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Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well-resourced, non-Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer's-related risk factors in those other groups. The Alzheimer's Association hosted a virtual conference on June 14-16, 2021, supported in part by the National Institute on Aging (R13 AG072859-01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities.

Background: Pilot project programs offer early-stage and other investigators support to pursue emerging research areas, explore new methodologies, gain experience as principal investigators, and collect pilot data needed to pursue larger extramural research funding, such as from the National Institutes of Health. Pilot project programs may be particularly important to early-stage investigators from underrepresented backgrounds, who must overcome unique challenges to launching careers in community-based participatory research. This paper describes the structure, function, and impact of the Native Center for Alcohol Research and Education (NCARE) Pilot Project Core. Methods: During four calls for applications from 2018 to 2021, research investigators interested in conducting alcohol use disorder research in partnership with Tribal communities were recruited, with a focus on early-stage and American Indian and Alaska Native investigators. Eligible investigators were required to submit letters of intent prior to preparing full applications, which underwent a rigorous review process. Results: Eight pilot projects were awarded. Of the eight pilot project investigators, seven were early-stage scholars, seven were female, and four identified as American Indian or Alaska Native. The funded projects included two primary areas of research, epidemiological studies and intervention projects. Once funded, the Pilot Project Core assisted pilot project investigators with securing approvals for their research studies, responding to methodological and analysis questions, and mentoring and monitoring their progress. At the time of writing this paper, three pilot project investigators have completed their pilot projects, three investigators are currently collecting data, and one is in the analysis phase. One pilot project investigator did not complete their project due to COVID-19 restrictions early in the pandemic. The pilot project investigators submitted 36 grant proposals for independent external funding and received 25 grants after funding of their pilot project; four were directly related to pilot project grants. Additionally, four peer-reviewed manuscripts resulting from Pilot Project Core support were published. Conclusions: Despite challenges related to the COVID-19 pandemic the pilot project funding through NCARE provided eight pilot grants, half of which identified as AI/AN and most of which led directly to multiple grants and papers. The NCARE pilot program provides a model for other similar programs seeking to support early-stage investigators who identify as AI/AN or other groups underrepresented in science.

Introduction Infant immunization programs using pneumococcal conjugate vaccines (PCVs) have reduced the rates of pneumococcal disease through direct vaccine-induced protection in vaccinated children and through indirect protection in non-vaccinated children and adults.Areas covered This review summarizes current evidence on the indirect protection of adults conferred by pediatric pneumococcal vaccination, including the impact on invasive pneumococcal disease (IPD) incidence and mortality, pneumonia admissions, and nasopharyngeal carriage prevalence. Factors affecting indirect protection against IPD are also discussed.Expert opinion Pediatric immunization with PCVs has substantially decreased vaccine-serotype IPD and pneumonia through indirect protection in both older (≥65 years of age) and younger adults, including those with underlying medical conditions. However, serotype replacement by non-vaccine serotypes, the persistence of some vaccine serotypes, and divergence of serotypes between children and adults have limited the impact of pediatric PCV programs on adult populations. Designing complementary vaccines that leverage indirect protection from pediatric immunization and target the most prevalent adult serotypes may be a preferred strategy to maximize the public health impact of pneumococcal vaccination.

Introduction Streptococcus pneumoniae is a causative agent of pneumonia and acute otitis media (AOM), as well as invasive diseases such as meningitis and bacteremia. PCV15 (V114) is a new 15-valent pneumococcal conjugate vaccine (PCV) approved for use in individuals ≥6 weeks of age for the prevention of pneumonia, AOM, and invasive pneumococcal disease.Areas Covered This review summarizes the V114 Phase 3 development program leading to approval in infants and children, including pivotal studies, interchangeability and catch-up vaccination studies, and studies in at-risk populations. An integrated safety summary is presented in addition to immunogenicity and concomitant use of V114 with other routine pediatric vaccines.Expert Opinion Across the development program, V114 demonstrated a safety profile that is comparable to PCV13 in infants and children. Immunogenicity of V114 is comparable to PCV13 for all shared serotypes except serotype 3, where V114 demonstrated superior immunogenicity. Higher immune responses were demonstrated for V114 serotypes 22F and 33F. Results of the ongoing study to evaluate V114 efficacy against vaccine-type pneumococcal AOM and anticipated real-world evidence studies will support assessment of vaccine effectiveness and impact, with an additional question of whether higher serotype 3 immunogenicity translates to better protection against serotype 3 pneumococcal disease.

