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ObjectiveTocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement. We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement.MethodsThe focuSSced trial was a phase III randomized placebo-controlled trial of TCZ in patients with SSc and progressive skin disease. Participants underwent baseline and serial spirometry along with high-resolution chest computed tomography at baseline and at week 48. Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software. We classified QILD into the following categories of lung involvement: mild (>5-10%), moderate (>10-20%), and severe (>20%).ResultsOf 210 participants recruited for the trial, 136 patients (65%) had ILD. The majority of these patients (77%) had moderate-to-severe involvement (defined as >10% lung involvement). The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were -4.1 ± 2.5% (n = 11), 0.7 ± 1.9% (n =19), and 2.1 ± 1.6% (n = 26), respectively, and in the placebo group were -10.0 ± 2.6% (n = 11), -5.7 ± 1.6% (n = 26), and -6.7 ± 2.0% (n = 16), respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity.ConclusionTCZ in early SSc-associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD.

OBJECTIVE: Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD. METHODS: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, β2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3β) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. RESULTS: Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). CONCLUSION: A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC.

Background:Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for rheumatoid arthritis (RA). The safety and efficacy of UPA has been evaluated across a spectrum of patients (pts) with RA in the phase 3 SELECT clinical program.1,2Objectives:To describe long-term laboratory profiles (cutoff date: June 30, 2020) associated with exposure to UPA, adalimumab (ADA), and methotrexate (MTX) in pts with RA treated in the SELECT trials.Methods:Data were analyzed from 6 randomized controlled UPA RA trials.1,2 The proportions of pts experiencing potentially clinically significant laboratory changes at a single time point were summarized for the following groups: pooled UPA 15 mg once daily (QD; UPA15; 6 trials), pooled UPA 30 mg QD (UPA30; 4 trials), ADA 40 mg every other week (EOW; 1 trial), and MTX monotherapy (1 trial). Pts received UPA with/without background conventional synthetic disease-modifying antirheumatic drugs. Treatment-emergent adverse events are reported as exposure-adjusted event rates (events/100 pt-years [E/100 PY]). Toxicity was graded per OMERACT criteria, or NCI CTCAE for creatine phosphokinase (CPK) and creatinine.Results:4413 pts received ≥1 dose of UPA (UPA15, n=3209; UPA30, n=1204). Exposures were comparable between treatment groups (Table). Proportions of pts with Grade (Gr) 3 and 4 decreases in hemoglobin were highest with UPA30 and MTX (Table). Rates of anemia, as reported by the investigator, were comparable between UPA15, ADA, and MTX groups (Figure); the frequency of UPA-treated pts who discontinued due to anemia was low in all arms. Gr 3 and 4 decreases in neutrophils and lymphocytes with UPA were dose-dependent and higher vs ADA or MTX. Discontinuations due to neutropenia and lymphopenia were rare (8.0 × ULN)5a (1.6)4c (0.7)26e (0.8)10h (0.8)AST, U/LGr 3 (3.0–8.0 × ULN)15a (4.8)9c (1.6)101e (3.2)36h (3.0)Gr 4 (>8.0 × ULN)1a (0.3)5c (0.9)18e (0.6)8h (0.7)CPK, U/LGr 3 (>5.0–10.0 × ULN)2a (0.6)3c (0.5)65e (2.0)36i (3.0)Gr 4 (>10.0 × ULN)0a (0)3c (0.5)27e (0.8)15i (1.3)Creatinine, μmol/LGr 3 (>3.0–6.0 × ULN)0a (0)1c (0.2)3e (6.0 × ULN)0a (0)4c (0.7)8e (0.3)1j (

