A prospective multicenter study of sirolimus for complicated vascular anomalies.

OBJECTIVE: Complicated vascular anomalies (VAs) can be intractable and uncontrollable using conventional treatment and can result in lethal outcomes. We undertook a prospective, multicenter phase II trial to evaluate the efficacy and safety of sirolimus in pediatric patients with complicated VAs. METHODS: Eligible patients were required to be aged 0 to 14 years and to have a complicated VA. The patients were treated with daily oral sirolimus for 12 months. The primary endpoint was the response, which was measured using sequential volumetric magnetic resonance imaging. The secondary endpoints were the disease severity score and quality of life. RESULTS: Of 126 patients enrolled on an intention-to-treat basis, 98 (77.8%) had had an objective response to sirolimus, with a ≥20% decrease in lesion volume. Compared with those with arteriovenous malformations, the response rates were higher (>80%) for patients with common lymphatic malformations, venous malformations, kaposiform hemangioendothelioma, and combined malformations with a prominent venous and/or lymphatic component (P < .05). Improvements in the disease severity score and quality of life were obtained in 83.3% and 79.4% of patients, respectively. The most common adverse event was mucositis in 47 patients. More serious adverse events included reversible grade 4 pneumonitis in 3 patients and grade 4 upper respiratory infection in 1 patient. All these adverse events were considered at least possibly related to the treatment. CONCLUSIONS: Sirolimus is an apparently effective option for pediatric patients with various types of complicated VAs. Close monitoring of possible adverse events is required. The results from the present trial are the basis for future prospective studies using new therapeutic approaches.

Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study.

BACKGROUND: Abdominal ultrasonography has been proposed to screen for infantile hepatic hemangioma (IHH) in patients with multiple cutaneous infantile hemangiomas (IHs). OBJECTIVES: The aim of this study was to establish the optimal cutoff point for the number of cutaneous IHs needed to screen for IHH. METHODS: We performed a prospective, multicenter study to screen for IHH in patients younger than 9 months who had multiple cutaneous IHs (n ≥ 3) on ultrasonography. For comparison, a group of patients with 1 or 2 focal cutaneous IHs was also recruited. RESULTS: In total, 676 patients with at least 3 cutaneous IHs and 980 patients with 1 or 2 focal cutaneous IHs were enrolled. Thirty-one patients were found to have IHH. A higher number of cutaneous IHs was associated with an increased risk of IHH (R = 0.973; P < .001). Receiver operating characteristic curve analysis showed that 5 cutaneous IHs was the optimal cutoff point to screen for IHH, with an area under the curve of 0.872 (P < .001; 95% confidence interval, 0.789-0.955). LIMITATIONS: This was an uncontrolled study. CONCLUSIONS: Screening for IHH is recommended in patients younger than 9 months who present with 5 or more cutaneous IHs.

Sestrin 2 attenuates sepsis-associated encephalopathy through the promotion of autophagy in hippocampal neurons.

Sepsis-associated encephalopathy (SAE) has typically been associated with a poor prognosis. Although sestrin 2 (SESN2) plays a crucial role in metabolic regulation and the stress response, its expression and functional roles in SAE are still unclear. In the present study, SAE was established in mice through caecal ligation and puncture (CLP). The adeno-associated virus 2 (AAV2)-mediated SESN2 expression (ie overexpression and knockdown) system was injected into the hippocampi of mice with SAE, and subsequently followed by electron microscopic analysis, the Morris water maze task and pathological examination. Our results demonstrated an increase of SESN2 in the hippocampal neurons of mice with SAE, 2-16 hours following CLP. AAV2-mediated ectopic expression of SESN2 attenuated brain damage and loss of learning and memory functions in mice with SAE, and these effects were associated with lower pro-inflammatory cytokines in the hippocampus. Mechanistically, SESN2 promoted unc-51-like kinase 1 (ULK1)-dependent autophagy in hippocampal neurons through the activation of the AMPK/mTOR signalling pathway. Finally, AMPK inhibition by SBI-0206965 blocked SESN2-mediated attenuation of SAE in mice. In conclusion, our findings demonstrated that SESN2 might be a novel pharmacological intervention strategy for SAE treatment through promotion of ULK1-dependent autophagy in hippocampal neurons.

