Objective:To investigate the incidence, clinical characteristics and prognosis of ornithine transcarbamylase deficiency(OCTD) in newborns in Zhejiang Province.Methods:A retrospective research was conducted.A total of 4 261 036 newborns from Department of Genetics and Metabolism, Children′s Hospital, Zhejiang University School of Medicine, between January 2009 and December 2021 were screened for inherited metabolic disorders using tandem mass spectrometry.OCTD was confirmed by urine organic acid and OTC gene analysis.Patients with OTCD received guidance on diet and lifestyle management, and were treated with citrulline and arginine.Long-term follow-up was performed.Their growth and intellectual development were evaluated. Results:A total of 7 patients with OCTD were diagnosed, with an incidence of 1.6/1 million.All patients were males.Two patients had neonatal-onset OCTD, and the other 5 had late-onset OCTD.Symptoms occurred several times in 6 patients, inducing hyperammonemia and hepatic impairment.One patient had no clinical manifestation.One patient died in the neonatal period.Blood citrulline levels were decreased in 7 patients to varying degrees.Uracil levels were increased in 4 patients, and 1 of them was complicated with elevated orotic acid levels.All patients had hemizygote variations in the OTC gene, including 6 missense variations(c.604C>T, c.386G>A, c.779T>C, c.1019C>T, c.594C>G, c.931G>A) and 1 intron variation(c.514-35C>G). Two variants(c.594C>G, c.514-35C>G) were never reported previously. Conclusions:The OTCD incidence by newborn screening is low with 1.6/1 million in Zhejiang province.All patients are males and present hypocitrullinemia.The clinical manifestations of OTCD are highly heterogeneous.The neonatal-onset form is severe and survivors always suffer serious sequelae.The late-onset form is mostly manifested with hyperammonemia and hepatic impairment.There may be association between phenotype and genotype.Two novel OTC variants are identified, which further expands the mutational spectrum.

OBJECTIVES: To analyze the results of neonatal screening for congenital hypothyroidism (CH) and hyperphenylalaninemia (HPA) in Zhejiang province from 1999 to 2022. METHODS: A total of 11 922 318 newborns were screened from September 1999 and December 2022 in Zhejiang province. The blood thyroid stimulating hormone (TSH) levels were measured by a fluorescence method and blood phenylalanine (Phe) levels were measured by fluorescence method or tandem mass spectrometry. TSH≥9 μIU/mL was considered positive for CH, while Phe>120 μmol/L and/or Phe/Tyr ratio>2.0 were considered positive for HPA. The positive newborns in screening were recalled, and the gene variations were detected by high-throughput sequencing and MassARRAY tests. RESULTS: The overall neonatal screening rate during 1999-2022 was 89.41% (11 922 318/13 333 929) and the screening rate was increased from 6.46% in 1999 to 100.0% in 2022. A total of 8924 cases of CH were diagnosed among screened newborns with an incidence rate of 1/1336. A total of 563 cases of HPA were diagnosed, including 508 cases of classic phenylketonuria (cPKU) and 55 cases of tetrahydrobiopterin deficiency (BH4D), with an incidence rate of 1/21 176. Ninety-seven out of 8924 cases of CH underwent genetic analysis. Gene mutations were detected in 9 CH related genes, the highest frequency mutations were found in DUOX2 gene (69.0%) with c.3329G>A (p.R1110Q) (18.2%) and c.1588A>T (p.K530X) (17.3%) as the hotspot mutations. There were 81 PAH gene variants detected in a total of 250 cases of cPKU, and c728G>A (p.R243Q) (24.4%), c.721C>T (p.R241C) (15.0%) were the hotspot mutations. Meanwhile 7 novel variants in PAH gene were detected: c.107C>A (p.S36*), c.137G>T (p.G46V), c.148A>G(p.K50E), c.285C>T (p.I95I), c.843-10delTTCC, exon4-7del and c.1066-2A>G. There were 12 PTS gene variants detected in 36 cases of BH4D, and c.259C>T (p.P87S) (31.9%) was the hotspot mutation. CONCLUSIONS The incident of CH has increased from 1999 to 2022 in Zhejiang province, and it is higher than that of national and global levels; while the incidence of HPA is similar to the national average. DUOX2 gene variation is the most common in CH patients; c.728G>A (p.R243Q) is the hotspot mutation in cPKU patients, while c.259C>T (p.P87S) is the hotspot mutation in BH4D patients.
Humans ; Infant, Newborn ; Neonatal Screening ; Dual Oxidases ; Congenital Hypothyroidism/genetics* ; Phenylketonurias/genetics* ; Thyrotropin

