Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

OBJECTIVE To study the efficacy and mechanism of Shugan Jianpi Jiedu decoction in the treatment of the precancerous lesions of breast cancer through animal experiment. METHODS SD rats were taken and divided into 6 groups(10 rats in each group), namely blank group, breast precancerous lesion model group, tamoxifen group, Shugan Jianpi Jiedu decoction groups with low dose, middle dose, and high dose. DMBA modeling method was used to carry out modeling for breast precancerous lesion. HE staining was used to observe the pathological changes of breast tissue. CD4+, CD8+ were detected by flow cytometry. ELISA was used to detect IL-2, IL-4, IL-6, IL-10, IL-12, E2, P. The protein expression of ER, PI3K, p-Akt and mTOR was detected by Western blotting. RESULTS HE staining showed changes in rat mammary tissue, indicating successful modeling. Compared with the blank group, the content of CD4+ decreased and the content of CD8+ increased in the model group(P<0.01); compared with model group, the content of CD4+ increased and the content of CD8+ decreased in low, middle, high dose groups of Shugan Jianpi Jiedu decoction and tamoxifen group(P<0.01). The levels of IL-2, IL-4 and IL-10 in the model group were significantly lower than those in the blank group(P<0.01), while IL-12 and IL-6 were significantly increased(P<0.01). Compared with the model group, the concentrations of IL-2, IL-4 and IL-10 in the low, middle and high dose groups of Shugan Jianpi Jiedu decoction and the tamoxifen group were significantly increased(P<0.01), while IL-12 and IL-6 decreased significantly(P<0.05 or P<0.01). Compared with the blank group, the contents of E2 and P in the model group increased significantly(P<0.05 or P<0.01), the contents of E2 and P in the low, middle and high dose groups of Shugan Jianpi Jiedu decoction and the tamoxifen group were significantly lower than those in the model group(P<0.01). The Western blotting results showed that compared with the blank group, the expression of ER, PI3K, p-Akt and mTOR in the model group was significantly increased(P<0.01). Compared with the model group, the expression of ER, PI3K, p-Akt and mTOR in the low, medium and high dose groups of Shugan Jianpi Jiedu decoction and the tamoxifen group were significantly decreased(P<0.01). CONCLUSION Shugan Jianpi Jiedu decoction may inhibit the expression of ER, thus inhibiting the expression of PI3K/Akt/mTOR signaling pathway. Meanwhile, it can affect the immune response and reverse the precancerous lesions of breast cancer.

177Lu-prostate specific membrane antigen(PSMA)radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China.Based on domestic clinical practice and experimental data and referred to international experience and viewpoints,the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Objective:To construct the quality evaluation scale of specification of management for humanistic caring in outpatients and test its reliability and validity.Methods:Referring to the group standards in Specification of Management for Humanistic Caring in Outpatients released by the China Association for Life Care,as well as relevant guidelines and literature,a pool of items for the quality evaluation scale of specification of management for humanistic caring in outpatients was formed.After expert consultation and expert argumentation,a quality evaluation scale of specification of management for humanistic caring in outpatients was constructed.From January to February 2024,243 hospital managers from 5 hospitals in Zhengzhou were selected as survey subjects to conduct item analysis,and reliability and validity testing on the scale.Results:Two rounds of expert inquiry and two rounds of expert argumentation were conducted,with questionnaire response rates of 92.00%and 100.00%,respectively,and expert authority coefficients of 0.952.In the second round of the expert inquiry scale,the mean importance score of the first-level indicators was 4.80 to 5.00,the full score ratio was 88.00%to 100.00%,the coefficient of variation was 0.04 to 0.17,and Kendall's coefficient of concordance was 0.857(P＜0.001);the mean importance score of the second-level indicators was 4.60 to 5.00,the full score ratio was 80.00%to 100.00%,the coefficient of variation was 0.00 to 0.21,and Kendall's coefficient of concordance was 0.775(P＜0.001);the mean importance score of the third-level indicators was 4.60 to 5.00,the full score ratio was 76.00%to 100.00%,the coefficient of variation was 0.00 to 0.21,and Kendall's coefficient of concordance was 0.830(P＜0.001).Finally,a quality evaluation scale of specification of management for humanistic caring in outpatients was formed,including 5 first-level indicators,25 second-level indicators,and 58 third-level indicators.Exploratory factor analysis produced 5 common factors with a cumulative variance contribution rate of 74.628%.The Pearson correlation coefficients between the five-factor scores ranged from 0.648 to 0.798,and the correlation coefficients between the factor scores and the total score of the scale ranged from 0.784 to 0.938.The scale-level content validity index(S-CVI)of the scale was 0.945,the item-content validity index(I-CVI)was 0.725 to 1.000,the Cronbach's alpha coefficient of the total scale was 0.973,and the retest reliability coefficient was 0.934.Conclusion:The constructed quality evaluation scale of specification of management for humanistic caring in outpatients has good scientific validity and reliability,and can be used as an evaluation tool for specification of management for humanistic caring in outpatients.

