Publications by authors named "David A Schwartz"

412 Publications

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

Transl Res 2021 Sep 18. Epub 2021 Sep 18.

Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA. Electronic address:

While the coronavirus disease 19 (COVID-19) pandemic has transformed the medical and scientific communites since it was first reported in late 2019, we are only beginning to understand the chronic health burdens associated with this disease. Although COVID-19 is a multi-systemic disease, the lungs are the primary source of infection and injury, resulting in pneumonia and, in severe cases, acute respiratory distress syndrome (ARDS). Given that pulmonary fibrosis is a well-recognized sequela of ARDS, many have questioned whether COVID-19 survivors will face long-term pulmonary consequences. This review is aimed at integrating our understanding of the pathophysiologic mechanisms underlying fibroproliferative ARDS with our current knowledge of the pulmonary consequences of COVID-19 disease.
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http://dx.doi.org/10.1016/j.trsl.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452088PMC
September 2021

Health Care Costs and Resource Utilization Among Patients With Crohn's Disease With and Without Perianal Fistula.

Inflamm Bowel Dis 2021 Sep 15. Epub 2021 Sep 15.

Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Perianal fistula (PAF), a complication of Crohn's disease (CD), is associated with substantial economic costs and poor prognosis. We determined prevalence of PAF CD in the United States and compared costs and health care resource utilization (HRU) of PAF CD patients with matched non-PAF CD patients.

Methods: This was a retrospective cohort study of claims data from the IBM MarketScan Commercial Database from October 1, 2015, to September 30, 2018. Eligible patients were aged 18 to 89 years with ≥2 CD diagnoses. Patients with PAF CD had ≥1 PAF diagnosis or procedure code and were matched with non-PAF CD patients. Cumulative prevalence of PAF CD in the US population was calculated across total patients in MarketScan. All-cause and gastrointestinal (GI)-related costs and HRU were compared between groups using a generalized linear model (GLM).

Results: Cumulative 3-year prevalence of PAF was 7.70% of patients with CD (N = 81,862) and 0.01% of the US population. Among PAF CD (n = 1218) and matched non-PAF CD (n = 4095) patients, most all-cause costs and HRU were GI-related. Mean total all-cause and GI-related health care costs per patient and per year for PAF CD were $85,233 and $71,612, respectively, vs $40,526 and $29,458 for non-PAF CD (P < .0001). Among PAF CD vs non-PAF CD patients, GLM-adjusted proportions of patients with GI-related inpatient, outpatient, or pharmacy visits, mean GI-related inpatient length of stay, and mean GI-related surgeries were higher (P < .0001 for all comparisons).

Conclusions: Costs and HRU are significantly higher for patients with PAF CD vs non-PAF CD patients, highlighting the economic burden of the disease.
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http://dx.doi.org/10.1093/ibd/izab198DOI Listing
September 2021

Molecular Pathology Demonstration of SARS-CoV-2 in Cytotrophoblast from Placental Tissue with Chronic Histiocytic Intervillositis, Trophoblast Necrosis and COVID-19.

J Dev Biol 2021 Aug 25;9(3). Epub 2021 Aug 25.

Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.

A subset of placentas from pregnant women having the SARS-CoV-2 infection have been found to be infected with the coronavirus using molecular pathology methods including immunohistochemistry and RNA in situ hybridization. These infected placentas can demonstrate several unusual findings which occur together-chronic histiocytic intervillositis, trophoblast necrosis and positive staining of the syncytiotrophoblast for SARS-CoV-2. They frequently also have increased fibrin deposition, which can be massive in some cases. Syncytiotrophoblast is the most frequent fetal-derived cell type to be positive for SARS-CoV-2. It has recently been shown that in a small number of infected placentas, villous stromal macrophages, termed Hofbauer cells, and villous capillary endothelial cells can also stain positive for SARS-CoV-2. This report describes a placenta from a pregnant woman with SARS-CoV-2 that had chronic histiocytic intervillositis, trophoblast necrosis, increased fibrin deposition and positive staining of the syncytiotrophoblast for SARS-CoV-2. In addition, molecular pathology testing including RNAscope and immunohistochemistry for SARS-CoV-2 and double-staining immunohistochemistry using antibodies to E-cadherin and GATA3 revealed that cytotrophoblast cells stained intensely for SARS-CoV-2. All of the cytotrophoblast cells that demonstrated positive staining for SARS-CoV-2 were in direct physical contact with overlying syncytiotrophoblast that also stained positive for the virus. The pattern of cytotrophoblast staining for SARS-CoV-2 was patchy, and there were chorionic villi having diffuse positive staining of the syncytiotrophoblast for SARS-CoV-2, but without staining of cytotrophoblast. This first detailed description of cytotrophoblast involvement by SARS-CoV-2 adds another fetal cell type from infected placentas that demonstrate viral staining.
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http://dx.doi.org/10.3390/jdb9030033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395857PMC
August 2021

Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium.

Lancet Gastroenterol Hepatol 2021 Oct 18;6(10):826-849. Epub 2021 Aug 18.

Division of Gastroenterology, Hepatology, and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA.

Restorative proctocolectomy with ileal pouch-anal anastomosis is an option for most patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the construction of an ileal pouch substantially improves patients' health-related quality of life, the surgery is, directly or indirectly, associated with various structural, inflammatory, and functional adverse sequelae. Furthermore, the surgical procedure does not completely abolish the risk for neoplasia. Patients with ileal pouches often present with extraintestinal, systemic inflammatory conditions. The International Ileal Pouch Consortium was established to create this consensus document on the diagnosis and classification of ileal pouch disorders using available evidence and the panellists' expertise. In a given individual, the condition of the pouch can change over time. Therefore, close monitoring of the activity and progression of the disease is essential to make accurate modifications in the diagnosis and classification in a timely manner.
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http://dx.doi.org/10.1016/S2468-1253(21)00101-1DOI Listing
October 2021

MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression.

Semin Arthritis Rheum 2021 Oct 10;51(5):996-1004. Epub 2021 Jul 10.

Université de Paris, AP-HP, Hôpital Avicenne, Service de Pneumologie, Bobigny, France.

Background: The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD.

Methods: Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline.

Results: Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern.

Conclusion: In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.
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http://dx.doi.org/10.1016/j.semarthrit.2021.07.002DOI Listing
October 2021

Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional.

Nat Commun 2021 07 27;12(1):4566. Epub 2021 Jul 27.

Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.
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http://dx.doi.org/10.1038/s41467-021-24853-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316442PMC
July 2021

Hofbauer cells and coronavirus disease 2019 (COVID-19) in pregnancy: Molecular pathology analysis of villous macrophages, endothelial cells, and placental findings from 22 placentas infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with and without fetal transmission.

Arch Pathol Lab Med 2021 Jul 23. Epub 2021 Jul 23.

Obstetrics & Gynecology, Skåne University Hospital, Malmö, Sweden and Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

Context: - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can undergo maternal-fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARSCoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases including HIV and Zika virus, but their involvement in SARS-CoV-2 in unknown.

Objective: - To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium and other villous stromal cells in infected placentas of liveborn and stillborn infants.

Design: - Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2-infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast and other fetal-derived cells.

Results: - Chronic histiocytic intervillositis and trophoblast necrosis was present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4/22 placentas (18%). Villous capillary endothelial staining was positive in 2/22 cases (9%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21/22 placentas (95%). Hofbauer cell hyperplasia was present in 3/22 placentas (14%). In the 7 cases having documented transplacental infection of the fetus, 2 occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2.

Conclusions: - SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement.
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http://dx.doi.org/10.5858/arpa.2021-0296-SADOI Listing
July 2021

Safety and Efficacy of Vedolizumab Versus Tumor Necrosis Factor α Antagonists in an Elderly IBD Population: A Single Institution Retrospective Experience.

Dig Dis Sci 2021 Jul 15. Epub 2021 Jul 15.

Division of Internal Medicine, Department of Gastroenterology, Vanderbilt Inflammatory Bowel Diseases Center, Vanderbilt University Medical Center, 719 Thompson Lane, Suite 20500, Nashville, TN, 37204, USA.

Background: Vedolizumab is a monoclonal antibody used to treat inflammatory bowel disease (IBD). There is little known about the safety and comparative efficacy of this agent in the elderly population.

Aims: Here, we present data on the safety and comparative efficacy of vedolizumab versus tumor necrosis factor α antagonists (anti-TNF) in elderly patients with IBD.

