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1. Variability in biopsy quality informs translational research applications in hepatocellular carcinoma

Author: Kelley Weinfurtner, Joshua Cho, Daniel Ackerman, James X. Chen, Abashai Woodard, Wuyan Li, David Ostrowski, Michael C. Soulen, Mandeep Dagli, Susan Shamimi-Noori, Jeffrey Mondschein, Deepak Sudheendra, S. William Stavropoulos, Shilpa Reddy, Jonas Redmond, Tamim Khaddash, Darshana Jhala, Evan S. Siegelman, Emma E. Furth, Stephen J. Hunt, Gregory J. Nadolski, David E. Kaplan, and Terence P. F. Gade
Subjects: Medicine, Science
Abstract: Abstract In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7–10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10–75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.
Published: 2021
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2. Practical Risk Scoring System for Predicting Severity of COVID-19 Disease

Author: Jeffrey Petersen and Darshana Jhala
Subjects: Pathology, RB1-214
Abstract: Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, has become an international pandemic with numerous casualties. It had been noted that the severity of the COVID-19 disease course depends on several clinical, laboratory, and radiological factors. This has led to risk scoring systems in various populations such as in China, but similar risk scoring systems based on the American veteran population are sparse, particularly with the vulnerable Veteran population. As a simple risk scoring system would be very useful, we propose a simple Jhala Risk Scoring System (JRSS) to assess the severity of disease risk. Methods: A retrospective review of all SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) tests collected and performed at the regional Veterans Administration Medical Center (VAMC) serving the Philadelphia and surrounding areas from March 17th, 2020 to May 20th, 2020. Data was collected and analyzed in the same year. These tests were reviewed within the computerized medical record system for demographic, medical history, laboratory test history, and clinical course. Information from the medical records were then scored based on the criteria of the Jhala Risk Scoring System (JRSS). Results: The JRSS, based on age, ethnicity, presence of any lung disease, presence of cardiovascular disease, smoking history, and diabetes history with laboratory parameters correlated and predicted (with statistical significance) which patients would be hospitalized. Conclusion: The JRSS may play a role in informing which COVID-19 positive patients in the emergency room/urgent care for risk stratification.
Published: 2022
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3. A cold scare: Formation of cold reactive anti-A1 coinciding with gross hemolysis

Author: Jeffrey Petersen and Darshana Jhala
Subjects: Medicine (General), R5-920, Chemistry, QD1-999
Abstract: Anti-A1 antibodies can be found as a usually clinically insignificant naturally occurring cold IgM antibody in A-subgroup patients. It is known from multiple prior case reports that warm-reactive anti-A1 that reacts at 37 °C can be clinically significant, and it has been previously reported that it could form after alloimmunization with donor A1 red blood cell (RBC) transfusion. In addition, the development of anti-A1, often as an autoantibody, have been described in the setting of various malignancies, perhaps due to expressed subtle alterations of the ABO antigens provoking an immune response.Here, we report a rare case of a cold-reactive anti-A1 alloantibody (after multiple transfusions with group A1 RBC units) in a 76 year old male patient (A2) with history of myelodysplastic syndrome and metastatic carcinoma who presented with hemolytic anemia and dark urine. The patient had previously typed as blood type A without reverse typing reaction for anti-A1; as a result, the patient had been transfused with group A1 RBCs. Four days prior to discovery of the ABO discrepancy, the patient had a febrile transfusion reaction associated with his A1 RBC transfusion. On admission, his immunohematology workup demonstrated an alloantibody to anti-A1 that coincidentally appeared during a new onset of hemolytic anemia. Case reports of patients with hemolytic anemia with a newly developed anti-A1 alloantibody are sparse in the literature, and this case is particularly interesting as the cold reactive anti-A1 (without demonstrable wide thermal amplitude) appeared to form after alloimmunization and in the setting of an underlying malignancy. Keywords: Immunohematology, Transfusion medicine, Blood transfusion, Hemolysis/immunology, Transfusion reactions, Laboratory medicine
Published: 2018
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4. Glaucoma Genetic Risk Scores in the Million Veteran Program

Author: Andrea R. Waksmunski, Tyler G. Kinzy, Lauren A. Cruz, Cari L. Nealon, Christopher W. Halladay, Piana Simpson, Rachael L. Canania, Scott A. Anthony, David P. Roncone, Lea Sawicki Rogers, Jenna N. Leber, Jacquelyn M. Dougherty, Paul B. Greenberg, Jack M. Sullivan, Wen-Chih Wu, Sudha K. Iyengar, Dana C. Crawford, Neal S. Peachey, Jessica N. Cooke Bailey, J. Michael Gaziano, Rachel Ramoni, Jim Breeling, Kyong-Mi Chang, Grant Huang, Sumitra Muralidhar, Christopher J. O’Donnell, Philip S. Tsao, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan-Mai T. Nguyen, Saiju Pyarajan, Kelly Cho, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, John Harley, Jeffrey Whittle, Jean Beckham, John Wells, Salvador Gutierrez, Gretchen Gibson, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Florez, Alan Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald Washburn, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard Servatius, Mary Oehlert, Agnes Wallbom, Ronald Fernando, Timothy Morgan, Todd Stapley, Scott Sherman, Gwenevere Anderson, Philip Tsao, Elif Sonel, Edward Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, and Robert Striker
Subjects: Ophthalmology, Cross-Sectional Studies, Risk Factors, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Glaucoma, Open-Angle, Genome-Wide Association Study, Veterans
Abstract: Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).Cross-sectional study.MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.GRS were significantly associated with POAG (Plt; 5 × 10sup-5/sup) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.
Published: 2022
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5. Approach to FNA of Pancreatic Cysts

Author: Nirag, Jhala and Darshana, Jhala
Subjects: Pancreatic Neoplasms, Biopsy, Fine-Needle, Humans, Pancreatic Cyst, Anatomy, Immunohistochemistry, Pathology and Forensic Medicine
Abstract: Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the type of cyst is important to provide appropriate care for patients. It is also very clear that not one single modality can provide adequate diagnostic information for pancreatic cysts. A multimodal approach to the diagnosis of pancreatic cyst is the key. This review will highlight how to approach to fine-needle aspiration of pancreatic cysts. The review will also highlight salient features of common neoplastic pancreatic cysts along with the use of ancillary testing which includes biochemical testing, commonly utilized molecular tests, and/or immunohistochemical tests to provide an accurate diagnosis.
Published: 2022
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6. Ethnicity, Comorbid Medical Conditions, and SARS-CoV-2 Test Cycle Thresholds in the Veteran Population

Author: Darshana Jhala and Jeffrey Petersen
Subjects: medicine.medical_specialty, Population demographics, Health (social science), Sociology and Political Science, Population, Ethnic group, Article, Epidemiology, medicine, Ethnicity, Humans, Medical history, education, Clinical pathology, Veterans, Molecular pathology, education.field_of_study, business.industry, SARS-CoV-2, Health Policy, Public health, Public Health, Environmental and Occupational Health, COVID-19, Quality control, Quality assurance, Test (assessment), Black or African American, Anthropology, Access to health care, business, Viral load, Demography
Abstract: Background and Aims It has been documented that African Americans have been significantly affected by COVID-19 infection due to systemic societal factors, which may lead to increases in comorbid medical history and subsequently vulnerability to having higher viral loads as measured by the cycle threshold/number (CT/CN) values by reverse transcriptase polymerase chain reaction (RT-PCR). Differences in CT/CN values by ethnicity and comorbid medical history could play an important role in public health research, particularly in elucidating the reasons for differential public health outcomes by ethnicity, as viral loads are known to correlate with disease severity. However, there is a gap in the literature regarding CT/CN values by ethnicity and comorbid medical history. Therefore, this study seeks to address this literature gap and its important implication for public health research. Methods A retrospective review of all SARS-CoV-2 RT-PCR tests collected at the regional Veterans Administration Medical Center (VAMC) serving the Philadelphia area from March 17, 2020, to May 20, 2020, was performed to collect demographic information such as race, gender, and age. In addition, comorbid medical conditions, clinical course, and CT/CN values were obtained for the positive cases. Results There was a total of 1524 patients tested for SARS-CoV-2. A total of 713/1524 patients (46.8%) were African American. A total of 187/1524 patients (12%) had tested positive for SARS-CoV-2 from which 139/187 (74%) were African American. African American patients required more intensive unit care. Both African Americans and other ethnicities had similar rates of comorbid medical conditions. On comparison of the ethnic groups, there were lower viral loads in African Americans on admission, though the difference was not statistically significant. Conclusion African American Veterans tested positive at higher rates and require more ICU care, despite similar rates of comorbid illness and viral loads.
Published: 2021

7. Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

Author: Derek Klarin, Shefali Setia Verma, Renae Judy, Ozan Dikilitas, Brooke N. Wolford, Ishan Paranjpe, Michael G. Levin, Cuiping Pan, Catherine Tcheandjieu, Joshua M. Spin, Julie Lynch, Themistocles L. Assimes, Linn Åldstedt Nyrønning, Erney Mattsson, Todd L. Edwards, Josh Denny, Eric Larson, Ming Ta Michael Lee, David Carrell, Yanfei Zhang, Gail P. Jarvik, Ali G. Gharavi, John Harley, Frank Mentch, Jennifer A. Pacheco, Hakon Hakonarson, Anne Heidi Skogholt, Laurent Thomas, Maiken Elvestad Gabrielsen, Kristian Hveem, Jonas Bille Nielsen, Wei Zhou, Lars Fritsche, Jie Huang, Pradeep Natarajan, Yan V. Sun, Scott L. DuVall, Daniel J. Rader, Kelly Cho, Kyong-Mi Chang, Peter W.F. Wilson, Christopher J. O’Donnell, Sekar Kathiresan, Salvatore T. Scali, Scott A. Berceli, Cristen Willer, Gregory T. Jones, Matthew J. Bown, Girish Nadkarni, Iftikhar J. Kullo, Marylyn Ritchie, Scott M. Damrauer, Philip S. Tsao, J. Michael Gaziano, Rachel Ramoni, Jean Beckham, Jim Breeling, Grant Huang, Sumitra Muralidhar, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan-Mai T. Nguyen, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Clement J. Zablocki, Jeffrey Whittle, John Wells, Salvador Gutierrez, Gretchen Gibson, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Florez, Alan Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald Washburn, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard Servatius, Mary Oehlert, Agnes Wallbom, Ronald Fernando, Timothy Morgan, Todd Stapley, Scott Sherman, Gwenevere Anderson, Philip Tsao, Elif Sonel, Edward Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, and Robert Striker
Subjects: medicine.medical_specialty, Genome-wide association study, 030204 cardiovascular system & hematology, Aortic disease, aortic diseases, 03 medical and health sciences, 0302 clinical medicine, Aneurysm, Original Research Articles, Physiology (medical), Internal medicine, medicine, Humans, Veterans, 030304 developmental biology, Cardiovascular mortality, 0303 health sciences, genome-wide association study, business.industry, medicine.disease, Abdominal aortic aneurysm, Genetic architecture, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, aneurysm, Cardiology, Cardiology and Cardiovascular Medicine, business, Aortic Aneurysm, Abdominal
Abstract: Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.
Published: 2020
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8. Differences in Pathology, Staging, and Treatment between HIV+ and Uninfected Patients with Microscopically Confirmed Hepatocellular Carcinoma

Author: Rajni Mehta, Amy C. Justice, Xuchen Zhang, Norbert Bräu, Darshana Jhala, Dena M. Carbonari, Farah Kidwai-Khan, Lesley S. Park, Tamar H. Taddei, Kisha Mitchell Richards, Vincent Lo Re, Kathryn D'Addeo, Michael J. Kallan, Melissa Skanderson, Robert J. Homer, and Jessie Torgersen
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Epidemiology, business.industry, Lymphovascular invasion, Proportional hazards model, Hazard ratio, Retrospective cohort study, medicine.disease, Tumor Pathology, BCLC Stage, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Carcinoma, medicine, business
Abstract: Background: The incidence of hepatocellular carcinoma (HCC) is substantially higher among HIV-infected (HIV+) than uninfected persons. It remains unclear if HCC in the setting of HIV infection is morphologically distinct or more aggressive. Methods: We evaluated differences in tumor pathology in a cohort of HIV+ and uninfected patients with microscopically confirmed HCC in the Veterans Aging Cohort Study from 2000 to 2015. We reviewed pathology reports and medical records to determine Barcelona Clinic Liver Cancer stage (BCLC), HCC treatment, and survival by HIV status. Multivariable Cox regression was used to determine the hazard ratio [HR; 95% confidence interval (CI)] of death associated with HIV infection after microscopic confirmation. Results: Among 873 patients with HCC (399 HIV+), 140 HIV+ and 178 uninfected persons underwent liver tissue sampling and had microscopically confirmed HCC. There were no differences in histologic features of the tumor between HIV+ and uninfected patients, including tumor differentiation (well differentiated, 19% vs. 28%, P = 0.16) and lymphovascular invasion (6% vs. 7%, P = 0.17) or presence of advanced hepatic fibrosis (40% vs. 39%, P = 0.90). There were no differences in BCLC stage (P = 0.06) or treatment (P = 0.29) by HIV status. After adjustment for risk factors, risk of death was higher among HIV-infected than uninfected patients (HR = 1.37; 95% CI, 1.02–1.85). Conclusions: We found no differences in HCC tumor characteristics or background hepatic parenchyma by HIV status, yet HIV was associated with poorer survival. Of note, pathology reports often omitted these characteristics. Impact: Systematic evaluation of HCC pathology by HIV status is needed to understand tumor characteristics associated with improved survival.
Published: 2020
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9. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. 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Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. 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O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards 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Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.
Subjects: LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract: Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551
Published: 2022
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10. Variability in biopsy quality informs translational research applications in hepatocellular carcinoma

Author: Shilpa N. Reddy, S. William Stavropoulos, David Ostrowski, Michael C. Soulen, Stephen J. Hunt, J. Redmond, Abashai Woodard, Jeffrey I. Mondschein, James X. Chen, David E. Kaplan, Wuyan Li, Susan Shamimi-Noori, Mandeep Dagli, Deepak Sudheendra, Gregory J. Nadolski, Evan S. Siegelman, Joshua Cho, Terence P. Gade, Tamim Khaddash, Emma E. Furth, Kelley Weinfurtner, Darshana Jhala, and Daniel Ackerman
Subjects: Male, medicine.medical_specialty, Percutaneous, Carcinoma, Hepatocellular, Hepatocellular carcinoma, Science, Tumour heterogeneity, Biopsy, Malignancy, Article, Specimen Handling, Translational Research, Biomedical, Interquartile range, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Multidisciplinary, medicine.diagnostic_test, business.industry, Clinical study design, Liver Neoplasms, Translational research, medicine.disease, Clinical trial, Medicine, Female, Radiology, business, Liver cancer
Abstract: In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7–10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10–75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.
Published: 2021

11. A MUC5Bgene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection

Author: Jennifer E. Huffman, Saiju Pyarajan, Lina Gao, Helene Garcon, Pradeep Natarajan, Seyedeh M. Zekavat, Mehrdad Arjomandi, John Michael Gaziano, Bryan R Gorman, Nallakkandi Rajeevan, Julie Lynch, Wen-Chih Wu, Anurag Verma, Darshana Jhala, Kyong-Mi Chang, Katherine P. Liao, Kelly Cho, Jacob Joseph, Peter W.F. Wilson, Curtis J. Donskey, Philip S. Tsao, Yan V. Sun, Richard L. Hauger, Kristine E. Lynch, Joel Gelernter, Elise Gatsby, James B. Meigs, Yuk-Lam Ho, Jin J Zhou, Ayako Suzuki, Christopher J. O'Donnell, Robert A. Bonomo, Sharvari Dalal, Ravi Madduri, Cecelia J Madison, Mat Freiberg, Renato Polimanti, Shiuh-Wen Luoh, John E. McGeary, Gita A. Pathak, Peter D. Reaven, Rose Dl Huang, Sudha K Iyengar, Quinn S. Wells, Jeffrey Petersen, Emily S. Wan, and Jessica Minnier
Subjects: medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Incidence (epidemiology), medicine.disease, MUC5B gene, Pathophysiology, Idiopathic pulmonary fibrosis, Pneumonia, Polymorphism (computer science), Internal medicine, medicine, Allele, business
Abstract: RationaleA commonMUC5Bgene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear.ObjectivesTo assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI).MethodsMVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of aMUC5Brs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2,and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions.Measurements and Main ResultsA COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement.ConclusionsTheMUC5Bvariant rs35705950-T is protective in COVID-19 infection.
Published: 2021
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12. Serous fluid: Reactive conditions

Author: Nirag Jhala, Darshana Jhala, and Vinod B. Shidham
Subjects: humanities, health care economics and organizations, Pathology and Forensic Medicine
Abstract: This chapter highlights the steps that would help to analyze any fluid. It highlights importance of knowing gross analysis of fluid along with biochemical information. These parameters along with clinical information are very important in arriving at a differential diagnosis. Morphologic appearances in the fluid can often become challenging and occasionally reactive conditions can reveal changes that may mimic malignancies. This chapter provides not only a framework of approach to assessment of fluid cytology but also shows how to distinguish some of the challenging reactive conditions from the diagnosis of carcinoma. The chapter also utilizes two cases to demonstrate approach to reactive conditions. This review article will be incorporated finally as one of the chapters in CMAS (CytoJournal Monograph/Atlas Series) #2. It is modified slightly from the chapter by the initial authors in the first edition of Cytopathologic Diagnosis of Serous Fluids.
Published: 2021

13. Schwannoma with Psammoma Body

Author: Lindsay M. Hummel, Opoku Adjapong, Robert Krouse, Darshana Jhala, S Dalal, and Susan Gamble
Subjects: Male, Pathology, medicine.medical_specialty, Psammoma body, business.industry, 030229 sport sciences, General Medicine, Schwannoma, Middle Aged, medicine.disease, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Melanocytic Schwannoma, otorhinolaryngologic diseases, Medicine, Humans, business, Carney complex, Neurilemmoma
Abstract: We present a case of a 59-year-old male veteran with a chronic history of right foot soft-tissue mass that was causing pain in his shoes, but not functional or neurologic symptoms. Excision of the mass and pathologic evaluation resulted in multidisciplinary involvement and evaluation. In this example, the mass was found to be either an unusual schwannoma that happens to be psammoma body–rich or an unusual psammomatous melanocytic schwannoma that deviates from conventional examples, as a diagnostic consensus was unable to be reached. Schwannomas are an uncommon finding in the foot, and even more uncommon are those that contain psammoma bodies. Although rare, these tumors can be concerning for more systemic, life-altering diseases such as Carney complex, for which our patient refused genetic testing.
Published: 2021

14. Critical Aspects of SARS-CoV-2 Testing During the Pandemic

Author: Jeffrey Petersen and Darshana Jhala
Published: 2021
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15. Criticality of In-House Preparation of Viral Transport Medium in Times of Shortage During COVID-19 Pandemic

