Medicine and Health Sciences Commons^™

Transcription Factor Runx3 Mediates Plasticity Of Thgm Cells Toward Th1 Phenotype, Javad Rasouli, Giacomo Casella, Weifeng Zhang, Dan Xiao, Gaurav Kumar, Paolo Fortina, Guang-Xian Zhang, Bogoljub Ciric, Abdolmohamad Rostami

Department of Neurology Faculty Papers

GM-CSF-producing T helper (Th) cells play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Recent studies have identified a distinct population of GM-CSF-producing Th cells, named ThGM cells, that also express cytokines TNF, IL-2, and IL-3, but lack expression of master transcription factors (TF) and signature cytokines of commonly recognized Th cell lineages. ThGM cells are highly encephalitogenic in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Similar to Th17 cells, in response to IL-12, ThGM cells upregulate expression of T-bet and IFN-γ and switch their phenotype to Th1. Here we show that …

Jefferson Digital Commons Quarterly Report: April-June 2022, Larissa Gordon, Mslis, Med, Ma, Anita Lai, Mlis

Jefferson Digital Commons Reports

This quarterly report includes:

• Articles
• Conferences and Symposia
• CREATE Day Presentations
• Thesis/Dissertations
• Grand Rounds and Lectures
• Capstone Presentations
• Journals and Newsletters
• Posters
• Misc.
• What People are Saying About the Jefferson Digital Commons

Drive Leg Ground Reaction Forces And Rate Of Force Development Over Consecutive Windmill Softball Pitches, Erin R. Pletcher, Kenzie B. Friesen, Gretchen D. Oliver, Mita Lovalekar, Keith Gorse, Takashi Nagai, Chris Connaboy

Department of Exercise Science Faculty Papers

BACKGROUND: Windmill softball pitching is a highly skilled movement, combining whole body coordination with explosive force. Successful pitching requires sequential movement to transfer energy produced by the lower extremity to the pitching arm. Therefore, drive leg ground reaction force (GRF) and the time over which a pitcher can develop force during push off, defined as rate of force development (RFD), is essential for optimal performance. The aim of this study was to examine GRF and RFD in the drive leg during the windmill softball pitch, as well as pitch velocity, throughout a simulated game.

METHODS: Fourteen softball pitchers (17.9±2.3 years, …

Improving Cancer Care Through Digital Health Coaching, Jennifer Nguyen, Pharmd, Vittorio Maio, Pharmd, Ms, Msph, Nathan Handley, Md, Mba

College of Population Health Faculty Papers

No abstract provided.

An Evaluation Of Patients With Abdominal Pain After Lateral Lumbar Interbody Fusion, Tristan B Fried, Khoa Tran, Mark J. Lambrechts, Nicholas D D'Antonio, Brian A Karamian, Justin Chu, Jose A Canseco, Alan S. Hilibrand, Christopher K Kepler, Alexander R Vaccaro, Gregory D. Schroeder

Department of Orthopaedic Surgery Faculty Papers

Context: Abdominal pain after surgery can occur for numerous reasons. Postoperative radiographs may be indicated to evaluate for ileus or other reasons for the pain. Whether outcomes are significantly different based on whether patients get radiographs following lateral lumbar interbody fusion (LLIF) are unclear.

Aims: To investigate the postoperative outcomes of patients experiencing abdominal pain after LLIF.

Settings and design: This retrospective cohort study included patients at a tertiary academic medical center and surrounding affiliated hospitals.

Materials and methods: Patients >18 years of age who underwent elective LLIF at a single institution were retrospectively identified. Patients were stratified into two …

Elevated Serum Levels Of Interleukin-15 In Pemphigus Vulgaris Patients: A Potential Therapeutic Target, Maedeh Kheirodin, Zohreh Tehranchinia, Yasaman Ketabi, Soheil Tavakolpour, Sahar Dadkhahfar, Masoomeh Faghankani, Hassan Vahidnezhad, Nikoo Mozafari

