Maternal health during pregnancy has a direct impact on the risk and severity of neurodevelopmental disorders (NDDs) in the offspring, especially in the case of drug exposure. However, little progress has been made to assess the risk of drug exposure during pregnancy due to ethical constraints and drug use factors. We collected and manually curated sub-pathways and pathways (sub-/pathways) and drug information to propose an analytical framework for predicting drug candidates. This framework linked sub-/pathway activity and drug response scores derived from gene transcription data and was applied to human fetal brain development and six NDDs. Further, specific and pleiotropic sub-/pathways/drugs were identified using entropy, and sex bias was analyzed in conjunction with logistic regression and random forest models. We identified 19 disorder-associated and 256 regionally pleiotropic and specific candidate drugs that targeted risk sub-/pathways in NDDs, showing temporal or spatial changes across fetal development. Moreover, 5443 differential drug-sub-/pathways exhibited sex-biased differences after filling in the gender labels. A user-friendly NDDP visualization website ( https://ndd-lab.shinyapps.io/NDDP ) was developed to allow researchers and clinicians to access and retrieve data easily. Our framework overcame data gaps and identified numerous pleiotropic and specific candidates across six disorders and fetal developmental trajectories. This could significantly contribute to drug discovery during pregnancy and can be applied to a wide range of traits.
Humans ; Female ; Pregnancy ; Neurodevelopmental Disorders/metabolism* ; Male ; Prenatal Exposure Delayed Effects ; Fetal Development/drug effects* ; Drug Discovery/methods* ; Brain/metabolism*

Objective To observe the value of artificial intelligence(AI)models based on non-contrast chest CT for measuring bone mineral density(BMD).Methods Totally 380 subjects who underwent both non-contrast chest CT and quantitative CT(QCT)BMD examination were retrospectively enrolled and divided into training set(n=304)and test set(n=76)at a ratio of 8∶2.The mean BMD of L1-L3 vertebrae were measured based on QCT.Spongy bones of T5-T10 vertebrae were segmented as RO1,radiomics(Rad)features were extracted,and machine learning(ML),Rad and deep learning(DL)models were constructed for classification of osteoporosis(OP)and evaluating BMD,respectively.Receiver operating characteristic curves were drawn,and area under the curves(AUC)were calculated to evaluate the efficacy of each model for classification of OP.Bland-Altman analysis and Pearson correlation analysis were performed to explore the consistency and correlation of each model with QCT for measuring BMD.Results Among ML and Rad models,MLBagging OP and RadBagging-OP had the best performances for classification of OP.In test set,AUC of MLBagging-OP,RadBagging-op and DLOP for classification of OP was 0.943,0.944 and 0.947,respectively,with no significant difference(all P＞0.05).BMD obtained with all the above models had good consistency with those measured with QCT(most of the differences were within the range of(x)±1.96s),which were highly positively correlated(r=0.910-0.974,all P＜0.001).Conclusion AI models based on non-contrast chest CT had high efficacy for classification of OP,and good consistency of BMD measurements were found between AI models and QCT.

