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Front Immunol 2020 4;11:1006. Epub 2020 Jun 4.

UO Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Autoimmune hemolytic anemia (AIHA) is characterized by immune mediated erythrocytes destruction by autoantibodies with or without complement activation. Additional pathologic mechanisms include cellular cytotoxicity, cytokline dysregulation, and inadequate bone marrow compensation with fibrosis/dyserythropoiesis. The latter resembles that of bone marrow failures, namely aplastic anemia and myelodysplastic syndromes. Read More

Clin Epidemiol 2020 22;12:497-508. Epub 2020 May 22.

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Background: Acquired hemolytic disorders-autoimmune hemolytic anemia (AIHA), cold agglutinin disease (CAD), paroxysmal nocturnal hemoglobinuria (PNH), drug-induced hemolysis (DIHA), and acquired hemolysis not otherwise specified (AHNOS)-are considered rare. Despite their potentially major health implications, data regarding their incidence and prevalence are scarce.

Methods: To fill this gap we collected data regarding all patients with acquired hemolytic disorder diagnoses in 1977-2016 from the Danish National Patient Register. Read More

J Clin Invest 2020 May;130(5):2152-2163

Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Read More

Transfus Clin Biol 2020 Apr 18;27(2):83-86. Epub 2020 Mar 18.

Department of pretransfusion testing and hemovigilance, Institute for Blood Transfusion of Serbia, Svetog Save 39, 11000 Belgrade, Serbia. Electronic address:

Paroxysmal cold hemoglobinuria is a rare form of autoimmune hemolytic anemia caused by the Donath-Landsteiner autoantibody. The condition is characterized by the presence of an IgG biphasic hemolysin with specificity to the P blood group antigen. The antibody biphasic action may be demonstrated in the Donath-Landsteiner test. Read More

Blood 2020 01;135(5):393

Johns Hopkins University.

Blood Adv 2019 11;3(22):3575-3578

Department of Pediatrics, University of California, San Francisco, San Francisco, CA; and.

Indian Pediatr 2019 10;56(10):879-880

Department of Transfusion Medicine, Max Superspeciality Hospital, Saket, New Delhi, India.

Paroxysmal Cold Hemoglobinuria is a rare cause of intravascular hemolysis presenting in children following an acute viral illness. It is usually self-limiting in nature. We present the details of a 4-year-old boy who presented with rapid onset intravascular hemolysis. Read More

Ther Adv Hematol 2019 9;10:2040620719873321. Epub 2019 Sep 9.

Department of Medicine, Henri Mondor Hospital, Université Paris-Est, Assistance Publique Hôpitaux de Paris Creteil, Creteil, France.

Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. Read More

Blood Adv 2019 06;3(12):1897-1906

Department of Research and Innovation, Haugesund Hospital, Haugesund, Norway.

The terminology applied to autoimmune hemolytic anemia (AIHA) seems inconsistent. We aimed to evaluate the consistency of definitions used for diagnosis and treatment. In this systematic review of literature from January 2006 to December 2015, we assessed heterogeneity in the definition of AIHA and its subtypes, refractory disease, disease phase, severity, criteria for treatment response, and response durability. Read More

Tidsskr Nor Laegeforen 2019 Mar 18;139(6). Epub 2019 Mar 18.

Immunohematology 2019 Jan;35(1):3-6

Medical Director of Donor Services, Associate Medical Director of Transfusion Medicine, Houston Methodist Hospital, Department of Pathology and Genomic Medicine, 6565 Fannin Street, MS 205, Houston, TX.

Conclusions: The Donath-Landsteiner (DL) test is a serologic test used to detect the presence of a biphasic hemolysin. This autoantibody is seen in patients with paroxysmal cold hemoglobinuria. The test relies on the characteristic cold binding of an IgG autoantibody with specificity to the P blood group antigen. Read More

Case Rep Hematol 2018 13;2018:7586719. Epub 2018 Nov 13.

Division of Hematology and Medical Oncology, Department of Medicine, Mount Sinai Beth Israel, Mount Sinai Hospital, New York, NY, USA.

