Publications by authors named "Vivek Iyer"

169 Publications

Outcomes of liver transplantation in patients with hepatopulmonary syndrome in the pre and post-MELD eras: A systematic review.

Respir Med Res 2021 Jul 30;80:100852. Epub 2021 Jul 30.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA; Mayo Epidemiology and Translational Research in Intensive Care group (METRIC), Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: The lack of large hepatopulmonary syndrome cohorts undergoing liver transplantation (LT) has resulted in limited information about post-LT outcomes and expectations.

Methods: The long and short-term outcomes of LT in patients with hepatopulmonary syndrome (HPS) were evaluated before and after the implementation of Model for Endstage Liver Disease (MELD) score in 2002, granting exception points for patients with HPS. PubMed/Medline, Embase, Web of Science and Scopus databases were searched for published and unpublished studies from 01/1990 to 04/2019. Studies that included HPS patients who underwent LT and reported post-LT outcomes and HPS severity were reviewed. After reviewing the full text of 1421 articles, 30 were included in the pre-MELD era (before 2002) and 60 in the post-MELD era.

Results: A total of 598 patients (210 children and 388 adults) with HPS who underwent LT were included in this systematic review. In children, 5-year survival probability was similar in the pre and post-MELD groups (85.7% vs. 97.4; p = 0.09). Median post-transplant PaO2 in room air was higher in the post-MELD group (71 [53-87] vs. 97 [80-108] mmHg: p = 0.008). In adults, 5-year survival probability was higher in the post-MELD era (73 vs. 87.3%; p = 0.008). Median post-transplant PaO2 in room air was higher in post-MELD group (75 [63-85] vs. 87 [75-95] mmHg; p = 0.001)..

Conclusions: After MELD exception implementation, survival rates and post-transplant oxygenation improved in adult patients with HPS who underwent liver transplantation, whereas only post-transplant oxygenation improved in children.
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http://dx.doi.org/10.1016/j.resmer.2021.100852DOI Listing
July 2021

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

N Engl J Med 2021 Aug 4;385(9):790-802. Epub 2021 Aug 4.