[High-risk factors for early failure of high-flow nasal cannula oxygen therapy in children].

OBJECTIVE: To determine the high-risk factors for early failure of high-flow nasal cannula (HFNC) oxygen therapy in children with acute respiratory insufficiency (ARI). METHODS: The clinical data of 123 children with ARI were reviewed who received HFNC oxygen therapy in the pediatric intensive care unit from January to June, 2018. The children who did not require an upgrade of respiratory support during hospitalization and were successfully weaned from HFNC were classified as HFNC success group (69 cases). Of the remaining children (54 cases) who required an upgrade of their respiratory support during hospitalization, those that needed to upgrade their respiratory support within 48 hours of receiving HFNC were classified as early HFNC failure group (46 cases). Risk factors for early failure of HFNC were determined using multivariate logistic regression analysis. RESULTS: The incidence rates of shock, sepsis, intracranial hypertension syndrome, and multiple organ dysfunction syndrome were significantly higher in the early HFNC failure group than in the HFNC success group (P<0.05). Before implementation of respiratory support, the early HFNC failure group had significantly lower Glasgow coma score, pH value, and oxygenation index and significantly higher Pediatric Risk of Mortality (PRISM) score and PaCO2/PaO2 ratio than the HFNC success group (P<0.05). Multivariate logistic regression analysis showed that PRISM score >4.5 and PaCO2/PaO2 ratio >0.64 were independent risk factors for early HFNC failure (OR=5.535 and 9.089 respectively; P<0.05). CONCLUSIONS: Pediatric ARI patients with PRISM score >4.5 or PaCO2/PaO2 ratio >0.64 have relatively high risk of early HFNC failure.

Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study.

Kaposiform hemangioendothelioma (KHE) is an aggressive disease with high morbidity and mortality. The aim of this study was to retrospectively evaluate the efficacy and safety of sirolimus for the treatment of progressive KHE. A multicenter, retrospective cohort study was conducted in patients with progressive KHE treated with sirolimus. A total of 52 patients were analyzed. Thirty-seven (71%) patients exhibited Kasabach-Merritt phenomenon (KMP) and were significantly younger than the patients without KMP [95% confidence interval (CI), 14.39-41.61; p < 0.001]. Patients without KMP were all treated with sirolimus alone, whereas 21 KMP patients with severe symptoms received short-term combination therapy with prednisolone. Overall, 96% and 98% of patients showed improved relief of notable symptoms and/or improved complications at 6 and 12 months after treatment, respectively. After sirolimus treatment, significant decreases in mean severity scores occurred at 6 months (95% CI, 2.23-2.54, p < 0.001) and 12 months (95% CI, 1.53-1.90, p < 0.001). Compared to KMP patients, patients without KMP showed a response that was similar to but less pronounced during the 12 months of treatment (95% CI, 40.87-53.80; p < 0.001). For subgroup analysis of KMP patients, there were no significant differences in tumor shrinkage between those treated with combination therapy and those receiving sirolimus alone (95% CI, 18.11-25.02; p > 0.05). No patients permanently discontinued treatment due to toxicity-related events, and no drug-related deaths occurred. Sirolimus was effective and safe for the treatment of progressive KHE. Sirolimus may be considered as a first-line therapy or as part of a multidisciplinary approach for the treatment of KHE.

[Role of c-Jun N-terminal kinase-mediated FOXO3a nuclear translocation in neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage].