Author: Darshana Jhala, Sharvari Dalal, and Jeffrey Petersen
Subjects: Quality Control, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Clinical Biochemistry, Economic shortage, emergency preparedness, laboratory workflow, quality assurance, viral transport media preparation, Specimen Handling, 03 medical and health sciences, 0302 clinical medicine, molecular pathology, Amphotericin B, supply shortage, Pandemic, Labmed/1080, Medicine, Humans, 030212 general & internal medicine, Special Report, Biochemistry, medical, Hanks Balanced Salt Solution, business.industry, SARS-CoV-2, Biochemistry (medical), COVID-19, Antimicrobial, Culture Media, Gentamicin Sulfate, 030220 oncology & carcinogenesis, Emergency medicine, Viral Transport medium, clinical pathology, business, AcademicSubjects/MED00690, medicine.drug
Abstract: ObjectiveWith the COVID-19 pandemic, there have been supply challenges necessitating that laboratories must prepare their own viral transport medium (VTM), which provides stability for clinical specimens for diagnostic viral testing.MethodsWithin a veteran affairs medical center clinical laboratory, VTM was prepared with a Hanks Balanced Salt Solution (HBSS) 500 mL bottle with phenol red, sterile heat-inactivated fetal bovine serum (FBS), gentamicin sulfate (50 mg/mL), and amphotericin B (250 μg/mL). An antimicrobial mixture was made of 50 mL each of amphotericin B and gentamicin sulfate. Ten mL of FBS and 2 mL of the antimicrobial mixture were mixed into the HBSS bottle, from which 3 mL aliquots were made. Sterility and efficacy check were assessed. These preparations were conducted at our VAMC’s clinical laboratory to assure adequate VTM supply during the COVID-19 shortage.ResultsThe VTM was successfully prepared in-house, supporting uninterrupted testing for the facility and other affiliated medical facilities/centers and community living centers.ConclusionThis quality assurance/improvement report represents the first published manuscript on feasible VTM preparation exclusively within a clinical microbiology laboratory during the COVID-19 pandemic.
Published: 2020

16. Mitigation of a Coronavirus Disease 2019 Outbreak in a Nursing Home Through Serial Testing of Residents and Staff

Author: Valerianna Amorosa, Ruby Love, Mary Hofmann, Daniel J Escobar, Darshana Jhala, Maria Lanzi, Jeffrey B. Doyon, Darren R. Linkin, John J. Kelly, and Pouné Saberi
Subjects: Outbreak response, Microbiology (medical), 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Outbreak, 030501 epidemiology, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Emergency medicine, Medicine, 030212 general & internal medicine, 0305 other medical science, business, Nursing homes
Abstract: Nursing homes and long-term care facilities represent highly vulnerable environments for respiratory disease outbreaks, such as coronavirus disease 2019 (COVID-19). We describe a COVID-19 outbreak in a nursing home that was rapidly contained by using a universal testing strategy of all residents and nursing home staff.
Published: 2020
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17. Moving Toward a Systematic Approach for Reporting Salivary Gland Cytopathology: An Institutional Experience and Literature Review

Author: He Wang, Christopher Fundakowski, Jasvir S Khurana, Nirag Jhala, Xunda Luo, and Darshana Jhala
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.diagnostic_test, Salivary gland, Pathology, Surgical, business.industry, Cytodiagnosis, General surgery, Biopsy, Fine-Needle, MEDLINE, General Medicine, Salivary Gland Neoplasms, Pathology and Forensic Medicine, 03 medical and health sciences, Medical Laboratory Technology, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Cytopathology, 030220 oncology & carcinogenesis, Biopsy, Humans, Medicine, business
Abstract: Context.—Despite the clinical utility of fine-needle aspiration for the diagnosis of salivary pathologies, salivary lesions remain one of the most challenging areas in cytopathology. This is partially because there is no consensus on how to report salivary gland cytopathology, which has resulted in inconsistent terminology among institutions and individual cytopathologists and in confusion in communication among cytopathologists and ordering providers.Objective.—To summarize our experience with an institutional salivary gland cytopathology reporting system, as an initiative to promote collaborative work toward a consensus on a reporting system.Design.—We developed an empirical 6-tier classification reporting system. Slides of 107 salivary gland fine-needle aspirations with subsequent histology slides were reviewed and reclassified using the 6-tier system. The performance of the cytology reporting system was evaluated with the histology diagnoses serving as the gold standard.Results.—Fine-needle aspiration diagnoses made based on the institutional 6-tier classification system were generally consistent with histology diagnoses for the disease spectrum reported in this study. The sensitivity, specificity, positive predictive value, and negative predictive value for diagnosing malignancies with the system were 86% (12 of 14), 93% (40 of 43), 80% (12 of 15), and 95% (40 of 42), respectively. The risk of malignancy increased from 0% (0 of 13) for negative for neoplasm to 7% (2 of 29) for benign neoplasm, 67% (2 of 3) for suspicious for malignancy, and 83% (10 of 12) for positive for malignancy.Conclusions.—The institutional 6-tier system provides a succinct, risk-of-malignancy–based system to report salivary gland cytology. Our experience with this system helps to pave the way for the adoption of the Milan System for Reporting Salivary Gland Cytopathology.
Published: 2018
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18. Alcohol Consumption and Risk of Coronary Artery Disease (from the Million Veteran Program)

Author: Rebecca J. Song, Xuan-Mai T. Nguyen, Rachel Quaden, Yuk-Lam Ho, Amy C. Justice, David R. Gagnon, Kelly Cho, Christopher J. O'Donnell, John Concato, J. Michael Gaziano, Luc Djoussé, Ildiko Halasz, Daniel Federman, Jean Beckham, Scott E. Sherman, Peruvemba Sriram, Philip S. Tsao, Edward J. Boyko, Junzhe Xu, Frank Lederle, Louis J. Dellitalia, Rachel McArdle, Laurence Kaminsky, Alan C. Swann, Mark B. Hamner, Hermes J. Florez, Prashant Pandya, Gerardo Villarreal, Peter Wilson, Timothy R. Morgan, Lori Davis, Robin A. Hurley, Laurence Meyer, Sunil K. Ahuja, Eric P. Konicki, David Cohen, Jack Lichy, Jeffrey Whittle, Kathlyn Sue Haddock, Karl D. Straub, John T. Callaghan, Samuel M. Aguayo, Samir Gupta, Ronald G. Washburn, Mary E. Oehlert, Adriana M. Hung, Agnes Wallbom, Robert Keith, Elif Sonel, Ronald B. Schifman, Richard D. Childress, Michael F. Godschalk, Alan R. Shuldiner, Padmashri Rastogi, Salvador Gutierrez, Ronald Fernando, Pran R. Iruvanti, Darshana Jhala, Carlos Rosado-Rodriguez, Stephen M. Mastorides, John B. Harley, Kristin Mattocks, Brooks Robey, Robert T. Striker, Michael Rauchman, John Wells, Zuhair K. Ballas, Susan S. Woods, Shing Shing Yeh, Nora R. Ratcliffe, Jon B. Klein, Adam G. Golden, Harold M. Ginzburg, Satish Sharma, Kris Ann K. Oursler, Mary A. Whooley, Gretchen Gibson, and null Heinz
Subjects: Male, medicine.medical_specialty, Alcohol Drinking, Population, Coronary Artery Disease, Alcohol use disorder, 030204 cardiovascular system & hematology, Lower risk, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, education, Aged, Proportional Hazards Models, Veterans, education.field_of_study, Proportional hazards model, business.industry, Alcoholic Beverages, Hazard ratio, Middle Aged, Protective Factors, medicine.disease, United States, Confidence interval, Alcoholism, Cardiology, Female, Self Report, Cardiology and Cardiovascular Medicine, business, Body mass index, Demography
Abstract: Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.
Published: 2018
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19. Access by Ethnicity for Clinically Indicated Molecular Tests in Patients with Pancreatic Adenocarcinoma

Author: Darshana Jhala and Jeffrey Petersen
Subjects: medicine.medical_specialty, business.industry, Internal medicine, Ethnic group, Medicine, Adenocarcinoma, In patient, business, medicine.disease, Gastroenterology, Pathology and Forensic Medicine
Published: 2021
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20. Tumor Molecular Gene Profiling of Pancreatic Adenocarcinoma and Compliance with the Latest NCCN Guideline: A Regional Veteran Affairs Medical Center Experience

Author: Jeffrey Petersen and Darshana Jhala
Subjects: Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, Adenocarcinoma, Profiling (information science), Center (algebra and category theory), Guideline, medicine.disease, business, Pathology and Forensic Medicine
Published: 2021
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21. Blood Provision for Cardiac Ablation (CA) Procedures in the Catheterization Laboratory; a Veteran Affairs Medical Center (VAMC) Experience in a Non-Trauma Center Setting

