Publications by authors named "Meghan E Kapp"

23 Publications

  • Page 1 of 1

Polyomavirus nephropathy with crescent formation.

Kidney Int 2021 Oct;100(4):953

Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.03.006DOI Listing
October 2021

Assessment of the Banff Working Group classification of definitive BK polyomavirus nephropathy.

Transpl Int 2021 Nov 2;34(11):2286-2296. Epub 2021 Sep 2.

Department of Medicine, Division of Nephrology, Eastern Virginia Medical School, Norfolk, VA, USA.

Polyomavirus associated nephropathy (PyVAN) continues to be a burden in renal transplantation leading to allograft insufficiency or graft failure. A presumptive diagnosis of PyVAN is made based on the presence of BK polyomavirus in patients' plasma; however, kidney biopsy remains the gold standard to establish a definitive diagnosis. The Banff Working Group on PyVAN proposed a novel classification of definitive PyVAN based on polyomavirus replication/load level and the extent of interstitial fibrosis. The aim of our study was to test the newly defined classes of PyVAN using independent cohorts of 124 kidney transplant patients with PyVAN with respect to the initial presentation and outcome, and to compare our analysis to that previously reported. Detailed analysis of our cohort revealed that the proposed classification of PyVAN did not stratify or identify patients at increased risk of allograft failure. Specifically, while class 3 was associated with the worst prognosis, there was no significant difference between the outcomes in classes 1 and 2. We also found that the timing post-transplantation and inflammation in areas of interstitial fibrosis and tubular atrophy might be additional factors contributing to an unfavorable allograft outcome in patients with PyVAN.
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http://dx.doi.org/10.1111/tri.14003DOI Listing
November 2021

Chloroquine Cardiotoxicity Leading to Cardiogenic Shock.

JACC Case Rep 2020 Dec 25;2(15):2381-2386. Epub 2020 Nov 25.

Division of Cardiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

A patient with a history of heart block and longstanding chloroquine use presented in cardiogenic shock refractory to medical therapy and mechanical circulatory support. Autopsy supported antimalarial-induced cardiomyopathy (AMIC). Progression of AMIC may be halted with early recognition and cessation of antimalarial therapy, highlighting importance of screening and timely diagnosis. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.09.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304572PMC
December 2020

Renal Considerations in COVID-19: Biology, Pathology, and Pathophysiology.

ASAIO J 2021 10;67(10):1087-1096

Departments of Medicine and Biomedical Engineering, Sarver Heart Center, University of Arizona, Tucson, Arizona.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.
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http://dx.doi.org/10.1097/MAT.0000000000001530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478105PMC
October 2021

Histopathological findings and clinicopathologic correlation in COVID-19: a systematic review.

Mod Pathol 2021 09 24;34(9):1614-1633. Epub 2021 May 24.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) pandemic has had devastating effects on global health and worldwide economy. Despite an initial reluctance to perform autopsies due to concerns for aerosolization of viral particles, a large number of autopsy studies published since May 2020 have shed light on the pathophysiology of Coronavirus disease 2019 (COVID-19). This review summarizes the histopathologic findings and clinicopathologic correlations from autopsies and biopsies performed in patients with COVID-19. PubMed and Medline (EBSCO and Ovid) were queried from June 4, 2020 to September 30, 2020 and histopathologic data from autopsy and biopsy studies were collected based on 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 58 studies reporting 662 patients were included. Demographic data, comorbidities at presentation, histopathologic findings, and virus detection strategies by organ system were collected. Diffuse alveolar damage, thromboembolism, and nonspecific shock injury in multiple organs were the main findings in this review. The pathologic findings emerging from autopsy and biopsy studies reviewed herein suggest that in addition to a direct viral effect in some organs, a unifying pathogenic mechanism for COVID-19 is ARDS with its known and characteristic inflammatory response, cytokine release, fever, inflammation, and generalized endothelial disturbance. This study supports the notion that autopsy studies are of utmost importance to our understanding of disease features and treatment effect to increase our knowledge of COVID-19 pathophysiology and contribute to more effective treatment strategies.
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http://dx.doi.org/10.1038/s41379-021-00814-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141548PMC
September 2021

Diagnostic renal mass biopsy is associated with individual categories of PADUA and RENAL nephrometry scores: Analysis of diagnostic and concordance rates with surgical resection.

Urol Oncol 2021 06 26;39(6):371.e7-371.e15. Epub 2021 Mar 26.