From the Peter Munk Cardiac Centre at University Health Network (P.R.L., M.E.F., V.D., J.P.G., L.C.G., G.H.), the University of Toronto (P.R.L., E.C.G., A.S.S., M.E.F., V.D., R.A.F., L.C.G., G.H., M.H.), University Health Network (E.C.G., M.H.), St. Michael's Hospital Unity Health (A.S.S., Z.B., J.C.M., M.S.), Ozmosis Research (L.B., L.P.G.D., V.W.), and Sunnybrook Health Sciences Centre (J.P.G.), Toronto, Ottawa Hospital Research Institute (M. Carrier, L.A.C., D.A.F., G.L.G., D.M.S.), Institut du Savoir Montfort (Marc Carrier, G.L.G.), and the University of Ottawa (L.A.C., D.A.F., D.M.S.), Ottawa, Université Laval (A.F.T.) and CHU de Québec-Université Laval Research Center (A.F.T.), Quebec, QC, the University of Manitoba (B.L.H., A. Kumar, R.Z., S.A.L., D.S., G.V.-G.), CancerCare Manitoba (B.L.H., R.Z.), and St. Boniface Hospital (N.M.), Winnipeg, MB, McGill University, Montreal (S.R.K., E.G.M.), McMaster University (P.L.G.) and the Thrombosis and Atherosclerosis Research Institute (P.L.G.), Hamilton, ON, Université de Sherbrooke, Sherbrooke, QC (F.L.), the University of British Columbia, Vancouver (S. Murthy, K.R.), and the University of Alberta, Edmonton (S.D.) - all in Canada; NYU Grossman School of Medicine (J.S.B., H.R.R., J.S.H., T.C., N.M.K., S.P.), the Icahn School of Medicine at Mount Sinai and Mount Sinai Heart (R.S.R.), NYU Langone Health, NYU Langone Hospital (T.C., J.M.H., E.Y.), and Bellevue Hospital (N.M.K.), New York, Montefiore Medical Center (M.N.G., H.H.B., S.C., J.T.C., R.N.) and Albert Einstein College of Medicine (M.N.G., H.H.B., B.T.G., A. Hope), Bronx, and NYU Langone Long Island, Mineola (R.D.H., A. Hindenburg) - all in New York; the University of Pittsburgh (M.D.N., B.J.M., D.T.H., M.M.B., D.C.A., A.J.K., C.M.L., K.L., S.K.M., C.W.S.), UPMC (M.D.N., B.J.M., D.C.A., K.L., S.K.M.), the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh (T.D.G.), and UPMC Children's Hospital of Pittsburgh (C. Horvat), Pittsburgh, and Emergency Medicine, Penn State Hershey Medical Center, Hershey (S.C.M.) - all in Pennsylvania; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (J.C.N., L.C.G., F.G.L.), Avanti Pesquisa Clínica (A.S.M.), Hospital de Julho (F.O.S.), and Hospital do Coracao (F.G.Z.), Sao Paulo, Hospital do Coração de Mato Grosso do Sul and the Federal University of Mato Grosso do Sul (M.P.), Hospital Universitário Maria Aparecida Pedrossia (D.G.S.J.), and Hospital Unimed Campo Grande (D.G.S.J.), Campo Grande, and INGOH, Clinical Research Center, Goiânia (M.O.S.) - all in Brazil; Instituto Mexicano del Seguro Social, Mexico City (J.E., Y.S.P.G.); the University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust (C.A.B.), Bristol, Imperial College London (A.C.G., F.A.-B., M.A.L.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), the London School of Hygiene and Tropical Medicine (B.-A.K.), University College London Hospital (R.H.), Kings Healthcare Partners (B.J.H.), the Intensive Care National Audit and Research Centre (P.R.M.), Guy's and St. Thomas' NHS Foundation Trust (M.S.-H.), and King's College London (M.S.-H.), London, Oxford University (A. Beane, S.J.S.) and NHS Blood and Transplant (L.J.E., S.J.S.), Oxford, and Queen's University Belfast and Royal Victoria Hospital, Belfast (D.F.M.) - all in the United Kingdom; Zuckerberg San Francisco General Hospital, University of California, San Francisco (L.Z.K., C. Hendrickson, M.M.K., A.E.K., M.A.M., B.N.-G.), Harbor-UCLA Medical Center, Torrance (R.J.L., S. Brouwer), Global Coalition for Adaptive Research (M. Buxton) and the University of California Los Angeles (G.L.), Los Angeles, the University of California San Diego School of Medicine, San Diego (T.W.C.), and Stanford University School of Medicine, Palo Alto (J.G.W.) - all in California; Larner College of Medicine at the University of Vermont, Burlington (M. Cushman); Australian and New Zealand Intensive Care Research Centre, Monash University (Z.M., A.M.H., C.J.M., S.A.W., A. Buzgau, C.G., S.P.M., A.D.N., J.C.P., A.C.C.), and Alfred Health (A.C.C., A.D.N.), Melbourne, VIC, St. John of God Subiaco Hospital (S.A.W., E. Litton) and Fiona Stanley Hospital (E. Litton), Perth, WA, and Flinders University, Bedford Park, SA (S. Bihari) - all in Australia; the University of Illinois (K.S.K., J.R.J., J.G.Q.), Cook County Health and Rush Medical College (S. Malhotra), and the University of Chicago (J.D.P.) - all in Chicago; SOCAR Research SA, Nyon (B.-A.K.), and Inselspital, Bern University Hospital, University of Bern (T.T.), Bern - all in Switzerland; Berry Consultants, Austin (R.J.L., E. Lorenzi, S.M.B., L.R.B., M.A.D., M.F., A.M., C.T.S.), University of Texas Southwestern Medical Center, Dallas (A.P.), and Baylor Scott and White Health, Temple (R.J.W.) - all in Texas; Auckland City Hospital (C.J.M., S.P.M., R.L.P.) and the University of Auckland (R.L.P.), Auckland, and the Medical Research Institute of New Zealand, Wellington (C.J.M., A.M.T.) - all in New Zealand; Vanderbilt University Medical Center (A.W.A.) and TriStar Centennial Medical Center (A.L.G.) - both in Nashville; Fédération Hospitalo Universitaire, Raymond Poincaré Hospital, Université de Versailles Saint-Quentin-en-Yvelines, Garches (D. Annane), and Aix-Marseille University, Marseille (B.C.) - both in France; King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.M.A.); Nepal Mediciti Hospital, Lalitpur, and Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal) - both in Nepal; Versiti Blood Research Institute, Milwaukee (L.B.K., L.J.E.), and the University of Wisconsin School of Medicine and Public Health, Madison (J.P.S.); National Intensive Care Surveillance-Mahidol Oxford Tropical Medicine Research Unit, Colombo, Sri Lanka (A. Beane); the University Medical Center Utrecht, Utrecht University, Utrecht (M. Bonten, R.E.G.S., W.B.-P.), and Radboud University Medical Center, Nijmegen (S. Middeldorp, F.L.V.) - both in the Netherlands; Jena University Hospital, Jena, Germany (F.B.); Cleveland Clinic (A.D.) and Case Western Reserve University, the Metro Health Medical Centre (V.K.) - both in Cleveland; Ochsner Medical Center, University of Queensland-Ochsner Clinical School, New Orleans (M.B.E.); Harvard Medical School (B.M.E., Y.K., N.S.R., A.B.S), Brigham and Women's Hospital (B.M.E., Y.K., S.M.H.), Boston University School of Medicine and Boston Medical Center (N.M.H.), and Massachusetts General Hospital (A.B.S., N.S.R.) - all in Boston; University of Alabama, Birmingham (S.G.); Hospital Ramón y Cajal (S.G.-M., J.L.L.-S.M., R.M.G.) and IdiPaz Research Institute, Universidad Autonoma (J.L.-S.), Madrid, and University Hospital of Salamanca-University of Salamanca-IBSAL, Salamanca (M.M.) - all in Spain; University of Antwerp, Wilrijk, Belgium (H.G.); Rutgers New Jersey Medical School, Newark (Y.Y.G.); University of Oxford, Bangkok, Thailand (R.H.); Ascension St. John Heart and Vascular Center, Tulsa (N.H.), and the University of Oklahoma College of Medicine, Oklahoma City (N.H.); the University of Cincinnati, Cincinnati (K.H.); University of Michigan, Ann Arbor (R.C.H., P.K.P.), Beaumont Health, Royal Oak, and the OUWB School of Medicine, Auburn Hills (G.B.N.) - all in Michigan; Mayo Clinic, Rochester (V.N.I.), and the Hennepin County Medical Center, Minneapolis (M.E.P.) - both in Minnesota; Apollo Speciality Hospital-OMR, Chennai, India (D.J.); Oregon Health and Science University, Portland (A. Khan, E.S.L.); the National Heart, Lung, and Blood Institute, Bethesda, MD (A.L.K.); University of Mississippi Medical Center, Jackson (M.E.K.); University College Dublin, Dublin (A.D.N.); University of Kansas School of Medicine, Kansas City (L.S.); Duke University Hospital, Durham, NC (L.W.); and Emory University, Atlanta (B.J.W.).