Author: Darshana Jhala, Vijal Patel, and Jeffrey Petersen
Subjects: medicine.medical_specialty, business.industry, General surgery, Trauma center, Medicine, Center (algebra and category theory), General Medicine, Cardiac Ablation, business
Abstract: Introduction/Objective Cardiac perforation is a life-threatening complication (~1% risk, with reported rates between 0.2% to 5%) of CA procedures. As cardiac perforation may lead to extensive bleeding, it would be reasonable for a medical center carrying out CA to be capable of arranging for a massive transfusion protocol and for surgical repair as required. However, there is sparse literature to guide a non-trauma medical center implementing a CA program on what the number of red blood cell (RBC) units for crossmatch should be for each case. Methods In interdisciplinary collaborative meetings, the CA program logistics were agreed to between the multiple clinical services. Given the case series on the amount of drained blood in complicated cases, there was agreement that three units of RBCs would be crossmatched for each case. Education was provided on the massive transfusion protocol and on blood bank procedures. As part of quality assurance/quality improvement, records were reviewed from the beginning of the CA program (10/1/2019) to 1/31/2019 to determine number of patient cases, crossmatched units, and transfused units for quality assurance purposes. Results A total of fifteen patients underwent CA procedures, for which three units were crossmatched for each patient. As there were no cardiac perforations with the cardiac ablation procedures so far, no units were transfused. The organized approach for ensuring adequate blood bank support and education led to the reassurance, alleviation of clinical anxiety, and building of a successful CA program. Education sessions completed with thorough understanding of blood bank procedures including the massive transfusion protocol, labeling of blood bank specimens, and on ordering of blood for crossmatch. Conclusion This study provides a reference that may provide helpful guidance to other blood banks on what the number of RBCs to be crossmatched prior to each CA procedure. Multidisciplinary collaborative meetings in advance are an essential component for ensuring adequate support for CA procedures or any new service that requires blood product support. Thorough education of clinical staff on blood bank procedures particularly the massive transfusion protocol is also recommended. This procedure for massive transfusion should be available to be referred to in real time.
Published: 2020
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22. Differences in Pathology, Staging, and Treatment between HIV

Author: Jessie, Torgersen, Tamar H, Taddei, Lesley S, Park, Dena M, Carbonari, Michael J, Kallan, Kisha, Mitchell Richards, Xuchen, Zhang, Darshana, Jhala, Norbert, Bräu, Robert, Homer, Kathryn, D'Addeo, Rajni, Mehta, Melissa, Skanderson, Farah, Kidwai-Khan, Amy C, Justice, and Vincent, Lo Re
Subjects: Ablation Techniques, Liver Cirrhosis, Male, Carcinoma, Hepatocellular, Hospitals, Veterans, Liver Neoplasms, virus diseases, HIV Infections, Kaplan-Meier Estimate, Middle Aged, United States, Article, Liver Transplantation, Treatment Outcome, Liver, Risk Factors, Hepatectomy, Humans, Female, Immunologic Surveillance, Neoplasm Staging, Retrospective Studies
Abstract: BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is substantially higher among HIV-infected (HIV+) than uninfected persons. It remains unclear if HCC in the setting of HIV infection is morphologically distinct or more aggressive. METHODS: We evaluated differences in tumor pathology in a cohort of HIV+ and uninfected patients with microscopically confirmed HCC in the Veterans Aging Cohort Study from 2000-2015. We reviewed pathology reports and medical records to determine Barcelona Clinic Liver Cancer stage (BCLC), HCC treatment, and survival by HIV status. Multivariable Cox regression was used to determine the hazard ratio (HR [95% confidence interval]) of death associated with HIV infection after microscopic confirmation. RESULTS: Among 873 patients with HCC (399 HIV+), 140 HIV+ and 178 uninfected persons underwent liver tissue sampling and had microscopically confirmed HCC. There were no differences in histologic features of the tumor between HIV+ and uninfected patients, including tumor differentiation (well differentiated, 19% versus 28%, p=0.16) and lymphovascular invasion (6% versus 7%, p=0.17) or presence of advanced hepatic fibrosis (40% versus 39%, p=0.90). There were no differences in BCLC stage (p=0.06) or treatment (p=0.29) by HIV status. After adjustment for risk factors, risk of death was higher among HIV-infected than uninfected patients (HR, 1.37 [1.02-1.85]). CONCLUSIONS: We found no differences in HCC tumor characteristics or background hepatic parenchyma by HIV status, yet HIV was associated with poorer survival. Of note, pathology reports often omitted these characteristics. IMPACT: Systematic evaluation of HCC pathology by HIV status is needed to understand tumor characteristics associated with improved survival.
Published: 2019

23. Role of Ancillary Testing on Endoscopic US-Guided Fine Needle Aspiration Samples from Cystic Pancreatic Neoplasms

Author: Nirag Jhala, Darshana Jhala, and Piyachat Srimunta
Subjects: medicine.medical_specialty, Histology, DNA Mutational Analysis, medicine.disease_cause, Pathology and Forensic Medicine, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Carcinoembryonic antigen, parasitic diseases, medicine, GNAS complex locus, Humans, Cyst, Endoscopic Ultrasound-Guided Fine Needle Aspiration, biology, Intraductal papillary mucinous neoplasm, medicine.diagnostic_test, business.industry, General Medicine, 030224 pathology, medicine.disease, Immunohistochemistry, Carcinoembryonic Antigen, Pancreatic Neoplasms, medicine.anatomical_structure, Fine-needle aspiration, 030220 oncology & carcinogenesis, Mutation, biology.protein, Radiology, KRAS, Pancreatic cysts, Pancreatic Cyst, Pancreas, business, Carcinoma, Pancreatic Ductal
Abstract: Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.
Published: 2019

24. Contributors

Author: Mohammad Al-Haddad, Jouke T. Annema, Ji Young Bang, Omer Basar, William R. Brugge, Suresh T. Chari, Laurence MMJ Crombag, Paul Fockens, Larissa L. Fujii-Lau, Ferga C. Gleeson, Steve Halligan, Kazuo Hara, Robert H. Hawes, Bronte Holt, Joo Ha Hwang, Takao Itoi, Darshana Jhala, Nirag Jhala, Abdurrahman Kadayifci, Mouen Khashab, Eun Young (Ann) Kim, Wilson T. Kwong, Alberto Larghi, Anne Marie Lennon, Michael J. Levy, Girish Mishra, Robert Moran, Dongwook Oh, Sarto C. Paquin, Do Hyun Park, Mihai Rimbaș, Thomas Rösch, Adrian Săftoiu, Anand V. Sahai, Thomas J. Savides, Thomas Smyrk, Anthony Yuen Bun Teoh, Mark Topazian, Shyam Varadarajulu, Peter Vilmann, and Sachin Wani
Published: 2019
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25. Criticality Of Adequate Quality Monitoring Of Pre-Type And Screen Orders For The Operating Room: Role Of The Education, Proactive Communication At VAMC

Author: Jeffrey Petersen, Darshana Jhala, and Vijal Patel
Subjects: Criticality, Computer science, Quality monitoring, General Medicine, Reliability engineering
Abstract: Introduction/Objective Ordering pre-operative type and screen specimens before the day of surgery is very important to prevent delays in provision of blood products due to unexpected alloantibody findings, unexpected ABO discrepancies, or need for a repeat ABO-RH testing due to lack of historical testing. However, the important pre- operative type and screen was not always ordered prior to the day of surgery by the clinician. Due to this observation, after discussion and collaboration with the Blood Utilization Committee (BUC), an educational and mentoring intervention for the pre-operative clinicians was undertaken. Methods Education and mentoring of clinicians involved in the pre-operative clinics, surgical services, and new incoming physicians on an ongoing basis was undertaken through the BUC since March 2018. As part of quality assurance, to track the results of this widespread educational effort, the daily OR lists from January 2017 to December 2019 were examined with the medical record to determine if a pre-operative type and screen was ordered prior to the day of surgery. The established Maximum Surgery Blood order Schedule (MSBOS) for the facility was used to determine if a pre-operative type and screen would be indicated for the listed procedure. Results As we started reinforced pre type and screen should be ordered there has been significant increase in percent of compliance rate average from 76% (2017), 87% (2018), and 95.6% (2019). By the T-test, there was a statistically significant change in the monthly ordering rates (p-value < 0.05). The VAMC’s preferred threshold value of at least 95% with pre-operative type and screen prior to the day of procedure was achieved in the 2019 calendar year with no operating room delays. Conclusion Appropriately performing the pre-operative type and screen prior to the day of the elective surgical procedure would reduce the risk of delays due to unexpected findings or lack of a historical ABO-RH type. Educational interventions help tremendously in ensuring this critical patient care practice is followed. The value of collaborating and educating clinicians cannot be understated as it is both cheap, simple, and highly effective.
Published: 2020
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26. Gender Differences in Demographic and Health Characteristics of the Million Veteran Program Cohort