OBJECTIVE: To explore the mechanisms of neuroprotective effects of c-Jun N-terminal kinase (JNK)/FOXO3a transcription factor signaling pathway inhibition on hypoxic-ischemic neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). METHODS: Sixty-four 7-day-old Sprague-Dawley rats were divided into four groups: hypoxia-ischemia (HI), sham-operated, JNK specific inhibitor AS601245-treated, and DMSO vehicle. Rats' cerebral cortexes were collected at 24 hours after HI. Western blot was used to detect the protein expression of JNK, p-JNK, FOXO3a, nuclear and cytoplasmic FOXO3a, Bim, and CC3. TUNEL staining was used to detect the apoptotic cells. RESULTS: Compared with the sham-operated group, p-JNK protein increased (P<0.01), nuclear protein of FOXO3a increased (P<0.01), cytoplasmic protein decreased (P<0.01), and pro-apoptotic proteins Bim and CC3 increased 24 hours after HI (P<0.01). Compared with the HI and DMSO vehicle groups, p-JNK protein was reduced (P<0.01), nuclear protein of FOXO3a was also reduced (P<0.01), cytoplasmic protein increased (P<0.01), and Bim and CC3 proteins decreased (P<0.01) in the AS601245-treated group 24 hours after HI. TUNEL positive cells were reduced in the AS601245-treated rats compared with the HI and DMSO vehicle groups 24 hours after HI (P<0.01). CONCLUSIONS: JNK activity increases in the neonatal rat brain with HI damage. JNK activity inhibition can inhibit FOXO3a translocation from cytoplasm to nucleus and downregulate the levels of pro-apoptotic proteins Bim and CC3, leading to the reduction of neuronal apoptosis.

A supercharged fluorescent protein as a versatile probe for homogeneous DNA detection and methylation analysis.

Supercharged proteins are a new class of functional proteins with exceptional stability and potent ability to deliver bio-macromolecules into cells. As a proof-of-principle, a novel application of supercharged proteins as a versatile biosensing platform for nucleic acid detection and epigenetics analysis is presented. Taking supercharged green fluorescent protein (ScGFP) as the signal reporter, a simple turn-on homogenous method for DNA detection has been developed based on the polyionic nanoscale complex of ScGFP/DNA and toehold strand displacement. This assay shows high sensitivity and potent ability to detect single-base mismatch. Furthermore, combined with bisulfite conversion, this ScGFP-based assay was further applied to analyze site-specific DNA methylation status of genomic DNA extracted from real human colon carcinoma tissue sample with ultrahigh sensitivity (4 amol methylated DNA).

Concurrent infection of Exophiala dermatitidis and Angiostrongylus cantonensis in central nervous system of a child with inherited CARD9 deficiency: A case report and literature review.

Exophiala dermatitidis is a relatively common environmental black yeast with a worldwide distribution that rarely causes fungal infection. Here, we report a case of a 6-year-old girl with central nervous system (CNS) encephalitis caused by E. dermatitidis and Angiostrongylus cantonensis. E. dermatitidis was identified by both cerebrospinal fluid culture and metagenomic next-generation sequencing (mNGS). Angiostrongylus cantonensis infection was confirmed by an enzyme linked immunosorbent assay (ELISA). Whole exome sequencing showed that this previously healthy girl carried a homozygous CARD9 mutation for c.820dupG (p.D274Gfs*61) that underlies invasive fungal and parasite infections. We chose glucocortieoid pulse therapy and anti-infective therapy based on the initial results of laboratory examination and cranial MRI images. With the aggravation of the disease and the evidence of the subsequent etiologic test, the combination of antifungal antiparasitic treatments (voriconazole, fluorocytosine and amphotericin B) were actively used. Unfortunately, the girl finally died due to severe systemic infection. mNGS performs a potential value for diagnosing rare CNS infections, and autosomal recessive CARD9 deficiency should be considered in patient with fatal invasive fungal infections.

Metagenomic next-generation sequencing in a diagnosis of Pneumocystis pneumonia in an X-linked immunodeficient child: a case report.

