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 investigate the clinical characteristics and risk factors of thyroid dysfunction(TD)in malignant tumor patients treated with immune checkpoint inhibitors(ICIs).Methods A total of 157 cancer patients who were hospitalized and received ICIs treatment in the First People's Hospital of Yunnan Province from January 2019 to June 2022 were collected and divided into the normal thyroid function group and abnormal thyroid function group based on whether TD had occurred.Fifty-eight patients with the normal thyroid function and 58 patients with the abnormal thyroid function were selected,and 58 healthy adults who underwent the physical examination in our hospital were randomly selected as the control group.The baseline data on the gender,age,tumor and ICIs type,history of surgery before medication,history of radiotherapy and chemotherapy,and the related indicators of liver and kidney function,blood lipids,thyroid hormone levels and so on were collected.The relevant indicators of the three groups were statistically analyzed,and the normal thyroid function group and abnormal thyroid function group were compared to evaluate the clinical characteristics and related risk factors of TD caused by ICIs.Results 1.Among 157 patients treated with ICIs,58 cases(36.9%)had thyroid dysfunction,including 39 cases of hypothyroidism(including subclinical hypothyroidism),9 cases of hyperthyroidism(including subclinical hyperthyroidism),and 10 cases of pure related antibody abnormality.2.The analysis of the data of the normal thyroid function group,the abnormal thyroid function group and the control group showed that the age,thyroid stimulating hormone(TSH),and thyroid function of the three groups were significantly different.TSH)baseline level,free triiodothyronine(FT3)baseline level and aspartate transaminase(AST)baseline level were statistically different(P<0.05).There were significant differences in TSH baseline and radiotherapy history between the normal thyroid function group and the abnormal thyroid function group(P<0.05);Multivariate analysis showed that the radiotherapy history(OR=7.291,95% CI= 1.579-33.663,P<.05),baseline TSH level(OR=3.917,95% CI= 1.697-9.038,P<0.05)were the independent risk factors for thyroid dysfunction in cancer patients after ICIs treatment.Conclusion Hypothyroidism is the most common type of TD caused by ICIs in cancer patients.The baseline TSH level and the history of radiotherapy are the independent risk factors for thyroid dysfunction.

BACKGROUND:As a dominant breed pig in southwest China,the southern Yunnan small-ear pig has been widely used as an experimental animal in the basic research of other disciplines,but there are still no reports on its application in anterior cruciate ligament reconstruction. OBJECTIVE:To establish a large animal model of the southern Yunnan small-ear pig with anterior cruciate ligament with autologous Achilles tendon was established. METHODS:Twenty adult female Yunnan small-ear pigs were equally randomized into two groups.In the autologous Achilles tendon group,the right knee anterior cruciate ligament was reconstructed with autologous Achilles tendon as a graft,while in the sham-operated group,a similar operation was performed on the right knee without any treatment of the anterior cruciate ligament.General conditions of each pig were observed and recorded before and 12 months after surgery.Ligaments and grafts were taken for gross observation and MAS scoring.Hematoxylin-eosin staining was performed to observe morphological characteristics of ligaments.The staining and arrangement of type I and type Ⅲ collagen were evaluated by immunohistochemistry.Transmission electron microscopy was used to observe the type,size,diameter,ratio,and distribution of collagen fibers in ligaments. RESULTS AND CONCLUSION:All animals had normal diet and activity,good wound healing,no obvious inflammatory reaction,no local purulent infection,and no significant changes in mental and urinary conditions compared with those before surgery.The reconstructed cruciate ligament of the knee was intact,with no stiffness and normal range of motion.Both the anterior drawer and Lachman tests were negative.Gross observation of the graft:12 months after surgery,the grafts was in good position,with good integrity,obvious tension,ligament color close to the original anterior cruciate ligament,and complete surface synovial coverage.Most of the intraarticular ligaments in the autologous Achilles tendon group were defined as MAS I type and a few were defined as MAS Ⅱ type.In the sham-operated group,the intraarticular ligament was defined as MAS I type.Hematoxylin-eosin staining indicated that,12 months after surgery,collagen fibers in the autologous Achilles tendon group began to appear bundled,isotropic,and uniformly arranged,with more obvious isotropic corrugations,and the nuclei were mainly linear or spindle-shaped,which were similar to those in normal anterior cruciate ligament tissue of the sham-operated group.Immunohistochemistry results indicated that,12 months after surgery,there was a higher expression of type I collagen and significantly less expression of type Ⅲ collagen in the reconstructed anterior cruciate ligament in the autologous Achilles tendon group.The degree of type I and type Ⅲ staining was similar in the two groups.Under the transmission electron microscope,the diameter,arrangement and density of collagen fibers in the reconstructed anterior cruciate ligament of the autologous Achilles tendon group were similar to those of the original anterior cruciate ligament at 12 months after surgery,indicating that the ligament remodeling process had been basically completed in the autologous Achilles tendon group at 12 months after surgery.Through a comprehensive evaluation of animal general conditions,ligament general view,MAS score,hematoxylin-eosin staining,immunohistochemistry,and transmission electron microscopy observation,we successfully established a large animal model of anterior cruciate ligament reconstruction using autogenous Achilles tendon in southern Yunnan small-ear pigs,with good morphological,histological and ultrastructural results.

