INTRODUCTION: Telehealth can potentially improve the quality of healthcare through increased access to primary care. While telehealth use increased during the COVID-19 pandemic, racial/ethnic disparities in the use of telemedicine persisted during this period. Little is known about the relationship between health coverage and patient race/ethnicity after the onset of the COVID-19 pandemic. OBJECTIVE: This study examines how differences in patient race/ethnicity and health coverage are associated with the number of in-person vs. telehealth visits among patients with chronic conditions before and after Californias stay-at-home order (SAHO) was issued on 19 March 2020. METHODS: We used weekly patient visit data (in-person (N = 63, 491) and telehealth visits (N = 55, 472)) from seven primary care sites of an integrated, multi-specialty medical group in Los Angeles County that served a diverse patient population between January 2020 and December 2020 to examine differences in telehealth visits reported for Latino and non-Latino Asian, Black, and white patients with chronic conditions (type 2 diabetes, pre-diabetes, and hypertension). After adjusting for age and sex, we estimate differences by race/ethnicity and the type of insurance using an interrupted time series with a multivariate logistic regression model to study telehealth use by race/ethnicity and type of health coverage before and after the SAHO. A limitation of our research is the analysis of aggregated patient data, which limited the number of individual-level confounders in the regression analyses. RESULTS: Our descriptive analysis shows that telehealth visits increased immediately after the SAHO for all race/ethnicity groups. Our adjusted analysis shows that the likelihood of having a telehealth visit was lower among uninsured patients and those with Medicaid or Medicare coverage compared to patients with private insurance. Latino and Asian patients had a lower probability of telehealth use compared with white patients. DISCUSSION: To address access to chronic care management through telehealth, we suggest targeting efforts on uninsured adults and those with Medicare or Medicaid coverage, who may benefit from increased telehealth use to manage their chronic care.

Follicular CD8+CXCR5+ T cells are a specialized CD8+ T cell subset with unique follicular-homing capabilities that have been reported to display effector functions in viral immunity, tumor immunity, and autoimmunity. CD8+CXCR5+ T cells exhibit B cell helper functions and express CD40L, ICOS, programmed cell death protein 1 (PD-1), and BCL-6, the transcriptional regulator of CD4+CXCR5+ T follicular helper cells and of germinal center B cells. HIV is known to be sequestered in lymphoid follicles, and CD8+CXCR5+ T cell frequency is a marker for disease severity, given that HIV-infected patients with lower numbers of circulating CD8+CXCR5+ T cells display lower CD4+ T cell counts. Likewise, several groups have reported a direct correlation between the quantity of CD8+CXCR5+ T cells and suppression of HIV viral load. In this study, we observed elevated absolute numbers of CD8+CXCR5+ and CD8+CXCR5+BCL-6+PD-1+ T cells in the blood of HIV-infected participants of the Multicenter AIDS Cohort Study. We further demonstrated in vitro that activated human CD8+CXCR5+ T cells isolated from peripheral blood and tonsil from healthy donors show increased CD40L expression and induce the production of PD ligand 1 (PD-L1)+IgG+ B cells. Moreover, absolute numbers of CD8+CXCR5+ T cells significantly and positively correlated with numbers of PD-L1+ B cells found in blood of HIV-infected individuals. Altogether, these results show that activated CD8+CXCR5+ T cells have the ability to activate B cells and increase the percentage of PD-L1+ and PD-L1+IgG+ B cells, which provides insights into the early events of B cell activation and differentiation and may play a role in disease progression and lymphomagenesis in HIV-infected individuals.

Introduction

Extracellular vesicles are membrane-bound structures secreted into the extracellular milieu by cells and can carry bioactive molecules. There is emerging evidence suggesting that EVs play a role in the diagnosis, treatment, and prognosis of certain cancers. In this study, we investigate the association of EVs bearing PD-L1 and molecules important in B-cell activation and differentiation with AIDS-NHL risk.

Methods

EVs were isolated from archived serum collected prior to the diagnosis of AIDS-NHL in cases (N = 51) and matched HIV+ controls (N = 52) who were men enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Serum specimens of AIDS-NHL cases were collected at a mean time of 1.25 years (range of 2 to 36 months) prior to an AIDS-NHL diagnosis. The expression of PD-L1 and other molecules on EVs (CD40, CD40L, TNF-RII, IL-6Rα, B7-H3, ICAM-1, and FasL) were quantified by Luminex multiplex assay.

