Objective:To explore the incidence, clinical features, genetic variant characteristics and prognosis of Glutaric acidemia type I (GA1) among neonates from Henan Province.Methods:A total of 814 625 neonates undergoing screening for inherited metabolic diseases by tandem mass spectrometry (MS/MS) at the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were selected as the study subjects. A retrospective method was adopted to collect the clinical data of the patients. Whole exome sequencing was carried out to detect GCDH gene variants in individuals with positive results by GA1 newborn screening, and Sanger sequencing was used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital (Approval Number: 2019 Medical Ethics Review No. 67). Results:Eight cases of GA1 were diagnosed among the 814 625 neonates. Blood glutaryl carnitine (C5DC) and urine glutaric acid (GA) levels of the 8 children were higher than the normal reference values. In total 12 variants were detected, all of which were missense variants. c. 1064G>A (p.Arg355His) was the most common one, accounting for 21.4% (3/14). Three GCDH gene variants, including 1297G>C (p.Ala433Pro), c. 467G>A (p.Gly156Asp) and c. 1125T>G (p.Cys375Trp), were previously unreported. REVEL software analysis predicted that all of the three variants were harmful. 3D protein structure modeling indicated that the three variants may cause amino acid residue alterations, and c. 1297G>C (p.Ala433Pro) and c. 1125T>G (p.Cys375Trp) may result in increase in hydrogen bonds and may affect the function of GCDH protein. By December 2023, one of the eight children had deceased, and another child had severe clinical symptoms with poor prognosis. Six children had a good prognosis, of which two had mild motor development delay and four had normal development without clinical symptoms. Conclusion:The incidence of GA1 in newborns screened by MS/MS in Henan Province is 1/101 828, and the carrier rate of pathogenic GCDH variants is 1/160. The c. 1064G>A (p.Arg355His) may be the hotspot variant of the GCDH gene among children with GA1 in Henan. Discovery of the three novel variants has enriched the mutational spectrum of the GCDH gene and provide a basis for the early diagnosis, treatment, prognosis and genetic counseling of this disease.

OBJECTIVE: To explore the incidence, clinical features, genetic variant characteristics and prognosis of Glutaric acidemia type I (GA1) among neonates from Henan Province. METHODS: A total of 814 625 neonates undergoing screening for inherited metabolic diseases by tandem mass spectrometry (MS/MS) at the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were selected as the study subjects. A retrospective method was adopted to collect the clinical data of the patients. Whole exome sequencing was carried out to detect GCDH gene variants in individuals with positive results by GA1 newborn screening, and Sanger sequencing was used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital (Ethics Number: 2019 Medical Ethics Review No. 67). RESULTS: Eight cases of GA1 were diagnosed among the 814 625 neonates. Blood glutaryl carnitine (C5DC) and urine glutaric acid (GA) levels of the 8 children were higher than the normal reference values. In total 12 variants were detected, all of which were missense variants. c.1064G>A (p.Arg355His) was the most common one, accounting for 21.4% (3/14). Three GCDH gene variants, including 1297G>C (p.Ala433Pro), c.467G>A (p.Gly156Asp) and c.1125T>G (p.Cys375Trp), were previously unreported. REVEL software analysis predicted that all of the three variants were harmful. 3D protein structure modeling indicated that the three variants may cause amino acid residue alterations, and c.1297G>C (p.Ala433Pro) and c.1125T>G (p.Cys375Trp) may result in increase in hydrogen bonds and affect the function of GCDH protein. By December 2023, one of the eight children had deceased, and another child had severe clinical symptoms with poor prognosis. Six children had a good prognosis, of which two had mild motor development delay and four had normal development without clinical symptoms. CONCLUSION The incidence of GA1 in newborns screened by MS/MS in Henan Province is 1/101 828, and the carrier rate of pathogenic GCDH variants is 1/160. The c.1064G>A (p.Arg355His) may be the hotspot variant of the GCDH gene among children with GA1 in Henan. Discovery of the three novel variants has enriched the mutational spectrum of the GCDH gene and provide a basis for the early diagnosis, treatment, prognosis and genetic counseling of this disease.
Humans ; Amino Acid Metabolism, Inborn Errors/epidemiology* ; Glutaryl-CoA Dehydrogenase/chemistry* ; Infant, Newborn ; Female ; Neonatal Screening/methods* ; Male ; Brain Diseases, Metabolic/epidemiology* ; China/epidemiology* ; Retrospective Studies ; Mutation ; Genetic Variation ; Glutarates

