Objective To investigate the rate of central lines (CLs) placement, the incidence and pathogen distribution of central line-associated bloodstream infection (CLABSI) in 25 neonatal intensive care units (NICU) in China.Methods This study used data from a standardized database initially established for a cluster randomized controlled study "Reduction of Infection in Neonatal Intensive Care Units using the Evidence-based Practice for Improving Quality (REIN-EPIQ)". All preterm infants with gestational age <34 weeks and admitted to 25 tertiary NICUs in China from May 2015 to April 2018 were enrolled in the study. Infants who did not receive active care and discharged against medical advice were excluded.Results A total of 24,884 preterm infants were enrolled. CLs were placed among 9,537 (38.3%) infants and PICC were placed among 7,532 (79.0%) infants. The overall incidence of CLABSI was 2.4/1,000 catheter days. CLABSI-related fatality rate was 6.7%(35/526). The incidence of CLABSI increased with decreasing gestational age. There was a remarkable variation of the incidences of CLABSI among 25 participating NICUs, ranging from 0.0-9.8/1,000 catheter days. The predominant pathogen of CLABSI were gram-negative bacteria (46.2%), followed by gram-positive bacteria (33.9%) and fungi (19.9%).Conclusion CLs were increasingly used in Chinese NICUs with incidence of CLABSI varying significantly among different NICUs. Gram-negative bacteria were the predominant pathogen causing CLABSI and the proportion of CLABSI caused by fungi was alarming high. Targeted quality improvement projects are needed to reduce the site variation and fungi infection.
Objective To explore the value of tandem mass spectrometry (MS/MS) and targeted next-generation sequencing (NGS) for the prevention and intervention of neonatal birth defects, we examined the incidence and spectrum of genomic disorders in newborns in Qinghai using MS/MS and NGS.Methods Dried blood spots were collected to determine amino acids and acylcarnitines by MS/MS (including 20 kinds of amino acid metabolic diseases, 12 kinds of fatty acid metabolic diseases and 17 kinds of organic acid metabolic diseases) conducted in neonates from Qinghai, which were recruited between January 8 and October 12 in 2018. Among them neonates with abnormal tandem mass spectrometry screening results,special facial features and structural abnormalities, and their mothers with bad obstetric history were screened by high throughput sequencing (NGS, including 2,742 known pathogenic genes). The positive samples were verified by sanger sequencing.Results Four thousand and sixteen newborns in Qinghai were enrolled in this project, including 2,125 male cases (51.6%). The total group consisted of 58.1% Han people, 18.8% Tibetans and 16.4% Hui people, with 59 MS/MS screening positive (1.47%), including 5 cases indicating IMD and 54 of secondary changes. Three cases of IMD (0.074%) were further diagnosed by NGS analysis. The observed abnormalities comprised 2 of amino acid metabolic diseases (PKU 2 cases) and 1 fatty acid metabolism disease (PCD), with an overall IMD incidence of 1 in 1,339. Eight cases with genetic variation (including 3 cases of IMD) and 6 cases with copy number variation were identified by NGS. Additionally, differences were observed between Han, Tibetan and Hui populations on the concentration levels of amino acids and acylcarnitines.Conclusion The incidence of IMD in newborns in Qinghai is higher than that in other areas reported in China. Our results suggest that NGS can not only confirm the suspicious but uncertain results indicated by MS/MS, but also effectively detect risk and carrier status for a wide range of neonatal birth defects that are not detectable by MS/MS.
