The Children's Hospital at Montefiore (CHAM) is a nationally ranked pediatric acute care children's teaching hospital located in the Bronx, New York. The hospital has 193 pediatric beds and is affiliated with the Albert Einstein College of Medicine. The hospital is a member of the Montefiore health network and is the only children's hospital in the network. The hospital provides comprehensive pediatric specialties and subspecialties to infants, children, teens, and young adults aged 0–21 throughout the Bronx and New York state. Children's Hospital at Montefiore also sometimes treats adults that require pediatric care. While CHAM does have a pediatric emergency department, they do not have a pediatric trauma center and sends all pediatric trauma cases to the nearby Jacobi Medical Center's level II pediatric trauma center. The Children's Hospital at Montefiore is one of the largest providers of pediatric health services in New York state. The hospital is attached to Montefiore Medical Center and is affiliated with the Ronald McDonald House of New York.
BACKGROUND:Type I interferons (IFN-I) and type II interferon (IFN-γ) contribute to the pathogenesis of inflammatory diseases, but measurement of these cytokines remains challenging in the clinical setting. OBJECTIVE:We aimed to develop a clinical test that rapidly captures the activity of IFN-I and IFN-γ. METHODS:We compared RNA sequencing data from healthy controls and patients with macrophage activation syndrome, multisystem inflammatory syndrome in children, and systemic lupus erythematosus to evaluate biomarkers of IFN-I and IFN-γ signaling. We utilized a flow cytometry assay to measure interferon-inducible markers. The findings were verified by a clinical laboratory that independently developed and validated this assay. RESULTS:We identified CD274 (programmed death ligand 1, or PD-L1) as a biomarker of IFN-γ signaling and confirmed CD169 (SIGLEC-1) as a readout of IFN-I activity. We utilized a flow cytometry assay to quantify CD169 and CD274 expression on monocytes and demonstrated the validity of this method for rapid screening of interferon dysregulation in patients with various inflammatory diseases including, among others, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, multisystem inflammatory syndrome in children, systemic lupus erythematosus, juvenile idiopathic arthritis, and juvenile dermatomyositis. We further demonstrated the utility of this test for assessment of interferon dysregulation in monogenic inflammatory diseases and for efficacy monitoring of medications that target the interferon pathways including Janus kinase inhibitors, emapalumab, and anifrolumab. Finally, we outlined the steps of assay validation and clinical implementation, and we showed reproducible findings in a clinical laboratory. CONCLUSION:Flow cytometry analysis of CD169 and CD274 is an effective method to rapidly quantify IFN-I and IFN-γ activity in the clinical setting.
OBJECTIVE:To assess the 2022 American College of Rheumatology (ACR)/EULAR classification criteria for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) in children with chronic small-to-medium vessel vasculitis. METHODS:A cohort of 574 patients, identified by physician's diagnosis (MD-diagnosis) in A Registry of Childhood Vasculitis, was classified by computation of registry data as having granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or eosinophilic GPA after applying (1) ACR/EULAR AAV criteria and (2) pediatric-adapted European Medicines Agency (Ped-EMA) classification algorithm (incorporating Ankara GPA criteria). Venn diagrams compared the resulting GPA and MPA cohorts with MD-diagnosis. Sensitivity and specificity of criteria for GPA were evaluated against MD-diagnosis. Fisher exact test evaluated differences in the frequencies of individual clinical features in GPA versus MPA. RESULTS:Comparing ACR/EULAR criteria against the Ped-EMA algorithm for classifying AAV, more patients were classified as GPA or MPA (n = 396 vs 360, respectively), fewer had GPA (n = 261 vs 288, respectively), more had MPA (n = 135 vs 72, respectively), and fewer GPA cases coclassified as MPA (12% vs 28%, respectively); there were more differences between GPA and MPA in Pediatric Vasculitis Activity Score-defined clinical features (n = 14 vs 10, respectively). When classifying GPA by ACR/EULAR or Ankara criteria, sensitivity (74.5% vs 72.1%, respectively) was comparable, and specificity for ACR/EULAR criteria (93.9% vs 79.9%, respectively) was improved. CONCLUSION:The 2022 ACR/EULAR classification criteria for AAV perform at least as well as previous pediatric criteria and provide categorical MPA criteria where none existed previously; the criteria for GPA and MPA now specifically differentiate each other, with more differences between them in the frequencies of clinical features. Our findings support the preferential use of ACR/EULAR over Ankara criteria for GPA in pediatrics.
