Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

Objective:To investigate the feasibility of digital reconstruction technology in virtual planning of the free perforator flap of anterior tibial artery (ATA) for reconstruction of soft tissue defects in foot and ankle.Methods:From May 2018 to April 2023, 10 patients, including 7 males and 3 females, with foot or ankle defects were admitted in the Department of Orthopaedics Surgery, 920th Hospital of Joint Logistics Support Force. There were 5 defects in dorsal foot, 3 in plantar foot and 2 in medial malleolus. The sizes of defects ranged from 3.0 cm×2.5 cm to 5.5 cm×4.0 cm, all with exposed bones or tendons. Preoperative CTA scans from aorta abdominalis to feet were performed, and 3D digital models of bones, arteries and skin were reconstructed with Mimics. The most suitable perforators were selected to design the perforator flaps of ATA with the software, then the digital virtual flaps were superimposed onto the surfaces of donor sites and marked under a translucent image by Sina. During the surgery, flaps were harvested according to preoperative digital designs with the size of 3.5 cm×3.0 cm-6.0 cm×4.0 cm. The perforating branches were dissected along the way, and the origin, diameter, course, location and length of the perforators were recorded. The perforating branches of the flaps were anastomosed to the proximal vessels in the recipient sites, and the flaps were sutured to cover the wound. For the 10 donor sites, skin graft was used in 2 donor sites and direct suture were performed on 8 donor sites. After discharge of the patients, scheduled outpatient or online follow-ups were carried out to assess the progress of fracture healing as well as the appearance, texture and colour of flaps, and the recovery of donor sites. Ankle function was evaluated by Maryland foot scoring system.Results:Three-dimensional digital reconstructions of donor sites were successfully performed on all patients, enabling successful design and harvest of the free perforator flaps of ATA. The flaps were able to be used in complete reconstruction of the respective defects and made the anatomical parameters of perforators of the donor sites closely matching with those of preoperative modeling. Follow-up periods ranged from 6 to 19 months, apart from 1 flap experienced partial necrosis at distal endge, and another flap with partial exfoliation after blistering. The rest of 8 flaps were all survived smoothly, with appropriate thickness, aesthetic appearance, good texture and colour. Sensations in both donor sites and dorsal feet were all normal. Seven patients achieved excellent and 3 were good according to Maryland's ankle-foot function score. The donor sites healed well without scar hyperplasia.Conclusion:Digital reconstruction technology enables an accurate identification of perforators as well as individualised design and harvest procedures for perforator flaps of ATA, thereby it facilitates precise reconstructions of small-to-medium-sized defects in foot or ankle. It is a good method for vascular anatomy and flap harvesting.

Objective:To compare the cumulative live birth rates per oocyte retrieval cycle in patients with normal ovarian response between the gonadotropin-releasing hormone agonist (GnRH-a) long protocol and the progestin-primed ovarian stimulation (PPOS) protocol.Methods:A retrospective cohort study was conducted in Centre of Assisted Reproduction, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine between January 2017 and December 2019. Women who underwent in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment with normal ovarian reserve and <40 years of age were included. Other inclusion criteria included regular menstrual cycles, serum follicle-stimulating hormone level <10 U/L, and the antral follicle count >5. The primary outcome was the cumulative live birth rate (CLBR) within 18 months from the start of ovarian stimulation. Results:A total of 995 patients were included in the study, with 509 patients in the PPOS group and 486 patients in the GnRH-a long group. Both groups had almost comparable demographic and cycle stimulation characteristics except for duration of infertility which was shorter in the PPOS group [3 (2,4) years] than in the GnRH-a long group [3 (2,5) years, P=0.015]. In the GnRH-a long group, 372 patients (77%) underwent fresh embryo transfer, resulting in 218 clinical pregnancies and 197 live births. The clinical pregnancy rate, the ongoing pregnancy rate, and the live birth rate per embryo transfer cycle were 58.6% (218/372), 54.0% (201/372) and 53.0% (197/372), respectively. No fresh embryo transfer was performed in the PPOS group. During the study period, there were 662 frozen-thawed embryo transfer (FET) cycles in the PPOS group and 257 FET cycles in the GnRH-a long group. The PPOS group had a live birth rate of 31.1% (206/662) per FET cycle, which was notably lower than the GnRH-a long group [42.8% (110/257), OR=0.727; 95% CI: 0.607-0.871; P<0.001]. The implantation rate of all FET cycles in the PPOS group was also lower than that in the GnRH-a long group [29.2% (293/1 004) vs. 34.5% (157/455), OR=0.846, 95% CI: 0.721-0.992; P=0.041]. CLBRs after one complete IVF/ICSI cycle including fresh and subsequent FET cycles within 18 months follow up were significantly lower in the PPOS group [40.5% (206/509)] than in the long agonist group [63.2% (307/486), OR=0.641, 95% CI: 0.565-0.726]. Compared with the PPOS group, the GnRH-a long group had a significantly shorter duration from the start of ovarian stimulation to pregnancy and live birth ( P<0.001). In Kaplan-Meier analysis, the CLBR was significantly higher in the GnRH-a long group than in the PPOS group (long rank test, P<0.001). Adjusted Cox-regression analysis revealed stimulation protocol adopted was strongly associated with the CLBR ( OR=1.917, 95% CI: 1.152-3.190, P=0.012). Conclusion:Progestin primed ovarian stimulation was associated with a lower cumulative live birth rates and a long time to pregnancy/live birth than the long agonist protocol in women with a normal ovarian reserve.

