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PURPOSE Chemoresistance remains the primary obstacle threatening the prognosis of retinoblastoma (RB). microRNAs (miRNAs) are acknowledged as critical regulators of drug resistance. This study explored the molecular mechanism of miR-130a-3p affecting the chemosensitivity of RB to vincristine (VCR). METHODS miR-130a-3p expression of human retinal astrocytes and RB cell lines (Y79, WERI-Rb-1, SO-Rb50, and SO-Rb70) was detected using RT-qPCR. VCR-resistant RB cell line Y79/VCR was induced. miR-130a-3p expression of Y79/VCR cell line and its corresponding parental cell line was detected. Y79/VCR cells were subjected to miR-130a-3p overexpression treatment. The cell proliferation was measured using MTT assay, and the IC50 value and drug resistance index were examined using CCK-8 assay. The targeting relationship between miR-130a-3p and PAX6 was predicted through bioinformatics analysis and verified using dual-luciferase assay. Functional rescue experiments were conducted to confirm the role of PAX6 in chemosensitivity of RB cells. The effect of miR-130a-3p on tumorigenesis and VCR sensitivity was observed in vivo. RESULTS miR-130a-3p was downregulated in VCR-resistant RB cells. Overexpression of miR-130a-3p repressed the proliferation of Y79/VCR cells and enhanced chemosensitivity. miR-130a-3p targeted PAX6 expression. Overexpression of PAX6 reversed the effect of miR-130a-3p on chemosensitivity of Y79/VCR cells. Overexpression of miR-130a-3p suppressed tumor growth and reduced VCR resistance in vivo. CONCLUSIONS miR-130a-3p enhanced the chemosensitivity of Y79 RB cells to VCR by targeting PAX6 expression.

Mutations in CSNK2B lead to Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), a rare neurodevelopmental disorder. Only 14 cases of POBINDS have been reported worldwide. The main manifestations are seizures, often tonic–clonic, with or without intellectual disability, growth retardation, and developmental language retardation. We conducted a comprehensive phenotypic mining and trio-whole exome sequencing on six children with POBINDS for gene diagnosis and analyzed the different variants using bioinformatics analysis software and related experiments. This paper reviews previous literature and discusses two common missense variants that lead to structural changes. Among the six patients, four, one, and one had tonic–clonic, myoclonic, and febrile seizures, respectively. Language development disorder, motor development disorder, and developmental delay/intellectual disability (DD/ID) are the main clinical features. All children had de novo mutations in CSNK2B, including three missense variants (c.410G > T/p.(Cys137Phe), c.494A > G/p.(His165Arg), and c.3G > A/p.(Met1Ile)), two splice variants (c.292-2A > T, c.558-3 T > G), and one frameshift variant (c.499delC/p.(Leu167Serfs*60)). Three missense variants were predicted to be harmful by various software programs, and two splicing variants were found to produce new exonic splicing enhancers by the minigene assay. Western blot analysis showed that the frameshift variant resulted in decreased protein expression. According to a literature review, c.3G > A/p.(Met1Ile), c.292-2A > T, c.558-3 T > G, and c.499delC/p.(Leu167Serfs*60) are novel variants of CSNK2B. The decrease or loss of protein function caused by CSNK2B mutations may be a pathogenic factor in this cohort. The severity of the POBINDS phenotype differs, and refractory epilepsy may be accompanied by a more serious DD/ID, language disorder, and motor retardation. At present, there is no specific treatment, and antiepileptic therapy usually requires the combination of two or more anti-epileptic drugs.

