Hematology Commons^™

Inhibition Of Nadph Oxidase Blocks Netosis And Reduces Thrombosis In Heparin-Induced Thrombocytopenia, Halina H L Leung, Jose Perdomo, Zohra Ahmadi, Feng Yan, Steven E. Mckenzie, Beng H Chong

Department of Medicine Faculty Papers

Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant neutrophil extracellular traps (NETs) and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis …

Predicting Risk Factors For Thromboembolic Complications In Patients With Sickle Cell Anaemia - Lessons Learned For Prophylaxis, Salam Alkindi, Anwaar R Al-Ghadani, Samah R Al-Zeheimi, Said Y Alkindi, Naglaa Fawaz, Samir K. Ballas, Anil V Pathare

Cardeza Foundation for Hematologic Research

Objective: To assess the clinical and laboratory predictors of venous thromboembolism (VTE) in patients with sickle cell anaemia (SCA) and its relationship to morbidity and mortality.

Methods: This retrospective case-control study analysed data from patients with SCA that experienced VTE compared with matched control patients with SCA but no VTE (2:1 ratio).

Results: A total of 102 patients with SCA were enrolled (68 cases with VTE and 34 controls). Amongst the 68 cases (median age, 29.5 years), 26 (38.2%) presented with isolated pulmonary embolism (PE). A higher prevalence of splenectomy (73.5% versus 35.3%) was observed in the cases compared with …

Vte And Anticoagulation In Menstruating Women, Ida Micaily, Bethany T. Samuelson Bannow

Department of Medicine Faculty Papers

Women of childbearing potential have a high prevalence of venous thromboembolism (VTE) due to high estrogen states, such as pregnancy and the use of estrogen-containing contraceptives. Abnormal uterine bleeding (AUB) affects up to two-thirds of menstruating women on anticoagulation (AC), and can severely impair a woman's quality of life. Rates of heavy menstrual bleeding (HMB) and other forms of AUB including inter-menstrual and postmenopausal bleeding are consistently underreported in the original clinical trials utilizing AC. VTE can occur at any time in a woman's life, and the aim of this review article is to discuss the current landscape of literature …

Blood Transfusions Increase The Risk For Venous Thromboembolism Events Following Total Joint Arthroplasty, Noam Shohat, Leanne Ludwick, Graham S Goh, Matthew Sherman, Joseph Paladino, Javad Parvizi

Rothman Institute Papers

The association between blood transfusions and thromboembolic events (VTE) following total joint arthroplasty (TJA) remains debatable. Using contemporary institutional data, this study aimed to determine whether blood transfusions increase the risk of VTE following primary and revision TJA. This was a single institution, retrospective cohort study. The clinical records of all patients (n = 34,824) undergoing primary and revision TJA between 2009 and 2020 were reviewed. Demographic variables, co-morbidities, type of chemoprophylaxis and intraoperative factors such as use of tranexamic acid were collected. Clinical notes, hospital orders, and discharge summaries were reviewed to determine if a patient received a blood …

Level Of Utilization And Provider-Related Barriers To The Use Of Hydroxyurea In The Treatment Of Sickle Cell Disease Patients In Jos, North-Central Nigeria, Akinyemi O.D. Ofakunrin, Edache S. Okpe, Tolulope O. Afolaranmi, Rasaq Olaosebikan, Patience U. Kanhu, Kehinde Adekola, Nantok Dami, Atiene S. Sagay

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: Hydroxyurea is underutilized by sickle cell health-care providers in Nigeria despite available evidence of its effectiveness in reducing the manifestations and complications of sickle cell disease (SCD).

Objectives: To assess the level of utilization and provider-related barriers to the use of hydroxyurea in SCD therapy in Jos, Nigeria.

Methods: A cross-sectional study conducted among 132 medical doctors providing care for SCD patients. Data on so- cio-demographics, utilization and barriers to hydroxyurea use were obtained. The barriers were fed cumulatively into the logistic regression model as predictors of utilization.