Background: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.

Methods: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.

Results: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.

Conclusions: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).
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http://dx.doi.org/10.1056/NEJMoa2105911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362594PMC
August 2021

Outcomes among patients with COVID-19 and asthma: A systematic review and meta-analysis.

Allergy Asthma Proc 2021 07;42(4):267-273

From the Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota.

It remains unclear if asthma is a risk factor associated with worse outcomes among patients with coronavirus disease 2019 (COVID-19). We performed a comprehensive database search for studies published from January 1, 2019, to October 2, 2020. We included studies that evaluated outcomes among patients with COVID-19 and underlying asthma. Outcomes of interest included the need for hospitalization, length of hospitalization, intensive care unit (ICU) admission, and death. The meta-analysis was conducted by using random-effects methodology. A total of 389 studies were identified through data base searches. After abstract and full-text screening, 16 observational studies with 92,275 patients were included in the analysis. Of the 16 studies, 15 were retrospective and 1 was a prospective cohort study. The average age was 39.6 years, with 48% female patients. Six of the studies included pediatric patients, and one of these studies only evaluated pediatric patients. One study only evaluated pregnant patients. Among patients with COVID-19, the presence of asthma was not associated with any significant increase in risk of hospitalization (odds ratio [OR] 1.46 [95% confidence interval {CI}, 0.29-7.28]), length of hospitalization (1.59 days [-0.55 to 3.74]), ICU admission (OR 1.65 [95% CI, 0.56-4.17]), or death (OR 0.73 [95% CI, 0.38-1.40]). The overall risk of bias of the included studies was high. Among the patients with COVID-19, asthma did not seem to significantly increase the risk of hospitalization, length of hospitalization, ICU admission, or death.
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http://dx.doi.org/10.2500/aap.2021.42.210041DOI Listing
July 2021

Acute thrombosis of a giant perimedullary arteriovenous fistula in a pediatric HHT patient.

Interv Neuroradiol 2021 May 29:15910199211022499. Epub 2021 May 29.

Division of Pediatric Pulmonology, Mayo Clinic, Rochester, MN, USA.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder that results in arteriovenous malformations (AVMs) in the nose, mucocutaneous surfaces and visceral organs, including lung, brain, liver, bowel and rarely spinal cord. We describe a case of a young child with HHT who presented with acute paraparesis due to acute thrombosis of a spinal perimedullary arteriovenous fistula. Patient underwent coil embolization of spinal arteriovenous shunt with resolution of clinical symptoms. This case highlights the possibility of catastrophic complications in young children with HHT, the potential preventive role of screening for spinal AVMs in HHT and the importance of timely intervention.
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http://dx.doi.org/10.1177/15910199211022499DOI Listing
May 2021

Stabbed in the Back! Neurosarcoidosis with Spinal Cord Involvement.

Am J Med 2021 May 23. Epub 2021 May 23.

Division of Pulmonary and Critical Care Medicine. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.04.029DOI Listing
May 2021

Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia.

Nat Commun 2021 04 30;12(1):2482. Epub 2021 Apr 30.

Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, UK.

While oncogenes promote tumorigenesis, they also induce deleterious cellular stresses, such as apoptosis, that cancer cells must combat by coopting adaptive responses. Whether tumor suppressor gene haploinsufficiency leads to such phenomena and their mechanistic basis is unclear. Here, we demonstrate that elevated levels of the anti-apoptotic factor, CASP8 and FADD-like apoptosis regulator (CFLAR), promotes apoptosis evasion in acute myeloid leukemia (AML) cells haploinsufficient for the cut-like homeobox 1 (CUX1) transcription factor, whose loss is associated with dismal clinical prognosis. Genome-wide CRISPR/Cas9 screening identifies CFLAR as a selective, acquired vulnerability in CUX1-deficient AML, which can be mimicked therapeutically using inhibitor of apoptosis (IAP) antagonists in murine and human AML cells. Mechanistically, CUX1 deficiency directly alleviates CUX1 repression of the CFLAR promoter to drive CFLAR expression and leukemia survival. These data establish how haploinsufficiency of a tumor suppressor is sufficient to induce advantageous anti-apoptosis cell survival pathways and concurrently nominate CFLAR as potential therapeutic target in these poor-prognosis leukemias.
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http://dx.doi.org/10.1038/s41467-021-22750-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087769PMC
April 2021

CRISPR activation screen in mice identifies novel membrane proteins enhancing pulmonary metastatic colonisation.

Commun Biol 2021 03 23;4(1):395. Epub 2021 Mar 23.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.

Melanoma represents ~5% of all cutaneous malignancies, yet accounts for the majority of skin cancer deaths due to its propensity to metastasise. To develop new therapies, novel target molecules must to be identified and the accessibility of cell surface proteins makes them attractive targets. Using CRISPR activation technology, we screened a library of guide RNAs targeting membrane protein-encoding genes to identify cell surface molecules whose upregulation enhances the metastatic pulmonary colonisation capabilities of tumour cells in vivo. We show that upregulated expression of the cell surface protein LRRN4CL led to increased pulmonary metastases in mice. Critically, LRRN4CL expression was elevated in melanoma patient samples, with high expression levels correlating with decreased survival. Collectively, our findings uncover an unappreciated role for LRRN4CL in the outcome of melanoma patients and identifies a potential therapeutic target and biomarker.
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http://dx.doi.org/10.1038/s42003-021-01912-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987976PMC
March 2021

Healthcare Utilization and Costs associated with Hereditary Hemorrhagic Telangiectasia Patients in a Large US Claims Database.