Background::Liver cancer remains the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide, causing a heavy burden globally. An updated assessment of the global epidemiology of the liver cancer burden that addresses geographical disparities is necessary to better understand and promote healthcare delivery.Methods::Data were extracted from the GLOBOCAN 2022 database, including the number, crude, and age-standardized rates of incidence and mortality at the global, country, continent, and human development index (HDI) regional levels. Age-standardized rates (incidence and mortality) per 100,000 person-years were adjusted based on the Segi-Doll World standard population. The mortality-to-incidence ratios (MIR) for each region and country were calculated. The HDI and gross national income (GNI) for 2022 were obtained, and a Pearson correlation analysis was conducted with the incidence, mortality, and MIR.Results::In 2022, approximately 866,136 new liver cancer cases and 758,725 related deaths were recorded worldwide, with a global MIR of 0.86. Males had a disproportionately higher burden than females across all levels, and the highest burden was observed in the elderly population. Geographically, the regions with the highest incidence rates included Micronesia, Eastern Asia, and Northern Africa, and the regions with the highest mortality rates included Northern Africa, Southeastern Asia, Eastern Asia, and Micronesia. Notably, Mongolia had a strikingly high burden compared to other countries. The highest MIR was observed in North America and the lowest in Africa. Negative associations of HDI and GNI with liver cancer mortality and MIR were identified, irrespective of sex.Conclusions::The current liver cancer burden underscores the presence of remarkable geographic heterogeneity, which is particularly evident across countries with varying HDI levels, highlighting the urgent need to prioritize health accessibility and availability to achieve health inequities.

Objective To investigate whether curdione inhibits the formation of deep vein thrombosis(DVT)in rats through thrombolytic effects.Methods Twenty-five rats were randomly divided into five groups,the normal control group,the sham operation group,the model group,the low dose group of curdione(60 mg/kg)and the high dose group of curdione(120 mg/kg),with five rats in each group.Using the inferior vena cava ligation model,blood was taken from the pulmonary aorta in a sodium citrate anticoagulant tube one week after drug administration.The coagulation and fibrinolytic indexes Fibrin Degradation Products,(FDP),D-dimer(D-D),plasminogen activator inhibitor(PAI)-1 and plasminogen(PLG)were detected in each group;the thrombus weight/weight-length ratio was detected;and the formation of venous thrombus in the lower limbs of rats was detected by hematoxylin-eosin(HE)staining nuclear factor;NF-κB protein expression in inferior vena cava tissues was dectected by Western Blot assay.Results There was no significant difference in plasma FDP levels among groups of rats(P＞0.05);compared with the model group,the plasma FDP and D-D levels of rats in each dosing group were increased,the plasma PAI-1 and PLG levels were elevated,and the fibrinolytic effect was better in the group with high dose of curdione administration than in the group with low dose of curdione administration(P＜0.05);compared with the model group,the thrombus weight/weight-length ratio,the thrombus mass and NF-κB protein expression in the curdione dosing group were decreased.Conclusion Curdione can inhibit the formation of DVT in rats by influencing the fibrinolytic regulators.

