Critically ill children with SARS-COV-2 Omicron infection at a national children medical center, Guangdong, China.

BACKGROUND: SARS-CoV-2 infection is described as asymptomatic, mild, or moderate disease in most children. SARS-CoV-2 infection related death in children and adolescents is rare according to the current reports. COVID-19 cases increased significantly in China during the omicron surge, clinical data regarding pediatric critical patients infected with the omicron variant is limited. In this study, we aim to provide an overview of the clinical characteristics and outcomes of critically ill children admitted to a national children's medical center in Guangdong Province, China, during the outbreak of the omicron variant infection. METHODS: We conducted a retrospective study from November 25, 2022, to February 8, 2023, which included 63 critically ill children, under the age of 18, diagnosed with SARS-CoV-2 infection. The patients were referred from medical institutions of Guangdong province. The medical records of these patients were analyzed and summarized. RESULTS: The median age of patients was 2 years (Interquartile Range, IQR: 1.0-8.0), sex-ratio (male/female) was 1.52. 12 (19%) patients (age ≥ 3 years) were vaccinated. The median length of hospital stay was 14 days (IQR: 6.5-23) in 63 cases, and duration of fever was 5 days (IQR: 3-8.5), pediatric intensive care unit (PICU) stay was 8 days (IQR 4.0-14.0) in 57 cases. 30 (48%) cases had clear contact history with family members who were infected with SARS-CoV-2. Three children who tested positive for SARS-CoV-2 infection did not show any abnormalities on chest imaging examination. Out of the total patients, 33 (52%) had a bacterial co-infection, with Staphylococcus aureus being the most commonly detected bacterial pathogen. Our cohort exhibited respiratory and nervous system involvement as the primary features. Furthermore, fifty (79%) patients required mechanical ventilation, with a median duration of 7 days (IQR 3.75-13.0). Among these patients, 35 (56%) developed respiratory failure, 16 (25%) patients experienced a deteriorating progression of symptoms and ultimately succumbed to the illness, septic shock was the most common condition among these patients (15 cases), followed by multiple organ failure in 12 cases, and encephalopathy identified in 7 cases. CONCLUSION: We present a case series of critically ill children infected with the SARS-CoV-2 omicron variant. While there is evidence suggesting that Omicron may cause less severe symptoms, it is important to continue striving for measures that can minimize the pathogenic impact of SARS-CoV-2 infection in children.

A Retrospective Study of Clinical and Immunological Features of a Pediatric Population with Talaromyces marneffei Infection.

BACKGROUND: Talaromyces marneffei (T. Marneffei) infection is considered as an indicator of immunosuppression in immunocompromised individuals, leading to multiple organ damage. Our study aimed to evaluate both the clinical characteristics and immunological features of pediatric patients infected with T. marneffei from our institute, providing novel insights into diagnosis and treatment for this life-threatening disease. METHOD: Thirteen pediatric patients with T. marneffei infection were enrolled in Guangzhou Women and Children's Medical Center during 2012 to 2020. Clinical data and laboratory findings were collected and further analyzed. Pearson correlation coefficient was calculated to determine the relationship between serum immunoglobulins (Igs) levels and white blood cell count, or the absolute lymphocyte count. RESULTS: Patients were diagnosed as having T. Marneffei infection mainly based on the results of fungal culture and Gram stain of specimens. The most common presentations were fever (69%), pneumonia (38%) and immunodeficiency (38%). The total levels of Igs (IgE, IgA, and IgM) were positively correlated with both white blood cell count and absolute lymphocyte count. CONCLUSION: Serum Ig expression Pattern in patients diagnosed with T. marneffei infection might serve as an effective prognostic marker which would help with the development of early interventions for children with this fatal disease.