Results and discussion

We observed significantly higher levels of EVs bearing PD-L1, CD40, TNF-RII and/or IL-6Rα in AIDS-NHL cases compared with controls. Using multivariate conditional logistic regression models adjusted for age and CD4⁺ T-cell count, we found that EVs bearing PD-L1 (OR = 1.93; 95% CI: 1.10 - 3.38), CD40 (OR = 1.97, 95% CI: 1.09 - 3.58), TNF-RII (OR = 5.06; 95% CI: 1.99 - 12.85) and/or IL-6Rα (OR = 4.67; 95% CI: 1.40 - 15.53) were significantly and positively associated with AIDS-NHL risk. In addition, EVs bearing these molecules were significantly and positively associated with non-CNS lymphoma: PD-L1 (OR = 1.94; 95% CI: 1.01 - 3.72); CD40 (OR = 2.66; 95% CI: 1.12 - 6.35); TNF-RII (OR = 9.64; 95% CI: 2.52 - 36.86); IL-6Rα (OR = 8.34; 95% CI: 1.73 - 40.15). These findings suggest that EVs bearing PD-L1, CD40, TNF-RII and/or IL-6Rα could serve as biomarkers for the early detection of NHL in PLWH.

People living with HIV (PLWH) are at higher risk of developing lymphoma. In this study, we performed cytometry by time-of-flight (CyTOF) on peripheral blood mononuclear cells of cART-naïve HIV+ individuals and cART-naïve HIV+ individuals prior to AIDS-associated non-Hodgkin lymphoma (pre-NHL) diagnosis. Participants were enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Uniform Manifold Approximation and Projection (UMAP) and unsupervised clustering analysis were performed to identify differences in the expression of B-cell activation markers and/or oncogenic markers associated with lymphomagenesis. CD10⁺CD27^- B cells, CD20⁺CD27^- B cells, and B-cell populations with aberrant features (CD20⁺CD27⁺CXCR4⁺CD71⁺ B cells and CD20⁺CXCR4⁺cMYC⁺ B cells) were significantly elevated in HIV+ cART-naïve compared to HIV-negative samples. CD20⁺CD27⁺CD24⁺CXCR4⁺CXCR5⁺ B cells, CD20⁺CD27⁺CD10⁺CD24⁺CXCR4⁺cMYC⁺ B cells, and a cluster of CD20⁺CXCR4^hiCD27^-CD24⁺CXCR5⁺CD40⁺CD4⁺AICDA⁺ B cells were significantly elevated in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. A potentially clonal cluster of CD20⁺CXCR4⁺CXCR5⁺cMYC⁺AICDA⁺ B cells and a cluster of germinal center B-cell-like cells (CD19^-CD20⁺CXCR4⁺Bcl-6⁺PD-L1⁺cMYC⁺) were also found in the circulation of HIV+ pre-NHL (cART-naïve) samples. Moreover, significantly elevated clusters of CD19⁺CD24^hiCD38^hi cMYC⁺ AICDA⁺ B regulatory cells were identified in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. The present study identifies unique B-cell subsets in PLWH with potential pre-malignant features that may contribute to the development of pre-tumor B cells in PLWH and that may play a role in lymphomagenesis.

Emerging evidence shows that tumor cells secrete extracellular vesicles (EVs) that carry bioactive cell surface markers, such as programmed death-ligand 1 (PD-L1), which can modulate immune responses and inhibit anti-tumor responses, potentially playing a role in lymphomagenesis and in promoting the growth of these cancers. In this study, we investigated the role of EVs expressing cell surface molecules associated with B cell activation and immune regulation. We measured levels of EVs derived from plasma from 57 subjects with AIDS-related non-Hodgkin lymphoma (AIDS-NHL) enrolled in the AIDS Malignancies Consortium (AMC) 034 clinical trial at baseline and post-treatment with rituximab plus concurrent infusional EPOCH chemotherapy. We found that plasma levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII were significantly reduced after cancer treatment. AIDS-NHL patients with the diffuse large B cell lymphoma (DLBCL) tumor subtype had decreased plasma levels of EVs bearing PD-L1, compared to those with Burkitt's lymphoma. CD40, CD40L and TNF-RII-expressing EVs showed a significant positive correlation with plasma levels of IL-10, CXCL13, sCD25, sTNF-RII and IL-18. Our results suggest that patients with AIDS-NHL have higher levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII in circulation before cancer treatment and that levels of these EVs are associated with levels of biomarkers of microbial translocation and inflammation.