Results: Of the 132 care providers, 88 (67%) had been in …

Therapeutic Potential Of Hla-I Polyreactive Mabs Mimicking The Hla-I Polyreactivity And Immunoregulatory Functions Of Ivig, Mepur H Ravindranath, Fatiha El Hilali, Edward Filippone

Department of Medicine Faculty Papers

HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing mice with HLA-E monomeric, α-heavy chain (αHC) open conformers (OCs). Two mAbs (TFL-006 and TFL-007) were bound to the αHC’s coated on a solid matrix. The binding was inhibited by the peptide117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by β2-microglobulin (β2-m) in intact HLA-I trimers (closed conformers, CCs). IVIg preparations administered to lower anti-HLA Abs in pre-and post-transplant patients have also shown HLA-I polyreactivity. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might also possess the immunomodulatory …

Ferumoxytol For The Treatment Of Iron Deficiency And Iron-Deficiency Anemia Of Pregnancy., Jesse Gerb, William Strauss, Richard Derman, Vanessa Short, Phd, Mph, Ben Mendelson, Huzefa Bahrain, Michael Auerbach

Department of Obstetrics and Gynecology Faculty Papers

Introduction: A litany of recent evidence supports the morbidity of intra-natal iron-deficiency anemia and its prodrome, iron deficiency. Oral iron administered during second and third trimesters does not get to the developing fetus if the mother is iron deficient. This is especially concerning as the rapidly developing fetal brain is in particular need of iron sufficiency. Intra-natal iron deficiency is associated with autism, schizophrenia and abnormal brain structure. The obstetrical literature reports an unacceptably high incidence of gastrointestinal adverse events with oral iron. The time iron honored standard in the United States for intravenous iron replenishment in gravidas is iron …

Opioids Are Not A Major Cause Of Death Of Patients With Sickle Cell Disease., Samir K. Ballas

Cardeza Foundation for Hematologic Research

According to the Center of Disease Control and Prevention (CDC) database, the total number of deaths due to opioid overdose from 1999 through 2018 was 840,629. Given the alarming nature of these statistics, patients who requested prescription for opioids became targets of suspicion and possible accusation of maladaptive behavior. Patients with sickle cell disease (SCD) were often not exempt from such accusations and became guilty by association. In order to clarify the effect of opioids on the mortality of patients with SCD, the mortality rates for children and adults with SCD were investigated using the CDC Wide-ranging Online Data for …

Platelets As Drivers Of Ischemia/Reperfusion Injury After Stroke., Noor F Shaik, Raymond F Regan, Ulhas P Naik

Cardeza Foundation for Hematologic Research

Ischemic stroke is a leading cause of morbidity and mortality worldwide and, despite reperfusion either via thrombolysis or thrombectomy, stroke patients often suffer from lifelong disabilities. These persistent neurological deficits may be improved by treating the ischemia/reperfusion (I/R) injury that occurs following ischemic stroke. There are currently no approved therapies to treat I/R injury, and thus it is imperative to find new targets to decrease the burden of ischemic stroke and related diseases. Platelets, cell fragments from megakaryocytes, are primarily known for their role in hemostasis. More recently, investigators have studied the nonhemostatic role of platelets in inflammatory pathologies, such …

Pctp Contributes To Human Platelet Activation By Enhancing Dense Granule Secretion, Shaji Abraham, Lin Ma, Xianguo Kong, Shayan Askari, Leonard Edelstein, Steven Mckenzie

Cardeza Foundation for Hematologic Research

PCTP (phosphatidylcholine transfer protein) was discovered recently to regulate aggregation of human platelets stimulated with PAR4 activating peptide (PAR4AP). However, the role of PCTP following thrombin stimulation, the mechanisms by which PCTP contributes to platelet activation, and the role of PCTP with other receptors remained unknown. As mouse platelets do not express PCTP, we treated human platelets with various agonists in the presence of the specific PCTP inhibitor A1. We observed that PCTP inhibition significantly reduced dense granule secretion in response to thrombin, PAR1AP, PAR4AP, convulxin (GPVI agonist) and FcγRIIA crosslinking. In contrast, among these agonists, PCTP inhibition reduced aggregation …