Immune Cell-Related Genes in Juvenile Idiopathic Arthritis Identified Using Transcriptomic and Single-Cell Sequencing Data.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. The heterogeneity of the disease can be investigated via single-cell RNA sequencing (scRNA-seq) for its gap in the literature. Firstly, five types of immune cells (plasma cells, naive CD4 T cells, memory-activated CD4 T cells, eosinophils, and neutrophils) were significantly different between normal control (NC) and JIA samples. WGCNA was performed to identify genes that exhibited the highest correlation to differential immune cells. Then, 168 differentially expressed immune cell-related genes (DE-ICRGs) were identified by overlapping 13,706 genes identified by WGCNA and 286 differentially expressed genes (DEGs) between JIA and NC specimens. Next, four key genes, namely SOCS3, JUN, CLEC4C, and NFKBIA, were identified by a protein-protein interaction (PPI) network and three machine learning algorithms. The results of functional enrichment revealed that SOCS3, JUN, and NFKBIA were all associated with hallmark TNF-α signaling via NF-κB. In addition, cells in JIA samples were clustered into four groups (B cell, monocyte, NK cell, and T cell groups) by single-cell data analysis. CLEC4C and JUN exhibited the highest level of expression in B cells; NFKBIA and SOCS3 exhibited the highest level of expression in monocytes. Finally, real-time quantitative PCR (RT-qPCR) revealed that the expression of three key genes was consistent with that determined by differential analysis. Our study revealed four key genes with prognostic value for JIA. Our findings could have potential implications for JIA treatment and investigation.

The role of PTEN in puromycin aminonucleoside-induced podocyte injury.

Podocytes are specialized cells of the glomerulus that play important structural and functional roles in maintaining the filtration barrier. Loss and injury of podocytes are leading factors of glomerular disease and kidney failure. Recent studies found that phosphatase and tensin homolog (PTEN) may play a critical role in maintaining the normal structure and function in podocytes. However, we still understand very little about how PTEN is regulated under podocyte injury conditions. In this study, We therefore investigated whether PTEN could play a role in podocyte injury induced by puromycin aminonucleoside (PAN), and whether dexamethasone (DEX) alleviates podocyte injury by PTEN/PI3K/Akt signaling. Our results showed that PI3K/Akt pathway was activated in podocytes exposed to PAN conditions, accompanied by down-regulation of the PTEN and microtubule-associated light chain 3 (LC3) expression.podocyte-specific knockout of PTEN significantly promoted podocyte injury, The potential renoprotection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and the inhibition of apoptosis.These novel findings also suggest that targeting PTEN might be a novel and promising therapeutic strategy against podocyte injury.

Characteristics of medicine use for children with asthma in China: a nationwide population-based study.

OBJECTIVE: To analyze the asthma medication use in Chinese children of different age groups, regions, and levels of cities in China, based on the 2015 Healthcare Insurance Data in China. METHODS: The China Healthcare Insurance Research Association (CHIRA) database was searched for children from 0 to 14 years old diagnosed as asthma based on the "J45" and "J46" coded in ICD-10. A cross-sectional study design was employed. RESULTS: A total of 308,550 children were identified, all of whom were treated under the coverage of healthcare insurance. Among them, 2,468 children were eligible for inclusion in the present study. Compared with the current status of asthma care in European and American countries, under the guidelines for the diagnosis and treatment of asthma in China, the use percentages of ICS and short-acting ß2 receptor agonist in children with asthma in China were lower, but the use percentages of oral corticosteroids, long-acting ß2 receptor agonist, and theophylline (especially intravenous theophylline) were higher, especially in the Central and West China. CONCLUSION: The asthma medication use was attributed to many factors, thus efforts are still needed to further popularize the GINA programs and China's guidelines for asthma diagnosis and treatment, especially in the Central and West China.

Vitronectin, a Novel Urinary Proteomic Biomarker, Promotes Cell Pyroptosis in Juvenile Systemic Lupus Erythematosus.

