Racial Disparities and Achievement of the Low Lupus Disease Activity State (LLDAS): A CARRA Registry Study.

OBJECTIVE: Differential disease control may contribute to racial disparities in outcomes of childhood-onset systemic lupus erythematosus (cSLE). We evaluated associations of race and individual- or neighborhood-level social determinants of health (SDoH) with achievement of low lupus disease activity state (LLDAS), a clinically relevant treatment target. METHODS: In this cSLE cohort study using the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, the primary exposure was self-reported race and/or ethnicity and collected SDoH included insurance status and area deprivation index (ADI). Outcomes included LLDAS, disease activity, and time-averaged prednisone exposure. Associations between race and/or ethnicity, SDoH, and disease activity were estimated with multivariable regression models, adjusting for disease-related and demographic factors. RESULTS: Among 540 children with cSLE, 27% identified as Black, 25% White, 23% Latino/a, 11% Asian, 9% more than one race, and 5% Other. More Black children (41%) lived in neighborhoods of highest ADI compared to White children (16%). Black race was associated with lower LLDAS achievement (adjusted OR 0.56, 95% CI: 0.38-0.82) and higher disease activity (adjusted ß: 0.94, 95% CI: 0.11, 1.78). Highest ADI was not associated with lower LLDAS achievement upon adjustment for renal disease and insurance. However, renal disease was found to be a significant mediator (p=0.04) of the association between ADI and prednisone exposure. CONCLUSIONS: Children with cSLE identifying as Black are less likely to achieve LLDAS and have higher disease activity. Living in areas of higher ADI may relate to renal disease and subsequent prednisone exposure. Strategies to address root causes will be important to design interventions mitigating cSLE racial disparities.

Racial and Ethnic Composition of Populations Served by Freestanding Children's Hospitals and Disparities in Outcomes of Pediatric Lupus.

OBJECTIVE: Health disparities may be driven by hospital-level factors. We assessed whether racial and ethnic composition of populations hospitals serve explain or modify disparities in hospital outcomes of children with systemic lupus erythematosus (SLE). METHODS: In this retrospective cohort study of patients 5 to 26 years old with SLE at 47 children's hospitals in the Pediatric Health Information System (2006-2021), race and ethnicity were assessed at the patient level and hospital level (proportion of total admissions composed of Black or Hispanic patients, respectively). Outcomes included intensive care unit (ICU) admission or adverse renal outcome (end-stage renal disease, dialysis, or transplant) during follow-up. We estimated racial and ethnic disparities, adjusted or stratified by hospital racial or ethnic composition. RESULTS: Of 8,125 patients with SLE, 2,293 (28%) required ICU admission, and 698 (9%) had an adverse renal outcome. Black and non-Hispanic White disparities in ICU admission were observed only at hospitals serving higher proportions of Black patients (odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.04-1.59 vs OR 1.07, 95% CI 0.83-1.38). Larger Black and non-Hispanic White disparities in adverse renal outcomes were observed at hospitals with higher Black racial composition (OR 2.0, 95% CI 1.4-2.8 vs OR 1.7, 95% CI 1.1-2.4). Conversely, Hispanic versus non-Hispanic disparities in renal outcomes persisted after adjustment for hospital-reported Hispanic ethnic composition but were observed only at hospitals with lower proportions of Hispanic patients. CONCLUSION: Worse Black and White disparities in SLE outcomes are observed at children's hospitals serving more Black children, whereas distinct patterns are observed for Hispanic and non-Hispanic disparities. Reporting of hospital characteristics related to populations served is needed to identify modifiable drivers of hospital-level variation.

NET formation is a default epigenetic program controlled by PAD4 in apoptotic neutrophils.