Background and aimsDeciding when to suspect hemophagocytic lymphohistiocytosis (HLH) and perform diagnostic tests in patients with acute infection of Epstein-Barr virus (EBV) is challenging, given the high prevalence of EBV infection, the life-threatening risk of EBV-HLH, the relatively low incidence of EBV-HLH, and the wide spectrum of disease presentations. The aim of this study was to develop an EBV-HLH screening model for pediatric patients diagnosed with acute infection of EBV.MethodsAn inpatient cohort with 3183 pediatric patients who were diagnosed with active infection of EBV was used to construct and validate the EBV-HLH screening score model. The model parameters were selected from common laboratory parameters using the method of Akaike Information Criterion-optimal selection through cross-validation under logistic regression. Performance of the score was evaluated and compared with the performance of screening methods using the number of cytopenias lineages.ResultsThe EBV-HLH screening score has five parameters, including hemoglobin, platelet, neutrophil, albumin, and lactate dehydrogenase. Using a cut-of value of 29, the scoring model had a sensitivity of 89.2% and a specificity of 89.5% in the validation set. The false negative rate, false positive rate, positive predictive value, and negative predictive value in the validation set was 10.8%, 10.5%, 26.8%, and 99.5%, respectively, similar to that of the training set.ConclusionsWith five common laboratory parameters, the EBV-HLH score provides a simple tool to assist the identification of EBV patients who require further evaluation of HLH. Further studies are needed to evaluate the generalizability of the score and optimize the diagnose process for EBV-HLH.

OBJECTIVES Pancreatic injury is multifactorial and potentially devastating for critically ill children. We aimed to evaluate whether serum amylase and lipase among critically ill children could serve as an independent biomarker to predict pancreatic injury. DESIGN Retrospective cohort. SETTING PICU of a tertiary, pediatric medical center. PATIENTS Seventy-nine autopsies. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A group of 79 children who died of different causes were investigated by autopsy. They were divided into pancreatic injury group and pancreatic noninjury group according to autopsy findings. Data based on patients' demographics, vital signs, laboratory findings, and clinical features at admission were collected and compared. Logistic regression was used to identify predictive factors for pancreatic injury. Receiver operating characteristic curve was constructed for assessing serum amylase and serum lipase to predicting pancreatic injury. Forty-one patients (51.9%) exhibited the pathologic changes of pancreatic injury. The levels of lactate, erythrocyte sedimentation rate, alanine transaminase, aspartate transaminase, and troponin-I in the injury group were significantly higher than that in the noninjury group, whereas the level of calcium was significantly lower than that in the noninjury group (p < 0.05). Multivariable logistic regression analysis showed that serum amylase, serum lipase, and septic shock were significantly associated with the occurrence rate of pancreatic injury. The statistically significant area under the curve results were as follows: serum amylase: area under the curve = 0.731, at a cutoff value of 97.5, sensitivity = 53.7, and specificity = 81.6; and serum lipase: area under the curve = 0.727, at a cutoff value of 61.1, sensitivity = 36.6, and specificity = 92.1. CONCLUSIONS Serum amylase and lipase could serve as independent biomarkers to predict pancreatic injury in critically ill children.

Patients with hemophagocytic lymphohistiocytosis (HLH) have high risk of early mortality. The purpose of this study was to test the hypothesis that the elevated level of serum myoglobin among patients with HLH is associated with disease severity and increased risk of mortality. We retrospectively investigated the serum myoglobin levels from 155 pediatric patients diagnosed with HLH in the Hunan Children's Hospital, China. The levels of myoglobin and creatine kinase at hospital admission among non-survivors and survivors were compared. The myoglobin level was dichotomized for the estimation of hazard ratio (HR) for mortality. Patients who died within 7 and 30 days of hospitalization had significantly higher myoglobin levels than did survivors (p 0.05). The myoglobin level was negatively associated with the days of survival among non-survivors (Spearman correlation coefficient = - 0.29, p = 0.04). An elevated myoglobin level ( 90 ng/mL) was significantly associated with increased mortality (unadjusted HR = 2.66, 95%CI: 1.41, 5.00, p = 0.0024) and persisted after adjusting for age, Epstein-Barr virus infection, admission department, acute kidney injury, myocardial damage, and shock. In conclusion, an elevated serum myoglobin level was associated with increased risk of early death among pediatric patients with HLH, suggesting the potential of myoglobin to be used as a reference indicator for monitoring and managing of HLH.