Objective To analyze the differential item functioning (DIF) of Fine Motor Function Measure (FMFM) between hemiplegic and non-hemiplegic cerebral palsy.Methods Data of children with cerebral palsy diagnosed by Rehabilitation Center of Children's Hospital of Fudan University and Children Rehabilitation Collaboration Network of Children's Hospital from 2001 to 2018 were collected and assessed by FMFM as well. The contralateral data of hemiplegic children were extracted from FMFM evaluation data, and 30% samples were randomly selected as focus group samples of DIF. According to the proportion of non-hemiplegic type and hemiplegic type in the whole sample, randomized stratified matching was used to match the control group sample. Conquest software was used to make Rasch analysis of the two groups of merged data samples and all 56 items in B to E area of FMFM, and single-handed items and double-handed items were separated by analysis item functioning. The single dimensionality of the scale was determined by the mean square of cohesive fit (Infit), the standard was MnSq 0.6-1.4, and differential item functioning of all 56 items and both single and double-handed items were analyzed.Results Tetally 3,442 times of FMFM assessments of 1,556 children with cerebral palsy were taken as whole samples and data. One hundred and ninety-eight FMFM assessments of focus group and 792 FMFM assessments of control group were included in this study. Single sample pairing test showed that there was no significant difference in FMFM scores between the two groups [112 (96, 146) vs 113 (95, 145)]. After three turns of item functioning analysis, 30 were classified as single-handed items and 26 as double-handed items. The absolute value >0.5 of the difference between the numerical of difficulty scale pair of total 56 items is 41. The absolute value >0.5 of the difference between the numerical of difficulty scale pair of 30 single-handed and 26 double-handed items are 23 (76.7%) and 9 (34.6%) respectively.Conclusion There exists DIF between hemiplegic and non-hemiplegic cerebral palsy in all 56 items of FMFM scale, especially in single-handed items. In order to accurately evaluate the fine motor function of hemiplegic children, it is necessary to re-establish the evaluation criteria and procedures.
Objective To establish age- and gender-specific reference intervals for 8 common liver function tests in healthy children aged 3 months to 18 years in Chongqing by dry chemical method.Methods Healthy children aged 3 months to 18 year were selected and divided into 3 months to 1 years, -3 years, -6 years, -12 years and -18 years old groups according to the rule of growth and development. Serum TB, TP, ALB, ALT, AST, ALP, GGT and LDH were detected by the VITROS 5600 system. Differences in test results of different ages and genders were compared and the reference intervals were calculated using nonparametric methods.Results During the study period, 3,758 healthy children aged 3 months to 18 years met the inclusion and exclusion criteri; 35 unqualified specimens were excluded, and 3,723 eligible specimens were included in the analysis. There were 241 children in the 3 months to 1 year, 251 in the -3 years, 939 in the -6 years old, 1,672 in the -12 years old, and 620 in the -18 years old. ① TP in early childhood, TP and AST in the preschool, TB, ALT, AST, GGT and LDH in the school age, and TB, ALB, ALT, AST, ALP, GGT and LDH in the adolescence were statistically significant between boys and girls (P<0.05), and in the adolescence boys were significantly higher than in those girls. ② ALT, AST and LDH results were negatively correlated with age, and TB, TP, ALB, ALP and GGT were positively correlated with age. ③ The reference intervals of serum TB(μmol·L-1): 3 months to 1 year 1.0-11.0,1-18 years 1.0-11.0; reference intervals of TP (g·L-1): 3 months to 3 years 60.2-74.2, -6 years 61.3-78.2, -12 years 62.8-81.5, -18 years 64.9-82.4; reference intervals of ALB (g·L-1): 3 months to 18 years 38.4-49.5; reference intervals of ALT (U·L-1): 3 months to 1 year 15.8-48.4,1-12 years 14.0-42.2, -18 years 14.7-45.7 (male), 12.5-44.8 (female); reference intervals of AST (U·L-1): 3 months to 1 year 23.9-54.3, -3 years 26.4-50.6,-6 years 22.8-45.8, -12 years 18.9-41.2, -18 years 15.7-36.8 (male), 14.2-33.7 (female); reference intervals of ALP (U·L-1): 3 months to 12 years 130.0-318.5, -18 years 124.2-416.1 (male), 79.9-320.3 (female); reference intervals of GGT (U·L-1): 3 months to 1 year 10.0-30.0,1-12 years 9.3-21.3, -18 years 9.6-28.7 (male), 9.5-26.2 (female); reference intervals of LDH (g·L-1): 3 months to 3 years 165.9-266.0, -6 years 155.3-256.2, -12 years 142.9-240.9, -18 years 134.3-225.3 (male), 111.3-207.0 (female).Conclusion There are differences in liver function levels among healthy children aged 3 months to 18 years in Chongqing. The age- and gender-specific pediatric reference intervals are important for the diagnosis and treatment of related diseases.