Objective: Identifying new markers of juvenile systemic lupus erythematosus (JSLE) is critical event to predict patient stratification and prognosis. The aim of the present study is to analyze alteration of urinary protein expression and screen potential valuable biomarkers in juvenile systemic lupus erythematosus (JSLE). Methods: The urine was collected from the patients with or without JSLE and detected by mass spectrometry to analyze proteomic changes. ELISA was used to verify the Vitronectin (VTN) changes in a new set of patients. The clinical correlation was performed to analyze between VTN and clinical pathological parameters. WB and ELISA were used to analyze VTN-mediated cell pyroptosis. Results: Herein, we have identified a group of 105 differentially expressed proteins with ≥1.3-fold upregulation or ≤0.77-fold downregulation in JSLE patients. These proteins were involved in several important biological processes, including acute phase inflammatory responses, complement activation, hemostasis, and immune system regulation through Gene Ontology and functional enrichment analysis. Interestingly, urinary ephrin type-A receptor 4 (EPHA4) and VTN were significantly reduced in both inactive and active JSLE patients, and VTN treatment in THP-1 derived macrophages led to a significant increased cell pyroptosis by activation of Nod-like receptor family protein 3 (NLRP3) inflammasomes, resulting in caspase-1 activation, cleaved gasdermin D (GSDMD), and IL-18 secretion. Most importantly, the urinary VTN was also linearly correlated with clinical characteristics of JSLE, implying that VTN could be a specific diagnostic biomarker to distinguish inactive and active JSLE. Conclusion: This study provided a novel role of VTN in pyroptosis in JSLE through the urinary proteomic profile for JSLE, which could be a nonintrusive monitoring strategy in clinical diagnosis.

Simultaneous determination of erythrocyte methotrexate polyglutamates by a novel and simple HPLC-MS/MS method with stable isotope-labeled internal standards.

Low-dose methotrexate is the first-line therapy for juvenile idiopathic arthritis. In vivo, methotrexate is converted into a series of methotrexate polyglutamates whose intracellular levels contribute significantly to its efficacy and toxicity. In this study, a novel high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to simultaneously determine erythrocyte methotrexate polyglutamates using stable isotope-labeled internal standards. Erythrocyte samples were precipitated by perchloric acid and then determined on an XBridge BEH C18 column with an XP vanguard precolumn in 12 min. The mobile phase consisted of 10 nM ammonium acetate (pH 10) and methanol under gradient elution. The detection was carried out in multiple reaction monitoring mode via an electrospray ionization source in positive ionization mode. The calibration curve for each metabolite was linear from 2.0 to 500.0 nmol/L (r2  > 0.99). The intraday and interday accuracies were between 93.0 and 107.0%, and the corresponding precisions were between 0.8 and 5.2%. The relative recovery ranged from 82.7 to 105.1%, and the relative matrix effect varied from 96.5 to 104.4%. The erythrocyte metabolites were stable for 30 days at -80°C. This simple and accurate method is applicable to routine monitoring of the concentration of erythrocyte methotrexate polyglutamates in patients to achieve individualized treatment.

Two novel mutations in TCIRG1 induced infantile malignant osteopetrosis: a case report.

BACKGROUND: Infantile malignant osteopetrosis (IMO) is a rare autosomal recessive disease characterized by a higher bone density in bone marrow caused by the dysfunction of bone resorption. Clinically, IMO can be diagnosed with medical examination, bone mineral density test and whole genome sequencing. CASE PRESENTATION: We present the case of a 4-month-old male infant with abnormal skull development, hypocalcemia and premature closure of the cranial sutures. Due to the hyper bone density showed by his radiographic examination, which are characteristic patterns of IMO, we speculated that he might be an IMO patient. In order to confirm this diagnosis, a high-precision whole exome sequencing of the infant and his parents was performed. The analysis of high-precision whole exome sequencing results lead to the identification of two novel heterozygous mutations c.504-1G > C (a splicing site mutation) and c.1371delC (p.G458Afs*70, a frameshift mutation) in gene TCIRG1 derived from his parents. Therefore, we propose that there is a close association between these two mutations and the onset of IMO. CONCLUSIONS: To date, these two novel mutations in gene TCIRG1 have not been reported in the reference gene database of Chinese population. These variants have likewise not been reported outside of China in the Genome Aggregation Database (gnomAD). Our case suggests that the use of whole exome sequencing to detect these two mutations will improve the identification and early diagnosis of IMO, and more specifically, the identification of homozygous individuals with TCIRG1 gene mutation. We propose that these mutations in gene TCIRG1 could be a novel therapeutic target for the IMO in the future.