Monkeypox is a zoonotic disease.Previous studies have shown that children are vulnerable to monkeypox and are also at high risk for severe disease or complications.In order to improve pediatricians′ understanding of monkeypox and achieve early detection, early diagnosis, early treatment and early disposal, the committee composed of more than 40 experts in the related fields of infectious diseases, pediatrics, infection control and public health formulate this expert consensus, on the basis of the latest clinical management and infection prevention and control for monkeypox released by the World Health Organization (WHO), the guidelines for diagnosis and treatment of monkeypox (version 2022) issued by National Health Commission of the People′s Republic of China and other relevant documents.During the development of this consensus, multidisciplinary experts have repeatedly demonstrated the etiology, epidemiology, transmission, clinical manifestations, laboratory examinations, diagnosis and differential diagnosis, treatment, discharge criteria, prevention, case management process and key points of prevention and control about monkeypox.

Objective:To investigate the safety and long-term outcomes of fully covered self-expanding metal stent (FCSEMS) placement in patients with benign refractory pancreatic stenosis.Methods:Data of 18 patients with benign refractory pancreatic stenosis who underwent endoscopic treatment with FCSEMS in Nanjing Drum Tower Hospital between March 2013 and July 2020 were collected. The technical success, clinical success, adverse events and long-term outcomes were analyzed.Results:FCSEMS placement was successful in all 18 patients, with technical success rate of 100.0% (18/18). After stenting, the visual analogue scale (VAS) significantly decreased [2.00 (1.75, 3.00) VS 6.00 (5.00, 7.00), Z=-3.572, P<0.001]. The VAS decreased by more than 50% in 15 cases, and the clinical success rate was 83.3% (15/18). Stent-related adverse events included intolerable pain in 3 patients, stented-induced de novo stricture in 2 patients, and distal migration of stent in 2 patients. The stents were successfully removed in all patients after 137.5 (59.0, 417.0) days. There was significant reduction in terms of decreased upstream ductal dilatation after stent removal [9.1 (6.7, 14.1) mm VS 11.0 (7.6, 16.2) mm, Z=10.508, P<0.001]. After stent removal, 10 of the 14 patients maintained the response to pancreatic stenting and 4 recurred during the follow-up of 37-1 246 days. Conclusion:FCSEMS placement appears to be safe and effective in the treatment of benign refractory pancreatic stenosis and can provide persistent improvement in the stricture.

