Digital Commons Network^™

Milvexian Vs Apixaban For Stroke Prevention In Atrial Fibrillation: The Librexia Atrial Fibrillation Trial Rationale And Design, Sneha S Jain, Kenneth W Mahaffey, Karen S Pieper, Wataru Shimizu, Tatjana Potpara, Christian T Ruff, Hooman Kamel, Basil S Lewis, Jan H Cornel, Peter R. Kowey, Jay Horrow, John Strony, Alexei N Plotnikov, Danshi Li, Stephen Weng, Julia Donahue, C Michael Gibson, P Gabriel Steg, Roxana Mehran, Jeffrey I Weitz, S Claiborne Johnston, Graeme J Hankey, Robert A Harrington, Carolyn S P Lam

Department of Medicine Faculty Papers

BACKGROUND: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk.

METHODS: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to …

High-Dose Intravenous Vitamin C Combined With Docetaxel In Men With Metastatic Castration-Resistant Prostate Cancer: A Randomized Placebo-Controlled Phase Ii Trial, Channing Paller, Marianna Zahurak, Adel Mandl, Nicole Metri, Aliya Lalji, Elisabeth Heath, William Kelly, Christopher Hoimes, Pedro Barata, Jason Taksey, Dominique Garrison, Kartick Patra, Ginger Milne, Nicole Anders, Julie Nauroth, Jennifer Durham, Catherine Marshall, Mark Markowski, Mario Eisenberger, Emmanuel Antonarakis, Michael Carducci, Samuel Denmeade, Mark Levine

Department of Medicine Faculty Papers

UNLABELLED: High-dose intravenous vitamin C (HDIVC) administered to produce pharmacologic concentrations shows promise in preclinical models and small clinical trials, but larger prospective randomized trials are lacking. We evaluated the clinical benefit of combining HDIVC with docetaxel in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). In this double-blind, placebo-controlled phase II trial, 47 patients were randomized 2:1 to receive docetaxel (75 mg/m2 i.v.) with either HDIVC (1 g/kg) or placebo. Coprimary endpoints were PSA50 response and adverse event rates. Secondary endpoints included overall survival, radiographic progression-free survival, and quality of life measured using the Functional Assessment of Cancer Therapy-Prostate …

Reversal Of Propofol-Induced Depression Of The Hypoxic Ventilatory Response By Bk-Channel Blocker Ena-001: A Randomized Controlled Trial, Simone Jansen, Maarten Van Lemmen, Erik Olofsen, Laurence Moss, Joseph Pergolizzi, Thomas Miller, Robert Colucci, Monique Van Velzen, Philip Kremer, Albert Dahan, Rutger Van Der Schrier, Marieke Niesters

Department of Medicine Faculty Papers

BACKGROUND: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response.

METHODS: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three …

Polymer-Based Drug-Eluting Stent Treatment Extends The Time To Reintervention For Patients With Symptomatic Femoropopliteal Artery Disease: Clinical Evidence And Potential Economic Value, William Gray, Yoshimitsu Soga, Masahiko Fujihara, Osamu Iida, Anvar Babaev, Daizo Kawasaki, Thomas Zeller, David O'Connor, Michael Jaff, Anna Chavez, Stefan Müller-Hülsbeck

Department of Medicine Faculty Papers

Aim: Use long-term follow-up data from the IMPERIAL study to determine whether drug-eluting polymer-based nitinol stent treatment can delay the time to repeat intervention for femoropopliteal artery disease and how such a delay may result in cost savings in a value-based episode of care. Patients & methods: The IMPERIAL randomized controlled trial was an international study of a paclitaxel-eluting polymer-coated stent (Eluvia, Boston Scientific, MA, USA) versus a polymer-free paclitaxel-coated stent (Zilver PTX, Cook Corporation, IN, USA) for treating lesions of the femoropopliteal arterial segment. Study patients (n = 465) had symptomatic lower limb ischemia. Safety and efficacy assessments were …

