Newborn screening for ornithine transcarbamylase deficiency in Zhejiang Province and the follow-up analysis / 中华实用儿科临床杂志

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.

Analysis of clinical features, biochemical indices and genetic variants among children with Short/branched-chain acyl-CoA dehydrogenase deficiency detected by neonatal screening / 中华医学遗传学杂志

OBJECTIVE@#To investigate the clinical manifestations, biochemical abnormalities and pathogenic variants among children with Short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency detected by neonatal screening.@*METHODS@#A total of 2 730 852 newborns were screened from January 2016 to December 2021 with liquid chromatography tandem mass spectrometry. Suspected SBCAD deficiency patients were diagnosed by urine organic acid analysis and high-throughput gene sequencing analysis. The clinical, biochemical and genetic changes of the confirmed cases were analyzed, in addition with guidance for diet and life management, L-carnitine supplement, and survey of growth and intellectual development.@*RESULTS@#Twelve cases of SBCAD deficiency were diagnosed, which yielded a prevalence of 1/227 571. The lsovaleryl carnitine (C5) of primary screening blood samples was between 0.6 and 2.1 µmol/L, all exceeded the normal range. C5/acety1 carnitine (C2) was between 0.02 and 0.12, with 6 cases exceeding the normal range. C5/propionyl carnitine (C3) was between 0.1 and 1.16, with 5 cases exceeding the normal range. Free carnitine (C0) was between 18.89 and 58.12 µmol, with 1 case exceeding the normal range. Three neonates with abnormal screening results were recommended to have appropriate restriction for protein intake and two were given L-carnitine. During follow-up, their C5 has ranged from 0.22 to 2.32 µmol/L, C5/C2 has ranged from 0.01 to 0.31, C5/C3 has ranged from 0.14 to 1.7. C5 or C5/C2 and C5/C3 were transiently normal in all patients except for case 8 during the neonatal screening and follow-up. C0 was 17.42 ∼ 76.83 µmol/L Urine organic acid analysis was carried out in 9 of the 12 cases, and 2-methylbutyroglycine was elevated in 8 cases. Urine organic acid analysis was carried out in 9 cases, and 2-methylbutyrylglycine was increased in 8 cases. Genetic analysis was carried out for 11 children, and in total 6 ACADSB gene variants were identified, which included 4 missense variants (c.655G>A, c.923G>A, c.461G>A, c.1165A>G), 1 frameshift variant (c.746del) and 1 nonsense variant (c.275C>G). Among these, the C.461G>A variant was unreported previously. The most common variants were c.1165A>G (40.9%) and C.275C>G (22.7%). The patients were followed up for 18 days to 55 months. Only one patient had mental retardation, with the remainders having normal physical and mental development.@*CONCLUSION@#SBCAD deficiency is a rare disease. The detection rate of newborn screening in this study was 1/227 571. Early intervention can be attained in most asymptomatic patients through neonatal screening. In this study, the common gene variants are c.1165A>G and c.275C>G.

ATAD3A gene variations in a family with Harel-Yoon syndrome / 浙江大学学报·医学版

An 11-day-old female neonate was admitted for cough with mouth foaming and feeding difficulties. The laboratory results indicated hyperlactatemia, elevated markers of myocardial injury and inflammation, and high levels of acylcarnitine octanoylcarnitine and decanoylcarnitine in tandem mass spectrometry. Ultrasonography and MRI suggested cardiac insufficiency and hypertrophic cardiomyopathy. Whole exome sequencing showed that both the proband and her elderly sister had a compound heterozygous variant of c.1492dup (p.T498Nfs*13) and c.1376T>C (p.F459S) in the ATAD3A gene, inherited from their father and mother, respectively. The diagnosis of Harel-Yoon syndrome was confirmed. The proband and her sister were born with clinical manifestations of metabolic acidosis, hyperlactatemia, feeding difficulties, elevated markers of myocardial injury as well as cardiac insufficiency, and both died in early infancy.

Results of neonatal screening for congenital hypothyroidism and hyperphenylalaninemia in Zhejiang province from 1999 to 2022 / 浙江大学学报·医学版

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.