Background: The diagnosis of Pneumocystis pneumonia (PCP) remains challenging in certain specific clinical situations. Metagenomic next-generation sequencing (mNGS), as a novel diagnostic method, may help in the diagnosis of PCP. Case presentation: A 6-month-old male child developed acute pneumonia and sepsis. This child had previously suffered from Escherichia coli septicemia and was cured. However, the fever and dyspnea relapsed. Blood tests revealed a low lymphocyte count (0.69 × 109/L) and acute inflammatory markers such as high-level procalcitonin (8.0 ng/ml) and C-reactive protein (19 mg/dl). Chest imaging showed inflammation and decreased translucency in both lungs but no thymus shadow. Various serology tests, the 1,3-beta-D-glucan test, culture, as well as sputum smear failed to detect any pathogens. mNGS with blood helped identify 133 specific nucleic acid sequences of Pneumocystis jirovecii, suggesting an infection with this pathogen. After treatment with trimethoprim-sulfamethoxazole for 5 days, the patient's condition improved, but the child still needed ventilator support. Unfortunately, the child died soon after because of respiratory failure after his parents decided to abandon treatment. The family declined an autopsy on the child, and therefore, an anatomical diagnosis could not be obtained. Whole-exome sequencing suggested X-linked immunodeficiency. A hemizygous mutation of c.865c > t (p.r289*) was detected in the IL2RG gene, which was inherited from the mother (heterozygous state). Conclusion: This case report highlights the value of mNGS in diagnosing PCP when conventional diagnostic methods fail to identify the agent. Early onset of recurrent infectious diseases may indicate the presence of an immunodeficiency disease, for which timely genetic analysis and diagnosis are crucial.

Association between hyponatremia and adverse clinical outcomes of heart failure: current evidence based on a systematic review and meta-analysis.

Background: Heart failure (HF) is a global health challenge. The perturbations in fluid and electrolyte equilibrium, particularly the compromised sodium balance associated with HF lead to high mortality rates. Hence, elucidating the correlation between serum sodium levels and the prognosis of HF is of paramount importance. This study aimed to conduct a comprehensive meta-analysis to thoroughly investigate the interplay between hyponatremia and the prognostic outlook of individuals with HF. Methods: A comprehensive search of bibliographic databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify relevant observational studies examining the association between hyponatremia and prognosis of HF. Data extraction, synthesis, and assessment of risk of bias were conducted. Meta-analytic methods, sensitivity analyses, and heterogeneity test were employed as appropriate to synthesize the data. Results: A total of 43,316 patients with HF were included spanning 25 selected studies. The pooled data revealed a notable association between hyponatremia and elevated risks across short and long-term mortality of HF. Specifically, hyponatremia was found to significantly increase the likelihood of all-cause mortality (Hazard ratio [HR] = 1.94, 95% confidence interval [CI]: 1.78-2.12); 1-year mortality (HR = 1.67, 95%CI: 1.46-1.90); 30-day mortality (HR = 2.03, 95%CI: 1.73-2.25); cardiac mortality (HR = 2.11, 95%CI: 1.81-2.46); and in-hospital mortality (HR = 1.64, 95%CI: 1.15-2.34). Conclusion: Our meta-analysis emphasizes the significant impact of hyponatremia on mortality in the HF patient population, highlighting the critical importance of maintaining stable serum sodium levels in HF management.

Mycoplasma infection aggravates cardiac involvements in Kawasaki diseases: a retrospective study.