Capillary electrophoresis based on nucleic acid analysis for diagnosing inherited diseases.

Most hereditary diseases are incurable, but their deterioration could be delayed or stopped if diagnosed timely. It is thus imperative to explore the state-of-the-art and high-efficient diagnostic techniques for precise analysis of the symptoms or early diagnosis of pre-symptoms. Diagnostics based on clinical presentations, hard to distinguish different phenotypes of the same genotype, or different genotypes displaying similar phenotypes, are incapable of pre-warning the disease status. Molecular diagnosis is ahead of harmful phenotype exhibition. However, conventional gold-standard molecular classifications, such as karyotype analysis, Southern blotting (SB) and sequencing, suffer drawbacks like low automation, low throughput, prolonged duration, being labor intensive and high cost. Also, deficiency in flexibility and diversity is observed to accommodate the development of precise and individualized diagnostics. The aforementioned pitfalls make them unadaptable to the increasing clinical demand for detecting and interpreting numerous samples in a rapid, accurate, high-throughput and cost-effective manner. Nevertheless, capillary electrophoresis based on genetic information analysis, with advantages of automation, high speed, high throughput, high efficiency, high resolution, digitization, versatility, miniature and cost-efficiency, coupled with flexible-designed PCR strategies in sample preparation (PCR-CE), exhibit an excellent power in deciphering cryptic molecular information of superficial symptoms of genetic diseases, and can analyze in parallel a large number of samples in a single PCR-CE, thereby providing an alternative, accurate, customized and timely diagnostic tool for routine screening of clinical samples on a large scale. Thus, the present study focuses on CE-based nucleic acid analysis used for inherited disease diagnosis. Also, the limitations and challenges of this PCR-CE for diagnosing hereditary diseases are discussed.

Gasdermins: pore-forming activities and beyond.

Gasdermins (GSDMs) belong to a protein superfamily that is found only in vertebrates and consists of GSDMA, GSDMB, GSDMC, GSDMD, DFNA5 (a.k.a. GSDME) and DFNB59 (a.k.a. Pejvakin (PJVK)) in humans. Except for DFNB59, all members of the GSDM superfamily contain a conserved two-domain structure (N-terminal and C-terminal domains) and share an autoinhibitory mechanism. When the N-terminal domain of these GSDMs is released, it possesses pore-forming activity that causes inflammatory death associated with the loss of cell membrane integrity and release of inflammatory mediators. It has also been found that spontaneous mutations occurring in the genes of GSDMs have been associated with the development of certain autoimmune disorders, as well as cancers. Here, we review the current knowledge of the expression profile and regulation of GSDMs and the important roles of this protein family in inflammatory cell death, tumorigenesis and other related diseases.

Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface.

BACKGROUND: Monogenic autoinflammatory disorders are characterized by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome-forming proteins, such as NOD-like receptor family CARD-containing 4 protein (NLRC4). OBJECTIVE: Here we investigate the mechanism by which a novel mutation in the leucine-rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease. METHODS: We studied 2 unrelated patients with early-onset macrophage activation syndrome harboring the same de novo mutation in NLRC4. In vitro inflammasome complex formation was quantified by using flow cytometric analysis of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 techniques and lentiviral transduction were used to generate THP-1 cells with either wild-type or mutant NLRC4 cDNA. Cell death and release of IL-1ß/IL-18 were quantified by using flow cytometry and ELISA, respectively. RESULTS: The p.W655C NLRC4 mutation caused increased ASC speck formation, caspase-1-dependent cell death, and IL-1ß/IL-18 production. ASC contributed to p.W655C NLRC4-mediated cytokine release but not cell death. Mutation of p.W655 activated the NLRC4 inflammasome complex by engaging with 2 interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012, and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or type 3 secretion system effector (PrgI) stimulation of the NLRC4 inflammasome complex. CONCLUSION: This is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important and previously unrecognized role in oligomerization of the NLRC4 inflammasome complex.

