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

Objective To analyze the mutation of common driver genes in patients with non-small cell lung cancer(NSCLC)in eastern Henan Province.Methods A retrospective analysis was performed on 661 patients with NSCLC admitted to the First People's Hospital of Shangqiu city from March 2022 to July 2023.Five kinds of gene mutation detection kits(fluorescent PCR)were used for gene detection in all enrolled patients.The relationship between the clinical features and the status of each driver gene was analyzed by statistical methods.Results In the 661 patients with NSCLC,the mutation rates of EGFR,KRAS,ALK,ROS1,PIK3CA,BRAF,HER2,RET,MET14 and NRAS were 47.35%,9.68%,5.45%,1.82%,2.87%,1.82%,1.21%,0.91%,0.61%and 0%.Mutations in EGFR,ROS1 and HER2 were more likely to occur in women(P<0.05),while KRAS mutations were more common in men(P<0.05).The mutation rates of EGFR,KRAS and ALK in adenocarcinoma was significantly higher than that in squamous cell carcinoma and NSCLC.NOS(P<0.05),and the mutation rate of PIK3CA in NSCLC.NOS was the highest.The mutation rate of KRAS gene in stage Ⅰ+Ⅱ was significantly higher than that in stage Ⅲ+Ⅳ(P<0.05),and there was no significant correlation between other genes and clinical stage.Compared with smokers,the mutation rate of total driver gene was significantly higher in non-smokers(P<0.05).EGFR,ALK,PIK3CA,ROS1,BRAF and HER2 were more common in non-smokers(P<0.05),while KRAS gene was more common in smokers(P<0.05).The mutation rate of 10 driver genes in sediment cell block samples was 78.67%,and the detection rate was significantly higher than that in other types of samples(P<0.05).Conclusion Com-mon driver genes such as EGFR,KRAS and ALK are correlated with gender,pathological type,clinical stage and smoking.Qualified samples of sediment cells have obvious advantages for gene detection and could be widely pro-moted in patients.ARMS-PCR combined detection of 10 genes could be used as the preferred gene detection method for newly diagnosed and treated NSCLC patients.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

This paper discussed the historic evolution of Juanbitang and similar decoctions， clarified the historic development of Yangshi Juanbitang and Chengshi Juanbitang， and probed into the key information of the meaning， original plants， processing methods， and modern dosage and usage of Chengshi Juanbitang. A total of 267 pieces of relevant information were collected from ancient traditional Chinese medicine （TCM） books， among which 53 pieces of effective data were included in this study. The results showed that both Chenshi Juanbitang and Yangshi Juanbitang were originated from Duhuo Jishengtang recoded in the Important Prescriptions Worth a Thousand Gold for Emergency （Bei Ji Qian Jin Yao Fang）. According to the standard of "1 qian roughly equals 3.73 g" in the measurement system of the Qing Dynasty， we suggest Chenshi Juanbitang is composed of 3.73 g Notopterygii Rhizoma et Radix， 3.73 g Angelicae Pubescentis Radix， 3.73 g Gentianae Macrophyllae Radix， 11.19 g Angelicae Sinensis Radix， 11.19 g Mori Ramulus， 2.61 g Chuanxiong Rhizoma， 1.87 g Cinnamomi Cortex， 1.87 g stir-fried Glycyrrhizae Radix et Rhizoma， 7.46 g Piperis Kadsurae Caulis， 2.98 g Olibanum， and 2.98 g Aucklandiae Radix， which should be decocted with 600 mL water to reach a volume of 300 mL. The decoction should be taken 3 times a day before meals. Juanbitang， a classical formula specialized for treating impediment diseases， has the effects of dispelling wind， removing dryness， and alleviating impediment to relieve pain. It can be used for treating vexing pain in body， spasm of nape and back， and heaviness in waists and legs. Modern studies have shown that Juanbitang can be used for treating rheumatoid arthritis， knee osteoarthritis， and periarthritis of shoulder. The above results served as a reference for the future development of Juanbitang.