Abstract Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Abstract Background Salivary hypofunction leads to debilitating oral symptoms and has major complications for overall quality of life. Two of the most frequent causes of xerostomia are radiotherapy in the head and neck and Sjögren’s syndrome. Only symptomatic treatment is available today. An increasing number of both preclinical and clinical studies have suggested that mesenchymal stem cell (MSC) transplantation treatment can increase the salivary flow rate and ameliorate symptoms of xerostomia. However, both adipose-derived and bone marrow–derived MSCs are used, although they differ in important ways. The primary objective of this study is an indirect comparison of the change in the unstimulated salivary flow rate after intervention between patients treated with adipose-derived or bone marrow–derived MSCs. Methods This systematic review and network meta-analysis will search for eligible studies in the MEDLINE, EMBASE, and Cochrane CENTRAL register of Controlled Trials. Eligible studies are as follows: clinical studies including human patients with salivary hypofunction due to either radiotherapy or Sjogren’s syndrome who were subsequently treated with either adipose-derived MSCs or bone marrow–derived MSCs. Studies with no control group will be excluded. The search phrase has been peer-reviewed following the PRESS guidelines. The primary outcome is the change in the unstimulated salivary flow rate after treatment with either adipose-derived or bone marrow–derived MSCs. Secondary outcomes are as follows: change in patient reported outcomes, methods of intervention administration, number of injected MSCs, and safety. Data from included studies will be pooled and compared with a fixed-effects or random effects model dependent on signs of heterogeneity, presented with a forest plot, and indirectly compared with a meta-regression in a network meta-analysis. Risk of bias will be assessed with the tools ROBINS-I or RoB-2 depending on type of study. Discussion Both adipose-derived and bone marrow–derived MSCs are used today for experimental treatment of salivary hypofunction in humans as no direct or indirect comparisons have been made. Therefore, an evaluation of the effect of adipose-derived vs bone marrow–derived MSC treatment is needed to support future decision-making on the type of MSC used in a clinical trial. Systematic review registration PROSPERO ID CRD42024527183.

We sought to evaluate the acceptability and feasibility of a culturally tailored food box intervention for improving blood pressure (BP), food security and Body Mass Index (BMI) among Chickasaw Nation adults with uncontrolled hypertension. As part of the Chickasaw Healthy Eating Environments Research Study (CHEERS), we administered a group randomized pilot study in four tribal communities (two intervention, two control). Participants in the intervention communities received six heart-healthy food boxes, culturally tailored to traditional Chickasaw diet and current food context. Outcomes were measured over 6 months. We enrolled 262 participants, and 204 with complete data on key variables were included in the analysis. The food boxes were very popular, and we achieved high retention for follow-up data collection. Intervention community participants had 2.6 mmHg lower mean systolic BP and improved diet quality and BMI compared with control participants, although, as expected for a pilot study, the differences were not statistically significant. The culturally tailored diet intervention and randomized trial study design were acceptable and feasible for Chickasaw Nation adults with uncontrolled hypertension. Our findings support the value of tribal-food bank partnerships as a potential approach for reducing food insecurity and hypertension-related disparities in Native American communities.

