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The hallmark of tuberculosis (TB) is the formation of immune cell-enriched aggregates called granulomas. While granulomas are pathologically diverse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues. By spatially mapping individual immune cells in every lesion across entire tissue sections, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages. The cellular composition of non-necrotizing structures also correlates with their proximity to necrotizing lesions, indicating these are foci of distinct immune reactions adjacent to necrotizing granulomas. Together, we show that during TB, diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.

PURPOSE: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM). PATIENTS AND METHODS: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS). UNLABELLED: Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses. RESULTS: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105-0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% CI, 1.06-3.51; P = 0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR, 0.565; 95% CI, 0.321-0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25-0.78; P = 0.005). CONCLUSIONS: Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.

Objective – Beginning in Fiscal Year 2023, a university initiated a multi-year transition to an incentive-based budget model, under which the University Libraries budget would eventually be dependent upon yearly contributions from colleges. Such a change could result in the colleges having a more profound interest in library services and resources. In anticipation of any changes in thoughts and perceptions on existing University Libraries services, researchers crafted a survey for administrators, faculty, and staff focused on academic units related to the health sciences. The collected information would inform library budget decisions with the goal of optimizing support for research and educational interests. Methods – An acquisitions and collection management librarian, electronic resources librarian, two health science liaisons, and a staff member reviewed and considered distributing validated surveys to health science faculty, staff, and administrators. Ultimately, researchers concluded that a local survey would allow the University Libraries to address health science community needs and gauge use of library services. In late October 2022, the researchers obtained Institutional Review Board approval and distributed the online survey from mid-November to mid-December 2022. Results – This survey collected 112 responses from health science administrators, faculty, and staff. Many faculty and staff members had used University Libraries services for more than 16 years. By contrast, most administrators started using the library within the past six years. Cost-share agreements intrigued participants as mechanisms for maintaining existing subscriptions or paying for new databases and e-journals. Most participants supported improving immediate access to full-text articles instead of relying on interlibrary loans. Participants desired to build upon existing knowledge of Open Access publishing. Results revealed inefficiencies in how the library communicates changes in collections (e.g., journals, books) and services. Conclusion – A report of the study findings sent to library administration fulfilled the research aim to inform budget decision making. With the possibility of reduced funds under the new internal budgeting model to both academic programs and the library, the study supports consideration of internal cost-sharing agreements. Findings exposed the lack of awareness of the library’s efforts at decision making transparency, which requires exploration of alternative communication methods. Research findings also revealed awareness of Open Educational Resources and Open Access publishing as areas that deserve heightened promotional efforts from librarians. Finally, this local survey and methodology provides a template for potential use at other institutions.

Background A substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To better inform adjuvant treatment selection, we have performed translational analyses to identify prognostic and predictive biomarkers.Patients and methods Two cohorts of patients with macroscopic stage III melanoma from an ongoing biobank study were included. Clinical data were compared between an observation cohort (cohort 1) and an adjuvant intention cohort (cohort 2). RNA sequencing for translational analyses was performed and treatment subgroups (cohort 1A and cohort 2A) were compared for possible biomarkers, using a cut-off based on the treatment-naïve patients. In addition, two validation cohorts (Melanoma Institute Australia (MIA) and University Medical Centre Utrecht (UMCU)) were obtained.Results After a median follow-up of 26 months of the 98 patients in our discovery set, median recurrence-free survival (RFS) was significantly longer for the adjuvant intention cohort (cohort 2, n=49) versus the observation cohort (cohort 1, n=49). Median overall survival was not reached for either cohort, nor significantly different. In observation cohort 1A (n=24), RFS was significantly longer for patients with high interferon-gamma (IFNγ) score (p=0.002); for adjuvant patients of cohort 2A (n=24), a similar trend was observed (p=0.086). Patients with high B cell score had a longer RFS in cohort 1A, but no difference was seen in cohort 2A. The B cell score based on RNA correlated with CD20+ cells in tumor area but was not independent from the IFNγ score. In the MIA validation cohort (n=44), longer RFS was observed for patients with high IFNγ score compared with low IFNγ score (p=0.046), no difference in RFS was observed according to the B cell score. In both the observation (n=11) and the adjuvant (n=11) UMCU validation cohorts, no difference in RFS was seen for IFNγ and B cell.Conclusions IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy. B cell score was prognostic but did not improve accuracy over IFNγ. Our study confirmed RFS benefit of adjuvant anti-PD-1 for patients with macroscopic stage III melanoma.

