A spatially resolved atlas of the human lung characterizes a gland-associated immune niche

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health

Clonal hematopoiesis is associated with risk of severe Covid-19.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10-3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10-3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Longitudinal trends in enrollees’ employment and student status after Medicaid expansion

Abstract Background Medicaid community engagement requirements previously received federal approval in 12 states, despite limited data on their impact on enrollees’ employment-related activities. Our objective was to assess longitudinal changes in enrollees’ employment and student status after implementation of Michigan’s Medicaid expansion. Methods Longitudinal telephone survey of Michigan Medicaid expansion enrollees in 2016 (response rate [RR] = 53.7%), 2017 (RR = 83.4%), and 2018 (N = 2,608, RR = 89.4%) serially assessing self-reported employment or student status. Survey responses were benchmarked against statewide changes in assessed similar low-income adults in the U.S. Census Bureau Current Population Survey. We used mixed models with individual random effects to assess changes in the proportion of enrollees who were employed or students by year. Results Most respondents had incomes < 100% FPL (61.7% with 0–35% of the federal poverty level [FPL], 22.9% with 36–99% FPL, and 15.4% with 100–133% FPL), 89.3% had at least a high school diploma/equivalent, and they ranged in age (39.6% age 19–34, 34.5% age 35–50, 25.9% age 51–64). Employment or student status increased significantly among Michigan Medicaid expansion respondents, from 54.5% in 2016 to 61.4% in 2018 (P < 0.001), including among those with a chronic condition (47.8% to 53.8%, P < 0.001) or mental health/substance use disorder (48.5% to 56.0%, P < 0.001). In contrast, the statewide proportion of low-income non-elderly adults who were employed or students did not change significantly (from 42.7% in 2016 to 46.0% in 2018, P = 0.57). Conclusions Medicaid expansion, absent a community engagement requirement, was associated with increased employment and related activities. The role of Medicaid in providing safety-net coverage to individuals during times of economic stress is likely to grow.http://deepblue.lib.umich.edu/bitstream/2027.42/173785/1/12913_2022_Article_7599.pd

Beneficiaries’ perspectives on improved oral health and its mediators after Medicaid expansion in Michigan: a mixed methods study

ObjectiveTo investigate self-reported improved oral health and its mediators, and job-related outcomes, of Medicaid expansion beneficiaries in Michigan.MethodsThis cross-sectional mixed-methods study of adult “Healthy Michigan Plan” (HMP) Medicaid expansion beneficiaries included qualitative interviews with a convenience sample of 67 beneficiaries enrolled for ≥6 months, a stratified random sample survey of 4,090 beneficiaries enrolled for ≥12 months; and Medicaid claims data. We examined unadjusted associations between demographic variables and awareness of dental coverage, self-reported dental care access, dental visits, and self-reported oral health; and between improved oral health and job seeking and job performance. Multivariate analysis examined factors associated with self-reported oral health improvement, adjusting for sociodemographic characteristics, prior health insurance, and having at least one dental visit claim.ResultsAmong surveyed beneficiaries, 60 percent received ≥1 dental visit and 40 percent reported improved oral health. Adjusted odds ratios (aOR) for improved oral health were higher for African-American beneficiaries [aOR = 1.61; confidence interval (CI) = 1.28-2.03] and those previously uninsured for ≥12 months (aOR = 1.96; CI = 1.58-2.43). Beneficiaries reporting improved oral health were more likely to report improved job seeking (59.9 percent vs 51 percent; P = 0.04) and job performance (76.1 percent vs 65.0 percent; P < 0.001) due to HMP. Interviewees described previously unmet oral health needs, and treatments that improved oral health, functioning, appearance, confidence, and employability.ConclusionMichigan’s Medicaid expansion contributed to self-reported improved oral health, which was associated with improved job outcomes. Policymakers should consider the importance of Medicaid dental coverage in reducing oral health disparities and improving the health and socioeconomic well-being of low-income adults and communities when considering this optional benefit.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171987/1/jphd12447_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171987/2/jphd12447.pd

Simultaneous FDG-PET/MRI detects hippocampal subfield metabolic differences in AD/MCI.

The medial temporal lobe is one of the most well-studied brain regions affected by Alzheimer's disease (AD). Although the spread of neurofibrillary pathology in the hippocampus throughout the progression of AD has been thoroughly characterized and staged using histology and other imaging techniques, it has not been precisely quantified in vivo at the subfield level using simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI). Here, we investigate alterations in metabolism and volume using [18F]fluoro-deoxyglucose (FDG) and simultaneous time-of-flight (TOF) PET/MRI with hippocampal subfield analysis of AD, mild cognitive impairment (MCI), and healthy subjects. We found significant structural and metabolic changes within the hippocampus that can be sensitively assessed at the subfield level in a small cohort. While no significant differences were found between groups for whole hippocampal SUVr values (p = 0.166), we found a clear delineation in SUVr between groups in the dentate gyrus (p = 0.009). Subfield analysis may be more sensitive for detecting pathological changes using PET-MRI in AD compared to global hippocampal assessment

Adjusted risk factors of major adjuvant chemotherapy complications in lobectomy patients who underwent adjuvant chemotherapy (n = 2,301).

Adjusted risk factors of major adjuvant chemotherapy complications in lobectomy patients who underwent adjuvant chemotherapy (n = 2,301).</p

Sensitivity analyses- chemotherapy mortality.

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Adjusted risk factors for death from non-lung cancer causes for patients with locoregional NSCLC treated with lobectomy and no adjuvant chemotherapy (n = 7,852).

Adjusted risk factors for death from non-lung cancer causes for patients with locoregional NSCLC treated with lobectomy and no adjuvant chemotherapy (n = 7,852).</p

Estimated quality-adjusted life expectancy.

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