Medical Pharmacology Commons^™

Evaluating Functional Inhibitors Of Acid Sphingomyelinase As Potential Negative Modulators Of Microvesicle Particle Release In Response To Skin Stressors, Taskin Sabit

Browse all Theses and Dissertations

Many diseases including lupus erythematosus, atopic eczema, and rosacea can be associated with photosensitivity, which is an abnormal response to sunlight. Recent studies by our group have implicated microvesicle particles (MVP) as playing an important role in causing inflammation and systemic immunosuppression. Previous studies show that functional inhibitors of acid sphingomyelinase (FIASMA) can block MVP release in response to ultraviolet B (UVB) radiation or Platelet-activating Factor (PAF) agonist, which are skin stressors. However, more research needs to be conducted to evaluate the role of PAF, UVB and FIASMA in MVP generation and to formulate a therapeutic medication to be potentially …

Fentanyl And Methamphetamine Mixture Interactions On Drug Choice In Male And Female Sprague Dawley Rats, Voisava Bokciu, Nick Heslep, Allison Ortiz, Matthew L. Banks Phd

IRBEH/Spit for Science Publications and Presentations

No abstract provided.

Protocol For A Feasibility Randomized Controlled Trial Of Gentle Yoga In Older Patients Discharged From Phase Ii Cardiac Rehabilitation, Geunyeong Cha, Misook L. Chung, Nicholas R. Heebner, Ulf G. Bronas, Martha J. Biddle, Chin-Yen Lin, Junghee Kang, Jia-Rong Wu, Jessica H. Thompson, Ashmita Thapa, Debra K. Moser

UK CARES Faculty Publications

Background: Physical activity (PA) is essential following an acute cardiac event. Cardiac rehabilitation (CR) is commonly prescribed, and PA after CR is recommended. Because of age-related changes in functional ability and multi-comorbidity, many older cardiac patients struggle to continue performing PA at home after CR. Depressive symptoms and anxiety are prevalent in cardiac patients and associated with poor self-care, including lack of daily PA. Yoga has been demonstrated to improve psychological and physical health outcomes in cardiac patients, but it is unknown whether yoga, modified for older CR patients – Gentle Yoga – is beneficial in managing psycho- logical distress …

Outpatient Fall Prevention In Ambulatory Adults 65 Years Old And Over, Dorothy L. Osborne-White

Doctor of Nursing Practice (DNP) Scholarly Projects - Archive

Background: In the United States (U.S.), falls are the leading cause of injury among adults 65 and over, resulting in 36 million falls yearly (Moreland et al., 2020). According to the Centers for Disease Control and Prevention (CDC, 2023), one in four older adults experiences a fall each year. Falls are the world's second most prominent cause of accidental deaths (World Health Organization [WHO], 2021). Falls are the leading cause of both fatal and non-fatal injuries among older adults (Moreland et al., 2020).

Methods: A quality improvement project that included a fall bundle was implemented in a primary clinic. A …

Aggravated Ulcerative Colitis Via Circnlgn-Mediated Suppression Of Nuclear Actin Polymerization., William W Du, Chi Zhou, Hui Yang, Shuoyang Wen, Yu Chen, Eric X Chen, Xiuwei H. Yang, Feiya Li, Kevin Y Du, Hui Yuan, Ting Ye, Javeria Qadir, Burton B Yang

Pharmacology and Nutritional Sciences Faculty Publications

Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to …

Adgrl1 Is A Glucose Receptor Involved In Mediating Energy And Glucose Homeostasis, Kavaljit H Chhabra, Siresha Bathina, Tumininu S Faniyan, Dennis J Samuel, Muhammad Ummear Raza, Leticia Maria De Souza Cordeiro, Gonzalo Viana Di Prisco, Brady K Atwood, Jorge Robles, Lauren Bainbridge, Autumn Davis

Pharmacology and Nutritional Sciences Faculty Publications

AIMS/HYPOTHESIS: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus.

