High-risk Growth Trajectory Related to Childhood Overweight/Obesity and Its Predictive Model at Birth.

CONTEXT: Childhood obesity increases the risk of chronic disease in adulthood. OBJECTIVE: To construct an early predictive model for a growth trajectory that is highly related to childhood overweight/obesity. DESIGN: Prospective cohort study. SETTINGS: Shanghai Birth Cohort (SBC) and US Collaborative Perinatal Project (CPP). PARTICIPANTS: A total of 848 mother-child pairs in the SBC (2013-2016) and 22 691 pairs in the CPP (1959-1965) with 2- and 7-year follow-up, respectively. MAIN OUTCOME MEASURES: A high-risk postnatal growth trajectory intimately associated with childhood overweight/obesity and its predictive model. RESULTS: We demonstrated that the shifts of postnatal body mass index (BMI) percentile had been completed around 1 year of age and identified a high-risk growth trajectory that was closely related to overweight/obesity [odds ratio 6.5 (95% CI 5.9, 7.2)] at 7 years old. Children with this trajectory presented with a consistent BMI around the 85th percentile after the age of 1 year. It could be recognized early after birth using a predictive model with 4 metabolites (tyrosine, glycine, octenoylcarnitine, and stearoylcarnitine), combined with sex, birth weight, and maternal prepregnancy BMI. The model had an area under the receiver operating characteristic curve of 0.869 (95% CI 0.779, 0.932), a sensitivity of 83.3% (95% CI 51.6%, 97.9%), and a specificity of 81.1% (95% CI 70.3%, 89.3%) in the validation data set. CONCLUSION: Children with postnatal high-risk growth trajectories were significantly associated with subsequent overweight/obesity at 7 years old. Metabolite profiles at birth combined with clinical measures were able to predict at-risk children before overweight/obesity occurrence.

Antibiotic resistance in neonates in China 2012-2019: A multicenter study.

BACKGROUND: To investigate antibiotic resistance of pathogens responsible for neonatal invasive bacterial infections (IBIs) in China. METHODS: Cross-sectional study of neonates with IBI evaluated in nine hospitals in China (January 2012-August 2019). Antibiotic resistance patterns of pathogens responsible for neonatal IBIs were analyzed. RESULTS: Of 3770 full-term neonates who were subjected to lumbar puncture and a blood culture, IBIs were diagnosed in 460 neonates (12.2%). Escherichia coli and Group B Streptococcus (GBS) were the leading pathogens, followed by Enterococcus spp, and Staphylococcus aureus. E. coli expressed high resistance to ampicillin (72.0%) and third-generation cephalosporins (cefotaxime, 34.8%; ceftriaxone, 38.1%). The prevalence of extended spectrum beta-lactamase (ESBL)-producing E. coli was 34.1%. The proportions of E. spp resistant to penicillin and ampicillin were 60% and 54.1%. All S. aureus showed resistance to ampicillin and penicillin. The resistance rate of S. aureus to methicillin was 50%. Although all GBS were susceptible to penicillin and ampicillin, the proportions of GBS resistant to erythromycin and clindamycin were 75.9% and 77.3%. Antibiotic susceptibility appeared to improve in 2019. Susceptibility of E. coli to ampicillin, cefotaxime, and ceftriaxone improved to 42.9%, 76.9%, and 71.4% in 2019, compared with 12.5%, 37.5%, and 50% in 2012. The prevalence of ESBL-producing E. coli declined to 20% in 2019, lower than 100% in 2012. Susceptibility of GBS to erythromycin and clindamycin improved from 0% in 2012 to 28.6% and 25% in 2019. CONCLUSIONS: The prevalence of antibiotic resistance is high in neonates in China, although there is a favorable declining trend in recent years.

[Efficacy and safety of lactase additive in preterm infants with lactose intolerance: a prospective randomized controlled trial].