OBJECTIVE: To provide a large-scale assessment of serum protein dysregulation in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: We investigated serum protein profiles of 66 participants with dcSSc at baseline who were enrolled in the Scleroderma: Cyclophosphamide or Transplant Trial and 66 age- and sex-matched healthy control subjects. A panel of 230 proteins, including several cytokines and chemokines, was investigated. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Among the participants with dcSSc, the mean disease duration was 2.3 years. All had interstitial lung disease (ILD), and none were being treated with immunosuppressive agents at baseline. Ninety proteins were differentially expressed in participants with dcSSc compared to healthy control subjects. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion, and diapedesis were the top overrepresented pathways. Eighteen proteins correlated with the modified Rodnan skin thickness score (MRSS). Soluble epidermal growth factor receptor was significantly down-regulated in dcSSc and showed the strongest negative correlation with the MRSS, being predictive of the scores course over time, whereas α1 -antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with the MRSS. Furthermore, higher levels of cancer antigen 15-3 correlated with more severe ILD, based on findings of reduced forced vital capacity and higher scores of disease activity on high-resolution computed tomography. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSION: Diffuse cutaneous SSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells.

Pathogenic E. coli pose a significant threat to public health, as strains of this species cause both foodborne illnesses and urinary tract infections. Using a rapid bioconjugation reaction, we selectively capture E. coli at a disposable gold electrode from complex solutions and accurately quantify the pathogenic microbes using electrochemical impedance spectroscopy.

The gut microbiota is a complex ecosystem of microorganisms residing in the human gastrointestinal tract, playing a crucial role in various biological processes and overall health maintenance. Dysbiosis, an imbalance in the composition and function of the gut microbiota, is linked to systemic autoimmune diseases (SAD). Short-chain fatty acids (SCFAs), especially butyrate, produced by the gut microbiota through the fermentation of dietary fibers, play a significant role in immunomodulation and maintaining intestinal homeostasis. Butyrate is essential for colonocyte energy, anti-inflammatory responses, and maintaining intestinal barrier integrity. Studies show reduced butyrate-producing bacteria in SAD patients, suggesting that increasing butyrate levels could have therapeutic benefits. Butyrate’s anti-inflammatory effects and its potential therapeutic role have been studied in rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, systemic sclerosis, and Behçet’s disease. Despite promising in vitro and animal model results, human studies are limited, and the optimal strategies for modulating dysbiosis in SADs remain elusive. This review explores the current evidence on the immunoregulatory role of butyrate and its potential therapeutic effects in SAD.

Pediatric high-grade gliomas (pHGG) are malignant and usually fatal central nervous system (CNS) WHO Grade 4 tumors. The majority of pHGG consist of diffuse midline gliomas (DMG), H3.3 or H3.1 K27 altered, or diffuse hemispheric gliomas (DHG) (H3.3 G34-mutant). Due to diffuse tumor infiltration of eloquent brain areas, especially for DMG, surgery has often been limited and chemotherapy has not been effective, leaving fractionated radiation to the involved field as the current standard of care. pHGG has only been classified as molecularly distinct from adult HGG since 2012 through Next-Generation sequencing approaches, which have shown pHGG to be epigenetically regulated and specific tumor sub-types to be representative of dysregulated differentiating cells. To translate discovery research into novel therapies, improved pre-clinical models that more adequately represent the tumor biology of pHGG are required. This review will summarize the molecular characteristics of different pHGG sub-types, with a specific focus on histone K27M mutations and the dysregulated gene expression profiles arising from these mutations. Current and emerging pre-clinical models for pHGG will be discussed, including commonly used patient-derived cell lines and in vivo modeling techniques, encompassing patient-derived xenograft murine models and genetically engineered mouse models (GEMMs). Lastly, emerging techniques to model CNS tumors within a human brain environment using brain organoids through co-culture will be explored. As models that more reliably represent pHGG continue to be developed, targetable biological and genetic vulnerabilities in the disease will be more rapidly identified, leading to better treatments and improved clinical outcomes.