Mayo Clin Proc Innov Qual Outcomes 2021 Feb 20;5(1):55-64. Epub 2020 Nov 20.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.

Objective: To assess the health care costs and utilization in patients with hereditary hemorrhagic telangiectasia (HHT) in the United States.

Patients And Methods: Retrospective analysis of patients with HHT diagnosed between 2007 and 2017 was performed using deidentified administrative claims data from the OptumLabs Data Warehouse. Adult patients with new (incident) diagnosis of HHT between January 1, 2007, and December 31, 2017, were included. Comparisons were made using the Wilcoxon rank sum test.

Results: Three thousand nine hundred seventy-seven patients with a first diagnosis of HHT between 2007 and 2017 were identified, of which 3590 were matched 1:1 to non-HHT patients with similar baseline characteristics and comorbidities. These 3590 patients with HHT were 63.1% female and 83.9% white with a mean age of 51.1 ± 18.5 years, and a mean follow-up period of 3.2 ± 2.2 years (range, 1.0-11.7 years). Compared with the control group, the cumulative 5-year median total health care cost for patients with HHT was 41.4% higher ($21,118 vs $14,929; < .001) in those with private commercial insurance and 31.7% higher ($35,462 vs $26,925; < .001) in those with Medicare Advantage coverage. The median annual health care costs were significantly higher in patients with HHT with commercial insurance and Medicare Advantage in the first year after diagnosis ($4,333 vs $1,804; < .001), and ($7,322 vs $5,245; < .001), respectively, and remained higher throughout the duration of follow-up. Further analysis showed that outpatient clinic visits, hospital admission, imaging rates, invasive procedures, iron infusions, and blood transfusions were all significantly higher in the HHT group.

Conclusion: Patients with HHT have significantly higher health care costs compared with a matched control group. A better understanding of the reasons underlying these cost differences will provide opportunities for patients, providers, and other stakeholders to better manage this rare condition.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930864PMC
February 2021

Combinatorial CRISPR screen identifies fitness effects of gene paralogues.

Nat Commun 2021 02 26;12(1):1302. Epub 2021 Feb 26.

Wellcome Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.

Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells.
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http://dx.doi.org/10.1038/s41467-021-21478-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910459PMC
February 2021

Cavitary lung lesions caused by in setting of common variable immune deficiency.

Respir Med Case Rep 2020 6;31:101277. Epub 2020 Nov 6.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

pneumonia affects immunocompromised hosts. The typical imaging finding is bilateral diffuse ground glass opacities. Here we presented a case of causing biopsy-confirmed cavitary lung lesions in a patient with a predominant B cell defect with common variable immune deficiency.
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http://dx.doi.org/10.1016/j.rmcr.2020.101277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658484PMC
November 2020

Diffuse Pulmonary Meningotheliomatosis: A Rare Lung Disease Presenting with Diffuse Ground-Glass Opacities and Cavitation.

Am J Case Rep 2020 Nov 9;21:e926172. Epub 2020 Nov 9.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

BACKGROUND Diffuse pulmonary meningotheliomatosis (DPM) is an exceedingly rare diffuse pulmonary disease with a female predominance. It is characterized by the presence of widespread bilateral minute pulmonary meningothelial-like nodules (MPMNs) on chest imaging. Patients are generally asymptomatic or may present with nonspecific symptoms such as dyspnea. The nodules are typically detected incidentally on imaging for other indications. Here, we present a rare case of DPM in a 55-year-old woman. CASE REPORT A 55-year-old woman presented to the clinic with non-exertional chest pressure and dry cough of 4-month duration. She had a history of hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, and impaired fasting blood glucose and was a lifelong nonsmoker. Physical examination was unremarkable. High-resolution chest computed tomography (CT) showed innumerable diffuse small ground-glass nodules. An extensive laboratory workup was negative for autoimmune and infectious etiologies. The patient underwent uncomplicated right video-assisted thoracoscopic surgery, and lung biopsy showed multiple well-circumscribed interstitial meningothelial-like nodules in perivenular distribution with occasional whorling of cells. The diagnosis of diffuse pulmonary meningotheliomatosis (DPM) was confirmed. The patient continued to complain of non-exertional chest pressure without pulmonary complaints, and a repeat chest CT showed stable findings 1 year after the diagnosis. CONCLUSIONS DPM should be considered in the differential diagnosis for patients presenting with diffuse bilateral pulmonary nodules. Patients are typically asymptomatic and it is most commonly detected incidentally. Further research is needed to better understand this disease and its clinical significance.
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http://dx.doi.org/10.12659/AJCR.926172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666436PMC
November 2020

The mutational signature profile of known and suspected human carcinogens in mice.

Nat Genet 2020 11 28;52(11):1189-1197. Epub 2020 Sep 28.

Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health.
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http://dx.doi.org/10.1038/s41588-020-0692-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610456PMC
November 2020

Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia.

Ann Intern Med 2020 12 8;173(12):989-1001. Epub 2020 Sep 8.

Mayo Clinic, Rochester, Minnesota (V.N.I.).

Description: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications.

Methods: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved.

Recommendations: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.
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http://dx.doi.org/10.7326/M20-1443DOI Listing
December 2020

Mobile Mitral and Aortic Valvular Masses in Patients With Hereditary Hemorrhagic Telangiectasia Receiving Intravenous Bevacizumab.

Mayo Clin Proc Innov Qual Outcomes 2020 Aug 8;4(4):460-463. Epub 2020 May 8.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.

Bevacizumab is now an emerging treatment option for severe hereditary hemorrhagic telangiectasia-related bleeding including epistaxis and gastrointestinal tract bleeding. The impact of long-term intravenous bevacizumab therapy on cardiac structure and function is unknown. We describe 3 patients receiving intravenous bevacizumab therapy for severe hereditary hemorrhagic telangiectasia-related bleeding who were found to have abnormal mobile masses on the mitral valve (n=2) and aortic valve (n=1). The clinical impact of these findings is unknown and requires further study.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411168PMC
August 2020

Marked hypereosinophilia secondary to endometrioid ovarian cancer presenting with asthma symptoms, a case report.

Respir Med Case Rep 2020 28;31:101178. Epub 2020 Jul 28.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Hypereosinophilia (HE) is defined by the presence of >1.5 × 10/L eosinophils in the peripheral blood. Paraneoplastic HE has been reported in a number of solid and hematologic malignancies including ovarian cancer. We present a case with paraneoplastic HE in the setting of underlying endometrioid ovarian carcinoma.

Case Presentation: An 88-year-old woman presented with cough, dyspnea and 20-pound unintentional weight loss of one month duration. Evaluation revealed peripheral hypereosinophilia (HE) with absolute eosinophil count of 15.38 × 10/L (53.8%) and an elevated exhaled nitric oxide at 172 parts per billion (normal < 39 PPB). Given the HE and unintentional weight loss, computed tomography (CT) scan was obtained and showed a pelvic mass. The patient underwent bilateral salpingo-ophorectomy with pathology consistent with endometrioid ovarian carcinoma. The patient experienced complete resolution of her cough, dyspnea, and peripheral eosinophilia following surgical resection.

Conclusion: This case highlights that solid malignancy should be considered in patients with marked HE.
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http://dx.doi.org/10.1016/j.rmcr.2020.101178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404536PMC
July 2020

Intravenous Bevacizumab in Hereditary Hemorrhagic Telangiectasia-Related Bleeding and High-Output Cardiac Failure: Significant Inter-Individual Variability in the Need for Maintenance Therapy.

Mayo Clin Proc 2020 08;95(8):1604-1612

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To present our center's experience with a maintenance treatment algorithm for intravenous bevacizumab that allows for personalized therapy decisions.

Patients And Methods: We reviewed all patients treated with intravenous bevacizumab for hereditary hemorrhagic telangiectasia-related bleeding and/or high-output cardiac failure (HOCF) from January 1, 2013, to July 1, 2019, at the Mayo Clinic, Rochester, Minnesota. Data regarding subsequent bevacizumab dosing were abstracted.

Results: A total of 57 patients (n=40, 70.2% females) were identified with a median age of 65 (55 to 74; range, 37 to 89) years. High-cardiac output state was present in 21 patients (36.8%) and 10 (17.5%) were treated with intravenous bevacizumab primarily for HOCF. The median duration of follow-up after completion of the initial intravenous bevacizumab treatment was 25 (12.3 to 40.8; range, 0.1 to 65.4) months. A total of 20 (35.1%) patients with a median follow-up of 13.5 (range, 0 to 48.4) months required no maintenance dosing throughout the duration of follow-up. Among those who required subsequent maintenance doses, only a small fraction (8 patients; 14.0%) required regular maintenance doses every 4 to 8 weeks during follow-up whereas the majority of patients required intermittent "as-needed" doses at varying intervals.

Conclusion: There is significant inter-individual variability in the need for maintenance intravenous bevacizumab when patients are followed using a predefined bevacizumab maintenance dosing treatment algorithm. The use of "as-needed" maintenance bevacizumab appears to be an effective strategy for management of hereditary hemorrhagic telangiectasia-related bleeding and HOCF.
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http://dx.doi.org/10.1016/j.mayocp.2020.03.001DOI Listing
August 2020

An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study.

Haematologica 2021 Aug 1;106(8):2161-2169. Epub 2021 Aug 1.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHT-associated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, epistaxis severity score, red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. 238 HHT patients received bevacizumab for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% CI, 2.9-3.5 g/dL) [mean hemoglobin 8.6 (8.5, 8.8) g/dL versus 11.8 (11.5, 12.1) g/dL, p.
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http://dx.doi.org/10.3324/haematol.2020.261859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327711PMC
August 2021

Pulmonary Arteriovenous Malformations in Non-hereditary Hemorrhagic Telangiectasia Patients: An 18-Year Retrospective Study.

Lung 2020 08 9;198(4):679-686. Epub 2020 Jul 9.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Purpose: Pulmonary arteriovenous malformations (PAVMs) are most commonly associated with hereditary hemorrhagic telangiectasia (HHT). Patients with PAVMs can present with serious complications including stroke, transient ischemic attack (TIA), and brain abscess. PAVMs are rare in non-HHT patients and little is known about this patient population. The aim of this retrospective study is to better understand clinical presentation and outcomes of PAVMs occurring exclusively in non-HHT patients.

Methods: Non-HHT patients with PAVMs at the Mayo Clinic-Rochester between 01/01/2000 and 12/31/2018 were reviewed. Patients with Curacao score > 1 were excluded. Demographics, imaging characteristics, neurological complications, and follow-up imaging were analyzed.