Vanderbilt University Medical Center, Department of Pathology, Immunology, and Microbiology; Nashville, TN. Electronic address:

Background: Renal mass biopsy (RMB) is a safe and accurate method for diagnosis and clinical management of renal masses. However, the non-diagnostic rate is a limiting factor. We tested the hypothesis that imaging characteristics and anatomic complexity of the mass may impact RMB diagnostic outcome using the preoperative aspects and dimensions used for an anatomical (PADUA) classification and radius-exophytic/endophytic-nearness-anterior/posterior-location (RENAL) score.

Material And Methods: Single institution, retrospective study of 490 renal masses from 443 patients collected from 2001 to 2018. Outcome measurements include (1) diagnostic and concordance rates amongst RMB types and RMB with surgical resection specimens; (2) association between diagnostic RMB and anatomical complexity of renal masses. The analysis was conducted in unselected masses and small renal masses (SRMs).

Results: RMB was performed by fine needle aspiration (FNA), core needle biopsy (CNB), or both (FNA+CNB). Non-diagnostic rate was significantly higher for FNA compared to CNB and FNA+CNB in both unselected and SRMs. Subset analysis in the FNA+CNB group showed similar diagnostic rates for FNA and CNB. In unselected masses, specificity for FNA, CNB, and FNA+CNB was 100%. Sensitivity was higher for CNB (90.1%, P = 0.002) and FNA+CNB (96.3%, P = 0.004) compared to FNA (66.7%). For unselected masses, endophytic growth predicted a non-diagnostic CNB. R.E.N.A.L location entirely between the polar lines (central) and entirely above the upper polar line predicted a diagnostic CNB. Sonography-guidance predicted a diagnostic FNA. For SRMs, non-diagnostic CNB was associated with endophytic growth, while diagnostic CNB was associated with renal sinus invasion and operator experience. More cystic masses were sampled by FNA, but diagnostic results were similar for FNA and CNB.

Conclusions: Endophytic growth consistently predicted a non-diagnostic CNB in unselected and SRMs, whereas sonography-guidance predicted a diagnostic FNA. Cystic masses could be adequately sampled by FNA.
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http://dx.doi.org/10.1016/j.urolonc.2021.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205938PMC
June 2021

Educational Case: AA Amyloidosis Complicating Common Variable Immunodeficiency.

Acad Pathol 2021 Jan-Dec;8:2374289521994236. Epub 2021 Feb 27.

Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

http://journals.sagepub.com/doi/10.1177/2374289517715040..
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http://dx.doi.org/10.1177/2374289521994236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923970PMC
February 2021

Spectrum of Kidney Diseases in Patients With Hepatitis C Virus Infection.

Am J Clin Pathol 2021 Aug;156(3):399-408

Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Objectives: To study the pathologic spectrum of kidney diseases in patients with hepatitis C virus infection (HCV+).

Methods: Native kidney biopsy specimens in HCV+ patients were reviewed.

Results: A total of 9,836 native kidney biopsy specimens were evaluated from January 2007 to December 2016, of which 273 (2.8%) were from HCV+ patients, and of these, 115 (42.1%) had diagnoses consistent with HCV-associated glomerulonephritis (GN). Non-HCV-associated kidney diseases comprised most diagnoses (158 cases, 57.9%) including non-immune complex-mediated kidney diseases (127 cases, 46.5%) and other immune complex-mediated glomerular diseases (31 cases, 11.4%). Forty-one (40.6%) patients had HCV-associated GN among 101 HCV+ patients from 2007 to 2011 vs 74 (43.0%) patients with HCV-associated GN among 172 HCV+ patients from 2012 to 2016. HCV-associated GN showed five morphologic patterns: focal proliferative (5.2%), diffuse mesangial proliferative (50.4%), diffuse membranoproliferative (28.7%), proliferative GN with crescentic lesions (7.8%), and membranous patterns (7.8%).

Conclusions: We found a spectrum of pathologic changes in renal biopsy specimens of HCV+ patients, with most having diseases unrelated to HCV infection, HCV-associated GN showing five morphologic patterns, and availability of effective HCV antiviral therapy not yet resulting in major changes in the spectrum of kidney diseases in these patients.
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http://dx.doi.org/10.1093/ajcp/aqaa238DOI Listing
August 2021

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study.

Arch Pathol Lab Med 2021 05;145(5):529-535

The Department of Pathology and Cell Biology, Columbia University, New York, New York (Sekulic).

Context.—: This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting.

Objective.—: To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy.

Design.—: Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses.

Results.—: Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited.

Conclusions.—: Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.
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http://dx.doi.org/10.5858/arpa.2020-0786-SADOI Listing
May 2021

Instance segmentation for whole slide imaging: end-to-end or detect-then-segment.

J Med Imaging (Bellingham) 2021 Jan 7;8(1):014001. Epub 2021 Jan 7.

