Real-World Use of Ruxolitinib Cream: Safety Analysis at 1 Year.

BACKGROUND: Ruxolitinib cream is the first topical Janus kinase (JAK) inhibitor approved in the United States (US) for the treatment of mild to moderate atopic dermatitis and nonsegmental vitiligo. A postmarketing study with oral tofacitinib, approved for rheumatoid arthritis, triggered class warnings for JAK inhibitors, including risk of serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis. Because ruxolitinib cream is indicated for inflammatory conditions, it is subject to the same warnings as oral JAK inhibitors in the US. Here, nearly 14,000 patient-years of postmarketing safety data from the first year following market approval of ruxolitinib cream were reviewed. METHODS: The Incyte global safety database (21 September 2021-20 September 2022) and US FDA Adverse Event Reporting System (as of 30 September 2022) were queried for adverse event (AE) reports received for ruxolitinib cream. RESULTS: The search identified 294 postmarketing individual case safety reports containing 589 events, including four serious AEs and no fatal AEs. AEs (i.e., any unfavorable sign, symptom, or disease) representing >2% of all events included application site pain (n = 16), atopic dermatitis (n = 15), skin irritation (n = 15), scratch (n = 14), and condition aggravated (n = 13). The four serious AEs were skin cancer (n = 2), pericarditis, and thrombocytopenia (both n = 1), none of which had sufficient information to assess possible relatedness to ruxolitinib cream. Serious AEs associated with the class warnings for JAK inhibitors were not reported. CONCLUSIONS: Postmarketing safety data from the year following approval suggest ruxolitinib cream is generally well tolerated, without significant systemic AEs, and with a low incidence of application site reactions.

Internal Operational Metrics and Center for Medicare and Medicaid Services Hospital Compare Quality Ratings.

ABSTRACT: The Center for Medicare and Medicaid Services (CMS) has made several refinements to their model for calculating hospital quality star ratings (Hospital Compare) amidst criticism and evidence of bias against some institutions. We argue that the CMS model does align with important internal quality metrics and encourage a measured approach to redesign, potentially using categorizations or tiers, rather than a complete abandonment of the ratings system. We find that institutional characteristics (available resources, average severity of illness, and academic affiliation) are associated with internal quality metrics related to patient flow. Furthermore, regression results from the original and revised CMS star rating methodologies suggest that patient flow metrics (discharges before noon [p < .01] and weekend discharges [p < .001]) have a positive relationship with the Hospital Compare rating. Hospitals with better patient flow, as measured by higher levels of discharges before noon and weekend discharges, are associated with higher CMS quality ratings. These findings suggest that CMS star ratings do reflect key aspects of operational performance, specifically efforts to improve patient flow, but the ranking system should consider hospital characteristics that influence internal operations as we move toward a system capable of quality and price transparency for consumers.

Accessibility of the Affordable Care Act (ACA) marketplace websites.

BACKGROUND: The Affordable Care Act (ACA) mandated that creation of online health insurance websites to ease the complex process of shopping for and enrolling into coverage. Ensuring that these sites are not only available but also meet digital accessibility standards is important so that individuals with disabilities are able to access healthcare services and efficiently obtain insurance coverage. METHOD: We evaluated each of the marketplace sites in 2020 to assess whether they are digitally accessible. We employed a custom audit tool based on a subset of the Web Content Accessibility Guidelines (WCAG) 1.0 and 2.0 AA and used content analysis to compare the site's accessibility statements with best practices. RESULTS: Nearly all of the ACA marketplace websites have significant room to improve their digital accessibility. Notable technical problem areas include lack of text equivalents for images, difficult site navigation, and lack of optimization for mobile use, particularly on those pages that provide instructions on how to get in-person help. CONCLUSIONS: Given that access to health insurance is a primary predictor of access to health care - sites must be easy to use and accessible to all individuals regardless of ability. Barriers to online enrollment, such as those identified in this work, may exacerbate disparities in quality of care, treatment continuity and affordability for individuals with mental and physical disabilities. Entities providing health-related online information & engagement should be aware of actionable opportunities to improve digital accessibility to optimize the enrollment process for both maintaining coverage and assisting those that remain uninsured.

Targeting TGF-ß for treatment of osteogenesis imperfecta.

BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-ß signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-ß signaling in children with OI and conducted a phase I clinical trial of TGF-ß inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-ß neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-ß pathway as the top activated signaling pathway, and IPA showed that TGF-ß1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-ß signaling is a driver pathogenic mechanism in OI. Anti-TGF-ß therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Gridded daily weather data for North America with comprehensive uncertainty quantification.

