Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

Objective To establish the methods of galvanic vestibular stimulation-vestibular evoked myogenic potentials(GVS-VEMPs)in healthy children and to obtain the normal value of GVS-cVEMP and GVS-oVEMP in these children in China.Methods Twenty(3～14 years)healthy children and 24 healthy adults(18～30 years)were enrolled for conventional examinations of GVS-cVEMP and GVS-oVEMP.Using the galvanic stimulation in-tensity under 3 mA/1 ms for children and 5 mA/1 ms for adults.The characteristics of elicitation and parameter re-sults of GVS-cVEMP and GVS-oVEMP in children and adults,as well as the pain scores and the elicitation of differ-ent stimulus intensities in the two age groups were recorded.Results The elicitation of GVS-cVEMP and GVS-oVEMP were both 100.0％in children and adult groups.The p1 latency,n1 latency and p1-n1 interval latency of GVS-cVEMP were 10.46±1.84 ms,16.98±2.12 ms and 6.52±1.42 ms respectively in children group,the n1 la-tency and p1-n1 interval latency were significantly shorter than the adult group(P＜0.05).The n1 latency,p1 la-tency and p1-n1 interval latency of GVS-oVEMP were 8.87±1.40 ms,12.25±1.80 ms and 3.39±1.07 ms re-spectively in children group with no significant difference between the two groups.The thresholds of GVS-cVEMP and GVS-oVEMP in children group were significantly lower than adult group(P＜0.01),but no differences were found in adult group regarding on the amplitude and interaural amplitude asymmetry ratio.In addition,with the in-crease of the intensity of galvanic stimulation,the correlation between pain scores and the elicitation rates of GVS-cVEMP and GVS-oVEMP also increased.Conclusion Using appropriate stimulus intensity and recording methods,GVS-cVEMP and GVS-oVEMP could be successfully assessed and detected in healthy children over 3 years old and adolescents.The latency of GVS-cVEMP in children is slightly shorter than that in adults,therefore we recommend selecting the matched age group for assessment in the children group.

Objective:To investigate the effectiveness of preeclampsia risk prediction models based on maternal risk factors during the first trimester in a local population.Methods:This was a diagnostic study. Pregnant women who underwent prenatal examination in People′s Hospital of Rizhao from May 2019 to May 2022 and had risk factors for preeclampsia were enrolled at 11-13 +6 weeks gestation, and were divided into preterm preeclampsia group, term preeclampsia group and non-preeclampsia group according to the occurrence and the gestational week. Baseline clinical data were collected. The effectiveness of different models in predicting preeclampsia risk was evaluated using receiver operating characteristic (ROC) curves. Results:Among the 559 pregnant women enrolled, 78(14.0%) had preeclampsia, including 35(6.3%) with preterm preeclampsia (preterm preeclampsia group), 43 (7.7%) with term preeclampsia (term preeclampsia group), and 481 (86.0%) without preeclampsia (non-preeclampsia group).The most effective model for predicting preterm preeclampsia in the first trimester was maternal risk factor+mean arterial pressure (MAP)+serum placental growth factor (PLGF)+uterine artery pulse index (UTPI). The area under ROC curve was 0.805, and the sensitivity was 56.6% with a false-positive rate of 10%; the most effective model for predicting term preeclampsia and preeclampsia was maternal risk factor+MAP+UTPI. The area under ROC curve was 0.777, and the sensitivity was 52.6% and 53.5% with a false-positive rate of 10%.Conclusion:The combined predicting strategy for preterm preeclampsia based on maternal risk factors in the first trimester maybe effective among our population.