Objective:To explore the incidence, clinical features, genetic variant characteristics and prognosis of Glutaric acidemia type I (GA1) among neonates from Henan Province.Methods:A total of 814 625 neonates undergoing screening for inherited metabolic diseases by tandem mass spectrometry (MS/MS) at the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were selected as the study subjects. A retrospective method was adopted to collect the clinical data of the patients. Whole exome sequencing was carried out to detect GCDH gene variants in individuals with positive results by GA1 newborn screening, and Sanger sequencing was used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital (Approval Number: 2019 Medical Ethics Review No. 67). Results:Eight cases of GA1 were diagnosed among the 814 625 neonates. Blood glutaryl carnitine (C5DC) and urine glutaric acid (GA) levels of the 8 children were higher than the normal reference values. In total 12 variants were detected, all of which were missense variants. c. 1064G>A (p.Arg355His) was the most common one, accounting for 21.4% (3/14). Three GCDH gene variants, including 1297G>C (p.Ala433Pro), c. 467G>A (p.Gly156Asp) and c. 1125T>G (p.Cys375Trp), were previously unreported. REVEL software analysis predicted that all of the three variants were harmful. 3D protein structure modeling indicated that the three variants may cause amino acid residue alterations, and c. 1297G>C (p.Ala433Pro) and c. 1125T>G (p.Cys375Trp) may result in increase in hydrogen bonds and may affect the function of GCDH protein. By December 2023, one of the eight children had deceased, and another child had severe clinical symptoms with poor prognosis. Six children had a good prognosis, of which two had mild motor development delay and four had normal development without clinical symptoms. Conclusion:The incidence of GA1 in newborns screened by MS/MS in Henan Province is 1/101 828, and the carrier rate of pathogenic GCDH variants is 1/160. The c. 1064G>A (p.Arg355His) may be the hotspot variant of the GCDH gene among children with GA1 in Henan. Discovery of the three novel variants has enriched the mutational spectrum of the GCDH gene and provide a basis for the early diagnosis, treatment, prognosis and genetic counseling of this disease.

Objective To investigate the effect of Pericarpium Citri Reticulatae on changes of the intestinal absorption of ginsenoside components in Yi Gong San based on the rat model of spleen deficiency and whether its effect is related to the exocytosis of P-gp protein.Methods The group design included the P-gp protein agonist rifampicin and the inhibitor verapamil,and 36 SD rats were randomly divided into a blank control group(6 rats)and a model group(30 rats),and then subcutaneously injected with rifampicin to establish a model of splenic deficiency,and then the model group was divided into the Yigong San fullparty(Y)group,the lack of Pericarpium Citri Reticulatae(Y-C)group,the YiGong San combined with rifampin(Y+R)group,the lack of Pericarpium Citri Reticulatae combined with verapamil(Y-C+V)group and the lack of Pericarpium Citri Reticulatae combined with rifampin(Y-C+R)group,Ginsenoside Rb1,ginsenoside Re and ginsenoside Rg1 were used as the index components in an in situ unidirectional intestinal perfusion test,and HPLC-MS was used to determine the content of the index components and to calculate the kinetic parameters of intestinal absorption,the effective permeability coefficient(Peff)and the absorption rate constant(Ka).Results Compared with group Y,Peff of ginsenoside Rb1 and Re were significantly lower in Y-C at multiple perfusion sessions,and Peff and Ka of ginsenoside Rb1,ginsenoside Re,and ginsenoside Rg1 were lower in Y+R at multiple perfusion sessions,suggesting that Pericarpium Citri Reticulatae promotes the intestinal absorption of ginsenoside Rb1 and ginsenoside Re and that this effect is related to the activity of the P-gp protein,but failed to change the intestinal absorption of ginsenoside Rg1.The P-gp protein inhibitor verapamil significantly increased the Peff of ginsenoside Rb1 and Re in the Y-C+V compared with the Y-C,while the P-gp protein agonist rifampicin significantly decreased the Peff and Ka of ginsenoside Rb1,ginsenoside Re,and ginsenoside Rg1 in the Y-C+R in multiple perfusion sessions.The significant decrease in Peff and Ka at multiple perfusion times suggests that ginsenoside Rb1,ginsenoside Re,and ginsenoside Rg1 may be substrates for P-gp proteins in the absence of Pericarpium Citri Reticulatae intervention.Conclusion Pericarpium Citri Reticulatae promotes the intestinal absorption of ginsenoside Rb1 and ginsenoside Re by exerting a verapamil-like effect that inhibits the activity of P-gp proteins in Yi Gong San.