OBJECTIVE: To study the efficacy and safety of lactase additive in improving lactose intolerance in preterm infants. METHODS: A total of 60 preterm infants with lactose intolerance who were admitted to the Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2018 to December 2019 were randomly divided into a lactase treatment group and a control group, with 30 infants in each group. The infants in the lactase treatment group were given 4 drops of lactase additive (180 mg) added into preterm formula or breast milk, and those in the control group were given placebo, oral administration of probiotics (live combined Bifidobacterium, Lactobacillus and Enterococcus powder) at half an hour after feeding (1 g each time, twice a day), and clockwise abdominal massage around the belly button at 1 hour after feeding for 15 minutes each time, 3 times a day. Fecal pH, fecal reducing sugar, growth indicators, symptoms of lactose intolerance, and laboratory markers were measured at the end of the first and second weeks after intervention. RESULTS: Finally 29 infants in the lactase treatment group and 26 infants in the control group completed the trial. At the end of the first week after intervention, compared with the control group, the lactase treatment group had significantly lower frequency of daily milk vomiting and gastric retention amount (P < 0.05) and a significantly higher proportion of infants with fecal pH > 5.0 (P < 0.05). At the end of the second week after intervention, compared with the control group, the lactase treatment group had significantly lower frequency of daily milk vomiting and 24-hour abdominal circumference difference (P < 0.05) and a significantly higher proportion of infants with the absence of gastric retention, fecal pH > 5.0, or negative reducing sugar in feces (P < 0.05). No adverse reactions associated with the lactase additive or probiotics were observed during the trial. CONCLUSIONS: Lactase additive can safely and effectively improve the clinical symptoms caused by lactose intolerance in preterm infants.

An improved clinical prediction rule for identifying neonatal bacterial meningitis: a multicenter cohort study.

BACKGROUND: To refine the bacterial meningitis (BM) score by improving its predictability of neonatal BM. METHODS: A multicenter, ambispective cohort study was conducted in China, comprising 9 hospitals (retrospective cohort: January 2001 to December 2017; prospective cohort: January 2018 to August 2019). Of 3,504 eligible full-term neonates, 475 neonates with cerebrospinal fluid (CSF) pleocytosis were included. Based on the receiver operating characteristic (ROC) curve and logistic regression analyses, the BM score was refined by changing the thresholds of CSF protein level and the CSF absolute neutrophil count (ANC), and removing some variables (the peripheral blood ANC and a history of seizure before or at the time of presentation). RESULTS: Of 475 neonates, 94 (19.8%) had BM. Based on the refined BM score, neonates with none of the following high-risk predictors were classified as being at very low risk for BM: CSF protein level ≥1,650 mg/L, CSF ANC ≥84×106 cells/L, and positive CSF Gram stain result. The refined score showed 100% sensitivity in identifying BM and much higher specificity compared to that for the BM score (70.9% vs. 19.4%). CONCLUSIONS: The refined BM score effectively identifies neonatal BM, and further studies are required to confirm our findings in prospective studies.

A risk score based on pediatric sequential organ failure assessment predicts 90-day mortality in children with Klebsiella pneumoniae bloodstream infection.

BACKGROUND: Klebsiella pneumoniae bloodstream infection (Kp-BSI) is a serious threat to pediatric patients. The objective of this study was to explore the risk factors, validate the prediction efficiency of pediatric Sequential Organ Failure Assessment (SOFA) and establish better early predictors of mortality in pediatric patients with Kp-BSI. METHODS: All children diagnosed with Kp-BSI were included in this retrospective cohort study from January 2009 to June 2019. Basic characteristics, symptoms and physical examinations, treatments, laboratory statistics, and SOFA at the onset of Kp-BSI were recorded. The Cox proportional hazard model and receiver operating characteristic curves were used to assess the association between the variables and the 90-day mortality and their predictive value. DeLong's test of receiver operating characteristic curves and integrated discrimination improvement index were used to determine the improvement in predictive capacity of the modified SOFA models. A predictive score was developed using multivariate logistic regression. RESULTS: Of the 146 children enrolled, 33 (22.6%) patients died within 90 days. Hospitalization in the last 6 months, intra-abdominal source of infection, presence of organ failure, and altered levels of blood biomarkers, including C-reactive protein, albumin, and lactate were significant risk factors for 90-day mortality. The area under the curve (AUC) of SOFA for predicting 90-day mortality was 0.80 (95% CI 0.71-0.89). Moreover, we found that a prediction model combining SOFA with two other parameters, namely hospitalization in the last 6 months and intra-abdominal source of infection, was better at predicting mortality (AUC = 0.89, 95% CI 0.82-0.96; sensitivity = 0.86; specificity = 0.84). According to this novel risk model, we defined three statistically different groups: low-risk, medium-risk and high-risk groups, with an observed 90-day mortality of 5.4, 35.7, and 72.0%, respectively. With reference to the low-risk patients, the medium-risk and high-risk groups had a higher mortality, with hazard ratios of 8.36 (95% CI 3.60-27.83) and 20.27 (95% CI 7.47-54.95), respectively. CONCLUSIONS: The modified SOFA may be better than the original score to predict 90-day mortality in pediatric patients with Kp-BSI. Future prospective studies are required to validate this novel scoring system in external cohorts.

