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Introduction: We describe the California Healthy Places Index (HPI) and its performance relative to other indexes for measuring community well-being at the census-tract level. The HPI arose from a need identified by health departments and community organizations for an index rooted in the social determinants of health for place-based policy making and program targeting. The index was geographically granular, validated against life expectancy at birth, and linked to policy actions. Materials and Methods: Guided by literature, public health experts, and a positive asset frame, we developed a composite index of community well-being for California from publicly available census-tract data on place-based factors linked to health. The 25 HPI indicators spanned 8 domains; weights were derived from their empirical association with tract-level life expectancy using weighted quantile sums methods. Results: The HPI's domains were aligned with the social determinants of health and policy action areas of economic resources, education, housing, transportation, clean environment, neighborhood conditions, social resources, and health care access. The overall HPI score was the sum of weighted domain scores, of which economy and education were highly influential (50% of total weights). The HPI was strongly associated with life expectancy at birth (r = 0.58). Compared with the HPI, a pollution-oriented index did not capture one-third of the most disadvantaged quartile of census tracts (representing 3 million Californians). Overlap of the HPI's most disadvantaged quartile of census tracts was greater for indexes of economic deprivation. We visualized the HPI percentile ranking as a web-based mapping tool that presented the HPI at multiple geographies and that linked indicators to an action-oriented policy guide. Practice Implications: The framing of indexes and specifications such as domain weighting have substantial consequences for prioritizing disadvantaged populations. The HPI provides a model for tools and new methods that help prioritize investments and identify multisectoral opportunities for policy action. [ABSTRACT FROM AUTHOR]

T follicular helper–like cells and IL-21 are drivers of skin fibrosis in systemic sclerosis. Scleroderma's little helpers: Scleroderma, also known as systemic sclerosis, is a devastating disease involving multi-organ fibrosis. Taylor et al. examined immune cells from patients and in the skin of a graft-versus-host disease–based mouse model to elucidate the key players in this disease. They observed that a subset of T follicular helper–like cells expressing inducible costimulator (ICOS) correlated with disease scores. Blocking these cells with anti-ICOS or anti–IL-21, an important T follicular helper cell cytokine, ameliorated disease in the mouse model. Targeting these not-so-helpful T cells could dampen dermal fibrosis and bring relief to scleroderma patients. Systemic sclerosis (SSc) is a debilitating inflammatory and fibrotic disease that affects the skin and internal organs. Although the pathophysiology of SSc remains poorly characterized, mononuclear cells, mainly macrophages and T cells, have been implicated in inflammation and fibrosis. Inducible costimulator (ICOS), which is expressed on a subset of memory T helper (TH) and T follicular helper (TFH) cells, has been shown to be increased in SSc and associated with disease pathology. However, the identity of the relevant ICOS+ T cells and their contribution to inflammation and fibrosis in SSc are still unknown. We show that CD4+ ICOS-expressing T cells with a TFH-like phenotype infiltrate the skin of patients with SSc and are correlated with dermal fibrosis and clinical disease status. ICOS+ TFH-like cells were found to be increased in the skin of graft-versus-host disease (GVHD)–SSc mice and contributed to dermal fibrosis via an interleukin-21– and matrix metalloproteinase 12–dependent mechanism. Administration of an anti-ICOS antibody to GVHD-SSc mice prevented the expansion of ICOS+ TFH-like cells and inhibited inflammation and dermal fibrosis. Interleukin-21 neutralization in GVHD-SSc mice blocked disease pathogenesis by reducing skin fibrosis. These results identify ICOS+ TFH-like profibrotic cells as key drivers of fibrosis in a GVHD-SSc model and suggest that inhibition of these cells could offer therapeutic benefit for SSc. [ABSTRACT FROM AUTHOR]

Objective Systemic sclerosis (SSc) is a fibrotic disease characterized by an obliterative vasculopathy with thrombosis and impairment of the coagulation-fibrinolysis balance. Plasminogen activator inhibitor 1 (PAI-1) is the major inhibitor of profibrinolytic plasminogen activators (PAs). This study was undertaken to evaluate the contribution of PAI-1 to SSc pathology in the skin. Methods PAI-1 was evaluated in skin from patients with diffuse SSc (dSSc) and those with limited SSc (lSSc) by immunohistochemistry. The contribution of PAI-1 to SSc pathology was tested in vivo in murine graft-versus-host disease (GVHD) and bleomycin models of progressive skin fibrosis and in vitro in dermal human microvascular endothelial cells (HMVECs) using a monoclonal antibody that selectively prevents the binding of PAI-1 to PA. Results Skin from patients with dSSc and those with lSSc showed increased PAI-1 levels in the epidermis and microvessel endothelium. PAI-1 neutralization in the GVHD model led to a dramatic, dose-dependent improvement in clinical skin score, concomitant with vasculopathy resolution, including a reduction in fibrinolysis regulators and vascular injury markers, as well as reduced inflammation. Resolution of vasculopathy and inflammation was associated with resolution of skin fibrosis, as assessed by reduction in collagen content and expression of key profibrotic mediators, including transforming growth factor β1 and tissue inhibitor of metalloproteinases 1. Similar to the GVHD model, PAI-1 neutralization reduced dermal inflammation and fibrosis in the bleomycin model. PAI-1 neutralization stimulated plasmin-mediated metalloproteinase 1 activation in dermal HMVECs. Conclusion Our findings indicate that neutralization of the antifibrinolytic function of PAI-1 resolves skin fibrosis by limiting the extent of initial vascular injury and connective tissue inflammation. These data suggest that PAI-1 represents an important checkpoint in disease pathology in human SSc. [ABSTRACT FROM AUTHOR]

Although respiratory syncytial virus (RSV) infection is the most important cause of bronchiolitis in infants, the pathogenesis of RSV disease is poorly described. We studied histopathologic changes in a panel of lung tissue specimens obtained from infants with fatal cases of primary RSV infection. In these tissues, airway occlusion with accumulations of infected, apoptotic cellular debris and serum protein was consistently observed. Similar observations were found after RSV infection in New Zealand black (NZB) mice, which have constitutive deficiencies in macrophage function, but not in BALB/c mice. A deficiency in the number of alveolar macrophages in NZB mice appears to be central to enhanced disease, because depletion of alveolar macrophages in BALB/c mice before RSV exposure resulted in airway occlusion. In mice with insufficient numbers of macrophages, RSV infection yielded an increased viral load and enhanced expression of type I interferon-associated genes at the height of disease. Together, our data suggest that innate, rather than adaptive, immune responses are critical determinants of the severity of RSV bronchiolitis. [ABSTRACT FROM AUTHOR]

We examined the requirement for and cooperation between CD28 and inducible costimulator (ICOS) in effective T helper (TH) cell responses in vivo. We found that both CD28 and ICOS were critical in determining the outcome of an immune response; cytolytic T lymphocyte?associated antigen 4?immunoglobulin (CTLA-4?Ig), ICOS-Ig and/or a neutralizing ICOS monoclonal antibody attenuated T cell expansion, TH2 cytokine production and eosinophilic inflammation. CD28-dependent signaling was essential during priming, whereas ICOS?B7RP-1 regulated TH effector responses, and the up-regulation of chemokine receptors that determine T cell migration. Our data suggests a scenario whereby both molecules regulate the outcome of the immune response but play separate key roles: CD28 primes T cells and ICOS regulates effector responses. [ABSTRACT FROM AUTHOR]