Objective: Metastases in the supragastric lesser sac (SGLS) are not only occult but are also barriers to complete resection of ovarian cancer. We describe a cohort of patients with SGLS disease undergoing debulking surgery. Methods: We identified all patients who underwent evaluation and eventual resection of SGLS disease as part of cytoreductive surgery for stage IIIC–IVB high-grade epithelial ovarian cancer at our institution from January 2018 to August 2022. Results: Thirty-three of 286 patients (11.5%) underwent resection of SGLS disease.Metastases in the SGLS were identified by preoperative imaging in 4 of 33 patients (12.1%). The median peritoneal cancer index score was 22 (range, 9–33). Through surgical exploration, metastases were frequently seen in the right diaphragm (100%), hepatorenal recess (97%), lesser omentum (81.8%), left diaphragm (78.8%), supracolic omentum (75.8%), anterior transverse mesocolon (72.7%), splenic hilum (63.6%), ligamentum teres hepatis (60.6%), and gallbladder fossa (51.5%). The lesser omentum was normal in 6 of 33 (18.2%) patients, despite metastases within the SGLS. A total of 54.5% of patients underwent complex surgery (surgical complexity scores; median, 8; range, 3–14). Complete resections were achieved in 19 (57.6%) patients. No complications were related to the resection of SGLS disease. The median length of progression-free survival was 24.8 months (95% confidence interval=16.6–32.9). Conclusion Metastases to the SGLS are not uncommon in advanced ovarian cancer, particularly those with widely disseminated disease. Disease in this recess is rarely identified by preoperative imaging and deserves systematic surgical exploration to attain complete cytoreduction.

Objective: Metastases in the supragastric lesser sac (SGLS) are not only occult but are also barriers to complete resection of ovarian cancer. We describe a cohort of patients with SGLS disease undergoing debulking surgery. Methods: We identified all patients who underwent evaluation and eventual resection of SGLS disease as part of cytoreductive surgery for stage IIIC–IVB high-grade epithelial ovarian cancer at our institution from January 2018 to August 2022. Results: Thirty-three of 286 patients (11.5%) underwent resection of SGLS disease.Metastases in the SGLS were identified by preoperative imaging in 4 of 33 patients (12.1%). The median peritoneal cancer index score was 22 (range, 9–33). Through surgical exploration, metastases were frequently seen in the right diaphragm (100%), hepatorenal recess (97%), lesser omentum (81.8%), left diaphragm (78.8%), supracolic omentum (75.8%), anterior transverse mesocolon (72.7%), splenic hilum (63.6%), ligamentum teres hepatis (60.6%), and gallbladder fossa (51.5%). The lesser omentum was normal in 6 of 33 (18.2%) patients, despite metastases within the SGLS. A total of 54.5% of patients underwent complex surgery (surgical complexity scores; median, 8; range, 3–14). Complete resections were achieved in 19 (57.6%) patients. No complications were related to the resection of SGLS disease. The median length of progression-free survival was 24.8 months (95% confidence interval=16.6–32.9). Conclusion Metastases to the SGLS are not uncommon in advanced ovarian cancer, particularly those with widely disseminated disease. Disease in this recess is rarely identified by preoperative imaging and deserves systematic surgical exploration to attain complete cytoreduction.

Objective: Metastases in the supragastric lesser sac (SGLS) are not only occult but are also barriers to complete resection of ovarian cancer. We describe a cohort of patients with SGLS disease undergoing debulking surgery. Methods: We identified all patients who underwent evaluation and eventual resection of SGLS disease as part of cytoreductive surgery for stage IIIC–IVB high-grade epithelial ovarian cancer at our institution from January 2018 to August 2022. Results: Thirty-three of 286 patients (11.5%) underwent resection of SGLS disease.Metastases in the SGLS were identified by preoperative imaging in 4 of 33 patients (12.1%). The median peritoneal cancer index score was 22 (range, 9–33). Through surgical exploration, metastases were frequently seen in the right diaphragm (100%), hepatorenal recess (97%), lesser omentum (81.8%), left diaphragm (78.8%), supracolic omentum (75.8%), anterior transverse mesocolon (72.7%), splenic hilum (63.6%), ligamentum teres hepatis (60.6%), and gallbladder fossa (51.5%). The lesser omentum was normal in 6 of 33 (18.2%) patients, despite metastases within the SGLS. A total of 54.5% of patients underwent complex surgery (surgical complexity scores; median, 8; range, 3–14). Complete resections were achieved in 19 (57.6%) patients. No complications were related to the resection of SGLS disease. The median length of progression-free survival was 24.8 months (95% confidence interval=16.6–32.9). Conclusion Metastases to the SGLS are not uncommon in advanced ovarian cancer, particularly those with widely disseminated disease. Disease in this recess is rarely identified by preoperative imaging and deserves systematic surgical exploration to attain complete cytoreduction.