Purpose Our aim was to investigate the age-associated plasma protein profiles in pneumonia-derived sepsis between infants and toddlers and identify potential age-adapted prognostic markers for poor outcome of pneumonia-derived pediatric sepsis. Experimental design A nested case-control study strategy was applied. The plasma proteomes of pneumonia-derived pediatric septic patients with different outcomes between infants and toddlers were respectivly analysed compared to their age-matched controls. Results Compared to toddlers, pneumonia-derived sepsis in infants was characterized by increased upregulation of protein processing in the ER, proteasome and antigen processing and presentation; and reduced downregulation in complement and coagulation cascades and cholesterol metabolism. Among them, the pentose phosphate pathway as well as the complement and coagulation cascades were possibly associated with poor outcome of pneumonia-derived sepsis. Furthermore, we confirmed that HP, THBS1, and SAA1/2 were potential prognostic markers for poor outcome of pneumonia-derived sepsis in infant patient groups. Conclusions and clinical relevance Age-associated plasma protein profiles of pneumonia-derived pediatric septic patients provided potential age-adapted biomarkers for a more precise prognosis of poor outcome in pneumonia-derived pediatric sepsis and helped to improve the survival of septic children. This article is protected by copyright. All rights reserved.

Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder. How to stratify high risk patients is one of the current challenges for the treatment of HLH. HLH patients usually fulfill multiple but not all eight diagnostic criteria. Different combinations of the fulfilled criteria may naturally cluster into previously undescribed subsets or phenotypes that may have different pathophysiology and demonstrate different risks for a poor outcome. The objectives of this study were to identify HLH subgroups according to the fulfillment of diagnostic criteria and evaluate the risk of multiple organ dysfunction syndrome (MODS) and 30-day mortality for subgroups. We retrospectively collect medical records of patients with discharge diagnosis of HLH between June 2015 and October 2018 from a tertiary children’s hospital in China. Latent class analysis was used to identify class defining variables from HLH diagnostic items, and subgroups were defined according to different combinations of the class defining variables. Results Triglyceride and fibrinogen were identified as the class defining variables. When evaluated in combinations, patients with hypertriglyceridemia and normal fibrinogen levels during hospitalization had the lowest risks for MODS (27.8%, OR = 1) and 30-day mortality (18.8%, OR = 1), and patients with normal triglyceride and hypofibrinogenemia had the highest risks for MODS (86.2%, OR = 16.24, P = 0.0002) and 30-day mortality (57.1%, OR = 5.78, P = 0.0187). The fulfillment status of hypertriglyceridemia and hypofibrinogenemia within 72 h of hospital admission was also associated with the risk of adverse outcomes. Conclusions The fulfillment status of hypertriglyceridemia and hypofibrinogenemia were associated with the risks of MODS and 30-day mortality among pediatric HLH patients. Further studies are needed to validate this association and investigate its clinical utility in the severity evaluation for HLH.

Objective This prospective study was performed to explore the change in sacrococcygeal pressure during an operation under general anesthesia in the supine position and identify the correlation between pressure injury and body mass index. Methods This study involved 99 patients who underwent general anesthesia. Sacrococcygeal pressure was measured and recorded at seven time points: before general anesthesia, 5 minutes after general anesthesia, and 1, 2, 3, 4, and 5 hours after the beginning of the operation. The pressure change at each time point was compared, and the factors affecting the pressure were analyzed. Results The correlation analysis showed that the operation time was significantly and positively associated with the occurrence of pressure injury. Conclusion Perioperative management should be strengthened to speed up the surgical process and shorten the operation time, which will help to reduce the occurrence of intraoperative pressure injury.