Author: Kelly M. Harrington, Xuan-Mai T. Nguyen, Rebecca J. Song, Keri Hannagan, Rachel Quaden, David R. Gagnon, Kelly Cho, Jennifer E. Deen, Sumitra Muralidhar, Timothy J. O’Leary, John Michael Gaziano, Stacey B. Whitbourne, J. Michael Gaziano, Rachel Ramoni, Jim Breeling, Kyong-Mi Chang, Grant Huang, Christopher J. O’Donnell, Philip S. Tsao, Jennifer Moser, Jessica V. Brewer, John Concato, Stuart Warren, Pharm D, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, John Harley, Jeffrey Whittle, Jean Beckham, John Wells, Salvador Gutierrez, Gretchen Gibson, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Florez, Alan Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald Washburn, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard Servatius, Mary Oehlert, Agnes Wallbom, Ronald Fernando, Timothy Morgan, Todd Stapley, Scott Sherman, Gwenevere Anderson, Philip Tsao, Elif Sonel, Edward Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, and Robert Striker
Subjects: Adult, Male, Health (social science), Health Status, Migraine Disorders, Physical fitness, Population, Veterans Health, Demographic profile, Article, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Sex Factors, Surveys and Questionnaires, Maternity and Midwifery, Health care, Prevalence, Medicine, Humans, 030212 general & internal medicine, Musculoskeletal Diseases, Sex Distribution, education, Veterans Affairs, Aged, Veterans, education.field_of_study, business.industry, 030503 health policy & services, Mental Disorders, Smoking, Public Health, Environmental and Occupational Health, Obstetrics and Gynecology, Middle Aged, Mental health, humanities, United States, United States Department of Veterans Affairs, Cardiovascular Diseases, Physical Fitness, Cohort, Female, 0305 other medical science, business, Demography, Cohort study
Abstract: Background The Department of Veterans Affairs Million Veteran Program (MVP) is the largest ongoing cohort program of its kind, with 654,903 enrollees as of June 2018. The objectives of this study were to examine gender differences in the MVP cohort with respect to response and enrollment rates; demographic, health, and health care characteristics; and prevalence of self-reported health conditions. Methods The MVP Baseline Survey was completed by 415,694 veterans (8% women), providing self-report measures of demographic characteristics, health status, and medical history. Results Relative to men, women demonstrated a higher positive responder rate (23.0% vs. 16.0%), slightly higher enrollment rate (13.5% vs. 12.9%), and, among enrollees, a lower survey completion rate (59.7% vs. 63.8%). Women were younger, more racially diverse, had higher educational attainment, and were less likely to be married or cohabitating with a partner than men. Women were more likely to report good to excellent health status but poorer physical fitness, and less likely to report lifetime smoking and drinking than men. Compared with men, women veterans showed an increased prevalence of musculoskeletal conditions, thyroid problems, gastrointestinal conditions, migraine headaches, and mental health disorders, as well as a decreased prevalence of gout, cardiovascular diseases, high cholesterol, diabetes, and hearing problems. Conclusions These results revealed some substantial gender differences in the research participation rates, demographic profile, health characteristics, and prevalence of health conditions for veterans in the MVP cohort. Findings highlight the need for tailoring recruitment efforts to ensure representation of the increasing women veteran population receiving care through the Veterans Health Administration.
Published: 2018

27. DASH Score and Subsequent Risk of Coronary Artery Disease: The Findings From Million Veteran Program

Author: Luc Djoussé, Yuk‐Lam Ho, Xuan‐Mai T. Nguyen, David R. Gagnon, Peter W.F. Wilson, Kelly Cho, J. Michael Gaziano, Ildiko Halasz, Daniel Federman, Jean Beckham, Scott E. Sherman, Peruvemba Sriram, Philip S. Tsao, Edward J. Boyko, Junzhe Xu, Frank Lederle, Louis J. Dellitalia, Rachel McArdle, Laurence Kaminsky, Alan C. Swann, Mark B. Hamner, Hermes J. Florez, Prashant Pandya, Gerardo Villarreal, Peter Wilson, Timothy R. Morgan, Lori Davis, Robin A. Hurley, Laurence Meyer, Sunil K. Ahuja, Eric P. Konicki, David Cohen, Jack Lichy, Jeffrey Whittle, Kathlyn Sue Haddock, Karl D. Straub, John T. Callaghan, Samuel M. Aguayo, Samir Gupta, Ronald G. Washburn, Mary E. Oehlert, Adriana M. Hung, Agnes Wallbom, Robert Keith, Elif Sonel, Ronald B. Schifman, Richard D. Childress, Michael F. Godschalk, Alan R. Shuldiner, Padmashri Rastogi, Salvador Gutierrez, Ronald Fernando, Pran R. Iruvanti, Darshana Jhala, Carlos Rosado‐Rodriguez, Stephen M. Mastorides, John B. Harley, Kristin Mattocks, Robert T. Striker, Michael Rauchman, John Wells, Zuhair K. Ballas, Susan S. Woods, Shing Yeh, Nora R. Ratcliffe, Jon B. Klein, Adam G. Golden, Harold M. Ginzburg, Satish Sharma, Kris Ann K. Oursler, Mary A. Whooley, and Gretchen Gibson
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Time Factors, Dietary Approaches To Stop Hypertension, Epidemiology, Population, Veterans Health, Coronary Artery Disease, Lower risk, Risk Assessment, Coronary artery disease, 03 medical and health sciences, Risk Factors, Internal medicine, Cardiovascular Disease, Dash, medicine, Humans, Prospective Studies, education, Aged, Original Research, education.field_of_study, 030109 nutrition & dietetics, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Middle Aged, Protective Factors, medicine.disease, Prognosis, Lifestyle, Confidence interval, United States, nutrition, Patient Compliance, Female, Diet, Healthy, Cardiology and Cardiovascular Medicine, business, Body mass index, Risk Reduction Behavior
Abstract: Background While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. Methods and Results We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow‐up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow‐up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person‐years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84–0.99), 0.87 (0.80–0.95), 0.86 (0.79–0.94), and 0.80 (0.73–0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use ( P linear trend, Conclusions Our data are consistent with an inverse association between Dietary Approach to Stop Hypertension diet score and incidence of CAD among US veterans.
Published: 2018

28. Adequacy and Incidence of Primary Pancreatic Cancer on Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) Cytology Samples: A Retrospective Review in Veteran Population at Corporal Michael J. Crescenz Veteran Affairs Medical Center (CMCVAMC)

Author: Jeffrey Petersen, S Dalal, and Darshana Jhala
Subjects: Endoscopic ultrasound, medicine.medical_specialty, education.field_of_study, Retrospective review, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Population, General Medicine, medicine.disease, Fine-needle aspiration, Cytology, Pancreatic cancer, medicine, Radiology, education, business
Abstract: Introduction Pancreatic cancer is the one of leading causes of cancer-related deaths, accounts for 7% of cancer related deaths, and generally is diagnosed at an advanced stage. The 5-year survival rate is about 62%. There are no current screening recommendations for pancreatic cancer, so primary diagnosis is of the utmost importance. EUS modality for FNA has revolutionized the ability for the early diagnosis and staging of cancers of the gastrointestinal tract as being safe, cost-effective, minimally invasive technology to assess the pancreas. To date, there is no study in English literature assessing the adequacy for diagnosis and ancillary studies on EUS-FNA of pancreatic mass lesions in veterans. The veteran patient population is a unique cohort with different risk factors and demographics. Methods As a part of quality assurance project, a search was conducted to identify all EUS of pancreatic lesions performed at our hospital from February 2, 2011, to March 3, 2019. We evaluated adequacy on the cell blocks and diagnostic accuracy of EUS-FNA among all pancreatic mass lesions. Results Out of the total 130 EUS-FNA pancreas cases, the diagnosis was established in 127 cases (97.6%). Three cases were insufficient and total 26 cases were diagnosed as atypia, suggesting repeat FNA for definitive diagnosis. A definitive diagnosis was made in 101 cases (77.7%). Four cases were suspicious for malignancy. Malignancy/severe dysplasia was diagnosed in total 45 cases, most being primary pancreatic adenocarcinoma (41) and four with other diagnoses. Conclusion EUS-FNA is highly successful for procuring adequate material on the cytology samples for pancreatic lesions. EUS-FNAs for pancreatic lesions have high sensitivity and specificity for diagnosing and directing early, appropriate clinical management in veterans. The percentage of primary pancreatic adenocarcinomas out of total tumors in this veteran population is high (91.1%).
Published: 2019
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29. Highly Effective Model for Implementation of In-House Platelets in a Tertiary Hospital Setting Without a Trauma Center: Corporal Michael J. Crescenz Veterans Affairs Medical Center (CMCVAMC) Experience

Author: Darshana Jhala, Jeffrey Petersen, and Vijal Patel
Subjects: Hospital setting, Cost effectiveness, business.industry, Trauma center, Medicine, Center (algebra and category theory), General Medicine, Medical emergency, business, medicine.disease, Veterans Affairs, Cost savings
Abstract: Introduction Platelet products have a limited shelf life and are costly. Hence, it remains crucial to balance clinical usage and wastage in a tertiary hospital setting without a trauma center. Considering this, an innovative system model was established to reduce wastage: the CMCVAMC—starting October 2017—arranged to transfer the platelet unit to a nearby facility with a trauma center when product has a short expiration date and there is no anticipated need for the product. This is a cost-effective measure to reduce platelet wastage and ensure the appropriate blood product availability. Method QA/QI data were reviewed to determine the degree of platelet wastage both a year prior to the implementation of this platelet transfer to another facility and after the past implementation of this transfer to February 2019. The cost of each platelet product was determined from the blood supplier (American Red Cross). From these comparisons prior to and after implementation, a determination of reduction of product wastage and cost savings was made. Results Since the implementation of this platelet transfer, there have been no platelets expiring on the shelf. In contrast, from October 2016 to October 2017 prior to implementation of platelet transfer, platelet products were often wasted or expired. In contrast, from October 2017 to February 2019, there has been no wastage of platelets. Conclusion This is a highly effective model for a tertiary hospital without a trauma center to bring in house platelets without wastage of a costly product while maintaining appropriate availability of the product. This quality improvement system study demonstrates that the measure resulted in significant savings and this serves as a model for other similar facilities. This is an innovative, easy to implement, and cost-effective system model that can be used in other tertiary facilities without a trauma center.
Published: 2019
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30. Brunner Glands

Author: Nirag Jhala, Darshana Jhala, Ricardo R. Lastra, and Nuzhat A. Ahmad
Subjects: Endoscopic ultrasound, medicine.anatomical_structure, Fine-needle aspiration, medicine.diagnostic_test, business.industry, medicine, Brunner Glands, Anatomy, business, Pancreas, Pathology and Forensic Medicine
Published: 2015
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31. Cytology of the gastrointestinal tract: opportunities to be tapped