Objective:To explore the prevalence, clinical features, genetic characteristics and prognosis of Citrin deficiency in Henan province of China.Methods:A total of 986 565 neonates screened by tandem mass spectrometry at the Third Affiliated Hospital of Zhengzhou University from January 2013 to December 2021 were retrospectively analyzed. Analysis of SLC25A13 gene variants and parental verification were carried out for neonates suspected for Citrin deficiency by next-generation sequencing. The clinical, biochemical and genetic characteristics of Citrin deficiency patients were integrated to guide the diet treatment and follow up the growth and development. Paired- t test was used to compare the amino acid levels in the peripheral blood samples before and after the treatment. Results:Nine cases of Citrin deficiency were diagnosed among the 986 565 neonates. Specific elevation of citrulline was observed in all of the 9 cases. Six variants were detected by genetic sequencing, among which c. 852_855delTATG, c. 615+ 5G>A, c. 550C>T and IVS16ins3kb were known pathogenic variants, whilst c. 1111_1112delAT and c. 837T>A were unreported previously. The detection rate for c. 852_855delTATG was the highest (61.6%, 11/18), followed by IVS16ins3kb (16.7%, 3/18). The clinical symptoms of all patients were relieved after the treatment, and the blood amino acid profile and biochemical parameters were significantly improved by gradually falling within the normal range. By June 2022, all patients had shown a good prognosis.Conclusion:The prevalence of Citrin deficiency among neonates from Henan Province by tandem mass spectrometry is 1/109 618, and the carrier rate for the pathogenic variants of the SLC25A13 gene was 1/166. The c. 852_855delTATG may be a hot spot variant among the patients. Discovery of the novel variants has enriched the mutational spectrum of the SLC25A13 gene. Above results have provided a basis for the early diagnosis, treatment, prognosis and genetic counseling for the affected families.

{L-End}Objective To understand the prevalence of work-related musculoskeletal disorders (WMSDs) and sickness absence due to WMSDs among key industry workers in Shenzhen City. {L-End}Methods A total of 14 949 workers exposed to dust, noise, chemical and radiation (hereinafter referred to as "traditional occupational groups") in some key industries in Shenzhen City, as well as bus drivers, teachers, medical staff, policemen, courier, sanitation workers and video operators were selected as the research subjects using stratified cluster sampling. The Musculoskeletal Disorders Questionnaire was used to investigate the prevalence of WMSDs and sickness absence due to WMSDs in the past year. {L-End}Results The overall prevalence of WMSDs among the study subjects was 56.3% (8 423/14 949). The prevalence of WMSDs in different body parts from high to low was neck, waist, shoulder, back, knee, wrist, ankle, hip, and elbow, which was 37.6%, 35.7%, 31.7%, 25.2%, 18.3%, 15.4%, 14.9%, 12.4%, and 11.6%, respectively (P<0.01). The overall prevalence of WMSDs among different occupational groups from high to low was teachers, video operators, bus drivers, couriers, medical staff, policemen, traditional occupational groups, and sanitation workers, which was 82.2%, 75.7%, 74.9%, 73.9%, 67.9%, 64.3%, 43.3%, and 31.9%, respectively (P<0.01). The overall rate of sickness absence due to WMSDs was 18.3% (2 736/14 949). The overall rate of sickness absence among different occupational groups from high to low was bus drivers, couriers, teachers, traditional occupational groups, policemen, video operators, medical staff, and sanitation workers, which was 31.6%, 24.5%, 20.9%, 20.2%, 15.2%, 12.4%, 9.3%, and 6.7%, respectively (P<0.01). Among different parts of the body, the highest correlation coefficient of WMSDs was found between neck and shoulder ［correlatioon cofficient (r)=0.648, P<0.01］, while the lowest was between neck and ankle (r=0.303, P<0.01). {L-End}Conclusion The prevalence of WMSDs and sickness absence due to WMSDs among key industry workers in Shenzhen City is relatively high. Comprehensive prevention and control measures should be taken according to the characteristics of occupational population to reduce the impact of WMSDs on the health of occupational population.