METHODS: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to …

Evaluation Of The Cellular And Physiologic Impact Of Mitomycin C On Colon Cancer, Hannah Mcdonald

Theses and Dissertations--Clinical and Translational Science

Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) with Mitomycin C (MMC) has more than doubled the overall and disease-free survival in patients with peritoneal metastases (PM) due to colorectal cancer (CRC) over the past two decades. Although MMC is the most used HIPEC drug for PM due to CRC, dosing protocols vary dramatically between and within institutions across the world. Additionally, little is known about the impact of hyperthermia and MMC on intracellular pathways for CRC. The aim of this work is to determine the optimal dosing strategy in the clinical application of MMC and hyperthermia for treatment of …

Exenatide As Chronopharmacotherapy For T2dm Associated Complications: Targeting Nondipping Blood Pressure And Sleep Insufficiency, Aaron Chacon

Theses and Dissertations--Pharmacology and Nutritional Sciences

Although largely impacted by age, race and ethnicity, and socioeconomic factors, Type 2 Diabetes Mellitus (T2DM) is primarily driven by obesity, currently affecting ~30 million in the U.S and ~463 million globally. T2DM carries numerous complications, including high prevalence of hypertension and nondipping blood pressure (BP), sleep insufficiency and fragmentation. Nondipping BP is an inadequate drop in BP (≤ 10%) during sleeping hours compared with waking hours. Lending to this, sleep disturbance acts as both precursor and consequence of metabolic dysregulation, greatly impacting circadian rhythmicity. To model these conditions, we utilized diabetic (db/db) mice. These mice carry a point mutation …

Effect Of Mitochondrial Oxidative Stress On Regulatory T Cell Manufacturing For Clinical Application In Transplantation: Results From A Pilot Study, Roberto Gedaly, Gabriel Orozco, Lillie J. Lewis, Deepa Valvi, Fanny Chapelin, Aman Khurana, Giovanna E. Hidalgo, Aaron Shmookler, Aashutosh Tripathi, Cuiping Zhang, Joseph B. Zwischenberger, Francesc Marti

Markey Cancer Center Faculty Publications

The manufacturing process of regulatory T (Treg) cells for clinical application begins with the positive selection of CD25⁺ cells using superparamagnetic iron oxide nanoparticle (SPION)-conjugated anti-CD25 antibodies (spCD25) and immunomagnetic cell separation technology. Our findings revealed that the interaction of spCD25 with its cell target induced the internalization of the complex spCD25–interleukin-2 receptor. Accumulation of intracellular spCD25 triggered oxidative stress, causing delayed Treg expansion and temporary reduction in suppressor activity. This activation delay hindered the efficient generation of clinically competent cells. During this early phase, Treg cells exhibited elevated mitochondrial superoxide and lipid peroxidation levels, with a concomitant decrease …

Anatomical And Physiological Characterization Of Striatal Activation Of The Cerebral Cortex, Yuhan Wang

Theses and Dissertations (ETD)

Purpose. The striatum receives excitatory glutamatergic input from nearly all parts of the cerebral cortex, and its output is delivered by direct pathway medium spiny neurons (dMSNs) expressing D1 type dopamine (DA) receptors (D1Rs) and indirect pathway MSNs (iMSNs) expressing D2 DA receptors (D2Rs). Loss of DA results in the imbalance between the activities of dMSNs and iMSNs in Parkinson’s disease (PD), leading to ab-normal interactions between the cerebral cortex and striatum. Thus, understanding the inter-actions between the cortex and striatum is important. The monosynaptic corticostriatal cir-cuit has been extensively studied. In contrast, due to the poly-synaptic nature of the …

Comparison Of Risk Factors Of Mortality During The Two Coronavirus Disease 2019 Waves In Delhi, India, Neena Katoch, Ajay K. Gupta, Rachna Gulati, Ketan Garg, Vikas Kumar

Journal of Medicine in Scientific Research

Objective To determine the risk factors of mortality (in terms of age, sex, and comorbidities) among hospitalized patients in an Indian tertiary care hospital during the first and second waves. Patients and methods A retrospective observational study was conducted, where the patients’ mortality data were collected over two coronavirus disease 2019 (COVID-19) periods, and their characteristics were compared. The first phase was from May 2020 to January 2021 and the second wave was from March 2021 to August 2021. Results A mortality rate of 23.84% (874 deaths among 3666 patients) and 1.36% (232 deaths among 17 000 patients) was noted …

A Suspected Case Of Levetiracetam Induced Rhabdomyolysis, Luke Merrill Ms, Layne Hohn Ms, Marlee Jones Ms, Sydney Gibson Ms, Ty Moody Md, Anthony Breemo Md

Aesculapius Journal (Health Sciences & Medicine)

Background: Levetiracetam is a broad-spectrum antiseizure drug which works to terminate convulsions and is used in the treatment of certain types of seizures. It is commonly used to treat epilepsy in adults, and has proven an effective treatment for adults with focal seizures. This drug is normally well tolerated, but commonly reported adverse effects include fatigue, somnolence, and dizziness. A few less common effects have been noted as well, including behavioral disturbances, thrombocytopenia, and—in very few cases—rhabdomyolysis.

