OBJECTIVE To analyze and identify the metabolites of pirtobrutinib （PTN） in rats， and clarify the possible metabolic pathways of PTN in rats. METHODS Six rats were intragastrically administered with 10 mg/kg PTN suspension. Blood samples were collected from the rats 30 minutes before administration and at 0.25， 0.5， 1， 2， 4， 6， 8， 12， 24 hours after administration. Urine and feces samples were collected 12 hours before administration and 24 hours after administration. UHPLC- Orbitrap Exploris 240 system combined with Compound Discoverer 3.0 and Xcalibur 2.0 software were adopted for structural identification and metabolic pathway analysis of PTN metabolites in rat plasma， urine， and feces. RESULTS A total of 29 PTN metabolites were identified， including 17， 19 and 22 metabolites in plasma， urine and feces， respectively. The metabolic pathways of PTN mainly included oxidation， sulfation， glucuronidation， etc.， and its metabolites were mostly combination products of two or more different metabolic forms. In detail， a total of 26 metabolites were associated with phase Ⅰ metabolic reactions （14 oxidation metabolites， 9 reduction/dehydrogenation metabolites， 8 demethylation metabolites， and 5 hydrolysis metabolites）. Meanwhile， a total of 20 products were involved in phase Ⅱ metabolites （14 sulfation metabolites and 8 glucuronic acid binding metabolites）. CONCLUSIONS PTN exhibits a diverse range of metabolites in rat fecal samples， with the primary metabolic pathways being oxidation， sulfation， glucuronidation， and others.

ObjectiveTo explore the potential mechanism of Huoxue Xiaoyi Formula （活血消异方， HXF） in treating ovarian endometriosis （OEM） from the perspective of T follicular helper （Tfh） cells and the Janus kinase/signal transducer and activator of transcription （JAK/STAT） signaling pathway. MethodsForty-five female SD rats with normal estrous cycles were randomly divided into three groups， HXF group， model group， and normal group， with 15 rats in each group. A rat model of OEM was established by autologous endometrial tissue implantation. After successful modeling， the treatment group received HXF at 5.85 g/（kg·d） by gavage for 14 consecutive days. The model group and normal group received 1 mL/d of normal saline by gavage. RNA-sequencing data from human proliferative-phase endometriotic and normal endometrial tissues were downloaded from the GEO database. Transcriptomic sequencing was used to analyze gene expression in rat ovarian ectopic tissues and normal uterine tissues， and comparisons were made with human data to verify JAK/STAT pathway activation in proliferative-phase ectopic tissues. Immunohistochemistry was used to detect the positive expression of CXC chemokine receptor 5 （CXCR5） and interleukin-21 （IL-21） in rat ovarian ectopic and normal uterine tissues. Western Blotting was performed to detect the protein levels of IL-21， IL-21 receptor （IL-21R）， Janus kinase 1 （JAK1）， signal transducer and activator of transcription 6 （STAT6）， and B-cell lymphoma 2 （Bcl-2）. Tfh cell infiltration was analyzed using immune cell infiltration methods. ResultsGene set enrichment analysis showed that the JAK/STAT pathway was significantly activated in human proliferative-phase endometriotic tissues compared to normal endometrial tissues. Similarly， the JAK/STAT pathway was markedly activated in rat ovarian ectopic tissues in the model group compared to the normal group， but suppressed in the HXF group compared to the model group. Compared with normal uterine tissues， ovarian ectopic tissues in the model group showed increased Tfh cell infiltration scores， higher CXCR5 and IL-21 expression， and elevated levels of IL-21， IL-21R， JAK1， STAT6， and Bcl-2 proteins. Compared with the model group， HXF group showed reduced CXCR5 and IL-21 expression and decreased protein levels of IL-21， IL-21R， JAK1， STAT6， and Bcl-2. ConclusionHXF may suppress activation of the JAK/STAT signaling pathway in ovarian endometriotic tissues by inhibiting IL-21 secretion from Tfh cells.