Capillary Electrophoresis Based on Nucleic Acid Detection as Used in Food Analysis.

Food safety and food production are closely related to the health of consumers. Food-related accidents often cause tremendous losses of personnel and property. Thus, rapid detection and analysis of ingredients in food, tracing food sources, studying the optimal conditions for food production, and more are vital for preventing incidents related to safety. Conventional analysis based on proteomics, microbial cultures, and morphology, as well as biochemical tests based on metabonomics, are considered gold standards and used frequently, but they are labor-intensive, time-consuming, tedious, error-prone, and incapable of meeting the demand for rapid and precise detection at a large scale. Alternative detection methods that utilize capillary electrophoresis have the advantages of high efficiency, high throughput, high speed, and automation; these methods are coupled with various nucleic acid detection strategies to overcome the drawbacks of traditional identification methods, and to prevent false results. Therefore, this review focuses on the application of capillary electrophoresis based on nucleic acid detection in food analysis and provides an introduction to the limitations, advantages, and future developments of this approach.

Clinical,biochemical and molecular analysis of five Chinese patients with Sandhoff disease.

Sandhoff disease (SD) is a rare autosomal recessive lysosomal storage disorder of sphingolipid metabolism resulting from the deficiency of ß-hexosaminidase (HEX). Mutations of the HEXB gene cause Sandhoff disease. In order to improve the diagnosis and expand the knowledge of the disease, we collected and analyzed relevant data of clinical diagnosis, biochemical investigation, and molecular mutational analysis in five Chinese patients with SD. The patients presented with heterogenous symptoms of neurologic deterioration. HEX activity in leukocytes was severely deficient. We identified seven different mutations, including three known mutations: IVS12-26G > A, p.T209I, p.I207V, and four novel mutations: p.P468PfsX62, p.L223P, p.Y463X, p.G549R. We also detected two different heterozygous mutations c.-122delC and c.-126C > T in the promoter which were suspected to be deleterious mutations. We attempted to correlate these mutations with the clinical presentation of the patients. Our study indicates that the mutation p.T209I and p.P468PfsX62 may link to the infantile form of SD. Our study expands the spectrum of genotype of SD in China, provides new insights into the molecular mechanism of SD and helps to the diagnosis and treatment of this disease.

[Analysis of genetic mutations and pathogenesis for two children with Omenn syndrome].

OBJECTIVE: To explore the clinical characteristics and genetic mutations in two children with Omenn syndromes. METHODS: Peripheral venous blood samples were collected from 2 children suspected with severe combined immunodeficiency (SCID) and their family members. The samples were subjected to RAG1 and RAG2 gene sequencing and TCR Vß subclone analysis. RESULTS: Both patients had recurrent infections, erythroderma rashes and alopecia baldness. One patient has fit with immunophenotype T-B-NK+, while another was consistent with typical Omenn syndrome combined with T+B-NK+ immunophenotype, IgE and eosinophil increase. Both children have carried compound heterozygous mutations of the RAG1 gene. The first patient carried c.1328 G>A (p.R443K) and c.2486-2490delGGAAA (p.R829fsX869) mutations, both were of de novel type. The second patient has carried c.1209C>T (p.R403W) and c.2892delT (p.ASN964LYSfs*14), with c.2892delT (p.ASN964LYSfs*14) being a de novel mutation. The parents of both patients were heterozygous carriers. The same mutations were not found in 100 healthy children. Both patients' 24 TCR Vß subfamilies have presented monoclonal or oligoclonal peaks, with TCR Vß polymorphism being severely disrupted. CONCLUSION: Three novel mutations have been identified in two children with Omenn syndrome, which featured early onset and rapid progression. Early recognition of the disease and prompt treatment may reduce the mortality.

[Analysis of single nucleotide polymorphisms at IL-6-174 and TNF-ß NcoI in Chinese Han children in Guangzhou, China].