Objective:To analyze the factors affecting delayed chemotherapy in children with Burkitt lymphoma (BL) and their influence on prognosis.Methods:Retrospective cohort study. Clinical data of 591 children aged ≤18 years with BL from May 2017 to December 2022 in China Net Childhood Lymphoma (CNCL) was collected. The patients were treated according to the protocol CNCL-BL-2017. According to the clinical characteristics, therapeutic regimen was divided into group A, group B and group C .Based on whether the total chemotherapy time was delayed, patients were divided into two groups: the delayed chemotherapy group and the non-delayed chemotherapy group. Based on the total delayed time of chemotherapy, patients in group C were divided into non-delayed chemotherapy group, 1-7 days delayed group and more than 7 days delayed group. Relationships between delayed chemotherapy and gender, age, tumor lysis syndrome before chemotherapy, bone marrow involvement, disease group (B/C group), serum lactate dehydrogenase (LDH) > 4 times than normal, grade Ⅲ-Ⅳ myelosuppression after chemotherapy, minimal residual disease in the interim assessment, and severe infection (including severe pneumonia, sepsis, meningitis, chickenpox, etc.) were analyzed. Logistic analysis was used to identify the relevant factors. Kaplan-Meier method was used to analyze the patients' survival information. Log-Rank was used for comparison between groups.Results:Among 591 patients, 504 were males and 87 were females, the follow-up time was 34.8 (18.6,50.1) months. The 3-year overall survival (OS) rate was (92.5±1.1)%,and the 3-year event-free survival (EFS) rate was (90.5±1.2)%. Seventy-three (12.4%) patients were in delayed chemotherapy group and 518 (87.6%) patients were in non-delayed chemotherapy group. The reasons for chemotherapy delay included 72 cases (98.6%) of severe infection, 65 cases (89.0%) of bone marrow suppression, 35 cases (47.9%) of organ dysfunction, 22 cases (30.1%) of tumor lysis syndrome,etc. There were 7 cases of chemotherapy delay in group B, which were seen in COPADM (vincristine+cyclophosphamide+prednisone+daunorubicin+methotrexate+intrathecal injection,4 cases) and CYM (methotrexate+cytarabine+intrathecal injection,3 cases) stages. There were 66 cases of chemotherapy delay in group C, which were common in COPADM (28 cases) and CYVE 1 (low dose cytarabine+high dose cytarabine+etoposide+methotrexate, 12 cases) stages. Multinomial Logistic regression analysis showed that the age over 10 years old ( OR=0.54,95% CI 0.30-0.93), tumor lysis syndrome before chemotherapy ( OR=0.48,95% CI 0.27-0.84) and grade Ⅲ-Ⅳ myelosuppression after chemotherapy ( OR=0.55,95% CI 0.33-0.91)were independent risk factors for chemotherapy delay.The 3-year OS rate and the 3-year EFS rate of children with Burkitt lymphoma in the delayed chemotherapy group were lower than those in the non-delayed chemotherapy group ((79.4±4.9)% vs. (94.2±1.1)%, (80.2±4.8)% vs. (92.0±1.2)%,both P<0.05). The 3-year OS rate of the group C with chemotherapy delay >7 days (42 cases) was lower than that of the group with chemotherapy delay of 1-7 days (22 cases) and the non-delay group (399 cases) ((76.7±6.9)% vs. (81.8±8.2)% vs. (92.7±1.3)%, P=0.002).The 3-year OS rate of the chemotherapy delay group (9 cases) in the COP (vincristine+cyclophosphamide+prednisone) phase was lower than that of the non-chemotherapy delay group (454 cases) ((66.7±15.7)% vs. (91.3±1.4)%, P=0.005). Similarly, the 3-year OS rate of the chemotherapy delay group (11 cases) in the COPADM1 phase was lower than that of the non-chemotherapy delay group (452 cases) ((63.6±14.5)% vs. (91.5±1.3)%, P=0.001). Conclusions:The delayed chemotherapy was related to the age over 10 years old, tumor lysis syndrome before chemotherapy and grade Ⅲ-Ⅳ myelosuppression after chemotherapy in pediatric BL. There is a significant relationship between delayed chemotherapy and prognosis of BL in children.

