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\"Chronicles the achievements and challenges of African American collective economic action and social entrepreneurship in the struggle for civil rights and economic equality\"--Provided by publisher.

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Purpose of ReviewSystemic sclerosis (SSc) is a life-threatening autoimmune disease that causes debilitating skin fibrosis. The skin in SSc is easily accessible, and skin biopsies may provide rich biological data regarding underlying disease pathophysiology. Here, we review literature relevant to the potential for skin histology to serve as a diagnostic, pharmacokinetic/response, and predictive biomarker in SSc.Recent FindingsMultiple histologic parameters correlate with SSc severity, including alpha smooth muscle actin (aSMA), CD34, collagen density, thickness, and inflammatory cell infiltration. Recent clinical trials incorporate skin histology as exploratory outcome measurements; however, a standard approach is not yet established. The possibility that skin histology may be useful as a predictive biomarker was suggested by a recent study that identified genes related to skin aSMA and CD34 staining intensity that were increased at baseline among improvers versus nonimprovers.SummaryCurrent literature supports skin histology as a mechanism to measure treatment response, but future work is needed to define minimally meaningful changes in key SSc skin histologic features.

TGF-β has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-β-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-β may benefit these patients. Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-β isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-β-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS). In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-β-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment. The rapid inhibition of TGF-β-regulated gene expression in response to fresolimumab strongly implicates TGF-β in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis. Clinicaltrials.gov NCT01284322.

Child undernutrition remains a global challenge, intricately linked to systemic inequities in access to maternal and child health and nutrition (MCHN) services. While SMS‐based behaviour change communication (BCC) offers a scalable strategy to address this challenge, its effectiveness is often undermined by low and inconsistent user engagement. This study extends the impact evaluation of the mNutrition programme in Tanzania—a nationwide SMS‐based BCC programme aimed at improving maternal and child nutrition (MCN)—to investigate what drives sustained, long‐term engagement—an important but underexplored gap. The objective is to explore the mechanisms driving sustained engagement among mothers in rural Tanzania and how these are triggered by specific contextual factors and inequities. A realist approach was used, combining realist interviews with 40 sustained engagers (conducted across three sites between February and April 2019) and quantitative endline survey data. Retroductive analysis iteratively tested initial programme theories (IPTs) and derived Context‐Mechanism‐Outcome (CMO) configurations explaining sustained engagement. Findings showed sustained engagement resulted from the interplay between programme elements—such as content, SMS delivery (regularity, convenience, privacy), message tone (non‐judgmental, supportive), and perceptions of the sender—and inequity‐laden contextual realities, including time poverty, social isolation, undervaluation of women, gendered power dynamics within households and healthcare settings. The study concludes that digital BCC programmes must be context‐sensitive and equity‐oriented to achieve sustained engagement. Designing messages and delivery systems that reflect users' lived experiences and address structural vulnerabilities can enhance engagement and support more equitable nutrition outcomes. Summary Sustained engagement is not driven by any single feature of a digital BCC programme but by the interactions between programme elements (e.g., content, tone, delivery mode) and users' specific contexts and needs. Sustained engagement is dynamic and evolves over time. Digital BCC programmes should include mechanisms for ongoing feedback from users to adapt to their changing needs and contexts. Digital BCC programmes for MCN should aim to go beyond delivering behaviour change content by addressing broader inequities such as time poverty, social isolation, undervaluation, and gender imbalances within households to foster greater impact and sustained engagement.

A growing number of states have passed laws that ban or restrict diversity, equity, and inclusion (DEI) initiatives in higher education; however, little is known about how such laws affect the prevalence of DEI centers and student-of-color groups, which are often housed within DEI centers. Through logistic regression analyses of longitudinal data on DEI centers and student-of-color organizations across 1,756 U.S. colleges and universities, the authors find that anti-DEI laws are associated with schools losing DEI offices between 2020 and 2024. Yet schools in states with anti-DEI laws were more likely to gain Black, Latinx, and Native American groups and less likely to lose existing Black and Latinx student groups. Additionally, anti-DEI laws were not associated with gains or losses in Asian or Asian American student groups. Our study thus suggests that students are organizing to create new inclusive spaces in response to anti-DEI legislation.

Background Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. Methods We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud’s phenomenon (RP) symptom. Results Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3–40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. Conclusion This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

Objective To assess the safety and effectiveness of imatinib mesylate in the treatment of diffuse cutaneous systemic sclerosis (dcSSc). Methods In this phase IIa, open-label, single-arm clinical trial, 30 patients with dcSSc were treated with imatinib 400 mg daily. Patients were monitored monthly for safety assessments. Modified Rodnan skin scores (MRSS) were assessed every 3 months. Pulmonary function testing, chest radiography, echocardiography and skin biopsies were performed at baseline and after 12 months of treatment. Results Twenty-four patients completed 12 months of therapy. 171 adverse events (AE) with possible relation to imatinib were identified; 97.6% were grade 1 or 2. Twenty-four serious AE were identified, two of which were attributed to study medication. MRSS decreased by 6.6 points or 22.4% at 12 months (p=0.001). This change was evident starting at the 6-month time point (Δ=−4.5; p<0.001) and was seen in patients with both early and late-stage disease. Forced vital capacity (FVC) improved by 6.4% predicted (p=0.008), and the diffusion capacity remained stable. The improvement in FVC was significantly greater in patients without interstitial lung disease. Health-related quality of life measures improved or remained stable. Blinded dermatopathological analysis confirmed a significant decrease in skin thickness and improvement in skin morphology. Conclusions Treatment with imatinib was tolerated by most patients in this cohort. Although AE were common, most were mild to moderate. In this open-label experience, improvements in skin thickening and FVC were observed. Further investigation of tyrosine kinase inhibition for dcSSc in a double-blind randomised placebo controlled trial is warranted. ClinicalTrials.gov, NCT00555581

Background To determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc). Methods Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs). Results Seventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration ( p  < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference − 0.24, 95% CI (− 1.46, 0.99), p  = 0.70). Four participants experienced five serious AE (four in riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the riociguat group ( p  = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the riociguat-riociguat arm had complete healing of their DUs. Conclusion In participants with SSc-DU, treatment with riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial. Trial registration ClinicalTrials.gov, NCT02915835 . Registered on September 27, 2016.