OBJECTIVE: To analyze the results of screening for hereditary tyrosinemia (HT) in newborns and its clinical features and genotype. METHODS: The HT screening was conducted among 2 188 784 newborns from November 2013 to November 2018. The tyrosine (TYR)/ succinylacetone (SA) levels were detected by tandem mass spectrometry (MS-MS). The clinical characteristics, genetic results and following up data of identified patients were analyzed. RESULTS: The normal ranges (0.5%-95.5%) of TYR and SA were 34.5-280.0 μmol/L and 0.16-2.58 μmol/L, respectively. Three HT cases were confirmed with a detection rate of 1∶729 595. There was 1 case of tyrosinemia type Ⅰ (HTⅠ) (homozygous variations of c.455G>A in gene), 1 case of tyrosinemia type Ⅱ(HTⅡ) (heterozygous variations of c.890G>T and c.408+1G>A in gene), and 1 case of tyrosinemia type Ⅲ (HT Ⅲ) (homozygous variations of c.257T>C in gene). The variations of c.890G>T, c.4081G>A of and c.257T>C of were novel. The positive predictive value of the screening was 3.4%. Case 1 (HTⅠ) with TYR and SA values of 666.9 μmol/L and 3.87 μmol/L respectively, presented cholestasis, mild elevated of liver enzyme and lactic acid, who were although fed with TYR and phenylalanine free milk, but died at 2 months of age. Case 2 (HTⅡ) with higher TYR (625.6 μmol/L) and normal SA at screening, received medical milk treatment; during the 7 months of follow-up the baby showed normal score of Bayley assessment and normal TYR without eye and skin symptoms. Case 3 (HT Ⅲ) with TYR of 1035.3 μmol/L and normal SA at screening; during the 29 months of follow-up the value of TYR fluctuated from 532.1 μmol/L to 1060.3 μmol/L due to irregular medical milk treatment, while the score of Bayley assessment was normal. CONCLUSIONS HT is rare in the southern Chinese population, and the gene spectrum is scattered. Early treatment with nitisinone is recommended in children with HTⅠ, otherwise the prognosis is poor; the prognosis of children with HTⅡ is good when early treated with special diet; the prognosis of children with HTⅢ needs to be determined with more data.
Child ; Cyclohexanones ; therapeutic use ; Genotype ; Humans ; Infant ; Infant, Newborn ; Neonatal Screening ; Nitrobenzoates ; therapeutic use ; Tandem Mass Spectrometry ; Tyrosinemias ; diagnosis ; drug therapy ; genetics

OBJECTIVETo screen fatty acid oxidation disorders (FAOD) in newborns in Zhejiang province.

METHODSA total of 1 861 262 newborns were screened for FAOD in Neonatal Screening Center of Zhejiang Province during January 2009 and December 2016. The blood samples from newborns were screened by tandem mass spectrometry, and diagnosis of FAOD was confirmed by urine organic acid measurement combined with genetic analysis. The prognosis and follow-up of patients with FAOD were also evaluated.

RESULTSOf 1 861 262 newborns screened, 121 cases of FAOD were diagnosed. Among 121 cases of FAOD, primary carnitine deficiency (PCD) was the most common type (=78, 64.5%), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD,=27, 22.3%), medium-chain acyl-CoA dehydrogenase deficiency (=5, 4.1%), multiple acyl-CoA dehydrogenase deficiency (MADD,=4, 3.3%), very long-chain acyl-CoA dehydrogenase deficiency (=3, 2.5%), carnitine palmitoyltransferase Ⅰ deficiency(=2, 1.7%)and carnitine palmitoyltransferase Ⅱ deficiency (CPTⅡD,=2, 1.7%). During 2-82 month follow-up, 15 patients were lost, 4 were dead (1 PCD, 1 MADD, and 2 CPTⅡD), and the remaining 102 subjects had normal intelligence and physical development without any clinical symptoms.

CONCLUSIONSPCD and SCADD are the most common FAODs in newborns in Zhejiang province. Most of FAOD patients are asymptomatic, and have normal growth and development after early intervention and management.

OBJECTIVETo analyze the results and follow up data of screening for newborn organic aciduria in Zhejiang province.

METHODSThe results and follow-up data of 1 861 262 newborns from Zhejiang province undergoing screening for organic aciduria during January 2009 and December 2016 were retrospectively analyzed. The acylcarnitine spectrum in urine samples was detected by tandem mass spectrum (MS/MS) and the positive patients were confirmed by urine gas chromatography mass spectrometry and/or gene analysis.

RESULTSNinety two cases of organic aciduria were confirmed with a prevalence of 1:20 200. Among 40 cases of methylmalonic academia (MMA), 13 (32.5%) were of MMA simple type and 27 (67.5%) were combined type. Genetic analysis showed 6 cases of MUT type and 1 case of CblB type out of 7 patients with MMA simple type, 10 cases of CblC and 1 case of CblF out of 11 patients with combined type, respectively. Six patients had propionic academia with a prevalence of 1:310 200, 7 had isovaleric academia (1:265 900), 6 had glutaric academia type 1 (1:310 200), 27 had 3-methylcrotonyl-CoA carboxylase deficiency (MCC, 1:68 900), 1 had 3-hydroxy-3-methylglutaric aciduria (1:1 861 300), 2 had β-ketothiolase deficiency (1:960 600), and 3 had biotinidase deficiency/holocarboxylase synthetase deficiency (1:620 400). Thirty-one patients had a disease onset at neonatal period, and 15 at post-neonatal period. Thirty-three patients had brain involvements or cranial imaging disorders. Three patients with MMA had kidney diseases or heomlytic uremic syndrome, and 3 had myocardial impairments. Twenty patients died during the follow-up.