Expanding The Access To Kidney Transplantation: Strategies For Kidney Transplant Programs, Angie Nishio Lucar, Ankita Patel, Shikha Mehta, Anju Yadav, Mona Doshi, Megan Urbanski, Beatrice Concepcion, Neeraj Singh, M. Lee Sanders, Arpita Basu, Jessica Harding, Ana Rossi, Oluwafisayo Adebiyi, Milagros Samaniego-Picota, Kenneth Woodside, Ronald Parsons

Department of Medicine Faculty Papers

Kidney transplantation is the most successful kidney replacement therapy available, resulting in improved recipient survival and societal cost savings. Yet, nearly 70 years after the first successful kidney transplant, there are still numerous barriers and untapped opportunities that constrain the access to transplant. The literature describing these barriers is extensive, but the practices and processes to solve them are less clear. Solutions must be multidisciplinary and be the product of strong partnerships among patients, their networks, health care providers, and transplant programs. Transparency in the referral, evaluation, and listing process as well as organ selection are paramount to build such …

Perspectives From Patients With Chronic Lung Disease On A Telehealth-Facilitated Integrated Palliative Care Model: A Qualitative Content Analysis Study, Jeannette Kates, Carrie Tompkins Stricker, Kristin L. Rising, Alexzandra Gentsch, Ellen Solomon, Victoria Powers, Venise J. Salcedo, Brooke Worster

Department of Medicine Faculty Papers

BACKGROUND: Chronic lung disease affects nearly 37 million Americans and often results in significant quality of life impairment and healthcare burden. Despite guidelines calling for palliative care (PC) integration into pulmonary care as a vital part of chronic lung disease management, existing PC models have limited access and lack scalability. Use of telehealth to provide PC offers a potential solution to these barriers. This study explored perceptions of patients with chronic lung disease regarding a telehealth integrated palliative care (TIPC) model, with plans to use findings to inform development of an intervention protocol for future testing.

METHODS: For this qualitative …

Delayed Onset Of Neonatal Compartment Syndrome Associated With Compound Fetal Presentation, Nicholas Manini, Hayato Unno

Department of Medicine Faculty Papers

Neonatal compartment syndrome, although rare, has a classic presentation with sentinel skin findings and development of swelling, erythema, and tenderness of the affected extremity. Neonatal compartment syndrome requires prompt surgical intervention to preserve the affected limb and ensure its normal growth and development. Our patient was born at term via vaginal delivery complicated by a compound presentation involving the left upper extremity. No physical exam abnormalities were noted at birth, but she developed signs of neonatal compartment syndrome by 15 h of life. She was surgically treated at 22 h of life and recovered well. At one year of age, …

Nf-Κb As An Inducible Regulator Of Inflammation In The Central Nervous System, Sudha Anilkumar, Elizabeth Wright-Jin

Department of Medicine Faculty Papers

The NF-κB (nuclear factor K-light-chain-enhancer of activated B cells) transcription factor family is critical for modulating the immune proinflammatory response throughout the body. During the resting state, inactive NF-κB is sequestered by IκB in the cytoplasm. The proteasomal degradation of IκB activates NF-κB, mediating its translocation into the nucleus to act as a nuclear transcription factor in the upregulation of proinflammatory genes. Stimuli that initiate NF-κB activation are diverse but are canonically attributed to proinflammatory cytokines and chemokines. Downstream effects of NF-κB are cell type-specific and, in the majority of cases, result in the activation of pro-inflammatory cascades. Acting as …

Isoform Alterations In The Ubiquitination Machinery Impacting Gastrointestinal Malignancies, Srimathi Kasturirangan, Derek Nancarrow, Ayush Shah, Kiran Lagisetty, Theodore Lawrence, David Beer, Dipankar Ray