Objective:To investigate the diagnostic value of serum serine protease (Corin) in chronic renal failure (CRF) complicated with heart failure.Methods:A retrospective analysis was conducted on 120 patients, (64.05±13.89) years old, 77 male (64.17%), with chronic renal failure combined with heart failure admitted to Zhengzhou People′s Hospital from January 1, 2023, to December 31, 2023. The control group consisted of 87 patients, (60.59±8.78) years old, 54 male (62.07%), with simple chronic renal failure. Clinical information, laboratory test indicators and echocardiographic parameters were collected. Serum Corin concentration was measured using enzyme-linked immunosorbent assay (ELISA). The experimental group was divided into grade Ⅱ(31 cases), grade Ⅲ(47 cases) and grade Ⅳ(42 cases) according to the New York College of Cardiology heart function classification system. Serum Corin levels were compared between the experimental group and the control group and among different cardiac function grades. Spearman correlation analysis was performed to evaluate the relationship between serum Corin and brain natriuretic peptide (BNP), D-dimer. ROC analysis was conducted to assess the predictive value of serum Corin in CRF complicated with heart failure and cardiac function classification; Binary Logistic regression was used to construct a multi-index joint prediction model, the joint prediction probability was obtained, and ROC curve was drawn to compare the diagnostic value of serum Corin and BNP in CRF combined with heart failure and the diagnostic value of serum Corin combined with D-dimer and BNP in CRF combined with heart failure.Results:The serum Corin level[2 568.97±477.70 pg/ml vs. 1 727.81±480.60 pg/ml, t=12.47, P<0.001], BNP [700.00(256.00, 2 089.75) pg/ml compared with 88.00 (43.00, 230.00) pg/ml, Z=-9.00, P<0.001], D-dimer [1 150.00(643.00, 1 874.75)μg/L compared with 556.00 (301.00, 865.00)μg/L, Z=-6.57, P<0.001] in chronic renal failure complicated with heart failure group was higher than that in simple CRF group, and the difference was statistically significant. Among patients with CRF complicated with heart failure, serum Corin[2 231.74±311.39 pg/ml vs. 2 562.09±365.30 pg/ml vs. 2 825.57±536.83 pg/ml, F=74.33, P<0.001], BNP [234.00(168.00, 612.00) pg/ml compared with 514.00(260.00, 1 455.00) pg/ml compared with 2 200.00(640.50, 4 682.75) pg/ml, H=29.42, P<0.001], D-dimer [753.00(514.00, 1 280.00) μg/L compared with 1 187.00(590.00, 1 840.00) μg/L compared with 1 603.00(810.00, 3 313.25) μg/L, H=14.98, P<0.001] increased with the increase of cardiac function grade, and the difference was statistically significant. According to Spearman correlation analysis, serum Corin was positively correlated with BNP ( r=0.409) and D-dimer ( r=0.299), P<0.001. According to the ROC analysis, the AUC of serum Corin in the diagnosis of CRF complicated with heart failure and cardiac function grade Ⅱ, Ⅲ, Ⅳ were 0.890(95% CI 0.846-0.935), 0.807 (95% CI 0.728-0.885), 0.911 (95% CI 0.864-0.959), 0.927 (95% CI 0.882-0.972) respectively; the AUC of BNP in the diagnosis of CRF complicated with heart failure was 0.867 (95% CI 0.817-0.916), the AUC of serum Corin combined with D-dimer, BNP combined with D-dimer, serum Corin combined with D-dimer and BNP in the diagnosis of CRF complicated with heart failure were respectively 0.930 (95% CI 0.897-0.962), 0.892 (95% CI 0.847-0.936), 0.952 (95% CI 0.927-0.977). Conclusions:Serum Corin expression is elevated in patients with CRF complicated with heart failure, and the degree of elevation is related to cardiac function grade. Serum Corin has a good diagnostic value for CRF complicated with heart failure and its severity. Serum Corin is expected to become a new biomarker for diagnosis of CRF complicated with heart failure.