Methods: This retrospective cohort study included IBD patients started on vedolizumab or anti-TNF at age 60 or older at a single tertiary IBD center. Safety was evaluated by assessing for the development of serious infection. The comparative needs for IBD-related surgery, IBD-related hospitalization, and drug discontinuation for any reason were obtained. Efficacy was assessed by comparing changes in endoscopic, histologic, and patient-report outcomes.

Results: 212 cases were identified-108 patients treated with vedolizumab and 104 patients treated with anti-TNF. There were no significant differences between cohorts in serious infection, surgical intervention, or IBD-hospitalization-free survival (p = NS). Drug discontinuation survival was different between anti-TNF and vedolizumab (p = 0.02) with more patients remaining on vedolizumab at the time of last follow-up (51.9% vs. 25.9%). Endoscopic remission and response rates were higher in the vedolizumab versus anti-TNF group (65.7% vs. 45.2%, p = 0.02; 80.0% vs. 59.3%, p < 0.001).

Conclusions: In a cohort of IBD patients over age 60, vedolizumab showed no statistically significant differences in infection, hospitalization, or surgical intervention-free survival as compared to anti-TNF. Vedolizumab was discontinued less frequently than anti-TNF. Patients on vedolizumab had higher rates of endoscopic remission and response.
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http://dx.doi.org/10.1007/s10620-021-07129-5DOI Listing
July 2021

Genetically increased circulating FUT3 level leads to reduced risk of Idiopathic Pulmonary Fibrosis: a Mendelian Randomisation Study.

Eur Respir J 2021 Jun 25. Epub 2021 Jun 25.

Department of Human Genetics, McGill University, Montréal, Québec, Canada

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments we used genetic determinants of circulating proteins which reside to the encoded gene (-SNPs), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalization analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.MR analyses of 834 proteins found that a one sd increase in circulating FUT3 and FUT5 was associated with a reduced risk of IPF (OR: 0.81, 95%CI: 0.74-0.88, p=6.3×10, and OR: 0.76, 95%CI: 0.68-0.86, p=1.1×10). Sensitivity analyses including multiple- SNPs provided similar estimates both for FUT3 (inverse variance weighted [IVW] OR: 0.84, 95%CI: 0.78-0.91, p=9.8×10, MR-Egger OR: 0.69, 95%CI: 0.50-0.97, p=0.03) and FUT5 (IVW OR: 0.84, 95%CI: 0.77-0.92, p=1.4×10, MR-Egger OR: 0.59, 95%CI: 0.38-0.90, p=0.01) FUT3 and FUT5 signals colocalized with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%. Further transcriptomic investigations supported the protective effects of for IPF.An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.
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http://dx.doi.org/10.1183/13993003.03979-2020DOI Listing
June 2021

Genes, other than Muc5b, play a role in bleomycin-induced lung fibrosis.

Am J Physiol Lung Cell Mol Physiol 2021 08 23;321(2):L440-L450. Epub 2021 Jun 23.

Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.

Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function promoter variant rs35705950 is the dominant genetic risk factor for IPF, yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of . Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for expression and lung fibrosis 3 wk after intratracheal bleomycin administration. Although we identified strains with low expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with and cause lung fibrosis.
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http://dx.doi.org/10.1152/ajplung.00615.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410112PMC
August 2021

Molecular Signatures of Idiopathic Pulmonary Fibrosis.

Am J Respir Cell Mol Biol 2021 May 26. Epub 2021 May 26.

University of Colorado, 1878, Department of Medicine, Denver, Colorado, United States.