Preliminary study of glyceryl phenylbutyrate therapy for Ornithine transcarbamylase deficiency and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To evaluate the efficacy and safety of glyceryl phenylbutyrate (GPB) therapy for patients with Ornithine transcarbamylase deficiency (OTCD).@*METHODS@#Two children with OTCD were selected as the study subjects, and their clinical manifestations, blood ammonia, liver enzymes, growth and development information following the treatment with GPB were retrospectively analyzed. A literature review was also carried out by searching the PubMed database for studies on the GPB treatment for urea cycle disorders.@*RESULTS@#With the GPB treatment, the blood ammonia and liver enzyme level in both patients have decreased to the normal range within 3 months. Motor development in child 2 has improved. No adverse reaction was noted, except for transient palmar greasy smell and loss of appetite in child 1. Analysis of the literature showed that patients had lower ammonia exposure, lower annual incidence of hyperammonemic crisis, more actual protein intake and fewer adverse events during GPB treatment.@*CONCLUSION@#GPB is safe and effective for the treatment of OTCD.

Research progress on clinical quality disparity and effects for quality improvement in patients with acute coronary syndromes / 上海预防医学

The United Nations Sustainable Development Goal proposes to achieve universal health coverage by 2030， and the key element is that everyone can enjoy high-quality healthcare services. Cardiovascular diseases， predominantly acute coronary syndromes， have become the largest disease burden on global health. However， the quality of healthcare services for acute coronary syndromes varies significantly across the populations and regions. This study aimed to investigate the difference in the quality of acute coronary syndrome services in multiple countries， regions， hospitals， and patient populations， and then determine the impact of quality improvement initiatives on quality disparity， which may facilitate further improving the equity of clinical service quality for acute coronary syndromes and promoting health equity and universal health coverage.

Effects of chemical labyrinthectomy on stress analgesia induced by rotation in mice / 药学实践杂志

Objective To investigate the role of vestibular organs on stress analgesia induced by rotation in mice. Methods Female mice were randomly divided into morphine group and rotation group. After 15 minutes of intraperitoneal injection of naloxone or normal saline, the hot plate latency of mice in each group was observed following morphine injection or rotation (250 r/min, 15 s on with 5 s off). After subcutaneous injecting morphine for 7 consecutive days, tolerance was formed and the hot plate latency in morphine-tolerant mice after rotation was observed. P-aminophenylarsonic acid was injected into the inner ear to damage the vestibular organs of the mice and the hot plate latency was observed in chemically labyrinthectomy mice. Results Compared with the normal saline group, the hot plate latency of mice in the naloxone group did not change significantly after rotation (P>0.05), and the hot plate latency decreased significantly after subcutaneous injection of morphine (P<0.05). The morphine-tolerant mice had no significant change in the hot plate latency after rotation compared with the normal saline group (P>0.05). After injection of p-aminophenylarsonic acid into the inner ear, the recovery time of the righting reflex in mice was significantly increased, and the swimming ability was significantly reduced (P<0.05), and the hot plate latency of mice with chemical labyrinthectomy was significantly shortened after rotation (P<0.05). Conclusion Chemical labyrinthectomy completely blocked the rotation-induced stress analgesia in mice. Vestibular organs play an important role in rotation-induced stress analgesia, and this stress analgesia may be mediated by a non-opioid system.

Influences of follow-up methods on rehabilitation and compliance of patients with severe scar after burns / 中华烧伤杂志

Objective@#To observe the influences of different follow-up methods on rehabilitation and compliance of patients with severe scar after burns.@*Methods@#From January 2012 to May 2016, medical records of 116 patients with severe scar after burns who were admitted to our unit, discharged after wound healing and conforming to the criteria, were retrospectively analyzed. They were divided into face-to-face follow-up group [n=59, 45 males and 14 females, aged (36±9) years] and routine follow-up group [n=57, 44 males and 13 females, aged (35±9) years] based on different follow-up methods they received. On the day of discharge and in post discharge month (PDM) 1, 3, and 6, the Vancouver Scar Scale (VSS) was used to evaluate the hypertrophic scar in joints, Activities of Daily Living (ADL) scale was used to evaluate the disability of patients in the 2 groups. In PDM 1, 3, and 6, Medical Compliance Behavior Questionnaire was used to investigate the medical compliance behaviors of patients in the 2 groups. Data were processed with chi-square test, t test with Bonferroni correction, and analysis of variance for repeated measurement.@*Results@#(1) The VSS score of patients in face-to-face follow-up group on the day of discharge was (11.1±0.7) points, which was close to (11.7±0.7) points of routine follow-up group (t=2.021, P>0.05). The VSS scores of patients in face-to-face follow-up group in PDM 1, 3, and 6 were (10.5±0.6), (8.6±0.7), and (4.7±0.5) points, which were significantly lower than (11.4±0.7), (10.9±1.0), and (9.4±0.8) points of routine follow-up group respectively (t=2.034, 2.033, 2.042, P<0.05 or P<0.01). (2) The ADL score of patients in face-to-face follow-up group on the day of discharge was close to that of routine follow-up group (t=1.781, P>0.05). The ADL scores of patients in face-to-face follow-up group in PDM 1, 3, and 6 were higher than those of routine follow-up group respectively (t=9.683, 8.584, 9.772, P<0.01). (3) The compliance rates of consisted rehabilitation, reasonable diet, and timing consultation of patients in face-to-face follow-up group were better than those of routine follow-up group respectively (χ2=19.015, 13.251, 8.652, P<0.01).@*Conclusions@#Compared with routine follow-up by phone, face-to-face follow-up can do better in evaluating the scar condition and ADL of patients with severe scar after burns, and improve the medical compliance rates of patients, which is worthy of clinical promotion.