Author: Darshana Jhala
Subjects: Endoscopic ultrasound, medicine.medical_specialty, Gastrointestinal tract, Histology, medicine.diagnostic_test, business.industry, Brush cytology, Patient care, Pathology and Forensic Medicine, Surgery, Fine-needle aspiration, Cytology, Medicine, Radiology, business
Abstract: Impact of utilization of GI tract cytology has followed technological advancements. Earlier brush cytology was extensively utilized for upper and lower GI tract pathology for diagnosis of infections and malignancies. Over a period of time this advantage of cytology assessment has been rapidly declining. Development of endoscopic ultrasound imaging and its associated fine needle aspiration continues to find new indications for performing this modality. Developments in area of translational research continue to find opportunities for utilizing cytology samples obtained from GI tract. At current times it is observed that EUS-FNA finds its greatest niche for diagnosis of submucosal lesions. Utilization of immunohistochemical stains as well as molecular studies now increases power of this technique. This article reviews areas where GI tract cytology could be utilized to the advantage of patient care.
Published: 2015
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32. 72 Evaluation (Correlation/Validation) of 0.109M BD Vacutainer Plus Plastic (2.7 mL) and 0.105M BD Vacutainer Glass Sodium Citrate Tubes (4.5 mL) for PT, APTT, and Fibrinogen Using Diagnostic Stago STA

Author: Darshana Jhala and Sahil Patel
Subjects: chemistry.chemical_compound, Chromatography, Chemistry, Sodium citrate, medicine, General Medicine, Fibrinogen, Vacutainer, medicine.drug
Published: 2018
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33. 118 High-Grade Angiosarcoma Masquerading As A Simple Cyst and Histiocytic/Dendritic Cell Neoplasm With Histiocyte-Like Cells—A Diagnostic Conundrum

Author: Darshana Jhala and S Dalal
Subjects: Pathology, medicine.medical_specialty, business.industry, Simple cyst, Medicine, Dendritic cell neoplasm, Angiosarcoma, General Medicine, business, Histiocyte
Published: 2018
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34. 364 Formation of a Cold Reactive Anti-A1 After Transfusion With A1 Red Blood Cell Units in the Setting of Gross Hemolysis

Author: Darshana Jhala and Jeffrey Petersen
Subjects: Hemolytic anemia, Blood type, Blood transfusion, biology, business.industry, medicine.medical_treatment, General Medicine, medicine.disease, Hemolysis, Isoantibodies, Red blood cell, medicine.anatomical_structure, Immunology, medicine, biology.protein, Hemoglobin, Antibody, business
Published: 2018
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35. Advantages of the Use of Alcor iSED Automated Sed Rate Analyzer vs Manual Sed Rate in Evaluation and/or Monitoring the Treatment in Patients, CMCVAMC Experience

Author: Sahilkumar Patel and Darshana Jhala
Subjects: Rouleaux, Spectrum analyzer, medicine.diagnostic_test, business.industry, sed, General Medicine, Photometry (optics), Erythrocyte sedimentation rate, Medicine, In patient, business, Nuclear medicine, computer, computer.programming_language
Abstract: Objectives The automated Alcor iSED automated instrument has a major impact on the proper management of the patients in a timely manner with use of a minimal amount of the blood (100 µL). The Alcor iSED analyzer has introduced a new technology that forgoes sample preparation by using a Load and Go technology. We were previously using the Westergren tube method, which required special preparation of the tube to load into a special provided sealed cup. The entire procedure was tedious and time-consuming. To overcome, we acquired and implemented the Alcor iSED analyzer for an efficient and prompt reporting of sedimentation rate. Methods A sample was aspirated and dispensed from a closed tube, then dispensed into a capillary, and quantitative capillary photometry (aggregation) was used to measure ESR faster than traditional methods by capturing the kinetics of red blood cell aggregation in a controlled testing environment during the most critical phase of sedimentation, commonly referred to as the lag or Rouleaux formation phase. As a part of quality assurance monitoring, retrospective split analysis was performed for 75 samples. Analysis was performed using a Passing-Bablok regression analysis with the MedCalc program. Results Our results demonstrated significant differences between the two methods for the TAT. The TAT was significantly decreased with Alcor iSED (3 minutes for the first specimen and then 15-20 seconds for each sequential specimen) as compared to the manual Westergren method (1 hour), which significantly improved the reporting of results to the providers to monitor the treatment. Conclusion The Alcor iSED analyzer has provided truly shortened TAT erythrocyte sedimentation rate, allowing for better patient care and treatment.
Published: 2019
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36. Complex analysis of a recurrent pleomorphic hyalinizing angiectatic tumor of soft parts

Author: Thomas S. Winokur, Zenggang Pan, Gene P. Siegal, Shi Wei, Andrew J. Carroll, and Darshana Jhala
Subjects: Adult, Hyalin, Pathology, medicine.medical_specialty, Abnormal Karyotype, Mesenchymal Neoplasm, Soft Tissue Neoplasms, Biology, Cytoplasmic Granules, Translocation, Genetic, Pathology and Forensic Medicine, Biomarkers, Tumor, medicine, Humans, Mesenchymoma, Pleomorphic hyalinizing angiectatic tumor, Chromosomes, Human, Pair 10, Foot, Precursor lesion, Intranuclear Inclusions, Karyotype, Anatomy, Combined Modality Therapy, Chromosomes, Human, Pair 1, Cytogenetic Analysis, Blood Vessels, Female, Chromosomes, Human, Pair 3, Hemosiderotic Fibrohistiocytic Lipomatous Lesion, Neoplasm Recurrence, Local, Dilatation, Pathologic
Abstract: Summary Pleomorphic hyalinizing angiectatic tumor of soft parts is a recently recognized, low-grade mesenchymal neoplasm of uncertain lineage. It is characterized by clusters of ectatic, fibrin-lined, thin-walled vessels surrounded by pleomorphic but mitotically inert spindled cells with frequent intranuclear inclusions and a variable inflammatory component. Here, we report a case of recurrent pleomorphic hyalinizing angiectatic tumor in a 37-year-old white woman. Touch imprint cytologic analysis revealed oval and spindled cells with fine chromatin, occasional prominent intranuclear inclusions, and intracytoplasmic pigment. The histologic features of the cells constituting the bulk of tumor were those characteristic of a putative precursor lesion ("early pleomorphic hyalinizing angiectatic tumor") as well as another recently described entity known as hemosiderotic fibrohistiocytic lipomatous lesion. Cytogenetic analysis revealed 2 unbalanced translocations involving chromosomes 1 and 3 and chromosomes 1 and 10, with a karyotype of 45,XX,der(1)t(1;3)(p31;q12),-3,der(10)t(1;10)(p31;q25)[11]/46,XX[4], thus suggesting that this disease is neoplastic. The controversies in classification of these lesions are also discussed.
Published: 2012
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37. Endoscopic ultrasound-guided fine-needle aspiration of intrathoracic and intra-abdominal spindle cell and mesenchymal lesions

Author: Sarah M. Bean, Ralph Crowe, Mohamad A. Eloubeidi, Isam A. Eltoum, Nirag Jhala, Darshana Jhala, David C. Chhieng, and Allyson C. Baker
Subjects: Adult, Male, Endoscopic ultrasound, Cancer Research, medicine.medical_specialty, Pathology, Solitary fibrous tumor, Gastrointestinal Stromal Tumors, Biopsy, Fine-Needle, Endosonography, Young Adult, Biopsy, medicine, Humans, Melanoma, Lymph node, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Cancer, Sarcoma, Middle Aged, Prognosis, medicine.disease, Pancreatic Neoplasms, medicine.anatomical_structure, Fine-needle aspiration, Oncology, Chondrosarcoma, Mesenchymal, Female, Lymph Nodes, Radiology, Differential diagnosis, business, Follow-Up Studies
Abstract: BACKGROUND. The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in the evaluation of spindle cell and mesenchymal lesions is unclear. This study reviews the use of EUS-FNA in diagnosing intrathoracic and intra-abdominal spindle and mesenchymal cell lesions at an academic institution. METHODS. All EUS-FNA specimens with a significant spindle or mesenchymal cell component were retrieved. Follow-up was comprised of clinical correlation, chart review, or evaluation of subsequent tissue specimens, including FNAs, biopsies, and/or surgical resections. Lesions were categorized as either inflammatory/reactive or neoplastic. RESULTS. Forty-four EUS-FNA specimens were retrieved from 39 patients (21 men and 18 women with a median age of 61 years [range, 20-88 years]). Anatomic sites included 19 lymph node specimens, 15 gastrointestinal tract specimens, 7 pancreatic specimens, and 4 other anatomic site specimens. Twenty-two cases were inflammatory/reactive lesions, including 17 granulomatous lesions and 5 cases of chronic pancreatitis. Twenty-two cases were neoplastic, including 14 gastrointestinal stromal tumors, 2 smooth muscle tumors, 2 sarcomatoid carcinomas, 2 melanomas, 1 sarcoma, and 1 solitary fibrous tumor. A specific cytologic diagnosis was rendered in 30 cases (81%). Immunocytochemistry was performed on 21 neoplastic cases and contributed to the differential diagnosis in 18 cases. No false-positive findings were encountered. Three false-negative results were identified and were attributed to sampling error. CONCLUSIONS. Spindle cell neoplasms are rarely encountered on EUS-FNA. The differential diagnosis encompasses a wide variety of benign and neoplastic entities. Correlation of cytomorphology and ancillary studies yields a high diagnostic accuracy of spindle cell and mesenchymal lesions on EUS-FNA. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.
Published: 2010
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38. Merkel cell carcinoma: correlation of KIT expression with survival and evaluation of KIT gene mutational status

