Initial indicators for the prognosis of Acinetobacter Baumannii bacteremia in children.

BACKGROUND: Risk factors related to mortality due to Acinetobacter baumannii (AB) bacteremia have been unveiled previously, but early clinical manifestations of AB bacteremia based on prognosis remain uncovered. METHODS: The demographic characteristics, clinical features, antibiotic susceptibility, and outcomes of 37 hospitalized children with laboratory-confirmed AB bacteremia from Suzhou, China, were collected and analyzed retrospectively. RESULTS: Of the 37 children with AB bacteremia included in this study, 23 were males and 14 were females, with a median age of 4.83 (0.60 to 10.15) years. Among the children, 18 died (48.65%, 18/37) and 19 survived (51.35%, 19/37). The dead group had a significantly higher incidence of respiratory failure (p = 0.008), shock (P = 0.000), MODS (p = 0.000), neutropenia (< 1.5 × 109/L) (p = 0.000) and serious neutropenia (< 0.5 × 109/L) (p = 0.000) than those in the survival group. The death group had significantly more invasive procedures (2 or more) than that in the survival group at 2 weeks before onset (p = 0.005). The proportion of MDR-AB in the death group was significantly higher than that in the survival group (p = 0.000), while the PICS score was significantly lower in the survival group than that in the death group (p = 0.000). There was no significant difference in effective antibiotic use within 24 h between these two groups (p = 0.295). Among the 37 children with bloodstream infection of AB, 56.76% (21/37) of the underlying diseases were hematological diseases and oncology. Among them, 17 (81.00%) were died in the hospital. The proportion of white blood cells (p = 0.000), neutrophils (p = 0.042), eosinophils (p = 0.029), the ANC (p = 0.000) and lymphocyte (p = 0.000), the NLR(p = 0.011), hemoglobin (p = 0.001), platelets (p = 0.000), prealbumin (P = 0.000), LDH (p = 0.017), blood gas pH (p = 0.000), and serum potassium (p = 0.002) in the death group were significantly lower than those in the survival group. However, CRP (p = 0.000) and blood glucose(p = 0.036) were significantly higher in the death group than those in the survival group. By further multivariate analysis, CRP [OR (95% CI): 1.022(1.003, 1.041), p = 0.021] and neutropenia [OR (95% CI): 21.634 (2.05, 228.313, p = 0.011] within 24 h of infection were independent risk factors for death in children with AB bacteremia. When CRP was higher than 59.02 mg/L, the sensitivity of predicting mortality was 88.9%, and the specificity was 78.9%. And the sensitivity and specificity of neutropenia for predicting mortality were 83.3% and 84.2%. CONCLUSIONS: AB bacteremia has a high mortality in children, especially in patients with hematological diseases and oncology. Many early indicators were associated with poor prognosis, while elevated CRP and neutropenia were the independent predictors for the 30-day mortality of children with laboratory-confirmed AB bacteremia.

Novel heterozygous compound TRMT5 mutations associated with combined oxidative phosphorylation deficiency 26 in a Chinese family: a case report.

BACKGROUND: Combined oxidative phosphorylation deficiency 26 (COXPD26) is an autosomal recessive disorder characterized by early onset, developmental delay, gastrointestinal dysfunction, shortness of breath, exercise intolerance, hypotonia and muscle weakness, neuropathy, and spastic diplegia. This disease is considered to be caused by compound heterozygous mutations in the TRMT5 gene. CASE PRESENTATION: In this study, we report a female child with COXPD26 manifesting as shortness of breath, gastrointestinal dysmotility, severe developmental delay, muscle hypotonia and weakness, exercise intolerance, renal and hepatic defects, and recurrent seizures with spastic diplegia. Interestingly, the hepatic feature was first observed in a COXPD26 patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the TRMT5 gene were detected, which were c.881A>C (p.E294A) from her mother and c.1218G>C (p.Q406H) and c.1481C>T (p.T494M) from her father. CONCLUSION: The newly emerged clinical features and mutations of this patient provide useful information for further exploration of genotype-phenotype correlations in COXPD26.

BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. METHODS: Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). RESULTS: BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. CONCLUSIONS: BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

Assessment of early renal angina index for prediction of subsequent severe acute kidney injury during septic shock in children.

BACKGROUND: Acute kidney injury (AKI) is independently related to the adverse outcome of septic shock, but it lacks effective early predictors. Renal anginal index (RAI) was used to predict subsequent severe AKI (AKIs) in critically ill patients. The application of RAI in children with septic shock has not been reported. This study aims to evaluate the efficacy of early RAI in predicting subsequent AKIs within 3 days after PICU admission in children with septic shock by comparing with early fluid overload (FO) and early creatinine elevation. METHODS: Sixty-six children admitted to PICU aged 1 month to 16 years old, with septic shock from January 2016 to December 2019 were analyzed retrospectively. According to the 2012 Kidney Disease Improving Global outcomes (KDIGO) criteria, AKIs was defined by the KDIGO stage ≥2 within 3 days after PICU admission. Early RAI positive (RAI+) was defined as RAI ≥ 8 within 12 h of PICU admission. Any elevation of serum creatinine (SCr) over baseline within 12 h after PICU admission was denoted as "Early SCr > base". Early FO positive (FO+) was defined as FO > 10% within 24 h of PICU admission. RESULTS: Of 66 eligible cases, the ratio of early RAI+, early SCr > base, early FO+ was 57.57, 59.09 and 16.67% respectively. The incidence of AKIs in early RAI+ group (78.94%) was higher than that in early RAI- group (21.42%) (p = 0.04), and there was no significant difference compared with the early FO+ group (71.79%) and early SCr > base group (81.82%) (P > 0.05). After adjustment for confounders, early RAI+ was independently associated with the occurrence of AKIs within 3 days (OR 10.04, 95%CI 2.39-42.21, p < 0.01). The value of early RAI+ (AUC = 0.78) to identify patients at high risk of AKIs was superior to that of early SCr > base (AUC = 0.70) and early FO+ (AUC = 0.58). A combination of serum lactate with early RAI+ improved the predictive performance for assessing AKIs (AUC = 0.83). CONCLUSIONS: Early RAI could be used as a more convenient and effective index to predict the risk of AKIs in children with septic shock within 3 days. Early RAI+ combined with serum lactate improved the predictive performance for assessing AKIs.