Phenotypes of some rare genetic diseases are atypical and it is a challenge for pediatric intensive care units (PICUs) to diagnose and manage such patients in an emergency. In this study, we investigated 58 PICU patients (39 deceased and 19 surviving) in critical ill status or died shortly without a clear etiology. Whole exome sequencing was performed of 103 DNA samples from their families. Disease-causing single-nucleotide variants (SNVs) and copy number variants (CNVs) were identified to do genotype-phenotypes analysis. In total, 27 (46.6%) patients received a genetic diagnosis. We identified 34 pathogenic or likely pathogenic SNVs from 26 genes, which are related to at least 19 rare diseases. Each rare disease involved an isolated patient except two patients caused by the same gene ACAT1. The genotypic spectrum was expanded by 23 novel SNVs from gene MARS1, PRRT2, TBCK, TOR1A, ECE1, ARX, ZEB2, ACAT1, CPS1, VWF, NBAS, COG4, and INVS. We also identified two novel pathogenic CNVs. Phenotypes associated with respiratory, multiple congenital anomalies, neuromuscular, or metabolic disorders were the most common. Twenty patients (74.1%) accompanied severe infection, 19 patients (70.1%) died. In summary, our findings expanded the genotypes and phenotypes of 19 rare diseases from PICU with complex characteristics.

Background Hemophagocytic lymphohistiocytosis (HLH) is a relatively rare and life-threatening disorder. Early mortality remains significantly high among patients with HLH. Our aim was to investigate clinical features and risk factors associated with 7-day and 30-day mortality among pediatric HLH patients. We retrospectively collected medical records of patients with discharge diagnosis of HLH between August 2014 and October 2018 from a tertiary children’s hospital in China. The main outcome measures were the 7-day and 30-day outcome after hospital admission. The associations between symptoms, concomitant diagnoses, laboratory test results, and the risk of 7-day and 30-day mortality were examined. Results Among 160 pediatric HLH patients, 18 (11.3%) patients were deceased within 7 days after admission, and 46 (28.8%) patients were deceased within 30 days. The identified strong risk factors (OR > 10 and p Conclusions The identified risk factors could help to stratify patients with high risk of early death, and need to be considered in the development of treatment protocols. As early mortality of HLH remains high, studies are needed to investigate how to initiate adequate HLH-directed treatment strategies for patients at higher risk of early death.

Objective: The aim of this study was to determine whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) can predict impending brainstem encephalitis, pulmonary edema, pulmonary hemorrhage, cardiopulmonary failure, and death in children with severe enterovirus 71 (EV71)-associated hand, foot, and mouth disease (HFMD). Methods: Plasma NT-proBNP levels of 282 children with severe EV71-associated HFMD were measured. Results: NT-proBNP levels were significantly higher in patients with elevated blood glucose (>7.8 mmol/l) and increased white blood cell counts (>14 × 109/l). HFMD patients who had no complications had significantly lower NT-proBNP values than patients who died or had complications (p

Hand, foot, and mouth disease (HFMD) is endemic in the Pacific region, especially in mainland China. The case-fatality ratio of HFMD is increasing steadily. Knowledge of the changing epidemiology of HFMD in different regions is necessary for implementing appropriate intervention strategies. In this study, we describe the clinical and epidemiological characteristics of HFMD in Hunan Children’s Hospital between 2013 and 2017. A total of 7203 patients with HFMD were admitted, with complication and mortality rates of 35.62% and 0.78%, respectively. The total number of children with HFMD, proportion of severely ill children, and HFMD mortality rate were the highest in 2014. The number of cases caused by EV-A71 and CV-A16 decreased continuously, while the number of cases caused by ‘other enteroviruses’ increased yearly since 2014, suggesting that other enteric viruses will gradually replace EV-A71 and CV-A16 as the main pathogenic HFMD agents. Furthermore, EV-A71 and mixed infections accounted for the high case fatality rates in children with severe HFMD, among whom EV-A71 infection resulted in the highest complication and mortality rates; the mild form of the disease was dominated by ‘other enteroviruses’. In conclusion, the changing etiological pattern highlights the need to improve pathogen surveillance and vaccine strategies for HFMD control.

