Jatin Mahesh Vyas

The American Board of Internal Medicine Research Pathway (ABIM RP) is designed to train physician-scientists by shortening postgraduate clinical training and increasing research time. We surveyed ABIM RP graduates to understand career trajectories, research engagement, and barriers to physician-scientist retention in academic research careers. We performed an anonymous, structured, web-based survey of 700 ABIM RP current and former trainees (2011–2022). We received 105 survey responses (97 RP graduates). The survey queried about demographics, training background, career outcomes, research involvement, and perceived barriers to retention in physician-scientist careers. Responses were stratified by trainee status, gender, and Medical Scientist Training Program (MSTP) participation, and select results were compared to test for statistical associations. Most respondents (79%) remained in academia, with 61% engaged in research-dominant roles. More MSTP graduates held research-focused academic positions than non-MSTP graduates. The most commonly reported barriers to sustaining research careers were funding instability, financial concerns, and lack of protected research time. Although many of the trainees in the ABIM RP who completed the survey remained in academia, systemic barriers such as funding instability and gaps in institutional support persist. Strategies to enhance financial stability, protected research time, and mentorship appear to be necessary to enhance physician-scientist career retention.

Physician-scientists represent one of the most impactful, yet underrecognized, innovations of 20th century academic medicine. Defined by a commitment to full-time careers in investigative work, physician-scientists have repeatedly demonstrated a unique ability to identify and solve problems of unmet medical need in a focused and intentional manner using their dual training in clinical medicine and the scientific method as both stethoscope and scalpel. Unfortunately, while the value of physician-scientists has never been greater, the institutional infrastructure to support them has never been explicitly defined (1), a deficiency now amplified by mounting financial pressures from both clinical revenue models and an increasingly constrained research funding landscape (2, 3). This white paper reports the output of a consortium of academic medical centers, foundations, and professional societies seeking to remedy this deficiency. This consortium specifically developed a framework to formalize the career path of physician-scientist faculty into a professionally unified and financially sustainable structure amenable to adoption across US academic medical centers and health systems. Key components of this framework included an administratively operational definition of physician-scientists, and 3 central and interconnected pillars (academic, financial, and organizational) that are rooted in this foundational definition. Herein, we detail core concepts and concrete recommendations.

The rate of invasive fungal infections has risen drastically over the last decade and continues to carry devastatingly high mortality rates. Currently, there are no licensed vaccines and limited antifungal agents in clinical trials for fungal-mediated diseases. The limited effectiveness of FDA-approved antifungal medications against invasive fungal infections and the lack of mechanistic understanding of how these infections manifest pose a significant burden on healthcare systems worldwide. Therefore, understanding the molecular details of the host-fungal interactions has never been more urgent. Here, we examine the role of fungal melanin as a virulence factor through its immunomodulatory effects during respiratory infections. Although previous literature on fungal pathogenicity has touched briefly on fungal pigments, they are incomplete in discussing how melanin dysregulates essential functions of the innate immune system. To provide a contemporary perspective, literature on melanized fungal species commonly associated with infections via the respiratory tract has been reviewed to detail holistic mechanisms by which melanin subverts the immune system and manipulates the respiratory epithelium.

Respiratory fungal infections pose a significant threat to human health. Animal models do not fully recapitulate human disease, necessitating advanced models to study human-fungal pathogen interactions. In this study, we utilized primary human airway epithelial cells (hAECs) to recapitulate the lung environment in vitro and investigate cellular responses to two diverse, clinically significant fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii . To understand the mechanisms of early pathogenesis for both fungi, we performed single-cell RNA sequencing of infected hAECs. Analysis revealed that both fungi induced cellular stress and cytokine production. However, the cellular subtypes affected and specific pathways induced differed between fungi, with A. fumigatus and C. posadasii triggering protein-folding-related stress in ciliated cells and hypoxia responses in secretory cells, respectively. This study represents one of the first reports of single-cell transcriptional analysis of hAECs infected with either A. fumigatus or C. posadasii , providing a vital data set to dissect the mechanism of disease and potentially identify targetable pathways. IMPORTANCE: Fungal infections in the lungs are lethal complications for those with compromised immune systems and have limited treatment strategies available. These options are restricted further by the increased prevalence of treatment-resistant fungi. Many studies focus on how our immune systems respond to these pathogens, yet airway epithelial cells remain an understudied component of fungal infections in the lungs. Here, the authors provide a transcriptional analysis of primary human airway epithelial cells stimulated by two distinct fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii . These data will enable further mechanistic studies of the contribution of the airway epithelium to initial host responses and represent a powerful new resource for future investigations.

The engagement of medical trainees to the field of infectious diseases has waned over recent years. While the reasons for this decline are multifactorial, one prominent concern is the perception that infectious disease specialists serve merely as gatekeepers of antibiotics. In this forward-looking perspective, we discuss a new paradigm for infectious diseases—host-directed therapies. Supported by the discovery of the mechanism of disease in many infectious diseases, coupled with the ever-expanding armamentarium of immune modulators, we envision that infectious disease physicians will soon be delivering immunotherapy coupled with antimicrobials to achieve cures that were previously impossible.

Background/Objectives: Despite the lifting of the COVID-19 public health emergency, SARS-CoV-2 infections continue to be recorded worldwide. The continued prevalence of infection has been attributed to the ability of the virus to evade host immune responses, including neutralizing antibody-derived immunity. The vast majority of antibody escape mutations has been associated with the S1 subunit of the spike protein. The other region of the spike, the S2 subunit, is the most conserved region amongst coronaviruses. We hypothesized that S2-specific antibody levels are modest in vaccinated and SARS-CoV-2-infected patients, resulting in suboptimal neutralization of distant coronaviruses. Methods: Here, we analyzed S1- and S2-specific antibody levels in SARS-CoV-2-infected individuals, including a mixed cohort of those with and without immunosuppression and prior vaccination. Results: We found that S2-specific antibody responses were generally lower than S1-specific antibody responses. Intriguingly, Omicron-S1-specific antibody levels were higher than Wuhan-S1-specific antibody levels despite all vaccinated participants having received Wuhan-spike-based immunogens. This emphasizes the importance of the infecting variant and vaccine immunogen in the production of spike-targeting antibodies and associated hybrid immunity. Although S1-specific antibody levels were generally higher than their S2-specific counterparts, the correlation between neutralization and binding antibody levels was mostly higher in S2- compared with S1-specific responses. Conclusions: We conclude that S2-based immunogens are suitable for the induction of antibody-based immunity against novel SARS-CoV-2 variants but also against more distant coronaviruses, which would support a better protection for the immunocompromised as well as other vulnerable populations.

With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood–brain barrier (BBB), such as Cryptococcus neoformans. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis.

With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in anti-fungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic science level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood brain barrier (BBB) such as Cryptococcus neoformans. We determined the effects of this fungal pathogen has on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis.