Nef is an HIV-encoded accessory protein that enhances pathogenicity by down-regulating major histocompatibility class I (MHC-I) expression to evade killing by cytotoxic T lymphocytes (CTLs). A potent Nef inhibitor that restores MHC-I is needed to promote immune-mediated clearance of HIV-infected cells. We discovered that the plecomacrolide family of natural products restored MHC-I to the surface of Nef-expressing primary cells with variable potency. Concanamycin A (CMA) counteracted Nef at subnanomolar concentrations that did not interfere with lysosomal acidification or degradation and were nontoxic in primary cell cultures. CMA specifically reversed Nef-mediated down-regulation of MHC-I, but not CD4, and cells treated with CMA showed reduced formation of the Nef:MHC-I:AP-1 complex required for MHC-I down-regulation. CMA restored expression of diverse allotypes of MHC-I in Nef-expressing cells and inhibited Nef alleles from divergent clades of HIV and simian immunodeficiency virus, including from primary patient isolates. Lastly, we found that restoration of MHC-I in HIV-infected cells was accompanied by enhanced CTL-mediated clearance of infected cells comparable to genetic deletion of Nef. Thus, we propose CMA as a lead compound for therapeutic inhibition of Nef to enhance immune-mediated clearance of HIV-infected cells.

Objective Distress among cancer patients has been broadly accepted as an important indicator of well‐being but has not been well studied. We investigated patient characteristics associated with high distress levels as well as correlations among measures of patient‐reported distress and “objective” stress‐related biomarkers among colorectal cancer patients. Methods In total, 238 patients with colon or rectal cancer completed surveys including the Distress Thermometer, Problem List, and the Hospital Anxiety and Depression Scale. We abstracted demographic and clinical information from patient charts and determined salivary cortisol level and imaging‐based sarcopenia. We evaluated associations between patient characteristics (demographics, clinical factors, and psychosocial and physical measures) and three outcomes (patient‐reported distress, cortisol, and sarcopenia) with Spearman's rank correlations and multivariable linear regression. The potential moderating effect of age was separately investigated by including an interaction term in the regression models. Results Patient‐reported distress was associated with gender (median: women 5.0, men 3.0, p < 0.001), partnered status (single 5.0, partnered 4.0, p = 0.018), and cancer type (rectal 5.0, colon 4.0, p = 0.026); these effects varied with patient age. Cortisol level was associated with “emotional problems” (ρ = 0.34, p = 0.030), anxiety (ρ = 0.46, p = 0.006), and depression (ρ = 0.54, p = 0.001) among younger patients. We found no significant associations between patient‐reported distress, salivary cortisol, and sarcopenia. Conclusions We found that young, single patients reported high levels of distress compared to other patient groups. Salivary cortisol may have limited value as a cancer‐related stress biomarker among younger patients, based on association with some psychosocial measures. Stress biomarkers may not be more clinically useful than patient‐reported measures in assessing distress among colorectal cancer patients.

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Background High-deductible health plans (HDHPs) are increasing in prevalence as a cost control device for slowing health care cost growth by reducing nonessential medical service utilization. High cost-sharing associated with HDHPs can lead to significant financial distress and worse disease outcomes. We hypothesize that chronic disease patients are delaying or foregoing necessary medical care due to health care costs. Methods A retrospective cohort analysis of IBD patients at risk for high medical service utilization with continuous enrollment in either an HDHP or THP from 2009 to 2016 were identified using the MarketScan database. Health care costs were compared between insurance plan groups by Kruskal-Wallis test. Temporal trends in office visits, colonoscopies, emergency department (ED) visits, and hospitalizations were evaluated using additive decomposition time series analysis. Results Of 605,862 patients with a diagnosis of IBD, we identified 13,052 eligible patients. Annual out-of-pocket costs were higher in the HDHP group (n = 524) than the THP group (n = 12,458) ($2870 vs $1,864; P &lt; 0.001) without any difference in total health care expenses ($23,029 vs $23,794; P = 0.583). Enrollment in an HDHP influenced colonoscopy, ED visit, and hospitalization utilization timing. Colonoscopies peaked in the fourth quarter, ED visits peaked in the first quarter, and hospitalizations peaked in the third and fourth quarter. Conclusions High-deductible health plan enrollment does not change the cost of care; however, it shifts health care costs onto patients and changes the timing of the care they receive. High-deductible health plans are incentivizing delays in obtaining health care with a potential to cause worse disease outcomes and financial distress. Further evaluation is warranted.