Abstract Background Female patients with cystic fibrosis (CF) have consistently poorer survival rates than males across all ages. To determine if gender differences exist in health-related quality of life (HRQOL) of adolescent patients with CF, we performed a cross-section analysis of CF patients recruited from 2 medical centers in 2 cities during 1997–2001. Methods We used the 87-item child self-report form of the Child Health Questionnaire to measure 12 health domains. Data was also collected on age and forced expiratory volume in 1 second (FEV1). We analyzed data from 98 subjects and performed univariate analyses and linear regression or ordinal logistic regression for multivariable analyses. Results The mean (SD) age was 14.6 (2.5) years; 50 (51.0%) were female; and mean FEV1 was 71.6% (25.6%) of predicted. There were no statistically significant gender differences in age or FEV1. In univariate analyses, females reported significantly poorer HRQOL in 5 of the 12 domains. In multivariable analyses controlling for FEV1 and age, we found that female gender was associated with significantly lower global health (p < 0.05), mental health (p < 0.01), and general health perceptions (p < 0.05) scores. Conclusion Further research will need to focus on the causes of these differences in HRQOL and on potential interventions to improve HRQOL of adolescent patients with CF.

Background Tumor microenvironment (TME) characteristics are potential biomarkers of response to immune checkpoint inhibitors in metastatic melanoma. This study developed a method to perform unsupervised classification of TME of metastatic melanoma.Methods We used multiplex immunohistochemical and quantitative pathology-derived assessment of immune cell compositions of intratumoral and peritumoral regions of metastatic melanoma baseline biopsies to classify TME in relation to response to anti-programmed cell death protein 1 (PD-1) monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 (ipilimumab (IPI)+PD-1).Results Spatial profiling of CD8+T cells, macrophages, and melanoma cells, as well as phenotypic PD-1 receptor ligand (PD-L1) and CD16 proportions, were used to identify and classify patients into one of three mutually exclusive TME classes: immune-scarce, immune-intermediate, and immune-rich tumors. Patients with immune-rich tumors were characterized by a lower proportion of melanoma cells and higher proportions of immune cells, including higher PD-L1 expression. These patients had higher response rates and longer progression-free survival (PFS) than those with immune-intermediate and immune-scarce tumors. At a median follow-up of 18 months (95% CI: 6.7 to 49 months), the 1-year PFS was 76% (95% CI: 64% to 90%) for patients with an immune-rich tumor, 56% (95% CI: 44% to 72%) for those with an immune-intermediate tumor, and 33% (95% CI: 23% to 47%) for patients with an immune-scarce tumor. A higher response rate was observed in patients with an immune-scarce or immune-intermediate tumor when treated with IPI+PD-1 compared with those treated with PD-1 alone.Conclusions Our study provides an automatic TME classification method that may predict the clinical efficacy of immunotherapy for patients with metastatic melanoma.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.

Background. A South African faculty of health sciences created a forum for the community to voice their relational experiences with interprofessional students through visual projections. No other studies that explore such experiences using the Mmogo method could be located. Objective. To gain an understanding of the relational experiences of community members participating in Lifestyle-groups as part of a rural health initiative with interprofessional student groups. Methods. The Mmogo method is a qualitative, structured, observation technique. Participants constructed visual projections representing specific relationships. Thereafter, during a group discussion, participants explained the meaning of their projections. The visual data were analysed according to their literal presentation and subjective, symbolic meaning. A thematic analysis was used for the transcribed data. Results. Thirteen of the 24 visual projections were of a quality that allowed visual analysis; all 24 members participated in the discussions. Light was identified as an overarching theme to represent the community-student interaction. Sub-themes and categories associated with light were healthier lifestyles (knowledge sharing, lifestyle transformation, improved health outcomes), solidarity (reciprocity, collaboration, person centredness, multidimensional approach) and affirmation (gratitude and acceptance). Conclusion. Though some statements by participants related to health education as opposed to health dialogue highlighted areas requiring improvement, the findings correlated with the outcomes prescribed for students by this rural health initiative. Emotional connections in relational experiences could facilitate higher levels of self-efficacy in communities. The question is whether a stronger emphasis on health dialogue can be a catalyst for improved self-efficacy.