Arsenic-induced changes in the gene expression of lung epithelial L2 cells: implications in carcinogenesis

Background: Arsenic is a carcinogen that is known to induce cell transformation and tumor formation. Although studies have been performed to examine the modulation of signaling molecules caused by arsenic exposure, the molecular mechanisms by which arsenic causes cancer are still unclear. We hypothesized that arsenic alters gene expression leading to carcinogenesis in the lung.Results: In this study, we examined global gene expression in response to 0.75 uM arsenic treatment for 1 - 7 days in a rat lung epithelial cell line (L2) using an in-house 10 k rat DNA microarray. One hundred thirty one genes were identified using the one-class statistical analysis of microarray (SAM) test. Of them, 33 genes had a fold change of >/= 2 between at least two time points. These genes were then clustered into 5 groups using K-means cluster analysis based on their expression patterns. Seven selected genes, all associated with cancer, were confirmed by real-time PCR. These genes have functions directly or indirectly related to metabolism, glycolysis, cell proliferation and differentiation, and regulation of transcription.Conclusion: Our findings provide important insight for the future studies of arsenic-mediated lung cancer.Peer reviewedPhysiological Science

Longitudinal Milestone Assessment Extending Through Subspecialty Training: The Relationship Between ACGME Internal Medicine Residency Milestones and Subsequent Pulmonary and Critical Care Fellowship Milestones

Purpose Accreditation Council for Graduate Medical Education (ACGME) milestones were implemented across medical subspecialties in 2015. Although milestones were proposed as a longitudinal assessment tool potentially providing opportunities for early implementation of individualized fellowship learning plans, the association of subspecialty fellowship ratings with prior residency ratings remains unclear. This study aimed to assess the relationship between internal medicine (IM) residency milestones and pulmonary and critical care medicine (PCCM) fellowship milestones. Method A multicenter retrospective cohort analysis was conducted for all PCCM trainees in ACGME-accredited PCCM fellowship programs, 2017–2018, who had complete prior IM milestone ratings from 2014 to 2017. Only professionalism and interpersonal and communication skills (ICS) were included based on shared anchors between IM and PCCM milestones. Using a generalized estimating equations model, the association of PCCM milestones ≤ 2.5 during the first fellowship year with corresponding IM subcompetencies was assessed at each time point, nested by program. Statistical significance was determined using logistic regression. Results The study included 354 unique PCCM fellows. For ICS and professionalism subcompetencies, fellows with higher IM ratings were less likely to obtain PCCM ratings ≤ 2.5 during the first fellowship year. Each ICS subcompetency was significantly associated with future lapses in fellowship (ICS01: β = −0.67, P = .003; ICS02: β = −0.70, P = .001; ICS03: β = −0.60, P = .004) at various residency time points. Similar associations were noted for PROF03 (β = −0.57, P = .007). Conclusions Findings demonstrated an association between IM milestone ratings and low milestone ratings during PCCM fellowship. IM trainees with low ratings in several professionalism and ICS subcompetencies were more likely to be rated ≤ 2.5 during the first PCCM fellowship year. This highlights a potential use of longitudinal milestones to target educational gaps at the beginning of PCCM fellowship

Community Benefit Agreements: A Report for the City of East Cleveland

Dr. Beth Nagy, Assistant Lecturer of Urban Planning Practice at the Levin College, worked with her UST 489 Senior Seminar class to produce a report for the City of East Cleveland on community benefit agreements (CBAs). Students examined CBAs across major cities throughout the United States to provide the City of East Cleveland with case studies on the different ways CBAs are utilized in other communities, while exploring the successes and limitations such efforts have encountered. The final report was presented to East Cleveland Mayor Brandon L. King in February 2020

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need

Implementation of a Professional Society Core Curriculum and Integrated Maintenance of Certification Program

Medical professional societies exist to foster collaboration, guide career development, and provide continuing medical education opportunities. Maintenance of certification is a process by which physicians complete formal educational activities approved by certifying organizations. The American Thoracic Society (ATS) established an innovative maintenance of certification program in 2012 as a means to formalize and expand continuing medical education offerings. This program is unique as it includes explicit opportunities for collaboration and career development in addition to providing continuing medical education and maintenance of certification credit to society members. In describing the development of this program referred to as the “Core Curriculum,” the authors highlight the ATS process for content design, stages of curriculum development, and outcomes data with an eye toward assisting other societies that seek to program similar content. The curriculum development process described is generalizable and positively influences individual practitioners and professional societies in general, and as a result, provides a useful model for other professional societies to follow