Objective: To compare the effects between second toe tibial dorsal artery flap (2-TDAF) and second toe tibial plantar proper artery flap (2-TPPAF) in repairing finger skin and soft tissue defects. Methods: A retrospective cohort study was conducted. From January 2019 to June 2020, 27 patients with skin and soft tissue defects at the fingertips with area of 1.5 cm×1.2 cm-2.6 cm×1.8 cm after debridement who met the inclusion criteria were admitted to Suzhou Ruihua Orthopaedic Hospital, including 21 males and 6 females, aged 19-59 (37±10) years. According to flap repair methods used in the defective fingers, the patients were divided into 2-TDAF group (12 cases) and 2-TPPAF group (15 cases). The area of 2-TDAF ranged from 1.5 cm×1.2 cm to 2.5 cm×1.6 cm, and the area of 2-TPPAF ranged from 1.7 cm×1.3 cm to 2.6 cm×1.8 cm. Full-thickness skin grafts from the medial side of the ipsilateral leg were grafted to the wounds in donor sites, and the wounds in donor sites of skin grafts were directly sutured. Flap arterial diameter, flap excision time, flap survival situation of patients in 2 weeks after operation, and follow-up time were recorded. At the last follow-up, the two-point discrimination distance of flap graft site, total action motion (TAM) of the finger joints, and wound healing of the flap donor site were recorded; the Vancouver scar scale (VSS) was used to score the scar in donor area of the second toe and the recipient area of fingers; the appearance and self-satisfaction subscales of the Michigan hand outcomes questionnaire (MHQ) were used to evaluate the affected finger. Data were statistically analyzed with independent sample t test or Fisher's exact probability test. Results: The flap artery diameter of patients in 2-TDAF group was 0.35-0.80 (0.56±0.14) mm and the flap cutting time was (14.0±2.7) min, which were significantly shorter than 0.80-1.35 (1.02±0.16) mm and (19.7±3.4) min in 2-TPPAF group (with t values of 7.81 and 4.79, respectively, P<0.01). The flaps of patients in the 2 groups in recipient areas survived well in 2 weeks after operation, and the wounds in donor areas of flaps of patients in the 2 groups healed well at the last follow-up. There was no statistically significant difference in the postoperative follow-up time, and two-point discrimination distance of flap graft site, TAM of the finger joints, VSS score of scar in the second toe donor site and the finger recipient site, and the appearance and self-satisfaction of MHQ scores of the affected finger at the last follow-up (P>0.05). Conclusions: Compared with 2-TPPAF, 2-TDAF has a shallower anatomical layer and shorter time for surgical flap removal, which can preserve the proper arteries and nerves at the base of the toes and reduce the damage to the donor site.
Male ; Female ; Humans ; Soft Tissue Injuries/surgery* ; Finger Injuries/surgery* ; Cicatrix/surgery* ; Plastic Surgery Procedures ; Retrospective Studies ; Treatment Outcome ; Surgical Flaps ; Skin Transplantation ; Toes/surgery* ; Arteries ; Perforator Flap

Objective: To explore the clinical effects of proximal ulnar artery perforator flap combined with iliac bone graft in the reconstruction of subtotal thumb or finger defects. Methods: A retrospective observational study was conducted. From August 2016 to August 2019, 7 patients with thumb or finger defects caused by mechanical damage who met the inclusion criteria were admitted to Ruihua Affiliated Hospital of Soochow University, including 6 males and 1 female, aged 46 to 58 years. Their length of fingers was repaired with iliac bone, with length of 2.0 to 3.0 cm. After the bone graft, the skin defect area of the affected finger ranged from 2.8 cm×2.2 cm to 6.0 cm×3.2 cm. Then the free proximal ulnar artery perforator flap with area of 3.0 cm×2.4 cm to 6.5 cm×3.5 cm was used to cover the wounds. The wounds in donor sites of iliac crest and flap were directly sutured. The survival of flap in one week post surgery and the donor site wound healing in 2 weeks post surgery were observed, respectively. During the follow-up, the appearance and sensory function of the affected finger, bone healing, and scar hypertrophy of wound in the donor site were observed and evaluated. At the last follow-up, the functional recovery of the affected finger was evaluated with trial standard for the evaluation of functions of the upper limbs of the Hand Surgery Society of Chinese Medical Association. Results: In one week post surgery, all the flaps survived. In 2 weeks post surgery, the iliac bone and the wounds in forearm donor site healed. During the follow-up of 5 to 13 months, the flap was good in appearance, without obvious pigmentation; the sensory recovery reached level S₂ in 5 patients and S₀ in 2 patients; all the grafted iliac bones were bony union without obvious resorption; the wounds in donor site healed well, with only mild scar formation. At the last follow-up, the shape of the reconstructed finger was close to the healthy finger, and the functional evaluation results were excellent in 3 cases and good in 4 cases. Conclusions: The use of proximal ulnar artery perforator flap combined with iliac bone graft to reconstruct subtotal thumb or finger can partially restore part of the appearance and function, with less damage to the donor site. It is a good choice for patients who have low expectations of appearance and function for the reconstructed finger.
Male ; Humans ; Female ; Soft Tissue Injuries/surgery* ; Perforator Flap/transplantation* ; Skin Transplantation/methods* ; Thumb/surgery* ; Plastic Surgery Procedures ; Ulnar Artery/surgery* ; Cicatrix/surgery* ; Ilium/surgery* ; Treatment Outcome