Department of Dermatology and Cutaneous Biology Faculty Papers

Introduction: Pemphigus vulgaris (PV) is a rare autoimmune disease that causes painful blistering. Interleukin-15 (IL-15) as a member of the immunoregulatory cytokines family is associated with the development of the chronic inflammatory or autoimmune disease. There is not much information available in the literature on the exact role IL-15 plays in PV. Objectives: The goal of this study was to evaluate the serum levels of IL-15 in patients with PV and assess the association of IL-15 with anti-desmoglein antibodies and the severity of the disease. Methods: Fifty-three individuals affected with active PV and 38 age- and gender-matched healthy controls were …

Innovative Use Of Biotrace Tempo Pacemaker Lead Following Cardiac Surgery, Jordan E Goldhammer, Regina E Linganna, Douglas S Pfeil, Scott D Witzeling, Alec Vishnevsky, Nicholas Ruggiero, T. Sloane Guy

Department of Anesthesiology Faculty Papers

The Tempo® Temporary Pacing Lead is a temporary, transvenous, active fixation pacemaker lead used exclusively in structural heart and electrophysiology procedures since regulatory approval in 2016. We utilized the Tempo lead for four patients undergoing redo-robotic cardiac surgery in which surgical epicardial leads could not be placed. No failure-to-pace events were encountered and patients were able to participate in various levels of physical activity without limitation.

The Bulletin: Sidney Kimmel Medical College At Thomas Jefferson University, Volume 71, Issue 2, Summer 2022

The Bulletin (formerly the Jefferson Medical College Alumni Bulletin)

This issue includes:

• 4 - Dean's Column
• 8 - Time Capsule - Dr. Marion Siegman
• 11 - A Message from Elizabeth A. Dale
• 14 - ICYMI (In Case You Missed It)
• 18 - At the Intersection of Health and Design
• 20 - Discovery - A Path Toward Digital Equity
• 26 - Mark L. Tykocinski Takes the Helm as President of Thomas Jefferson University
• 28 - Student Profile - Kayla Holston
• 30 - Faculty Profile - Stephen D. Silberstein, MD
• 34 - Alumni Profile - Mahesh Krishnan, MD ’94
• 36 - Class Notes
• 42 - Reimagine
• 43 - Bookshelf
• 44- In …

Association Of Underweight And Weight Loss With Poor Prognosis And Poor Therapy Effectiveness In Brain Metastases: A Retrospective Study, Yan He, Yu Zhang, Weelic Chong, Yiyan Pei, Renjie Zhang, Zheran Liu, Jiayi Yu, Xingchen Peng, Fang Fang

Department of Medical Oncology Faculty Papers

Background: The prognostic role of body mass index (BMI) in patients with brain metastases is controversial. We aim to investigate the impact of BMI on prognosis and anti-cancer therapy effectiveness in brain metastases.

Methods: Patients diagnosed with brain metastases between Oct 2010 and July 2019 were followed for mortality through April 2021. The prognostic role of BMI on overall survival was assessed by a restricted cubic spline (RCS) using a flexible model to visualize the relationship between the BMI values and hazard ratios of all-cause mortality, followed by a cox regression model. The disparity of survival outcomes in patients receiving …

Socioeconomic Status And Gastric Cancer Surgical Outcomes: A National Cancer Database Study., Ryan Lamm, D Brock Hewitt, Michael Li, Adam C Powell, Adam C Berger

Department of Surgery Faculty Papers

INTRODUCTION: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Surgical resection is the gold standard of treatment. In the United States, race and socioeconomic status are associated with the diagnosis of GC; however, no studies have examined these as independent risk factors for surgical outcomes. Our study sought to investigate socioeconomic factors and GC surgical outcomes using a national cancer registry.

METHODS: GC patients between 2004 and 2016 were identified using the National Cancer Database. Univariate and multivariate logistic regression was used to analyze associations between socioeconomic factors and 30-d mortality, 90-d mortality, and unplanned readmission …

A Word From The Writing Team (July 2022), Pam Walter, Mfa, Liz Declan, Ma, Mfa

A Word From the Writing Team (Newsletter)

This issue includes:

• Research Support News from Liz D’Angel in the Academic Commons
• Writing Prize Deadline
• Writing Tip: Accountability
• Reminder