Determinants Of The Outcome Of The Transition Of Children With Sickle Cell Disease To Adult Programs., Samir K. Ballas, Gaye Riddick-Burden, Elisabeth Congdon-Martin

Cardeza Foundation for Hematologic Research

Transition of adolescents with sickle cell disease to adult programs is associated with increased morbidity and mortality. The reasons for this poor outcome are not well known. This report describes the various factors that affect the outcome of the transition process. These include four inter-personal factors: country of residence, region within the country of residence, the health care system and intra-personal factors. Each factor is described in some detail. Understanding these factors and the establishment of guidelines or recommendations could improve the outcome of this critical transition in the life of patients with sickle cell disease.

Voxelotor Modulates The Analgesic Effect Of Certain Opioids., Samir K. Ballas

Cardeza Foundation for Hematologic Research

No abstract provided.

Opioids And Sickle Cell Disease: From Opium To The Opioid Epidemic., Samir K. Ballas

Cardeza Foundation for Hematologic Research

Sickle cell disease (SCD) is an inherited disorder of hemoglobin structure. The clinical effects of the sickle gene are pleiotropic in nature causing multiple phenotypic expressions associated with the various complications of the disease. The hallmark of the disease is pain that could be acute, chronic, nociceptive, or neuropathic that could occur singly or in various combinations. The acute vaso-occlusive painful crisis (VOC) is the most common cause of admissions to the Emergency Department and/or the hospital. Although progress has been made in understanding the pathophysiology of SCD as well as in developing preventive and curative therapies, effective pain management …

International Evidence-Based Consensus Diagnostic And Treatment Guidelines For Unicentric Castleman Disease., Frits Van Rhee, Eric Oksenhendler, Gordan Srkalovic, Peter Voorhees, Megan Lim, Angela Dispenzieri, Makoto Ide, Sophia Parente, Stephen Schey, Matthew Streetly, Raymond Wong, David Wu, Ivan Maillard, Joshua Brandstadter, Nikhil Munshi, Wilbur Bowne, Kojo S Elenitoba-Johnson, Alexander Fössa, Mary Jo Lechowicz, Shanmuganathan Chandrakasan, Sheila K Pierson, Amy Greenway, Sunita Nasta, Kazuyuki Yoshizaki, Razelle Kurzrock, Thomas S Uldrick, Corey Casper, Amy Chadburn, David C Fajgenbaum

Department of Surgery Faculty Papers

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, …

Case Series And Review Of Hematological And Non-Hematological Malignancies In Aging Patients With Sickle Cell Disease In The Hydroxyurea Era., Sanaa Rizk, David J. Axelrod, Rasaq Olaosebikan, Samir K. Ballas

Cardeza Foundation for Hematologic Research

Survival of adult patients with sickle cell disease has increased progressively since the 1970s. Aging patients with sickle cell disease are at risk of developing comorbidities that are not due to sickle cell disease itself, including malignancies. Many studies tried to assess the incidence of malignancy in patients with sickle cell disease. However, no studies have been done to evaluate cancer incidences in aging sickle cell patients, especially in the hydroxyurea (HU) era. In this review, we assessed the prevalence of malignancies in aging patients with sickle cell disease at our institution with or without HU therapy. Retrospective analysis of …

The Vaso-Occlusive Pain Crisis In Sickle Cell Disease: Definition, Pathophysiology, And Management., Deepika S. Darbari, Vivien A. Sheehan, Samir K. Ballas

