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 provide a reference for improving the relevant standard operating procedures （SOP） and biological sample management in drug clinical trials. METHODS According to Good Clinical Practice， Data On-site Verification Points of Drugs Clinical Trials， Human Genetic Resources Management Regulations Implementation Rules， Qualification Examination Rules of Drug Clinical Trials Institution， based on the experience of managing clinical trials programs， the irregularities in biological samples management were analyzed by using statistical quality control tables and protocol deviation （PD） reported by sponsors， in the context of the quality control of drug clinical trials projects managed by the author from July 2016 to May 2023. The precautions in various aspects of sample management were put forward. RESULTS & CONCLUSIONS A total of 101 biospecimen- related irregularities were found in the 60 drug clinical trials projects. Biological sample collection， preservation， and handling were the aspects with the highest incidence of irregular operations in biological sample management， accounting for 37.62%， 25.74%， and 21.78%， respectively. Regulating the management of biospecimens requires multiple efforts. The institutional office and the ethics committee carefully reviewed the consistency of the protocols， informed consent， and genetic office application involving biospecimen collection and handling when the project was initiated. Institutional office quality controllers should pay attention to the attendance and training of authorized personnel at project initiation. The principal investigator， research nurse， collector， handler， transporter， relevant personnel of the central laboratory， and institutional office quality controller have their roles during the project implementation phase. On this basis， all parties involved in the management of biological samples should do a good job of effective communication， find problems and report them in time， and conduct special studies on key aspects.

Objective:To retrospectively analyze the bone marrow characteristics of methimazole-induced agranulocytosis and other hematologic damage, and to explore its correlation with clinical features and prognosis.Methods:The bone marrow and clinical parameters of 20 patients of Graves′ disease diagnosed with methimazole-induced agranulocytosis at the First Affiliated Hospital of Xi′an Jiaotong University from January 2000 to December 2022 were collected. The intergroup differences in bone marrow characteristics and granulocyte recovery time were analyzed. Differences in peripheral blood and bone marrow characteristics between patients with single agranulocytosis and pancytopenia were compared. Besides, literature review of the bone marrow characteristics of methimazole-induced hematologic diseases was conducted.Results:Compared to patients with bone marrow characteristics of granulocyte and precursor maturation disorders(Type Ⅱ), patients with aplastic marrow(Type Ⅰ) had significant decreases in the proportions of granulocytes in all phases( P<0.05). Patients with bone marrow characteristics of Type Ⅰ had a significant increase in the proportion of the lymphocyte system [51.00%(41.50%, 75.50%) vs 22.00%(14.00%, 35.00%), P=0.002], and got a longer to recovery time [(6.58±1.68)d vs(3.71±1.60)d, P=0.003]; Correlation analysis suggested the granulocyte to erythrocyte ratio was negatively correlated with the granulocyte recovery time( r=-0.520, P=0.023), and the proportion of the bone marrow lymphocyte was positively correlated with granulocyte recovery time( r=0.622, P=0.004). Compared to patients with single agranulocytosis, patients with pancytopenia had a markedly longer hospital stay duration [(27.14±5.27)d vs(14.15±7.36)d, P=0.001]. Literature review suggestsed that methimazole may cause various degrees of damage to blood system and bone marrow. Conclusion:Methimazole can induce a variety of hematologic damages. Analysis of bone marrow characteristics can aid in further prognosis assessment. Clinicians should be vigilant about potential hematologic adverse reactions when using methimazole and promptly diagnose and treat them to prevent serious consequences.

OBJECTIVE To investigate the current situation of clinical trial institutions in Chongqing after the recording system of clinical trial institutions, and to put forward suggestions. METHODS A total of 34 clinical trial institutions in Chongqing were selected as the research objects. The research contents mainly included the basic situation of the institutions, staffing, hardware and software construction, project operation and work difficulties, etc. Combined with the research results, suggestions were put forward for the difficulties of the new and old institutions in the operation of clinical trial institutions. RESULTS A total of 29 questionnaires were collected and 29 were valid. The release of clinical trial resources in Chongqing were not sufficient and uniform, there were problems such as insufficient incentive policies, lack of information platform construction, and the number and professional degrees of practitioners need to be improved. The new institutions had certain advantages in project load, office space and willingness to undertake, but it was restricted by principle investigator qualification, project experience and institutional reputation. CONCLUSION It is suggested to clarify the incentive mechanism, enhance the enthusiasm of clinical trials and establish a standardized training mechanism for clinical trial professionals. Make full use of the information platform to improve the efficiency of clinical trials, build a regional information platform to share information and resources, and accelerate the development of regional clinical trials.