Disease Burden And Management Of Crigler-Najjar Syndrome: Report Of A World Registry, Sem J Aronson, Norman Junge, Mediha Trabelsi, Wided Kelmemi, Aurelie Hubert, Karlla W Brigatti, Michael D. Fox, Robert J De Knegt, Johanna C Escher, Virginia M Ginocchio, Raffaele Iorio, Yan Zhu, Figen Özçay, Fakher Rahim, Mortada H F El-Shabrawi, Eyal Shteyer, Angelo Di Giorgio, Lorenzo D'Antiga, Federico Mingozzi, Nicola Brunetti-Pierri, Kevin A Strauss, Philippe Labrune, Ridha Mrad, Ulrich Baumann, Ulrich Beuers, Piter J Bosma

Department of Pediatrics Faculty Papers

Background and Aims Crigler-Najjar syndrome (CNS) is a disorder of bilirubin conjugation leading to brain damage and death without treatment. Although cohort studies of limited size have been published, uncertainty about outcome, co-morbidities, occurence of liver fibrosis and treatment outcome remains. With this worldwide cohort study, we aim to add substantial knowledge to the previously published data.

Methods Anonymized retrospective data of CNS patients were collected in a web-based registry platform.

Results Clinical data of 221 CNS patients (46% female, severe phenotype n = 209) were collected. At the time of analysis, 59 CNS patients were deceased. Mean serum total …

Effect Of Preoperative Mri Coracoid Dimensions On Postoperative Outcomes Of Latarjet Treatment For Anterior Shoulder Instability., Ryan W. Paul, Dennis A Debernardis, Daniel Hameed, Ari Clements, Sarah Kamel, Md, Kevin Freedman, Md, Meghan Bishop

Rothman Institute Papers

Background: Preoperative coracoid dimensions may affect the size of the bone graft transferred to the glenoid rim and thus the postoperative outcomes of Latarjet coracoid transfer.

Purpose: To determine the effect of coracoid length and width as measured on preoperative magnetic resonance imaging (MRI) on outcomes after Latarjet treatment of anterior shoulder instability.

Study Design: Cohort study; Level of evidence, 3.

Methods: Included were patients who underwent primary Latarjet surgery between 2009 and 2019 and had preoperative MRI scans and minimum 2-year postoperative outcomes. Longitudinal coracoid length was measured on axial MRI sequences as the distance from the coracoclavicular ligament …

The 2-Methoxymethyl Modification Of P -Phenylenediamine Reduces The Sensitization Risk For Hairdressers To Hair Dyes-An Occupational Hand Exposure-Based Risk Assessment, Emanuele Marco Gargano, Brunhilde Blömeke, Anthony Gaspari, Carsten Goebel

Department of Dermatology and Cutaneous Biology Faculty Papers

Background: Allergic contact dermatitis involving the hands is a common occupational skin disease for hairdressers and the potent sensitizers p -phenylenediamine (PPD) and toluene-2,5-diamine (PTD) are associated with the development of occupational allergic contact dermatitis.

Objective: The aim of the study was to analyze whether the use of the moderate sensitizer 2-methoxymethyl-PPD (ME-PPD) in professional hair dyes is a suitable tool to reduce the occupational contact allergy risk for hairdressers.

Methods: Hand exposure of hairdressers (N = 11) to ME-PPD was analyzed under routine hair coloring conditions in commercial salons. By accounting for wet work and uneven hand exposure, the …

Does Ligamentous Laxity Protect Against Chondral And Osteochondral Injuries In Patients With Patellofemoral Instability?, Lauren H Redler, Elizabeth R Dennis, Gabrielle M Mayer, Irene L Kalbian, Joseph T Nguyen, Beth E Shubin Stein, Sabrina M Strickland

Department of Medicine Faculty Papers

Background: Many patients undergoing medial patellofemoral ligament (MPFL) reconstruction for patellofemoral instability have chondral or osteochondral injuries requiring treatment.

Hypothesis: In patients undergoing MPFL reconstruction for patellofemoral instability, those with ligamentous laxity (LAX) would be less likely to have chondral or osteochondral defects requiring surgical intervention compared with those with no laxity (NLX).

Study Design: Cohort study; Level of evidence, 2.