Objective　To measure the platelet to lymphocyte ratio (PLR) of young acute cerebral infarction (young acute cerebral infarction,YACI) patients,and to analyze its possible correlation with hemorrhagic transformation (HT) in YACI patients.Methods　According to the occurrence of HT,152 YACI patients admitted were divided into HT group (36 cases) and non hemorrhagic transformation group (116 cases).According to the bleeding volume,HT group was divided into large bleeding group (8 cases),medium bleeding group (11 cases) and small bleeding group (17 cases).The degree of neurological deficit was evaluated according to NIHSS score.The relationship between PLR and HT and NIHSS score in YACI patients was analyzed.Results　The PLR value in the observation group was significantly higher than that in the control group,there were significant differences in the NIHSS score of mild group,moderate group and severe group,the PLR value in HT group was higher than that in non HT group,there were significant differences among SH group,MH group and LH group (all P<0.05).The PLR value in the observation group was positively correlated with NIHSS score (r=0.638,P=0.036),and the PLR value in HT group was positively correlated with bleeding volume (r=0.714,P=0.029).Conclusion　The increase of PLR in YACI patients was positively correlated with post YACI bleeding volume and NIHSS score,which could predict the possibility of HT in YACI patients to a certain extent.

The research and development of chronic hepatitis B (CHB) therapeutic drugs has been undergoing rapid development in recent years in order to achieve the World Health Organization's goal of eliminating viral hepatitis as a major public health threat by 2030. The focus of early stage clinical trials (including the first human trial) is the selection of subjects, study design, dose selection, administration method, dose escalation, monitoring, observation and reporting procedures for adverse events/reactions (tolerability evaluation), and criteria for subjects to continue and discontinue administration. Therefore, quantitative pharmacology knowledge is required to analyze the relationship between in vivo drug exposure, efficacy and adverse reactions, and the inclusion of exploratory indicators such as HBV RNA, hepatitis B virus core-related antigen (HBcrAg), etc., to analyze the mechanism and target of innovative drugs and the efficacy of cccDNA in anti-hepatocytes. On the other hand, Phase II-III clinical trials prioritize the optimal dose, efficacy and safety indicators to verify the efficacy and safety of new drugs in a wider range of subjects. This paper refers to the relevant domestic and foreign literature, combined with the author's practical experience in early clinical research, and then briefly introduces the clinical issues that should be paid attention to in the design of clinical trials of CHB innovative drugs.

Objective　To study the effects of platelet to lymphocyte ratio and D-dimer to fibrinogen ratio combined with WELLS score on the prediction of lower extremity deep vein thrombosis in young cerebral hemorrhage (YCH) patients.Methods　One hundred and nine YCH patients in our hospital were divided into thrombus group (33 cases) and non-thrombus group (76 cases).The diagnostic value of PLR and DFR combined with WELLS score was evaluated by areas under the curve (AUC),sensitivity and specificity of receiver operating characteristic curve (ROC).Results　PLR,DFR and WELLS score of thrombus group were (149.20±52.17),(118.46±8.37) and (2.67±0.48) respectively,and those of non-thrombus group were (95.27±29.48),(75.28±10.16) and (0.72±0.34) respectively,the differences were statistically significant (P<0.05).The sensitivity,specificity,missed diagnosis rate and misdiagnosis rate were 97.65%,92.43%,2.35% and 7.57%,respectively.AUC value of area under ROC curve was 0.951 (P<0.05).Conclusion　PLR,DFR combined with WELLS score has high specificity in predicting LDVTE in YCH patients,and the missed diagnosis rate and misdiagnosis rate are low.It has good clinical practical value and is worthy of popularization and application.