BackgroundGiven high rates of cancer mortality in Native communities, we examined how urban American Indian and Alaska Native elders talk about colorectal cancer (CRC) and CRC screening.MethodsWe conducted seven focus groups with a total of 46 participants in two urban clinics in the Pacific Northwest to assess participant awareness, perceptions, and concerns about CRC and CRC screening. Using speech codes theory, we identified norms that govern when and how to talk about CRC in this population.ResultsOur analyses revealed that male participants often avoided screening because they perceived it as emasculating, whereas women often avoided screening because of embarrassment and past trauma resulting from sexual abuse. Both men and women used humor to mitigate the threatening nature of discussions about CRC and CRC screening.ConclusionsWe offer our analytic results to assist others in developing culturally appropriate interventions to promote CRC screening among American Indians and Alaska Natives.

Aim: The aim of this study is to explore the possibilities of the metaverse environment in the context of simulating the evacuation of people from a building. The research hypothesis assumes the feasibility of applying the metaverse environment to conduct a scenario of simulating the evacuation of people. This environment provides the opportunity for a realistic representation of the building’s topology and the behaviour of people. Additionally, through the interaction among people, it is possible to reflect basic aspects of the human factor related to user interaction in the evacuation process. The article presents the possibilities of evacuating users from a virtual building using two evacuation scenarios and the potential to gather measurement results related to evacuation time in the metaverse environment. Furthermore, simulated evacuation scenarios aim to answer the question of whether conveying information about the dynamically changing situation during the exit of people from a building can accelerate evacuation time. Introduction: Środowisko metawersum pozwala na realistyczne odzwierciedlenie topologii budynku oraz zachowania się ludzi. Dodatkowo dzięki uwzględnieniu interakcji między osobami umożliwia ukazanie podstawowych aspektów czynnika ludzkiego, które wpływają na samą ewakuację. Artykuł przedstawia propozycje realizacji ewakuacji użytkowników z wirtualnego budynku przy wykorzystaniu dwóch scenariuszy ewakuacyjnych oraz zebrania w środowisku metawersum wyników pomiarowych związanych z czasem ewakuacji. Dodatkowo symulowane scenariusze ewakuacyjne mają dać odpowiedź na pytanie, czy przekazywanie informacji o dynamicznie zmieniającej się sytuacji podczas wyjścia osób z budynku może przyspieszyć czas ewakuacji. Project and methods: In the study, an empirical research method was employed, involving the implementation of a simulator application operating on the spatial.io platform. Using the unity 3D visualization design tool, a building model was reflected, which was utilized for conducting a virtual evacuation. Business logic was programmed through scripts in the C# programming language, enabling the measurement of the evacuation times of individual users from the building and their movement to the assembly point. To detect the optimal exit route at any given moment, an analysis of the graph was performed based on the Neo4j graph database. After publishing the simulator application, it was possible to simulate the evacuation of people from the building in a virtual environment and gather measurement results related to evacuation times. Results: The proposed research method provided the opportunity to gather evacuation time results from people using two evacuation scenarios. In evacuation scenarios where users were provided with information about dynamically changing situations on the evacuation route (e.g. the emergence of impassable paths), the times for people to exit the building in simulated evacuations were shorter. The design of a virtual evacuation simulator application demonstrated the utility of the metaverse environment in training individuals on the principles of safe building evacuation and showcased the potential for collecting data on people’s behaviour during evacuations. Conclusions: Based on the obtained experimental results and the analysis of global trends presented in the literature, which demonstrate the use of VR simulators in building evacuation simulations, it can be concluded that the presented simulation method may prove useful both in the field of education and in gathering fundamental results or simulating evacuation scenarios. Keywords: evacuation simulator, metaverse, unity 3d, spatial.io, graph analysis