Neutrophil extracellular traps (NETs) not only counteract bacterial and fungal pathogens but can also promote thrombosis, autoimmunity, and sterile inflammation. The presence of citrullinated histones, generated by the peptidylarginine deiminase 4 (PAD4), is synonymous with NETosis and is considered independent of apoptosis. Mitochondrial- and death receptor-mediated apoptosis promote gasdermin E (GSDME)-dependent calcium mobilization and membrane permeabilization leading to histone H3 citrullination (H3Cit), nuclear DNA extrusion, and cytoplast formation. H3Cit is concentrated at the promoter in bone marrow neutrophils and redistributes in a coordinated process from promoter to intergenic and intronic regions during apoptosis. Loss of GSDME prevents nuclear and plasma membrane disruption of apoptotic neutrophils but prolongs early apoptosis-induced cellular changes to the chromatin and cytoplasmic granules. Apoptotic signaling engages PAD4 in neutrophils, establishing a cellular state that is primed for NETosis, but that occurs only upon membrane disruption by GSDME, thereby redefining the end of life for neutrophils.

Assessment of Physical Tests in 6-11 Years Old Children: Findings from the Play Lifestyle and Activity in Youth (PLAY) Study.

The purpose was to evaluate selected physical tests in children and to compare the outcomes by sex. A cross-sectional study design was used to evaluate children 6-11 years who completed five physical tests: hand grip, vertical jump, sit and reach, Y-balance, and obstacle course (time and score). The outcome measures including test results were descriptively examined and compared by sex. The study participants consisted of 133 children (62 males and 71 females, with a median age of 7.8 years). Girls showed superior sit and reach performance (p = 0.002) compared with boys. Boys demonstrated better Y-balance scores (p = 0.007) and faster obstacle time (p = 0.042) than girls. Sex comparison within three age groups (6-<8 years, 8-<10 years, and 10-<12 years) showed that girls performed better on the sit and reach compared with boys in the in 6-<8 years (p = 0.009). Boys demonstrated higher Y-balance scores (p = 0.017) and faster obstacle time (p = 0.007) compared with girls in the 8-<10-year age group. These data will serve to guide future efforts to evaluate normative measures of physical literacy and guide targeted training interventions to promote sustained physical activity in children with deficits relative to their age and sex norms.

Clinical Assessment of Mechanical Allodynia in Youth With Complex Regional Pain Syndrome: Development and Preliminary Validation of the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense).

Youth with complex regional pain syndrome (CRPS) commonly experience mechanical allodynia and disability. Assessment of mechanical allodynia is typically binary (present or absent), making it difficult to assess the quality and degree of mechanical allodynia before and after treatment. This study developed and validated the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) to provide an easy way for rehabilitation clinicians to evaluate mechanical allodynia before and after intensive interdisciplinary pain treatment. The 6 Pedi-Sense items demonstrated adequate internal consistency reliability (CR) at admission (CR = .956) and discharge (CR = .973), reasonably fit the hypothesized linear model of stimulus intensity (P < .0001), and significantly loaded onto a single latent factor, mechanical allodynia (P < .0001), at admission and discharge. Pedi-Sense scores significantly correlated with disability (rs = .40; P = .004) and pain catastrophizing (rs = .33; P = .017) at admission. The Pedi-Sense appeared responsive to intervention as participants' total scores improved by 1.44 points (95% CI: .72, 2.15) after IIPT interventions that included daily tactile desensitization. However, test-retest and interrater reliability and the specific contribution of desensitization treatment to the overall success of multi-modal pain rehabilitation still needs to be evaluated. PERSPECTIVE: This article presents the development and preliminary validation of a novel clinical assessment of static and dynamic mechanical allodynia. The Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) allows rehabilitation clinicians to easily evaluate mechanical allodynia at the bedside with minimal training and simple equipment to guide desensitization treatment in clinical settings.

The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice.