Role of Interleukin-33 in Staphylococcus epidermidis-Induced Septicemia.

Interleukin (IL)-33 is a member of the IL-1 family, which plays an important role in inflammatory response. In this study, we evaluated the effect of IL-33 on septicemia and the underlying mechanisms by establishing a Staphylococcus epidermidis (S. epidermidis)-induced septicemic mouse model. The expression of IL-33, IL-1α, IL-1ß, IL-6, IL-17A, IL-22, and PGE2 were measured by double antibody sandwich enzyme-linked immunosorbent assay, and bacterial colony formation in peripheral blood and kidneys were counted postinfection. The percentages of neutrophils, eosinophils, and inflammatory monocytes were evaluated by flow cytometry, and tissue damage was assessed by hematoxylin and eosin (H&E) staining. The survival of septicemic mice was monitored daily. IL-33 expression was significantly augmented following S. epidermidis infection. High IL-33 expression significantly decreased the survival of model mice, and aggravated the damage of lung, liver, and kidney tissues. However, administration of ST2 (receptor for IL-33) to the S. epidermidis-infected mice blocked the IL-33 signaling pathway, which elevated PGE2, IL-17A, and IL-22, and promoted healing of organ damage. In addition, ST2 suppressed the mobilization of inflammatory monocytes, but promoted the accumulation of neutrophils and eosinophils in S. epidermidis-infected mice. Inhibition of PGE2, IL-17A, and IL-22 facilitated the development of septicemia and organ damage in S. epidermidis-infected mice, as well as reducing their survival. Our findings reveal that IL-33 aggravates organ damage in septicemic mice by inhibiting PGE2, IL-17A, and IL-22 production.

Clinical utility in infants with suspected monogenic conditions through next-generation sequencing.

BACKGROUND: Rare diseases are complex disorders with huge variability in clinical manifestations. Decreasing cost of next-generation sequencing (NGS) tests in recent years made it affordable. We witnessed the diagnostic yield and clinical use of different NGS strategies on a myriad of monogenic disorders in a pediatric setting. METHODS: Next-generation sequencing tests are performed for 98 unrelated Chinese patients within their first year of life, who were admitted to Xin Hua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, during a 2-year period. RESULTS: Clinical indications for NGS tests included a range of medical concerns. The mean age was 4.4 ± 4.2 months of age for infants undergoing targeting specific (known) disease-causing genes (TRS) analysis, and 4.4 ± 4.3 months of age for whole-exome sequencing (WES) (p > 0.05). A molecular diagnosis is done in 72 infants (73.47%), which finds a relatively high yield with phenotypes of metabolism/homeostasis abnormality (HP: 0001939) (odds ratio, 1.83; 95% CI, 0.56-6.04; p = 0.32) and a significantly low yield with atypical symptoms (without a definite HPO term) (odds ratio, 0.08; 95% CI, 0.01-0.73; p = 0.03). TRS analysis provides molecular yields higher than WES (p = 0.01). Ninety-eight different mutations are discovered in 72 patients. Twenty-seven of them have not been reported previously. Nearly half (43.06%, 31/72) of the patients are found to carry 11 common disorders, mostly being inborn errors of metabolism (IEM) and neurogenetic disorders and all of them are observed through TRS analysis. Eight positive cases are identified through WES, and all of them are sporadic, of highly variable phenotypes and severity. There are 26 patients with negative findings in this study. CONCLUSION: This study provides evidence that NGS can yield high success rates in a tertiary pediatric setting, but suggests that the scope of known Mendelian conditions may be considerably broader than currently recognized.

