Faculty Bibliography

The Ca_v1.3 L-type calcium (Ca²⁺) channel plays a critical role in cardiac excitation-contraction coupling, regulating heart rate, contractility, and gene expression. The C-terminus of Ca_v1.3 has recently been shown to translocate to the nucleus and act as a transcriptional factor to modulate the function of Ca²⁺-activated K⁺ channels in atrial cardiomyocytes. However, the role of the Ca_v1.3-C-terminus in the regulation of transcription of its own Ca_v1.3 gene remains unknown. We evaluated the impact of the nuclear translocation of the Ca_v1.3-C-terminus on the transcription of the Ca_v1.3 gene and Ca_v1.3 promoter activity in vitro using cultured neonate rat ventricular myocytes (NRVMs), and mouse atrial cardiomyocytes (HL-1). Lentiviral infection of NRVMs demonstrated that the cleaved Ca_v1.3-C-terminus translocates to the nucleus where it acts as a trans-regulator. The C-terminus of Ca_v1.3 increased transcription of Ca_v1.3 in vitro in NRVMs and in vivo in mice ventricles. Additionally, MEF2 transcription factor binding sites within the Ca_v1.3 promoter may contribute to the regulatory effect of the Ca_v1.3-C-terminus. These data are the first to demonstrate unique upregulation of Ca_v1.3 transcription by its own mobile Ca_v1.3-C-terminus both in vitro and in vivo. These findings suggest that the Ca_v1.3-C-terminus has intrinsic properties as a trans-regulator of gene expression and may contribute to the modulation of cardiac function.

The 2025 Leon Thal Summit convened an international panel of clinicians, neuroscientists, neuropathologists, and neuroimaging specialists to evaluate the current state of biomarker development for chronic traumatic encephalopathy (CTE) and to outline priorities for advancing translational research for this important area. Discussions integrated emerging findings from longitudinal cohorts, new molecular and neuroimaging approaches, expanding post mortem evidence, and evolving insights into exposure biology and genetic modifiers. Consensus themes emphasized the need for biomarkers that detect CTE-specific tau proteoforms, integration of existing imaging and fluid markers into traumatic encephalopathy syndrome research criteria, and refinement of multimodal magnetic resonance imaging and blood-based tools that capture early CTE pathology. The group underscored the importance of coordinated, longitudinal clinicopathological studies and collaborative research frameworks to validate candidate biomarkers and accelerate progress toward accurate diagnosis, disease monitoring, and therapeutic development for individuals at risk for or exhibiting signs of CTE.

BACKGROUND:Testosterone replacement therapy (TRT) may cause side effects after orthopedic procedures. With total hip arthroplasty (THA) rates increasing, this study evaluates the relationship between TRT and postoperative complications in THA patients. METHODS:A retrospective review in a large academic hospital was conducted of hypogonadal patients treated with TRT, who underwent primary, elective THA between 2012 and 2024. These were 1:2 propensity-matched based on age, body-mass index, and comorbidities to a "control" group that was not treated with TRT. Patient and TRT characteristics including serum testosterone levels, form of administration, 90-day emergency department visits (ED) and readmissions, reoperations and revisions were explored. RESULTS:Among 152 patients aged 61.3 years who underwent THA with a 2.7-year follow-up, TRT was mainly administered intramuscularly (51.3%) or via transdermal gel (46.1%), followed by pellets (2.0%), and oral tablets (1.6%). Overall rates of 90-day ED visits and readmissions did not differ significantly between TRT and control patients (7.9% vs. 5.3%, P = 0.270 and 7.9% vs. 5.6%, P = 0.225, respectively). TRT patients had a significantly lower rate of 90-day ED visits due to surgery-related causes (0.7% vs. 2.3%, P = 0.048) but a significantly higher rate due to non-surgery-related causes (7.2% vs. 3.0%, P = 0.034). The incidence of PJI did not differ significantly between the groups (2.0% vs. 1.0%, P = 0.319). Reoperations and revisions were not different between the groups (P = 0.650 and P = 0.057, respectively). TRT administration form was not associated with 90-day ED visits (P = 0.380), readmissions (P = 0.563), reoperations (P = 0.441) or revisions (P = 0.669). Testosterone levels demonstrated a weak, negative, yet significant correlation with 90-day ED visits (r = -0.35, P = 0.040), but not with reoperations or revisions (P = 0.348 and P = 0.431, respectively). CONCLUSIONS:TRT in THA patients was associated with a reduced rate of surgery-related 90-day ED visits but an increased rate of non-surgery-related 90-day ED visits. Incidence of PJI and overall 90-day ED visits and readmission rates did not significantly differ. Administration form had no significant impact, while higher testosterone levels were linked to fewer 90-day ED visits. Although limited by its retrospective design and patient exclusions, further investigation is warranted to guide perioperative management in these patients, particularly given the known immunomodulatory effects of exogenous TRT.

