JAK inhibitors in systemic juvenile idiopathic arthritis

ObjectiveSystemic juvenile idiopathic arthritis (SJIA) is characterized by excessive and inappropriate production of proinflammatory cytokines. Janus kinase inhibitors (JAKi) can block the downstream pathway of many cytokines. The use of JAKi in SJIA or macrophage activation syndrome (MAS) has only been described in a limited number of case reports. In this study, we aimed to assess the efficacy and potential adverse effects of JAKi in SJIA patients.MethodsPatients with SJIA who received JAKi and underwent at least one assessment of efficacy and safety after JAKi initiation were eligible for this study. Data were collected retrospectively from inpatient or outpatient medical records at JAKi initiation, at 1, 3, 6, 9, and 12 months, after disease flare, after JAKi discontinuation, or at the last follow-up.ResultsTen patients with SJIA were included in the study. At the start of JAKi treatment, all patients presented with active disease; five showed variable adverse effects secondary to glucocorticoids. Seven patients received tofacitinib (one later switched to ruxolitinib). Of these, only two patients showed a complete response of persistent arthritis associated with tocilizumab; tofacitinib was used without a biological DMARD only in two patients, together with MTX, showing a partial response; three patients were nonresponders. Four patients with SJIA-related MAS or persistent hyperferritinemia were treated with ruxolitinib. Ruxolitinib allowed a good response on MAS parameters in three of them. All these four patients required an adjunction or switch to canakinumab later. The median decrease in the daily glucocorticoid dose between JAKi initiation and the last follow-up was 90.6% in patients with complete remission and 77.4% in other patients. Three patients discontinued glucocorticoid treatment after the introduction of JAKi. Severe adverse events, notably serious infection or thrombosis, were not observed during JAKi treatment.ConclusionJAKi may be an alternative or adjuvant agent for SJIA patients, especially in those with persistently active disease, glucocorticoid-related adverse reactions, or SJIA-MAS

Diagnosis of mixed infection and a primary immunodeficiency disease using next-generation sequencing: a case report

Major Histocompatibility Complex Class II (MHC II) deficiency is a rare primary immunodeficiency disorder (PID) with autosomal recessive inheritance pattern. The outcome is almost fatal owing to delayed diagnosis and lacking of effective therapy. Therefore, prompt diagnosis, timely and effective treatment are critical. Here, we report a 117-day-old boy with diarrhea, cough, cyanosis and tachypnea who was failed to be cured by empiric antimicrobial therapy initially and progressed to severe pneumonia and respiratory failure. The patient was admitted to the pediatric intensive care unit (PICU) immediately and underwent a series of tests. Blood examination revealed elevated levels of inflammatory markers and cytomegalovirus DNA. Imaging findings showed signs of severe infection of lungs. Finally, the diagnosis was obtained mainly through next-generation sequencing (NGS). We found out what pathogenic microorganism he was infected via repeated conventional detection methods and metagenomic next-generation sequencing (mNGS) of sputum and bronchoalveolar lavage fluid (BALF). And his whole exome sequencing (WES) examination suggested that CIITA gene was heterozygous mutation, a kind of MHC II deficiency diseases. After aggressive respiratory support and repeated adjustment of antimicrobial regimens, the patient was weaned from ventilator on the 56th day of admission and transferred to the immunology ward on the 60th day. The patient was successful discharged after hospitalizing for 91 days, taking antimicrobials orally to prevent infections post-discharge and waiting for stem cell transplantation. This case highlights the potential importance of NGS in providing better diagnostic testing for unexplained infection and illness. Furthermore, pathogens would be identified more accurately if conventional detection techniques were combined with mNGS

Whole exome sequencing identifies frequent somatic mutations in cell-cell adhesion genes in chinese patients with lung squamous cell carcinoma

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy

Identification of Potential Diagnostic Biomarkers and Biological Pathways in Hypertrophic Cardiomyopathy Based on Bioinformatics Analysis