Objective:To analyze the epidemiological characteristics of etiology from patients with hand, foot and mouth disease(HFMD) in ji’an of Jiangxi from 2013 to 2020, and provide effective prevention and control measures for the diagnosis and treatment of HFMD in the region.Methods:We collected 5089 stool and other clinical specimens from patients with HFMD. Fluorescence quantitative PCR was used for enterovirus detection and typing, SAS statistical software was used to analyze the epidemiological characteristics of pathogens from the types of specimens, time, age, gender, and regional distribution.Results:A total of 3 062 positive samples for enterovirus (EV) were detected out of 5 089 samples, with a total positive rate of 60.17%. The proportions of EV71, CoxA16 and other enteroviruses were 15.15%, 16.36% and 68.49%, and other enterovirus infections were the main ones; the positive rate of enterovirus showed a downward trend from 2013 to 2020; the difference in the positive rate of enterovirus in different years was statistically significant ( χ2=118.47, P<0.05). In the past 8 years, the EV71 type of HFMD in Ji’an showed a downward trend year by year. The number of positive cases was mainly concentrated in April-November, with the peak around May and September. There was no significant difference in the positive detection rate between male and female ( χ2=3.44, P>0.05). The positive rate of stool, anal swab and herpes fluid was higher than that of throat swab, and the difference was significant ( χ2=78.76, P<0.01). Conclusions:In recent years, the surveillance result showed that the pathogenic spectrum of enterovirus had changed in Ji’an, relevant surveillance should be carried out according to the actual situation of HFMD etiology in this region, which is conducive to the prevention and control of HFMD in this region.

Objective:To investigate the prevalence, gene variation and prognosis of very long chain acyl CoA dehydrogenase deficiency (VLCADD) in newborns in Henan Province.Methods:From January 2013 to December 2019, 867 103 newborns were investigated for VLCADD by tandem mass spectrometry.Children who diagnosed as VLCADD and their families were subjected to next-generation sequencing and Sanger sequencing.Clinical data, biochemical changes and gene variation characteristics of the confirmed cases of VLCADD were analyzed.Dietary guidance was given, and their growth and development were followed up.Results:Six neonates were diagnosed as VLCADD, and the prevalence of VLCADD in the Henan Province was 1/144 517.A total of 11 mutations in the ACADVL gene were found, including 5 new variants c. 692-2_692-1delAG, c.753-23_753-22del, c.960delG, c.1361A>G, and c. 1955C>T.The newborns were given a high-carbohydrate, low-fat diet, and followed up for 8-56 months.Except for two deaths, all patients had a good outcome. Conclusions:The prevalence of neonatal VLCADD in Henan Province is 1/144 517.This results has enriched the ACADVL gene mutation spectrum and provided an important basis for the screening and diagnosis of VLCADD.

Along with the develoipment of high-throughput sequencing technologies, both sample size and SNP number are increasing rapidly in genome-wide association studies (GWAS), and the associated computation is more challenging than ever. Here, we present a memory-efficient, visualization-enhanced, and parallel-accelerated R package called"rMVP"to address the need for improved GWAS computation. rMVP can 1) effectively process large GWAS data, 2) rapidly evaluate population structure, 3) efficiently estimate variance components by Efficient Mixed-Model Association eX-pedited (EMMAX), Factored Spectrally Transformed Linear Mixed Models (FaST-LMM), and Haseman-Elston (HE) regression algorithms, 4) implement parallel-accelerated association tests of markers using general linear model (GLM), mixed linear model (MLM), and fixed and random model circulating probability unification (FarmCPU) methods, 5) compute fast with a globally efficient design in the GWAS processes, and 6) generate various visualizations of GWAS-related information. Accelerated by block matrix multiplication strategy and multiple threads, the association test methods embedded in rMVP are significantly faster than PLINK, GEMMA, and FarmCPU_pkg. rMVP is freely available at https://github.com/xiaolei-lab/rMVP.

Objective: To study the prevalence, clinical and genetic characteristics of primary carnitine deficiency (PCD). Methods: From January 2013 to December 2017, 720 667 newborns and their mothers were tested for PCD by tandem mass spectrometry. Potential mutations of carnitine transporter gene SLC22A5 among suspected PCD patients were analyzed. Dietary guidance and L-carnitine supplementation were provided to the parents. Growth and intelligence development were surveyed during follow-up. Results: In total 21 neonates and 6 mothers were diagnosed with PCD, which yielded an incidence of 1 in 34 317. Eighteen SLC22A5 mutations were detected, which included 4 novel mutations, namely c. 1484T>C, c. 394-1G>T, c. 431T>C and c. 265-266insGGCTCGCCACC. Eighteen patients were found to carry compound heterozygous mutations and 3 have carried homozygous SLC22A5 mutations. Three mothers carried compound heterozygous mutations and 2 carried homozygous mutations. Common mutations included c. 1400C>G (42.3%), c. 760C>T (11.5%) and c. 51C>G (7.7%). During the 8 ~ 42 month follow-up, neonates with PCD showed no clinical symptoms but normal growth. Blood level of free carnitine was raised in all mothers after the treatment. Conclusion The incidence of neonatal PCD in Henan is 1 in 34 317, with the most common mutation being c. 1400C>G. Above finding has enriched the spectrum of SLC22A5 gene mutations.