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CC042 Mice Reveal a Mechanism of BCG-mediated Protection to TB Independent of Memory T Cell Responses in the Lung
No full textTB is a contagious lung disease caused by Mycobacterium tuberculosis (Mtb). The only approved vaccine for TB prevention is BCG, however, its efficacy among adults varies from 0-70%. To improve TB prevention, we need to better understand how vaccines work. How genetic variation affects BCG’s ability to protect is incompletely understood. To mimic genetic variation, we have used the Collaborative Cross (CC) resource of genetically diverse inbred mice. One of these, the CC042 strain is susceptible to Mtb infection due to its loss of lymphocyte function-associated antigen 1 (LFA-1) expression, which results in defective T cell trafficking to the lung. Despite this defect in T cell recruitment, BCG vaccination protects CC042 mice against TB. We hypothesized that this defect in T cell immunity reveals alternative mechanisms of protective immunity against Mtb.
In this dissertation I investigate the requirement for LFA-1 in generating immunity to BCG and Mtb using LFA-1-deficient CD11a–/– and CC042 mice. I find that adaptive immunity to BCG occurs independently of LFA-1. BCG vaccination provides lasting protection to CC042 mice against Mtb infection by reducing their lung disease and extends their lifespan. We discovered that BCG-induced protection of CC042 is maintained even when lymphocyte migration is disrupted, and neither concurrent depletion of memory T nor B cells disrupt BCG-elicited protection against Mtb infection in CC042 mice. However, memory T cells were crucial for long-term protection of CC042 mice. These findings provide key insights into different phases of protective immunity that are generated following BCG vaccination.MD/PhD6 months02/26/2
Building Community Through Data: The value of a Researcher Driven Open Science Ecosystem
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A Novel Communication Rating Scale to Mitigate the Effect of Implicit Bias
Get PDFImportance: Implicit bias recognition and management (IBRM) training is a promising strategy for improving clinician communication but is underevaluated.
Objective: To describe the development and psychometric properties of the Respect, Empathize, Listen, Ask, Talk, and Engage (RELATE) rating scale, based on a theoretical framework of communication skills, to mitigate negative influences of implicit bias by using strategies for interrupting unconscious decision-making in patient-centered communication.
Design, setting, and participants: In this cross-sectional study, between September 2019 and April 2022, standardized patients used the RELATE rating scale to evaluate communication skills of participating clinical trainees at an academic medical center who completed an IBRM training and engaged in simulated clinical encounters with standardized patients representing those with low socioeconomic status and African American, Latino or Hispanic, and African immigrant patients. Statistical analyses were ongoing from June 2021 to January 2024.
Main outcome and measures: Gwet agreement coefficient (AC) was calculated using data from the 2019 to 2020 cohort year to assess standardized patient interrater reliability (IRR). To assess construct validity and internal consistency reliability, factor analysis techniques were used, and Cronbach α was calculated using data from 3 cohorts (2019-2020, 2020-2021, and 2021-2022).
Results: Twenty-seven standardized patients generated 226 independent RELATE ratings for 123 consenting clinical trainees (14 family medicine residents [11.4%], 48 internal medicine residents [39.0%], and 61 doctor of nursing practice students [49.6%]; mean [SD] age, 30.4 [4.1] years; 82 [66.7%] female), who each had 2 RELATE scores. Of the 3-level item responses of whether a behavior was observed ("present," "partial," or "absent"), for all 19 items, at least 1 trainee (0.4%) was noted who did not complete the evaluated behavior, and all items had some responses of "partial" (range, 13 [5.8%] to 70 [31.0%]). Twelve of the 19 RELATE items (63.2%) showed either substantial or almost perfect IRR (Gwet AC, >0.60), and 6 items (31.6%) had moderate IRR (Gwet AC, 0.41-0.60). Factor analyses resulted in a final 4-factor solution with excellent model fit indices and strong factor loadings: respect (4 items), empathy (5 items), listening and talking (6 items), and engaging in partnership with patients (4 items). Each factor showed sound internal consistency (Cronbach α range, 0.64-0.77).
Conclusions and relevance: This cross-sectional study of the RELATE rating scale demonstrated high construct validity and good internal consistency in simulated clinician-patient encounters. The findings suggest that the RELATE rating scale is an efficient, theoretically consistent tool to evaluate implicit bias-management communication behavior among clinicians.No embarg
Multicenter evaluation of the safety and efficacy of varying doses of cangrelor used in acute cerebrovascular stenting in patients with acute ischemic stroke
No full textBackground: Acute ischemic stroke often necessitates neuroendovascular interventions such as thrombectomy and, occasionally, stenting for large vessel occlusions or intracranial atherosclerotic disease. Effective antiplatelet therapy is essential during stenting to mitigate thrombosis risks, but consensus on optimal cangrelor dosing remains elusive. This study evaluates the safety and efficacy of various cangrelor doses used in acute cerebrovascular stenting.