Objective To explore the effect of traditional Chinese medicine enema combined with acupoint massage on postoperative intestinal function recovery.Methods A total of 80 patients with abdominal surgery admitted to First Affiliated Hospital of Huzhou University from January 2022 to June 2023 were selected and divided into study group and control group according to random number table method,with 40 cases in each group.The control group was treated with conventional Western medicine,while the study group was treated with traditional Chinese medicine enema combined with acupoint massage on the basis of conventional Western medicine treatment.The therapeutic effect,postoperative recovery time,gastrointestinal hormone level,abdominal distension pain and gastrointestinal reaction score were compared between two groups.Results Postoperative bowel sound recovery time,first anal defecation time and full-flow diet recovery time in study group were significantly shorter than those in control group(P<0.05).At 5 days after surgery,the levels of motilin(MTL),gastrin(GAS)and gastric inhibitory peptide(GIP)in two groups were significantly higher than those in this group at 1 day after surgery(P<0.05).The levels of MTL,GAS and GIP in study group were significantly higher than those in control group(P<0.05).At 5 days after surgery,abdominal distension score and gastrointestinal reaction score in two groups were significantly lower than those in this group 1 day after surgery(P<0.05),and abdominal distension score and gastrointestinal reaction score in study group were significantly lower than those in control group(P<0.05).The total effective rate of study group was significantly higher than that of control group(χ2=3.914,P=0.048).Conclusion Traditional Chinese medicine enema combined with acupoint massage can effectively shorten the recovery time of intestinal function,improve the level of gastrointestinal hormone,relieve abdominal distension pain and gastrointestinal reaction after abdominal operation,and the effect is significant,worthy of clinical application.

Heat stroke can be divided into two types: exertional and classic, mainly manifested as a clear history of exposure to hot temperature/high heat environment or intense physical activity in hot environment, core temperature exceeding 40 ℃, accompanied by central nervous system changes (altered consciousness, epilepsy, psychiatric symptoms, etc.) and multiple organ damage, including respiratory failure, impaired liver and kidney function, rhabdomyolysis, coagulation disorders, abdominal distension, and diarrhea. Its pathology may be manifested as organ endothelial cell damage, inflammatory response, extensive thrombosis, and bleeding tendency. The main treatment measures are cooling therapy, and when combined with other organ damage, organ support or replacement therapy should be carried out in time, including blood transfusion to improve coagulation function and blood purification therapy. Hyperbaric oxygen therapy may improve the prognosis of patients with ischemic hypoxic encephalopathy. We reported a case of a firefighter with sudden impaired consciousness and high fever during forest fire fighting. The patient was sent to a local hospital and his head computed tomography (CT) results showed unclear cerebral gyrus, suggesting severe cerebral edema, and finally diagnosed as heat stroke. After being transferred to Liuzhou Workers' Hospital, his condition continued to deteriorate and signs of multiple organ failure appeared. The patient's cerebral edema was reversed and further development of heat stroke was prevented through early cooling, sedation and anti-epilepsy, endotracheal intubation ventilator-assisted breathing, anti-infection, fluid resuscitation, infusion of fresh frozen plasma and platelets to improve coagulation function, immunomodulatory therapy, renal replacement therapy, and timely artificial liver therapy. Hyperbaric oxygen therapy was ordered during the rehabilitation phase, and the patient recovered well at discharge, leaving no obvious neurological sequelae. Its prognosis is much better than that predicted at admission.

