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.

Hemodynamic monitoring can reflect cardiac function and blood perfusion and is an indispensable monitoring method in clinical practice. Invasive hemodynamic monitoring methods represented by the thermodilution method are limited in their clinical application scope because they require vascular cannulation. Non-invasive hemodynamic monitoring has attracted extensive attention from medical companies and clinicians at home and abroad in recent years due to its advantages such as safety, non-invasiveness, continuous monitoring, simple operation, and low cost. This paper designs a non-invasive hemodynamic monitoring system based on the impedance cardiography, including hardware, algorithm, software design, and performance parameter evaluation. Among them, the hardware part mainly includes a differential high-frequency constant current source stimulation circuit, impedance cardiogram signal acquisition, and ECG signal acquisition circuit. Signal processing includes wave filtering, impedance cardiogram signal calibration, and ECG signal and impedance cardiogram signal feature point recognition. According to the collected impedance cardiogram and ECG signals, hemodynamic parameters such as heart rate (HR), stroke volume (SV), cardiac output (CO), stroke index (SI), cardiac index (CI), and cardiac contractility index (ICON) are calculated based on the Nyboer thoracic cylinder model. After testing, the key technical indicators of the system hardware are better than that of the relevant medical device standards. The system was used to collect impedance cardiogram and ECG signal data from 40 volunteers. The calculated HR, SV, and CO, three important hemodynamic indicators, were compared with the ICONCore non-invasive cardiac output monitor of OSYPKA Medical in Germany. Their Pearson correlation coefficients were 0.992 ( P<0.001), 0.948 ( P<0.001), and 0.933 ( P<0.001), respectively, verifying that the designed system has high accuracy and reliability.
Cardiography, Impedance/methods* ; Humans ; Hemodynamic Monitoring/methods* ; Equipment Design ; Signal Processing, Computer-Assisted ; Hemodynamics ; Algorithms ; Monitoring, Physiologic/methods* ; Electrocardiography

End-tidal carbon dioxide monitoring is an important means of evaluating human lung function and is widely used in fields such as clinical emergency treatment and cardiopulmonary resuscitation. This paper develops a microstream end-tidal carbon dioxide monitoring system. It adopts an integrated gas circuit design to further reduce the size of the equipment. The system uses the method of calculating the root mean square (RMS) of differential pressure signals to regulate the gas circuit flow, enabling the system to stably operate at a flow state of 30 mL/min. In addition, by simultaneously detecting multiple environmental parameters such as temperature and pressure, the system realizes system state monitoring and gas parameter compensation. The test results show that various indicators of the system meet the requirements of relevant standards, laying a good foundation for subsequent engineering applications.
Carbon Dioxide/analysis* ; Equipment Design ; Monitoring, Physiologic/methods* ; Humans

In order to improve the effect of transcranial electrical stimulation treatment and realize personalized treatment for patients with varying severity levels, this paper designed an integrated four-channel EEG recording multimodal transcranial electrical stimulation system. This system can conduct real-time monitoring on EEG and related characteristic analysis before stimulation, in stimulation, and after stimulation. This enables physicians and researchers to resolve real-time brain states, evaluate transcranial electrical stimulation effect, and then artificially adjust the stimulation parameters. After relevant testing and verification, the system can select four stimulation modes: TACS, TDCS, TPCS and TRNS, which can output the constant stimulation current of 0.03 mA accuracy in the range of ±2 mA and the stimulation frequency of low frequency of 0~4 kHz (precision of 0.01 Hz) and high frequency 50~100 kHz, which can obtain more accurate EEG signals under stimulation interference, demonstrating a good market application prospect.
Electroencephalography/methods* ; Transcranial Direct Current Stimulation/instrumentation* ; Humans ; Equipment Design

This paper introduces a 16-channel multimodal high-precision transcranial electrical stimulation system specifically for non-invasive brain stimulation. This system added TMCS mixed four traditional stimulation modes with TACS, TDCS, TPCS and TRNS. By designing a compensated high-precision constant current source, the constant stimulation current with an accuracy of 0.03 mA in the range of ±2 mA and the stimulation frequency of 50~200 kHz with low frequency of 0~4 kHz (high frequency of 0.1 Hz) are realized. In TACS stimulation mode, there are five adjustable wave forms: triangular wave, sine wave, sawtooth wave, square wave and mixed wave. The system has dual closed-loop control overcurrent detection and simultaneous real-time electrode contact impedance detection. After relevant tests and verification, the system has good stimulation accuracy, high safety and reliability. Compared with the existing products at home and abroad, it features lower cost, richer stimulation mode and waveforms, demonstrating a certain market application value.
Transcranial Direct Current Stimulation/instrumentation* ; Equipment Design ; Humans