Aim: Exploration and developing mechanisms of advanced data acquisition necessary for training an artificial intelligence model capable of effectively detecting areas with increased susceptibility to fire situations. The study focuses on utilizing data from satellite missions and ground-based sensors, which provide both high-resolution imagery and precise data on temperature, humidity, and other environmental factors. By analysing these diverse data sources, the research aims to create a comprehensive and efficient model capable of early detection of potential fire hazards, which is crucial for prevention for fire-prone situations. Project and methods: It centres on a project that aims to enhance fire detection and management through the integration of artificial intelligence with data acquired from satellite systems and internet of things devices. The methodologies employed in this project involve a combination of advanced data acquisition, machine learning techniques, and the synthesis of diverse environmental data to train artificial intelligence models that can predict and detect fire incidents more effectively. Results: Significant advancements in fire detection and management have been demonstrated through the integration of artificial intelligence (AI) with satellite data and IoT: 1. Enhanced monitoring capabilities the use of satellite data systems enabled real-time monitoring of thermal anomalies and vegetation health, crucial for early detection and effective monitoring of wildfires. This real-time capability allowed for quicker responses and more informed decision-making in firefighting efforts. 2. Effective integration of data sources: the integration of satellite and surface data proved to be effective in enhancing the predictive capabilities of the fire management systems. This comprehensive approach allowed for a better understanding of fire dynamics and contributed to more accurate and timely predictions. Conclusions: It could be emphasize the significant benefits and future potential of integrating artificial intelligence with satellite and internet of things data for improving fire detection and management. The integration of satellite imagery and internet of things sensor data is essential for enhancing the predictive accuracy of artificial intelligence systems. This integration allows for a comprehensive assessment of fire risks, providing actionable intelligence that is critical for prevention for fire-prone situations. These conclusions underscore the transformative potential of artificial intelligence in enhancing fire management systems. Keywords: data acquisition, artificial intelligence, IoT, satellite data systems, fire management systems

Microtubule-associated protein 2 (MAP2) is a crucial regulator of dendritic structure and neuronal function, orchestrating diverse protein interactions within the microtubule network. We have shown MAP2 is hyperphosphorylated at serine 1782 (S1782) in schizophrenia and phosphomimetic mutation of S1782 in mice (MAP2S1782E) is sufficient to impair dendritic architecture. We sought to determine how this hyperphosphorylation affects the MAP2 interactome to provide insights into the disorder's mechanisms. We investigated the MAP2 interactome using co-immunoprecipitation and mass spectrometry in MAP2S1782E and MAP2WT mice. We found that S1782E MAP2 led to a substantial disruption of protein-protein interactions relative to WT MAP2. Reduced interactions with PDZ domain-containing proteins, calmodulin-binding proteins, ribosome proteins, and kinesin proteins may all contribute to dendritic impairments induced by S1782E, and may be linked to schizophrenia pathogenesis. Interestingly, novel gain-of-function interactions with PPM1L and KLHL8 nominated these as regulators of phosphoS1782 MAP2 abundance and potential therapeutic targets in schizophrenia.

T lymphocytes expressing CD57 and lacking costimulatory receptors CD27/CD28 have been reported to accumulate with aging, chronic infection, and cancer. These cells are described as senescent, with inability to proliferate but enhanced cytolytic and cytokine-producing capacity. However, robust functional studies on these cells taken directly from cancer patients are lacking. We isolated these T cells and their CD27/28+ counterparts from blood and tumor samples of 50 patients with previously untreated head and neck cancer. Functional studies confirmed that these cells have enhanced ability to degranulate and produce IFN-γ. They also retain the ability to proliferate, thus are not senescent. These data suggest that CD27/28-CD57+ CD8+ T cells are a subset of highly differentiated, CD45RA+ effector memory (TEMRA) cells with retained proliferative capacity. Patients with > 34% of these cells among CD8+ T cells in the blood had a higher rate of locoregional disease relapse, suggesting these cells may have prognostic significance.