Objective To explore the WT1 mutation-induced nephrotic syndrome (NS), proteinuria or Wilms tumor in children and its long-term renal prognosis.Methods We analyzed the clinical features in patients with NS, proteinuria or Wilms tumor since from January 2001 to December 2018 in our medical center. Patients were divided by genotypes or divided into two subgroups of early detection and late detection of WT1.Results Twelve different mutations were detected in 22 patients, which all located between exon 8 and exon 9, including diagnosis of Denys-Drash syndrome (10 cases), Fraiser syndrome (3 cases) and isolated NS (9 cases). Five cases presented with pseudohermaphroditism. During follow up, 15 cases progressed into end stage renal disease (ESRD) and 5 cases into CKD 2-4 stage. Patients in early detection group had a significant longer duration of ESRD progression compared with the patients in late detection group by Kaplan-Meier survival analysis (P=0.011).Conclusion Detection of WT1 mutations should be performed in children with Wilms tumor, proteinuria/NS or chronic kidney disease. Early detection of WT1 mutations before developing into ESRD could help to delay the ESRD progression.
Objective To summarise the clinical characteristics, pathology,treatment and prognosis of blastic plasmacytoid dendritic cell neoplasm(BPDCN) in children.Methods We retrospectively analysed the olinical data of 5 children with BPDCN admitted to Peking University People's Hospital from 2014 to 2018 and analyzed the follow-up statistics.The median follow-up time was 37months.Results The sex ratio is 2∶3 and 5 children manifested with cutaneous involvement at presentation. All patients confined organs including skin,others including spleen and/or liver,lymph nodes,vertebrae, peripheral blood and no central nervous system was confined. All patients confirmed by the skin or bone marrow pathology and they all expressed CD4, CD56, CD123. All children had no specific gene expression, 1 case had chromosomal abnormalities. Induction chemotherapy was performed with ALL or NHL regimen and AML regimen was not selected. All patients got remission after induction chemotherapy.All of them were followed by Allo-HSCT with 4 patients having long-term survival and 1 in treatment- related death. All patients have no disease-related death.Conclusion Children with BPDCN are less invasive than adults, and sensitive to chemotherapy.The prognosis is better for Allo-HSCT.
Objective To investigate the association of maternal age and adverse neonatal outcomes in singleton pregnancies.Methods A retrospective cohort study was conducted to obtain the sociodemographic data, maternal history and pregnancy status of pregnant women in our hospital Obstetrics and Gyncology Hospital of Fudan University from January 2006 to December 2018 by reviewing obstetric and neonatal information. According to maternal age, the pregnant women were divided into three groups of low age group(<20 years old), appropriate age group (20-34 years old) and advanced age group (35 years of age or older). We analyzed the baseline maternal characteristics in all maternal age groups, prevalence of pregnancy outcomes in relation to the maternal age groups and the incidence of adverse neonatal outcomes. We analyzed the comparisons between groups using χ2 or Fisher exact test. The association between each maternal age group and each adverse outcome was analyzed by a multivariate logistic regression model. At the same time, a subgroup analysis of maternal age was performed. The mothers aged 20-34 years as the reference group and the odds ratio (crude OR) and adjusted odds ratio (adjusted OR) and 95% confidence intervals (95%CI) were used to indicate the risk of neonatal adverse outcomes associated with subgroups.Results In recent years, the proportion of advanced maternal age in total pregnancy women has increased. From 2006 to 2014, the proportion of advanced age group in total pregnancy women 6.9%-9.9%, and the proportion of advanced age group in 2015, 2016, 2017 and 2018 was 13.1%, 13.8%, 17.6% and 19.6%, respectively. There were significant differences in the proportion of floating population, parturients and cesarean section between the low age group and the appropriate age group, the advanced age group and the appropriate age group as well (P all < 0.001). The non-cephalic birth type, abverse pregnancy history and the proportion of male newborns in advanced age group were higher than those in the appropriate age group (P < 0.05). After adjusting a variety of factors, the incidence of premature infants in low age group and advanced age group was 1.88 times (95%CI:1.34-2.65) and 1.31 times (95%CI:1.21-1.42) higher than that in the appropriate age group, respectively. The incidence of mid-term premature infants in the low age group and the advanced age group was 2.83 times (95%CI:1.45-5.54) and 1.34 times (95%CI:1.13-1.60) higher than that in the appropriate age group, respectively. The incidence of late premature infants in the low age group and the advanced age group was 1.75 times (95%CI:1.22-2.51) and 1.27 times (95%CI:1.17-1.36) higher than that in the appropriate age group, respectively. The incidence of low birth weight infants in the low age group and the advanced age group was 2.35 times (95%CI:1.66-3.33) and 1.26 times (95%CI:1.16-1.37) higher than that in the appropriate age group, respectively. The incidence of birth defects in the advanced age group was 1.39 times higher than that in the appropriate age group (95%CI:1.20-1.62).Conclusion The risk of preterm, moderate preterm, late preterm infants, low birth weight in both the low age group and the advanced age group were significantly higher than women aged 20-34 years, respectively. The management of floating population should be strengthened and prenatal examination should be carried out regularly. For the advanced age group, we should prevent the occurrence of birth defects, actively deal with complications during pregnancy, strengthen monitoring in the middle and late pregnancy, and prevent perinatal infection. The results of this study can contribute to the prenatal counseling and management of pregnant women of different gestational ages.