Molecular patterns and pathways in idiopathic pulmonary fibrosis (IPF) have been extensively investigated but few studies have assimilated multi-omic platforms to provide an integrative understanding of molecular patterns that are relevant in IPF. Herein, we combine coding and non-coding transcriptome, DNA methylome, and proteome from IPF and healthy lung tissue to identify molecules and pathways associated with this disease. RNA sequencing, Illumina MethylationEPIC array, and liquid chromatography-mass spectrometry (LC-MS) proteomic data were collected on lung tissue from 24 IPF cases and 14 control subjects. Significant differential features were identified using linear models adjusting for age and sex, inflation and bias where appropriate. Data Integration Analysis for Biomarker discovery using a Latent component method for Omics studies (DIABLO) was used for integrative multi-omic analysis. We identified 4,643 differentially expressed transcripts aligning to 3,439 genes, 998 differentially abundant proteins, 2,500 differentially methylated regions (DMRs), and 1,269 differentially expressed lncRNAs that were significant after correcting for multiple tests (false discovery rate [FDR]<0.05). Unsupervised hierarchical clustering using 20 coding mRNA, protein, methylation, and lncRNA features with highest loadings on the top latent variable from the four datasets demonstrates perfect separation of IPF and control lungs. Our analysis confirmed previously validated molecules and pathways known to be dysregulated in disease, and implicated novel molecular features as potential drivers and modifiers of disease. For example, four proteins, 18 DMRs, and 10 lncRNAs were found to have strong correlations (|r|>0.8) with MMP7. Therefore, using a systems biology approach, we have identified novel molecular relationships in IPF.
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http://dx.doi.org/10.1165/rcmb.2020-0546OCDOI Listing
May 2021

A patient education intervention improved rates of successful video visits during rapid implementation of telehealth.

J Telemed Telecare 2021 May 11:1357633X211008786. Epub 2021 May 11.

Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, USA.

Introduction: The need to rapidly implement telehealth at large scale during the COVID-19 pandemic led to many patients using telehealth for the first time. We assessed the effect of structured pre-visit preparatory telephone calls on success of telehealth visits and examined risk factors for unsuccessful visits.

Methods: A retrospective cohort study was carried out of 45,803 adult patients scheduled for a total of 64,447 telehealth appointments between March and July 2020 at an academic medical center. A subset of patients received a structured pre-visit phone call. Demographic factors and inclusion of a pre-visit call were analysed by logistic regression. Primary outcomes were non-completion of any visit and completion of phone-only versus audio-visual telehealth visits.

Results: A pre-visit telephone call to a subset of patients significantly increased the likelihood of a successful telehealth visit (OR 0.54; 95% CI: 0.48-0.60). Patients aged 18-30 years, those with non-commercial insurance or those of Black race were more likely to have incomplete visits. Compared to age 18-30, increasing age increased likelihood of a failed video visit: 31-50 years (OR 1.31; 95% CI: 1.13-1.51), 51-70 years (OR 2.98; 2.60-3.42) and >70 years (OR 4.16; 3.58-4.82). Those with non-commercial insurance and those of Black race (OR 1.8; 95% CI 1.67-1.92) were more likely to have a failed video visit.

Discussion: A structured pre-call to patients improved the likelihood of a successful video visit during widespread adoption of telehealth. Structured pre-calls to patients may be an important tool to help reduce gaps in utilization among groups.
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http://dx.doi.org/10.1177/1357633X211008786DOI Listing
May 2021

Coronavirus Diseases in Pregnant Women, the Placenta, Fetus, and Neonate.

Adv Exp Med Biol 2021 ;1318:223-241

Boston University School of Medicine, Boston, MA, USA.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), is similar to two other coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), in causing life-threatening respiratory infections and systemic complications in both children and adults. As the COVID-19 pandemic has continued to spread globally, increasing numbers of pregnant women have become infected, raising concern not only for their health but also for the health of their infants. This chapter discusses the effects of coronavirus infections, e.g., MERS, SARS, and COVID 19, on pregnancy and describes the evolving knowledge of COVID 19 among pregnant women. The physiological changes that occur in pregnancy, especially changes in the immune system, are reviewed in terms of their effect on susceptibility to infectious diseases. The effects of COVID-19 on the placenta, fetus, and neonate are also reviewed, including potential clinical outcomes and issues relating to testing and diagnosis. The potential mechanisms of vertical transmission of the virus between pregnant women and their infants are analyzed, including intrauterine, intrapartum, and postpartum infections. Several recent studies have reported the detection of SARS-CoV-2 in tissues from the fetal side of the placenta, permitting the diagnosis of transplacental infection of the fetus by SARS-CoV-2. Placentas from infected mothers in which intrauterine transplacental transmission of SARS-CoV-2 has occurred demonstrate an unusual combination of pathology findings which may represent risk factors for placental as well as fetal infection.
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http://dx.doi.org/10.1007/978-3-030-63761-3_14DOI Listing
May 2021

Molecular Pathology Analysis of SARS-CoV-2 in Syncytiotrophoblast and Hofbauer Cells in Placenta from a Pregnant Woman and Fetus with COVID-19.