Paroxysmal cold hemoglobinuria (PCH) is a rare form of cold autoimmune hemolytic anemia first discovered in the early 20th century in adults with tertiary syphilis. Today, it is more commonly seen in children as a life-threatening anemia during a viral upper respiratory tract infection (URI). Although respiratory syncytial virus (RSV) has previously been reported to cause PCH in a child, herein we present the first documented case in an adult. Read More

BMJ Case Rep 2018 Nov 8;2018. Epub 2018 Nov 8.

Medicine, Nassau University Medical Center, East Meadow, New York, USA.

Donath-Landsteiner haemolytic anaemia (DLHA), also known as paroxysmal cold haemoglobinuria, is a very rare and difficult condition to diagnose as well as treat. Here, we present a case of a 55-year-old Hispanic woman who presented with severe intravascular haemolytic anaemia in the setting of a viral illness 2 weeks prior to presentation. Direct antiglobulin testing revealed mixed results: positive for either complement, IgG or both on various occasions which led to a battery of tests including the Donath-Landsteiner antibody testing which turned out positive establishing the diagnosis of DLHA. Read More

Vnitr Lek Summer 2018;64(5):514-519

Autoimmune hemolytic anemia (AIHA) is caused by auto-antibodies directed against self red blood cell (RBC) surface antigens. A consequence may be an intravascular hemolysis mediated by activated complement or extravascular hemolysis caused by destruction of complex of RBC with autoantibody in spleen and liver. The basic classification subdivides AIHA in primary/idiopathic and secondary with known underlying disease. Read More

Semin Hematol 2018 07 10;55(3):141-149. Epub 2018 Apr 10.

Department of Research and Innovation, Haugesund Hospital, Helse Fonna HF, Haugesund, Norway. Electronic address:

The classical complement pathway and, to some extent, the terminal pathway, are involved in the immune pathogenesis of autoimmune hemolytic anemia (AIHA). In primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, the hemolytic process is entirely complement dependent. Complement activation also plays an important pathogenetic role in some warm-antibody AIHAs, especially when immunoglobulin M is involved. Read More

Blood 2018 05;131(22):2506

Pathology Queensland.

Ugeskr Laeger 2018 Mar;180(10)

Epstein-Barr virus (EBV) is globally prevalent and in adolescents mostly observed as infectious mononucleosis. Abnormal liver blood tests are common, whereas more serious hepatitis is less prevalent. Autoimmune haemolytic anaemia may also occur in the course of this infection. Read More

Cent Eur J Immunol 2017 30;42(4):404-406. Epub 2017 Dec 30.

Department of Paediatrics and Nephrology, Medical University of Warsaw, Poland.

Paroxysmal cold haemoglobinuria (PCH) is a form of autoimmune haemolytic anaemia (AIHA) characterised by a sudden onset of haemoglobinuria, either spontaneously or following exposure to cold. In children, it is commonly seen following a viral illness or after immunisation. Diagnosis of PCH is confirmed by a positive Donath Landsteiner (DL) test in which biphasic haemolysins are detected. Read More

Am J Hematol 2018 05 30;93(5):718-721. Epub 2018 Jan 30.

Department of Haematology, Royal Infirmary of Edinburgh, United Kingdom.

J Investig Med High Impact Case Rep 2017 Oct-Dec;5(4):2324709617740905. Epub 2017 Nov 13.

East Tennessee State University, Johnson City, TN, USA.

Autoimmune hemolytic anemia (AIHA) is a disease process that involves the destruction of red blood cells mediated by the humoral immune system. It can be characterized as a cold agglutinin syndrome, paroxysmal cold hemoglobinuria, and warm, mixed type, and drug-induced AIHA. Although a well-established relationship exists between the presence of AIHA and lymphoproliferative malignancy, AIHA rarely presents in association with solid malignancies. Read More

Transfusion 2017 06;57(6):1332-1335

Department of Pathology, University of Michigan, Ann Arbor, MI.

Transfusion 2017 06 31;57(6):1401-1406. Epub 2017 Mar 31.