Objective To analyze the clinical characteristics, genotype (epimutation), and the correlation between phenotype and genotype of children with Russel Silver syndrome (RSS) diagnosed by methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) to improve the understanding of the disease.Methods RSS patients were enrolled from the Molecular Medicine Center of Children's Hospital of Fudan University from January 2015 to June 2019. MS-MLPA was used for the detection of 11p15 methylation level and copy number variations, and GeneMarker software was used to analyze the experimental data. The correlationship between the phenotype and genotype of RSS was analyzed using Fisher exact test.Results Nineteen RSS patients were diagnosed by MS-MLPA, including 8 females and 11 males, with a median age of 3.3 years (3 months to 10 years). The presence of small for gestational age (SGA) was identified in 18 cases. The height and weight of 18 children were lower than P3 and P10 of the same age, respectively. The common craniofacial features include frontal bossing (9 cases), triangular face (7 cases), body asymmetry (6 cases), short or curved fingers (6 cases) and micrognathia (5 cases). Patients also presented with hypertelorism, low-set ears, high palate, irregular teeth, thoracic deformity, scoliosis and atrial septal defect. There were 3 cases with 11p15 duplication and hypomethylation of H19 differentially methylated region (DMR), while the remaining 16 cases all showed H19-DMR hypomethylation without CNV abnormality.Conclusion MS-MLPA can provide the basis for accurate diagnosis of RSS and thus be helpful for appropriate treatment and family genetic counseling.
Objective To discuss the clinical features,diagnosis, treatment and prognosis of hemophilia A in neonates.Methods The clinical records of 11 neonates with hemophilia A who were referred to Children's Hospital of Fudan University from February 2016 to June 2019 were reviewed retrospectively.Results All 11 cases of neonatal hemophilia A were males, and only 3 cases had hemophilia family history. There was no bleeding in 2 cases, only skin ecchymosis in 2 cases, and bleeding in other 7 cases. The bleeding sites included subdural, intracranial, subcutaneous areas and digestive tracts. All patients had prolonged activated partial thromboplastin time(APTT) and deficiency of factor Ⅷ,including 9 intermediate cases, 1 severe case and 1 mild case. FⅧ gene mutation was confirmed in 5 cases, including deletion in 2 cases and point mutation in 3 cases. After diagnosis, they were treated with factor Ⅷ infusion. Up to June 2019, 1 case has lost follow-up; 4 cases have had no bleeding; only 1 case has had spontaneous hemorrhage of ankle joint, and the remaining cases have showed skin bruise/subcutaneous hematoma after trauma.Conclusion For multiple abnormal of coagulation function especially APTT prolonged three times in neonatal period, with or without hemophilia, the possibility of hemophilia should be considered. It is supposed to complete the determination of coagulation factor activity level and gene detection should be completed as soon as possible to make a definite diagnosis, and early diagnosis and prophylactic infusion of coagulation factors can improve the prognosis.
Objective To search for characteristic markers for neonatal screening in FGFR2-related diseases by applying a corpus callosum morphological evaluation model.Methods The morphological modeling included 2D thickness measurements of each part and computer-aided analysis of 3D virtural corpus callosum.Results Six neonates with FGFR2 gene pathogenic mutation or suspected pathogenic mutation in neonatal genome project were enrolled and all of them had different degrees of special facial features and abnormal cranial morphology. Four of them underwent corpus callosum morphological evaluation, of whom 3 were diagnosed as abnormal by MRI and cranial ultrasonography and 1 of them undergoing only cranial ultrasonography was also diagnosed as abnormal.Conclusion The application of corpus callosum morphologic evaluation in FGFR2-related diseases is expected to identify the potential marker phenotype which could be used in perinatal screening.