Etiology and Clinical Features of Full-Term Neonatal Bacterial Meningitis: A Multicenter Retrospective Cohort Study.

Objective: Neonatal bacterial meningitis is a severe infectious disease with a high risk of neurodevelopmental sequelae. The causative pathogens may be related to specific clinical features of the disease. Therefore, this study aimed at determining the pathogen-specific and clinical features of bacterial meningitis in full-term neonates. Methods: We enrolled neonates from the Shanghai Neonate Meningitis Cohort (2005-2017), which is a multicenter retrospective cohort that recruits almost all full-term neonates in Shanghai who underwent lumbar puncture. Patient history and clinical examination results were extracted from the computer-documented information systems of four hospitals. The trends of pathogen distribution were analyzed and differences in the clinical manifestations, treatment, and clinical outcomes at discharge were compared according to the causative pathogen. Logistic regression was used to evaluate the pathogen-specific risk of neurological complications. Results: In total, 518 cases of neonatal meningitis, including 189 proven cases, were included. Group B Streptococcus (GBS) and Escherichia coli (E. coli) were the leading pathogens in proven cases of early-onset and late-onset neonatal meningitis, respectively. The proportion of early-onset and late-onset GBS and late-onset E. coli meningitis cases increased gradually. GBS meningitis had the highest risk of neurological complications, whereas the overall incidence of hydrocephalus and brain abscess in E. coli was higher than that in GBS. Conclusions: Rates of neonatal GBS and E. coli meningitis were high in 2005-2017 in Shanghai, and the risk of neurological complications was also high. Therefore, active prevention, rational use of antibiotics, and continuous monitoring of GBS and E. coli in neonates should be initiated in Shanghai.

Comparing Single vs. Combined Cerebrospinal Fluid Parameters for Diagnosing Full-Term Neonatal Bacterial Meningitis.

Objectives: To identify and compare the cerebrospinal fluid (CSF) parameters that predict the presence of neonatal bacterial meningitis using optimal cutoff values, and to derive and compare predictive profiles based on a combination of individual parameters for the same purpose. Study Design: The retrospective component of the Shanghai Neonate Meningitis Cohort included all term neonates who underwent lumbar puncture between 2000 and 2017. Those with severe neurological diseases, histories of ventricular drainage, or traumatic lumbar punctures were excluded. Reference ranges were determined for non-bacterial meningitis neonates based on the 5th, 25th, 50th, 75th, and 95th CSF parameter quantiles, and their relationships with age were calculated using generalized additive models that tested for linear relationships. The optimal cutoff value for each measured CSF parameter was calculated using receiver operating characteristic analysis and by deriving the Youden's index. Parameters with good diagnostic efficacies were combined to produce predictive profiles using logistic regression. The diagnostic efficacies of the single parameters and profiles were compared in neonates with confirmed bacterial meningitis. Results: White blood cells (WBCs) in CSF showed a higher diagnostic ability for neonatal bacterial meningitis than CSF protein, glucose, lactate dehydrogenase, or chloride. The sensitivity and specificity of the diagnostic cutoff value for WBCs (20 × 106/L) were 95.1 and 98.7%, respectively. Profiles based on CSF parameter combinations improved the specificities slightly to 99.0-99.7%. However, employing predictive profiles did not improve sensitivities, which remained at 95.1-96.0%. Conclusions: Profiles for predicting neonatal bacterial meningitis improve the sensitivity and specificity of diagnosis slightly, although not appreciably, compared to the single parameter of CSF WBC alone.

[Early rehabilitation intervention reduces the incidence of extrauterine growth retardation in preterm infants].

