Moving Career Development Upstream: Evaluation of a Course for Internal Medicine Trainees Contemplating Career Pathways in Academic Medicine.

OBJECTIVES: Despite training in academic medical centers, many residents and fellows lack an understanding of the different career paths in academic medicine. Without this fundamental knowledge, choosing an academic career pathway and transitioning to junior faculty is challenging. We started the Pathways in Academic Medicine course ("Pathways") to introduce residents and fellows to the wide array of academic career pathways and to expose them to the concepts and resources needed to transition successfully from trainee to junior faculty. RESULTS: Sixty-nine medicine residents and fellows participated in Pathways programming. Surveys and focus groups revealed high satisfaction with the course sessions. Trainees indicated that Pathways helped them to envision an academic career, clarified the steps needed to pursue an academic career, and normalized common challenges. CONCLUSIONS: Pathways is an important educational innovation that gives participants experiences to jumpstart successful careers in academic medicine. We hope that our program will serve as an example for other institutions interested in improving the trainee-to-faculty transition.

Intratumoral TREX1 Induction Promotes Immune Evasion by Limiting Type I IFN.

Chromosomal instability is a hallmark of human cancer that is associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking a cGAS-STING immune response through the accumulation of cytosolic DNA. The mechanisms of how tumors benefit from chromosomal instability while mitigating associated risks, such as enhanced immune surveillance, are poorly understood. Here, we identify cGAS-STING-dependent upregulation of the nuclease TREX1 as an adaptive, negative feedback mechanism that promotes immune evasion through digestion of cytosolic DNA. TREX1 loss diminishes tumor growth, prolongs survival of host animals, increases tumor immune infiltration, and potentiates response to immune checkpoint blockade selectively in tumors capable of mounting a type I IFN response downstream of STING. Together, these data demonstrate that TREX1 induction shields chromosomally unstable tumors from immune surveillance by dampening type I IFN production and suggest that TREX1 inhibitors might be used to selectively target tumors that have retained the inherent ability to mount an IFN response downstream of STING. See related article by Lim et al., p. 663.

A Case Report on Brachial Plexus Anomaly, Embryological Basis, and Clinical Implications.

This study presents the routine prosection findings of a 74-year-old male anatomical donor, whose cause of death was attributed to anoxic brain injury secondary to cardiac arrest and acute exacerbation of chronic obstructive pulmonary disease (COPD). The patient exhibited a significant medical history, including severe COPD, chronic heart failure, atrial fibrillation, hypertension, stage III chronic kidney disease, heavy alcohol abuse, obesity, coronary artery disease, peripheral edema, triple bypass surgery, and right hip replacement. A detailed examination of the upper extremities revealed anomalies within the brachial plexus, with a more pronounced presence on the left side. This particular donor deviates from the expected "typical" brachial plexus anatomy, with a lack of convergence into a lateral cord and an anomalous convergence into a superior trunk. To ensure optimal patient care and procedural outcomes, a collaborative approach between surgeons and anesthesiologists that is grounded in a comprehensive understanding of these anatomical nuances is essential. Therefore, this study aims to comprehensively investigate the identified brachial plexus anomalies, elucidate their embryological origins, and explore their clinical implications. Through these objectives, this research contributes to a broader understanding of anatomical variations and their relevance in medical practice.

Community Partners' Perspectives on Partnering With an Academic Research Team to Promote Disability-inclusive Fitness Programming.

BACKGROUND: Community-based fitness programs can support public health by providing access to physical activity opportunities for a vulnerable population with significant barriers. Unfortunately, programs specifically designed for people with disabilities (PWD) and staff training to promote inclusion for PWD in general population programs is limited. The current study aimed to review an on-going partnership that had formed to address this need. OBJECTIVES: The purpose of this study was to assess community partners' experiences with a community-academic partnership designed to implement a fitness program for people with multiple sclerosis and also to promote inclusion for PWD in community-based fitness programming. METHODS: Semi-structured interviews were conducted with six community partners who had been engaged in a formal partnership with the academic institution for 2 or more years to understand partners' experiences and perspectives about the partnership. Interviews were audio/video recorded, transcribed verbatim, and analyzed thematically. RESULTS: Participants described their experiences as falling into four main areas. Pre-partnership experiences (or lack thereof) shaped participants views on entering into academic partnerships. Communication and planning for mutual benefit were key to getting the partnership started. Partners identified challenges and factors for success while they were in the thick of partnership activities. Finally, evaluation allowed for assessment and improvement of the partnership itself and its ultimate goals. CONCLUSIONS: Findings suggest that academic-community partnerships can be ideal for promoting inclusion for PWD and highlight insights that can be used in the development of future partnerships.

Acute Care Utilization at End of Life in Sickle Cell Disease: Highlighting the Need for a Palliative Approach.