ObjectiveTo explore the mechanism of Bushen Huoxue enema in treating the rat model of kidney deficiency and blood stasis-thin endometrium （KDBS-TE） by transcriptome sequencing. MethodThe rat model of KDBS-TE was established by administration of tripterygium polyglycosides tablets combined with subcutaneous injection of adrenaline. The pathological changes of rat endometrium in each group were then observed. Three uterine tissue specimens from each of the blank group， model group， and Bushen Huoxue enema group were randomly selected for transcriptome sequencing. The differentially expressed circRNAs， lncRNAs， and miRNAs were screened， and the disease-related specific competitive endogenous RNA （ceRNA） regulatory network was constructed. Furthermore， the gene ontology （GO） functional annotation and the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment were performed for the mRNAs in the network. ResultCompared with the blank group， the model group showed endometrial dysplasia， decreased endometrial thickness and endometrial/total uterine wall thickness ratio （P<0.01）， and differential expression of 18 circRNAs， 410 lncRNAs， and 7 miRNAs. Compared with the model group， the enema and estradiol valerate groups showed improved endometrial morphology and increased endometrial thickness and ratio of endometrial to total uterine wall thickness （P<0.05）. In addition， 21 circRNAs， 518 lncRNAs， and 17 miRNAs were differentially expressed in the enema group. The disease-related specific circRNA-miRNA-mRNA regulatory network composed of 629 nodes and 664 edges contained 2 circRNAs， 34 miRNAs， and 593 mRNAs. The lncRNA-miRNA-mRNA regulatory network composed of 180 nodes and 212 edges contained 5 lncRNAs， 10 miRNAs， and 164 mRNAs. The mNRAs were mainly enriched in Hippo signaling pathway， autophagy-animal， axon guidance， etc. ConclusionBushen Huoxue enema can treat KDBS-TE in rats by regulating specific circRNAs， lncRNAs， and miRNAs in the uterus and the ceRNA network.

Objective:To compare the perioperative outcomes of laparoscopic duodenal-preserving pancreatic head resection(LDPPHR) with laparoscopic pancreaticoduodenectomy(LPD) in the treatment of borderline and benign diseases of the pancreatic head.Methods:This is a retrospective cohort study. Perioperative data from 87 patients with non-malignant pancreatic head diseases who underwent LDPPHR or LPD were retrospectively collected in the Department of Biliary-Pancreatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 2020 to December 2022. There were 49 male and 38 female patients with an age ( M(IQR)) of 57.0(16.5) years (range: 20 to 75 years). Forty patients underwent LDPPHR and 47 patients underwent LPD. Quantitative data following a normal distribution were compared using Student′s t-test, while quantitative data not following a normal distribution were compared using the Mann-Whitney U test. Comparisons of categorical or ordinal variables were made using χ2 test or Fisher′s exact test. Logistic regression analysis was used to estimate the risk factors associated with the rate of complications. Results:There were no statistically significant differences between the LDPPHR group and the LPD group in terms of reoperation rate,total hospital stay duration,postoperative hospital stay duration,90-day mortality rate,30-day and 90-day readmission rates,and 2-year tumor recurrence rate (all P>0.05). The complication rate was higher in the LDPPHR group compared to the LPD group (80.0%(32/40) vs. 51.1%(24/47), χ2=7.89, P=0.005),but there was no difference in the rate of Clavien-Dindo classification of surgical complications ≥Ⅲ between the two groups (10.0%(4/40) vs. 12.8%(6/47), χ2<0.01, P=0.947). Additionally,the rate of delayed gastric emptying (DGE) was higher in the LDPPHR group compared to the LPD group ( χ2=10.79, P=0.001),but there was no statistically significant difference in the rate of B,C grade DGE between the two groups ( χ2=0.48, P=0.487). There were no statistically significant differences in the rates of postoperative pancreatic fistula,bile leakage,post-pancreatectomy hemorrhage,intra-abdominal infection,and pulmonary infection between the two groups (all P>0.05). The results of the univariate logistic regression analysis showed that LDPPHR (compared to LPD, OR=3.83, 95% CI: 1.46 to 10.04, Z=2.73, P=0.006) and preoperative biliary stent placement (compared to non-use of biliary stent, OR=5.30, 95% CI: 1.13 to 25.00, Z=2.11, P=0.035) were risk factors for the complication rate,but neither was an independent risk factor for complication rate (all P>0.05). Conclusion:The preliminary results suggest that LDPPHR can achieve perioperative safety and effectiveness comparable to LPD.