Flavonoids are a diverse class of polyphenolic secondary metabolites found in fruits, vegetables, tea, and medicinal plants, known for their antioxidant, anti-inflammatory, neuroprotective, and anticancer properties. This review summarizes recent advances in flavonoid research, focusing on their roles in aging, neuroprotection, cardiovascular health, metabolic regulation, inflammation, and cancer therapy. Flavonoids exert their effects by modulating key signaling pathways, such as NF-κB, Nrf2, PI3K/Akt, MAPK, and Wnt/β-catenin. They mitigate oxidative stress, enhance mitochondrial function, regulate autophagy, and modulate immune responses, offering potential therapeutic benefits against chronic diseases. Additionally, flavonoids improve chemotherapy sensitivity, inhibit tumor metastasis, and suppress angiogenesis. However, their poor bioavailability and individual metabolic variability present challenges for clinical translation. Future research should focus on nanotechnology-based delivery systems, personalized medicine strategies, and large-scale clinical trials to optimize flavonoid efficacy and facilitate their application in functional foods and pharmaceuticals.
Importance:Congenital cytomegalovirus (cCMV) is the most common nongenetic cause of sensorineural hearing loss in children and a cause of long-term neurological disabilities. In the absence of universal screening, cCMV disease in many newborns will go undiagnosed and untreated. Objective:To determine the feasibility, screen-positive rate, and parental acceptance of newborn screening for cCMV using dried blood spot (DBS) specimens. Design, Setting, and Participants:In this population-based diagnostic study, newborns whose DBS specimens were submitted to the New York State Newborn Screening Program from October 2, 2023, through September 30, 2024, for routine screening were also screened for CMV. Parents were given the option to opt out of receiving CMV results. Infectious disease specialists at designated medical centers performed follow-up of referred newborns. Of the 208 322 newborns whose specimens were submitted, 245 (0.1%) were opted out of the CMV screen by their parents; 22 families did so after CMV results were released. Exposure:DBS screening of newborns. Main Outcomes and Measures:CMV was detected in DBS specimens from newborns using a quantitative polymerase chain reaction analysis. Appropriate follow-up and treatment were provided to referred newborns. Results:Of the 208 099 newborns (48.6% female and 51.0% male; mean [SD] age at specimen collection, 3.5 [12.3] days [median, 1.0 days]) whose CMV results were reported, 529 had positive CMV screen results (0.3%). Following referral and initial diagnostic evaluation, 276 of the 529 newborns (52.2%) were diagnosed with cCMV (overall rate of 0.1%). Among the 276 newborns with cCMV, 68 (24.6%) had symptomatic cCMV disease, 197 (71.4%) had asymptomatic infection, and 11 (4.0%) had isolated sensorineural hearing loss. Additionally, 131 of the 529 referred newborns (24.8%) had likely acquired CMV postnatally, 17 (3.2%) had false-positive screen results, 43 (8.1%) had unknown CMV classification, and 62 (11.7%) were lost to follow-up or their parents declined follow-up. Of the 68 newborns with symptomatic cCMV disease, 48 (70.6%) were treated with antiviral medication. Conclusions and Relevance:In this diagnostic study, early identification of cCMV allowed newborns to be evaluated, which provided an opportunity for improved outcomes. Although the intent of the screening was to detect cCMV, a sizeable minority of cases identified had postnatally acquired CMV infections. Further studies that incorporate long-term data are needed to better understand the impact of cCMV identification among newborns with asymptomatic infection.
BACKGROUND:Newborn screening (NBS) for severe combined immunodeficiency (SCID) using T-cell receptor excision circles in dried blood spots has been implemented in the United States and many other regions and countries globally. The Clinical Immunology Society and the Association of Public Health Laboratories jointly formed the SCID Harmonization Initiative to facilitate comparison of NBS reporting practices to promote global consensus and collaboration. OBJECTIVE:To assess current NBS SCID practices using a global survey and to report the findings from the phase 1 component. METHODS:An 18-question survey was distributed to all known SCID screening programs worldwide. Only 1 response per region was analyzed. Examples of international screening algorithms were also solicited and included. RESULTS:A total of 200 responses were received, of which 80 responses were unique and used for further analysis. Of the 39 non-US countries, 15 (38%) reported national universal screening and 24 (62%) reported regional, pilot, or other screening. Additional questions pertained to methodology and reporting, with particular emphasis on communication of the clinical urgency of an abnormal T-cell receptor excision circle result. CONCLUSIONS:This global survey confirmed that the approach to NBS SCID varies widely, underscoring the need for harmonization at multiple steps, particularly for reporting and interpretation. This is the first study to capture global NBS SCID practices, and these findings provide the basis for creation of a phase 2 consensus reporting framework, which will be developed by the same SCID Harmonization Committee that created the current study.