OBJECTIVE: To investigate the single nucleotide polymorphisms (SNPs) at interleukin 6 (IL-6)-174 and TNF-ß NcoI in Chinese Han children in Guangzhou, China and to provide basic information for study on the association between IL-6-174 and TNF-ß NcoI polymorphisms and systemic inflammatory response syndrome (SIRS). METHODS: Allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism were used to determine the SNPs at IL-6-174 and TNF-ß NcoI in 481 children selected from the Han population in Guangzhou in 2012. Genotype analysis and comparison with other populations were made with reference to relevant literature. RESULTS: Chinese Han children in Guangzhou had only GG genotype at IL-6-174, and the SNP at this locus was rare or not seen in the Han population in Guangzhou. At TNF-ß NcoI, the frequencies of TNF-ß 1*1, TNF-ß 1*2, and TNF-ß 2*2 genotypes were 24.7%, 49.7%, and 25.6%, respectively. The sample distribution was in accordance with Hardy-Weinberg equilibrium. The TNF-ß 1 allele frequency was significantly higher in Guangzhou Han population than in European and American white population (P<0.05). CONCLUSIONS: TNF-ß NcoI SNP is prevalent in the Han population in Guangzhou, and the distribution of alleles is significantly different from that in the white population. The sample from an Hardy-Weinberg equilibrium population can be further used for study on the association between TNF-ß NcoI SNP and SIRS in Chinese Han children in Guangzhou. IL-6-174 SNP is rare or not seen in the Han population in Guangzhou, so SNP at this locus cannot be selected for disease association analysis.

Multicentric carpotarsal osteolysis syndrome with variants of MAFB gene: a case report and literature review.

BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) is a rare genetic disorder characterized by the progressive loss of bone in the hands, feet, and other skeletal structures. It presents with symptoms that may resemble those of juvenile idiopathic arthritis, making diagnosis challenging for clinicians. The identification of MAF BZIP Transcription Factor B (MAFB) mutations as significant contributors to MCTO represents a major breakthrough in our understanding of the pathogenesis of this rare skeletal disorder. CASE PRESENTATION: Our objective was to present the phenotype, treatment, and outcome of a patient with a variant of MAFB-induced MCTO to broaden the range of clinical features associated with MCTO and share our clinical experience for improved diagnosis and treatment. In our case, early MRI examination of the bones and whole exome sequencing enabled an early and accurate MCTO diagnosis, and timely Denosumab administration resulted in no deterioration. CONCLUSION: This suggests that MRI examination and whole exome sequencing should be considered when MCTO is suspected, and Denosumab might be an option in the treatment of MCTO.

Single-cell profiling of peripheral blood and muscle cells reveals inflammatory features of juvenile dermatomyositis.

Introduction: Juvenile dermatomyositis (JDM) is a rare yet serious childhood systemic autoimmune condition that primarily causes skin rashes and inflammatory myopathy of the proximal muscles. Although the associated immune response involves the innate and adaptive arms, a detailed analysis of the pertinent immune cells remains to be performed. This study aims to investigate the dynamic changes of cell type, cell composition and transcriptional profiles in peripheral blood and muscle tissues, and in order to clarify the involvement of immune cells in the pathogenesis of JDM and provide a theoretical reference for JDM. Methods: Single-cell RNA sequencing combined with bioinformatic analyses were used to investigate the dynamic changes in cell composition and transcriptional profiles. Results: Analysis of 45,859 cells revealed nine and seven distinct cell subsets in the peripheral blood and muscle tissues respectively. IFITM2+ and CYP4F3+ monocytes were largely produced, and CD74+ smooth muscle cells (SMCs) and CCL19+ fibroblasts were identified as inflammatory-related cell subtypes in JDM patients, exhibiting patient-specific cell population heterogeneity.The dynamic gene expression patterns presented an enhanced type I interferon response in peripheral blood monocytes and T-cells, and SMCs and fibroblasts in muscle of untreated JDM patients. EGR1 and IRF7 may play central roles in the inflammation in both CD74+ SMCs and CCL19+ fibroblasts. Moreover, inflammatory-related monocytes could regulate T-cells, and the interaction between immune cells and SMCs or fibroblasts in muscle was enhanced under the inflammatory state. Conclusions: Immune dysregulation is one of the key pathogenic factors of JDM, and type I interferon responses are significantly enhanced in peripheral blood Monos and T cells as well as SMCs and fibroblasts. EGR1 and IRF7 may play central roles in the inflammation and are considered as potential therapeutic targets for JDM.

