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Pharmacologic inhibition of the mammalian target of rapamycin (mTOR) in the setting of renal transplantation has previously been associated with lower human immunodeficiency virus 1 (HIV-1) DNA burden, and in vitro studies suggest that mTOR inhibition may lead to HIV transcriptional silencing. Because prospective clinical trials are lacking, we conducted an open-label, single-arm study to determine the impact of the broad mTOR inhibitor, everolimus, on residual HIV burden, transcriptional gene expression profiles, and immune responses in HIV-infected adult solid organ transplant (SOT) recipients on antiretroviral therapy. Whereas everolimus therapy did not have an overall effect on cell-associated HIV-1 DNA and RNA levels in the entire cohort, participants who maintained everolimus time-averaged trough levels >5 ng/mL during the first 2 months of therapy had significantly lower RNA levels up to 6 months after the cessation of study drug. Time-averaged everolimus trough levels significantly correlated with greater inhibition of mTOR gene pathway transcriptional activity. Everolimus treatment also led to decreased PD-1 expression on certain T cell subsets. These data support the rationale for further study of the effects of mTOR inhibition on HIV transcriptional silencing in non-SOT populations, either alone or in combination with other strategies. Trial Registration: ClinicalTrials.gov NCT02429869.

Introduction: Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Methods: Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. Results: MUC1 vaccine responders had higher frequencies of CD4 cells prevaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NFkB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. Discussion: These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness. [ABSTRACT FROM AUTHOR]

Background Vaccines and vaccine boosting have blunted excess morbidity and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in older nursing home residents (NHR). However, the impact of repeated vaccination on the T-cell response based on biological sex and prior infection of NHR remain understudied. Methods We examined T-cell responses to SARS-CoV-2 mRNA vaccines in a cohort of NHR and healthcare workers (HCW) over 2 years. We used interferon-γ ELIspot and flow cytometry to assess T-cell response before, 2 weeks, and 6 months after the initial series and each of 2 booster vaccines. We analyzed these data longitudinally with mixed-effect modeling and also examined subsets of our cohorts for additional changes in T-cell effector function. Results Prior SARS-CoV-2 infection and female sex contributed to higher T-cell response in NHR but not HCW. When looking across time points, NHR but not HCW with prior infection had significantly higher T-cell responses than infection-naive subjects. These patterns of response were maintained across multiple booster vaccinations. Conclusions These results suggest that the age, multimorbidity, and/or frailty of the NHR cohort may accentuate sex and infection status differences in T-cell response to mRNA vaccination. [ABSTRACT FROM AUTHOR]

Dental Service Organizations (DSOs) are an increasingly visible and available practice option for new dental graduates. While guidance has been published to help dental students make informed decisions when considering a DSO affiliation, they have not focused on the complexities of assessing compliance with controlling state laws. Accordingly, this Perspectives article provides a concise summary of the common components of state regulatory provisions across the United States to support an understanding of the corporate practice of dentistry and compliance considerations. The guiding principles to consider include ownership or proprietorship of and control over a dental practice; control over dental offices, equipment, and materials; employment of dental personnel; and control over clinical judgment. This article should be helpful to students who are considering a DSO affiliation and educators who prepare them to enter dental practice. [ABSTRACT FROM AUTHOR]

Introduction: Paramedic practice is highly variable, occurs in diverse contexts, and involves the assessment and management of a range of presentations of varying acuity across the lifespan. As a result, attempts to define paramedic practice have been challenging and incomplete. This has led to inaccurate or under-representations of practice that can ultimately affect education, assessment, and the delivery of care. In this study, we outline our efforts to better identify, explore, and represent professional practice when developing a national competency framework for paramedics in Canada. Methods: We used a systems-thinking approach to identify the settings, contexts, features, and influences on paramedic practice in Canada. This approach makes use of the role and influence of system features at the microsystem, mesosystem, exosystem, macrosystem, supra-macrosystem, and chronosystem levels in ways that can provide new insights. We used methods such as rich pictures, diagramming, and systems mapping to explore relationships between these contexts and features. Findings: When we examine the system of practice in paramedicine, multiple layers become evident and within them we start to see details of features that ought to be considered in any future competency development work. Our exploration of the system highlights that paramedic practice considers the person receiving care, caregivers, and paramedics. It involves collaboration within co-located and dispersed teams that are composed of other health and social care professionals, public safety personnel, and others. Practice is enacted across varying geographical, cultural, social, and technical contexts and is subject to multiple levels of policy, regulatory, and legislative influence. Conclusion: Using a systems-thinking approach, we developed a detailed systems map of paramedic practice in Canada. This map can be used to inform the initial stages of a more representative, comprehensive, and contemporary national competency framework for paramedics in Canada. [ABSTRACT FROM AUTHOR]

Proliferation of latently infected [CD4.sup.+] T cells with replication- competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating [CD4.sup.+] memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA-treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of [CD4.sup.+] TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir., Introduction The advent of antiretroviral therapy (ART) has dramatically improved the life expectancy of people with HIV (PWH) infection. However, current ART regimens act by blocking de novo infection of [...]

Introduction: Significant heterogeneity exists within the tumor-infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and may retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted T cell subpopulations critical to the improvement of therapeutic approaches. Methods: To investigate mechanisms associated with terminally exhausted T cells, we sorted and performed transcriptional profiling of CD8+ tumor-infiltrating lymphocytes (TILs) co-expressing the exhaustion markers PD-1 and TIM-3 from large-volume melanoma tumors. We additionally performed immunologic phenotyping and functional validation, including at the single-cell level, to identify potential mechanisms that underlie their dysfunctional phenotype. Results: We identified novel dysregulated pathways in CD8+ PD-1+ TIM-3+ cells that have not been well studied in TILs; these include bile acid and peroxisome pathway-related metabolism and mammalian target of rapamycin (mTOR) signaling pathways, which are highly correlated with immune checkpoint receptor expression. Discussion: Based on bioinformatic integration of immunophenotypic data and network analysis, we propose unexpected targets for therapies to rescue the immune response to tumors in melanoma. [ABSTRACT FROM AUTHOR]

As part of the development of a scoring algorithm for a simulation-based dental hygiene initial licensure examination, this effort conducted a task analysis of the dental hygiene domain. Broad classes of behaviors that distinguish along the dental hygiene expert-novice continuum were identified and applied to the design of nine paper-based cases which were analyzed by 31 dental hygiene students/practitioners. (Author/DB)

The Dental Interactive Simulations Corporation (DISC) is a nonprofit organization that creates interactive patient simulations for dental and dental hygiene education. The simulations present highly realistic patient care delivery scenarios. Twelve organizations representing the education, practitioner, examination, and student communities cooperate in the venture. The six-phase development of the DISC system and its future directions are described. (MSE)

This publication reports analytical conditions and secondary standard results for electron probe microanalysis (EPMA) of glass in support of tephra studies in Alaska between 2018 and 2023. Long-term accuracy and precision are evaluated for our standardized method and compared between analytical sessions and instruments at the University of Alaska Fairbanks (UAF) and the U.S. Geological Survey (USGS) Menlo Menlo Park, California. Future versions will provide updates with secondary standard results from future analytical session and any changes to the analytical routine and conditions. [ABSTRACT FROM AUTHOR]