Case Report: Our case reports a 55-year-old male who presented to a rural emergency department for active convulsing and unresponsiveness. Initial …

Maternal Western Diet Programs Cardiometabolic Dysfunction And Hypothalamic Inflammation Via Epigenetic Mechanisms Predominantly In The Male Offspring, Mona Elgazzaz, Clara Berdasco, Jone Garai, Melody Baddoo, Shiping Lu, Hisham Daoud, Jovanny Zabaleta, Franck Mauvais-Jarvis, Eric Lazartigues

School of Medicine Faculty Publications

Objective; Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring. Methods; C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups …

The Concise Guide To Pharmacology 2023/24: Catalytic Receptors, Stephen P.H. Alexander, Doriano Fabbro, Eamonn Kelly, Alistair A. Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Jamie A. Davies, Annie Beuve, Peter Brouckaert, Clare Bryant, John C. Burnett, Richard W. Farndale, Andreas Friebe, John Garthwaite, Adrian J. Hobbs, Gavin E. Jarvis, Doris Koesling, Michaela Kuhn, David Macewan, Tom P. Monie, Lincoln R. Potter, Michael Russwurm, Harald H.H.W. Schmidt, Johannes-Peter Stasch, Scott A. Waldman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It …

The Pharmacological Deprescription In Elderly Patients, Chelsey Ali, Daniel Huang, Charlene Tugwete, Stefano Del Canale, Vittorio Maio

College of Population Health Faculty Papers

No abstract provided.

Shorter Duration Of Dual Antiplatelet Therapy Following Second Generation Drug Eluting Stent Placement, Alexandra Coy, Caitlyn M. Murtha

Physician Assistant Capstones, 2020-current

Heart disease is the leading cause of death in both men and women in The United States. Because advanced heart disease is often treated with percutaneous coronary intervention (PCI) for stent implantation, many patients will be put on dual antiplatelet therapy to prevent adverse effects such as stent thrombosis or restenosis. The purpose of this literature review is to determine if the development of second-generation drug eluting stents allows for a shorter, 6-month, duration of dual antiplatelet therapy (DAPT) versus the currently recommended 12 months. The articles discussed in this review were obtained on PubMed and narrowed using search terms …

Central Activation Of Orl-1 Receptors In Heart Failure Models, Jeffrey Angell

Theses & Dissertations

Heart failure is a prevalent and debilitating disease associated with high morbidity and mortality rates worldwide and is the leading cause of death in the United States. While various therapeutic strategies have been developed and approved to manage heart failure, exploration of novel targets and mechanisms are essential for improving patient outcomes. This thesis investigates the therapeutic potential of the central activation of opioid receptor-like 1 (ORL-1) by nociceptin in a rodent heart failure model.

Furthermore, this study aims to elucidate the central mechanisms underlying nociceptin induced cardiovascular and renal effects in heart failure. This involves investigating neuronal pathways and …

Evaluation Of Current Monitoring Practices For Patients Receiving Infliximab, Yujin Hong Pharmd, Michael Schaedler Pharmd, Bcps, Bcop, Vincent Do Pharmd, Bcps, Bctxp

Posters

• Infliximab is used for a wide range of inflammatory conditions including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
• Patients should be closely monitored for development of signs and symptoms of active tuberculosis and latent infection, hepatitis B virus, and human immunodeficiency virus (HIV) during treatment with infliximab following termination of therapy.
• Hematologic abnormalities have also been reported in patients receiving infliximab and caution should be exercised in patients being treated with infliximab who have ongoing or a history of significant hematologic abnormalities.
• Patients with symptoms of signs of liver dysfunction should be evaluated for …

Evaluation Of Compliance To Brivaracetam Restrictions Within A Large Multicenter Health System, Meghan Mcnulty Pharmd, Mahmoud Amir Pharmd, Fccm, Bcps, Bcccp, Paul Ahearn, Michele Moura Pharmd, Bcps, Bcccp

Posters

This evaluation aims to assess whether the health-system is adhering to brivaracetam prescribing restrictions and determine if there are any opportunities for improvement to the current ordering workflow.

Dietary Analysis For Hashimoto’S Thyroiditis: An Integrative Review, Evan Thompson, Alison Hultquist

Master of Science in Nursing Final Projects

Abstract

Hashimoto’s Thyroiditis (HT) is the leading cause of primary hypothyroidism in the United States. In HT, there is an infiltration by lymphocytes which leads to the production of autoantibodies against the thyroid gland. Throughout this integrative review, the aim was to evaluate the effectiveness of micronutrient supplementation and dietary management as adjunct treatments in HT. The purpose was to assist primary care providers in the development of a more holistic plan of care. Literature published within the past seven years was gathered and reviewed from PubMed, CINAHL, and Cochrane Library. Findings indicate that many patients with HT may benefit …

Canagliflozin Ameliorates Autistic-Like Features And Mitigates Brain Oxidative Stress Levels In Valproic Acid-Induced Autism, Mohammad Moutaz Nakhal

Thesis/ Dissertation Defenses

Autism spectrum disorder (ASD) is a neurodevelopmental disease with a substantially increasing incidence rate. It is mainly characterized by repetitive behavior, intellectual difficulties, social communication and interactions deficits. Many medications, dietary supplements, and behavioral treatments have been recommended for ASD management, however, there is no cure yet. Recent studies have examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in neurodevelopmental diseases, based on their proved anti-inflammatory and antioxidant effects. The main objective of this study is to assess the ability of canagliflozin in improving the behavioural characteristics of autistic rats and investigate the efficacy of canagliflozin in …

Prescribing Protocol For Postoperative Opioids In An Orthopedic Spine Practice, Kelly M. Manda

All Doctor of Nursing Practice (DNP) Scholarly Projects

Problem: The opioid epidemic is magnified by excessive post-surgery prescriptions. Over six months at an orthopedic spine practice, 50% of patients received two or more opioid refills beyond their first. This highlighted the absence of a clear prescribing policy and emphasized the need for a structured protocol and to promote patient safety.

Aim of the Project: The primary aim was to implement a prescribing protocol to lower opioid refills provided to post-surgical patients in this surgical practice. The desired result was to reduce the number of opioid refills provided to patients after surgery.

Review of the Evidence: Evidence highlighted …

Therapeutic Effects Of Combining Curcumin And Swimming In Osteoarthritis Using A Rat Model, Mona M Saber, Manal Moustafa Mahmoud, Hesham M Amin, Reham M Essam

Faculty, Staff and Student Publications

Osteoarthritis (OA) is a common debilitating degenerative disease of the elderly. We aimed to study the therapeutic effects of combining curcumin and swimming in monosodium iodoacetate (MIA)-induced OA in a rat model. The rats were divided into 5 groups (n = 9). Group 1 received saline and served as a control group. Groups 2-5 were injected intra-articularly in the right knee with 100 μL MIA. One week later, groups 3 and 5 were started on daily swimming sessions that gradually increased to 20-mins per session, and for groups 4 and 5, oral curcumin was administered at a dose of 200 …

Dpyd Pathogenic Variants Associated With Fluoropyrimidines Toxicity, Diana Cristina Pérez-Ibave, Noé Israel Oliva-García, Irasema Ramos-Martínez, Francisco Javier Villarreal Alvarado, Valeria Jimena Gómez Ordaz, Jonatán Isaí Cortes Alfaro, Carlos Horacio Burciaga-Flores, Juan Francisco González-Guerrero, Oscar Vidal-Gutiérrez, Maria De Lourdes Garza-Rodriguez

Research Symposium

Background: Genetic variants in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism. DPYD contributes to the development of severe FPs-related toxicity, and pathogenic DPYD variants detection reduces side effects and complications associated with FP-toxicity. The allelic frequency of these variants in the Mexican population is currently unknown.

Methods: The study was carried out at the Centro Universitario Contra el Cáncer (CUCC) of the Universidad Autónoma de Nuevo León (UANL) in Monterrey México. Genomic DNA was isolated from 154 subjects using the QIAamp DNA Blood Midi kit (QIAGEN) following the manufacturer's recommendations. We …

Oral Dosages Of The Nsaid Aspirin Decreased The Growth Rate Of Species Found In The Human Gut Microbiome Including Akkermansia Muciniphila, Bacteroides Fragilis, Clostridium Sordellii, And Clostridium Difficile, Wyatt H. Greenbaum, Garrett J. Greenbaum, Anna Spiezio

PANDION: The Osprey Journal of Research and Ideas

Over past few decades, new insight has been revealed in the scientific community about the importance of the human gut microbiome relating to general health. It is known that imbalances in the species that reside in the human gut can cause organism-wide problems in humans. When prescribing or injecting oral medications, the thought of the downstream effects on the gut microbiome are not always considered. By exposing known healthy members of the gut; Akkermansia muciniphila, Bacteroides fragilis, Clostridium sordellii, and Clostridium difficile to the Aspirin, this study attempted to provide insight into the effects of the drug on bacterial growth. …