Objective To investigate the clinical observations, laboratory tests and genetic characteristics of glucose/galactose malabsorption caused by mutations in SLC5A1 gene.Methods The clinical and genetic features of two glucose/galactose malabsorption children that carried compound heterozygous mutations in SLC5A1 gene were reported, and the related literature from domestic and international databases were reviewed.Results Two patients (one boy and one girl), were referred to the hospital for further evaluation of neonatal onset of watery diarrhea and severe dehydration. The stool was yellow and watery-like and 7-10 times a day. The diarrhea persisted even with lactose-free formula and amino acid-based formula, but ceased when fasted. Whole-exome sequencing revealed compound heterozygous mutations in both patients, indicating a diagnosis of glucose/galactose malabsorption. Patient 1 carried c.325dupG and c.1107_1109delAGT mutations, while patient 2 and her brother with similar symptoms harboured c.781G>A and c.1298T>C mutations. Searching on PubMed, CNKI and Wanfang databases, 18 reports have been discovered to give both the clinical and genetic features, and 74 cases of glucose/galactose malabsorption have been reported, including the two cases in our report. All the patients were recorded with diarrhea of different severity and 89.2% (66/74) with dehydration. The diarrhea has been significantly improved in all patients after the introduction of a fructose-based formula or a carbohydrate-free formula. We examined possible differences in sex, age of onset and the presence of signs and symptoms with mutation type(missence versus other types of mutations). No specific genotype-phenotype correlation could be established.Conclusion For neonates manifested as watery stools and dehydration, glucose/galactose malabsorption should be taken into consideration. Genetic test can help to get an early and accurate diagnosis.
Objective To summarize the clinical features and the characteristics of a mutation in ZMPSTE24 gene in a stillborn fetus with restrictive dermopathy (RD), and to provide evidence for prenatal counseling.Methods We analyzed the clinical and genetic data of the stillborn fetus with RD. According to HGMD and PubMed,literature on clinical symptoms of the diseases caused by ZMPSTE24 mutation was reviewed.Results The neonate panel sequencing combined Sanger sequencing in proband and parents confirmed a homozygous frameshift mutation in ZMPSTE24 gene (c.1085dupT,p.Leu362PhefsTer19), which has been reported as a disease-causing mutation of RD and the hotspot mutation with high frequency up to 57.14%. Searching from HGMD and PubMed with "ZMPSTE24", and 32 disease-causing mutations were found to be related to 4 types of diseases. Up to July 2019, a total of 63 cases that caused by ZMPSTE24 mutations were retrieved in PubMed while there is no domestic report in Wanfang and CNKI database. The 49 cases of RD were summarized in this article. The severity of diseases caused by the mutation in ZMPSTE24 gene has a high correlation with the activity of zinc metalloprotease and the accumulation of prelamin A.Conclusion Leu362PhefsTer19 detected in this stillborn neonate is a hotspot mutation in ZMPSTE24 gene. The genotype of ZMPSTE24 gene is closely related to the phenotype. This article suggests that abnormal fetal development may consider the possibility of RD. The genetic test provides the basis not only for accurate diagnosis of RD but also for the appropriate intervention and family genetic counseling.
Objective To screen disease-specific mutations in the coding region of TGFBR3 gene in congenital heart disease (CHD) and to study the biological functions of the mutations.Methods The study subjects were from Chinese Han population of Shandong province, composed of 404 sporadic CHD samples collected from CHD patients diagnosed during the period from Aug.2008 to Jan.2011. A total of 213 control samples were collected from healthy children without CHD or familial heart diseases in the same hospital during the same time period. The genomic DNAs were extracted from the peripheral blood of CHD and control samples and the target sequencing for the exons of TGFBR3 of the patients and controls was performed. Bioinformatics methods were used to screen case-specific new missense mutations or rare missense mutations, which were further verified by Sanger Sequencing. Wild-type and mutant TGFBR3 expression vectors were constructed and were then transfected into HEK293T cells for evaluating TGFBR3 protein levels by Western Blot and the effects of the mutants on TGF-β signaling pathway by luciferase reporter assay.Results Three disease-specific heterozygous mutations were identified from three different CHD patients separately, TGFBR3K685R is a newly discovered mutation, while TGFBR3A791V and TGFBR3A804S were rare mutations and were predicted to be deleterious mutations by SIFT and PolyPhen-2 software. The protein levels of TGFBR3K685R and TGFBR3A804S mutants were significant lower than that of wild type TGFBR3 and all three mutations significantly impaired their function to inhibit TGF-β signaling.Conclusion Mutations TGFBR3K685R, TGFBR3A791V and TGFBR3A804S may participate in the development of congenital heart disease by reducing their inhibition of TGF-β signaling.