Objective: To explore the difference in H4 clustered histone 6(H4C6) methylation level and circulating cell-free DNA (cfDNA) concentration between 94 normal group and 122 tumor groups (65 patients with lung cancer，22 patients with gastric cancer，23 patients with colorectal cancer，and 12 patients with liver cancer) ，and the age of total 216 subjects were between 18 and 85 years old．To construct a cancer risk prediction model based on H4C6 methylation level and cfDNA concentration and evaluate the predictive performance of the model． Methods: cfDNA was extracted from blood samples using magnetic beads．Qubit 4. 0 fluorescence quantitative meter was used to detect the concentration of cfDNA. Real-time quantitative PCR( RT-qPCR) technology was used to detect the methylation level of H4C6 in cfDNA．Logistic regression algorithm was used to construct a cancer risk prediction model of H4C6 methylation level combined with cfDNA concentration．The accuracy of the model was assessed using receiver operating characteristic (ROC) curve and calibration curve．The clinical benefit of the model was as- sessed using decision curve analysis (DCA) . Results: The model was constructed by combining H4C6 methylation level and cfDNA concentration to distinguish lung cancer，liver cancer，colorectal cancer，gastric cancer，pancancer from healthy control group had the area under curve (AUC) of 0. 769，0. 988，0. 934，0. 922，0. 830，respectively．The mean absolute error of the calibration curve was less than 0. 05 ; the net benefit of the DCA curve was greater than 0． Conclusion The cancer risk prediction model based on H4C6 methylation level and cfDNA concentration has good predictive performance，which helps to provide reasonable and effective suggestions for preclinical decision-making，and ultimately may provide patients with targeted and personalized cancer detection and diagnosis program.

Objective:To investigate any change in the effective connectivity between the bilateral anterior central gyruses after transcranial magnetic stimulation (TMS).Methods:Twenty-one healthy subjects were examined using resting state functional magnetic resonance imaging (rs-fMRI) before and after receiving continuous theta burst stimulation (cTBS). The brain atlas of the Institute of Automation of the Chinese Academy of Sciences was used for fine partitioning of the bilateral anterior central gyruses. Granger causality analysis was used to compare any changes in the effective connectivity between them.Results:After the cTBS inhibited the right M1 area, significant changes in effective connectivity among the sub-regions of the bilateral M1 area were observed. The effective connectivity of the right upper limb to the left upper limb and the left head to face were weakened, while that of the left upper limb to the right head, as well as of the face to the right upper limb was enhanced.Conclusion:For people whose right M1 area has been inhibited by cTBS, the effective connectivity changes in both upper limb functional areas of the M1 region reflect inter-hemispheric inhibition. Opposite changes were found in the trunk and upper limbs.

Objective:To explore the effectiveness of evaluating voice disorders in dysarthria patients after brain injury using speech production measurements and analyze their phonics characteristics.Methods:Twenty-nine patients were divided into a severe dysarthria group ( n=19) and a mild dysarthria group ( n=10) through the subjective evaluation of their speech, and then evaluated using a computer speech monitor. The maximum phonation time (MPT), maximum counting ability (MCA), basic frequency (F0), standard deviation of F0 (F0SD), F0 range, intensity, formant, and the distance of jaw and tongue movements were recorded. Results:All of the patients displayed abnormal MPTs and MCAs, with the average MPT and MCA of the severe dysarthria group significantly lower than the mild group′s averages. In the severe dysarthria group, the abnormal F0s, F0SDs, F2(i)s and tongue movement distances were significantly greater than in the mild group.Conclusions:Speech production measurements can be applied to evaluate the speech dysarthria patients after brain injury. It is very common for such patients to have impaired speech and respiratory function, so this is worthy of attention.

Objective: To explore and construct the cognitive response model for patients suffering conflicts with nurses, and to provide guidance cues for the prevention and treatment of nurse-patient conflict. Methods: According to the grounded theory approach devoloped by Strauss, a total of 9 patients were observed and interviewed in a semi-structured way, and the collected data was analysed to extract the cognitive response theme. Results: A cognitive response model for patients with nurse-patient conflicts was established, which included three phases, i.e., the demands of expectations, the emotional catharsis, and the introspection of right and wrong. Conclusion The established congnitive response model confirmes the relationships among environmental factors, patients′ cognitive processes, and patients′ reponse, and can be used to prevent and deal with the conflicts between patients and nurses.