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T cell receptor excision circles (TRECs) are small circularized DNA elements produced during rearrangement of T cell receptor (TCR) genes. Because TRECs are fairly stable, do not replicate during mitosis, and are not diluted during division of naïve T cells (Dion et al. [1]), they are suitable for assessing the number of newly formed T cells (Ping and Denise [2]). In this study, we detected TRECs in 521 healthy Chinese children aged 0–18 years in different clinical settings. The TRECs decrease with aging and show lower levels in preterm and low birth weight (BW) babies compared to those in full-term infants, while the preterm babies can also show comparable levels of TRECs when they have a gestation age (GA)–matched BW. We found a strong correlation between TRECs and peripheral CD4 naïve T cell numbers, which was age-related. We also analyzed the TRECs in different PIDs. Since T cell defects vary in PIDs, TREC levels change inconsistently. For example, in Wiskott-Aldrich syndrome (WAS), combining the level of TREC with lymphocyte subsets can help to distinguish subtypes of disease. Conclusion: We established the reference value range for TRECs by evaluating children below 18 years old in China, which could be used to screen for PIDs during early life. What is Known: • The TREC levels are decreased with age, and there is a positive correlation between TRECs and the numbers of naïve T cells. What is New: • This is the largest study to determine TREC reference levels in healthy Chinese pediatric, we provide solid data showing a correlation between CD4 naïve T cell counts and TREC levels according to age. We point out the GA matched BW is need to be considered during the SCID newborn screening. We are the first group showed that TREC levels can help clinician distinguish different WAS phenotype. [ABSTRACT FROM AUTHOR]

Background: TYK2 deficiency is a rare primary immunodeficiency disease caused by loss‐of‐function mutations of TYK2 gene, which is initially proposed as a subset of hyper‐IgE syndrome (HIES). However, accumulating evidence suggests TYK2‐deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system. Method: Pathogenic effects of patients were confirmed by qRT‐PCR, Western blot, and protein stability assays. The responses to cytokines including IFN‐α/β/γ, IL‐6, IL‐10, IL‐12, and IL‐23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by Western blot, qRT‐PCR, and flow cytometry. The differentiation of T and B cells was detected by flow cytometry. Results: We described five more TYK2‐deficient cases presenting with or without hyper‐IgE levels, atopy, and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high‐throughput sequencing and confirmed by Sanger sequencing. The patients showed heterogeneous responses to various cytokine treatments, including IFN‐α/β/γ, IL‐6, IL‐10, IL‐12, and IL‐23. The homeostasis of lymphocytes is also disrupted. Conclusion: Based on our findings, we propose that TYK2 works as a multi‐tasker in orchestrating various cytokine signaling pathways, differentially combined defects which account for the expressed clinical manifestations. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate demographic, clinical, laboratory, imaging, histopathology characteristics, and treatment responses of children with Chronic nonbacterial osteomyelitis (CNO). Methods: Retrospective multi-center case series study of pediatric patients diagnosed with CNO treated at five tertiary centers in south China. Results: Totally there were 18 patients diagnosed as CNO between 2014 and 2020. The median age of onset was 9.2 years (range 3.7–13.1) and 55.6% were female. Median delay in diagnosis was 10.9 months (range 1.0–72.0). The most frequent presenting symptoms were bone pain (100%) and fever (44.4%). Most patients had more than one lesion (median of 5, range 1–7). Most frequently affected bones were tibiofibula (88.9%) and femur (77.8%). The MRI characteristics mainly presented as bone edema and hyperintensity in bone marrow. Bone biopsy was conducted in 11 patients (61.1%) with inflammatory cells infiltration manifested as chronic osteomyelitis, and none showed bacterial infection or tumor. In treatment, non-steroid anti-inflamatory drugs (NSAIDs) is used as the first-line drug followed by steriods, methotexate (MTX), salazosulfadimidine (SASP), Bisphosphonates and TNF-α inhibitor. Two refractory cases received combination therapy with Bisphosphonates and TNF-α inhibitor, and achieved good therapeutic effect. Conclusions: The present study described a multicenter series of CNO from south China and highlighted the clinical features, laboratory tests, imaging characteristics and treatment outcomes. Increasing awareness of this disease is important to decrease time to diagnosis, improve access to treatment, and reduce complications. [ABSTRACT FROM AUTHOR]

The immune context of the tumor microenvironment (TME) is critical for effective immunotherapy. Nonetheless, DNA-based biomarkers for the immune-sensitive TME and the identification of immune checkpoint inhibitor (ICI) responders are under-explored. This study aims to comprehensively landscape the homologous recombination deficiency (HRD) score, an emerging hallmark for tumor genome instability that triggers immune responsiveness across major cancer types, and to unveil their link to the TME and immunotherapeutic response. The HRD-associated genomic scars were characterized in 9088 tumor samples across 32 cancer types from TCGA. We evaluated the HRD score's performance in classifying ICI responders using an independent breast cancer cohort (GSE87049) and 11 in vivo murine mammary tumor models treated with anti-PD1/CTLA4 regimen (GSE124821). This study revealed a broad association between HRD-high genotype and neoantigenesis in the major cancer types including bladder cancer, breast cancer, head and neck squamous carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, and sarcoma. Tumors with high HRD score bears increased leukocyte infiltration and lymphocyte fraction and demonstrated immune-sensitive microenvironment. The tumor immune dysfunction and exclusion (TIDE) model further confirmed HRD score-high genotype as a potential predictor for ICI immunotherapy responders in breast cancer. In conclusion, tumors with high HRD score exhibit an immune-sensitive TME. The HRD-high genotype is a promising marker for identifying ICI therapy responders among breast cancer patients. [ABSTRACT FROM AUTHOR]