Vanderbilt University, Department of Electrical Engineering and Computer Science, Nashville, United States.

Automatic instance segmentation of glomeruli within kidney whole slide imaging (WSI) is essential for clinical research in renal pathology. In computer vision, the end-to-end instance segmentation methods (e.g., Mask-RCNN) have shown their advantages relative to detect-then-segment approaches by performing complementary detection and segmentation tasks simultaneously. As a result, the end-to-end Mask-RCNN approach has been the standard method in recent glomerular segmentation studies, where downsampling and patch-based techniques are used to properly evaluate the high-resolution images from WSI (e.g., on ). However, in high-resolution WSI, a single glomerulus itself can be more than in original resolution which yields significant information loss when the corresponding features maps are downsampled to the resolution via the end-to-end Mask-RCNN pipeline. We assess if the end-to-end instance segmentation framework is optimal for high-resolution WSI objects by comparing Mask-RCNN with our proposed detect-then-segment framework. Beyond such a comparison, we also comprehensively evaluate the performance of our detect-then-segment pipeline through: (1) two of the most prevalent segmentation backbones (U-Net and DeepLab_v3); (2) six different image resolutions ( , , , , , and ); and (3) two different color spaces (RGB and LAB). Our detect-then-segment pipeline, with the DeepLab_v3 segmentation framework operating on previously detected glomeruli of resolution, achieved a 0.953 Dice similarity coefficient (DSC), compared with a 0.902 DSC from the end-to-end Mask-RCNN pipeline. Further, we found that neither RGB nor LAB color spaces yield better performance when compared against each other in the context of a detect-then-segment framework. The detect-then-segment pipeline achieved better segmentation performance compared with the end-to-end method. Our study provides an extensive quantitative reference for other researchers to select the optimized and most accurate segmentation approach for glomeruli, or other biological objects of similar character, on high-resolution WSI.
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http://dx.doi.org/10.1117/1.JMI.8.1.014001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790159PMC
January 2021

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 Are Expressed in the Microvasculature and Ducts of Human Pancreas but Are Not Enriched in β Cells.

Cell Metab 2020 12 13;32(6):1028-1040.e4. Epub 2020 Nov 13.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address:

Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into β cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single β cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in β cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects β cells in vivo through ACE2 and TMPRSS2.
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http://dx.doi.org/10.1016/j.cmet.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664344PMC
December 2020

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium.

J Clin Invest 2021 01;131(1)

Department of Pediatrics.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.
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http://dx.doi.org/10.1172/JCI140766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773394PMC
January 2021

Kidney epithelial targeted mitochondrial transcription factor A deficiency results in progressive mitochondrial depletion associated with severe cystic disease.

Kidney Int 2021 03 4;99(3):657-670. Epub 2020 Nov 4.

Department of Medicine, Vanderbilt University Medical Center and Vanderbilt University School of Medicine, Nashville, Tennessee, USA; The Vanderbilt O'Brien Kidney Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA; Department of Molecular Physiology and Biophysics, and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. Electronic address:

Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. TFAM deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation and the development of severe postnatal cystic disease, which resulted in premature death. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption and increased glycolytic flux. Furthermore, we found that TFAM expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis.
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http://dx.doi.org/10.1016/j.kint.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209657PMC
March 2021

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells.

bioRxiv 2020 Oct 20. Epub 2020 Oct 20.

Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. and transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.
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http://dx.doi.org/10.1101/2020.08.31.275719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587777PMC
October 2020

Rapidly fatal pneumonitis from immunotherapy and concurrent SARS-CoV-2 infection in a patient with newly diagnosed lung cancer.

medRxiv 2020 May 1. Epub 2020 May 1.

Immune checkpoint inhibitors (ICIs) are used for the treatment of numerous cancers, but risks associated with ICI-therapy during the COVID-19 pandemic are poorly understood. We report a case of acute lung injury in a lung cancer patient initially treated for ICI-pneumonitis and later found to have concurrent SARS-CoV-2 infection. Post-mortem analyses revealed diffuse alveolar damage in both the acute and organizing phases, with a predominantly CD68+ inflammatory infiltrate. Serum was positive for anti-SARS-CoV-2 IgG, suggesting that viral infection predated administration of ICI-therapy and may have contributed to a more fulminant clinical presentation. These data suggest the need for routine SARS-CoV-2 testing in cancer patients, where clinical and radiographic evaluations may be non-specific.
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http://dx.doi.org/10.1101/2020.04.29.20085738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276992PMC
May 2020

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 infection in the lung epithelium.

bioRxiv 2020 Aug 3. Epub 2020 Aug 3.

Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN.

The SARS-CoV-2 novel coronavirus global pandemic (COVID-19) has led to millions of cases and hundreds of thousands of deaths around the globe. While the elderly appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of the developing mouse lung with temporally-resolved RNA-in-situ hybridization (ISH) in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer was highest in ciliated cells and type I alveolar epithelial cells (AT1), and expression was increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases revealed SARS-CoV-2 RNA was detected most frequently in ciliated and secretory cells in the airway epithelium and AT1 cells in the peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing . Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in the lung epithelium, and suggest that developmental regulation of may underlie the relative protection of infants and children from severe respiratory illness.
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http://dx.doi.org/10.1101/2020.05.22.111187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263492PMC
August 2020

Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction.

J Clin Immunol 2020 05 17;40(4):554-566. Epub 2020 Apr 17.

Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.
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http://dx.doi.org/10.1007/s10875-020-00778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253386PMC
May 2020

Standardization in the MSPE: Key Tensions for Learners, Schools, and Residency Programs.

Acad Med 2021 01;96(1):44-49

R. Sterling is associate professor, Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; ORCID: https://orcid.org/0000-0003-2963-3162.

The Medical Student Performance Evaluation (MSPE), which summarizes a medical student's academic and professional undergraduate medical education performance and provides salient information during the residency selection process, faces persistent criticisms regarding heterogeneity and obscurity. Specifically, MSPEs do not always provide the same type or amount of information about students, especially from diverse schools, and important information is not always easy to find or interpret. To address these concerns, a key guiding principle from the Recommendations for Revising the MSPE Task Force of the Association of American Medical Colleges (AAMC) was to achieve "a level of standardization and transparency that facilitates the residency selection process." Benefits of standardizing the MSPE format include clarification of performance benchmarks or metrics, consistency across schools to enhance readability, and improved quality. In medical education, standardization may be an important mechanism to ensure accountability of the system for all learners, including those with varied backgrounds and socioeconomic resources. In this article, members of the aforementioned AAMC MSPE task force explore 5 tensions inherent in the pursuit of standardizing the MSPE: (1) presenting each student's individual characteristics and strengths in a way that is relevant, while also working with a standard format and providing standard content; (2) showcasing school-specific curricular strengths while also demonstrating standard evidence of readiness for internship; (3) defining and achieving the right amount of standardization so that the MSPE provides useful information, adds value to the residency selection process, and is efficient to read and understand; (4) balancing reporting with advocacy; and (5) maintaining standardization over time, especially given the tendency for the MSPE format and content to drift. Ongoing efforts to promote collaboration and trust across the undergraduate to graduate medical education continuum offer promise to reconcile these tensions and promote successful educational outcomes.
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http://dx.doi.org/10.1097/ACM.0000000000003290DOI Listing
January 2021

Association of medication non-adherence with short-term allograft loss after the treatment of severe acute kidney transplant rejection.

BMC Nephrol 2019 10 17;20(1):373. Epub 2019 Oct 17.

Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, 1161 21st Ave. S., MCN S-3223, Nashville, TN, 37232, USA.

Background: Medication non-adherence is a risk factor for acute kidney transplant rejection. The association of non-adherence with short-term allograft loss in patients who develop acute rejection and are subsequently treated with maximal therapy is unknown.

Methods: We conducted a retrospective single center cohort study of adult patients who developed acute rejection from January 2003 to December 2017 and were treated with lymphocyte depletion. Clinicopathologic characteristics including adherence status were collected and descriptive statistics utilized to compare groups. The primary outcome was all-cause graft loss at 6 months after acute rejection treatment. A multivariable logistic regression quantified the association of non-adherence with the outcome.

Results: A total of 182 patients were included in the cohort, of whom 71 (39%) were non-adherent. Compared to adherent patients, non-adherent patients were younger (mean age 37y vs 42y), more likely to be female (51% vs 35%) and developed acute rejection later (median 2.3y vs 0.5y from transplant). There were no differences in estimated glomerular filtration rate or need for dialysis on presentation, Banff grade, or presence of antibody mediated rejection between the 2 groups. Overall, 48 (26%) patients lost their grafts at 6 months after acute rejection treatment. In adjusted analysis, non-adherence was associated with all-cause graft loss at 6 months after acute rejection treatment [OR 2.64 (95% CI 1.23-5.65, p = 0.012].

Conclusions: After adjusting for common confounders, non-adherent patients were at increased risk for short-term allograft loss after a severe acute rejection despite lymphocyte depletion. This finding may aid clinicians in risk stratifying patients for poor short-term outcomes and treatment futility.
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http://dx.doi.org/10.1186/s12882-019-1563-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796330PMC
October 2019

Genomic landscape of a metastatic malignant proliferating tricholemmal tumor and its response to PI3K inhibition.