BACKGROUND:While EM departments have designated new leadership roles to focus on diversity, equity, and inclusion (DEI) in recent years, the experiences of DEI leaders have not been thoroughly investigated. The purpose of this study was to describe the factors that impact the effectiveness of DEI leaders within EM. METHODS:We conducted a national qualitative study of DEI leaders in EM. Participants participated in a 60-min semi-structured interview. An interview guide was pilot-tested and iteratively refined. The interview audio was recorded and professionally transcribed. Two team members developed a codebook, independently coded transcripts, and generated categories using content analysis. We analyzed the interview transcripts using inductive and deductive content analysis. Inductive analysis allowed us to identify emerging categories, while deductive analysis allowed us to overlay Camara Jones' Allegory of the Levels of Racism to our data. RESULTS:We completed 24 interviews, representing 21 unique institutions in 14 states. In our adapted allegory, the DEI leader is represented centrally within the ecosystem. The effectiveness of the DEI leader is influenced by institutionally mediated, personally mediated, and internally mediated factors. Institutionally mediated factors included the macroenvironment, administrative positioning, and promotion pathways. Personally mediated factors included communication skills, ongoing leadership development, change management prowess, and seeking colleagues' support. Internally mediated factors included personal commitment to DEI work, as well as feelings of workplace inclusion, imposter syndrome, and tokenism. CONCLUSIONS:This qualitative analysis of EM DEI leaders highlights how factors at various levels influence their experience. Jones's allegory helps conceptualize how a DEI leader functions in a dynamic, continually evolving environment that is sometimes beyond the leader's control. Our research identifies opportunities at the personal, departmental, and institutional levels, such as maintaining a personal commitment to the work, supporting leadership development, and improving administrative positioning that can assist DEI leaders' effectiveness.

IMPORTANCE/UNASSIGNED:The physician-scientist workforce has been in decline for decades, and the shortage of physician-scientists from racial and ethnic groups that are underrepresented in medicine (URiM) is particularly acute. Medical school is a key developmental period during which research career intentions (RCI) may change, yet little is known about RCI evolution during this period. OBJECTIVE/UNASSIGNED:To evaluate factors associated with RCI among first-year medical students, overall and by URiM status. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This is a cross-sectional analysis of baseline data from the ongoing Longitudinal Evaluation of Research Career Intentions Among Medical Students Study. Participants were first-year medical students enrolled during the 2024 to 2025 academic year at US medical schools accredited by the Liaison Committee on Medical Education. MD-PhD students were excluded. EXPOSURES/UNASSIGNED:The baseline survey collected information on sociodemographic factors, pre-medical school and first-year research experiences (eg, research education, research participation, mentorship, and authorship), medical school learning environment, and psychosocial characteristics. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was RCI in year 1 of medical school, defined as intending to be significantly or exclusively involved in research during one's medical career. Characteristics associated with RCI were evaluated using stability selection. RESULTS/UNASSIGNED:Among 1136 first-year medical student respondents (mean [SD] age, 24.7 [2.7] years; 790 female [69.5%]) at 134 US medical schools, 26.9% (306 students) reported RCI, with a slightly higher prevalence among URiM students than non-URiM students (246 students [28.2%] vs 60 students [23.9%]; standardized mean difference, 0.097). Prematriculation factors associated with RCI among all students included research participation (odds ratio [OR], 1.51; 95% CI, 1.13-2.00), conference presentation (OR, 1.56; 95% CI, 1.16-2.09), and manuscript authorship (OR, 1.38; 95% CI, 1.03-1.86). Postmatriculation factors included research participation (OR, 1.74; 95% CI, 1.31-2.30) and having a physician-scientist role model (OR, 1.72; 95% CI, 1.31-2.30). Factors uniquely associated with RCI among URiM students included prematriculation research experiences (OR, 1.51; 95% CI, 1.14-2.01) and presentation of research (OR, 1.57; 95% CI, 1.17-2.11) and postmatriculation manuscript authorship (OR, 1.84; 95% CI, 1.04-3.25). Among non-URiM students, only postmatriculation factors were uniquely associated with RCI, including having a research mentor (OR, 1.76; 95% CI, 1.34-2.31) and receiving education about physician-scientist work-life balance (OR, 1.63; 95% CI, 1.24-2.15). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This cross-sectional analysis of baseline data from an ongoing cohort study found that RCI was prevalent among first-year medical students and was associated with characteristics and experiences prior to matriculation and during year 1. Some factors associated with RCI differed between URiM and non-URiM medical students, suggesting distinct pipelines to research career development. These findings highlight opportunities to support physician-scientist training through tailored education, exposure, and mentorship.