Department of Medicine Faculty Papers

The advancement of RNAseq and isoform-specific expression platforms has led to the understanding that isoform changes can alter molecular signaling to promote tumorigenesis. An active area in cancer research is uncovering the roles of ubiquitination on spliceosome assembly contributing to transcript diversity and expression of alternative isoforms. However, the effects of isoform changes on functionality of ubiquitination machineries (E1, E2, E3, E4, and deubiquitinating (DUB) enzymes) influencing onco- and tumor suppressor protein stabilities is currently understudied. Characterizing these changes could be instrumental in improving cancer outcomes via the identification of novel biomarkers and targetable signaling pathways. In this review, we …

Relationship Of Race With Functional And Clinical Outcomes With The Rehab-Hf Multidomain Physical Rehabilitation Intervention For Older Patients With Acute Heart Failure, Olivia N. Gilbert, Robert J. Mentz, Alain G. Bertoni, Dalane W. Kitzman, David J. Whellan, Gordon R. Reeves, Pamela W. Duncan, Michael Benjamin Nelson, Vanessa Blumer, Haiying Chen, Shelby D. Reed, Bharathi Upadhya, Christopher M. O'Connor, Amy M. Pastva

Department of Medicine Faculty Papers

Background

The REHAB‐HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) randomized trial demonstrated that a 3‐month transitional, tailored, progressive, multidomain physical rehabilitation intervention improves physical function, frailty, depression, and health‐related quality of life among older adults with acute decompensated heart failure. Whether there is differential intervention efficacy by race is unknown.

Methods and Results

In this prespecified analysis, differential intervention effects by race were explored at 3 months for physical function (Short Physical Performance Battery [primary outcome], 6‐Minute Walk Distance), cognition, depression, frailty, health‐related quality of life (Kansas City Cardiomyopathy Questionnaire, EuroQoL 5‐Dimension‐5‐Level Questionnaire) and at 6 months for …

Impact Of Detectable Monoclonal Protein At Diagnosis On Outcomes In Marginal Zone Lymphoma: A Multicenter Cohort Study, Narendranath Epperla, Qiuhong Zhao, Reem Karmali, Pallawi Torka, Lauren Shea, Timothy S. Oh, Andrea Anampa-Guzmán, Heather Reves, Montreh Tavakkoli, Irl Brian Greenwell, Emily Hansinger, Elvira Umyarova, Kaitlin Annunzio, Yazeed Sawalha, Beth Christian, Colin Thomas, Stefan K. Barta, Praveen Ramakrishnan Geethakumari, Nancy L. Bartlett, Natalie S. Grover, Adam J Olszewski

Department of Medicine Faculty Papers

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein …

Transmission Of Yellow Fever Vaccine Virus Through Blood Transfusion And Organ Transplantation In The Usa In 2021: Report Of An Investigation, Carolyn V. Gould, Rebecca J. Free, Julu Bhatnagar, Raymond A. Soto, Tricia L. Royer, Warren R. Maley, Sean Moss, Matthew A. Berk, Rebecca Craig-Shapiro, Rosy Priya L. Kodiyanplakkal, Lars F. Westblade, Thangamani Muthukumar, Yoram A. Puius, Amresh Raina, Azam Hadi, Kymberly A. Gyure, Danielle Trief, Marcus Pereira, Matthew J. Kuehnert, Vennus Ballen, Debra A. Kessler, Kimberly Dailey, Charles Omura, Thuy Doan, Steve Miller, Michael R. Wilson, Jennifer A. Lehman, Jana M. Ritter, Elizabeth Lee, Luciana Silva-Flannery, Sarah Reagan-Steiner, Jason O. Velez, Janeen J. Laven, Kelly A. Fitzpatrick, Amanda Panella, Emily H. Davis, Holly R. Hughes, Aaron C. Brault, Kirsten St George, Amy B. Dean, Joel Ackelsberg, Sridhar V. Basavaraju, Charles Y. Chiu, J. Erin Staples

Department of Medicine Faculty Papers

BACKGROUND: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients.