Objective To establish the pharmacokinetic model of linezolid in neonates,and to optimize the administration regimen. Methods A prospective study was conducted among 64 neonates with sepsis who received linezolid as anti-infective therapy,and liquid chromatography-tandem mass spectrometry was used to measure the plasma concentration of the drug. Clinical data were collected,and nonlinear mixed effects modeling was used to establish a population pharmacokinetic (PPK) model. Monte Carlo simulation and evaluation was performed for the optimal administration regimen of children with different features. Results The pharmacokinetic properties of linezolid in neonates could be described by a single-compartment model with primary elimination,and the population typical values for apparent volume of distribution and clearance rate were 0.79 L and 0.34 L/h,respectively. The results of goodness of fit,visualization verification,and the Bootstrap method showed that the model was robust with reliable results of parameter estimation and prediction. Monte Carlo simulation results showed that the optimal administration regimen for linezolid in neonates was as follows:6 mg/kg,q8h,at 28 weeks of gestational age (GA);8 mg/kg,q8h,at 32 weeks of GA;9 mg/kg,q8h,at 34-37 weeks of GA;11 mg/kg,q8h,at 40 weeks of GA. Conclusions The PPK model established in this study can provide a reference for individual administration of linezolid in neonates. GA and body weight at the time of administration are significant influencing factors for the clearance rate of linezolid in neonates.

Objective:To evaluate the relationship between pelvimetric parameters and surgical difficulty in robot-assisted total mesorectal excision (TME) performed by experienced colorectal surgeons, and to build a nomogram model.Methods:This was a retrospective observational study. The inclusion criteria were as follows: (1) tumor within 10 cm of the anal verge; (2) cancer confirmed by pathological examination of the postoperative specimen; (3) preoperative complete magnetic resonance imaging (MRI) data available; (4) depth of tumor invasion T1-3; (5) circumferential resection margin assessed as negative by MRI; and (6) R0 resection achieved. The exclusion criteria comprised (1) history of pelvic fractures; (2) history of pelvic surgery; and (3) emergency required because of tumor-related intestinal obstruction and/or perforation. Application of above criteria yielded 82 patients who had undergone robot-assisted total mesorectal excision of mid and low rectal cancer in the Department of Colorectal Surgery of the First Affiliated Hospital of Zhengzhou University from January 2021 to December 2022 (modeling group). Additionally, data of 35 patients with mid and low rectal cancer who had undergone robotic-assisted TME at the same center in 2023 January–August were collected for validation of the model (validation group). The following 13 pelvic parameters were studied: pelvic inlet diameter, pelvic outlet diameter, pubic tubercle height, sacral height, sacral depth, interspinous distance, inter-tuberosity distance, lateral mesorectal span, anterior-posterior mesorectal span, anterior mesorectal thickness, posterior mesorectal thickness, rectal area, and mesorectal area. Operating time was used as an indicator of the degree of surgical difficulty, this being defined as the time from the start of skin incision to the end of abdominal closure. Variables related to the duration of surgery were subjected to univariate and multivariate logistic regression analyses to identify factors associated with the difficulty of TME, after which a nomogram for predicting the difficulty of the procedure was established. We constructed receiver operating characteristic and calibration curves to validate the predictive power of nomogram. Furthermore, data from the validation group were used for external validation of the model.Results:The model group comprised 82 patients, including 54 men and 28 women of median age 61.0 years. The median body mass index (BMI) was 23.7 kg/m 2, median distance between the tumor and anal verge 6.1 cm, and median tumor diameter 4.5 cm. Fourteen of these patients had received preoperative adjuvant therapy and 12 had a history of abdominal surgery. There were 35 patients (24 men and 11 women) of median age 64.0 years in the validation group. Their median BMI was 23.7 kg/m 2 and median distance between the tumor and anal verge 6.3 cm. Multivariable analyses of the model group showed that BMI (OR=1.227, 95%CI: 1.240–1.469, P=0.026), distance between the tumor and anal verge (OR=0.733, 95%CI: 0.562–0.955, P=0.022), and interspinous distance (OR=0.468, 95%CI: 0.270–0.812, P=0.007) were independent predictors of surgical difficulty. We then built and validated a predictive nomogram based on the above three variables (AUC=0.804, 95%CI: 0.707–0.900). Calibration curves showed that the S:P in this model was 0.987 and the C-index 0.804. Area under the receiver operating characteristic curve of the predictive model in the validation dataset was 0.767 (95%CI: 0.606–0.928). Conclusion:MRI-based measurements of pelvic parameters are associated with difficulty of performing robot-assisted TME for mid and low rectal cancer. Our nomogram model constructed based on measurements of pelvic parameters has a good predictive ability.

