Providing Outpatient Telehealth Services in the United States: Before and During Coronavirus Disease 2019.

Before coronavirus disease 2019 (COVID-19), telehealth evaluation and management (E/M) services were not widely used in the United States and often were restricted to rural areas or locations with poor access to care. Most Medicare beneficiaries could not receive telehealth services in their homes. In response to the COVID-19 pandemic, Medicare, Medicaid, and commercial insurers relaxed restrictions on both coverage and reimbursement of telehealth services. These changes, together with the need for social distancing, transformed the delivery of outpatient E/M services through an increase in telehealth use. In some cases, the transition from in-person outpatient care to telehealth occurred overnight. Billing and claim submission for telehealth services is complicated; has changed over the course of the pandemic; and varies with each insurance carrier, making telehealth adoption burdensome. Despite these challenges, telehealth is beneficial for health-care providers and patients. Without additional legislation at the federal and state levels, it is likely that telehealth use will continue to decline after the COVID-19 public health emergency.

Gene signatures common to allograft rejection are associated with lymphocytic bronchitis.

Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E-grade rejection) to small airway (A- and B-grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology-free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB-associated metagene. We observed statistically increased expression in Cohort 2 for this LB-associated metagene and four other established allograft rejection metagenes in rejection vs paired non-rejection biopsies for both E-grade and A-grade subtypes, but not B-grade pathology. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.

Adipose tissue 12/15 lipoxygenase pathway in human obesity and diabetes.

CONTEXT: Visceral adipose tissue (VAT) is a key contributor to chronic inflammation in obesity. The 12/15-lipoxygenase pathway (ALOX) is present in adipose tissue (AT) and leads to inflammatory cascades that are causal for the onset of insulin resistance in rodent models of obesity. OBJECTIVE: The pathophysiology of the ALOX 12/15 pathway in human AT is unknown. We characterized the ALOX pathway in different AT depots in obese humans with or without type 2 diabetes (T2D). DESIGN: This study includes a cross-sectional cohort of 46 morbidly obese (body mass index >39 kg/m(2)) nondiabetic (n = 25) and T2D (n = 21) subjects. SETTING: This study was conducted at Eastern Virginia Medical School (Norfolk, Virginia) in collaboration with Sentara Metabolic and Weight Loss Surgery Center (Sentara Medical Group, Norfolk, Virginia). PATIENTS: Twenty-five obese (body mass index 44.8 ± 4.4 kg/m(2)) nondiabetic (hemoglobin A1c 5.83% ± 0.27%) and 21 obese (43.4 ± 4.1 kg/m(2)) and T2D (hemoglobin A1c 7.66% ± 1.22%) subjects were included in the study. The subjects were age matched and both groups had a bias toward female gender. MAIN OUTCOMES AND MEASURES: Expression of ALOX isoforms along with fatty acid substrates and downstream lipid metabolites were measured. Correlations with depot-specific inflammatory markers were also established. RESULTS: ALOX 12 expression and its metabolite 12(S)-hydroxyeicosatetraenoic acid were significantly increased in the VAT of T2D subjects. ALOX 15A was exclusively expressed in VAT in both groups. ALOX 12 expression positively correlated with expression of inflammatory genes IL-6, IL-12a, CXCL10, and lipocalin-2. CONCLUSIONS: ALOX 12 may have a critical role in regulation of inflammation in VAT in obesity and T2D. Selective ALOX 12 inhibitors may constitute a new approach to limit AT inflammation in human obesity.

ERK1/2 regulation of CD44 modulates oral cancer aggressiveness.