Methods: Included were 171 patients with patellofemoral instability (32 men, 139 women; mean age, 22 years [range, 11-57 years]) who underwent MPFL reconstruction between 2005 and 2015. Patients with a Beighton-Horan score ≥5 were considered LAX (n = 96), …

The Curious Case Of An Isolated Right Coronary Artery Aneurysm Complicated By Thrombosis And Distal Embolization, Hussam Al Hennawi, Mohammad F. Mathbout, Katrina Bidwell, Christopher D. Nielsen

Abington Jefferson Health Papers

No abstract provided.

The Undesirable Communication: A Case Of Cerebral Air Emboli In The Setting Of Atrio-Esophageal Fistula Following Atrial Fibrillation Catheter Ablation, Momin Islam, Hussam Al Hennawi, Anwar Khedr, Khaled Harmouch, Mohammad F. Mathbout

Abington Jefferson Health Papers

Atrial-esophageal fistula is an extremely rare condition but is often a deleterious complication following catheter ablation for atrial fibrillation. The associated iatrogenic communication acts as a conduit for air and bacterial translocation, which may lead to cerebral air embolism and polymicrobial sepsis, respectively. Coupled with a history of invasive procedures, the diagnosis is largely based on the accompanying neurological symptoms. In this report, we present the case of a 73-year-old female who presented with neurological deficits attributed to cerebral vascular emboli three weeks after catheter ablation for the treatment of chronic atrial fibrillation.

Feasible Stenting Of A Large Septal Perforator Providing A Sizeable Coronary Collaterals, Hussam Al Hennawi, Mohammad F. Mathbout,, Abdulrahman Taftafa, Christopher D. Nielsen

Division of Internal Medicine Faculty Papers & Presentations

While coronary artery disease involving the septal perforator branches presents similar to diseases of major coronary arteries, management can present a challenge. Owing to their relatively small size, performing interventional procedures is often impractical in terms of selecting appropriate devices. Although larger septal perforator branches have been managed percutaneously, similar to major vessels, long-term sequelae and clinical effectiveness have been indeterminate. We present our experience in managing a patient with a stenosed septal perforator branch and challenging comorbidities.

Emerging Applications Of Contrast-Enhanced Ultrasound In Trauma, Brenda Tester, Ji-Bin Liu, John R. Eisenbrey, George Koenig

Department of Radiology Faculty Papers

The use of contrast-enhanced ultrasound (CEUS) has expanded over the past decade to include a variety of diagnostic and therapeutic applications. These include urgent clinical situations that require timely diagnosis and subsequent treatment. With the introduction of microbubble ultrasound contrast agents (UCAs), CEUS provides increased sensitivity and specificity over conventional ultrasound. Within the trauma setting, CEUS benefits include point of care imaging and an ability to monitor perfusion in real-time. Additionally, UCAs are non-nephrotoxic, and can be used when contrast enhanced CT is contraindicated. In this review, we discuss recent advancements of CEUS within trauma settings.

Popliteal Artery Entrapment Syndrome Treated By A Posterior Approach In A 15-Year-Old Athlete, Lili Sadri, Robert L Myers, Casey Paterson, Quyngdiem Lam, Danielle M Pineda

Department of Surgery Faculty Papers

Popliteal artery entrapment syndrome is a rare source of claudication in young people. We present the case of a 15-year-old male athlete who presented with intermittent numbness of his right foot with exertion. Imaging revealed classic compression from a right type III popliteal artery entrapment. The left popliteal artery was chronically occluded with a large collateral vessel. He underwent release of the accessory bands of the gastrocnemius muscle with significant arteriolysis on the right side via a posterior approach. Chronic popliteal artery entrapment can be treated from a posterior approach, resulting in arterial occlusion and will be asymptomatic if well …

The Overestimation Of Concentric Hypertrophy In Patients With Hfpef As Determined By 2d-Echocardiography, Mohammad F. Mathbout, Hussam Al Hennawi, Anwar Khedr, Gaurang N. Vaidya, Marcus Stoddard