ObjectiveTo determine the optimal dose of Dachengqi Decoction （大承气汤， DCQD） for the treatment of acute intestinal obstruction （AIO） through a randomized， double-blind， dosage parallel controlled， multi-center clinical trial， and to providee evidence support for the reasonable dosage of DCQD in clinical practice. MethodsBased on the commonly used clinical dose of DCQD， three different groups were set up， including low-dose group which used Dahuang （Radix et Rhizoma Rhei） 12 g， Houpo （Cortex Magnoliae Officinalis） 9 g， Zhishi （Fructus Aurantii Immaturus） 9 g， and Mangxiao （Natrii Sulfas） 4.5 g， medium-dose group using Dahuang 36 g， Houpo 27 g， Zhishi 27 g， Mangxiao 13.5 g， and high-dose group using Dahuang 60 g， Houp0 45 g， Zhishi 45 g and Mangxiao 22.5 g. Initially， 149 AIO patients with Yangming （阳明） bowel excess syndrome were randomly assigned to three groups using a stratified randomization method， and both the patients and the doctors were blinded. In addition to conventional western medicine treatment， each group was given 12 bags of granules made from the raw herbs of DCQD at different doses， taken orally or injected through a gastric catheter once every 6 hours， 3 bags each time， for 3 consecutive days. After treatment， the indicators of the three groups of patients with primary AIO and non-primary AIO were evaluated respectively， and the full analysis set （FAS） and per-protocol set （PPS） were used for analysis. The primary outcomes were the time to recover voluntary bowel movements and voluntary flatulence. The secondary outcomes were the ideal rate of spontaneous defecation and the ideal rate of spontaneous flatus. The occurrence of adverse events during the study was recorded and analyzed using the safety analysis set （SS）. ResultsA total of 91 patients with primary AIO and 58 patients with non-primary AIO were included in the FAS and SS analysis， while 80 primary AIO patients and 56 non-primary AIO patients were included in the PPS analysis. Both FAS and PPS analysis showed significant differences in the time to recover voluntary bowel movements and voluntary flatulence among primary AIO patients in different dose groups of DCQD （P＜0.01）， and the high- and medium-dose groups assumed less time than the low-dose group （P＜0.05）. There was no statistically significant difference in the ideal rate of spontaneous defecation and spontaneous flatus among the three groups （P＞0.05）. And consistent results were seen in the non-primary AIO patients among the three groups. Five adverse events occurred in primary AIO patients （3 in the low-dose group， 1 in the medium-dose group， and 1 in the high-dose group）， mainly manifested as abdominal distension and abdominal pain， and there was no statistically significant difference in the incidence of adverse events （P＞0.05）. No adverse events occurred in patients with non-primary AIO. ConclusionDCQD， as an effective treatment for patients with AIO， is commonly used at a medium dose for patients with primary AIO and at a high dose for patients with non-primary AIO. The therapeutic advantage is mainly reflected in the shorter time to recover spontaneous defecation and spontaneous flatulence and the improvement of intestinal function.