Addressing endemic stunting remains a primary United Nations development goal. One potential contributor to global linear growth failure is environmental enteric dysfunction (EED). However, it has proven challenging to address with interventions focused on water, sanitation and hygiene. Initial theories of EED placed primacy on recurrent enteric exposures; however, it appears that these exposures are inadequate to explain the phenotype and sequelae. Children in EED endemic regions are at high risk of having inadequate nutrition, and strong associations can be found between malnutrition and stunting. In this review, we summarize the clinical, translational and mechanistic evidence linking intake of animal source foods as a source of protein and micro-nutrients and, in their absence, essential amino acid (EAA) deficiency with stunted growth and features of EED such as altered immune behaviour. EAA deficiency has been linked to growth failure through several mechanistic pathways including intestinal inflammation, barrier disruption and chondral plate closure, and amino acid supplementation has shown clinical efficacy. By better understanding this linkage, we will be able to better study not only EED but also pathways in which dietary sources mechanistically alter systemic signalling in metabolism and immune function. This article is part of the theme issue 'Biological, biomedical and environmental drivers of stunting'.

Hypertension is a modifiable risk factor for cardiovascular disease (CVD) and its prevalence is high in the United States and worldwide. Adequate characterization of blood pressure (BP) is essential for the diagnosis and management of hypertension. However, BP assessment can be challenging because of the unique influences across the lifespan, disease conditions, and physical environmental context. Moreover, complex uncertainties in BP assessment may contribute to underdiagnosis, undertreatment, and preventable morbidity and mortality. Recent advances in BP measurement devices have enabled comprehensive characterization of BP that could dramatically change how hypertension is managed to optimize CVD risk reduction, avoid complications of low BP, and improve hypertension control rates. To address the rapidly evolving landscape in BP assessment, the National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health convened a 2-day workshop of clinicians and researchers in December 2024. The present report summarizes the topics presented and discussed during the meeting, which focused on the latest evidence on BP assessment as well as obstacles and knowledge gaps to be addressed to advance BP assessment in clinical practice and research.

Dpep is a cell-penetrating peptide that targets transcription factors ATF5, CEBPB and CEBPD to selectively suppress growth and survival of diverse tumor cell types in vitro and in vivo. Due to these actions and its apparent safety, the peptide has potential as a cancer therapeutic. How Dpep might be combined with other anti-cancer agents to achieve synergistic efficacy and to overcome possible peptide resistance has not been assessed in depth. Based on prior work indicating that Dpep promotes apoptotic cancer cell death and up-regulates multiple pro-apoptotic and tumor suppressor genes, we studied combinations of Dpep with ABT-263, a pro-apoptotic BCL2 family inhibitor, and decitabine, a hypomethylating drug. Combining Dpep with each agent alone or together synergistically suppressed the growth of a range of solid and liquid tumor cell types. Moreover, the combinations synergistically inhibited the growth of cells lines that were selected either in vivo or in vitro for Dpep resistance. Finally, we tested the combination of Dpep with ABT-263 in a mouse melanoma xenograft model. The combination more effectively inhibited tumor growth than either agent alone and, in contrast to vehicle or ABT-263, produced a 40% durable survival rate. Taken together, these observations highlight potential drug partners for the therapeutic development of Dpep.

In the face of a growing mismatch between candidates awaiting transplantation and the supply of conventional donor organs, attention has shifted toward novel methods to increase the donor pool, including the use of donation after circulatory death (DCD) and the refinement of procurement techniques that safeguard graft quality. Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a new strategy, leveraging extracorporeal support to curtail warm-ischemic injury while permitting in situ functional assessment. This review covers the rationale behind the use of TA-NRP, while outlining its use during procurement and the current body of evidence gathered on it implementation in lung transplantation specifically.

Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder that develops after exposure to a severe traumatic event. PTSD is characterized by intrusive re-experiencing of traumatic memories, avoidance of trauma reminders, negative alterations in cognition and mood, and changes in arousal and reactivity. PTSD is prevalent, with tens of millions of patients in the USA alone affected. The lifetime prevalence worldwide is estimated to be about 4-6%, but it can occur in up to 25-30% of people who experience severe psychological trauma, such as combat veterans, refugees and assault victims. PTSD is highly comorbid with major depressive disorder, anxiety disorders and substance use disorders, and it is a leading cause of suicide. PTSD also increases the risk of multiple medical problems including cardiovascular and metabolic disorders. We review the epidemiology and diagnostic aspects of PTSD in adults, the mechanistic and neurobiological understanding of the syndrome - from neural circuitry to genetic mechanisms - as well as medication, psychotherapy and other trauma-informed treatment approaches to PTSD and trauma-related syndromes.