METHODS: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by …

Self-Administered Intranasal Etripamil Using A Symptom-Prompted, Repeat-Dose Regimen For Atrioventricular-Nodal-Dependent Supraventricular Tachycardia (Rapid): A Multicentre, Randomised Trial, Bruce S Stambler, A John Camm, Marco Alings, Paul Dorian, Hein Heidbuchel, Jaco Houtgraaf, Peter R. Kowey, Jose L Merino, Blandine Mondésert, Jonathan P Piccini, Sean D Pokorney, Philip T Sager, Atul Verma, J Marcus Wharton, David B Bharucha, Francis Plat, Silvia Shardonofsky, Michael Chen, James E Ip

Department of Medicine Faculty Papers

BACKGROUND: Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min.

METHODS: RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes …

The Impact Of Essential Trace Elements On Ovarian Response And Reproductive Outcomes Following Single Euploid Embryo Transfer, Roberto Gonzalez-Martin, Andrea Palomar, Alicia Quiñonero, Nuria Pellicer, Rocio Fernandez-Saavedra, Estefania Conde-Vilda, Alberto J Quejido, Christine Whitehead, Richard T. Scott, Francisco Dominguez

Department of Medicine Faculty Papers

Essential trace elements are required in extremely small amounts and obtained through diet. This research focuses on detecting major trace elements in different biofluids of sixty women undergoing ICSI with PGT-A and SET/FET at IVI-RMA, New Jersey, and assessing their impact on their IVF outcomes. Urine, plasma, and follicular fluid samples were collected on the vaginal oocyte retrieval day to measure the concentrations of eight essential trace elements (copper, zinc, molybdenum, lithium, selenium, manganese, chromium, and iron) using ICP-MS. After analysis, ovarian response and preimplantation outcomes had significant positive associations with both copper alone and the copper/zinc ratio in the …

Phytoestrogens Present In Follicular Fluid And Urine Are Positively Associated With Ivf Outcomes Following Single Euploid Embryo Transfer, Roberto Gonzalez-Martin, Andrea Palomar, Alicia Quiñonero, Nuria Pellicer, Caroline Zuckerman, Christine Whitehead, Richard T. Scott, Francisco Dominguez

Department of Medicine Faculty Papers

The impact and safety of phytoestrogens, plant-derived isoflavones with estrogenic activity predominantly present in soy, on female reproductive health and IVF outcomes continues to be hotly debated. In this prospective cohort study, 60 women attending IVI-RMA New Jersey undergoing IVF with single frozen embryo transfer (SET/FET) of good-quality euploid blastocyst after PGT-A analysis were recruited. Concentrations of two phytoestrogens (daidzein and genistein) in follicular fluid (FF) and urine (U) were measured by UPLC-MSMS, both collected on vaginal oocyte retrieval day. These measurements correlated with IVF clinical outcomes. In models adjusted for age, BMI, race/ethnicity, and smoking status, higher FF phytoestrogen …

Development Of A Biomarker Panel For Assessing Cardiovascular Risk In Diabetic Patients With Chronic Limb-Threatening Ischemia (Clti): A Prospective Study, Elisabetta Nardella, Federico Biscetti, Maria Margherita Rando, Andrea Leonardo Cecchini, Maria Anna Nicolazzi, Enrica Rossini, Flavia Angelini, Roberto Iezzi, Luis H. Eraso, Paul J. Dimuzio, Dario Pitocco, Massimo Massetti, Antonio Gasbarrini, Andrea Flex

Department of Medicine Faculty Papers

BACKGROUND: Lower-extremity endovascular revascularization (LER) is often required for diabetic patients with chronic limb threatening ischemia (CLTI). During the post-revascularization period patients may unpredictably experience major adverse cardiac events (MACE) and major adverse limb events (MALE). Several families of cytokines are involved in the inflammatory process that underlies the progression of atherosclerosis. According to current evidence, we have identified a panel of possible biomarkers related with the risk of developing MACE and MALE after LER. The aim was to study the relationship between a panel of biomarkers - Interleukin-1 (IL-1) and 6 (IL-6), C-Reactive Protein (CRP), Tumor Necrosis Factor-α (TNF-α), …

Real-World Utilization Of The Pill-In-The-Pocket Method For Terminating Episodes Of Atrial Fibrillation: Data From The Multinational Antiarrhythmic Interventions For Managing Atrial Fibrillation (Aim-Af) Survey, James A Reiffel, Carina Blomström-Lundqvist, Giuseppe Boriani, Andreas Goette, Peter R Kowey, Jose L Merino, Jonathan P Piccini, Sanjeev Saksena, A John Camm

Department of Medicine Faculty Papers

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as 'pill-in-the-pocket' (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated.

METHODS …

Mechanisms Underlying The Antiarrhythmic Effect Of Arumenamide-787 In Experimental Models Of The J Wave Syndromes And Hypothermia, José M. Di Diego, Hector Barajas-Martinez, Robert Cox, Victoria M Robinson, Joseph Jung, Mohamed Fouda, Mena Abdelsayed, Peter C Ruben, Charles Antzelevitch

Department of Medicine Faculty Papers

BACKGROUND: Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia.

METHODS: We studied the effects of AR-787 on INa and IKr in HEK-293 cells stably expressing the α- and β1-subunits of the cardiac (NaV1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on Ito, INa and ICa in dissociated canine ventricular myocytes along with action potentials and ECG …

Impact Of Early Relapse Within 24 Months After First-Line Systemic Therapy (Pod24) On Outcomes In Patients With Marginal Zone Lymphoma: A Us Multisite Study, Narendranath Epperla, Rina Li Welkie, Pallawi Torka, Geoffrey Shouse, Reem Karmali, Lauren Shea, Andrea Anampa-Guzmán, Timothy S Oh, Heather Reaves, Montreh Tavakkoli, Kathryn Lindsey, Irl Brian Greenwell, Emily Hansinger, Colin Thomas, Sayan Mullick Chowdhury, Kaitlin Annunzio, Beth Christian, Stefan K Barta, Praveen Ramakrishnan Geethakumari, Nancy L Bartlett, Alex F Herrera, Natalie S Grover, Adam J Olszewski

Department of Medicine Faculty Papers

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of …

Rerupture Outcome Of Conservative Versus Open Repair Versus Minimally Invasive Repair Of Acute Achilles Tendon Ruptures: A Systematic Review And Meta-Analysis, Haidong Deng, Xin Cheng, Yi Yang, Fang Fang, Jialing He, Yixin Tian, Tiangui Li, Yangchun Xiao, Yuning Feng, Peng Wang, Weelic Chong, Yang Hai, Yu Zhang

Department of Medicine Faculty Papers

OBJECTIVE: To compare the rerupture rate after conservative treatment, open repair, and minimally invasive surgery management of acute Achilles tendon ruptures.

DESIGN: Systematic review and network meta-analysis.

DATA SOURCES: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to August 2022.

METHODS: Randomised controlled trials involving different treatments for Achilles tendon rupture were included. The primary outcome was rerupture. Bayesian network meta-analysis with random effects was used to assess pooled relative risks (RRs) and 95% confidence intervals. We evaluated the heterogeneity and publication bias.

RESULTS: Thirteen trials with 1465 patients were included. In direct comparison, …

A Phase Ib/Ii Study Of Lenvatinib And Pembrolizumab In Advanced Endometrial Carcinoma (Study 111/Keynote-146): Long-Term Efficacy And Safety Update., Vicky Makker, Carol Aghajanian, Allen L Cohn, Margarita Romeo, Raquel Bratos, Marcia S Brose, Mark Messing, Lea Dutta, Corina E Dutcus, Jie Huang, Emmett V Schmidt, Robert Orlowski, Matthew H Taylor