Paradoxes Of Cellular Sumoylation Regulation: A Role Of Biomolecular Condensates?, Xiaodong Cheng, Wenli Yang, Wei Lin, Fang Mei

Faculty, Staff and Student Publications

Protein SUMOylation is a major post-translational modification essential for maintaining cellular homeostasis. SUMOylation has long been associated with stress responses as a diverse array of cellular stress signals are known to trigger rapid alternations in global protein SUMOylation. In addition, while there are large families of ubiquitination enzymes, all small ubiquitin-like modifiers (SUMOs) are conjugated by a set of enzymatic machinery comprising one heterodimeric SUMO-activating enzyme, a single SUMO-conjugating enzyme, and a small number of SUMO protein ligases and SUMO-specific proteases. How a few SUMOylation enzymes specifically modify thousands of functional targets in response to diverse cellular stresses remains an …

Topiramate (Topamax): Evolving Role In Weight Reduction Management: A Narrative Review, Irza Wajid, Alexis Vega, Katherine Thornhill, Jack Jenkins, Chandler Merriman, Debbie Chandler, Sahar Shekoohi, Elyse M. Cornett, Alan D. Kaye

School of Medicine Faculty Publications

Obesity has emerged as a widespread disease with epidemic proportions, necessitating effective management to enhance the overall health outcomes of patients. Medical intervention for weight loss becomes necessary when diet and exercise prove ineffective, and topiramate emerges as a potential treatment option for this global problem. Currently approved as an anti-epileptic and migraine prophylaxis medication, topiramate is frequently utilized as adjunctive therapy for patients with mood and eating disorders, as well as for alcohol use disorders. Its multifaceted mechanisms of action contribute to reducing neuronal excitation and enhancing neuronal inhibition. Given its variety of mechanisms, topiramate shows several off-label outcomes, …

The Role Of Pharmacogenetics On Breast Cancer Treatment Efficacy And Toxicity, Noor Alani, Nicholas Barber, Britt Benn, Justin M. Gambini

Doctor of Medical Science (DMSc)

Purpose: This research article aims to shed light on the pivotal role of pharmacogenetics in breast cancer treatment by examining genetic variations that influence the efficacy and toxicity of commonly used drugs. Furthermore, this study highlights the significance of personalized treatment approaches in optimizing patient outcomes.

Method: A comprehensive literature search was conducted using databases such as PubMed. Search terms included "pharmacogenetics," "breast cancer treatment," "genetic markers," and "adverse effects." This review critically analyzes relevant studies that focus on the impact of genetic variations on the response to drugs used in breast cancer treatment.

Results: The review …

Severe Covid-19 Following Rituximab And Nirmatrelvir/Ritonavir Treatment In A Patient With Mctd, Case Report, Rohail A. Baig, Faieja Chowdhury, Omar Siddiqui, Adnaan Sheikh, Varun Mehta, Pranjali Dakwale

Advances in Clinical Medical Research and Healthcare Delivery

This is an article about how the use of medications such as nirmatrelvir/ritonavir can cause rebound COVID-19 and how the use of Rituximab, a biologic agent, can prolong the duration and increase severity of symptoms of COVID-19 in patients with pre-disposed autoimmune diseases that are on chronic pharmacotherapy.

Identification Of A Β-Arrestin-Biased Negative Allosteric Modulator For The Β2-Adrenergic Receptor, Michael Ippolito, Francesco De Pascali, Nathan Hopfinger, Konstantin E. Komolov, Daniela Laurinavichyute, Poli Adi Narayana Reddy, Leon A. Sakkal, Kyle Z. Rajkowski, Ajay P. Nayak, Justin Lee, Jordan Lee, Gaoyuan Cao, Preston S. Donover, Melvin Reichman, Stevens. An, Joseph M. Salvino, Raymond B. Penn, Roger S S. Armen, Charles P. Scott, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

Catecholamine-stimulated β2-adrenergic receptor (β2AR) signaling via the canonical Gs–adenylyl cyclase–cAMP–PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous β-agonists in the treatment of airway disease. β2AR signaling is tightly regulated by GRKs and β-arrestins, which together promote β2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias β2AR signaling toward the Gs pathway while avoiding β-arrestin-mediated effects may provide a strategy to improve the functional consequences of β2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the β2AR have been largely unsuccessful, here we …