CONCLUSIONSMMA is the most common newborn organic aciduria in Zhejiang province. Except MCC, most organic aciduria may lead to metabolism decompensation, complications or even death.

OBJECTIVETo analyze the result and follow-up data of screening for newborn amino acid metabolic disorders in Zhejiang province.

METHODSA total of 1 861 262 newborns were screened for amino acid metabolic disorders during January 2009 and December 2016 in Zhejiang province. The screening results and the follow-up data were analyzed retrospectively.

RESULTSOne hundred and sixty four cases were diagnosed as amino acid metabolic disorders with a prevalence of 1:11 349, including 83 with hyperphenylalaninaemia (1:22 400), 29 with neonatal intrahepatic cholestasis caused by citrin deficiency (1:64 138), 16 with methionine S-adenosyltransferase deficiency (1:116 250), 9 with maple syrup urine disease (1:206 667), 8 with argininemia (1:232 500), 7 with citrullinemia type Ⅰ (1:265 700), 6 with hyperprolinemia type Ⅰ (1:310 000), and 2 with carbamylphosphate synthetase Ⅰ deficiency(1:930 000). In addition, ornithine transcarbamylase deficiency, cystathionine β-synthase deficiency, argininosucoinate aciduria and tyrosinemia type Ⅰ were detected in one patient for each, respectively. Two patients had developmental delay, 7 patients were dead, and 2 cases of maple syrup urine disease were lost to follow-up.

CONCLUSIONSHyperphenylalaninaemia is the most common amino acid metabolic disease in newborns in Zhejiang province. Patients with amino acid metabolic disorders identified in newborn screening program can have chance for normal growth development by intervention.

Aim To investigate the protective effect of astragaloside IV (AS-Ⅳ) on human retinal pigment epithelium injury induced by methylglyoxal (MGO), and explore its molecular mechanism.Methods The injury of ARPE-19 cells was induced by MGO and the cell viability was measured by CCK-8 method.The morphology of cell nucleus was analyzed by Hoechst 33342 staining and the cell apoptosis was analyzed by flow cytometry to detect labbled Annexin V-FITC/PI.JC-1 staining and fluorescence probe DCFH-DA were employed to evaluate the change of mitochondrial membrane potential and reactive oxygen species (ROS).The levels of SOD, MDA, caspase-9 and caspase-3 were determined by respective kits.Western blot was used to analyse the expression of Bcl-2, Bax and PARP.Results AS-Ⅳ could significantly inhibit the decrease of cell viability induced by MGO, improve the morphology of cell nucleus, reduce the ARPE-19 cell apoptosis rate and the level of ROS and MDA, and increase the activity of SOD.Furthermore, AS-Ⅳ could enhance mitochondrial membrane potential, the ratio of Bcl-2/Bax and the expression of PARP, and inhibit the activation of caspase-9 and caspase-3.Conclusion AS-Ⅳ may protect ARPE-19 cells from the injury induced by MGO by increasing the antioxidant ability of ARPE-19 cells and inhibiting cell apoptosis.

In recent years, the role of immune cells in hepatitis B virus (HBV)-related liver diseases has attracted more and more attention. This article reviews the roles of regulatory T cells (Treg) and T-helper cell type 17 (Th17) in the development, progression, and prognosis of HBV-related liver diseases, especially HBV-related liver fibrosis and liver failure, as well as hepatocellular carcinoma. It is pointed out that the dynamic changes of Treg and Th17 cells in different stages of HBV infection and their roles in hepatocellular carcinoma need further investigation, and future studies on the regulatory effects of various signaling pathways on Treg or Th17 cells are needed to provide a more precise direction for the treatment of HBV-related diseases.