The impact of separating drug sales from medical services reform on mechanism of controlling outpatient and emergency expenses in Beijing / 中国卫生政策研究

Objective:To evaluate the impact and analyze the mechanism of separating drug sales from medical services reform on the total medical expenditure containment of outpatient services in Beijing. Methods:The monitoring data and historical data from 89 third-level,78 second-level public hospitals,and 206 primary health institutions and community health service agencies,which participated in the reform,were analysed to estimate the impacts on outpa-tient service utilization and service price. The analysis was based on the data of the first and second quarters of 2016 outpatient and emergency department fee changes,and analysis of service utilization and service price factors on the im-pact of changes in outpatient and emergency services mechanism. Results:The total outpatients'expenditure in Beijing in the second quarter of 2017 was 17.38 billion yuan,representing a slight decrease of 1.14% than the expenditure in 2016. The growth rate reduced by 2.46%. Expenditure in third-level and second-level hospitals decreased by 2.82% and 3.02%,respectively,with reductions in growth rates of 4.06% and 3.74% respectively. Expenditure in primary institutions increased by 17.09%. The increase rate in the second quarter of 2017 was 26.28%,representing a remark-able increase compared to the rate in 2016(15.84%). The contribution from the medical institution service prices and service utilization to the change of outpatient and emergency medical expenditure containment was 6.98% and -7. 65%,respectively. For third-level hospitals,the contribution was 10.37% and -12.00%,respectively;second-level hospitals were 0.72% and -3.35%,respectively;and the primary health institutions was 6.08% and 9.57%. Con-clusions:Beijing's comprehensive reform of separating drug sales from medical services reform has effectively controlled the rising medical expenditure of outpatient services,mainly by adjusting outpatients service utilization between differ-ent level healthcare institutions.

Experimental study on physical dependence of total Ervatamia yunnansis alkaloid / 药学实践杂志

Objective To evaluate the physical dependence of total Ervatamia yunnansis alkaloid .Methods The physi-cal dependence of total Ervatamia yunnansis alkaloid was observed by jump test in mice and spontaneous withdrawal test in rats .Results In the jump test ,after injecting total Ervatamia yunnansis alkaloid (total dosage of 140 and 430 mg/kg) for 7 days continuously ,the mice didn't show any withdrawal symptom and the loss of body weight .In the spontaneous withdrawal test ,two dosages of total Ervatamia yunnansis alkaloid (total dosage of 210 and 775 mg/kg) were continuously given for 30 days .The withdrawal response and the loss of body weight were not found in rats after drug withdrawal .Conclusion Total Ervatamia yunnansis alkaloid showed no obvious withdrawal symptoms in mice and rats ,which suggests that it has no physical dependence .

Advances in measles virus for cancer therapy / 浙江大学学报·医学版

Oncolytic virotherapy is a novel cancer therapy. Vaccine-attenuated strains of measles virus(MV)is an ideal candidate for oncolytic virotherapy which has an excellent safety record. Vaccine-attenuated MV uses CD46 and Nectin-4 molecule as major entry receptors into cells. Vaccine-attenuated MV can selectively infect and kill a wide variety of cancer cells in vitro and in vivo. With the development of molecular cloning, scientists have successfully rescued cDNA of vaccine-attenuated MV and increased its oncolytic efficiency with molecular engineering techniques. Phase I clinical trials of virotherapy for ovarian cancer and multiple myeloma with vaccine-attenuated MV are underway. The preliminary results indicate the promising antitumor potential of vaccine-attenuated MV.