Cardeza Foundation for Hematologic Research

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents …

How I Treat Acute And Persistent Sickle Cell Pain., Samir K. Ballas

Cardeza Foundation for Hematologic Research

Sickle pain is the hallmark of sickle cell disease (SCD). It could be acute, persistent/relapsing, chronic, or neuropathic. Although there is a general consensus that pain is a major manifestation of SCD, there is a controversy as to the types of pain and their interrelationship between acute, chronic, relapsing, persistent, etc. This report first reviews the general approach to the management of acute vaso-occlusive crisis (VOC) pain, including education, counseling, pharmacotherapy, non-pharmacotherapy, and fluid therapy. This is followed by the presentation of five patients that represent typical issues that are commonly encountered in the management of patients with SCD. These …

Menopause In Brazilian Women With Sickle Cell Anemia With And Without Hydroxyurea Therapy., Ana Mach Queiroz, Clarisse Lopes De Castro Lobo, Samir K. Ballas

Cardeza Foundation for Hematologic Research

Women with sickle cell anemia (SCA) require special attention for myriad obstetric and gynecologic issues associated with this complex hematologic disorder. These affect all aspects of female life from menarche through menopause. Information regarding obstetric and gynecologic complications of sickle cell disease (SCD), with a few exceptions, is based primarily on observational, anecdotal, retrospective, or cohort studies that may not reflect current aspects of obstetric care.¹ Similarly, there are no recent reports about menopause (also known as climacteric) in women with SCA. The fact that life expectancy of women with SCA was determined to be 46–48 years² delayed …

The Roles Of Grks In Hemostasis And Thrombosis, Xi Chen, Xuefei Zhao, Matthew Cooper, Peisong Ma

Department of Medicine Faculty Papers

Along with cancer, cardiovascular and cerebrovascular diseases remain by far the most common causes of death. Heart attacks and strokes are diseases in which platelets play a role, through activation on ruptured plaques and subsequent thrombus formation. Most platelet agonists activate platelets via G protein-coupled receptors (GPCRs), which make these receptors ideal targets for many antiplatelet drugs. However, little is known about the mechanisms that provide feedback regulation on GPCRs to limit platelet activation. Emerging evidence from our group and others strongly suggests that GPCR kinases (GRKs) are critical negative regulators during platelet activation and thrombus formation. In this review, …

Bayesian Modelling Of High-Throughput Sequencing Assays With Malacoda., Andrew R Ghazi, Xianguo Kong, Ed S Chen, Leonard C Edelstein, Chad A Shaw

Cardeza Foundation for Hematologic Research

NGS studies have uncovered an ever-growing catalog of human variation while leaving an enormous gap between observed variation and experimental characterization of variant function. High-throughput screens powered by NGS have greatly increased the rate of variant functionalization, but the development of comprehensive statistical methods to analyze screen data has lagged. In the massively parallel reporter assay (MPRA), short barcodes are counted by sequencing DNA libraries transfected into cells and the cell's output RNA in order to simultaneously measure the shifts in transcription induced by thousands of genetic variants. These counts present many statistical challenges, including overdispersion, depth dependence, and uncertain …

Iron Deficiency Anemia: An Unexpected Cause Of An Acute Occipital Lobe Stroke In An Otherwise Healthy Young Woman, Qian Zhang, Khine S. Shan, Conor O'Sullivan, Travis C. Nace

Abington Jefferson Health Papers

A 29-year-old caucasian woman who presented to the hospital with an acute onset of right eye visual disturbance and headache was found to have an acute left occipital lobe infarction. Past medical history was significant for iron deficiency anemia (IDA) secondary to menorrhagia. Her initial hemoglobin level was 7.8 G/DL, and her symptoms improved after iron and blood transfusions. Hypercoagulable studies were completed in the outpatient setting, and the results were unremarkable. Her acute stroke was most likely related to IDA as she had low cardiovascular risk factors along with a negative complete stroke workup.