Sirolimus-induced secondary pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome that is characterized by the accumulation of excess surfactant in the alveolar space, leading to impaired gas exchange. Sirolimus-induced PAP is an extremely rare entity that has only been described in the literature in a small number of case reports. We present a case of a 39-year-old female with acute lymphocytic leukemia who underwent stem cell transplant, complicated by graft-versus-host-disease (GVHD) involving the skin for which she was treated with steroids, photopheresis, sirolimus, and ruxolitinib. She was admitted to the intensive care unit (ICU) for acute on chronic hypoxic respiratory failure requiring intermittent mechanical ventilation. Computed tomography (CT) of the chest showed thickened inter- and intralobular septa with ground glass opacities and consolidation with a limited geographic pattern. Bronchoalveolar lavage fluid was stained with Periodic acid-Schiff (PAS), which was positive for extracellular proteinaceous material. Autoimmune studies including antibody levels for primary autoimmune pulmonary alveolar proteinosis (PAP) were negative. The patient was diagnosed with sirolimus-induced secondary PAP, and sirolimus was discontinued. A year later, she no longer required supplemental oxygen, and repeat CT imaging showed only faint residual disease. This is the only documented case of sirolimus-induced PAP in a stem cell transplant recipient and the first case reported in which the patient developed severe hypoxic respiratory failure requiring mechanical ventilation. In the right clinical context, PAP can be diagnosed with characteristic high resolution computed tomography (HRCT) findings, serum GM-CSF antibody levels, and bronchoscopy with bronchoalveolar lavage

Opportunistic Infection Associated With Elevated GM-CSF Autoantibodies: A Case Series and Review of the Literature.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to play a key role in enhancing multiple immune functions that affect response to infectious pathogens including antigen presentation, complement- and antibody-mediated phagocytosis, microbicidal activity, and neutrophil chemotaxis. Reduced GM-CSF activity and immune response provides a mechanism for increased infection risk associated with autoimmune pulmonary alveolar proteinosis (aPAP) and other disorders involving the presence of GM-CSF autoantibodies. We present a case series of five patients with persistent or unusual pulmonary and central nervous system opportunistic infections (Cryptococcus gattii, Flavobacterium, Nocardia) and elevated GM-CSF autoantibody levels, as well as 27 cases identified on systematic review of the literature

A Prospective Trial of an In-house Overnight Fellow Rotation in the Intensive Care Unit.

BACKGROUND: Although previous studies in academic intensive care units (ICUs) have found no improvement in patient care outcomes with in-house overnight attending physician coverage compared with home call coverage, the effect of in-house supervision on trainee education and well-being is less clear. In addition, no studies have examined the effect of in-house coverage by fellow physicians overnight. OBJECTIVE: What is the impact of an in-house overnight critical care fellow on resident, fellow, and attending perception of patient safety, house staff education, and house staff well-being? METHODS: A prospective trial alternating 2-week periods of in-house overnight critical care fellow coverage with 2-week periods of home call coverage was performed in our tertiary medical ICU. Residents, fellows, and attendings were surveyed to evaluate perceptions of the night fellows impact on patient care, communication, supervision, educational experience, autonomy, well-being, and job satisfaction. RESULTS: Over the 6-month study period, surveys were sent to 83 residents, 22 fellows, and 23 attendings, with completion by 56 (67%), 22 (100%), and 16 (70%), respectively. Overall, 89% of residents, 68% of fellows, and 81% of attendings reported perceived improvements in patient care with an in-house fellow. The in-house fellow was also associated with improved well-being in 79% of residents and 73% of fellows, and 82% of residents felt that it positively impacted education. CONCLUSION: As compared with the traditional home call system, an in-house night critical care fellow can improve the perception of patient care, trainee well-being, and education in a tertiary ICU at an academic hospital

Prognostic significance of infections in critically ill adult patients with acute liver injury: a retrospective cohort study

Background and aimsPatients with acute liver failure have high rates of infections, likely from defects in immune function. Whether infections are independently associated with poor outcomes is unclear. We hypothesized that patients with acute liver injury who developed infections were at increased risk of adverse outcomes.MethodsWe conducted a retrospective analysis of 150 critically ill adult patients admitted with acute liver dysfunction at a single academic institution between 2005 and 2011. We excluded patients with immunocompromised states, patients with chronic liver disease and patients who died or were discharged within 48 h of admission. Our primary endpoint was a 30-day event-free survival, with events defined as either death or liver transplantation. Our secondary endpoint was length of stay. Univariate and multivariate analyses were performed to determine associations between presence of infection and our primary and secondary endpoints.ResultsOf our cohort of 150 patients, 62 (41%) were infected and 88 (59%) were not infected. Of the infected patients, 45% died or underwent transplantation, compared to 22% for the non-infected patients (P = 0.003). Univariate and multivariate analyses demonstrated that infections in patients with acute liver dysfunction were an independent predictor of poor outcome (i.e. death or transplantation). In addition, specific types of infection, including pneumonia, independently led to a 48% increase in length of stay (P = 0.002).ConclusionsInfections in patients with acute liver dysfunction are associated with increased risk of death or transplant and increased hospital length of stay