Access to daily high-resolution gridded surface weather data based on direct observations and over long time periods is essential for many studies and applications including vegetation, wildlife, soil health, hydrological modelling, and as driver data in Earth system models. We present Daymet V4, a 40-year daily meteorological dataset on a 1 km grid for North America, Hawaii, and Puerto Rico, providing temperature, precipitation, shortwave radiation, vapor pressure, snow water equivalent, and day length. The dataset includes an objective quantification of uncertainty based on strict cross-validation analysis for temperature and precipitation results. The dataset represents several improvements from a previous version, and this data descriptor provides complete documentation for updated methods. Improvements include: reductions in the timing bias of input reporting weather station measurements; improvement to the three-dimensional regression model techniques in the core algorithm; and a novel approach to handling high elevation temperature measurement biases. We show cross-validation analyses with the underlying weather station data to demonstrate the technical validity of new dataset generation methods, and to quantify improved accuracy.

Using a Social Capital Framework to Explore a Broker's Role in Small Employer Wellness Program Uptake and Implementation.

PURPOSE: Small employers, while motivated to implement wellness programs, often lack knowledge and resources to do so. As a result, these firms rely on external decision-making support from insurance brokers. The objective of this study was to analyze brokers' familiarity with wellness programs and to characterize their role and interactions with small employers. DESIGN: Using a newly developed common interview guide (20 questions), protocol and analysis plan, 20 interviews were conducted with health insurance brokers in Illinois, Minnesota, North Carolina and Washington in 2016 and 2017. In addition to exploring patterns of broker interactions and familiarity by segment, we propose a framework to conceptualize the broker-client relationship using social capital theory and the RE-AIM model. METHODS: Interviews were transcribed, summarized and a common codebook was established using DeDoose. Themes were identified following multi-rater coding and structured within the framework. RESULTS: Participating brokers reported having a high to moderate familiarity with wellness programs (65%) and a majority (80%) indicated that they have previously advised their small business clients on the availability and features of them. Further, we find that brokers may help eliminate barriers to resources and act as a connector to wellness opportunities within their professional network. CONCLUSION: New initiatives to promote small employer wellness programs can benefit from examining the influence of brokers on the decision-making process. When engaged and supported with resources, brokers may be effective champions for employer wellness programs.

Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer.

RATIONALE: Chronic obstructive lung disease (COPD) is a common and disabling lung disease for which there are few therapeutic options. OBJECTIVES: We reasoned that gene expression profiling of COPD lungs could reveal previously unidentified disease pathways. METHODS: Forty-eight human lung samples were obtained from tissue resected from five nonsmokers, 21 GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 0, 9 GOLD stage 1, 10 GOLD stage 2, and 3 GOLD stage 3 patients. mRNA from the specimens was profiled using Agilent's Functional ID v2.0 array (Agilent, Santa Clara, CA) containing 23,720 sequences. MEASUREMENTS AND MAIN RESULTS: The gene expression pattern was influenced by the percentage of the sample made up of parenchyma. Gene expression was related to forced expiratory flow between 25 and 75% of forced expiratory volume (FEF(25-75%) % predicted) revealing a signature gene set of 203 transcripts. Genes involved in extracellular matrix synthesis/degradation and apoptosis were among the up-regulated genes, whereas genes that participate in antiinflammatory responses were down-regulated. Immunohistochemistry confirmed expression of urokinase plasminogen activator (PLAU), urokinase plasminogen activator receptor (PLAUR), and thrombospondin (THBS1) by alveolar macrophages and airway epithelial cells. Genes in this pathway have been shown to be involved in the activation of transforming growth factor (TGF)-beta1 and matrix metalloproteinases and are subject to inhibition by SERPINE2. Interestingly, both TGF-beta1 and SERPINE2 have been identified as candidate genes in COPD genetic linkage and association studies. CONCLUSIONS: The results provide evidence that genes involved in tissue remodeling and repair are differentially regulated in the lungs of obstructed smokers and suggest that they are potential therapeutic targets. Data deposited in GEO at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE8500.

Measles, mumps, and rubella virus vaccine (M-M-R™II): a review of 32 years of clinical and postmarketing experience.

M-M-R™II (measles, mumps, and rubella virus vaccine live; Merck, Sharp, & Dohme Corp.) is indicated for simultaneous vaccination against measles, mumps, and rubella in individuals ≥ 12 months of age. Before the vaccine era, these viruses infected most exposed individuals, with subsequent morbidity and mortality. One of the greatest achievements of public health has been to eliminate these 3 diseases in large geographic areas. The safety profile of M-M-R™II is described using data from routine global postmarketing surveillance. Postmarketing surveillance has limitations (including incomplete reporting of case data), but allows collection of real-world information on large numbers of individuals, who may have concurrent medical problems excluding them from clinical trials. It can also identify rare adverse experiences (AEs). Over its 32-year history, ≈ 575 million doses of M-M-R™II have been distributed worldwide, with 17,536 AEs voluntarily reported for an overall rate of 30.5 AEs/1,000,000 doses distributed. This review provides evidence that the vaccine is safe and well-tolerated.