OBJECTIVE To learn the common proto col deviation （PD）in the process of drug clinical trials and discuss the methods and precautions for preventing and reducing PD so as to provide reference for the standardization of drug clinical trials. METHODS According to Good Clinical Practice ，Notice on Issuing Guidelines for Planning and Reporting of Data Management and Statistical Analysis of Drug Clinical Trials ，Guidelines for Ethical Review of Drug Clinical Trials ，ICH E 3，ICH E 6（R2）and other regulations ，the PD reported in the relevant projects managed by the author from March 2017 to February 2022，as well as the PD found in the submission materials and project quality control ，were sorted out and statistically analyzed. RESULTS & CONCLUSIONS A total of 39 drug clinical trials were included ，and 212 subjects were selected. In all projects ，258 PDs were reported，including 28 major PD （accounting for 10.85％）and 230 ordinary PD （accounting for 89.15％）. The report of PD mainly included missed inspections/tests （93 reports，accounting for 36.05％），lack of visits （36 reports，accounting for 13.95％）， inspection/testing out-of-window （29 reports，accounting for 11.24％），dosage and usage of test drugs （28 reports，accounting for 10.85％），drug over-temperature/missing temperature （21 reports，accounting for 8.14％），etc. Avoiding and reducing the occurrence of PD requires the efforts of multiple parties ：the sponsor designs a reasonable protocol with appropriate interview rate and window period after listening to the opinions of multiple parties ；the investigators and clinical research coordinator should strengthen their own learning and training ，and be familiar with the protocol ，Good Clinical Practice and corresponding regulations；the compliance education of the subjects should be strengthened ；the institutional offices and ethics committees should conduct multi-angle and whole-process supervision and management when a drug clinical trial is approved ，in progress ，and jsyj- concluded，to ensure the safety rights and interests of the zdcxX0079） subjects and the quality of clinical trials. On this basis ，all parties should communicate effectively and timely ，report PD in time ，and conduct special studies on major PD that have com occurred and key links that are prone to PD.

Objective:To explore the performance of the commonly used whole blood C-reactive protein (CRP) detection systems and give related recommendation on the performance requirements of detection systems.Methods:A total of 7 540 venous blood samples from 26 maternal, child and children′s hospitals were collected to conduct this multi-center study on the analytical performance of 5 commonly used whole blood CRP detection systems from March to April in 2019. The blank check, carryover, repeatability, intermediate precision, linearity, sample stability, influence of hematocrit/triglyceride/bilirubin, comparison with SIEMENS specific protein analyzer and trueness were evaluated. The 5 systems included BC-5390CRP autohematology analyzer, AstepPLUS specific protein analyzer, Ottoman-1000 Automated Specific Protein POCT Workstation, i-CHROMA Immunofluorometer equipment Reader and Orion QuikRead go detecting instrument. The 5 systems were labeled as a, b, c, d and e randomly.Results:Within the 5 systems, all values of blank check were less than 1.00 mg/L, the carryovers were lower than 1.00%. The repeatability of different ranges of CRP concentrations including 3.00-10.00, 10.00-30.00 and>30.00 mg/L were less than 10.00%, 6.00% and 5.00%, respectively, and the intermediate precision was less than 10.00%. The linearity correlation coefficients of the 5 systems were all above 0.975, while the slope was within 0.950-1.050. Whole blood samples were stable within 72 hours both at room temperature (18-25 ℃) and refrigerated temperature (2-8 ℃). The CRP results were rarely influenced by high triglyceride or bilirubin, except for the immmunoturbidimetric test based on microparticles coated with anti-human CRP F(ab) 2 fragments. When triglyceride was less than 15.46 mmol/L, the deviation of CRP was less than 10.00%. When bilirubin was less than 345.47 μmol/L, the deviation of CRP was less than 10.00%. CRP was more susceptible to Hct on the systems without Hct correction. The deviation of CRP between different Hct dilution concentration and 40% dilution concentration can reach as high as 67.48%. The correlation coefficients ( r) of 5 systems were all more than 0.975 in the range of 0-300.00 mg/L compared with Siemens specific protein analyzer. All systems passed the trueness verification using the samples with specified values of 12.89 and 30.60 mg/L. Conclusion:The performance of 5 systems can basically meet the clinical needs, but it is suggested that the whole blood CRP detection system without automatic Hct correction should be modified manually.