Hypertrophic cardiomyopathy (HCM) is a genetic heterogeneous disorder and the main cause of sudden cardiac death in adolescents and young adults. This study was aimed at identifying potential diagnostic biomarkers and biological pathways to help to diagnose and treat HCM through bioinformatics analysis. We selected the GSE36961 dataset from the Gene Expression Omnibus (GEO) database and identified 893 differentially expressed genes (DEGs). Subsequently, 12 modules were generated through weighted gene coexpression network analysis (WGCNA), and the turquoise module showed the highest negative correlation with HCM (cor = −0.9, p-value = 4 × 10−52). With the filtering standard gene significance (GS) < −0.7 and module membership (MM) > 0.9, 19 genes were then selected to establish the least absolute shrinkage and selection operator (LASSO) model, and LYVE1, MAFB, and MT1M were finally identified as key genes. The expression levels of these genes were additionally verified in the GSE130036 dataset. Gene Set Enrichment Analysis (GSEA) showed oxidative phosphorylation, tumor necrosis factor alpha-nuclear factor-κB (TNFα-NFκB), interferon-gamma (IFNγ) response, and inflammatory response were four pathways possibly related to HCM. In conclusion, LYVE1, MAFB, and MT1M were potential biomarkers of HCM, and oxidative stress, immune response as well as inflammatory response were likely to be associated with the pathogenesis of HCM

Urban Green Space Planning and Design Based on Big Data Analysis and BDA-UGSPD Model

Green cities are described as the environmental influences by expanding recycling, decreasing waste, increasing housing density, lowering emissions while intensifying open space, and boosting sustainable local businesses. Green infrastructures (GI) are progressively related to urban water management for long-term transitions and immediate solutions towards sustainability. Urban green spaces (UGS) play a vital role in conserving urban environment sustainability by giving various ecology services. In this study, big data analytics-based urban green space planning design (BDA-UGSPD) has been introduced. Luohe city and the Shali River area have been chosen as the study area owing to the high number and a considerable assortment of UGS. Monitoring has been conducted in the Shali river to evaluate water quality for irrigation for agriculture. The Master Plan Scenario had a compact green space system, and the urban land use layout has been categorized by systematization and networking, and it did not consider the service capacity of green spaces. The Planning Guidance Scenario initialized constraint states, which provide more rigorous and effective urban spaces. It enhanced the service functions of the green space model layout. The simulation findings illustrate that the proposed BDA-UGSPD model enhances the land-use classification accuracy ratio by 92.0%, probability ratio by 90.6%, decision-making ratio by 95.0%, climate change adaptation ratio by 94.5%, water quality assessment ratio by 95.9%, and reduces the root mean square error ratio by 9.7% compared to other popular approaches

Effect of AM Fungi Inoculation on Litter Bacterial Community Characteristics under Heavy Metal Stress

Because microorganisms are the primary driving force behind litter decomposition, they play an important role in maintaining ecosystem material and chemical cycling. Arbuscular mycorrhizal (AM) fungi can improve host plant tolerance to various environmental stressors, making their application in mining area remediation important. In this study, litter from the dominant plant species (Imperata cylindrica) in a copper tailings mining area was selected as the experimental material. We conducted a greenhouse-based heavy metal stress experiment to investigate how AM fungi affect litter microbial community characteristics and key ecological factors. Results showed that AM fungi species, heavy metal treatments, and their combined interaction had significant impacts on litter pH. Additionally, enzyme activities in litter were significantly affected by interactions between AM fungi species and heavy metal contaminates. Ralstonia was significantly positively correlated to lead (Pb) content, indicating that Ralstonia had a certain tolerance to Pb pollution. Sucrase and urease activity were increased when plants were inoculated with Rhizophagus irregularis under Pb stress. Furthermore, Microbacterium, Brevundimonas, and Pseudonocardia all may play important roles in litter decomposition, while a certain tolerance was observed in Kushneria and Roseivivax to heavy metal pollution when plants were inoculated with Glomus mosseae. Results showed that AM fungi affected litter bacterial community structure and function by influencing plant litter properties. By exploring interactions between AM fungi and bacterial communities in plant litter under heavy metal stress, we will better understand associative processes that promote the cycling of soil organic matter and nutrients contaminated by non-ferrous metal tailings