Methods: A multicenter, retrospective cohort study was conducted across 11 comprehensive stroke centers. Patients aged 18-85 with ischemic stroke who underwent emergent cerebrovascular stenting with cangrelor were included. Patients were categorized into low-dose cangrelor (<2 mcg/kg/min; LDC) and high-dose cangrelor (≥2 mcg/kg/min; HDC) cangrelor groups. Outcomes included thrombotic and bleeding complications both intra-procedurally and within 48 hours post-procedure.
Results: A total of 230 patients were included in the analysis (LDC: 68; HDC: 162). Baseline characteristics were similar between groups. Thrombotic outcomes, including intraprocedural thrombosis (13% LDC vs 6% HDC; P=0.078) and thrombosis within 48 hours of the procedure (9% LDC vs 4% HDC; P=0.093), showed no statistical differences. Similarly, intraprocedural bleeding (6% LDC vs 5% HDC; P=0.753) and intracranial hemorrhage within 48 hours of the procedure (19% LDC vs 25% HDC; P=0.360) were not statistically different.
Conclusion: Different cangrelor dosing regimens demonstrated no significant differences in thrombotic or bleeding complications during acute neuroendovascular stenting for ischemic stroke. Larger, prospective studies are warranted to refine optimal dosing strategies for cangrelor in this population.No embarg
Myocardial ultrastructure in dogs and cats: review of normal structure, abnormal findings, and rationale for use in veterinary medicine
Get PDFElectron microscopy is an important imaging tool to identify ultrastructural abnormalities of the myocardium, diagnose certain diseases, and expand the understanding of mechanisms of cardiovascular disease processes. Transmission electron microscopy (TEM) is still an important part of human cardiovascular pathology, but its use in veterinary medicine has become uncommon. Even in patients with minimal histopathological changes on light microscopy, there can be important ultrastructural findings that help to achieve a diagnosis. In addition, TEM can be valuable for research by shedding light on underlying mechanisms or investigating new forms of cardiomyopathies. This review highlights the importance of TEM, details normal and pathological ultrastructural findings, and provides insight into clinical and research uses. We also provide tips on tissue preparation, processing, and analysis that are key to successful use of this valuable tool.No embarg
Single-cell transcriptomic and genomic changes in the ageing human brain
Get PDFOver time, cells in the brain and in the body accumulate damage, which contributes to the ageing process. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.No embarg
Beyond Aggregated Race and Ethnicity Codes: An Examination of Additional Methods to Identify Asian American and Native Hawaiian and Other Pacific Islander Veteran Subgroups in Administrative Databases
No full textIntroduction: Veterans who identify either as Asian American or as Native Hawaiian and Other Pacific Islander (NHPI) are growing (in percentage points) more rapidly than veterans of other racial groups. Substantial variation in COVID-19 death rates among Americans of Asian and NHPI ethnic origins underscored within-Asian and-NHPI health disparities-disparities that healthcare systems need to identify and measure. Yet healthcare utilization data within the U.S. Department of Veterans Affairs (VA) aggregates Asian American and NHPI groups, making it challenging to distinguish VA patients by subgroup membership and hampering efforts to identify subgroup variations.
Materials and methods: We piloted the combined use of 2 administrative data sources-the VA Corporate Data Warehouse (CDW) and DaVINCI, derived from the U.S. DoD Military Health System-to identify Asian American and NHPI VA-enrolled veterans. Our sample consisted of individuals within CDW whose fiscal year (FY) 2022 records included a veteran flag and non-missing values for race and ethnicity. We examined all variables related to race and ethnicity; however, we primarily used CDW's race variable, which categorized individuals as Asian, NHPI, White, Black, and/or American Indian/Alaska Native. We used DaVINCI's ethnicity variable in FY2022 records to identify individuals belonging to Asian subgroups (i.e., Chinese, Filipino, Japanese, Korean, Indian, Vietnamese, and Other Asian) or NHPI subgroups (i.e., Guamanian, Melanesian, Micronesian, Pacific Islander NEC, and Polynesian). We created 4 groups of VA-enrolled veterans by race: (1) Asian, (2) NHPI, (3) both Asian and NHPI, and (4) neither Asian nor NHPI. Within each group, we then calculated counts and proportion of individuals by Asian or NHPI ethnic subgroup.
Results: The merging of CDW and DaVINCI provided information on 1,300,499 unique veterans. In group (1) (Asian race; n = 38,384), nearly half reported at least one Asian ethnicity. In group (2) (NHPI race; n = 20,282), 15% reported at least one NHPI ethnicity and 16% reported Asian ethnicity. In group (3) (both Asian and NHPI; n = 1,468), 34.3% reported Asian ethnicity and 10% reported NHPI ethnicity. In group (4) (neither Asian nor NHPI; n = 1,240,365), 0.4% reported at least one Asian or NHPI ethnicity. Among VA-enrolled veterans with reported Asian or NHPI race in CDW, 26,166 had additional information from DaVINCI about Asian or NHPI subgroup membership.
Conclusions: Our study is the first, to the best of our knowledge, to merge administrative datasets to characterize VA-enrolled veterans of Asian or NHPI race with a corresponding Asian or NHPI ethnicity. Despite incomplete ethnicity data, the merging of CDW race and DaVINCI ethnicity variables (over the use of one or the other) may inform research and quality improvement studies, e.g., by enabling recruitment of vulnerable veterans from diverse ethnic backgrounds. This effort to disaggregate data is key to expanding our knowledge of heterogeneity in the health of veterans in Asian and NHPI communities.No embarg
Medications Reported to the Medicare Hospice Program after Medicare Drug Policy Changes, 2014-2018
No full textContext: In 2014, Medicare hospice policy changed to shift medication payments from Part D to the hospice benefit.
Objective: To describe patterns of medications reported to the Medicare hospice benefit after the 2014 policy change.
Methods: Repeated cross-sectional analysis of medications reported to the Medicare hospice benefit between 2014 and 2018. Data sources include the Medicare Master Beneficiary Summary File and national revenue center claims submissions by Medicare-certified hospices. Main outcome measures by year were the mean number of overall and chronic disease medication dispensings per enrollee, the most common medications billed to the Medicare hospice program, and the proportion of medications for end-of-life, chronic diseases, and potentially inappropriate by Screening Tool of Older Persons Prescriptions in Frail criteria.
Results: Between 2014 and 2015, the mean number of dispensings per enrollee covered by hospice temporarily increased from 12.1 (standard deviation (SD) 21.5) to 12.4 (SD 23.4) (p<.001) and returned to 12.1 (SD 23.0) in 2016, while the mean number of chronic disease medication dispensings per enrollee increased from 2.8 (SD 2.2) to 3.2. (SD 2.4) (p<.001) and remained stable. Between 2014 to 2018, the proportion of the top 100 drugs covered by hospice that were for chronic disease or met STOPPFrail criteria remained stable, while the proportion of EOL drugs declined temporarily before returning to 2014 levels.
Conclusions: The Medicare hospice program experienced small but statistically significant increases in chronic disease dispensings per enrollee after 2014 policy changes. Whether these were clinically significant or impacted patient outcomes requires further study.No embarg
Establishing community partnerships to maintain social connection and healthcare access during an emergency declaration: virtual veterans socials
Get PDFThis community case study reflects the transition of a community-based social intervention at a Veterans Affairs (VA) Medical Center in the northeastern United States (U.S.) from in-person to virtual gatherings during COVID-19 restrictions. Initially, the Veterans Socials program began in 2014 to address social support challenges of veterans who received care from VA, then evolved into community-based social groups delivered with and for the veteran community. These consist of veteran-led weekly meetups aimed at fostering social connection and reducing isolation. This evaluation explores the challenges and opportunities involved in shifting to a virtual platform, focusing on how community partnerships, including collaboration between private and government organizations, supported the continuity of this inclusive social support initiative. Leveraging these partnerships expanded access to health-related resources and services, while maintaining critical social networks. Findings include program-level data and three individual case studies that underscore the role of social support systems in mitigating loneliness and improving healthcare accessibility in times of crisis. This evaluation highlights how community partnerships were essential for sustaining social support, enhancing access to healthcare information, and disseminating vital information to the community during an emergency declaration.No embarg
Large Osteolipoma of the Posterior Ankle: A Rare Tumor in an Unusual Location
No full textOsteolipoma is a rare lipoma variant characterized by mature osseus metaplasia within mature adipose tissue, most commonly found in the head and neck, and seldom reported in the extremities. We present a case of a large osteolipoma of the posterior ankle associated with antecedent trauma. These tumors are typically slow growing and can be associated with pain and stiffness, depending on tumor size and location. Treatment is surgical excision, and recurrence is not reported. Interdisciplinary care involving radiology, pathology, and the surgical service is necessary for proper diagnosis and treatment of this rare benign neoplasm.No embarg