Transcutaneous Electrical Nerve Stimulation (Tens) For Pain Management In Sickle Cell Disease., Sudipta Pal, Ruchita Dixit, Soe Moe, Myron Anthony Godinho, Adinegara Bl Abas, Samir K. Ballas, Shanker Ram, Uduman Ali M. Yousuf

Cardeza Foundation for Hematologic Research

BACKGROUND: Sickle cell disease (SCD), one of the most common inherited disorders, is associated with vaso-occlusive pain episodes and haemolysis leading to recurrent morbidity, hospital admissions and work or school absenteeism. The crises are conventionally treated with opioids, non-opioids and other adjuvants with the risk of developing complications, addictions and drug-seeking behaviour. Different non-pharmacological treatments, such as transcutaneous electrical nerve stimulation (TENS) have been used for managing pain in other painful conditions. Hence, the efficacy of TENS for managing pain in SCD needs to be reviewed.

OBJECTIVES: To assess the benefits and harms of TENS for managing pain in people …

Review/Overview Of Pain In Sickle Cell Disease., Samir K. Ballas, Deepika S. Darbari

Cardeza Foundation for Hematologic Research

Sickle cell disease (SCD) is a highly complex inherited disorder of hemoglobin structure. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of the disease. Its manifestations could be acute, chronic, nociceptive, neuropathic that could occur singly or in various combinations. Pain continues to be the major factor of SCD phenotypic complications and the most common cause of admissions to the Emergency Department and/or the hospital. Although progress has been made in understanding the pathophysiology of SCD as well as in developing curative therapies such …

Predictors Of Impending Acute Chest Syndrome In Patients With Sickle Cell Anaemia., Salam Alkindi, Ikhlas Al-Busaidi, Bushra Al-Salami, Samir Raniga, Anil Pathare, Samir K. Ballas

Cardeza Foundation for Hematologic Research

Acute chest syndrome (ACS) is a major complication of sickle cell anaemia (SCA) and a leading cause for hospital admissions and death. We aimed to study the spectrum of clinical and laboratory features of ACS and to assess the predisposing factors and predictors of severity. A retrospective case-control cohort was studied by retrieving patient information from electronic medical records after ethical approval. One hundred adolescents and adults with SCA and hospital admissions for ACS were identified through the discharge summaries, along with 20 additional patients presenting with VOC, but without ACS (controls). Among the patients with ACS, fever (>38.5 …

Grk6 Regulates The Hemostatic Response To Injury Through Its Rate-Limiting Effects On Gpcr Signaling In Platelets., Xi Chen, Shuchi Gupta, Matthew Cooper, Daniel Dehelian, Xuefei Zhao, Meghna U. Naik, Jeremy G.T. Wurtzel, Timothy J. Stalker, Lawrence E. Goldfinger, Jeffrey Benovic, Lawrence F. Brass, Steven E. Mckenzie, Ulhas P. Naik, Peisong Ma

Cardeza Foundation for Hematologic Research

G protein-coupled receptors (GPCRs) mediate the majority of platelet activation in response to agonists. However, questions remain regarding the mechanisms that provide negative feedback toward activated GPCRs to limit platelet activation and thrombus formation. Here we provide the first evidence that GPCR kinase 6 (GRK6) serves this role in platelets, using GRK6-/- mice generated by CRISPR-Cas9 genome editing to examine the consequences of GRK6 knockout on GPCR-dependent signaling. Hemostatic thrombi formed in GRK6-/- mice are larger than in wild-type (WT) controls during the early stages of thrombus formation, with a rapid increase in platelet accumulation at the site of injury. …

A Report From The Grndad Multi-Site Registry For Sickle Cell Disease: Iron Overload Is Under-Recognized And Under-Managed, Matthew Sears, Phd, Sophie Lanzkron, Md, Mhs, Carolyn Hoope, Md, Joshua J. Field, Md, E. Leila Jerome Clay, Md, Mcts, Faap, Susan Padrino, Md, Payal C. Desai, Md, Lynne D. Neumayr, Deepa Manwani, Md, Jane Little, Md

Phase 1

Introduction: GRNDaD is a prospective registry for people with SCD that opened to enrollment in 2016. Nine comprehensive SCD centers from across the United States are currently enrolling patients. The registry includes iron status and management data, important in SCD because chronic transfusion therapy is a mainstay of prophylactic management. Each unit of transfused blood introduces approximately 250 mg of iron into the blood, which can lead to systemic iron deposition, and untreated may lead to organ dysfunction or death.