Clinical Features and Risk Factors of Kawasaki Disease Complicated with Deep Neck Space Involvement: A Summary of 38 Cases

Objective  To summarize the clinical characteristics and explore the risk factors of Kawasaki disease(KD) with deep neck space involvement(DNSI).  Methods  This study was a case-control study. We reviewed KD complicated with DNSI patients in Department of Rheumatology and Immunology of Shenzhen Children's Hospital from January 2018 to December 2020 as DNSI group. Meanwhile, children with KD withoutDNSI during this period were selected by systematic sampling at a ratio of 1∶7 as control group. The clinical characteristics were analyzed by Chi-square test and the Mann-Whitney test and risk factors of KD complicated with DNSI were analyzed by Logistic regression.  Results  A total of 38 children in the DNSI group who met the inclusion and exclusion criteria and 288 children in the control group were selected. In the DNSI group, 38 children (100%) had fever and cervical lymph node enlargement, and the cervical lymph node enlargement occurred within 5 days of onset; 30 patients (78.9%) had cervical lymph node pain and 25 patients suffered (65.8%) limited movement of neck. Compared with the control group, the clinical data of children in the DNSI group showed a variety of significant changes. In terms of clinical characteristics, the age of onset in the DNSI group was older, the hospital stay was longer and the proportions of cervical lymphadenopathy, cervical lymph node pain, limited neck movement and upper airway obstruction were all higher (all P < 0.05); in terms of laboratory tests, the neutrophil count and its percentage, C-reactive protein (CRP), ferritin (FER), total bile acid, total bilirubin, direct bilirubin, and globulin levels all increased, while platelet and lymphocyte counts and their percentages all decreased(all P < 0.05); in terms of coronary artery damage and treatment effect, the Kobayashi score, Sano score and the proportion of hormone therapy in the DNSI group all increased (all P < 0.05). Multivariate Logistic regression analysis showed that neck lymph node pain (OR=5.523, 95% CI: 1.443-21.141, P=0.013), limited cervical movement (OR=3.947, 95% CI: 1.044-14.928, P=0.043), higher CRP (OR=1.016, 95% CI: 1.002-1.030, P=0.024) and higher FER(OR=1.004, 95% CI: 1.001-1.006, P=0.002) were independent risk factors for KD combined with DNSI.  Conclusions  Most children with KD complicated with DNSI have clinical symptoms such as cervical lymph node enlargement, cervical lymph node pain, and limited cervical movement, and hematology shows that there is a high-intensity inflammatory response. For KD children with neck pain and limited cervical movement as the main clinical manifestations, accompanied by elevated serum CRP and FER, we should be alert to the possibility of DNSI

Vertebral fractures in Ireland: A sub-analysis of the DXA HIP project

Osteoporosis is an important global health problem resulting in fragility fractures. The vertebrae are the commonest site of fracture resulting in extreme illness burden, and having the highest associated mortality. International studies show that vertebral fractures (VF) increase in prevalence with age, similarly in men and women, but difer across diferent regions of the world. Ireland has one of the highest rates of hip fracture in the world but data on vertebral fractures are limited. In this study we examined the prevalence of VF and associated major risk factors, using a sample of subjects who underwent vertebral fracture assessment (VFA) performed on 2 dual-energy X-ray absorptiometry (DXA) machines. A total of 1296 subjects aged 40 years and older had a valid VFA report and DXA information available, including 254 men and 1042 women. Subjects had a mean age of 70 years, 805 (62%) had prior fractures, mean spine T-score was &#8722; 1.4 and mean total hip T-scores was &#8722; 1.2, while mean FRAX scores were 15.4% and 4.8% for major osteoporotic fracture and hip fracture, respectively. Although 95 (7%) had a known VF prior to scanning, 283 (22%) patients had at least 1 VF on their scan: 161 had 1, 61 had 2, and 61 had 3 or more. The prevalence of VF increased with age from 11.5% in those aged 40 49 years to>33% among those aged&#8805;80 years. Both men and women with VF had signifcantly lower BMD at each measured site, and signifcantly higher FRAX scores, POpen Access funding provided by the IReL Consortium.peer-reviewe