Results: Seventy-seven patients with PAVMs were identified. The mean age at diagnosis was 48.2 ± 18.3 years with female preponderance (59.7%). The majority of PAVMs had lower lobe predominance (66.7%) and were simple and single in 75.3% and 89.6% of cases, respectively. Most patients were asymptomatic (46.8%) with dyspnea being the most common symptom (28.6%). Neurologic complications occurred in 19.5% of patients. The majority of PAVMs were idiopathic (61%). Thirty patients (39%) had one or more possible risk factors including previous thoracic surgery (23.4%), congenital heart disease (19.5%), and chest trauma (10.4%). Embolization was performed in 37 (48.1%) patients and only 4 (5.2%) underwent surgical resection.

Conclusions: Non-HHT PAVMs occur more commonly in females, are most commonly simple and single, and have lower lobe predominance and a high rate of neurologic complications. Potential predisposing risk factors were identified in about 40% of the cases. Clinicians should be aware of the risk of PAVM development in patients with history of chest trauma, congenital heart disease, lung infection/abscess, and thoracic surgery.
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http://dx.doi.org/10.1007/s00408-020-00367-wDOI Listing
August 2020

Successful treatment of coronavirus disease 2019 in a patient with asthma.

Allergy Asthma Proc 2020 07;41(4):296-300

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.

Underlying lung disease, especially asthma, has recently been found to be associated with a higher risk of hospitalization with coronavirus disease 2019 (COVID-19) infection. Inhaled corticosteroids (ICS) are the most commonly used controller medications in patients with asthma. It is unclear whether ICS use increases the risk for severe COVID-19 infection. At the current time, asthma organizations are still recommending the continued use of ICS and other asthma medications to minimize the risk of uncontrolled asthma. However, for patients with asthma and who have recovered from COVID-19 infection, the timing of resumption of asthma therapy is equally uncertain. Pulmonary function testing and exhaled oral nitric oxide testing are aerosol-generating procedures and are currently being severely restricted at most health-care facilities. We presented a case of a patient with cough-variant asthma who developed severe COVID-19 associated acute respiratory distress syndrome with the need for intubation and prolonged mechanical ventilation. We highlighted the potential utility of using COVID-19 RNA detection as well as immunoglobulin G antibody testing to help guide the timing of resumption of asthma therapy.
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http://dx.doi.org/10.2500/aap.2020.41.200044DOI Listing
July 2020

Newer Biological Agents in the Treatment of Severe Asthma: Real-World Results from a Tertiary Referral Center.

Lung 2020 08 24;198(4):653-659. Epub 2020 Jun 24.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic-Rochester, Rochester, MN, USA.

Purpose: To determine the efficacy of IL-5 inhibitory therapy in severe, refractory asthma in a real-world clinical setting from a tertiary referral center.

Methods: A retrospective chart review of patients with severe asthma treated with IL-5 biologic therapy for ≥ 6 months at Mayo Clinic in Rochester, Minnesota between January 1, 2013 and August 31, 2019.

Results: Over the study period, we identified 63 patients with a mean age of 54 who received an IL-5 inhibitor for ≥ 6 months. A total of 55 patients received mepolizumab, 2 received benralizumab, and 9 patients received both. Patients were followed up for a mean of 25 months. The mean number of months of oral prednisone use prior to biologic initiation was 64. There was a significant reduction in the median dose of prednisone in the 24 months after drug initiation (15 mg vs. 0 mg; p = < 0.0001). Similarly; there was a significant decline in the median number of asthma exacerbations in the 24 months before and after drug initiation (7 vs. 2; p = < 0.0001). The mean number of emergency room (ER) visits and hospitalizations decreased from 5.1 and 2.0 to 1.6 and 0.4 in the 24 months before and after therapy initiation (p < 0.0001 and p = 0.007, respectively) CONCLUSIONS: IL-5 inhibitory therapy is associated with significant and long-term sustained reductions in asthma exacerbation frequency, ER visits, hospitalizations, as well as oral steroid usage in a patient population with refractory steroid-dependent asthma referred to a tertiary referral center.
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http://dx.doi.org/10.1007/s00408-020-00369-8DOI Listing
August 2020

A rare case of chemotherapy induced phrenic neuropathy.

Respir Med Case Rep 2020 5;30:101117. Epub 2020 Jun 5.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

Background: While chemotherapeutic agents result in an improvement in both disease-free and overall survival in cancer patients, treatment can result in short and long-term complications. One well-known complication is neuropathy which can result from a number of chemotherapeutic agents. However, chemotherapy-induced phrenic neuropathy is an exceedingly rare phenomenon with few cases reported in the literature.

Case: A 34-year-old male with metastatic testicular cancer presented with progressive dyspnea on exertion after initiation of chemotherapy with bleomycin, cisplatin, and etoposide. Multiple diagnostic studies were performed including pulmonary function testing, chest computed tomography, fluoroscopic sniff evaluation, in addition to phrenic nerve electromyography. Based on results of these tests, the diagnosis of chemotherapy-induced phrenic neuropathy was made.

Conclusion: Chemotherapy-induced phrenic neuropathy, although rare, should be considered as a cause of dyspnea in cancer patients following initiation of chemotherapy.
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http://dx.doi.org/10.1016/j.rmcr.2020.101117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284070PMC
June 2020

An international survey to evaluate systemic bevacizumab for chronic bleeding in hereditary haemorrhagic telangiectasia.