Methods: GRNDaD currently contains prospective baseline and annual update information on approximately 1000 people with SCD. We analyzed ferritin levels …

The Evolving Pharmacotherapeutic Landscape For The Treatment Of Sickle Cell Disease., Samir K Ballas

Cardeza Foundation for Hematologic Research

Sickle cell disease (SCD) is an extremely heterogeneous disease that has been associated with global morbidity and early mortality. More effective and inexpensive therapies are needed. During the last five years, the landscape of the pharmacotherapy of SCD has changed dramatically. Currently, 54 drugs have been used or under consideration to use for the treatment of SCD. These fall into 3 categories: the first category includes the four drugs (Hydroxyurea, L-Glutamine, Crizanlizumab tmca and Voxelotor) that have been approved by the United States Food and Drug Administration (FDA) based on successful clinical trials. The second category includes 22 drugs that …

Treatment Of Dental Complications In Sickle Cell Disease., Priti Mulimani, Samir K. Ballas, Adinegara Bl Abas, Laxminarayan Karanth

Cardeza Foundation for Hematologic Research

BACKGROUND: Sickle cell disease is the most common single gene disorder and the commonest haemoglobinopathy found with high prevalence in many populations across the world. Management of dental complications in people with sickle cell disease requires special consideration for three main reasons. Firstly, dental and oral tissues are affected by the blood disorder resulting in several oro-facial abnormalities. Secondly, living with a haemoglobinopathy and coping with its associated serious consequences may result in individuals neglecting their oral health care. Finally, the treatment of these oral complications must be adapted to the systemic condition and special needs of these individuals, in …

Pharmacological Interventions For Painful Sickle Cell Vaso-Occlusive Crises In Adults., Tess E. Cooper, Ian R. Hambleton, Samir K. Ballas, Brydee A. Johnston, Philip J. Wiffen

Cardeza Foundation for Hematologic Research

BACKGROUND: Sickle cell disease (SCD) is a group of inherited disorders of haemoglobin (Hb) structure in a person who has inherited two mutant globin genes (one from each parent), at least one of which is always the sickle mutation. It is estimated that between 5% and 7% of the world's population are carriers of the mutant Hb gene, and SCD is the most commonly inherited blood disorder. SCD is characterized by distorted sickle-shaped red blood cells. Manifestations of the disease are attributed to either haemolysis (premature red cell destruction) or vaso-occlusion (obstruction of blood flow, the most common manifestation). Shortened …

Validation Of A Miniaturized Permeability Assay Compatible With Crispr-Mediated Genome-Wide Screen., Claire Simonneau, Junning Yang, Xianguo Kong, Robert Kilker, Leonard Edelstein, Paolo Fortina, Eric R. Londin, Arie Horowitz

Cardeza Foundation for Hematologic Research

The impermeability of the luminal endothelial cell monolayer is crucial for the normal performance of the vascular and lymphatic systems. A key to this function is the integrity of the monolayer's intercellular junctions. The known repertoire of junction-regulating genes is incomplete. Current permeability assays are incompatible with high-throughput genome-wide screens that could identify these genes. To overcome these limitations, we designed a new permeability assay that consists of cell monolayers grown on ~150 μm microcarriers (MCs). Each MC functions as a miniature individual assay of permeability (MAP). We demonstrate that false-positive results can be minimized, and that MAP sensitivity to …