Pathogens 2021 Apr 15;10(4). Epub 2021 Apr 15.

Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.

A small number of neonates delivered to women with SARS-CoV-2 infection have been found to become infected through intrauterine transplacental transmission. These cases are associated with a group of unusual placental pathology abnormalities that include chronic histiocytic intervillositis, syncytiotrophoblast necrosis, and positivity of the syncytiotrophoblast for SARS-CoV-2 antigen or RNA. Hofbauer cells constitute a heterogeneous group of immunologically active macrophages that have been involved in transplacental infections that include such viral agents as Zika virus and human immunodeficiency virus. The role of Hofbauer cells in placental infection with SARS-CoV-2 and maternal-fetal transmission is unknown. This study uses molecular pathology techniques to evaluate the placenta from a neonate infected with SARS-CoV-2 via the transplacental route to determine whether Hofbauer cells have evidence of infection. We found that the placenta had chronic histiocytic intervillositis and syncytiotrophoblast necrosis, with the syncytiotrophoblast demonstrating intense positive staining for SARS-CoV-2. Immunohistochemistry using the macrophage marker CD163, SARS-CoV-2 nucleocapsid protein, and double staining for SARS-CoV-2 with RNAscope and anti-CD163 antibody, revealed that no demonstrable virus could be identified within Hofbauer cells, despite these cells closely approaching the basement membrane zone of the infected trophoblast. Unlike some other viruses, there was no evidence from this transmitting placenta for infection of Hofbauer cells with SARS-CoV-2.
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http://dx.doi.org/10.3390/pathogens10040479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071113PMC
April 2021

Endoscopic evaluation of surgically altered bowel in inflammatory bowel disease: a consensus guideline from the Global Interventional Inflammatory Bowel Disease Group.

Lancet Gastroenterol Hepatol 2021 06 17;6(6):482-497. Epub 2021 Apr 17.

Clinical and Research Centre for Inflammatory Bowel Disease, Clinical Centre ISCARE, Prague, Czech Republic.

The majority of patients with Crohn's disease and a proportion of patients with ulcerative colitis will ultimately require surgical treatment despite advances in diagnosis, therapy, and endoscopic interventions. The surgical procedures that are most commonly done include bowel resection with anastomosis, strictureplasty, faecal diversion, and ileal pouch. These surgical treatment modalities result in substantial alterations in bowel anatomy. In patients with inflammatory bowel disease, endoscopy plays a key role in the assessment of disease activity, disease recurrence, treatment response, dysplasia surveillance, and delivery of endoscopic therapy. Endoscopic evaluation and management of surgically altered bowel can be challenging. This consensus guideline delineates anatomical landmarks and endoscopic assessment of these landmarks in diseased and surgically altered bowel.
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http://dx.doi.org/10.1016/S2468-1253(20)30394-0DOI Listing
June 2021

In Reply.

Authors:
David A Schwartz

Arch Pathol Lab Med 2021 08;145(8):921-922

Department of Pathology, Medical College of Georgia, Augusta.

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http://dx.doi.org/10.5858/arpa.2021-0170-LEDOI Listing
August 2021

Demographic Factors Associated With Successful Telehealth Visits in Inflammatory Bowel Disease Patients.

Inflamm Bowel Dis 2021 Mar 26. Epub 2021 Mar 26.

Vanderbilt University Medical Center, Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Nashville, Tennessee, USA.

Background: This study evaluated synchronous audiovisual telehealth and audio-only visits for patients with inflammatory bowel disease (IBD) to determine frequency of successful telehealth visits and determine what factors increase the likelihood of completion.

Methods: Data were collected from March to July 2020 in a tertiary care adult IBD clinic that was transitioned to a fully telehealth model. A protocol for telehealth was implemented. A retrospective analysis was performed using electronic medical record (EMR) data. All patients were scheduled for video telehealth. If this failed, providers attempted to conduct the visit as audio only.