Haemophilia 2020 Nov 20;26(6):1038-1045. Epub 2020 May 20.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

Introduction: Systemic bevacizumab is a novel targeted therapy for severe epistaxis and chronic gastrointestinal bleeding in hereditary haemorrhagic telangiectasia (HHT), but published data are very limited.

Aim: We conducted a survey-based study to characterize current treatment practices and physician-reported safety and effectiveness of systemic bevacizumab for bleeding in (HHT).

Methods: A 27-item survey was sent to physician centre directors of 31 International HHT Centers of Excellence.

Results: Response rate was 84%. Approximately half of centres had treated >10 HHT patients with systemic bevacizumab for chronic bleeding for a total of 291 patients treated. All centres utilize a 5 mg/kg dose for induction treatment and most administer six doses (range, 4-8) every 2 weeks. However, maintenance regimens varied considerably between centres. Bevacizumab was highly effective, with 86% reporting significant (>50%) improvement in GI bleeding and/or epistaxis and haemoglobin rise in most patients treated with bevacizumab; 52% reported haemoglobin normalization in most patients. All centres reported adverse event rates <30% and two-thirds of centres reported adverse event rates <10%. Discontinuation for adverse events or inefficacy was rare. Bleeding severity thresholds for initiation of bevacizumab were highly variable, and it is typically administered by haematologists (76% of centres). Two-thirds of centres reported obtaining insurance approval for bevacizumab for most or all patients but 48% reported difficulty in obtaining coverage.

Conclusion: Systemic bevacizumab is widely used to treat bleeding in HHT with excellent physician-reported effectiveness and safety. There is considerable variation in maintenance treatment practices and thresholds for initiation of bevacizumab among HHT centres.
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http://dx.doi.org/10.1111/hae.14034DOI Listing
November 2020

Catheter Ablation Lesion Visualization With Intracardiac Strain Imaging in Canines and Humans.

IEEE Trans Ultrason Ferroelectr Freq Control 2020 09 15;67(9):1800-1810. Epub 2020 Apr 15.

Catheter ablation is a common treatment for arrhythmia, but can fail if lesion lines are noncontiguous. Identification of gaps and nontransmural lesions can reduce the likelihood of treatment failure and recurrent arrhythmia. Intracardiac myocardial elastography (IME) is a strain imaging technique that provides visualization of the lesion line. Estimation of lesion size and gap resolution were evaluated in an open-chest canine model ( n = 3 ), and clinical feasibility was investigated in patients undergoing ablation to treat typical cavotricuspid isthmus (CTI) atrial flutter ( n = 5 ). A lesion line consisting of three lesions and two gaps was generated on the canine left ventricle via epicardial ablation. One lesion was generated in one canine right ventricle. Average lesion and gap areas were measured with high agreement (33 ± 14 and 30 ± 15 mm, respectively) when compared against gross pathology (34 ± 19 and 26 ± 11 mm, respectively). Gaps as small as 11 mm (3.6 mm on epicardial surface) were identifiable. Absolute error and relative error in estimated lesion area were 9.3 ± 8.4 mm and 31% ± 34%; error in estimated gap area was 11 ± 9.0 mm and 40% ± 29%. Flutter patients were imaged throughout the procedure. Strain was shown to be capable of differentiating between baseline and after ablation completion as confirmed by conduction block. In all patients, strain decreased in the CTI after ablation (mean paired difference of -17% ± 11%, ). IME could potentially become a useful ablation monitoring tool in health facilities.
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http://dx.doi.org/10.1109/TUFFC.2020.2987480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483419PMC
September 2020

A Genome-Wide Screen in Mice To Identify Cell-Extrinsic Regulators of Pulmonary Metastatic Colonisation.

G3 (Bethesda) 2020 06 1;10(6):1869-1877. Epub 2020 Jun 1.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.

Metastatic colonization, whereby a disseminated tumor cell is able to survive and proliferate at a secondary site, involves both tumor cell-intrinsic and -extrinsic factors. To identify tumor cell-extrinsic (microenvironmental) factors that regulate the ability of metastatic tumor cells to effectively colonize a tissue, we performed a genome-wide screen utilizing the experimental metastasis assay on mutant mice. Mutant and wildtype (control) mice were tail vein-dosed with murine metastatic melanoma B16-F10 cells and 10 days later the number of pulmonary metastatic colonies were counted. Of the 1,300 genes/genetic locations (1,344 alleles) assessed in the screen 34 genes were determined to significantly regulate pulmonary metastatic colonization (15 increased and 19 decreased; < 0.005 and genotype effect <-55 or >+55). While several of these genes have known roles in immune system regulation (, , , , , , , , , , and ) most are involved in a disparate range of biological processes, ranging from ubiquitination () to diphthamide synthesis () to Rho GTPase-activation ( and ), with no previous reports of a role in the regulation of metastasis. Thus, we have identified numerous novel regulators of pulmonary metastatic colonization, which may represent potential therapeutic targets.
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http://dx.doi.org/10.1534/g3.120.401128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263671PMC
June 2020

Noninvasive localization of cardiac arrhythmias using electromechanical wave imaging.