Carcinogen-induced oral cavity squamous cell carcinoma (OSCC) incurs significant morbidity and mortality and constitutes a global health challenge. To gain further insight into this disease, we generated cell line models from 7,12-dimethylbenz(a)anthracene-induced murine primary OSCC capable of tumor formation upon transplantation into immunocompetent wild-type mice. Whereas several cell lines grew rapidly and were capable of metastasis, some grew slowly and did not metastasize. Aggressively growing cell lines displayed ERK1/2 activation, which stimulated expression of CD44, a marker associated with epithelial to mesenchymal transition and putative cancer stem cells. MEK (MAP/ERK kinase) inhibition upstream of ERK1/2 decreased CD44 expression and promoter activity and reduced cell migration and invasion. Conversely, MEK1 activation enhanced CD44 expression and promoter activity, whereas CD44 attenuation reduced in vitro migration and in vivo tumor formation. Extending these findings to freshly resected human OSCC, we confirmed a strict relationship between ERK1/2 phosphorylation and CD44 expression. In summary, our findings identify CD44 as a critical target of ERK1/2 in promoting tumor aggressiveness and offer a preclinical proof-of-concept to target this pathway as a strategy to treat head and neck cancer.

CXCR3 enhances a T-cell-dependent epidermal proliferative response and promotes skin tumorigenesis.

The chemokine receptor CXCR3 has been proposed to play a critical role in host antitumor responses. In this study, we defined CXCR3-expressing immune cell infiltration in human skin squamous cell carcinomas and then used CXCR3-deficient mice to assess the contribution of CXCR3 to skin tumorigenesis. Our studies employed two established protocols for chemical skin carcinogenesis [methylcholanthrene (MCA) or 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) models]. CXCR3 deletion did not affect tumor development in the MCA model; however, CXCR3 was important in the DMBA/TPA model where gene deletion reduced the incidence of skin tumors. This decreased incidence of skin tumors did not reflect differences in epidermal development but rather was associated with reduced epidermal thickness and proliferation in CXCR3(-/-) mice, implicating the CXCR3 pathway in DMBA/TPA-induced epidermal inflammation and proliferation. Notably, CXCR3 expressed in CD4(+) and CD8(+) T cells was found to be important for enhanced epidermal proliferation. Specifically, CXCR3-deficient mice reconstituted with T cells isolated from wild-type mice treated with DMBA/TPA restored wild-type levels of epidermal proliferation in the mutant mice. Taken together, our findings establish that CXCR3 promotes epidermal tumorigenesis likely through a T-cell-dependent induction of keratinocyte proliferation.

Prolongation of cardiac and islet allograft survival by a blocking hamster anti-mouse CXCR3 monoclonal antibody.

BACKGROUND: Acute allograft rejection requires a multifaceted immune response involving trafficking of immune cells into the transplant and expression of effector cell functions leading to graft destruction. The chemokine receptor CXCR3 and its ligands, CXCL9, CXCL10 and CXCL11, constitute an important pathway for effector cell recruitment posttransplant. However, analysis of CXCR3 expression and function has been hampered by a general lack of availability of a neutralizing anti-CXCR3 monoclonal antibody (mAb) for use in experimental models. METHODS: We report the generation, characterization, and use of CXCR3-173, a new hamster mAb specific for mouse CXCR3 that recognizes CXCR3 on cells from wild-type but not CXCR3-/- mice. RESULTS: Using CXCR3-173 mAb, we demonstrate CXCR3 expression on primary memory phenotype CD4+ and CD8+ T cells, naturally occurring CD4+CD25+ Foxp3+ regulatory T cells, natural killer T cells, and approximately 25% of NK cells. CXCR3-173 blocked chemotaxis in vitro in response to CXCL10 or CXCL11 but not CXCL9. When injected into mice, this mAb significantly prolonged both cardiac and islet allograft survival. When combined with a subtherapeutic regimen of rapamycin, CXCR3-173 mAb induced long-term (>100 day) survival of cardiac and islet allografts. The in vivo effects of CXCR3-173 mAb were not associated with effector lymphocyte depletion. CONCLUSION: These data highlight the utility of CXCR3-173 mAb in developing immunotherapeutic approaches to inhibit transplant rejection and potentially other immune-mediated diseases in murine models.