The co-existence of juvenile idiopathic arthritis (JIA)/rheumatoid arthritis (RA) and focal segmental glomerulosclerosis (FSGS) is rare, and the existence of co-pathogenesis remains unknown. In this study, we analyzed the clinical and gene mutation characteristics of a patient with JIA and FSGS caused by a NPHS2 gene mutation, and evaluated the potential connections between these two diseases. We summarized the clinical manifestations, related examination results, and gene mutation characteristics of the patient who presented at our center and six reported cases of arthritis with renal disease. Most of the cases were polyarticular arthritis with varying degrees of renal damage (hematuria, proteinuria, and renal dysfunction) and different prognoses. Among these patients, two developed end-stage renal disease (ESRD), with one dying as a result, while the other patients had a relatively good prognosis. Patients with a family history of renal disease had a poor prognosis. After excluding occasional factors and drug influences, our analysis indicated the existence of co-pathogenesis of arthritis with renal damage (especially FSGS). NPHS2 mutations might account for the family aggregation. Therefore, evaluation of more clinical cases is necessary to further clarify the underlying co-pathogenesis of these diseases. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the efficacy and safety of anti-TNFα therapy in patients with juvenile idiopathic arthritis associated uveitis (JIA-U). Methods: Embase, PubMed, Cochrane Library, and Web of Science were systematically searched for studies reporting anti-TNFα treatment in patients with JIA-U. The primary outcome was the control of intraocular inflammation (CII). The pooled proportion of CII was assessed by the random-effects method when I2 > 50%, otherwise, by the fixed-effect method. This study was registered with PROSPERO (CRD42020161749). Results: Three randomized clinical trials (RCTs), twelve case series, three retrospective cohort studies, and three case reports were identified. A total of 399 patients were receiving anti-TNFα therapy, of which 201 patients were treated with adalimumab (ADA), 139 with infliximab (IFX), 36 with etanercept (ETA), 20 with golimumab (GLM), and 3 with certolizumab pegol (CZP). The pooled proportions of CII on observational studies were 82% (95% CI 63–96%) in patients receiving ADA, 56% (95% CI 30–80%) in IFX, 38% (95% CI 8–73%) in ETA and 65% (95% CI 42–86%) in GLM, respectively. All three patients treated with CZP reached improved activity. ADA therapy led to a significantly higher proportion of CII compared to IFX therapy (χ2 = 26.24, P < 0.001), or to ETA therapy (χ2 = 13.43, P < 0.001); but no statistical difference was observed between IFX and ETA (χ2 = 0.13, P = 0.71). As to safety, most reported adverse events were tolerable and two cohort studies consistently showed that ADA was safer than IFX. Conclusions: The existing evidence suggests that ADA is better than IFX regarding efficacy and safety. The effectiveness of IFX is higher than ETA with no statistical difference. GLM and CZP may be proxies for ADA but the evidence is limited. [ABSTRACT FROM AUTHOR]

Acetamiprid (AAP) is a common neonicotinoid pesticide and their residues have emerged as a widely concerned issue on vegetables and fruits. In this work, a facile electrochemical surface-enhanced Raman spectroscopy (EC-SERS) method with one step of "mixing and detection" was proposed for detection of AAP. Wherein, screen printed electrode (SPE) was modified by dropping silver nanoparticles (AgNPs) onto the SPE surface. Compared to the normal SERS detection, the EC-SERS had a 5-fold enhancement in SERS signal with an applied potential at –0.7 V. Under the optimal applied potential, a wide linear range from 0.1 μM to 1000 μM was achieved with a low limit of detection (LOD, 0.04 μM), about 7-fold lower than that of the normal SERS method (LOD, 0.31 μM). Density functional theory (DFT) calculation revealed that the van der Waals force between AAP molecules and AgNPs was greatly enhanced. Besides, the EC-SERS method was successfully applied for the detection of AAP in Brassica chinensis L., and the results correlated well (R2 =0.9760) with those obtained from liquid chromatography-tandem mass spectrometry (HPLC-MS). The proposed method featured in easy operation, rapid detection and high sensitivity, which can act as a promising tool for monitoring pesticide residues in food samples. • Potential-powered EC-SERS strategy was developed for acetamiprid detection. • An electrochemical potential of − 0.7 V was applied to enhance AAP SERS signal. • DFT was used to investigate the non-covalent interaction between AgNPs and molecules. • EC-SERS strategy exhibits 7 times higher detection sensitivity than SERS. [ABSTRACT FROM AUTHOR]