Division of Internal Medicine Faculty Papers & Presentations

Background: Heart failure with preserved ejection fraction continues to pose multiple challenges in terms of accurate diagnosis, treatment, and associated morbidity. Accurate left ventricular (LV) mass calculation yields essential prognostic information relating to structural heart disease. Two-dimensional (2D) echocardiography-based calculations are solely limited to LV geometric assumptions of symmetry, whereas three-dimensional (3D) echocardiography could overcome these limitations. This study aims to compare the performance of 2D and 3D LV mass calculations. Methods: A prospective review of echocardiography findings at the University of Louisville, Kentucky, was conducted and assessed. Normal ejection fraction (EF) was defined as >=52% in males and >=54% …

Endothelial Autophagy In Coronary Microvascular Dysfunction And Cardiovascular Disease, Fujie Zhao, Ganesh Satyanarayana, Zheng Zhang, Jianli Zhao, Xin-Liang Ma, Yajing Wang

Department of Emergency Medicine Faculty Papers

Coronary microvascular dysfunction (CMD) refers to a subset of structural and/or functional disorders of coronary microcirculation that lead to impaired coronary blood flow and eventually myocardial ischemia. Amid the growing knowledge of the pathophysiological mechanisms and the development of advanced tools for assessment, CMD has emerged as a prevalent cause of a broad spectrum of cardiovascular diseases (CVDs), including obstructive and nonobstructive coronary artery disease, diabetic cardiomyopathy, and heart failure with preserved ejection fraction. Of note, the endothelium exerts vital functions in regulating coronary microvascular and cardiac function. Importantly, insufficient or uncontrolled activation of endothelial autophagy facilitates the pathogenesis of …

Recognition Of The Tdp-43 Nuclear Localization Signal By Importin Α1/Β, Steven G Doll, Hamed Meshkin, Alexander J Bryer, Fenglin Li, Ying-Hui Ko, Ravi K Lokareddy, Richard E Gillilan, Kushol Gupta, Juan R Perilla, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Cytoplasmic mislocalization of the TAR-DNA binding protein of 43 kDa (TDP-43) leads to large, insoluble aggregates that are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we study how importin α1/β recognizes TDP-43 bipartite nuclear localization signal (NLS). We find that the NLS makes extensive contacts with importin α1, especially at the minor NLS-binding site. NLS binding results in steric clashes with the C terminus of importin α1 that disrupts the TDP-43 N-terminal domain (NTD) dimerization interface. A putative phosphorylation site in the proximity of TDP-43 R83 at the minor NLS site destabilizes binding to importins by reducing …

Criminal, Legal, And Ethical Kidney Donation And Transplantation: A Conceptual Framework To Enable Innovation, Alvin E Roth, Ignazio R Marino, Kimberly D Krawiec, Michael A Rees

Department of Surgery Faculty Papers

No abstract provided.

Post-Discharge And Long-Term Follow-Up After An Acute Coronary Syndrome: International Collaborative Group Of Cncf Position Paper, Pierre Sabouret, Gilles Lemesle, Anne Bellemain-Appaix, Pierre Aubry, Pier-Paolo Bocchino, Erik Rafflenbeul, Loïc Belle, Jim Nolan, Marco Bernardi, Giuseppe Biondi-Zoccai, Michael P. Savage, Maciej Banach, Guillaume Cayla

Division of Cardiology Faculty Papers

Introduction: Long-term follow-up after an acute coronary syndrome (ACS) presents a crucial challenge due to the high residual cardiovascular risk and the potential for major bleeding events. Although several treatment strategies are available, this article focuses on patients who have undergone percutaneous coronary intervention (PCI) for ACS, which is a frequent clinical situation. This position paper aims to support physicians in daily practice to improve the management of ACS patients.

Material and methods: A group of recognized international and French experts in the field provides an overview of current evidence-based recommendations - supplemented by expert opinion where such evidence is …

A Mathematical Model Of Glut1 Modulation In Rods And Rpe And Its Differential Impact In Cell Metabolism, Andrea Aparicio, Erika T Camacho, Nancy J. Philp, Stephen A Wirkus