Department of Medicine Faculty Papers

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff …

Postibrutinib Relapse Outcomes For Patients With Marginal Zone Lymphoma, Narendranath Epperla, Qiuhong Zhao, Sayan Mullick Chowdhury, Lauren Shea, Tamara K. Moyo, Nishitha Reddy, Julia Sheets, David M. Weiner, Praveen Ramakrishnan Geethakumari, Malathi Kandarpa, Ximena Jordan Bruno, Colin Thomas, Michael C. Churnetski, Andrew Hsu, Luke Zurbriggen, Xiao-Wei Cherie Tan, Kathryn Lindsey, Joseph Maakaron, Paolo F. Caimi, Pallawi Torka, Celeste Bello, Sabarish Ayyappan, Timothy S. Oh, Reem Karmali, Seo-Hyun Kim, Anna Kress, Shalin Kothari, Yazeed Sawalha, Beth Christian, Kevin A. David, Irl Brian Greenwell, Murali Janakiram, Vaishalee P. Kenkre, Adam J. Olszewski, Jonathon B. Cohen, Neil Palmisiano, Elvira Umyarova, Ryan A. Wilcox, Farrukh T. Awan, Juan Pablo Alderuccio, Stefan K. Barta, Natalie S. Grover, Nilanjan Ghosh, Nancy L. Bartlett, Alex F. Herrera, Geoffrey Shouse

Department of Medicine Faculty Papers

No abstract provided.

Perioperative Outcomes Of Patients With Bleeding Disorders Undergoing Major Surgery At An Academic Hemophilia Treatment Center, Ruben Rhoades, Zachary French, Amy Yang, Karen Walsh, Douglass A. Drelich, Steven E. Mckenzie

Department of Medicine Faculty Papers

Persons with bleeding disorders (PwBD) are at high risk for bleeding with invasive procedures. However, the risk of bleeding in PwBD undergoing major surgery and outcomes of patients managed perioperatively at a hemophilia treatment center (HTC) are not well described. We performed a retrospective review of surgical outcomes among PwBD undergoing major surgery between January 1st, 2017 and December 31st, 2019 at the Cardeza Foundation Hemophilia and Thrombosis Center in Philadelphia, PA. The primary outcome was postoperative bleeding, assessed according to the ISTH-SSC's 2010 definition. Secondary outcomes included use of unplanned postoperative hemostatic therapy, LOS, and 30-day readmission rate. Results …

Pathogenicity And Impact Of Hla Class I Alleles In Aplastic Anemia Patients Of Different Ethnicities, Timothy S Olson, Benjamin F Frost, Jamie L Duke, Marian Dribus, Hongbo M Xie, Zachary D Prudowsky, Elissa Furutani, Jonas Gudera, Yash B Shah, Deborah Ferriola, Amalia Dinou, Ioanna Pagkrati, Soyoung Kim, Yixi Xu, Meilun He, Shannon Zheng, Sally Nijim, Ping Lin, Chong Xu, Taizo A Nakano, Joseph H Oved, Beatriz M Carreno, Yung-Tsi Bolon, Shahinaz M Gadalla, Steven Ge Marsh, Sophie Paczesny, Stephanie J Lee, Dimitrios S Monos, Akiko Shimamura, Alison A Bertuch, Loren Gragert, Stephen R Spellman, Daria V Babushok

Department of Medicine Faculty Papers

Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we …

Sex-Specific Considerations In Degenerative Aortic Stenosis For Female-Tailored Transfemoral Aortic Valve Implantation Management, Giulia Masiero, Valeria Paradies, Anna Franzone, Barbara Bellini, Chiara De Biase, Nicole Karam, Francesca Sanguineti, Mamas A Mamas, Hélène Eltchaninoff, Chiara Fraccaro, Battistina Castiglioni, Tiziana Attisano, Giovanni Esposito, Alaide Chieffo

Department of Medicine Faculty Papers

The impact of sex on pathophysiological processes, clinical presentation, treatment options, as well as outcomes of degenerative aortic stenosis remain poorly understood. Female patients are well represented in transfemoral aortic valve implantation (TAVI) trials and appear to derive favorable outcomes with TAVI. However, higher incidences of major bleeding, vascular complications, and stroke have been reported in women following TAVI. The anatomical characteristics and pathophysiological features of aortic stenosis in women might guide a tailored planning of the percutaneous approach. We highlight whether a sex-based TAVI management strategy might impact on clinical outcomes. This review aimed to evaluate the impact of …