NPJ Precis Oncol 2019 15;3. Epub 2019 Feb 15.

Division of Hematology/Oncology, Department of Medicine, Nashville, TN USA.

Proliferating tricholemmal tumors (PTTs) are rare benign neoplasms that arise from the outer sheath of a hair follicle. Occasionally, these PTTs undergo malignant transformation to become malignant proliferating tricholemmal tumors (MPTTs). Little is known about the molecular alterations, malignant progression, and management of MPTTs. Here, we describe the case of a 58-year-old female that had a widely metastatic MPTT that harbored an activating mutation and was sensitive to the PI3K inhibitor, alpelisib (BYL719). We review the available literature on metastatic MPTT, detail the patient's course, and present a whole genome analysis of this rare tumor.
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http://dx.doi.org/10.1038/s41698-019-0077-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377617PMC
February 2019

A unique evolution of the kidney phenotype in a patient with autosomal recessive Alport syndrome.

Hum Pathol 2018 11 9;81:229-234. Epub 2018 Mar 9.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Electronic address:

Alport syndrome is due to mutations in one of the genes encoding (α3,4,5) type IV collagen resulting in defective type IV collagen, a key component of the glomerular basement membrane (GBM). The GBM is initially thin and, with ongoing remodeling, develops a thickened basket-woven appearance. We report a unique case of a 9-year-old boy who underwent biopsy for hematuria and proteinuria, diagnosed as IgA nephropathy, with normal GBM appearance and thickness. Because of a family history of hematuria and chronic kidney disease, he subsequently underwent genetic evaluation, and a mutation of α3 type IV collagen (COL4A3) was detected. Additional studies of the initial biopsy demonstrated abnormal type IV collagen immunostaining. A repeat biopsy 4 years later showed characteristic glomerular basement membrane morphology of Alport syndrome and scarring consistent with sequelae of IgA nephropathy. This is the first description of this unusual transition from an initial normal appearance of the glomerular basement membrane to the classic Alport phenotype.
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http://dx.doi.org/10.1016/j.humpath.2018.02.024DOI Listing
November 2018

Core Needle Biopsy and Fine Needle Aspiration Alone or in Combination: Diagnostic Accuracy and Impact on Management of Renal Masses.

J Urol 2017 06 16;197(6):1396-1402. Epub 2017 Jan 16.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address:

Purpose: Fine needle aspiration with and without concurrent core needle biopsy is a minimally invasive method to diagnose and assist in management of renal masses. We assessed the pathological accuracy of fine needle aspiration compared to and associated with core needle biopsy and the impact on management.

Materials And Methods: We performed a single institution, retrospective study of 342 cases from 2001 to 2015 with small and large renal masses (4 or less and greater than 4 cm, respectively). Diagnostic and concordance rates, and the impact on management were analyzed.

Results: Adequacy rates for fine needle aspiration only, core needle biopsy only and fine needle aspiration plus core needle biopsy were 21%, 12% and 8% (aspiration vs aspiration plus biopsy p <0.026). In the aspiration plus biopsy group adding aspiration to biopsy and biopsy to aspiration reduced the inadequacy rate from 23% to 8% and from 27% to 8% for a total reduction rate of 15% and 19%, respectively, corresponding to 32 cases (9.3%). Rapid on-site examination contributed to a 22.5% improvement in fine needle aspiration adequacy rates. In this cohort 30% of aspiration only, 5% of biopsy only and 12% of aspiration plus biopsy could not be subtyped (aspiration vs biopsy p <0.0001, aspiration vs aspiration plus biopsy p <0.0127 and biopsy vs aspiration plus biopsy p = 0.06). The diagnostic concordance rate with surgical resection was 99%. Conversion of an inadequate specimen to an adequate one by a concurrent procedure impacted treatment in at least 29 of 32 patients. Limitations include the retrospective design and accuracy measurement based on surgical intervention.

Conclusions: Fine needle aspiration plus core needle biopsy vs at least fine needle aspiration alone may improve diagnostic yield when sampling renal masses but it has subtyping potential similar to that of core needle biopsy only.
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http://dx.doi.org/10.1016/j.juro.2017.01.038DOI Listing
June 2017

Metastatic Breast Carcinoma to the Prostate Gland.

Case Rep Oncol Med 2016 26;2016:8264140. Epub 2016 Jun 26.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC) to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903) and no expression of P501S. The patient's previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors.
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http://dx.doi.org/10.1155/2016/8264140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939205PMC
July 2016
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