Objective:To evaluate the relationship between pelvimetric parameters and surgical difficulty in robot-assisted total mesorectal excision (TME) performed by experienced colorectal surgeons, and to build a nomogram model.Methods:This was a retrospective observational study. The inclusion criteria were as follows: (1) tumor within 10 cm of the anal verge; (2) cancer confirmed by pathological examination of the postoperative specimen; (3) preoperative complete magnetic resonance imaging (MRI) data available; (4) depth of tumor invasion T1-3; (5) circumferential resection margin assessed as negative by MRI; and (6) R0 resection achieved. The exclusion criteria comprised (1) history of pelvic fractures; (2) history of pelvic surgery; and (3) emergency required because of tumor-related intestinal obstruction and/or perforation. Application of above criteria yielded 82 patients who had undergone robot-assisted total mesorectal excision of mid and low rectal cancer in the Department of Colorectal Surgery of the First Affiliated Hospital of Zhengzhou University from January 2021 to December 2022 (modeling group). Additionally, data of 35 patients with mid and low rectal cancer who had undergone robotic-assisted TME at the same center in 2023 January–August were collected for validation of the model (validation group). The following 13 pelvic parameters were studied: pelvic inlet diameter, pelvic outlet diameter, pubic tubercle height, sacral height, sacral depth, interspinous distance, inter-tuberosity distance, lateral mesorectal span, anterior-posterior mesorectal span, anterior mesorectal thickness, posterior mesorectal thickness, rectal area, and mesorectal area. Operating time was used as an indicator of the degree of surgical difficulty, this being defined as the time from the start of skin incision to the end of abdominal closure. Variables related to the duration of surgery were subjected to univariate and multivariate logistic regression analyses to identify factors associated with the difficulty of TME, after which a nomogram for predicting the difficulty of the procedure was established. We constructed receiver operating characteristic and calibration curves to validate the predictive power of nomogram. Furthermore, data from the validation group were used for external validation of the model.Results:The model group comprised 82 patients, including 54 men and 28 women of median age 61.0 years. The median body mass index (BMI) was 23.7 kg/m 2, median distance between the tumor and anal verge 6.1 cm, and median tumor diameter 4.5 cm. Fourteen of these patients had received preoperative adjuvant therapy and 12 had a history of abdominal surgery. There were 35 patients (24 men and 11 women) of median age 64.0 years in the validation group. Their median BMI was 23.7 kg/m 2 and median distance between the tumor and anal verge 6.3 cm. Multivariable analyses of the model group showed that BMI (OR=1.227, 95%CI: 1.240–1.469, P=0.026), distance between the tumor and anal verge (OR=0.733, 95%CI: 0.562–0.955, P=0.022), and interspinous distance (OR=0.468, 95%CI: 0.270–0.812, P=0.007) were independent predictors of surgical difficulty. We then built and validated a predictive nomogram based on the above three variables (AUC=0.804, 95%CI: 0.707–0.900). Calibration curves showed that the S:P in this model was 0.987 and the C-index 0.804. Area under the receiver operating characteristic curve of the predictive model in the validation dataset was 0.767 (95%CI: 0.606–0.928). Conclusion:MRI-based measurements of pelvic parameters are associated with difficulty of performing robot-assisted TME for mid and low rectal cancer. Our nomogram model constructed based on measurements of pelvic parameters has a good predictive ability.

AIM:To identify transcriptional differences between the ocular surface ectoderm(OSE)and surface ectoderm(SE)using RNA-seq, and elucidate the OSE transcriptome landscape and the regulatory networks involved in its development.METHODS:OSE and SE cells were differentiated from human embryonic stem(hES)cells. Differentially expressed genes(DEGs)between OSE and SE were analyzed using RNA-seq. Based on the DEGs, we performed gene ontology(GO)analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis, and protein-protein interaction(PPI)network analysis. Transcription factors(TFs)and hub genes were screened. Subsequently, TF-gene and TF-miRNA regulatory networks were constructed using the NetworkAnalyst platform.RESULTS:A total of 4 182 DEGs were detected between OSE and SE cells, with 2 771 up-regulated and 1 411 down-regulated genes in OSE cells. GO-BP analysis revealed that up-regulated genes in OSE were enriched in the regulation of ion transmembrane transport, axon development, and modulation of chemical synaptic transmission. Down-regulated genes were primarily involved in nuclear division, chromosome segregation, and regulation of cell cycle phase transition. KEGG analysis indicated that up-regulated genes in OSE cells were enriched in signaling pathways such as cocaine addiction, axon guidance, and amphetamine addiction, while down-regulated genes were enriched in proteoglycans in cancer, ECM-receptor interaction, protein digestion and absorption, and cytokine-cytokine receptor interaction. Additionally, compared with SE, 204 TFs(including FOS, EGR1, POU5F1, SOX2, and PAX6)were up-regulated, and 80 TFs(including HAND2, HOXB6, HOXB5, HOXA5, and HOXB8)were down-regulated in OSE cells. Furthermore, we identified 6 up-regulated and 9 down-regulated hub genes in OSE cells, and constructed TF-gene and TF-miRNA regulatory networks based on these hub genes.CONCLUSIONS:The transcriptome characteristics of OSE and SE cells were elucidated through RNA-seq analysis. These findings may provide a novel insight for studies on the development and in vitro directed induction of OSE and corneal epithelial cells.