Objective:To compare the cumulative live birth rates per oocyte retrieval cycle in patients with normal ovarian response between the gonadotropin-releasing hormone agonist (GnRH-a) long protocol and the progestin-primed ovarian stimulation (PPOS) protocol.Methods:A retrospective cohort study was conducted in Centre of Assisted Reproduction, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine between January 2017 and December 2019. Women who underwent in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment with normal ovarian reserve and <40 years of age were included. Other inclusion criteria included regular menstrual cycles, serum follicle-stimulating hormone level <10 U/L, and the antral follicle count >5. The primary outcome was the cumulative live birth rate (CLBR) within 18 months from the start of ovarian stimulation. Results:A total of 995 patients were included in the study, with 509 patients in the PPOS group and 486 patients in the GnRH-a long group. Both groups had almost comparable demographic and cycle stimulation characteristics except for duration of infertility which was shorter in the PPOS group [3 (2,4) years] than in the GnRH-a long group [3 (2,5) years, P=0.015]. In the GnRH-a long group, 372 patients (77%) underwent fresh embryo transfer, resulting in 218 clinical pregnancies and 197 live births. The clinical pregnancy rate, the ongoing pregnancy rate, and the live birth rate per embryo transfer cycle were 58.6% (218/372), 54.0% (201/372) and 53.0% (197/372), respectively. No fresh embryo transfer was performed in the PPOS group. During the study period, there were 662 frozen-thawed embryo transfer (FET) cycles in the PPOS group and 257 FET cycles in the GnRH-a long group. The PPOS group had a live birth rate of 31.1% (206/662) per FET cycle, which was notably lower than the GnRH-a long group [42.8% (110/257), OR=0.727; 95% CI: 0.607-0.871; P<0.001]. The implantation rate of all FET cycles in the PPOS group was also lower than that in the GnRH-a long group [29.2% (293/1 004) vs. 34.5% (157/455), OR=0.846, 95% CI: 0.721-0.992; P=0.041]. CLBRs after one complete IVF/ICSI cycle including fresh and subsequent FET cycles within 18 months follow up were significantly lower in the PPOS group [40.5% (206/509)] than in the long agonist group [63.2% (307/486), OR=0.641, 95% CI: 0.565-0.726]. Compared with the PPOS group, the GnRH-a long group had a significantly shorter duration from the start of ovarian stimulation to pregnancy and live birth ( P<0.001). In Kaplan-Meier analysis, the CLBR was significantly higher in the GnRH-a long group than in the PPOS group (long rank test, P<0.001). Adjusted Cox-regression analysis revealed stimulation protocol adopted was strongly associated with the CLBR ( OR=1.917, 95% CI: 1.152-3.190, P=0.012). Conclusion:Progestin primed ovarian stimulation was associated with a lower cumulative live birth rates and a long time to pregnancy/live birth than the long agonist protocol in women with a normal ovarian reserve.

Objective:To investigate the feasibility of digital reconstruction technology in virtual planning of the free perforator flap of anterior tibial artery (ATA) for reconstruction of soft tissue defects in foot and ankle.Methods:From May 2018 to April 2023, 10 patients, including 7 males and 3 females, with foot or ankle defects were admitted in the Department of Orthopaedics Surgery, 920th Hospital of Joint Logistics Support Force. There were 5 defects in dorsal foot, 3 in plantar foot and 2 in medial malleolus. The sizes of defects ranged from 3.0 cm×2.5 cm to 5.5 cm×4.0 cm, all with exposed bones or tendons. Preoperative CTA scans from aorta abdominalis to feet were performed, and 3D digital models of bones, arteries and skin were reconstructed with Mimics. The most suitable perforators were selected to design the perforator flaps of ATA with the software, then the digital virtual flaps were superimposed onto the surfaces of donor sites and marked under a translucent image by Sina. During the surgery, flaps were harvested according to preoperative digital designs with the size of 3.5 cm×3.0 cm-6.0 cm×4.0 cm. The perforating branches were dissected along the way, and the origin, diameter, course, location and length of the perforators were recorded. The perforating branches of the flaps were anastomosed to the proximal vessels in the recipient sites, and the flaps were sutured to cover the wound. For the 10 donor sites, skin graft was used in 2 donor sites and direct suture were performed on 8 donor sites. After discharge of the patients, scheduled outpatient or online follow-ups were carried out to assess the progress of fracture healing as well as the appearance, texture and colour of flaps, and the recovery of donor sites. Ankle function was evaluated by Maryland foot scoring system.Results:Three-dimensional digital reconstructions of donor sites were successfully performed on all patients, enabling successful design and harvest of the free perforator flaps of ATA. The flaps were able to be used in complete reconstruction of the respective defects and made the anatomical parameters of perforators of the donor sites closely matching with those of preoperative modeling. Follow-up periods ranged from 6 to 19 months, apart from 1 flap experienced partial necrosis at distal endge, and another flap with partial exfoliation after blistering. The rest of 8 flaps were all survived smoothly, with appropriate thickness, aesthetic appearance, good texture and colour. Sensations in both donor sites and dorsal feet were all normal. Seven patients achieved excellent and 3 were good according to Maryland's ankle-foot function score. The donor sites healed well without scar hyperplasia.Conclusion:Digital reconstruction technology enables an accurate identification of perforators as well as individualised design and harvest procedures for perforator flaps of ATA, thereby it facilitates precise reconstructions of small-to-medium-sized defects in foot or ankle. It is a good method for vascular anatomy and flap harvesting.

Humans ; Consensus ; Hypersensitivity ; Desensitization, Immunologic/adverse effects* ; Immunotherapy/adverse effects* ; Injections, Subcutaneous ; Allergens