Outbreaks of hand, foot and mouth disease (HFMD) have increased recently, as has the case fatality rate in severe cases. No scoring system currently exists to predict mortality risk for severe HFMD in previous study. We retrospectively collected laboratory parameters for 546 patients with severe HFMD (a derivation and a validation cohort) at Hunan Children’s Hospitals between January 2012 and December 2014. We developed a mortality risk score comprising four laboratory parameters: blood glucose (GLU), white blood cells (WBC), lactate (LAC), and N-terminal-probrain natriuretic peptide (NT-proBNP). Using an “optimal” cutoff score of 4, the sensitivity, specificity, positive predictive value and negative predictive value was 88.00%, 96.14%, 62.86% and 99.08%, respectively, in the derivation cohort. Among severe HFMD patients with low- and high-risk scores in the validation cohort, case fatality rates were 1.49% and 74.07%, respectively. According to the “optimal” cut-off in the derivation cohort, the sensitivity, specificity, positive predictive value, and negative predictive value were 80.95%, 93.83%, 62.96% and 97.44%, respectively, in the derivation cohort. The mortality risk score demonstrated good discrimination (AUC > 0.9) and calibration (P > 0.05) in both cohorts. The mortality risk score, comprising WBC, GLU, LAC and NT-proBNP, has been demonstrated good discrimination and calibration in the both cohorts.

Pediatric sepsis is a burdensome public health problem. Assessing the mortality risk of pediatric sepsis patients, offering effective treatment guidance, and improving prognosis to reduce mortality rates, are crucial. We extracted data derived from electronic medical records of pediatric sepsis patients that were collected during the first 24 hours after admission to the pediatric intensive care unit (PICU) of the Hunan Children's hospital from January 2012 to June 2014. A total of 788 children were randomly divided into a training (592, 75%) and validation group (196, 25%). The risk factors for mortality among these patients were identified by conducting multivariate logistic regression in the training group. Based on the established logistic regression equation, the logit probabilities for all patients (in both groups) were calculated to verify the model's internal and external validities. According to the training group, 6 variables (brain natriuretic peptide, albumin, total bilirubin, D-dimer, lactate levels, and mechanical ventilation in 24 hours) were included in the final logistic regression model. The areas under the curves of the model were 0.854 (0.826, 0.881) and 0.844 (0.816, 0.873) in the training and validation groups, respectively. The Mortality Risk Model for Pediatric Sepsis we established in this study showed acceptable accuracy to predict the mortality risk in pediatric sepsis patients.

To assess the performance of pediatric risk of mortality (PRISM), pediatric index of mortality 2 (PIM2) in predicting mortality in critically ill pediatric patients via a prospective study.The outcome and the variables required to calculate PRISM and PIM2 were collected. The efficiency of PRISM and PIM2 in differentiation between death and survival by calculating the area under the receiver operating characteristic curve (ROC). Calibration across deciles of risk was evaluated using the Hosmer-Lemeshow goodness-of-fit χ(2) test.A total of 412 critically ill pediatric patients transferred to Hunan Children's Hospital during August 1, 2012 and May 31, 2013 were enrolled in the study, and more than two-thirds of the children were suffering from respiratory and miscellaneous diseases; 45 (10.9%) inter-hospital transport of critically ill pediatric patients died at the time of hospitalization. The expected number of deaths were 45.01 by PRISM, and the expected number of deaths were 44.99 by PIM2. The expected mortality rate was 10.9% for PRISM or PIM2. The standardized mortality rate was 1.000 (0.710-1.290) for PRISM and 1.000 (0.710-1.290) for PIM2. The Hosmer-Lemeshow test gave a chi-square of 8.75 (P=0.364) for PRISM and 22.75 (P0.05) for PIM2, PRISM had better fitting with the actual mortality than PIM2. The area under the receiver-operating characteristics (ROC) curve (95% confidence intervals, CI) were 0.829 (0.768-0.890) for PRISM and 0.758 (0.667-0.849) for PIM2.Although the PIM2 test is less well calibrated overall, both PRISM and PIM2 can offer a good capacity for discriminating between survivors and moribund patients. The good performance of PRISM and PIM2 are demonstrated in predicting mortality probability in critically ill pediatric patients.