Objective To investigate the changes of serum sclerostin(SOST)and secreted frizzled related protein 5(SFRP5)levels and their prognostic value in patients with post-traumatic osteoarthritis(PTOA).Methods 84 patients with PTOA admitted to the hospital from January 2020 to January 2022 were selected as the disease group,and 84 healthy patients who underwent physical examination in the hospital during the same period were selected as the health group.Serum SOST and SFRP5 levels were detected in the diseased and healthy groups by enzyme-linked immunosorbent assay.The patients in the disease group were followed up for 1 year and the prognosis of PTOA patients was evaluated by Lysholm knee function score.Spearman correla-tion analysis was used to analyze the correlation between serum SOST,SFRP5 and Lysholm knee function score in PTOA patients.Multivariate Logistic regression was used to analyze the prognostic factors of PTOA patients.The predictive value of serum SOST and SFRP5 levels in poor prognosis of PTOA patients was ana-lyzed by receiver operating characteristic(ROC)curve.Results Compared with the healthy group,the serum SOST and SFRP5 levels in the disease group were significantly decreased,and the difference was statistically significant(P＜0.05).Spearman correlation analysis showed that serum SOST and SFRP5 levels were posi-tively correlated with Lysholm knee function score.Multivariate Logistic regression analysis showed that body mass index＞25 kg/m2,Kelgran-Lawrence grade Ⅲ/Ⅳ at admission and cartilage Outerbridge grade Ⅲ/Ⅳ at admission were independent risk factors for poor prognosis in PTOA patients(P＜0.05).Long-term exercise,SOST and SFRP5 levels were protective factors(P＜0.05).ROC curve analysis showed that the area under ROC curve(AUC)of serum SOST and SFRP5 combined in predicting poor prognosis of PTOA patients was higher than that of SOST and SFRP5 alone in predicting poor prognosis of PTOA patients(Z=2.316,P=0.021;Z=2.356,P=0.019).Conclusion Serum SOST and SFRP5 levels are reduced in PTOA patients compared to healthy individuals,both of which are associated with poor prognosis in PTOA patients and have some predictive efficacy for patient prognosis.

Objective To investigate the needs and feedback from clinical medical students on the diversified teaching mode adopted by the Department of Endocrinology in Peking Union Medical College Hospital.Methods Questionnaires were distributed to the medicine students who were in clinical rotation in Peking Union Medical Col-lege,and the teaching status and teaching effect was investigated.Results A total of 95 valid questionnaires were received.The attending physicians and the teaching resident physicians performed well in the daily teaching activi-ties.The medical students believed that outpatient training was necessary in addition to ward rotations.After the ro-tation in the endocrinology department,the self-evaluated score of mastery of endocrinology knowledge had been significantly improved,especially in those who rotated in outpatient clinic,suggesting that outpatient teaching was of great significance.In addition,the establishment of a self-learning platform including clinical cases and videos in endocrinology could be used as an important supplementary means for clinical teaching.Conclusions Outpatient training improves learning outcomes of medical students,so must be kept and further strengthened in the future.Building a database of typical clinical cases and teaching videos can improve the training quality.