Objective:To investigate the effects of an immersive virtual reality system for nasal anatomy in improving the learning interest and theoretical level of eight-year program medical students for nasal anatomy in otolaryngology.Methods:A total of 57 medical students of the 2019 eight-year program in Peking University Health Science Center were divided into three groups naturally, with 19 students in each group. Two of the groups (38 students) were randomly selected as experimental group to receive traditional teaching in combination with the immersive virtual reality system for nasal anatomy, while the remaining group (19 students) served as control group to receive traditional teaching. The teaching effectiveness of the two groups was evaluated through questionnaire surveys and theoretical assessment scores in otolaryngology and nasal anatomy. SPSS 27.0 was used to perform statistical analysis. The two groups were compared using the independent samples t-test and the chi-squared test. Results:According to the survey results, both groups considered rhinology theory and anatomy learning as a challenge during rhinology internship. A significantly higher proportion of students in the experimental group believed that they gained the greatest achievement in rhinology theory and anatomy learning during internship, as compared with the control group (33/38 vs. 12/19, P=0.039). The theoretical score for nasal anatomy-related assessment was significantly higher in the experimental group than in the control group [(19.0±1.3) vs. (18.1±1.3), P=0.024]. Conclusions:The use of the immersive virtual reality system for nasal anatomy in otolaryngology teaching can promote eight-year program medical students' interest in learning and improve teaching effectiveness.

OBJECTIVE: To review the research progress of the feasibility of a new treatment method for atrophic rhinitis (ATR) based on tissue engineering technology (seed cells, scaffold materials, and growth factors), and provide new ideas for the treatment of ATR. METHODS: The literature related to ATR was extensively reviewed. Focusing on the three aspects of seed cells, scaffold materials, and growth factors, the recent research progress of ATR treatment was reviewed, and the future directions of tissue engineering technology to treat ATR were proposed. RESULTS: The pathogenesis and etiology of ATR are still unclear, and the effectiveness of the current treatments are still unsatisfactory. The construction of a cell-scaffold complex with sustained and controlled release of exogenous cytokines is expected to reverse the pathological changes of ATR, promoting the regeneration of normal nasal mucosa and reconstructing the atrophic turbinate. In recent years, the research progress of exosomes, three-dimensional printing, and organoids will promote the development of tissue engineering technology for ATR. CONCLUSION Tissue engineering technology can provide a new treatment method for ATR.
Humans ; Tissue Engineering/methods* ; Tissue Scaffolds ; Rhinitis, Atrophic ; Printing, Three-Dimensional ; Cytokines

Objective:Reflux esophagitis (RE) may be negatively correlated with Helicobacter pylori ( H. pylori) infection, but the conclusion and relevant mechanism is still controversial. This study proposed to explore the correlation between RE and H. pylori infection based on natural population. Methods:From July 2013 to December 2014, 3 940 residents aged 40-69 years were recruited in Linqu County of Shandong Province and Hua County of Henan Province by the whole sampling method. All the subjects underwent gastroscopy, and gastric mucosa biopsy specimens were collected for pathological diagnosis and Warthin-Starry (WS) staining to identify H. pylori infection. Venous blood samples of some subjects were collected for H. pylori immunoglobulin G ( H. pylori-IgG) detection. Also, demographic and sociological data were collected. Chi-square test and logistic regression were used to analyze the correlation between RE and H. pylori infection. Results:A total of 359 cases of RE were detected. Excluding RE and other upper gastrointestinal organic diseases, 3 382 cases were considered as controls. Chi-square test showed that WS staining positive rate in RE group was significantly lower than that in control group ( P=0.023), but there was no significant difference in the positive rate of H. pylori-IgG between the two groups ( P=0.281). There were significant differences between RE group and control group in gender composition, age, body mass index (BMI), smoking, alcohol consumption, education level and mucosal active inflammation. Multivariate regression analysis showed that RE was negatively correlated with gastric mucosa active inflammation [ OR=0.754 (95% CI 0.600-0.949), P=0.016], and positively correlated with male [ OR=4.231 (95% CI 3.263-5.486), P<0.001], age ≥60 years, BMI≥24 kg/m 2 [ OR=1.540 (95% CI 1.220-1.945), P<0.001]. Compared to those aged 40-49 years and 50-59 years, the odds ratio ( OR) of RE in these aged ≥60 years were 1.566 (95% CI 1.144-2.143, P=0.005) and 1.405 (95% CI 1.093-1.805, P=0.008). Conclusion:RE is more closely related to H. pylori present infection. Multivariate analysis showed that RE is negatively correlated with active inflammation of gastric mucosa caused by H. pylori infection, and positively correlated with male, overweight and aged ≥60 years.