Objective: To investigate the clinical effects of extra-long lateral femoral supercharged perforator flaps in repair of ankle and foot wounds. Methods: From March 2014 to October 2018, 16 patients with foot and ankle injuries were admitted to our hospital and left large area of wounds on foot and ankle after emergency treatment. There were 13 males and 3 females, with age of 27 to 60 years. The area of the wounds ranged from 14 cm×10 cm to 40 cm×17 cm. The wounds were repaired with extra-long lateral femoral supercharged perforator flaps. The widths of flaps in 8 patients were longer than 8 cm, and the bilobed flaps were designed to repair the wounds. The area of the flaps ranged from 12 cm×5 cm to 40 cm×9 cm. During the operation, 54 perforators were detected, with an average of 3.2 perforators in each flap, and 36 source arteries of perforators were detected. The blood vessel trunk of 15 patients was descending branch of the lateral femoral circumflex artery, and their supercharged mode was anastomosis of the bulky perforator of descending branch of the lateral femoral circumflex artery with the oblique branch of the lateral femoral circumflex artery and/or medial femoral circumflex artery or the descending branch of superficial illiac circumflex artery. The blood vessel trunk of 1 patient was oblique branch of the lateral femoral circumflex artery, and the supercharged mode of the patient was anastomosis of the oblique branch of the lateral femoral circumflex artery with the bulky perforator of the descending branch of the lateral femoral circumflex artery. The wounds were covered with the flaps after supercharged blood vessel anastomosis, and blood vessels in the donor sites were anastomosed with those in the recipient sites. The donor site was sutured directly. The survival of the flap after the operation and healing time of the wound, and the flap condition, the two-point discrimination distance of flap in patients who were reconstructed with sensation, the recovery of the ankle function, and the appearance of the donor site during follow-up were recorded. Results: A total of 17 flaps in 16 patients were designed, including 8 bilobed flaps and 9 non-lobulated flaps. Sixteen flaps in 15 patients survived. Vascular crisis occurred in the flap of one patient, and the flap survived when the vascular crisis was relieved by the second operation. The healing time of foot and ankle wounds ranged from 12 to 90 days. All the lateral femoral donor sites healed completely. During follow-up of 8 to 48 months, flaps in 2 patients were slightly bloated and were trimmed in 6 months after the operation. The other flaps were with good appearance, soft texture, good elasticity, and no rupture or ulceration. The two-point discrimination distances of flaps ranged from 7 to 16 mm in 8 patients who were reconstructed with sensation, and the other flaps recovered protective sensation. The flexion and extension function of ankle joint recovered well, and the walking function was not affected significantly. All donor sites formed linear scar, with no deep tissue infection such as osteomyelitis. Conclusions The application of extra-long lateral femoral supercharged perforator flaps to repair the large area of wounds in foot and ankle can significantly reduce damage to donor sites and has advantages of rich blood supply and good safety, thus it has satisfactory clinical effects.

Objective: To explore the clinical effect of bilateral anterolateral thigh flaps in repairing complex wounds of foot and ankle. Methods: From April 2014 to June 2017, 16 patients with complex foot and ankle wounds were treated in Ruihua Hospital Affiliated to Soochow University. There were 15 males and 1 female, aged from 12 to 73 years. Two of them had two wounds for each, the area of which was from 4 cm ×5 cm to 6 cm×10 cm. Fourteen cases were single-wounds, the area of which ranged from 11 cm×8 cm to 42 cm×15 cm. According to the wound surfaces, the wide wound cloth was divided into two pieces of cloth with a width less than 8 cm. The double-leaf skin flap was designed at the point of the perforating branch of the skin flap located by B-ultrasound on the iliac-patellar connecting line of the donor area. The course of the origin artery of the skin perforating branch of the skin flap was observed by DSA image. If the perforating branch of the double-leaf skin flaps was the common origin artery, the two adjacent wounds would be repaired directly. If the perforator of the double-leaf skin flaps is not the common artery, the double-leaf skin flaps were cut separately. After the pedicle division, the perforator vessels of the high perforator skin flaps were anastomosed with the distal end of the medial circumflex lateral femoral artery of the low perforator skin flaps to form a new parallel double-leaf skin flaps, which were then assembled or lobed to the recipient area. Flap donor sites were sutured directly. Results: 11 cases were repaired with parallel bilateral anterolateral thigh flaps with double perforators, and 5 cases were repaired with new parallel bilateral thigh flaps formed by anastomotic bridging of perforator vessels. The area of the flaps ranged from 5 cm×6 cm to 8 cm×22 cm. All the 16 flaps survived and the donor site wounds healed in one stage. Five cases underwent internal fixation removal and skin flap thinning 6 to 10 months after operation. Follow-up for 6 to 18 months showed that the skin flaps were of good color and texture, and the sensation of the flaps ranged from S1 to S3. Linear scars were left in all donor sites and lower limb movements were normal. Conclusions It is a good method to repair complex foot and ankle wounds with bilateral anterolateral thigh flaps, and it has the advantages of flexible design, less damage to donor site and good blood supply of the flap.