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We present a mathematical model of key glucose metabolic pathways in two cells of the human retina: the rods and the retinal pigmented epithelium (RPE). Computational simulations of glucose transporter 1 (GLUT1) inhibition in the model accurately reproduce experimental data from conditional knockout mice and reveal that modification of GLUT1 expression levels of both cells differentially impacts their metabolism. We hypothesize that, under glucose scarcity, the RPE’s energy producing pathways are altered in order to preserve its functionality, impacting the photoreceptors’ outer segment renewal. On the other hand, when glucose is limited in the rods, aerobic glycolysis is preserved, which …

Advance Trends In Targeting Homology-Directed Repair For Accurate Gene Editing: An Inclusive Review Of Small Molecules And Modified Crispr-Cas9 Systems, Forough Shams, Hadi Bayat, Omid Mohammadian, Somayeh Mahboudi, Hassan Vahidnezhad, Mohsen Soosanabadi, Azam Rahimpour

Jefferson Institute of Molecular Medicine Papers and Presentations

Introduction: Clustered regularly interspaced short palindromic repeat and its associated protein (CRISPR-Cas)-based technologies generate targeted modifications in host genome by inducing site-specific double-strand breaks (DSBs) that can serve as a substrate for homology-directed repair (HDR) in both in vitro and in vivo models. HDR pathway could enhance incorporation of exogenous DNA templates into the CRISPR-Cas9-mediated DSB site. Owing to low rate of HDR pathway, the efficiency of accurate genome editing is diminished. Enhancing the efficiency of HDR can provide fast, easy, and accurate technologies based on CRISPR-Cas9 technologies. Methods: The current study presents an overview of attempts conducted on the …

Bilateral Upper Extremity Motor Priming (Bump) Plus Task-Specific Training For Severe, Chronic Upper Limb Hemiparesis: Study Protocol For A Randomized Clinical Trial, Mary Ellen Stoykov, Olivia M Biller, Alexandra Wax, Erin King, Jacob M Schauer, Louis F Fogg, Daniel M Corcos

Department of Occupational Therapy Faculty Papers

BACKGROUND: Various priming techniques to enhance neuroplasticity have been examined in stroke rehabilitation research. Most priming techniques are costly and approved only for research. Here, we describe a priming technique that is cost-effective and has potential to significantly change clinical practice. Bilateral motor priming uses the Exsurgo priming device (Exsurgo Rehabilitation, Auckland, NZ) so that the less affected limb drives the more affected limb in bilateral symmetrical wrist flexion and extension. The aim of this study is to determine the effects of a 5-week protocol of bilateral motor priming in combination with task-specific training on motor impairment of the affected …

Effect Of Musculature On Mortality, A Retrospective Cohort Study, Amy L Shaver, Mary E Platek, Anurag K Singh, Sung Jun Ma, Mark Farrugia, Gregory Wilding, Andrew D Ray, Heather M Ochs-Balcom, Katia Noyes

Department of Medical Oncology Faculty Papers

Background: While often life-saving, treatment for head and neck cancer (HNC) can be debilitating resulting in unplanned hospitalization. Hospitalizations in cancer patients may disrupt treatment and result in poor outcomes. Pre-treatment muscle quality and quantity ascertained through diagnostic imaging may help identify patients at high risk of poor outcomes early. The primary objective of this study was to determine if pre-treatment musculature was associated with all-cause mortality.

Methods: Patient demographic and clinical characteristics were abstracted from the cancer center electronic database (n = 403). Musculature was ascertained from pre-treatment CT scans. Propensity score matching was utilized to adjust for confounding …

Monocarboxylate Transporter 4 In Cancer-Associated Fibroblasts Is A Driver Of Aggressiveness In Aerodigestive Tract Cancers, Marina Domingo-Vidal, Diana Whitaker Menezes, Mehri Mollaee, Zhao Lin, Madalina Tuluc, Nancy J. Philp, Jennifer Johnson, Tingting Zhan, Joseph Curry, Ubaldo E. Martinez-Outshoorn

Department of Medical Oncology Faculty Papers

The most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor stroma of ADT cancers and exert pro-tumorigenic functions. Metabolically, glycolytic CAFs support the energy needs of oxidative (OXPHOS) carcinoma cells. Upregulation of the monocarboxylate transporter 4 (MCT4) and downregulation of isocitrate dehydrogenase 3α (IDH3α) are markers of glycolysis in CAFs, and upregulation of the …