Objective:To evaluate the diagnostic capabilities of PCR-flow Fluorescence Hybridization technology in prenatal genetic diagnosis of thalassemia.Methods:8 005 cases of prenatal genetic diagnosis of thalassemia in Guangdong Women and Children Hospital from September 2017 to December 2020 were retrospectively analyzed. All samples were diagnosed by traditional genetic methods include multiple Gap-PCR, PCR-RDB, MLPA and Sanger sequencing. Meanwhile, PCR-flow Fluorescence Hybridization technology was used as a verification platform for detecting common mutation sites of thalassemia. The results were analyzed to evaluate the diagnostic capabilities of PCR-flow Fluorescence Hybridization technology compared with traditional methods in prenatal genetic diagnosis of thalassemia.Results:By traditional methods, 1 939 cases (24.22%, 1 939/8 005) were normal and 6 066 cases (75.78%, 6 066/8 005) were diagnosed as thalassemia, including 4 513 cases of α-thalassemia, 1 475 cases of β-thalassemia, and 78 cases of αβ-thalassemia. By PCR-flow Fluorescence Hybridization technology, 7 845 samples were successfully diagnosed after initial interpretation by software. Compared with traditional methods, all the sensitivity, specificity and accuracy were 100%. The other 160 samples which failed in the initial interpretation can be successfully interpreted after review or manual interpretation.Conclusion:There were no differences between the two methods on the detecting of common mutation sites of thalassemia.

Background Indoor air pollution is an important risk factor affecting health of the respiratory system. Studies on indoor air pollution in China are mostly limited to the central and eastern regions, and there are few studies in the rural areas of northwest China. Objective To explore the influencing factors of lung ventilation function and its relationship with indoor air pollution in rural areas of Gansu Province based on a cross-sectional investigation. Methods A total of 399 subjects were selected from four villages in Baiyin and Yuzhong of Gansu Province. Questionnaires were used to collect demographic information, lifestyle, disease history, fuel use, and other information, and physical and functional tests were ordered such as height, weight, and lung function. The Indoor Air Pollution (IAP) exposure index was calculated based on smoking, fuel type, and weekly ventilation. IAP > 5 was defined as a high level of indoor air pollution. Lung function indexes included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC, forced vital capacity as a percentage of predicted value (FVC%), and forced expiratory volume in the first second as a percentage of predicted value (FEV1%), which were used to determine pulmonary ventilation dysfunction. Logistic regression model was used to evaluate the relationship between indoor air pollution and pulmonary ventilation function, and subgroup analysis was further conducted according to home address and BMI , in order to identify the high-risk population of pulmonary ventilation dysfunction. Results The mean age of the subjects was (56.75±7.31) years old; 155 subjects (38.85%) had normal pulmonary ventilation function, and the other 244 subjects (61.14%) had impaired pulmonary ventilation function; about 89.97% of the subjects were exposed to high level of indoor air pollution (IAP > 5). We found that IAP > 5 (OR=2.327, 95%CI: 1.089-4.974) and use of bituminous coal as the main heating fuel in winter (OR=3.467, 95%CI: 1.197-10.037) increased the risk of pulmonary ventilation dysfunction after adjusting for age, BMI, residence, gender, smoking, drinking, and cardiovascular disease. The subgroup analysis results showed that no ventilation in the living room/bedroom (OR=3.460, 95%CI: 1.116-10.268) increased the risk of pulmonary ventilation dysfunction in Baiyin. Heating with coal stoves and Chinese Kang in the bedroom (OR=2.092, 95%CI: 1.030-4.247) and cooking in the bedroom in winter ( OR =2.954, 95% CI : 1.046-8.344) also increased the risk of pulmonary ventilation dysfunction in the residents with BMI≤24 kg·m⁻². IAP > 5 (OR=3.739, 95%CI: 1.147-12.182) was associated with a significantly increased risk of pulmonary ventilation dysfunction in the BMI > 24 kg·m⁻² subgroup. Conclusion The pulmonary ventilation function of rural residents in Gansu is poor, which is negatively correlated with indoor air pollution. Coal use, overweight, cooking in bedroom, and use of coal stoves and Chinese Kang for heating may increase the risk of pulmonary ventilation dysfunction, while room ventilation is a beneficial factor.

