Medical University. Among them,there were 380 males and 324 females,aged ( M(IQR)) 61(15) years(range:27 to 88 years). Twenty-six (3.7%) patients received neoadjuvant therapy before surgery. The overall survival(OS) and disease-free survival(DFS) rates were estimated by life table method, and Kaplan-Meier survival curves were plotted. Log-rank test was used to compare the survival difference among tumor-node-metastasis(TNM) staging or three periods. The OS and DFS differences among lymph node groups or adjuvant treatment groups were quantified as HR with 95% CI estimated using Cox proportional-hazards model with adjustment for prognostic factors. Results:Among the 704 patients,349 cases(49.6%) underwent major hepatectomy (≥3 segments),331(47.0%) had lymph node resection during surgery,and 524 cases(74.4%) achieved R0 resection. The morbidity of Clavien-Dindo grade Ⅲ or higher complications was 16.5%(116/704),with a mortality rate of 3.0%(21/704) within 30 days post-surgery. The median OS time was 27.1 months, and the OS rates at 1-,3-,5- and 10-year were 69.1%, 42.4%,34.1% and 24.5%,respectively. The median DFS time was 10.5 months,and the corresponding DFS rates were 46.0%,25.4%,21.9% and 16.9%,respectively. According to the 8 th edition of AJCC staging system, the 5-year survival rates for ⅠA,ⅠB,Ⅱ,ⅢA,ⅢB and Ⅳ were 68.4%, 43.2%, 30.3%,32.2%,14.0% and 0,respectively. The corresponding DFS rates were 55.8%, 28.1%,13.8%,21.2%,3.3% and 0,respectively. There were no statistically significant differences of OS or DFS between stage ⅠB and Ⅱ, stage ⅠB and ⅢA, or between stage Ⅱ and ⅢA(Log-rank test:all P>0.05),while there were significant differences of OS and DFS among other stages(Log-rank test:all P<0.05). Using Cox model with adjustment for prognostic factors, there were no statistically significant differences of OS and DFS between non-lymphadenectomy group or the biopsy-N0 group and dissection-N0 group(both P>0.05). However,the overall and disease-free survival of the biopsy-N1 group or dissection-N1 group were worse than those of dissection-N0 group(both P<0.05),with overall survival being better in dissection-N1 group than biopsy-N1 group( P=0.017). Overall survival in the period from 2019 to 2022 were significantly superior to that during the periods from 2009 to 2013 and 2014 to 2018(both P<0.01). Adjusting for prognostic factors, the disease-free and overall survival of the postoperative adjuvant therapy group were significantly better than those of the observation group in the period 2019 to 2022(both P<0.01). Conclusions:Surgery remains a milestone for achieving long-term survival for patients with intrahepatic cholangiocarcinoma. Regional lymph node dissection is required for patients with lymph node metastasis. Adjuvant therapy can significantly reduce tumor recurrence and prolong overall survival.