Background: Mycoplasma pneumoniae (MP) infection serves as a substantial cofactor in Kawasaki disease (KD) among patients. Although the dominant issue triggering KD has recently focused on MP infection, the complete demonstration of the relationship between MP infection and KD remains elusive. This study endeavors to scrutinize and compare the clinical manifestations and cardiac involvement between MP-triggered KD and non-infection-associated KD. Method: This retrospective study (2023-039, approved by the Institutional Review Board of West China Second University Hospital of Sichuan University) encompassed 247 consecutive patients diagnosed with KD between June 2017 and December 2022. Patients were categorized into two groups: the MP group (n = 38) and the non-MP group (n = 209). Univariable analysis was utilized to discern differences in clinical features, severity of inflammation, and initial or persistent cardiac complications between the two groups. Results: The MP group exhibited a more intricate clinical profile compared with the non-MP group, characterized by prolonged hospital stays, a higher incidence of incomplete KD, and elevated comorbidities. In addition, MP infection correlated with severe hematological disorders, coagulation dysfunction, and myocardial injuries. Our findings revealed that MP infection led to prolonged inflammation after initial treatment with intravenous immunoglobulin. Although initial cardiac assessments failed to discern disparities between the two groups, MP infection notably exacerbated coronary artery aneurysms (CAAs), resulting in sustained dilation. Conclusions: Recognizing MP infection as a significant infectious factor associated with KD is imperative. In patients with KD, MP infection significantly prolongs inflammation and causes hematological disturbances during the initial treatment phase. Moreover, the presence of MP infection exacerbates the progression of CAAs and myocardial injuries during the subacute phase of KD, consequently contributing to the persistence of CAAs.

A novel homozygous variant of TMEM260 induced cardiac malformation and neurodevelopmental abnormality: case report and literature review.

Background: Congenital heart disease (CHD) represents the most widespread congenital birth defect among neonates worldwide, leading to substantial expenses and contributing significantly to premature death caused by birth defects. Despite the significance of CHD, research on its etiology remains limited and has failed to provide substantial evidence for the molecular basis of the disease. With the advancement of next-generation sequencing (NGS), genetic screening has become increasingly accessible, offering a greater capability for identifying potential genetic variants associated with CHD. Case presentation: Exome sequencing and variant analysis of TMEM260 were performed to obtain genetic data, and clinical characteristics were determined. A complex and severe form of CHD, comprising a persistent truncus arteriosus type I, ventricular septal defect, right aortic arch, as well as critical neurodevelopmental delay and neurological dysfunction, was observed in a patient. This proband presented global muscle hypotonia and a significant delay in gross and fine motor development. Cranial computed tomography scanning showed the presence of bilateral apical, occipital, and temporal subdural effusions; slightly wider bilateral lateral ventricles and annular cisterns; and bilateral cerebral hemispheric parenchyma atrophy. Upon genetic analysis of the patient, a novel homozygous mutation was identified in the TMEM260 gene. The mutation, c.1336_1339DEL, was found to be homozygous and resulted in a frameshift mutation, causing a p.L447Vfs*9 amino acid change. This mutation led to the deletion of a TCTC sequence from positions 1336 to 1339 in the TMEM260 gene, changing leucine to valine at amino acid 447 and introducing a stop codon after the ninth amino acid. This structural deletion in the TMEM260 protein resulted in the loss of gene function. Conclusion: This case report presents a newly discovered variant site in the TMEM260 gene and reinforces the relationship between TMEM260 molecular function and differentiation of mesoderm and ectoderm. Furthermore, our findings broaden the spectrum of variants in the TMEM260 gene and contribute to advancing the genetic understanding of CHD.

Single cell RNA-seq resolution revealed CCR1+/SELL+/XAF+ CD14 monocytes mediated vascular endothelial cell injuries in Kawasaki disease and COVID-19.