Objective:This study aims to survey the changes of the nutritional status of the children with primary acute lymphoblastic leukemia (ALL) using L-asparaginase (L-Asp) and evaluate the effect of Oral nutritional supplements (ONS) added high protein and medium-chain triglyceride (MCT)(FSMP) improving their nutritional status and clinical outcome.Methods:121 ALL patients receiving the L-Asp chemotherapy were randomized administered conventional low-fat formula (control group, 63 cases) and high protein and MCT FSMP (intervention group, 58 cases). We recorded the one-week diet and performed dietary analysis. The changes of body weight and albumin were recorded on admission and discharge, and the body composition was determined, the nutritional status, number of hospitalization days, and medical costs were assessed.Results:ALL patients had lower intake than the guideline′s recommended value during chemotherapy. The control group was significantly lower in calorie intake and nutrients intake than the intervention group. Weight changes during chemotherapy were positivelycorrelated with calorie intake ( P=0.009), protein intake( P=0.014), and carbohydrate intake( P=0.003). Conclusions:ALL children have different degrees of weight loss and protein level decline during chemotherapy, and their nutritional status was closely related to nutritional intake.ONS is an important nutritional therapy. The appropriate addition of high protein and MCT FSMP can alleviate the loss of thin body weight and the decline of albumin in ALL children.

Objective:To evaluate the clinical value of sonography based volume computer aided display heart (SonoVCADheart) in the display of key diagnostic elements in basic fetal echocardiographic views.Methods:4D volume data based on fetal four-chamber view of 80 singleton fetuses (including 57 normal fetuses and 23 fetuses with heart abnormalities) were collected by using a volumetric probe from the Sir Run Run Shaw Hospital, Zhejiang University College of Medicine from January 8-22, 2019. Four to five volume datasets based on four-chamber view of the heart were rapidly acquired from each fetus. Three doctors (Doctor A: Engaged in fetal echocardiography diagnosis for more than 15 years, Doctor B and C: 6 months of regular fetal echocardiography training but lack of experience) with different fetal echocardiographic experiences performed off-line processing using SonoVCADheart combined tomographic ultrasound imaging (TUI) at different times to obtain eight standard echocardiographic diagnostic views, and to score the elementary contents of each echocardiographic view. The scores of the same doctor at different times, the scores of less experienced doctors and experienced doctor, and the scores between normal and abnormal fetuses, and the time required for analysis and diagnosis among all doctors were analyzed and compared, respectively. The diagnostic coincidence rates of SonoVCADheart for fetuses with cardiac malformations were also assessed.Results:A total of 279 volume datasets obtained from 57 normal fetuses, an average of 4.89/fetus, and 109 volume datasets obtained from 23 fetuses with cardiovascular abnormalities, an average of 4.74/fetus, and all volume datasets were used for SonoVCADheart analysis. The volume percentage of all the elements in the 8 diagnostic views with image quality≥2 points shown by SonoVCADheart in the normal fetuses was about 70.61%-74.91%, in the abnormal fetuses was about 53.21%-55.96%. There were no significant differences in the scores between the same doctor at different times, the scores between inexperienced doctors, and the scores among experienced and less experienced doctors(all P>0.05). There were significant differences in the scores between normal and abnormal fetuses except for all of the superior and inferior vena cava view and the aorticarch view of doctors A and C(all P<0.05). The time required for experienced doctor A and inexperienced doctors B and C to obtain 8 diagnostic views and to complete the diagnosis was statistically significant ( P<0.05). There was no significant difference in the time required for the inexperienced doctors B and C to obtain 8 diagnostic sections and to complete the diagnosis ( P>0.05). There was statistically significant difference in the diagnosis time required for doctor A using SonoVCADheart and two-dimensional echocardiography in fetuses with cardiovascular malformations ( P<0.05). However, there was no statistically significant difference in the time required in the normal fetus between SonoVCADheart and two-dimensional echocardiography ( P>0.05). The diagnostic coincidence rate of SonoVCADheart for fetuses with cardiac malformations is about 89.91%-90.83%. Conclusions:SonoVCADheart is a repeatable and stable novel fetal heart processing tool enabling displaying eight standard diagnostic sections of the fetal heart, and has potential clinical application value in the standardization of image acquisition and sequence display.