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 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.

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 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 explore the effect of the physician-nurse-social worker linkage rehabilitation model on the psychological status in patients receiving methadone maintenance treatment(MMT).Methods Ninety-four patients who received MMT were enrolled and randomly divided into experimental group(n = 48)and control group(n = 46).The experimental group received physician-nurse-social worker linkage rehabilitation model intervention,while the control group received conventional methadone treatment service.The anxiety,depression and quality of life of the two groups were evaluated before the intervention,3 months and 6 months after the intervention.Results After 6 months of physician-nurse-social worker linkage rehabilitation mode intervention,the depression status and the anxiety status of the experimental group subjects were significantly improved compared with those before intervention,and both BDI and BAI scores were significantly lower than those of the control group subjects(P＜0.05).Moreover,the proportion of"had depression"and"had anxiety"in the experimental group were significantly lower than those in the control group(P＜0.05).After 6 months of intervention,the QOL-DA score of the experimental group subjects(183.77±8.90)was significantly higher than that of the control group sub-jects(174.76±11.14)(P＜0.01).Conclusion The physician-nurse-social worker linkage rehabilitation model had certain advantages in improving the psychological state of MMT patients,which is worthy of promotion.

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.

This article reports the diagnosis and treatment of a case of acromegaly in a pregnant patient who took bromocriptine during pregnancy and delivered successfully. A retrospective summary of the clinical data and treatment outcomes before and after two pregnancies of the patient is provided. The patient took bromocriptine during the second pregnancy, and her condition remained stable. A baby girl was delivered by caesarean section at full term. The article suggests that pregnancy in acromegaly patients, after the stabilization of the condition, can lead to favorable outcomes. The use of dopamine receptor agonists during pregnancy does not increase adverse events during the perinatal period.

ObjectiveTo investigate the objective characteristics of tongue manifestations in patients with coronary heart disease （CHD）. MethodsA total of 315 participants with CHD were recruited in the CHD group， and 211 healthy participants who underwent physical examination were recruited as the healthy control group. In addition， according to the common comorbidities （primary hypertension， carotid atherosclerosis， type 2 diabetes mellitus， fatty liver， hyperlipidaemia， heart failure， and cerebral infarction） in 315 participants with CHD， each comorbidity was classified into a group of comorbidities with that disease and a group of non-comorbidities. Tongue images were captured using a TFDA-1 tongue diagnostic instrument to characterise the tongue body （TB） and tongue coating （TC）， comparing the RGB， HIS， and Lab colour spaces in the chromaticity index （R， red； G， green； B， blue； H， hue； I， intensity； S， saturation； L， lightness； a， red-green axis； b， yellow-blue axis）， the tongue coating thickness index （per-All）， contrast （CON）， angular second moment （ASM）， entropy （ENT）， and mean （MEAN） in texture metrics. ResultsCompared with the healthy control group， the characteristic indexes of tongue body in CHD group showed lower TB-R， TB-G， TB-B， TB-I， TB-L and higher TB-H， TB-b； and the characteristic indexes of tongue coating in CHD group showed lower TC-R， TC-B and higher TC-CON， TC-MEAN， TC-H， TC-b （P＜0.05 or P＜0.01）. Compared with non-combined primary hypertension group， CHD combined primary hypertension group showed higher per-All， TB-G， TB-L， and lower TB-a， TC-a （P＜0.05）； compared with the non-combined carotid atherosclerosis group， CHD combined carotid atherosclerosis group showed higher TB-CON， TB-ENT， TB-MEAN， and lower TB-ASM （P＜0.05 or P＜0.01）； compared with the non-combined type 2 diabetes mellitus group， CHD combined type 2 diabetes mellitus group showed lower per-All and higher TB-H （P＜0.05 or P＜0.01）； compared with the non-combined fatty liver group， CHD combined fatty liver group showed higher TB-CON， TB-MEAN， TB-ENT， and lower TB-ASM and TC-S （P＜0.05 or P＜0.01）； compared with the non-combined hyperlipidaemia group， CHD combined hyperlipidaemia group showed lower TB-S and TB-a （P＜0.05）； compared with non-combined heart failure group， CHD combined heart failure group showed lower TB-R， TB-G， TB-I， TB-L， and higher TB-a （P＜0.05 or P＜0.01）； compared with non-combined cerebral infarction group， CHD combined cerebral infarction group showed higher TC-CON， TC-ENT， TC-MEAN， and lower TC-ASM （P＜0.05 or P＜0.01）. ConclusionCompared to healthy individuals， patients with CHD tend to have darker tongue colours and rougher TC textures. Compared with non-comorbidity participants， those with primary hypertension tended to be lighter tongue colour and thicker tongue coating， those with carotid atherosclerosis had paler tongue body， those with type 2 diabetes mellitus had thinner tongue coating， those with fatty liver disease had paler tongue body and whiter tongue colour， those with hyperlipidaemia and heart failure had paler tongue colour， and those with cerebral infarction had rougher tongue texture.