Objectives To investigate the effects of low level of ambient NO₂ on the death of cardiovascular and cerebrovascular diseases in Enshi city and to identify sensitive population, so as to provide a scientific basis for formulating health policies. Methods The data of air pollutants, meteorological factors and death of cardiovascular and cerebrovascular diseases in Enshi city from 2015 to 2018 were collected. The generalized additive model based on Poisson distribution was used to analyze the effects of low ambient NO₂ level on the death risk of cardiovascular and cerebrovascular diseases in Enshi city. A subgroup analysis was performed on age, gender, and season. Results The average concentrations of major gaseous air pollutants in Enshi city from 2015 to 2018 were NO₂ (21.40 μg/m³), SO₂ (9.68 μg/m³), CO (0.88 mg/m³), and O₃ (61.21 μg/m³), respectively, all of which did not exceed the national secondary standard. The results of single pollutant model analysis showed that each 1 μg/m3 increase in NO₂ concentration in lag0 day was associated with a 0.33% increase (95% CI: 0.06 - 0.72) (P>0.05) in mortality risk of cardiovascular and cerebrovascular diseases. In the female population, each 1 μg/m3 increase in NO2 concentration in lag01 day was associated with a 0.92% increase (95% CI: 0.26 - 1.56) (P<0.05) in mortality risk of cardiovascular and cerebrovascular diseases. In the cold season, each 1 μg/m3 increase in NO₂ concentration in lag0 day was associated with a 0.62% increase (95% CI: 0.12 - 1.12) (P<0.05) in mortality risk of cardiovascular and cerebrovascular diseases. The results of the two-pollutant model showed that after controlling other gaseous pollutants (SO₂, CO or O₃), the effect of NO₂ on the mortality risk of cardiovascular and cerebrovascular diseases in women and the whole population in cold season still existed. Conclusion The low ambient level of NO₂ in Enshi city was significantly associated with increased mortality risk of cardiovascular and cerebrovascular diseases in female population as well as in cold seasons in the whole population. Attention should be paid to the health protection of special populations in areas with low ambient pollution level of NO₂ in special seasons.

Objective To analyze the basic characteristics and variation trend of death causes of permanent residents in Enshi City during 2013-2018, to assess the burden of different diseases, and to provide a scientific basis for formulating disease prevention and control strategies. Methods The death monitoring data of permanent residents in Enshi City, Hubei Province from 2013 to 2018 was collected. The crude mortality, standardized mortality, life expectancy, potential years of life loss (PYLL), standard potential years of life loss (SPYLL), average years of life lost (AYLL), and annual percentage change (APC) were calculated to describe the distribution and trend of death causes. Results The average annual crude death rate and standardized death rate of residents in Enshi City from 2013 to 2018 were 679.43 per 100 000 and 615.02 per 100 000, respectively. The top 5 causes of death were circulatory system diseases, respiratory system diseases, malignant tumors, injuries, and digestive system diseases, accounting for 91.2% of the total deaths. Analysis of life expectancy found that the average life expectancy of local residents from 2013 to 2018 was 78.02 years, and the value in the male group (75.57 years) was lower than that in the female group (80.78 years). Life loss analysis revealed that PYLL caused by various diseases was 171 620 person-years, SPYLL was 171 284.62 person-years, and AYLL was 15.03 years/person in Enshi City from 2013 to 2018. Among all the death causes, the top five in terms of life loss were injuries, malignant tumors, circulatory diseases, respiratory diseases and digestive diseases. Conclusion From 2013 to 2018, the death rate of residents in Enshi City was relatively higher compared with those in other cities in China, the average annual crude death rate was on the rise, and the average annual standardized death rate was on the decline, indicating a highly ageing region. Chronic diseases such as circulatory system diseases, malignant tumors, and respiratory diseases, as well as injuries were the main death causes and caused a heavy burden of diseases, which should be the focus of future prevention and control work. Considering the higher levels of death and life loss indicators of male residents than those of women, targeted prevention and control measures should be taken to narrow the gap between men and women and improve the overall life quality of the whole population.