Division of Pediatric Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Paroxysmal cold hemoglobinuria (PCH) is a form of autoimmune hemolytic anemia caused by the Donath-Landsteiner antibody (D-L antibody). In children, this is typically a transient immune-mediated hemolysis that follows a viral illness and does not recur. Recurrent acute or chronic PCH due to D-L antibody is very rare. Read More

J Pediatr Hematol Oncol 2017 05;39(4):320-321

Department of Pediatrics, Musashino Red Cross Hospital, Musashino City, Tokyo, Japan.

Blood Rev 2017 07 6;31(4):213-223. Epub 2017 Feb 6.

Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address:

The complement system is an essential part of the innate immune system that requires careful regulation to ensure responses are appropriately directed against harmful pathogens, while preventing collateral damage to normal host cells and tissues. While deficiency in some components of the complement pathway is associated with increased susceptibility to certain infections, it has also become clear that inappropriate activation of complement is an important contributor to human disease. A number of hematologic disorders are driven by complement, and these disorders may be termed "complementopathies". Read More

Br J Haematol 2017 02 22;176(3):395-411. Epub 2016 Dec 22.

Department of Haematology, Leeds Teaching Hospitals, Leeds, UK.

J Pediatr Hematol Oncol 2017 01;39(1):e25-e26

Department of Pediatrics, Beaumont Children's Hospital, Oakland University William Beaumont School of Medicine, Royal Oak, MI.

Autoimmune hemolytic anemia (AIHA) in childhood, including paroxysmal cold hemoglobinuria, is an uncommon, potentially life-threatening disorder. AIHA is a recognized complication of several varieties of lymphoproliferative disorders, including high-grade B-cell lymphoma, but it has not been associated with Burkitt lymphoma in people without an underlying immunodeficiency. When AIHA occurs in association with lymphoproliferative disorders, it may precede or accompany the diagnosis of malignant disease or herald relapse. Read More

Transfusion 2017 01 2;57(1):137-143. Epub 2016 Nov 2.

Department of Medicine, McMaster University.

Background: Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia caused by a biphasic (Donath-Landsteiner [DL]) immunoglobulin G autoantibody. Estimates of disease frequency after syphilis are lacking and the diagnostic yield of testing for PCH is uncertain. The objectives of this study were: 1) to describe DL testing practices in Canada, 2) to determine how often a biphasic RBC antibody is detected in adults and children, and 3) to evaluate inter-rater reliability of interpretations of positive DL test results in adults. Read More

Am J Dermatopathol 2017 Sep;39(9):637-662

*Associate Staff of the Department of Dermatology, Department of Dermatology, Hospital Universitario de la Princesa, Universidad Autónoma, Madrid, Spain; †Associate Staff of the Department of Dermatology, Department of Dermatology, Fundación Jiménez Diaz, Universidad Autónoma, Madrid, Spain; ‡Director of Dermatopathology, Department of Dermatology, Hospital Clínico Universitario, Salamanca, Spain; §Director of Dermatopathology, Dermatopathology Research Unit, Medical University of Graz, Graz, Austria; ¶Director of Dermatopathology, Dermatopathologie Laboratory, Friedrichschafen, Germany; and ‖Chairman of the Department of Dermatology, Department of Dermatology, Hospital Clínico Universitario, Salamanca, Spain.

We review the most characteristic clinical and histopathologic findings of the cutaneous manifestations of the occlusive nonvasculitic vasculopathic disorders. Clinically, most of these conditions are characterized by retiform purpura. Histopathologic findings consist of occlusion of the vessel lumina with no vasculitis. Read More

Ann Hematol 2016 Sep 4;95(9):1547-9. Epub 2016 Jun 4.

Department of Hematology, Rinku General Medical Center, Izumisano, Osaka, Japan.

Am J Emerg Med 2016 Nov 23;34(11):2252.e5-2252.e6. Epub 2016 Apr 23.

Pediatrics, Texas Children's Hospital, 6621 Fannin St, Houston, TX, USA, 77030; Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA 77030. Electronic address:

Transfus Apher Sci 2016 Apr 25;54(2):191-8. Epub 2016 Apr 25.

Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine-New York Presbyterian, New York, NY, USA.

Objective: The objective of this study was to describe complement activation in hemostatic and pathologic states of coagulation and in the acquired and congenital hemolytic anemias.