Author: Aleodor A. Andea, Isam E. Eltoum, Raj Patel, Sanjay Kumar, Selvarangan Ponnazhagan, Patricia DeVilliers, Gene P. Siegal, and Darshana Jhala
Subjects: Adult, Male, Silent mutation, Pathology, medicine.medical_specialty, animal structures, Skin Neoplasms, Biology, Article, Pathology and Forensic Medicine, Metastasis, medicine, Carcinoma, Humans, Point Mutation, skin and connective tissue diseases, Aged, Aged, 80 and over, integumentary system, Merkel cell carcinoma, virus diseases, Cancer, Middle Aged, medicine.disease, Immunohistochemistry, Carcinoma, Merkel Cell, Survival Rate, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, Tumor progression, Cancer research, Female, Merkel cell, Tyrosine kinase
Abstract: Merkel cell carcinoma is one of the most aggressive primary cutaneous malignancies. Because some Merkel cell carcinomas express the receptor tyrosine kinase KIT, we aimed to evaluate the correlation of KIT expression with the outcome and the presence of activating mutations in the KIT gene in Merkel cell carcinoma. A total of 49 tumors from 40 patients with a diagnosis of Merkel cell carcinoma were identified, of which 30 cases from 21 patients were used in the study. KIT expression was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded material. Cases were divided into low expressors (0-1+ staining intensity) and high expressors (2-3+ staining intensity). Direct sequencing of exons 9, 11, 13, 17, and 18 of the KIT gene spanning the extracellular, juxtamembrane, and tyrosine kinase domains was performed for cases with high KIT expression. Thirty tumors from 21 patients were analyzed for KIT expression. High KIT expression was seen in 67% of the patients. Five-year survival rates in tumors expressing high versus low levels of KIT were 0% versus 57.8%, respectively; however, this dramatic difference did not reach statistical significance (P = .07). A total of 4 point mutations were identified in 18 tumors analyzed. Two of these were silent mutations involving exons 17 and 18, and 2 involved intron 16-17. Two of the identified mutations may represent novel polymorphisms. Our work suggests a correlation between KIT expression and a worse prognosis in Merkel cell carcinoma patients, raising the possibility of an active role of this receptor in tumor progression and metastasis. However, we did not identify KIT activating mutations in any of the tumors analyzed.
Published: 2010
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39. Diagnostic Yield of Cytology and Surgical Specimen in Non–Small Cell Carcinoma of the Lung in Veteran Population in Era of Personized Diagnostic

Author: Opoku Adjapong and Darshana Jhala
Subjects: education.field_of_study, medicine.medical_specialty, Yield (engineering), Lung, medicine.diagnostic_test, business.industry, Population, General Medicine, Surgical specimen, medicine.disease, medicine.anatomical_structure, Cytology, Biopsy, medicine, Carcinoma, Radiology, Non small cell, education, business
Published: 2018
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40. Advantages of the Use of AQUIOS CL Flow Cytometer in Evaluation of CD4 and CD8 in HIV Patients: CMCVAMC Experience

Author: Sahil Patel, Brenda Wolf, and Darshana Jhala
Subjects: biology, medicine.diagnostic_test, business.industry, General Medicine, Binding (Molecular Function), medicine.disease, Flow cytometry, Pulmonary aspiration, Flow (mathematics), Antigen, Immunology, biology.protein, Hiv patients, Medicine, Antibody, business, CD8
Published: 2018
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41. E-Cadherin/β-Catenin and CD10

Author: Darshana Jhala, Gene P. Siegal, Xiuli Liu, Holly Burford, Zubair W. Baloch, and Nirag Jhala
Subjects: Endoscopic ultrasound, Pathology, medicine.medical_specialty, Pancreatic disease, medicine.diagnostic_test, biology, business.industry, Chromogranin A, General Medicine, medicine.disease, Fine-needle aspiration, medicine.anatomical_structure, Biopsy, medicine, Synaptophysin, biology.protein, Immunohistochemistry, business, Pancreas
Abstract: Pancreatic endocrine neoplasm (PEN) and solid pseudopapillary neoplasm of the pancreas (SPN) frequently pose diagnostic challenges. We sought to determine which markers could provide the best immunophenotypic characterization of PEN and SPN, allowing separation on limited cytology samples. We retrieved 22 resected PEN (n = 12) and SPN (n = 10) tumors to serve as a training set for the performance of extensive immunohistochemical staining. Based on these results, we selected a subset of antibodies for application to 25 fine-needle aspiration (FNA) samples from PEN (n = 16) and SPN (n = 9). Chromogranin A, synaptophysin, CD56, and progesterone receptor (PR) highlighted PEN cases in the training set; E-cadherin was noted in a membranous pattern. SPN cases were most immunoreactive for α1-antitrypsin, vimentin, CD10, and PR, with nuclear staining for β-catenin; E-cadherin did not show a membranous pattern. Among all FNA samples tested, the immunohistochemical staining of E-cadherin (P = .0003), β-catenin (P = .00004), and CD10 (P = .00006) demonstrated the greatest difference between PEN and SPN. The pattern of E-cadherin/β-catenin expression was highly specific for distinguishing PEN from SPN. On limited FNA samples, the characteristic expression of E-cadherin/β-catenin and the expression of CD10 can be used to distinguish PEN from SPN.
Published: 2009
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42. Juvenile juxtacortical chondromyxoid fibroma of bone: a case report

Author: Frank Yen, Gene P. Siegal, Pullivarthi Rao, Darshana Jhala, and Susan Coventry
Subjects: Male, Pathology, medicine.medical_specialty, Chromosomes, Human, Pair 21, Chondrosarcoma, Robertsonian translocation, Bone Neoplasms, Fibroma, Biology, medicine.disease_cause, Disease-Free Survival, Translocation, Genetic, Pathology and Forensic Medicine, law.invention, Benign tumor, Diagnosis, Differential, Intramedullary rod, Lesion, law, medicine, Humans, Child, Chromosomes, Human, Pair 14, Tibia, Chondromyxoid fibroma, Karyotype, medicine.disease, Magnetic Resonance Imaging, Clone Cells, Treatment Outcome, Pleomorphism (cytology), Chromosomes, Human, Pair 6, medicine.symptom, Chondroma
Abstract: Conventional intramedullary chondromyxoid fibroma (CMF) is a rare benign tumor of bone; juxtacortical lesions are rarer still, and juxtacortical lesions occurring in children are heretofore essentially unreported. We present a case of such a lesion in a 12-year-old boy. This patient, who was previously healthy, presented with a 1-week history of poorly defined pain and mild swelling in the region of the left proximal tibia. Magnetic resonance imaging and bone scan showed changes most consistent with an aggressive biological process. However, the permanent histologic sections showed a (pseudo) lobular pattern of spindle cells with minimal pleomorphism and other features consistent with CMF. A clonal abnormality was detected in 15% of tumor cells karyotyped, characterized by a break in the long arm of chromosome 6 and a balanced Robertsonian translocation involving chromosomes 14 and 21. The patient has remained well and free of recurrence for more than 4 years. In general, CMF needs to be distinguished from its mimicker low-grade chondrosarcoma, and it must be recognized as occurring on bone surfaces among a wide age range of individuals. Juxtacortical CMF has not proven to be unusually aggressive in adults nor in this child, and marginal (en-block) resection remains the treatment of choice.
Published: 2008
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43. Diagnostic usefulness and challenges in the diagnosis of mesothelioma by endoscopic ultrasound guided fine needle aspiration

Author: Khldoun Bakdounes, Darshana Jhala, and Nirag Jhala
Subjects: Male, Mesothelioma, Endoscopic ultrasound, medicine.medical_specialty, Lung Neoplasms, Histology, Biopsy, Fine-Needle, Endosonography, Pathology and Forensic Medicine, Diagnosis, Differential, medicine, Humans, neoplasms, Aged, medicine.diagnostic_test, business.industry, General Medicine, medicine.disease, Immunohistochemistry, Triage, Patient management, Fine-needle aspiration, Radiology, Differential diagnosis, business
Abstract: Malignant mesothelioma is a rare neoplasm. It has been noted in the literature that fine needle aspiration (FNA) is a useful tool for the diagnosis of mesothelioma. However, the differential diagnosis may require use of a battery of immunohistochemical stains. Clinico-radiologic correlation is also crucial. Real time endoscopic ultrasound (EUS) combined with FNA has been shown to be a very sensitive technique to obtain samples from different organ sites, including mediastinal lesions. The use of EUS-FNA for the diagnosis of mesothelioma, reinforces the role of a cytopathologist as a cohesive team player along with a radiologist and a clinician during on-site assessment for the proper triage of additional specimens for ancillary studies leading to a better patient management. Diagn. Cytopathol. 2008;36:503–507. © 2008 Wiley-Liss, Inc.
Published: 2008
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44. Fine-Needle Aspiration

Author: Nirag Jhala, Darshana Jhala, and Gene P. Siegal
Subjects: medicine.medical_specialty, Modality (human–computer interaction), medicine.diagnostic_test, business.industry, medicine.disease, Pathology and Forensic Medicine, Fine-needle aspiration, medicine.anatomical_structure, medicine, Neoplasm, Endocrine system, Radiology, Pancreas, business
Abstract: Fine-needle aspirates of the pancreas are increasingly being performed to obtain preoperative diagnoses of pancreatic lesions. This has also led to an increased recognition of nonductal pancreatic malignancies such as solid pseudopapillary neoplasm of the pancreas and pancreatic endocrine t
Published: 2007
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45. Cytology Primer for Endosonographers

Author: Darshana Jhala and Nirag Jhala
Subjects: Primer (paint), business.industry, Cytology, engineering, Medicine, engineering.material, business, Molecular biology
Published: 2015
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46. Contributors