OBJECTIVES/GOALS: The goal of the study is to provide insights into the use of machine learning methods as a means to predict heterogeneity of treatment effect (HTE) in participants of randomized clinical trials. METHODS/STUDY POPULATION: Using data from 2,441 participants enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial of daily low-dose aspirin vs placebo in the United States, we developed multivariable risk prediction models for the composite outcome of dementia, disability, or death. We used two machine learning techniques, decision trees and random forests, to develop novel non-parametric outcomes classifiers and generate risk-based subgroups. The comparator method was an extant semi-parametric proportional hazards predictive risk model. We then assessed HTE by examining the 5-year absolute risk reduction (ARR) of aspirin vs placebo in each risk subgroup. RESULTS/ANTICIPATED RESULTS: In the random forest classifier, the ARR at 5 years in the highest risk quintile was 13.7% (95% CI 3.1% to 24.4%). For the semi-parametric proportional hazards model, the ARR in the highest risk quintile was 15.1% (95% CI 4.0% to 26.3%). These results were comparable and provide evidence of the viability of internally developed parsimonious non-parametric machine learning models for HTE analysis. The decision tree model results (5-year ARR = 17.0%, 95% CI= -5.4% to 39.4% in the highest risk subgroup) exhibited more uncertainty in the results. DISCUSSION/SIGNIFICANCE: None of the models detected significant HTE on the relative scale; there was substantial HTE on the absolute scale in three of the models. Treatment benefit on the absolute scale may be regarded as bearing greater clinical importance and may be present even in the absence of benefit on the relative scale.

Background: This study evaluates the dementia care system in a local area and aimed to include all specialised services designed to provide health and social services to people with dementia or age-related cognitive impairment, as well as general services with a high or very high proportion of clients with dementia. Methods: The study used an internationally standardised service classification instrument called Description and Evaluation of Services and DirectoriEs for Long Term Care (DESDE-LTC) to identify and describe all services providing care to people with dementia in the Australian Capital Territory (ACT). Results: A total of 47 service providers were eligible for inclusion. Basic information about the services was collected from their websites, and further information was obtained through interviews with the service providers. Of the 107 services offered by the 47 eligible providers, 27% (n = 29) were specialised services and 73% (n = 78) were general services. Most of the services were residential or outpatient, with a target population mostly of people aged 65 or older, and 50 years or older in the case of Aboriginal and Torres Strait Islander Australians. There were government supports available for most types of care through various programmes. Conclusions: Dementia care in the ACT relies heavily on general services. More widespread use of standardised methods of service classification in dementia will facilitate comparison with other local areas, allow for monitoring of changes over time, permit comparison with services provided for other health conditions and support evidence-informed local planning.

Introduction An important consideration in the treatment of patients with psoriatic arthritis (PsA) is whether the addition of methotrexate (MTX) to biologics has greater efficacy than biologic monotherapy with respect to efficacy outcomes in these patients.Objectives To conduct a network meta-analysis (NMA) comparing biologics by treatment class with and without MTX for treatment of adults with active PsA.Methods A systematic literature review (SLR) identified randomised, double-blinded, controlled trials, and a Bayesian NMA compared biologics with and without MTX by treatment class (tumour necrosis factor inhibitors (TNFi), interleukin-23 inhibitors (IL-23i) and IL-17i). Efficacy outcomes included American College of Rheumatology 20%, 50% and 70% (ACR20, ACR50 and ACR70) improvement response.Results The SLR initially identified 31 studies, of which 17 met feasibility criteria for the NMA by containing the ‘without MTX’ subgroup. For ACR20 efficacy (the most robust assessment examined), all active treatments were significantly better than placebo. No statistically significant differences were demonstrated between biologic monotherapy (for all classes examined) and biologics in combination with MTX for ACR20/50. IL-17i were comparable to IL-23i, and IL-17i were significantly better than TNFi for ACR20. Although limited by fewer trials, TNFi, IL-23i and IL-17i were not statistically different for ACR50/70.Conclusions Concomitant use of MTX and biologics did not improve ACR efficacy outcomes versus biologic monotherapy. MTX does not appear to be necessary as a background therapy when biologics are used for the achievement of ACR20/50 responses in patients with PsA.