BACKGROUND: Atopic dermatitis (AD) is characterized by TH2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The TH2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity. OBJECTIVE: We sought to investigate whether the IL-4Rα R576 polymorphism is associated with AD severity and exaggerates allergic skin inflammation in mice. METHODS: Nighttime itching interfering with sleep, Rajka-Langeland, and Eczema Area and Severity Index scores were used to assess AD severity. Allergic skin inflammation following epicutaneous sensitization of mice 1 or 2 IL-4Rα R576 alleles (QR and RR) and IL-4Rα Q576 (QQ) controls was assessed by flow cytometric analysis of cells and quantitative RT-PCR analysis of cytokines in skin. RESULTS: The frequency of nighttime itching in 190 asthmatic inner-city children with AD, as well as Rajka-Langeland and Eczema Area and Severity Index scores in 1116 White patients with AD enrolled in the Atopic Dermatitis Research Network, was higher in subjects with the IL-4Rα R576 polymorphism compared with those without, with statistical significance for the Rajka-Langeland score. Following epicutaneous sensitization of mice with ovalbumin or house dust mite, skin infiltration by CD4+ cells and eosinophils, cutaneous expression of Il4 and Il13, transepidermal water loss, antigen-specific IgE antibody levels, and IL-13 secretion by antigen-stimulated splenocytes were significantly higher in RR and QR mice compared with QQ controls. Bone marrow radiation chimeras demonstrated that both hematopoietic cells and stromal cells contribute to the mutants' exaggerated allergic skin inflammation. CONCLUSIONS: The IL-4Rα R576 polymorphism predisposes to more severe AD and increases allergic skin inflammation in mice.

Imputation methods for missing failure times in recurrent-event survival analysis: Application to suicide attempts in the transgender population.

Suicide risk among transgender populations is an important public health issue. In a project evaluating association between gender affirmation and suicide attempts in the US Transgender Survey, we evaluated the relationship between gender affirmation and risk for suicide attempts. One of the challenges is that the age at suicide attempts was only collected for the first and last attempt. The initial zero-inflated negative binomial model enabled us to evaluate the association between gender affirmation and number of suicide attempts per 5 years adjusting for other covariates. However, ignoring missing failure times of recurrent events may have caused bias and loss of efficiency. In this paper, we use a recurrent-event survival analysis incorporating time-varying covariates with three approaches to impute the age at suicide attempt, estimates from three imputation approaches are similar. We were able to confirm the findings from the initial model and identify additional associations that were not detected in the initial analysis. Findings suggest the need to consider additional analytical approaches in settings with high data missingness by design. Research to validate and compare measures that ask first and last attempt to those which enumerate all attempts in this population will be important for future surveys.

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

Health Impairments in Children and Adolescents After Hospitalization for Acute COVID-19 or MIS-C.

OBJECTIVES: To evaluate risk factors for postdischarge sequelae in children and adolescents hospitalized for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C). METHODS: Multicenter prospective cohort study conducted in 25 United States pediatric hospitals. Patients <21-years-old, hospitalized May 2020 to May 2021 for acute COVID-19 or MIS-C with follow-up 2 to 4 months after admission. We assessed readmissions, persistent symptoms or activity impairment, and new morbidities. Multivariable regression was used to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI). RESULTS: Of 358 eligible patients, 2 to 4 month survey data were available for 119 of 155 (76.8%) with acute COVID-19 and 160 of 203 (78.8%) with MIS-C. Thirteen (11%) patients with acute COVID-19 and 12 (8%) with MIS-C had a readmission. Thirty-two (26.9%) patients with acute COVID-19 had persistent symptoms (22.7%) or activity impairment (14.3%) and 48 (30.0%) with MIS-C had persistent symptoms (20.0%) or activity impairment (21.3%). For patients with acute COVID-19, persistent symptoms (aRR, 1.29 [95% CI, 1.04-1.59]) and activity impairment (aRR, 1.37 [95% CI, 1.06-1.78]) were associated with more organ systems involved. Patients with MIS-C and pre-existing respiratory conditions more frequently had persistent symptoms (aRR, 3.09 [95% CI, 1.55-6.14]) and those with obesity more frequently had activity impairment (aRR, 2.52 [95% CI, 1.35-4.69]). New morbidities were infrequent (9% COVID-19, 1% MIS-C). CONCLUSIONS: Over 1 in 4 children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least 2 months. Patients with MIS-C and respiratory conditions or obesity are at higher risk of prolonged recovery.

Metformin for treatment of cytopenias in children and young adults with Fanconi anemia.

Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.