Therapeutics That Promote Sympathetic Reinnervation Modulate the Inflammatory Response After Myocardial Infarction.

Myocardial infarction (MI) triggers an inflammatory response that transitions from pro-inflammatory to reparative over time. Restoring sympathetic nerves in the heart after MI prevents arrhythmias. This study investigated if reinnervation altered the immune response after MI. This study used quantitative multiplex immunohistochemistry to identify the immune cells present in the heart 2 weeks after ischemia-reperfusion. Two therapeutics stimulated reinnervation, preventing arrhythmias and shifting the immune response from inflammatory to reparative, with fewer pro-inflammatory macrophages and more regulatory T cells and reparative macrophages. Treatments did not alter macrophage phenotype in vitro, which suggested reinnervation contributed to the altered immune response.

Nowcasting unemployment insurance claims in the time of COVID-19.

Near-term forecasts, also called nowcasts, are most challenging but also most important when the economy experiences an abrupt change. In this paper, we explore the performance of models with different information sets and data structures in order to best nowcast US initial unemployment claims in spring of 2020 in the midst of the COVID-19 pandemic. We show that the best model, particularly near the structural break in claims, is a state-level panel model that includes dummy variables to capture the variation in timing of state-of-emergency declarations. Autoregressive models perform poorly at first but catch up relatively quickly. The state-level panel model, exploiting the variation in timing of state-of-emergency declarations, also performs better than models including Google Trends. Our results suggest that in times of structural change there is a bias-variance tradeoff. Early on, simple approaches to exploit relevant information in the cross sectional dimension improve forecasts, but in later periods the efficiency of autoregressive models dominates.

Leukocyte Heterogeneity in Pancreatic Ductal Adenocarcinoma: Phenotypic and Spatial Features Associated with Clinical Outcome.

Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)-treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. SIGNIFICANCE: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired.This article is highlighted in the In This Issue feature, p. 1861.

Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer.

Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27-CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGNIFICANCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.See related commentary by Krysan et al., p. 1442.This article is highlighted in the In This Issue feature, p. 1426.

The Significance of Taking Antiretroviral Medications for African-Born People Living with HIV and Residing in Minnesota.

Thanks to the development of antiretroviral (ART) medications, HIV is now a chronic and manageable disease. This study aimed to (1) capture the experiences of African-born persons living with HIV and taking antiretroviral treatment, and (2) explore the impact of social and cultural factors on their decisions to follow the prescribed treatment. For this study, a qualitative approach was used. The participants were recruited via fliers, then screened for inclusion and exclusion criteria. Recruitment of the participants continued until data saturation occurred. The interview guide was developed based on the extensive literature and recommendations from the clinical team. In-person narrative interviews were conducted with 14 participants-African-born persons living with HIV and residing in Minnesota. Thematic Analysis revealed three emergent themes: "To exist I have to take the medicine"; barriers and facilitators in taking ART medications; and the power of spirituality and prayers. The findings of this study paint a picture of African-born persons living with HIV, and their experiences with ART medications. This study not only presents the participants' medication experiences and their significance, but also tells their stories of how God and prayers play a significant role in helping them to get through the difficult moments of their lives.

"Stigma and HIV Are Like Brother and Sister!": The Experience of African-Born Persons Living with HIV in the US.

Minnesota has seen an increase in the number of immigrants from Africa, notably in the mid-1990s, making up around 2% of Minnesota's total population. This population also faces many impediments that cause important difficulties not only for HIV prevention but also for treatment and care options. The objectives of this study were to capture the experiences of Persons Living with HIV (PLWH) in Minnesota (US) and to elicit their stories about their diagnosis news and what management strategies they use for coping with the stigma associated with the disease. Participants were recruited via fliers in pharmacies, clinics, and HIV service centers located in Minnesota. Recruitment continued until thematic saturation was obtained. Fourteen subjects participated in audio-recorded, semi-structured interviews that were transcribed verbatim into written text. The transcriptions were analyzed using Thematic Analysis. Three themes emerged from the data. Theme 1: Cruel News: "HIV-Oooooo! I wish I was dead", Theme 2: This is My Secret! and Theme 3: "Stigma and HIV are brother and sister". The results demonstrate that stigma is an ever-present problem in African-born PLWH living in the US. Participants perceived the stigma associated with HIV status to affect their lives and culture at individual, familial, and societal levels.

High-dimensional multiplexed immunohistochemical characterization of immune contexture in human cancers.

Biomarker assessments of tumor specimens is widely used in cancer research to audit tumor cell intrinsic as well as tumor cell extrinsic features including the diversity of immune, stromal, and mesenchymal cells. To comprehensively and quantitatively audit the tumor-immune microenvironment (TiME), we developed a novel multiplex immunohistochemistry (mIHC) platform and computational image processing workflow using a single formalin-fixed paraffin-embedded (FFPE) tissue section. Herein, we validated this platform using nine matched primary newly diagnosed and recurrent head and neck squamous cell carcinoma (HNSCC) sections sequentially subjected to immunodetection with a panel of 29 antibodies identifying malignant tumor cells, and 17 distinct leukocyte lineages and their functional states. Image cytometric analysis was applied to interpret chromogenic signals from digitally scanned and coregistered light microscopy-based images enabling identification and quantification of individual tumor cells, structural features, immune cell phenotypes and their functional state. In agreement with our previous study via a 12-plex imaging mIHC platform, myeloid-inflamed status in newly diagnosed primary tumors associated with significantly short progression free survival, independent of lymphoid-inflamed status. Spatial distribution of tumor and immune cell lineages in TiME was also examined and revealed statistically significant CD8+ T cell exclusion from tumor nests, whereas regulatory T cells and myeloid cells, when present in close proximity to tumor cells, highly associated with rapid cancer recurrence. These findings indicate presence of differential immune-spatial profiles in newly diagnosed and recurrent HNSCC, and establish the robustness of the 29-plex mIHC platform and associated analytics for quantitative analysis of single tissue sections revealing longitudinal TiME changes.

Narrative experiences of interactions with pharmacists among African-born persons living with HIV: "It's mostly business."

BACKGROUND: African-born persons constitute 1% of the total Minnesota population, yet 24% of new HIV infections occurred in this population in 2016. Furthermore, 32% of the African born persons living with HIV [PLWH] did not check their CD4 counts or viral load in 2018. Little is known of the role of pharmacists in antiretroviral (ARV) management in the PLWH of African origin. OBJECTIVE: This study aimed to describe the experiences of African-born PLWH in their interactions with pharmacists and perceptions of pharmacists' roles in fostering adherence to ARV therapy. METHODS: A qualitative approach was used for this study. Recruitment via fliers for in-person interviews with African-born PLWH in Minnesota continued until saturation was achieved. Narrative Interviews with 14 participants lasting up to 2 h were conducted over five months. All interviews were audio recorded and transcribed verbatim by a professional transcription service. Conventional Content Analysis was used to analyze the data. RESULTS: Three themes emerged from analyzed data "Interaction with the pharmacists," "Revealing the diagnosis to a pharmacist," and "Lack of disclosure of HIV status to a pharmacist." CONCLUSIONS: The participants referred to the interaction with pharmacists as a "business" or "transactional interaction." To better understand the interaction between pharmacists and PLWH of African-born, future studies could benefit from interviewing pharmacists from different practice settings.