INTRODUCTION: The COVID-19 pandemic provide the opportunities to explore the numerous similarities in clinical symptoms with Kawasaki disease (KD), including severe vasculitis. Despite this, the underlying mechanisms of vascular injury in both KD and COVID-19 remain elusive. To identify these mechanisms, this study employs single-cell RNA sequencing to explore the molecular mechanisms of immune responses in vasculitis, and validate the results through in vitro experiments. METHOD: The single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs) was carried out to investigate the molecular mechanisms of immune responses in vasculitis in KD and COVID-19. The analysis was performed on PBMCs from six children diagnosed with complete KD, three age-matched KD healthy controls (KHC), six COVID-19 patients (COV), three influenza patients (FLU), and four healthy controls (CHC). The results from the scRNA-seq analysis were validated through flow cytometry and immunofluorescence experiments on additional human samples. Subsequently, monocyte adhesion assays, immunofluorescence, and quantitative polymerase chain reaction (qPCR) were used to analyze the damages to endothelial cells post-interaction with monocytes in HUVEC and THP1 cultures. RESULTS: The scRNA-seq analysis revealed the potential cellular types involved and the alterations in genetic transcriptions in the inflammatory responses. The findings indicated that while the immune cell compositions had been altered in KD and COV patients, and the ratio of CD14+ monocytes were both elevated in KD and COV. While the CD14+ monocytes share a large scale of same differentiated expressed geens between KD and COV. The differential activation of CD14 and CD16 monocytes was found to respond to both endothelial and epithelial dysfunctions. Furthermore, SELL+/CCR1+/XAF1+ CD14 monocytes were seen to enhance the adhesion and damage to endothelial cells. The results also showed that different types of B cells were involved in both KD and COV, while only the activation of T cells was recorded in KD. CONCLUSION: In conclusion, our study demonstrated the role of the innate immune response in the regulation of endothelial dysfunction in both KD and COVID-19. Additionally, our findings indicate that the adaptive immunity activation differs between KD and COVID-19. Our results demonstrate that monocytes in COVID-19 exhibit adhesion to both endothelial cells and alveolar epithelial cells, thus providing insight into the mechanisms and shared phenotypes between KD and COVID-19.

Impact of age and tumor size on the development of the Kasabach-Merritt phenomenon in patients with kaposiform hemangioendothelioma: a retrospective cohort study.

Introduction: The Kasabach-Merritt phenomenon (KMP) is a severe complication of kaposiform hemangioendothelioma (KHE). The risk factors for KMP need further investigation. Methods: The medical records of patients with KHE were reviewed. Univariate and multivariate logistic regression models were used for the risk factors for KMP, and the area under the receiver operator characteristic (ROC) curve was used to assess the predictive power of risk factors. Results: A total of 338 patients with KHE were enrolled. The incidence of KMP was 45.9%. Age of onset (P < 0.001, odds ratio [OR] 0.939; 95% confidence interval [CI] 0.914-0.966), lesion size (P < 0.001, OR 1.944; 95% CI 1.646-2.296), mixed type (P = 0.030, OR 2.428; 95% CI 1.092-5.397), deep type (P = 0.010, OR 4.006; 95% CI 1.389-11.556), and mediastinal or retroperitoneal lesion location (P = 0.019, OR 11.864; 95% CI 1.497-94.003) were correlated with KMP occurrence through multivariate logistic regression. ROC curve analysis revealed that the optimal cutoffs were 4.75 months for the age of onset (P < 0.001, OR 7.206, 95% CI 4.073-12.749) and a lesion diameter of 5.35 cm (P < 0.001, OR 11.817, 95% CI 7.084-19.714). Bounded by a lesion size of 5.35 cm, we found significant differences in tumor morphology, age of onset, treatments, and hematological parameters. Using an onset age of 4.75 months as a cutoff, we found significant differences in tumor morphology, lesion size, hematological parameters, and prognosis. Conclusion: For KHE patients with an onset age <4.75 months and/or lesion diameter >5.35 cm, clinicians should be wary of the occurrence of KMP. Active management is recommended to improve the prognosis.

A Leigh syndrome caused by compound heterozygous mutations on NDUFAF5 induce early infant death: A case report.