Results: Between March and July 2020, 2571 telehealth visits were scheduled for adult patients with IBD. Of these, 2498 (99%) were successfully completed by video or phone. Sixty percent were female, and the median age was 41 years. Eighty six percent of the population was white, 8% black, 2% other, and 4% were missing. Seventy-five percent had commercial insurance, 15% had Medicare, 5% had Medicaid, and 5% had other insurance. No significant factors were found for an attempted but completely failed visit. Using a multivariate logistic regression model, increasing age (odds ratio, 1.80; 95% CI, 1.55-2.08; P < 0.05), noncommercial insurance status (odds ratio, 1.89; 95% CI, 1.61-2.21; P < 0.05), and black race (odds ratio, 2.07; 95% CI, 1.38-3.08; P < 0.05) increased the likelihood of a video encounter failure.

Conclusions: There is a high success rate for telehealth within an IBD population with defined clinic protocols. Certain patient characteristics such as age, race, and health insurance type increase the risk of failure of a video visit.
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http://dx.doi.org/10.1093/ibd/izab068DOI Listing
March 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

Effects of tumor necrosis factor (TNF) gene polymorphisms on the association between smoking and lung function among workers in swine operations.

J Toxicol Environ Health A 2021 07 15;84(13):536-552. Epub 2021 Mar 15.

School of Public Health, University of Alberta, Edmonton, Canada.

Workers in swine operations may be at increased risk of developing respiratory problems. These respiratory conditions are more prevalent among workers who are smokers. Tumor necrosis factor () genes play an important role in human immune responses to various respiratory hazards. This study aimed to investigate whether polymorphisms in genes might alter the effects of smoking on lung function among workers in swine operations. Three hundred and seventy-four full-time workers from large swine operations and 411 non-farming rural dwellers in Saskatchewan were included in this study. Information on demographic and lifestyle characteristics, pulmonary function, and blood samples were obtained. Multiple linear regression analyses were used in the statistical analysis. Three promoter polymorphisms () in the gene were investigated. Only the interaction term between smoking status and was significant in the multiple regression models. Among workers with the polymorphism (TT+TC), current smokers exhibited significantly lower lung function than nonsmokers. These associations were not observed among workers with the wild-type (CC). These findings were not observed among non-farming rural dwellers. Data demonstrated the possible involvement of gene in (1) development of adverse respiratory conditions among workers who are smokers, (2) importance of smoking cessation among workers, especially those with polymorphisms in the gene, and (3) potential implications in treatment, screening, and prevention.
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http://dx.doi.org/10.1080/15287394.2021.1896404DOI Listing
July 2021

Advancing Diversity, Equity, and Inclusion in Hospital Medicine.

J Hosp Med 2021 04;16(4):198-203

Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.

Background: In nearly all areas of academic medicine, disparities still exist for women and underrepresented minorities (URMs).

Objectives: Develop a strategic plan for advancing diversity, equity, and inclusion (DEI); implement and evaluate the plan, specifically focusing on compensation, recruitment, and policies.

Design, Setting, Participants: Programmatic evaluation conducted in the division of hospital medicine (DHM) at a major academic medical center involving DHM faculty and staff.

Measurements: (1) Development and implementation of strategic plan, including policies, processes, and practices related to key components of DEI program; (2) assessment of specific DEI outcomes, including plan implementation, pre-post salary data disparities based on academic rank, and pre-post disparities for protected time for similar roles.

Results: Using information gathered from a focus group with DHM faculty, an iterative strategic plan for DEI was developed and deployed, with key components of focus being institutional structures, our people, our environments, and our core mission areas. A director of DEI was established to help oversee these efforts. Using a two-phase approach, salary disparities by rank were eliminated. Internally funded protected time was standardized for leadership roles. A data dashboard has been developed to track high-level successes and areas for future focus.

Conclusion: Using a systematic evidence-based approach with key stakeholder involvement, a division-wide DEI strategy was developed and implemented. While this work is ongoing, short-term wins are possible, in particular around salary equity and development of policies and structures to promote DEI.
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http://dx.doi.org/10.12788/jhm.3574DOI Listing
April 2021

COVID-19: A Time to Reinvest in Our Scientists.

Am J Respir Crit Care Med 2021 05;203(9):1190-1191

University of Colorado Aurora, Colorado.

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http://dx.doi.org/10.1164/rccm.202012-4497LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314905PMC
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Identification of Influential Variants in Significant Aggregate Rare Variant Tests.

Hum Hered 2021 Feb 10:1-13. Epub 2021 Feb 10.

Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA.

Introduction: Studies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association.