To explore the effectiveness of "near peer learning" (NPL) in the electromyography(EMG)teaching module for neurology residents.

Objective:To investigate the clinical features and prognosis of male with anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody.Methods:The clinical data of 246 patients with DM and anti-MDA5 autoantibodies hospitalized by Jiangsu Myositis Cooperation Group from 2017 to 2020 were collected and retrospectively analyzed. Chi-square test was performed to compared between counting data groups; Quantitative data were expressed by M ( Q1, Q3), and rank sum test was used for comparison between groups; Single factor survival analysis was performed by Kaplan-Meier method and Log rank test; Cox regression analysis were used for multivariate survival analysis. Results:①The male group had a higher proportion of rash at the sun exposure area [67.1%(47/70) vs 52.8%(93/176), χ2=4.18, P=0.041] and V-sign [50.0%(35/70) vs 30.7%(54/176), χ2=8.09, P=0.004] than the female group. The male group had higher levels of creatine kinase [112(18, 981)U/L vs 57 (13.6, 1 433)U/L, Z=-3.50, P<0.001] and ferritin [1 500 (166, 32 716)ng/ml vs 569 (18, 14 839)ng/ml, Z=-5.85, P<0.001] than the female group. The proportion of ILD [40.0%(28/70) vs 59.7%(105/176), χ2=7.82, P=0.020] patients and the red blood cell sedimentation rate[31.0(4.0, 101.5)mm/1 h vs 43.4(5.0, 126.5)mm/1 h, Z=-2.22, P=0.026] in the male group was lower than that of the female group, but the proportion of rapidly progressive interstitial lung disease (PR-ILD) [47.1%(33/70) vs 31.3%(55/176), χ2=5.51, P=0.019] was higher than that of the female group. ②In male patients with positive anti-MDA5 antibodies,the death group had a shorter course of disease[1.0(1.0, 3.0) month vs 2.5(0.5,84) month, Z=-3.07, P=0.002], the incidence of arthritis [16.7%(4/24) vs 42.2%(19/45), χ2=4.60, P=0.032] were low than those in survival group,while aspartate aminotransferase (AST)[64(22.1, 565)U/L vs 51(14,601)U/L, Z=-2.42, P=0.016], lactate dehydrogenase (LDH) [485(24,1 464)U/L vs 352(170, 1 213)U/L, Z=-3.38, P=0.001], C-reactive protein (CRP) [11.6(2.9, 61.7) mg/L vs 4.95(0.6, 86.4) mg/L, Z=-1.96, P=0.050], and ferritin levels [2 000(681, 7 676) vs 1 125 (166, 32 716)ng/ml, Z=-3.18, P=0.001] were higher than those in the survival group, and RP-ILD [95.8%(23/24) vs 22.2%(10/45), χ2=33.99, P<0.001] occurred at a significantly higher rate. ③Cox regression analysis indicated that the course of disease LDH level, and RP-ILD were related factors for the prognosis of male anti-MDA5 antibodies [ HR (95% CI)=0.203(0.077, 0.534), P=0.001; HR (95% CI)=1.002(1.001, 1.004), P=0.003; HR (95% CI)=95.674 (10.872, 841.904), P<0.001]. Conclusion:The clinical manifestations of male anti-MDA5 antibody-positive patients are different from those of female. The incidence of ILD is low, but the proportion of PR-ILD is high. The course of disease, serum LDH level, and RP-ILD are prognostic factors of male anti-MDA5 antibody-positive patients.

Objective To evaluate the efficacy and safety of brexpiprazole in treating acute schizophrenia.Methods Patients with schizophrenia were randomly divided into treatment group and control group.The treatment group was given brexpiprozole 2-4 mg·d-1 orally and the control group was given aripiprazole 10-20 mg·d-1orally,both were treated for 6 weeks.Clinical efficacy of the two groups,the response rate at endpoint,the changes from baseline to endpoint of Positive and Negative Syndrome Scale(PANSS),Clinical Global Impression-Improvement(CGI-S),Personal and Social Performance scale(PSP),PANSS Positive syndrome subscale,PANSS negative syndrome subscale were compared.The incidence of treatment-related adverse events in two groups were compared.Results There were 184 patients in treatment group and 186 patients in control group.After treatment,the response rates of treatment group and control group were 79.50％(140 cases/184 cases)and 82.40％(150 cases/186 cases),the scores of CGI-I of treatment group and control group were(2.00±1.20)and(1.90±1.01),with no significant difference(all P＞0.05).From baseline to Week 6,the mean change of PANSS total score wese(-30.70±16.96)points in treatment group and(-32.20±17.00)points in control group,with no significant difference(P＞0.05).The changes of CGI-S scores in treatment group and control group were(-2.00±1.27)and(-1.90±1.22)points,PSP scores were(18.80±14.77)and(19.20±14.55)points,PANSS positive syndrome scores were(-10.30±5.93)and(-10.80±5.81)points,PANSS negative syndrome scores were(-6.80±5.98)and(-7.30±5.15)points,with no significant difference(P＞0.05).There was no significant difference in the incidence of treatment-related adverse events between the two group(69.00％vs.64.50％,P＞0.05).Conclusion The non-inferiority of Brexpiprazole to aripiprazole was established,with comparable efficacy and acceptability.