BACKGROUND: The NADH:ubiquinone oxidoreductase complex assembly factor gene (NDUFAF5) has been linked to the occurrence of Leigh syndrome, but few causative mutations have been identified. Here we report a rare case of Leigh syndrome in an infant who died in the early postnatal period. METHODS: We performed whole-exome sequencing (WES) and mutation analysis of NDUFAF5 to obtain genetic data on the patient and describe the clinical and genetic characteristics. RESULTS: The proband was a 2-month-old male infant who suffered from recurrent vomiting and persistent seizure and died at 2 months of age after early medical support and treatment. His parents reported the unexplained death of the infant's older brother at 1 year of age. WES of the patient's DNA revealed c.357C>G and c.611C>T compound heterozygous mutations in NDUFAF5; analysis with the MutationTaster application indicated that both were pathogenic (p = 0.99). Significant structural changes in the transport domain of the protein were predicted using SWISS-MODEL. We estimated the stability of the mutant protein using a mutation cutoff scanning matrix and found reductions in Gibbs free energy (-0.623 kcal/mol for p.D119E and -0.813 kcal/mol for p.A204V), indicating that the mutations led to an unstable protein structure. We speculated that the patient died as a result of impaired mitochondrial function caused by the NDUFAF5 mutations, and made a diagnosis of Leigh syndrome. CONCLUSION: Our results demonstrate that molecular genetic screening is useful for the diagnosis of mitochondrial diseases, especially in children with a positive family history. Leigh syndrome should be considered in the diagnosis of patients presenting with severe recurrent vomiting and feeding difficulties with persistent seizure. Our findings expand the mutation spectrum of the NDUFAF5 gene and contribute to the genotype-phenotype map of mitochondrial respiratory chain complex I deficiency.

Exome sequencing contributes to identify comorbidities in a rare case of infant ARDS induced by the CD40LG mutation.

BACKGROUND: Acute respiratory distress syndrome (ARDS) causes significant mortality in young children with certain diseases. Early diagnosis and treatment can reduce infant mortality. Here, we report a rare case of exome sequencing in the early diagnosis of immunodeficiency in an infant. CASE PRESENTATION: A four-month-old full-term male infant presented with severe shortness of breath, hypoxemia, and unexplained parenchymal lung lesions. A series of examinations were performed to search for potential culprit viruses but negative results were obtained with the only exception being the rhinovirus that tested positive. The child's family history revealed he had a brother who died of severe infection at the age of two years. We performed an exome sequencing analysis and a mutation analysis of CD40LG to obtain genetic data on the patient. Besides, we used flow cytometry to measure the CD40LG expression levels of activated T cells. A retrospective review of all the CD40LG mutant-induced X-linked hyper IgM syndromes (XHIGM) had been conducted to assess the differences between clinical and genetic molecular features. Finally, a regular intravenous immunoglobulin (IVIG) regimen led to steady breathing, the correction of hypoxemia, and a progressive improvement of lung CT scans. During follow-up, the patient received an IVIG regimen and his CT images improved. Moreover, his parents took advantage of pre-implantation genetic testing with in vitro fertilization to have a healthy twin offspring who did not carry such a mutation according to the early exome sequencing for the proband. Compared with other CD40LG mutant cases in our center, this proband displayed a normal plasma immunoglobulin level and he should be the youngest infant to have a molecular diagnosis of XHIGM. CONCLUSION: Usually, XHIGM would not be suspected with a normal plasma immunoglobulin concentration. However, as we could not identify a potential comorbidity or risk factor, exome sequencing helps target this patient's real facts. Thus, this case report calls for exome sequencing to be performed in the case of unexplained infections when immunodeficiency is suspected after general immunological tests, especially for cases with a contributive family history among infants as the maternal transfused immunoglobulin might mask immune deficiency.

U-shaped association between serum albumin and pediatric intensive care unit mortality in critically ill children.