As part of our work to develop small-molecule inhibitors (SMIs) of the CD40-CD40L(CD154) costimulatory protein-protein interaction, here, we describe the ability of two of our most promising SMIs, DRI-C21041 and DRI-C21095, to prolong the survival and function of islet allografts in two murine models of islet transplantation (under the kidney capsule and in the anterior chamber of the eye) and to prevent autoimmune type 1 diabetes (T1D) onset in NOD mice. In both transplant models, a significant portion of islet allografts (50%-80%) remained intact and functional long after terminating treatment, suggesting the possibility of inducing operational immune tolerance via inhibition of the CD40-CD40L axis. SMI-treated mice maintained the structural integrity and function of their islet allografts with concomitant reduction in immune cell infiltration as evidenced by direct longitudinal imaging in situ. Furthermore, in female NODs, three-month SMI treatment reduced the incidence of diabetes from 80% to 60% (DRI-C21041) and 25% (DRI-C21095). These results (i) demonstrate the susceptibility of this TNF superfamily protein-protein interaction to small-molecule inhibition, (ii) confirm the in vivo therapeutic potential of these SMIs of a critical immune checkpoint, and (iii) reaffirm the therapeutic promise of CD40-CD40L blockade in islet transplantation and T1D prevention. Thus, CD40L-targeting SMIs could ultimately lead to alternative immunomodulatory therapeutics for transplant recipients and prevention of autoimmune diseases that are safer, less immunogenic, more controllable (shorter half-lives), and more patient-friendly (i.e., suitable for oral administration, which makes them easier to administer) than corresponding antibody-based interventions.

Immune checkpoint blockade (ICB) therapies are one of the greatest advances in the history of cancer care and are now commonly used in the management of many different malignancies. However, much remains unknown about the factors that affect the efficacy and side effect profile of these agents. This review delves into the published literature that evaluates the intricate interplay between race, age, gender, and social determinants in shaping outcomes following ICB across solid tumors and hematologic malignancies. We examine the pivotal phase 2 and 3 trials to evaluate the demographics of participants and outcomes based on these variables, if reported. Most, but not all, trials reported some basic demographic information like age, sex, race, ethnicity, and/or geographic area for enrollment. Clinically relevant biological markers that could affect ICB outcomes such as obesity or markers of social determinants of health were largely not reported. Trials were generally representative for men and women based on expected prevalence for a given malignancy, but often under-represented non-white participants and rarely enrolled patients from the global south. Subgroup analyses were conducted in many ICB trials for solid malignancies, but rarely conducted for hematologic malignancies. These analyses largely showed similar qualitative benefit across subgroups, but adverse events were rarely reported by subgroup. This review adds to our understanding of the populations that these clinical trials have studied and highlight the urgent need to redouble our efforts at increasing the diversity of the population in future ICB trials.

We describe an efficient implementation of cluster perturbation and Møller–Plesset Lagrangian energy series through the fifth order that targets the coupled cluster singles and doubles energy utilizing the resolution of the identity approximation. We illustrate the computational performance of the implementation by performing ground state energy calculations on systems with up to 1200 basis functions using a single node and by comparison to conventional coupled cluster singles and doubles calculations. We further show that our hybrid message passing interface/open multiprocessing parallel implementation that also utilizes graphical processing units can be used to obtain fifth order energies on systems with almost 1200 basis functions with a 90 min "time to solution" running on Frontier at Oak Ridge National Laboratory. [ABSTRACT FROM AUTHOR]

PurposeThe number of American Indian and Alaska Native (AI/AN) people living with dementia is expected to increase 5-fold by 2060. Social determinants of health may explain disparities in the incidence of Alzheimer disease (AD) but remain largely overlooked.MethodsWe examined the time trend of AD mortality rates and associations of the percentage of AI/ANs, density of primary care physicians and neurologists, area deprivation index, rurality, and Indian Health Service region with AD mortality in 646 purchased/referred care delivery area counties.ResultsAD mortality rates significantly increased over time. Counties with higher concentrations of AI/AN people had lower AD mortality. More deprived counties had 34% higher AD mortality compared with less deprived counties. AD mortality was 20% lower in nonmetro counties than in metro counties.ConclusionsFindings have implications for prioritizing areas where more resources for AD care, education, or outreach are needed.