Objective To observe the value of intravascular ultrasound(IVUS)for assisting endovascular therapy for renal artery stenosis(RAS).Methods Thirty patients with RAS who underwent endovascular therapy were retrospectively analyzed.Parameters of renal artery and plaques in RAS segment measured with CT angiography(CTA)and IVUS before treatment were compared.Bland-Altman diagram was performed to evaluate the consistency of lumen cross-sectional stenosis rate and plaque eccentricity index between CTA and IVUS.The stent parameters measured with IVUS were recorded immediately after implantation of balloon-expandable covered stents.Results Before treatment,the minimum lumen diameter,lumen cross-sectional stenosis rate and stenotic segment length of IVUS were all larger,while maximum lumen diameter and lumen eccentricity index of IVUS were both smaller than those of CTA(all P＜0.05).No significant difference of plaque eccentricity index,plaque type nor stenosis distal remodeling was found between CTA and IVUS(all P＞0.05).The average difference between IVUS and CTA for evaluating lumen cross-sectional stenosis rate and plaque eccentricity index was-0.020(-0.096,0.050)and-0.020(-0.130,0.091),respectively.The consistency of IVUS and CTA for evaluating plaque eccentricity index was better than that of lumen cross-sectional stenosis rate.The stent symmetry,stent eccentricity index,stent expansion coefficient and stenosis coverage rate immediately after implantation measured with IVUS was(82.69±14.61)%,(1.54±9.16)%,(99.81±10.70)%and 100%,respectively.Among 30 cases,2 cases(2/30,6.67%)underwent postdilation since poor stent apposition.Conclusion IVUS could assist evaluating lumen and plaque parameters of stenotic renal arteries,guiding stent release and real-timely monitoring the effect of endovascular therapy.

Objective:To evaluate the long-term outcomes and prognostic factors of locally advanced gastric cancer with serosa-invasion.Methods:This study is a retrospective cohort study. The clinical and pathological data of 495 patients with locally advanced gastric cancer with serosa-invasion who underwent laparoscopic radical gastrectomy in Department of General Surgery, the First Hospital Affiliated to Army Medical University from October 2012 to October 2018 was analyzed retrospectively. There were 356 males and 139 females with an age ( M(IQR)) of 59 (16) years (range: 18 to 75 years). Observation indicators included postoperative results and long-term prognosis. The survival curve was drawn by the Kaplan-Meier method. Univariate and multivariate prognostic analysis was performed using the Cox proportional hazards model. Results:Among the 495 patients, a total of 57 patients (11.5%) were lost to follow-up, with a follow-up time of 89 (40) months (range: 23 to 134 months). The 5-year disease-free survival rate (DFS) and the 5-year overall survival rate (OS) were 56.0% and 58.2%, respectively. The 5-year DFS for patients with stage ⅡB, ⅢA, ⅢB, ⅢC were 71.2%, 60.5%, 51.6%, 33.3%, respectively. The 5-year OS for patients with stage ⅡB, ⅢA, ⅢB, ⅢC were 71.2%, 62.2%, 54.1%, 39.3%, respectively. Multivariate analysis showed that age >65 years (DFS: HR=1.402, 95% CI: 1.022 to 1.922, P=0.036; OS: HR=1.461, 95% CI: 1.057 to 2.019, P=0.022), lymph node dissection number less than 25 (DFS: HR=1.348, 95% CI: 1.019 to 1.779, P=0.036; OS: HR=1.376, 95% CI: 1.035 to 1.825, P=0.028), pathological stage Ⅲ (DFS: HR=2.131, 95% CI: 1.444 to 3.144, P<0.01; OS: HR=2.079, 95% CI: 1.406 to 3.074, P<0.01), and no postoperative chemotherapy (DFS: HR=3.127, 95% CI: 2.377 to 4.113, P<0.01; OS: HR=3.768, 95% CI: 2.828 to 5.020, P<0.01) were independent prognostic factors for the decrease in DFS and OS rates. Conclusions:Laparoscopic radical gastrectomy for locally advanced gastric cancer with serosa-invasion could achieve satisfactory long-term oncological outcomes. More lymph node dissection and standardized postoperative adjuvant chemotherapy are expected to further improve the prognosis of patients with locally advanced gastric cancer with serous invasion after laparoscopic radical surgery.