Objective To investigate the effectiveness and safety of volumetric modulated arc therapy (VMAT) hypofractionated radiotherapy and intensity modulated conformal radiotherapy technique (IMRT) conventional fractionated radiotherapy after breast cancer radical operation.Methods Eighty-five patients with breast cancer modified radical operation admitted and treated in this hospital from March 1,2021 to De-cember 30,2021 were selected as the research subjects and divided into the VMAT group (n=41) and the IM-RT group (n=42) according to the random number table method.The VMAT group adopted the hypofrac-tionated radiotherapy,with the single fractionated dose of 2.9 Gy/frequency and radiotherapeutic total dose of 43.5 Gy/15 frequencies;the IMRT group adopted the IMRT conventional fractionated radiotherapy,with the single fractionated dose of 2.0 Gy/frequency and radiotherapeutic total dose of 50.0 Gy/25 frequencies.The planning target region V95,V110,conformity index,homogeneity index,treatment time,V5,V20,V30,average dose (Dmean) in the affected side lung,humeral head Dmean and heart V30,Dmean were compared between the two groups.Meanwhile,local recurrence,distant metastasis,disease-free survival and acute and chronic radiation injury were compared between the two groups.Results Compared with the IMRT group,V95 in the VMAT was higher,V110 and homogeneity index were lower,the treatment time was shorter,V5 in the affected lung,Dmean and Dmean in the affected humeral head were lower,V30 in the affected lung was higher,heart V30 in the left side breast cancer was lower,heart Dmean in the right side breast cancer was lower,and the differences were statistically significant (P<0.05).All patients survived without local relapse.The distant metastasis rate and disease free survival rate had no statistical difference between the two groups (P>0.05).Follow up lasted for 12 months,the incidence rates of grade Ⅰ-Ⅱ acute radiodermatitis,radiation esophagitis,chronic radioder-matitis and radiation pneumonia had no statistical differences between the two groups (P>0.05).The inci-dence rate of grade Ⅰ-Ⅱ shoulder dysfunction in the VMAT group was lower than that in the IMRT group with statistical difference (P<0.05).No grade Ⅱ and above acute and chronic radiation injury in the two groups occurred.Conclusion VMAT hypofractionated radiotherapy after breast cancer radical operation is safe and effective.

Objective To investigate the reliability and validity of the assessment tools of Brief ICF Core Sets for Arthroplasty of Knee Osteoarthritis in Perioperative Period(ICSAKOPP). Methods From May,2022 to April,2023,320 patients undergoing knee arthroplasty were selected in Peking University Third Hospital,China-Japan Friendship Hospital,Peking University First Hospital and Chinese PLA General Hospital.Trained assessors used Brief ICSAKOPP to evaluate all enrolled patients before arthroplasty,three days(±one day)after arthroplasty,three weeks(±one week)after arthroplasty,and three months(±one month)after ar-throplasty.Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC)scores were recorded at the same time.Five professionals were asked to score all the items of Brief ICSAKOPP,and the content validity index(CVI)was caculated. Results A total of 64 cases were dropped down.CVI of all the items of the Brief ICSAKOPP were above 0.8,with a av-erage CVI of the scale of 0.938.The Cronbach's α coefficient of the Brief ICSAKOPP was 0.813.There was a moderate correlation(r=0.681,P<0.001)between the overall Brief ICSAKOPP and WOMAC scores,as well as body functional dimension score(r=0.668,P<0.001)and activities and participation dimension score(r=0.657,P<0.001). Conclusion Brief ICSAKOPP is good in content validity,internal consistency reliability and criterion validity.

Gait deficits and balance disturbances are prevalent clinical features in Parkinson′s disease (PD). There is an increasing body of evidence pointing towards the degeneration of central cholinergic neurons as a crucial factor leading to these disturbances in PD. This paper presents a comprehensive review of the relevant research on the involvement of the central cholinergic system in the mechanisms underlying gait deficits and balance disturbance in PD. The aim is to provide new perspectives and insights for the treatment of gait deficits and balance disturbances in PD.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease, which is characterized by a combination of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Among them, the incidence of non-motor pain is as high as 40%-88%, which is the main factor leading to emotional disorders and affecting the quality of life of patients. Currently, clinical recognition and management of MSA-related pain are inadequate. In this paper, the recent advances in clinical characteristics, influencing factors, pathogenesis, clinical assessment, therapeutic management of MSA-related pain are reviewed, in order to provide references for identification and management of clinical MSA-related pain.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

OBJECTIVES: The aim of this study was to evaluate the disease burden of prostate cancer (PC) and assess key influencing factors associated with the disease expenditures of PC in the United States. METHODS: The total deaths, incidence, prevalence, and disability-adjusted life-years of PC were obtained from the Global Burden of Disease Study 2019. The Medical Expenditure Panel Survey was used to estimate healthcare expenditures and productivity loss and to investigate patterns of payment and use of healthcare resources in the United States. A multivariable logistic regression model was conducted to identify key factors influencing expenditures. RESULTS: For patients aged 50 and older, the burden for all age groups showed a modest increase over the 6-year period. Annual medical expenditures were estimated to range from US$24.8 billion to US$39.2 billion from 2014 to 2019. The annual loss in productivity for patients was approximately US$1,200. The top 3 major components of medical costs were hospital inpatient stays, prescription medicines, and office-based visits. Medicare was the largest source of payments for survivors. In terms of drug consumption, genitourinary tract agents (57.0%) and antineoplastics (18.6%) were the main therapeutic drugs. High medical expenditures were positively associated with age (p=0.005), having private health insurance (p=0.016), more comorbidities, not currently smoking (p=0.001), and patient self-perception of fair/poor health status (p<0.001). CONCLUSIONS From 2014 to 2019, the national real-world data of PC revealed that the disease burden in the United States continued to increase, which was partly related to patient characteristics.