Serpinb3 Drives Cancer Stem Cell Survival In Glioblastoma, Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen Mccortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia

Department of Medicine Faculty Papers

Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced …

Libretto-531: A Phase Iii Study Of Selpercatinib In Multikinase Inhibitor-Naïve, Lori J Wirth, Marcia S Brose, Rossella Elisei, Jaume Capdevila, Ana O Hoff, Mimi I Hu, Makoto Tahara, Bruce Robinson, Ming Gao, Meng Xia, Patricia Maeda, Eric Sherman

Department of Medicine Faculty Papers

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. …

Grk2 Regulates Adp Signaling In Platelets Via P2y1 And P2y12., Xuefei Zhao, Matthew Cooper, James V Michael, Yanki Yarman, Aiden Baltz, J Kurt Chuprun, Walter J Koch, Steven E. Mckenzie, Maurizio Tomaiuolo, Timothy J Stalker, Li Zhu, Peisong Ma

Department of Medicine Faculty Papers

The critical role of G protein-coupled receptor kinase 2 (GRK2) in regulating cardiac function has been well documented for >3 decades. Targeting GRK2 has therefore been extensively studied as a novel approach to treating cardiovascular disease. However, little is known about its role in hemostasis and thrombosis. We provide here the first evidence that GRK2 limits platelet activation and regulates the hemostatic response to injury. Deletion of GRK2 in mouse platelets causes increased platelet accumulation after laser-induced injury in the cremaster muscle arterioles, shortens tail bleeding time, and enhances thrombosis in adenosine 5'-diphosphate (ADP)-induced pulmonary thromboembolism and in FeCl3-induced carotid …

Predictive Factors And Outcomes For Ibrutinib In Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter Cohort Study, Narendranath Epperla, Qiuhong Zhao, Sayan Mullick Chowdhury, Lauren Shea, Tamara K Moyo, Nishitha Reddy, Julia Sheets, David M Weiner, Praveen Ramakrishnan Geethakumari, Malathi Kandarpa, Ximena Jordan Bruno, Colin Thomas, Michael C Churnetski, Andrew Hsu, Luke Zurbriggen, Cherie Tan, Kathryn Lindsey, Joseph Maakaron, Paolo F Caimi, Pallawi Torka, Celeste Bello, Sabarish Ayyappan, Reem Karmali, Seo-Hyun Kim, Anna Kress, Shalin Kothari, Yazeed Sawalha, Beth Christian, Kevin A David, Irl Brian Greenwell, Murali Janakiram, Vaishalee P Kenkre, Adam J Olszewski, Jonathon B Cohen, Neil D. Palmisiano, Elvira Umyarova, Ryan A Wilcox, Farrukh T Awan, Juan Pablo Alderuccio, Stefan K Barta, Natalie S Grover, Nilanjan Ghosh, Nancy L Bartlett, Alex F Herrera, Geoffrey Shouse

Department of Medicine Faculty Papers

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% …

Analyzing The Effect Of Interview Time And Day On Emergency Medicine Residency Interview Scores, Alanna O'Connell, Sean Greco, Tingting Zhan, Tracy Brader, Megan Crossman, Robin Naples, Anthony Sielicki, Megan Stobart Gallagher, Peter Tomaselli, Dimitrios Papanagnou

Department of Medicine Faculty Papers

Background: When it comes to scheduling interviews, medical students may wonder if they need a strategy to increase their likelihood of matching. Previous studies examined the temporal effects of the residency interview on overall match rate; however, there are additional factors that affect the match process, including board examination scores and letters of recommendation. Only few studies have examined the effect interview time of day has on match success. The current study examines the impact date and time of interview during the interview season have on candidates' respective interview scores.

Methods: Interview data over a three-year period (i.e., three interview …