IntroductionGulf War Illness is a type of chronic multisymptom illness, that affects about 30% of veterans deployed to the 1990–91 Persian Gulf War. Veterans deployed to Iraq/Afghanistan after 2000 are reported to have a similar prevalence of chronic multisymptom illness. More than 30 years after the Persian Gulf War, Gulf War Illness still has an unexplained symptom complex, unknown etiology and lacks definitive diagnostic criteria and effective treatments. Our recent studies have found that substantially smaller brainstem volumes and lower fiber integrity are associated with increased sleep difficulty and pain intensity in 1990–91 Persian Gulf War veterans. This study was conducted to investigate whether veterans deployed to Iraq/Afghanistan present similar brainstem damage, and whether such brainstem structural differences are associated with major symptoms as in Gulf War Illness.MethodsHere, we used structural magnetic resonance imaging and diffusion tensor imaging to measure the volumes of subcortices, brainstem subregions and white matter integrity of brainstem fiber tracts in 188 veterans including 98 Persian Gulf War veterans and 90 Iraq/Afghanistan veterans.ResultsWe found that compared to healthy controls, veterans of both campaigns presented with substantially smaller volumes in brainstem subregions, accompanied by greater periaqueductal gray matter volumes. We also found that all veterans had reduced integrity in the brainstem-spinal cord tracts and the brainstem-subcortical tracts. In veterans deployed during the 1990–91 Persian Gulf War, we found that brainstem structural deficits significantly correlated with increased sleep difficulties and pain intensities, but in veterans deployed to Iraq/Afghanistan, no such effect was observed.DiscussionThese structural differences in the brainstem neurons and tracts may reflect autonomic dysregulation corresponding to the symptom constellation, which is characteristic of Gulf War Illness. Understanding these neuroimaging and neuropathological relationships in Gulf War and Iraq/Afghanistan veterans may improve clinical management and treatment strategies for modern war related chronic multisymptom illness.

ObjectiveWe investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA1c) and the associations with selected phenotypic characteristics.Research design and methodsThis is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed

OBJECTIVE: To evaluate short- and long-term outcomes of African American (AA) participants of Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomized 158 participants with systemic sclerosis-interstitial lung disease (SSc-ILD) to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 participants with SSc-ILD to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF). Joint models compared the course of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) between AA and non-AA, and Cox proportional hazard models assessed long-term morbidity and mortality outcomes. RESULTS: In SLS I, there was no difference in the course of the FVC or DLCO between AA and non-AA in either treatment arm. In SLS II, AA had an improved course of the FVC compared with non-AA in the CYC arm; in the MMF arm, there was no difference in FVC course. There was no difference in DLCO course in either arm. Time to death and respiratory failure were similar for AA and non-AA in SLS I. There was a trend for improved survival and time to respiratory failure in AA compared with non-AA in SLS II. AA race was not independently associated with mortality in the SLS I or II in the Cox models. CONCLUSION: Data from two randomized controlled trials demonstrated that AA patients with SSc-ILD have similar morbidity and mortality outcomes compared with non-AA patients. These findings contrast with the racial disparities described in prior observational studies and warrant further investigation.