Sci Transl Med 2020 03;12(536)

Division of Cardiology, Department of Medicine and Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. The 12-lead electrocardiogram (ECG) is the current noninvasive clinical tool used to diagnose and localize cardiac arrhythmias. However, it has limited accuracy and is subject to operator bias. Here, we present electromechanical wave imaging (EWI), a high-frame rate ultrasound technique that can noninvasively map with high accuracy the electromechanical activation of atrial and ventricular arrhythmias in adult patients. This study evaluates the accuracy of EWI for localization of various arrhythmias in all four chambers of the heart before catheter ablation. Fifty-five patients with an accessory pathway (AP) with Wolff-Parkinson-White (WPW) syndrome, premature ventricular complexes (PVCs), atrial tachycardia (AT), or atrial flutter (AFL) underwent transthoracic EWI and 12-lead ECG. Three-dimensional (3D) rendered EWI isochrones and 12-lead ECG predictions by six electrophysiologists were applied to a standardized segmented cardiac model and subsequently compared to the region of successful ablation on 3D electroanatomical maps generated by invasive catheter mapping. There was significant interobserver variability among 12-lead ECG reads by expert electrophysiologists. EWI correctly predicted 96% of arrhythmia locations as compared with 71% for 12-lead ECG analyses [unadjusted for arrhythmia type: odds ratio (OR), 11.8; 95% confidence interval (CI), 2.2 to 63.2; = 0.004; adjusted for arrhythmia type: OR, 12.1; 95% CI, 2.3 to 63.2; = 0.003]. This double-blinded clinical study demonstrates that EWI can localize atrial and ventricular arrhythmias including WPW, PVC, AT, and AFL. EWI when used with ECG may allow for improved treatment for patients with arrhythmias.
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http://dx.doi.org/10.1126/scitranslmed.aax6111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234276PMC
March 2020

Intravenous bevacizumab as a novel treatment for refractory left ventricular assist device-related gastrointestinal bleeding.

J Heart Lung Transplant 2020 05 24;39(5):492-495. Epub 2020 Feb 24.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

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http://dx.doi.org/10.1016/j.healun.2020.02.012DOI Listing
May 2020

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice.

Nat Commun 2020 01 20;11(1):394. Epub 2020 Jan 20.

UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA.

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.
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http://dx.doi.org/10.1038/s41467-019-14261-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971050PMC
January 2020

Adherence to Global Initiative for Chronic Obstructive Lung Disease guidelines in the real world: current understanding, barriers, and solutions.

Curr Opin Pulm Med 2020 Mar;26(2):149-154

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Purpose Of Review: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides a comprehensive review and guidance for clinicians managing patients with chronic obstructive pulmonary disease (COPD). However, adherence to GOLD guidelines has been suboptimal over the years. The current review summarizes the current body of literature addressing the multitude of reasons for the lack of adherence to GOLD guidelines in clinical practice.

Recent Findings: There continue to be several reasons for suboptimal adoption of GOLD guidelines in clinical practice. A primary and recurrent theme appears to be both delayed as well as missed diagnosis of COPD. There are several reasons for this including lack of awareness about current COPD guidelines, lack of availability as well as utilization of office spirometry and improper symptom assessment. Other issues include improper selection of proper pharmacotherapy options, misdiagnosis/mislabeling of COPD phenotypes, lack of smoking cessation counselling as well as enrollment in pulmonary rehabilitation. Potential solutions include adoption of clinical decision support systems, self-care models and careful phenotyping of COPD patients.

Summary: There are currently several barriers for the adoption of GOLD guidelines into routine clinical practice. These barriers are all amenable to systematic solutions that will increase adherence to current GOLD guidelines.
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http://dx.doi.org/10.1097/MCP.0000000000000655DOI Listing
March 2020

Intravenous Bevacizumab Reduces Transfusion Requirements and Endoscopic Interventions in Patients With Gastric Antral Vascular Ectasia and Small Bowel Angioectasia.

Gastroenterology 2020 03 21;158(4):1162-1163.e4. Epub 2019 Nov 21.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2019.11.027DOI Listing
March 2020

Systemic bevacizumab for high-output cardiac failure in hereditary hemorrhagic telangiectasia: an international survey of HHT centers.

Orphanet J Rare Dis 2019 11 14;14(1):256. Epub 2019 Nov 14.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Systemic bevacizumab is a novel targeted anti-angiogenic therapy for high-output cardiac failure (HOCF) in hereditary hemorrhagic telangiectasia (HHT) but published data is limited. This survey-based study measured physician-reported safety, effectiveness and current treatment practices for systemic bevacizumab in HHT-HOCF.

Methods: A 27-item survey was sent to center directors of 31 international HHT Centers of Excellence.

Results: Response rate was 74% with centers reporting 150 total patients receiving systemic bevacizumab for HHT-HOCF. Approximately two-thirds of centers had treated ≥5 patients. All centers utilize a 5 mg/kg dose for induction treatment and most administer 6 doses (range, 4-6) every 2 weeks, although maintenance regimens varied considerably. Center directors reported bevacizumab to be effective, with 55% reporting significant improvement in cardiac index and HOCF symptoms in most patients treated with bevacizumab, although normalization of cardiac parameters was uncommon. Adverse events were uncommon with three-quarters of centers reporting adverse event rates < 10%. Discontinuation for adverse events or ineffectiveness was rare. Bevacizumab was typically administered by hematologists and pulmonologists (50 and 39% of centers, respectively), with highly variable thresholds for initiation. Although half the centers reported difficulty with the insurance approval process, 70% of centers were ultimately able to obtain coverage for most or all of their patients.

Conclusions: Systemic bevacizumab is a widely-used therapy for HHT-HOCF with reasonable safety and effectiveness. HHT centers appear to vary considerably in maintenance treatment practices and disease severity thresholds for initiation of bevacizumab in HHT-related HOCF.
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http://dx.doi.org/10.1186/s13023-019-1239-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857247PMC
November 2019
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