Introduction: The detailed association between albumin levels and mortality has not been studied in critically ill children. The aim of this study was to reveal an association between albumin levels in detail and mortality in critically ill children. Materials and methods: We retrospectively collected data from children admitted to four pediatric intensive care units (PICUs) in China between January 2015 and October 2020. Restricted cubic spline curves based on logistic regression models were generated to evaluate the detailed associations between serum albumin levels and PICU mortality. Threshold effect analysis was performed using two piecewise regression models. Results: The study included 9,123 children. The overall mortality was 5.3%. The detailed association between serum albumin levels and the risk of mortality followed a U-shape. The risk of mortality decreased with increasing serum albumin levels (OR = 0.919; 95% CI: 0.886, 0.954) in children with serum albumin levels < 43.2 g/L and increased with increasing serum albumin levels (OR = 1.174; 95% CI: 1.044, 1.316) in children with serum albumin levels ≥ 43.2 g/L. Conclusion: There was a U-shaped association between serum albumin levels and mortality in critically ill children in the PICU.

Performance of the PRISM I, PIM2, PELOD-2 and PRISM IV scoring systems in western China: a multicenter prospective study.

BACKGROUND: The aim of this study was to evaluate the performance of the four scoring tools in predicting mortality in pediatric intensive care units (PICUs) in western China. METHODS: This was a multicenter, prospective, cohort study conducted in six PICUs in western China. The performances of the scoring systems were evaluated based on both discrimination and calibration. Discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUC) for each model. Calibration was measured across defined groups based on mortality risk using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: A total of 2034 patients were included in this study, of whom 127 (6.2%) died. For the entire cohort, AUCs for Pediatric Risk of Mortality Score (PRISM) I, Pediatric Index of Mortality 2 (PIM2), Pediatric Logistic Organ Dysfunction Score-2 (PELOD-2) and PRISM IV were 0.88 [95% confidence interval (CI) 0.85-0.92], 0.84 (95% CI 0.80-0.88), 0.80 (95% CI 0.75-0.85), and 0.91 (95% CI 0.88-0.94), respectively. The Hosmer-Lemeshow goodness-of-fit Chi-square value was 12.71 (P = 0.12) for PRISM I, 4.70 (P = 0.79) for PIM2, 205.98 (P < 0.001) for PELOD-2, and 7.50 (P = 0.48) for PRISM IV [degree of freedom (df) = 8]. The standardized mortality ratios obtained with the PRISM I, PIM2, PELOD-2, and PRISM IV models were 0.87 (95% CI, 0.75-1.01), 0.97 (95% CI, 0.85-1.12), 1.74 (95% CI, 1.58-1.92), and 1.05 (95% CI, 0.92-1.21), respectively. CONCLUSIONS: PRISM IV performed best and can be used as a prediction tool in PICUs in Western China. However, PRISM IV needs to be further validated in NICUs.

SLC10A2 deficiency-induced congenital chronic bile acid diarrhea and stunting.

BACKGROUND: Diarrhea is a common occurrence in children below the age of 5 years. In chronic cases, it induces malnutrition that severely stunts growth. Bile acid diarrhea (BAD), caused by malabsorption of bile acid (BA), is a rare form of chronic diarrhea seldom observed in pediatric patients. Here, we present a clinical report on a novel case of chronic BAD, with severe stunting in an infant, induced by a homozygous mutation of SLC10A2. METHODS: We performed DNA extraction, whole-exome sequencing analysis, and mutation analysis of SLC10A2 to obtain genetic data on the patient. We subsequently analyzed the patient's clinical and genetic data. RESULTS: The patient's clinical manifestations were chronic diarrhea with increased BAs in the feces and extreme stunting, which was diagnosed as BAD. A homozygous mutation of SLC10A2 at the c.313T>C (rs201206937) site was detected. CONCLUSION: Our report reveals the youngest case illustrating the characteristics of BAD induced by genetic variant at 313T>C, and the second case entailing a clear association between a SLC10A2 genetic mutation and the onset of BAD. Our findings expand the mutant spectrum of the SLC10A2 gene and contribute to the refinement of the genotype-phenotype mapping of severe stunting induced by pediatric BAD. Moreover, they highlight the value of molecular genetic screening for diagnosing BAD in young patients.