Case report: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay: Three cases and a literature review.

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is a serious autosomal recessive syndrome caused by biallelic mutations in cytosine-cytosine-adenosine tRNA nucleotidyltransferase 1 (TRNT1). The main clinical features of SIFD are periodic fevers, developmental delay, sideroblastic or microcytic anemia, and immunodeficiency. Herein, we report three cases of SIFD with compound heterozygous variants of TRNT1. Patients 1 and 2 were siblings; they presented with periodic fevers, arthritis, low immunoglobulin A, bilateral cataracts, anemia, and neurodevelopmental and developmental delay. Patient 3 had severed clinical features with recurrent fever and infections. She was treated with infliximab and symptomatic treatments but without therapeutic effect. She received a stem cell transplantation of umbilical cord blood but died of posttransplant infection and posttransplant graft-vs.-host disease 17 days after transplantation. Finally, a literature review revealed that TRNT1 variants differed among SIFD patients. Our cases and literature review further expand existing knowledge on the phenotype and TRNT1 variations of SIFD and suggest that the early genomic diagnosis of TRNT1 is valuable to promptly assess bone marrow transplantation and tumor necrosis factor inhibitor treatments, which might be effective for the immunodeficiency and inflammation caused by SIFD.

Tacrolimus in the treatment of childhood nephrotic syndrome: Machine learning detects novel biomarkers and predicts efficacy.

STUDY OBJECTIVE: The pharmacokinetics and pharmacodynamics of tacrolimus (TAC) vary greatly among individuals, hindering its precise utilization. Moreover, effective models for the early prediction of TAC efficacy in patients with nephrotic syndrome (NS) are lacking. We aimed to identify key factors affecting TAC efficacy and develop efficacy prediction models for childhood NS using machine learning algorithms. DESIGN: This was an observational cohort study of patients with pediatric refractory NS. SETTING: Guangzhou Women and Children's Medical Center between June 2013 and December 2018. PATIENTS: 203 patients with pediatric refractory NS were used for model generation and 35 patients were used for model validation. INTERVENTION: All patients regularly received double immunosuppressive therapy comprising TAC and low-dose prednisone or methylprednisolone. In this observational cohort study of 203 pediatric patients with refractory NS, clinical and genetic variables, including single-nucleotide polymorphism (SNPs), were identified. TAC efficacy was evaluated 3 months after administration according to two different evaluation criteria: response or non-response (Group 1) and complete remission, partial remission, or non-remission (Group 2). MEASUREMENTS: Logistic regression, extremely random trees, gradient boosting decision trees, random forest, and extreme gradient boosting algorithms were used to develop and validate the models. Prediction models were validated among a cohort of 35 patients with NS. MAIN RESULTS: The random forest models performed best in both groups, and the area under the receiver operating characteristics curve of these two models was 80.7% (Group 1) and 80.3% (Group 2). These prediction models included urine erythrocyte count before administration, steroid types, and eight SNPs (ITGB4 rs2290460, TRPC6 rs3824934, CTGF rs9399005, IL13 rs20541, NFKBIA rs8904, NFKBIA rs8016947, MAP3K11 rs7946115, and SMARCAL1 rs11886806). CONCLUSIONS: Two pre-administration models with good predictive performance for TAC response of patients with NS were developed and validated using machine learning algorithms. These accurate models could assist clinicians in predicting TAC efficacy in pediatric patients with NS before utilization to avoid treatment failure or adverse effects.