Objectives The aim of this study is to describe blood lead levels (BLLs) and the prevalence of elevated blood lead levels (EBLLs) in children aged 0–6 years old and to analyze the BLL trend in children from 2009 to 2013 in China. Methods A total of 124,376 children aged 0–6 years old were recruited for this study from January 1st 2009 to December 31st 2013. Their blood lead levels were analyzed using atomic absorption spectrometry. Results The median BLL was 64.3 μg/L (IQR: 49.6–81.0), and the range was 4.3–799.0 μg/L. Blood lead levels were significantly higher in boys (66.0 μg/L) than in girls (61.9 μg/L) (P

Although beta cell dysfunction has been proved to predict prognosis among humans and animals, its prediction on severity of disease remains unclear among children. The present study was aimed to examine the relationship between beta cell dysfunction and severity of disease among critically ill children. This prospective study included 1146 critically ill children, who were admitted to Pediatric Intensive Care Unit (PICU) of Hunan Children's Hospital from November 2011 to August 2013. Information on characteristics, laboratory tests, and prognostic outcomes was collected. Homeostasis model assessment (HOMA)-β, evaluating beta cell function, was used to divide all participants into 4 groups: HOMA-β = 100% (group I, n = 339), 80% ≤ HOMA-β < 100% (group II, n = 71), 40% ≤ HOMA-β < 80% (group III, n = 293), and HOMA-β < 40% (group IV, n = 443). Severity of disease was assessed using the worst Sequential Organ Failure Assessment (SOFA) score, Pediatric Risk of Mortality (PRISM) III score, incidence of organ damage, septic shock, multiple organ dysfunction syndrome (MODS), mechanical ventilation (MV) and mortality. Logistic regression analysis was used to evaluate the risk of developing poor outcomes among patients in different HOMA-β groups, with group I as the reference group. Among 1146 children, incidence of HOMA-β < 100% was 70.41%. C-peptide and insulin declined with the decrement of HOMA-β (P

To evaluate the nibble technology in the therapy of diabetic retinopathy.Eighty-three patients (ninety-two eyes) with proliferative diabetic retinopathy were treated in our department. All the patients received a standard pars plana vitrectomy. Fifty-two of them (fifty-eight eyes) were treated with nibble technology, while the other thirty-one (thirty-four eyes), who were treated with common procedure to tear the proliferative membrane, were served as a control group.The operative complication of iatrogenic retinal tears was observed in 2 eyes of the test group and 7 eyes of the control group (P0.05). Another operative complication of hemorrhage was observed in 4 eyes of the test group and 15 eyes of the control group (P0.01). There were 6 eyes of the test group and 5 eyes of the control group presented with grade-III postoperative responds (P0.01).The nibble technology is safe in the therapy of proliferative diabetic retinopathy and could reduce the complications during or after the operation.

To document the anatomic and functional improvement of six patients with branch retinal vein occlusion (BRVO) following successful arteriovenous adventitial sheathotomy (AAS).Retrospective study of 6 patients (6 eyes) with BRVO treated with AAS. All patients were not eligible for laser photocoagulation and had both macular edema and intraretinal hemorrhage. The visual acuity was in the range of 0.4 to 0.02. All patients underwent pars plana vitrectomy and AAS. The clinical improvement was determined by fundus photograph, fluorescein angiography (FAG), optical coherence tomography (OCT) and multifocal electroretinography (ERG). All patients were followed postoperatively for an average of 20 months ranging from 12 to 24 months.Sheathotomy and decompression of the arteriole/venule (A/V) crossing were achieved in all 6 patients. 5 patients have improved their best-corrected visual acuity 4 lines or more. The best one could reach to 1.0. One month after the operation, fundus photograph and FAG demonstrated the resolution of intraretinal hemorrhage, reduction of non-perfusion area and apparent resolution of retinal venous dilation and tortuosity. OCT confirmed remarkable reduction of retinal thickness. The microcysts at the fovea diminished. Multifocal ERG showed the recovery of the central peak at the macular and the peripheral response density. However, capillary nonperfusion area and microaneurysm were found out by FAG in four patients at the points distal to the sheathotomy three months after the operation.Anatomic and functional improvement of retina can be achieved in patients with BRVO through AAS. However, the capillary nonperfusion and microaneurysm may follow this surgical procedure in some cases that need further treatment with laser photocoagulation. The better visual improvement may be expected in the patients with earlier surgical intervention.