Prevalence of Low Bone Mass and Osteoporosis in Ireland: the Dual‐Energy X‐Ray Absorptiometry (DXA) Health Informatics Prediction (HIP) Project

ABSTRACT Osteoporosis is a common disease that has a significant impact on patients, healthcare systems, and society. World Health Organization (WHO) diagnostic criteria for postmenopausal women were established in 1994 to diagnose low bone mass (osteopenia) and osteoporosis using dual‐energy X‐ray absorptiometry (DXA)‐measured bone mineral density (BMD) to help understand the epidemiology of osteoporosis, and identify those at risk for fracture. These criteria may also apply to men ≥50 years, perimenopausal women, and people of different ethnicity. The DXA Health Informatics Prediction (HIP) project is an established convenience cohort of more than 36,000 patients who had a DXA scan to explore the epidemiology of osteoporosis and its management in the Republic of Ireland where the prevalence of osteoporosis remains unknown. In this article we compare the prevalence of a DXA classification low bone mass (T‐score < −1.0) and of osteoporosis (T‐score ≤ −2.5) among adults aged ≥40 years without major risk factors or fractures, with one or more major risk factors, and with one or more major osteoporotic fractures. A total of 33,344 subjects met our study inclusion criteria, including 28,933 (86.8%) women; 9362 had no fractures or major risk factors, 14,932 had one or more major clinical risk factors, and 9050 had one or more major osteoporotic fractures. The prevalence of low bone mass and osteoporosis increased significantly with age overall. The prevalence of low bone mass and osteoporosis was significantly greater among men and women with major osteoporotic fractures than healthy controls or those with clinical risk factors. Applying our results to the national population census figure of 5,123,536 in 2022 we estimate between 1,039,348 and 1,240,807 men and women aged ≥50 years have low bone mass, whereas between 308,474 and 498,104 have osteoporosis. These data are important for the diagnosis of osteoporosis in clinical practice, and national policy to reduce the illness burden of osteoporosis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

Utility of osteoporosis self-assessment tool as a screening tool for osteoporosis in Irish men and women: Results of the DXA-HIP project

Many algorithms have been developed and publicised over the past 2 decades for identifying those most likely to have osteoporosis or low BMD, or at increased risk of fragility fracture. The Osteoporosis Self-assessment Tool index (OSTi) is one of the oldest, simplest, and widely used for identifying men and women with low BMD or osteoporosis. OSTi has been validated in many cohorts worldwide but large studies with robust analyses evaluating this or other algorithms in adult populations residing in the Republic of Ireland are lacking, where waiting times for public DXA facilities are long. In this study we evaluated the validity of OSTi in men and women drawn from a sampling frame of more than 36,000 patients scanned at one of 3 centres in the West of Ireland. 18,670 men and women aged 40 years and older had a baseline scan of the lumbar spine femoral neck and total hip available for analysis. 15,964 (86%) were female, 5,343 (29%) had no major clinical risk factors other than age, while 5,093 (27%) had a prior fracture. Approximately 2/3 had a T-score ¿-1.0 at one or more skeletal sites and 1/3 had a T-score ¿-1.0 at all 3 skeletal sites, while 1 in 5 had a DXA T-score ¿-2.5 at one or more skeletal sites and 5% had a T-score ¿-2.5 at all 3 sites. OSTi generally performed well in our population with area under the curve (AUC) values ranging from 0.581 to 0.881 in men and 0.701 to 0.911 in women. The performance of OSTi appeared robust across multiple sub-group analyses. AUC values were greater for women, proximal femur sites, those without prior fractures and those not taking osteoporosis medication. Optimal OSTi cut-points were '2' for men and '0' for women in our study population. OSTi is a simple and effective tool to aid identification of Irish men and women with low BMD or osteoporosis. Use of OSTi could improve the effectiveness of DXA screening programmes for older adults in Ireland.peer-reviewed2022-03-0