Author: Mohammad Al-Haddad, Tiing Leong Ang, Jouke T. Annema, William R. Brugge, John DeWitt, Mohamad A. Eloubeidi, Douglas O. Faigel, Paul Fockens, Larissa L. Fujii, Ferga C. Gleeson, Steve Halligan, Robert H. Hawes, Bronte Holt, Joo Ha Hwang, Takao Itoi, Darshana Jhala, Nirag Jhala, Abdurrahman Kadayifci, Tatiana D. Khokhlova, Eun Young (Ann) Kim, Michael B. Kimmey, Alberto Larghi, Anne Marie Lennon, Michael J. Levy, Leticia Perondi Luz, John Meenan, Faris M. Murad, Nikola Panić, Sarto C. Paquin, Ian D. Penman, Shajan Peter, Joseph Romagnuolo, Thomas Rösch, Adrian Săftoiu, Anand V. Sahai, Wajeeh Salah, Thomas J. Savides, Stefan Seewald, Mark Topazian, Shyam Varadarajulu, Peter Vilmann, and Charles Vu
Published: 2015
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47. Mandatory fortification with folic acid in the United States is not associated with changes in the degree or the pattern of global DNA methylation in cells involved in cervical carcinogenesis

Author: William E. Grizzle, Alain Niveleau, Edmond K. Kabagambe, Maurizio Macaluso, Nirag Jhala, Darshana Jhala, Ilene Brill, Maria Azrad, and Chandrika J. Piyathilake
Subjects: Adult, Cancer Research, Pathology, medicine.medical_specialty, Uterine Cervical Neoplasms, Physiology, Biology, Cervical intraepithelial neoplasia, Folic Acid, Genetics, medicine, Humans, Cervix, Carcinoma in situ, Antibodies, Monoclonal, General Medicine, Methylation, DNA Methylation, Middle Aged, Uterine Cervical Dysplasia, medicine.disease, Immunohistochemistry, United States, Epithelium, Cell Transformation, Neoplastic, medicine.anatomical_structure, Oncology, Food, Fortified, DNA methylation, 5-Methylcytosine, biology.protein, Female, Antibody, Edible Grain
Abstract: The purpose of this study was to evaluate whether mandatory fortification of grain products with folic acid in the USA is associated with changes in global DNA methylation in cells involved in cervical carcinogenesis. Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-92) and after mandatory folic acid fortification (2000-02) were used to examine for global DNA methylation in specific lesions involved in cervical carcinogenesis by using a monoclonal antibody specific for 5 methyl cytosine (5-mc). The total number of lesions examined was 152 in the pre-fortification period and 172 in the post-fortification period. Immunohistochemical staining for 5-mc, the assessment of methylation status and data entry were blinded with regard to the fortification status. Age- and race-adjusted mean percentage of cells positive for 5-mc or the 5-mc score was not significantly different (P0.05) between the pre- and post fortification periods in any of the individual lesions evaluated (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN or carcinoma in situ). The degree of global DNA methylation was significantly higher (P0.0001) inor= CIN 2 lesions compared toor= CIN 1 lesions, regardless of the fortification group. These results suggest that mandatory fortification with folic acid in the United States has not resulted in a change in the degree or the pattern of global DNA methylation in cells involved in cervical carcinogenesis.
Published: 2006
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48. Biomarkers in Diagnosis of Pancreatic Carcinoma in Fine-Needle Aspirates

Author: William E. Grizzle, Jennifer J. Jones, Isam A. Eltoum, Surinder K. Batra, Selwyn M. Vickers, Nirag Jhala, Upender Manne, Mohamad A. Eloubeidi, and Darshana Jhala
Subjects: Pathology, medicine.medical_specialty, Pancreatic disease, medicine.diagnostic_test, biology, business.industry, General Medicine, medicine.disease, Genetic translation, Fine-needle aspiration, Cytopathology, Biopsy, medicine, biology.protein, Adenocarcinoma, Pancreatitis, Mesothelin, sense organs, skin and connective tissue diseases, business
Abstract: This study was undertaken to determine whether recently identified proteins could be translated to clinical practice as markers to distinguish pancreatic adenocarcinoma from chronic pancreatitis on fine-needle aspirate (FNA) samples. Resected pancreatic tissue sections (n = 40) and FNA samples (n = 65) were stained for clusterin-beta, MUC4, survivin, and mesothelin. For each biomarker, the staining patterns in adenocarcinoma and in reactive ductal epithelium were evaluated and compared. Clusterin-beta stained reactive ductal epithelium significantly more frequently than pancreatic adenocarcinoma (P < .001). In comparison, MUC4 and mesothelin were expressed more frequently in pancreatic adenocarcinoma on tissue sections. Positive staining for MUC4 (91% vs 0%; P < .001) and mesothelin (62% vs 0%; P = .01) and absence of staining for clusterin-beta (90% vs 7%; P < .001) were noted significantly more frequently in adenocarcinoma cells than in reactive cells in FNA samples. Clusterin-beta and MUC4 can help distinguish reactive ductal epithelial cells from the cells of pancreatic adenocarcinoma in FNA samples.
Published: 2006
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49. Transgastric Endoscopic Ultrasound-Guided Fine-Needle Aspiration Biopsy and Flow Cytometry of Suspected Lymphoma of the Spleen

Author: David Chhieng, Shyam Varadarajulu, M. A. Eloubeidi, Darshana Jhala, Isam A. Eltoum, and Nirag Jhala
Subjects: Adult, Male, Endoscopic ultrasound, medicine.medical_specialty, Abdominal pain, Lymphoma, medicine.medical_treatment, Biopsy, Fine-Needle, Splenectomy, Endoscopy, Gastrointestinal, Endosonography, Diagnosis, Differential, Biopsy, medicine, Humans, Aged, Retrospective Studies, Splenic Diseases, Aged, 80 and over, medicine.diagnostic_test, business.industry, Stomach, Gastroenterology, Reproducibility of Results, Middle Aged, Flow Cytometry, medicine.disease, digestive system diseases, Endoscopy, Fine-needle aspiration, Splenic Tissue, Female, Radiology, medicine.symptom, business, Follow-Up Studies
Abstract: Background and study aims Masses in the spleen can be sampled by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) but the diagnosis of lymphoma using EUS-FNA and flow cytometry has not been reported. We report our experience with transgastric EUS-FNA and flow cytometry in the investigation of patients with suspected lymphoma of the spleen. Patients and methods All patients with splenic lesions that had been detected by computed tomography and who were referred for transgastric EUS-FNA over a 3-year period were enrolled in this study. The tissue obtained by EUS-FNA was evaluated by flow cytometry in all patients. Results Six patients with splenic masses were enrolled (four men, two women; median age 58.5 years, range 41 - 82 years). The mean size of the short axis of the lesions was 37.8 mm (SD 23.76 mm) and the mean size of the long axis was 45.6 mm (SD 31.72 mm). EUS-FNA was performed successfully in all patients and the tissue obtained was evaluated by flow cytometry. Two patients were diagnosed with lymphoma; no pathology was identified in the other four patients. Lymphoma of the spleen appeared as sharply demarcated echo-poor lesions; benign lesions appeared echo-rich in comparison with the surrounding splenic tissue. The two patients who were diagnosed with lymphoma underwent chemotherapy. Of the four patients in whom no pathology was identified, one patient subsequently underwent splenectomy for evaluation of persistent abdominal pain and was diagnosed with lymphoma; the three other patients had true-negative disease on the evidence of long-term follow-up (mean 8 months; range 6 - 12 months). No complications related to the EUS-FNA procedure were encountered in any patient. Conclusions EUS-FNA of spleen masses is a safe technique that aids in the diagnosis of lymphoma when used in conjunction with flow cytometry.
Published: 2006
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50. Non-Hodgkin's lymphoma of the breast: a review of 18 primary and secondary cases

Author: Vishnu Reddy, Virginia E. Duncan, Darshana Jhala, David C. Chhieng, and Nirag Jhala
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Biopsy, Fine-Needle, Breast Neoplasms, Immunophenotyping, Pathology and Forensic Medicine, hemic and lymphatic diseases, Biopsy, Humans, Medicine, Aged, Retrospective Studies, Aged, 80 and over, Gene Rearrangement, medicine.diagnostic_test, business.industry, Lymphoma, Non-Hodgkin, Lymphoblastic lymphoma, General Medicine, Gene rearrangement, Middle Aged, Plasma cell neoplasm, medicine.disease, Non-Hodgkin's lymphoma, Lymphoma, Fine-needle aspiration, Female, Differential diagnosis, business
Abstract: We evaluated the clinical features, morphology, and incidence of 18 cases of breast lymphoma over 10 years at the University of Alabama at Birmingham. Fine needle aspiration was performed in 7 of 18 patients, and tissue biopsy/resection was available for all 18 cases. Patients were 33 to 91 years old (median, 61); 17 were women and 1 was a man. Fine needle aspiration was consistent with the tissue diagnosis in 6 of the 7 cases (86%). One case was diagnosed by fine needle aspiration as atypical cells, favor benign; the biopsy revealed diffuse large B-cell lymphoma. Tissue diagnoses revealed that 11 cases (61%) represented diffuse large B-cell lymphoma and 3 (17%) were follicular lymphomas. The remaining 4 cases (22%) were plasma cell neoplasm, T-cell neoplasm, Burkitt's lymphoma, and precursor B-cell lymphoblastic lymphoma. Flow cytometry and/or gene rearrangement supported the diagnosis of lymphoma in 8 cases. Although rare, lymphoma should be considered in the differential diagnosis of a breast mass. Fine needle aspiration can facilitate appropriate triage of patients for further management.
Published: 2006
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