OBJECTIVE: To investigate the effect of early rehabilitation intervention on the incidences of extrauterine growth retardation (EUGR) and early diseases in preterm infants. METHODS: The appropriate-for-gestational-age preterm infants with a gestational age of <34 weeks and a birth weight of 1 000 to <2 000 g who were admitted to the neonatal intensive care unit (NICU) within 24 hours after birth were enrolled in a prospective randomized controlled trial. These infants were randomly divided into rehabilitation intervention group and control group. The infants in the rehabilitation intervention group were given early rehabilitation after their vital signs became stable, including oral sensory and muscle strength training and pressure touching of the head, chest, abdomen, extremities, hands, and feet. The primary outcome measures were the time to independent oral feeding, length of hospital stay, and incidence rate of EUGR. The secondary outcome measures were the incidence rates of related diseases in preterm infants, such as apnea, feeding intolerance, and sepsis. RESULTS: A total of 97 preterm infants who met the inclusion criteria and had complete data were enrolled, with 48 in the control group and 49 in the rehabilitation intervention group. The rehabilitation intervention group had a shorter time to independent oral feeding than the control group (P<0.05). Compared with the control group, the rehabilitation intervention group had a shorter length of hospital stay and a lower corrected gestational age at discharge (P<0.05), as well as a lower incidence rate of EUGR (P<0.05). The rehabilitation intervention group ONCLUSIONS: Early rehabilitation intervention for preterm infants in the NICU may reduce the incidence rates of apnea, feeding intolerance, and EUGR and help them to achieve independent oral feeding early.

Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein.

Neonates are at high risk of meningitis and of resulting neurologic complications. Early recognition of neonates at risk of poor prognosis would be helpful in providing timely management. From January 2008 to June 2014, we enrolled 232 term neonates with bacterial meningitis admitted to 3 neonatology departments in Shanghai, China. The clinical status on the day of discharge from these hospitals or at a postnatal age of 2.5 to 3 months was evaluated using the Glasgow Outcome Scale (GOS). Patients were classified into two outcome groups: good (167 cases, 72.0%, GOS = 5) or poor (65 cases, 28.0%, GOS = 1-4). Neonates with good outcome had less frequent apnea, drowsiness, poor feeding, bulging fontanelle, irritability and more severe jaundice compared to neonates with poor outcome. The good outcome group also had less pneumonia than the poor outcome group. Besides, there were statistically significant differences in hemoglobin, mean platelet volume, platelet distribution width, C-reaction protein, procalcitonin, cerebrospinal fluid (CSF) glucose and CSF protein. Multivariate logistic regression analyses suggested that poor feeding, pneumonia and CSF protein were the predictors of poor outcome. CSF protein content was significantly higher in patients with poor outcome. The best cut-offs for predicting poor outcome were 1,880 mg/L in CSF protein concentration (sensitivity 70.8%, specificity 86.2%). After 2 weeks of treatment, CSF protein remained higher in the poor outcome group. High CSF protein concentration may prognosticate poor outcome in neonates with bacterial meningitis.

Bone Morphogenetic Protein 9 and 13 Induce C3H10T1/2 Cell Differentiation to Cardiomyocyte-Like Cells In Vitro.

The present study aimed to evaluate the effect of bone morphogenetic protein 9 (BMP9) and BMP13 on cardiac differentiation of C3H10T1/2 cells in vitro and to characterize the differentiated cells on their ultrastructure and transmembrane electrophysiological features. C3H10T1/2 cells were transfected with the vectors for BMP9 or BMP13 and differentiated into cardiomyocytes in vitro for up to 28 days. The expression of cardiac-specific genes Gata4 and Mef2c and proteins troponin T (cTnT) and connexin 43 (Cx43) was significantly increased in the cells transfected with BMP9 or BMP13 after differentiation over the controls as evaluated using quantitative RT-PCR, Western blotting, and immunofluorescence staining. Transmission electron microscopy and Masson trichrome staining showed that the specific myocardial leap dish and myofilament-like structure were present in the cells overexpressing BMP9 or BMP13, not in the control cells. Whole-cell patch-clamping study demonstrated the presence of delayed rectifier potassium current, inward rectifier potassium current, and T-type calcium current in the cells overexpressing BMP9 or BMP13. Sodium current was detected in a small number of cells overexpressing BMP9, not in the BMP13-transfected cells or the control cells. The expression of Mef2c gene and Cx43 and cTnT proteins was also significantly higher in the cells overexpressing BMP9 than those overexpressing BMP13. Our data indicate that BMP9 and BMP13 (BMP9 might be more effective) promoted the differentiation of C3H10T1/2 cells into cardiomyocyte-like cells with cellular ultrastructures and ion channel currents similar to mature cardiomyocytes in vitro.