Methods: In addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation, and SD. We performed 1,000 simulations for 50 regions of size 3 kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to 2 existing methods: adaptive combination of p values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF).

Results: All outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 < minor allele frequency, MAF > 0.03) compared to very rare variants (MAF <0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to 2 regions found previously associated with IPF including 100 rare variants, we identified 6 polymorphisms with the greatest evidence for influencing the association with IPF.

Discussion: In summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.
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http://dx.doi.org/10.1159/000513290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353006PMC
February 2021

The Public Health and Clinical Importance of Accurate Neonatal Testing for COVID-19.

Pediatrics 2021 02;147(2)

Hôpital Antoine Béclère, Université Paris Saclay, Paris, France.

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http://dx.doi.org/10.1542/peds.2020-036871DOI Listing
February 2021

Genetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into Immunopathogenesis.

J Inflamm Res 2020 5;13:1305-1318. Epub 2021 Jan 5.

Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.

Idiopathic pulmonary fibrosis is an etiologically complex interstitial lung disease characterized by progressive scarring of the lungs with a subsequent decline in lung function. While much of the pathogenesis of IPF still remains unclear, it is now understood that genetic variation accounts for at least one-third of the risk of developing the disease. The single-most validated and most significant risk factor, genetic or otherwise, is a gain-of-function promoter variant in the gene. While the functional impact of these IPF risk variants at the cellular and tissue levels are areas of active investigation, there is a growing body of evidence that these genetic variants may influence disease pathogenesis through modulation of innate immune processes.
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http://dx.doi.org/10.2147/JIR.S280958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801923PMC
January 2021

Molecular markers of telomere dysfunction and senescence are common findings in the usual interstitial pneumonia pattern of lung fibrosis.

Histopathology 2021 Jul 14;79(1):67-76. Epub 2021 Apr 14.

Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, CO, USA.

Aims: Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.

Methods And Results: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.

Conclusions: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.
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http://dx.doi.org/10.1111/his.14334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195814PMC
July 2021

Chronic Histiocytic Intervillositis With Trophoblast Necrosis Is a Risk Factor Associated With Placental Infection From Coronavirus Disease 2019 (COVID-19) and Intrauterine Maternal-Fetal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission in Live-Born and Stillborn Infants.

Arch Pathol Lab Med 2021 05;145(5):517-528

The Department of Obstetrics and Gynecology, Antoine Béclère Hospital, APHP, Université Paris Saclay, Clamart, France (Vivanti).

Context.—: The number of neonates with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is increasing, and in a few there are reports of intrauterine infection.

Objective.—: To characterize the placental pathology findings in a preselected cohort of neonates infected by transplacental transmission arising from maternal infection with SARS-CoV-2, and to identify pathology risk factors for placental and fetal infection.

Design.—: Case-based retrospective analysis by a multinational group of 19 perinatal specialists of the placental pathology findings from 2 cohorts of infants delivered to mothers testing positive for SARS-CoV-2: live-born neonates infected via transplacental transmission who tested positive for SARS-CoV-2 after delivery and had SARS-CoV-2 identified in cells of the placental fetal compartment by molecular pathology, and stillborn infants with syncytiotrophoblast positive for SARS-CoV-2.

Results.—: In placentas from all 6 live-born neonates acquiring SARS-CoV-2 via transplacental transmission, the syncytiotrophoblast was positive for coronavirus using immunohistochemistry, RNA in situ hybridization, or both. All 6 placentas had chronic histiocytic intervillositis and necrosis of the syncytiotrophoblast. The 5 stillborn/terminated infants had placental pathology findings that were similar, including SARS-CoV-2 infection of the syncytiotrophoblast, chronic histiocytic intervillositis, and syncytiotrophoblast necrosis.

Conclusions.—: Chronic histiocytic intervillositis together with syncytiotrophoblast necrosis accompanies SARS-CoV-2 infection of syncytiotrophoblast in live-born and stillborn infants. The coexistence of these 2 findings in all placentas from live-born infants acquiring their infection prior to delivery indicates that they constitute a pathology risk factor for transplacental fetal infection. Potential mechanisms of infection of the placenta and fetus with SARS-CoV-2, and potential future studies, are discussed.
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http://dx.doi.org/10.5858/arpa.2020-0771-SADOI Listing
May 2021
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