Methods And Results: We review published and emerging data on the involvement of the classic, alternative and lectin-based complement pathways in coagulation and the hemolytic anemias. The alternative pathway in particular is always "on," at low levels, and is particularly sensitive to hyper-activation in a variety of physiologic and pathologic states including infection, autoimmune disorders, thrombosis and pregnancy, requiring tight control predicated on a variety of soluble and membrane bound regulatory proteins. Read More

Transfus Med Hemother 2015 Sep 7;42(5):303-10. Epub 2015 Sep 7.

Department of Research and Development, Haugesund Hospital, Helse Fonna HF, Haugesund, Norway.

The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. Read More

Hematology Am Soc Hematol Educ Program 2015 ;2015:385-91

Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. Read More

Blood 2015 Nov 18;126(22):2459-65. Epub 2015 Nov 18.

Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. Read More

Transfus Clin Biol 2015 Oct-Dec;22(5-6):291-8. Epub 2015 Nov 10.

Laboratoire d'hématologie, hôpital d'Enfants Béchir Hamza de Tunis, Bab Saadoun, 1004 Jabbary, Tunis, Tunisie.

Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Read More

Dtsch Med Wochenschr 2015 Aug 25;140(17):1302-10; quiz 1311-2. Epub 2015 Aug 25.

Hämato-onkologische Schwerpunktpraxis, Herrsching.

Hemolytic anemias consist of corpuscular, immun-hemolytic and toxic hemolytic anemias. Within the group of corpuscular hemolytic anemias, except for the paroxysmal nocturnal hemoglobinuria (PNH), all symptoms are caused by underlying heredetiary disorders within the red blood cell membran (hereditary spherocytosis), deficiencies of red cell enzymes (G6PDH- and pyrovatkinase deficiency) or disorders in the hemoglobin molecule (thalassaemia and sickle cell disease). Immune-hemolytic anemias are acquired hemolytic anemias and hemolysis is caused by auto- or allo-antibodies which are directed against red blood cell antigens. Read More

Pediatr Blood Cancer 2015 Nov 5;62(11):2044-6. Epub 2015 Jun 5.

Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA) characterized by the presence of a Donath-Landsteiner (D-L) antibody. PCH occurs most commonly in young children and is associated with acute, often self-limited hemolytic anemia. The D-L antibody is classically a biphasic IgG anti-P autoantibody identified by the D-L test. Read More

Hematol Oncol Clin North Am 2015 Jun 7;29(3):473-8. Epub 2015 Mar 7.

Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Suite 4500, 301 building 4940 Eastern Ave, Baltimore, MD 21224, USA.

Paroxysmal cold hemoglobinuria is a rare cause of autoimmune hemolytic anemia predominantly seen as an acute form in young children after viral illnesses and in a chronic form in some hematological malignancies and tertiary syphilis. It is a complement mediated intravascular hemolytic anemia associated with a biphasic antibody against the P antigen on red cells. The antibody attaches to red cells at colder temperatures and causes red cell lysis when blood recirculates to warmer parts of the body. Read More

Biomed Res Int 2015 29;2015:363278. Epub 2015 Jan 29.

Department of Immunology and Transfusion Medicine, Haugesund Hospital, Helse Fonna, P.O. Box 2170, 5504 Haugesund, Norway.

Autoimmune hemolytic anemia (AIHA) is a collective term for several diseases characterized by autoantibody-initiated destruction of red blood cells (RBCs). Exact subclassification is essential. We provide a review of the respective types of AIHA with emphasis on mechanisms of RBC destruction, focusing in particular on complement involvement. Read More

BMC Hematol 2015 13;15. Epub 2015 Feb 13.

Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA USA.

Background: Paroxysmal cold hemoglobinuria is caused by a biphasic IgG autoantibody that triggers complement-mediated intravascular hemolysis. Paroxysmal cold hemoglobinuria has not previously been reported to occur in association with pregnancy.

Case Presentation: We report a case of an 18 year old female who presented in early pregnancy with acute hemolytic anemia and a positive Donath-Landsteiner antibody test. Read More

Case Rep Med 2014 9;2014:316010. Epub 2014 Oct 9.