Objective:To compare the perioperative outcomes of laparoscopic duodenal-preserving pancreatic head resection(LDPPHR) with laparoscopic pancreaticoduodenectomy(LPD) in the treatment of borderline and benign diseases of the pancreatic head.Methods:This is a retrospective cohort study. Perioperative data from 87 patients with non-malignant pancreatic head diseases who underwent LDPPHR or LPD were retrospectively collected in the Department of Biliary-Pancreatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 2020 to December 2022. There were 49 male and 38 female patients with an age ( M(IQR)) of 57.0(16.5) years (range: 20 to 75 years). Forty patients underwent LDPPHR and 47 patients underwent LPD. Quantitative data following a normal distribution were compared using Student′s t-test, while quantitative data not following a normal distribution were compared using the Mann-Whitney U test. Comparisons of categorical or ordinal variables were made using χ2 test or Fisher′s exact test. Logistic regression analysis was used to estimate the risk factors associated with the rate of complications. Results:There were no statistically significant differences between the LDPPHR group and the LPD group in terms of reoperation rate,total hospital stay duration,postoperative hospital stay duration,90-day mortality rate,30-day and 90-day readmission rates,and 2-year tumor recurrence rate (all P>0.05). The complication rate was higher in the LDPPHR group compared to the LPD group (80.0%(32/40) vs. 51.1%(24/47), χ2=7.89, P=0.005),but there was no difference in the rate of Clavien-Dindo classification of surgical complications ≥Ⅲ between the two groups (10.0%(4/40) vs. 12.8%(6/47), χ2<0.01, P=0.947). Additionally,the rate of delayed gastric emptying (DGE) was higher in the LDPPHR group compared to the LPD group ( χ2=10.79, P=0.001),but there was no statistically significant difference in the rate of B,C grade DGE between the two groups ( χ2=0.48, P=0.487). There were no statistically significant differences in the rates of postoperative pancreatic fistula,bile leakage,post-pancreatectomy hemorrhage,intra-abdominal infection,and pulmonary infection between the two groups (all P>0.05). The results of the univariate logistic regression analysis showed that LDPPHR (compared to LPD, OR=3.83, 95% CI: 1.46 to 10.04, Z=2.73, P=0.006) and preoperative biliary stent placement (compared to non-use of biliary stent, OR=5.30, 95% CI: 1.13 to 25.00, Z=2.11, P=0.035) were risk factors for the complication rate,but neither was an independent risk factor for complication rate (all P>0.05). Conclusion:The preliminary results suggest that LDPPHR can achieve perioperative safety and effectiveness comparable to LPD.

OBJECTIVE To comprehensively evaluate the three oral Janus kinase inhibitors （JAKi） such as upadacitinib， abrocitinib and baricitinib in the treatment of atopic dermatitis. METHODS The six dimensions of safety， efficacy， economy， appropriateness， accessibility and innovativeness were used for evaluation. Meta-analysis was conducted to evaluate the safety and efficacy of three oral JAKi； pharmacoeconomic studies were searched， and the treatment costs were calculated to evaluate the economy of each JAKi. Appropriateness was described based on literature review and drug labels. Accessibility of three oral JAKi was assessed by using a questionnaire survey. The innovation of JAKi was elucidated from the perspective of its mechanism of action. RESULTS In terms of safety， the incidence of upper respiratory tract infection （OR＝1.47， 95%CI of 1.04-2.08， P＝0.03） and nasopharyngitis （OR＝1.44， 95%CI of 1.06-1.95， P＝0.02） in the upadacitinib 30 mg group was significantly higher than that in the placebo group； the incidence of nasopharyngitis in baricitinib 4 mg group was significantly higher than that in the placebo group （OR＝2.24， 95%CI of 1.39-3.61， P＝0.000 8） and baricitinib 2 mg group （OR＝0.48， 95%CI of 0.31-0.74，P＝0.001）. In terms of efficacy， regardless of the dosage， all three JAKi groups were superior to the placebo group， and the high-dose groups of upadacitinib and abrocitinib were superior to the low-dose groups （P＜0.000 1）. In terms of economy， the annual treatment cost of baricitinib was the lowest （13 870.0 yuan）， but it has not been approved for atopic dermatitis indication in China； next was upadacitinib （27 192.5 yuan）. In terms of appropriateness， the overall appropriateness of the three JAKis was good， but none of them was suitable for patients with severe liver injury. In terms of accessibility， baricitinib had the highest availability rate （59.4%）， but the affordability of upadacitinib was relatively good under China’s medical insurance system. In terms of innovation， among the three types of JAKi， upadacitinib and abrocitinib had better innovation. CONCLUSIONS Three oral JAKi treatments for atopic dermatitis have controllable safety and good efficacy. Considering the issue of medical insurance reimbursement， it is recommended that Chinese patients use upadacitinib.

Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.