BackgroundChildren with central nervous system (CNS) tumors undergo frequent imaging for diagnosis and follow-up, but few studies have characterized longitudinal imaging patterns. We described medical imaging in children before and after malignant CNS tumor diagnosis.ProcedureWe conducted a retrospective cohort study of children aged 0-20 years diagnosed with CNS tumors between 1996-2016 at six U.S. integrated healthcare systems and Ontario, Canada. We collected computed topography (CT), magnetic resonance imaging (MRI), radiography, ultrasound, nuclear medicine examinations from 12 months before through 10 years after CNS diagnosis censoring six months before death or a subsequent cancer diagnosis, disenrollment from the health system, age 21 years, or December 31, 2016. We calculated imaging rates per child per month stratified by modality, country, diagnosis age, calendar year, time since diagnosis, and tumor grade.ResultsWe observed 1,879 children with median four years follow-up post-diagnosis in the U.S. and seven years in Ontario, Canada. During the diagnosis period (±15 days of diagnosis), children averaged 1.10 CTs (95% confidence interval [CI] 1.09-1.13) and 2.14 MRIs (95%CI 2.12-2.16) in the U.S., and 1.67 CTs (95%CI 1.65-1.68) and 1.86 MRIs (95%CI 1.85-1.88) in Ontario. Within one year after diagnosis, 19% of children had ≥5 CTs and 45% had ≥5 MRIs. By nine years after diagnosis, children averaged one MRI and one radiograph per year with little use of other imaging modalities.ConclusionsMRI and CT are commonly used for CNS tumor diagnosis, whereas MRI is the primary modality used during surveillance of children with CNS tumors.

ObjectiveTo investigate the prevalence of the MUC5B promoter variant rs35705950 in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and whether its presence predicts response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF).MethodsSSc-ILD patients who participated in Scleroderma Lung Study (SLS) II (MMF versus CYC) were included in this study (N = 142). TaqMan Genotyping Assays were used to determine the MUC5B rs35705950 single nucleotide polymorphism. Joint models were created to examine how the presence of this variant affected the course of the forced vital capacity (FVC) over 2 years. Linear regression models were used to investigate the relationship between the presence of this variant and the change in quantitative radiographic fibrosis.ResultsAmong 128 participants who were tested for this variant, 18% possessed at least one copy of the MUC5B minor allele. Patients with at least one copy of this allele were similar to those without the allele with respect to age, sex, SSc subtype, ILD disease severity; however, this variant was rare among African Americans (3.7%). The presence of the MUC5B variant did not affect the course of the FVC, nor the change in quantitative radiographic fibrosis, ground glass or ILD scores in either treatment arm.ConclusionIn the context of a randomized controlled trial for SSc-ILD, the presence of the MUC5B variant did not predict disease severity, nor affect treatment response to MMF or CYC. Future studies are needed to determine whether this variant affects ILD progression in other SSc cohorts and in patients receiving anti-fibrotic therapy.

OBJECTIVE: Our objective was to determine if treatment with cyclophosphamide (CYC) and mycophenolate mofetil (MMF) improves patient-reported outcomes (PROs) among patients with systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: This study examined PROs in patients with SSc-ILD (N = 142) who participated in the Scleroderma Lung Study II, a randomized controlled trial comparing MMF for 2 years with oral CYC for 1 year followed by 1 year of a placebo. Joint models were created to evaluate the course of PROs over 2 years. The difference in PRO scores from baseline to 24 months was measured, and the percentage of patients meeting the minimum clinically important difference (MCID) was calculated. Correlations between PROs and SSc-ILD disease severity measures were also examined. RESULTS: Treatment with CYC and MMF led to improvements in several PROs with no between-treatment differences. Scores for the Transitional Dyspnea Index (TDI) and St. Georges Respiratory Questionnaire (SGRQ) improved significantly over 2 years, and 29%/24% and 28%/25% of participants in the CYC/MMF groups met or exceeded the MCID estimates for TDI and SGRQ, respectively. At baseline, the forced vital capacity (FVC) percentage predicted (FVC%-predicted) did not correlate with the Baseline Dyspnea Index or SGRQ. However, improvements in the FVC%-predicted were weakly associated with improvements in dyspnea (assessed by the TDI) and SGRQ scores. CONCLUSION: Treatment with CYC and MMF improved overall health-related quality of life in patients with SSc-ILD. The relationship between PRO measures and the FVC was relatively weak, suggesting that PROs provide complementary information about treatment efficacy not captured by changes in the FVC alone in this patient population.

ObjectiveWe evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes.Research design and methodsThis was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for