Hematology Department, Hematopoietic Transplant and Cellular Therapy Unit, Virgen de la Arrixaca Clinical University Hospital, IMIB-Arrixaca, University of Murcia, Carretera Madrid-Cartagena, s/n, El Palmar, 30120 Murcia, Spain.

PCH is a rare autoimmune hemolytic anemia (AIHA) but is one of the most common causes of AIAH in children. For the diagnosis, it is important to perform the appropriate methods of serological investigation and show the typical biphasic reaction. This is a case report of a child who presented with features of haemolysis and was diagnosed with PCH of this way. Read More

Haematologica 2014 Oct;99(10):1547-54

U.O. Ematologia, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. Read More

Lab Med 2014 ;45(3):253-8; quiz e92

Indiana Blood Center, Indianapolis, Indiana;

Paroxysmal cold hemoglobinuria (PCH) is an acquired hemolytic anemia caused by immunoglobulin G (IgG) antibodies that sensitize red blood cells (RBCs) at cold temperatures by fixing complement to the RBCs causing intravascular hemolysis on rewarming. PCH usually appears in young children as recurrent high fevers, chills, and passage of red-brown urine. The diagnostic test for PCH is the Donath-Landsteiner test, an in vitro assay for biphasic hemolysis. Read More

BMJ Case Rep 2014 Jun 4;2014. Epub 2014 Jun 4.

Department of Cardiology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.

A 28-year-old man presented with a history of intermittent haematuria over the past 10 years usually following fever episodes and requiring blood transfusions during the episodes. History of any thrombotic complications, chest pain or erectile dysfunction was not forthcoming. Examination revealed severe pallor with mild icterus and mild splenomegaly. Read More

Arch Dis Child 2014 Jul 5;99(7):668-73. Epub 2014 Mar 5.

Autoimmune haemolytic anaemias (AIHAs) are extracorpuscular haemolytic anaemias produced by antierythrocyte autoantibodies which cause a shortened red blood cell life span. There are several reasons why the diagnosis and treatment of AIHAs in children represent a bigger challenge than in adult patients, including the presence of particular AIHA types, the uncertainty of serological tests and the limited clinical experience. All these facts have added up to a poor understanding and management of some topics in childhood AIHA. Read More

Pediatr Int 2013 Oct;55(5):664-6

Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Yoshida, Japan.

We report on a 4-year-old boy who developed paroxysmal cold hemoglobinuria (PCH) following the first dose of a seven-valent pneumococcal conjugate vaccine. He was admitted because of dark urine after exposure to cold air. Laboratory tests indicated anemia, increased serum indirect bilirubin and lactate dehydrogenase, and decreased serum haptoglobin. Read More

Vnitr Lek 2013 Sep;59(9):828-40

Acquired autoimmune haemolytic anaemia is divided according to the characteristics of immunoglobulin causing haemolysis. The most frequent are haemolytic anaemia with thermal antibodies. They bind to erythrocytes and initiate their destruction in the reticuloendothelial system cells, leading to extravascular haemolysis. Read More

Blood Transfus 2014 Jan 3;12 Suppl 1:s141-3. Epub 2013 Jul 3.

Department of Cellular Biotechnologies and Haematology, Division of Haematology, "Sapienza" University, Rome, Italy.

Indian J Hematol Blood Transfus 2012 Jun 31;28(2):112-3. Epub 2011 Jul 31.

Faculty of Medicine, University of Sri Jayawardenapura, Gangodawila, Nugegoda, Sri Lanka.

PCH is one of the most common causes of acute AIHA in young children, although it affects patients of all ages. In children it is commonly seen following a viral illness or after immunization. Donath Landsteiner test is the diagnostic test. Read More

Immunohematology 2012 ;28(4):118-23

Department of Medical Laboratory, Imaging and Radiologic Sciences, Georgia Health Sciences University, Augusta, GA 30909, USA.

A 15-month-old white male child was admitted to the pediatric intensive care unit with symptoms of upper respiratory tract infection, increased somnolence, pallor, jaundice, fever, and decreased activity level. The purpose of this case study is to report the clinical findings associated with the patient's clinical symptoms and differential laboratory diagnosis. Read More