Background: People with sickle cell disease (SCD) have a life expectancy of <50 years, so understanding their end-of-life care is critical. Objective: We aimed to determine where individuals with SCD were dying and their patterns of care in the year preceding death to highlight end-of-life research priorities and possible opportunities for intervention. Design: Using the California SCD Data Collection Program database (containing administrative data, vital records, and Medicaid claims), we examined people with SCD who died between 2006 and 2015 (cases) at age <80 years and examined their hospital and emergency department (ED) utilization in their last year of life. Comparators included living controls with SCD matched 1:1 based on age, analysis year, insurance, and income. Results: We identified 486 people with SCD (cases) who died at a median age of 45 years (SD: 16 years). Most died in the hospital (63%) and ED (15%). In their last year of life, people with SCD were hospitalized for an average of 42 days (SD: 49 days) over five admissions. Inpatient admissions and ED visits were stable throughout the year until the month before death when acute care utilization sharply increased. In their last year of life, cases had more hospitalizations than controls, but similar ED utilization. Conclusions: People with SCD are dying acutely at a young age and most die in the hospital and the ED. Since clinicians caring for people with SCD currently cannot predict which acute events may be life-threatening, a comprehensive palliative approach to people with SCD must extend beyond chronic pain management and psychosocial support to include advance care planning.

A molecular switch regulating transcriptional repression and activation of PPARγ.

Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.

Heterogeneity and Plasticity of Human Breast Cancer Cells in Response to Molecularly-Targeted Drugs.

Non-responsive subpopulation of tumor cells, and acquired resistance in initially responsive cells are major challenges for cancer therapy with molecularly-targeted drugs. While point mutations are considered the major contributing factor to acquired resistance, in this study we explored the role of heterogeneity and plasticity of selected human breast cancer cell lines (MDA-MB-231, MDA-MB-468, and AU565) in their initial and adjusted response, respectively, to ruxolitinib, everolimus, and erlotinib. After determination of lethal concentration for 50% cell death (LC50), cells were exposed to selected drugs using three different approaches: single exposure to 4 × LC50 and collection of surviving cells, multiple exposures to 1.5 × LC50 and monitoring the surviving population, and exposure to gradually increasing concentrations of selected drugs (range of concentrations equivalent to 10% of LC50 to 1.5 × LC50). Surviving cells were studied for adjustments in expression level of selected proteins using quantitative PCR and Western Blot. Our data indicated overexpression of a variety of proteins in resistant populations, which included cell membrane receptors EGFR and HER2, anti-apoptotic proteins Bcl-2 and BIRC8, and other proteins involved in cell signaling (e.g., Akt1, MAPK7, and RPS6KA5). Silencing the identified alternative proteins via siRNA resulted in significant drop in the LC50 of the selected molecularly-targeted drugs cells resistant to ruxolitinib (via targeting Akt), everolimus (via targeting EGFR, MAPK7, RPS6KA5, and HER2), and erlotinib (via silencing Bcl2 and BIRC8). Our data indicates that targeting well-selected alternative proteins could potentially sensitize the resistant cells to the effect of the molecularly-targeted treatment.

Looking Back, Moving Forward: A Retrospective Review of Care Trends in an Academic Palliative and Supportive Care Program from 2004 to 2016.

Objective: To examine a rural-serving HBPC program's 12-year experience and historical trends to inform future program direction and expansion. Background: There is limited information about longitudinal trends in mature hospital-based palliative care (HBPC) programs serving racially diverse rural populations. Methods: This is a retrospective cross-sectional study of operational and patient-reported outcomes from the University of Alabama at Birmingham (UAB) Center for Palliative and Supportive Care (CPSC) inpatient (n=11,786) and outpatient (n=315) databases from October 2004 to March 2016. Results: Inpatients were a mean age of 63.7 years, male (50.1%), white (62.3%), general medicine referred (19.5%), primarily for goals of care (84.4%); 47.1% had "do not resuscitate/do not intubate" status and 46.9% were transferred to the Palliative Care and Comfort Unit (PCCU) after consultation. Median time from admission to consultation was three days, median PCCU length of stay (LOS) was four days, and median hospital LOS was nine days. Increased emergency department and cardiology referrals were notable in later years. Outpatients' mean age was 53.02 years, 63.5% were female, 76.8% were white, and 75.6% had a cancer diagnosis. Fatigue, pain, and disturbed sleep were the most common symptoms at the time of the visit; 34.6% reported mild-to-moderate depressive symptoms. Of patients reporting pain (64.8%), one-third had 50% or less relief from pain treatment. Discussion: The CPSC, which serves a racially diverse rural population, has demonstrated robust growth. We are poised to scale and spread our lessons learned to underserved communities.