Hematology Commons^™

The Mathematical Model Predicts Peripheral Blood Cd34+ Cell Yield And Blood Volume Processing For Peripheral Blood Stem Cell Apheresis., Rattaporn Vichitratchaneekorn, Kanokpol Siriphanthong, Kanokwan Chinbordee, Phandee Watanaboonyongcharoen, Ponlapat Ronjnuckarin

Chulalongkorn Medical Journal

Introduction: The accurate prediction of stem cell yields is important for planning peripheral blood stem cell (PBSC) collection. This study aimed to develop a formula forecasting required blood volume processing to ensure adequate CD34+ cell products.

Methods: Data from donors and patients who underwent PBSC apheresis conducted at a tertiary care hospital were reviewed. BD FACSCanto™ II and Navios EX flow cytometry machines were used to determine the pre-collection CD34+ cell counts (preCD34).

Results: Of 50 donors and 85 patients, 145 leukapheresis procedures were performed. Linear regression models accurately predicted absolute CD34+ cell yields from pre-apheresis values, supporting optimal procedural …

Machine Learning-Based Gene Signature Detection Highlights Cxcl12 As A Key Marker For Aml Prediction, Selahattin Alperen Uysal, Burçin Kaymaz

Chulalongkorn Medical Journal

Background: Acute myeloid leukemia (AML) is a severe hematologic malignancy marked by uncontrolled proliferation and impaired differentiation of myeloid cells, disrupting normal hematopoiesis and resulting in poor clinical outcomes. Conventional diagnostic approaches often lack the precision to accurately classify AML subtypes, necessitating the integration of advanced computational methods to improve diagnostic and therapeutic strategies.

Objectives: This study aimed to apply machine learning (ML) techniques to transcriptomic data in order to identify a concise and informative gene signature capable of distinguishing AML cases from normal samples. Additionally, the study sought to evaluate the performance of predictive models in supporting AML prediction …

Knowledge Of Parents About Thalassemia In Tabuk City: A Cross-Sectional Study, Sawsan Mohammed Alblewi, Amirah M. Alatawi, Ehab Mahmoud Hanafy, Faisal Mayudh Althobaiti, Abdulelah Hamad Al-Balawi, Faisal Mohammed Alamrani, Yazeed Mahmoud Ajwah, Omar Muslih Albalawi, Mohammed Majed Alquayr, Sultan Ibrahim Alhamdi

Makara Journal of Health Research

Background: Thalassemia is a common inherited blood disorder and remains a significant public health concern in Saudi Arabia. Parental knowledge is essential for effective prevention, screening, and early intervention. This study aimed to assess the knowledge of thalassemia among parents in Tabuk City, Saudi Arabia, and identify factors associated with knowledge levels.

Methods: A cross-sectional study was conducted among 392 parents residing in Tabuk City between March and May 2025. Data were collected using a validated Arabic questionnaire distributed online. Knowledge was assessed using 21 items covering general thalassemia knowledge, thalassemia major, carrier status, and prevention. Knowledge levels …

The Role Of Social Determinants Of Health In Hydroxyurea Adherence Among Persons With Sickle Cell Disease: A Systematic Review, Doreen O. Ugwu, Lori L. Vick, Terika Williams, Aurela Nikaj, Seyi Omeh, Benjamin Becerra Dr., Tilicia Mayo-Gamble

Journal of the Georgia Public Health Association

Objective: Georgia has one of the highest prevalences of sickle cell disease (SCD). For Georgians living with SCD, inadequate medication adherence is associated with important clinical outcomes. One important area that is understudied in SCD is the impact of social determinants of health (SDoH) on medication adherence. A foundational understanding of SDoH is needed to introduce, inform and carry out programs and interventions designed to facilitate hydroxyurea adherence through the state of Georgia.

Method: We conducted a systematic literature review to synthesize the literature on SDoH addressed in studies to improve hydroxyurea adherence in persons with SCD. SDoH were based …

Evaluating The Market Withdrawal Of Andexanet Alfa, Jordyn Linfield, Addisyn Cooper, Alexander Defranco, Emma Gerding, Jessica Kelley, Tyler Henney, Connor Dains, Brenna Hissong, Brittany Bates

Pharmacy and Wellness Review

The coagulation cascade comprises intrinsic, extrinsic, and common pathways that converge when thrombin converts fibrinogen (factor I) into fibrin, leading to fibrin mesh formation, stabilization of the platelet plug, and ultimately thrombus formation. Inhibition of the coagulation cascade can be achieved with a variety of anticoagulant medications, including direct oral anticoagulants (DOACs). The mechanism of action of DOACs is to inhibit either factor Xa or thrombin. Reversal of anticoagulation remains an important clinical consideration when managing patients on DOACs who experience serious bleeding events. Andexanet alfa is a recombinant, modified human factor Xa protein previously indicated for patients receiving rivaroxaban …

Understanding Monoclonal Gammopathy Of Undetermined Significance, Scott Winkel Msph, Mhs, Pa-C

Lynchburg Journal of Medical Science

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder characterized by serum monoclonal protein (M-protein) levels less than 3.0 g/dL, less than 10% plasma cells in the bone marrow, and absence of end-organ damage. It mainly affects older adults and is often an incidental finding. While most cases remain indolent, a subset progresses to malignancies such as multiple myeloma, smoldering myeloma, AL amyloidosis, lymphoproliferative disorders, macroglobulinemia, and monoclonal gammopathy of renal significance. This review summarizes current insights into MGUS pathophysiology, risk factors, molecular mechanisms, clinical features, diagnostic approaches, including laboratory assessments and imaging, and emphasizes early detection …

Accidental Daily Dosing: Severe Methotrexate Toxicity In A Patient With Rheumatoid Arthritis, Sidra Memon, Kavitha Vemuri, Syed Uzair Mahmood, Darshit Patel

Advances in Clinical Medical Research and Healthcare Delivery

This case highlights a crucial complication of oral methotrexate therapy: toxicity due to dosing errors. A patient’s daily dosing regimen, instead of the intended weekly schedule, led to a significantly excessive cumulative dose of methotrexate over a short period, resulting in severe hematologic and mucosal toxicity. This underscores the importance of clear patient education and vigilant prescription practices to prevent such errors.

Plasmacytoma As The Initial Presentation Of Multiple Myeloma: A Case Report, Chantelle Martin, Sidra Memon, Austin Kim, Saleha Asghar

Advances in Clinical Medical Research and Healthcare Delivery

We report an unusual case of a woman who presented with nonspecific symptoms of unilateral facial mass and bleeding from her lower lip over several weeks. The mass was found to be relatively fixed and irregular with destruction of facial bone as evidenced by imaging. Initial investigations indicated the possibility of multiple myeloma, which was later confirmed with serum protein electrophoresis and bone marrow biopsy. Cervical lymph node biopsy confirmed presence of plasmacytoid cells positive for CD 20.

Upper Respiratory Tract Infection Leading To A New Diagnosis Of Sweet Syndrome And Monoclonal Gammopathy Of Unknown Significance, Nidhi Rawat, Meron Gebrehiwot, Jason Raw, Jeyaprakash Ramachandran

HCA Healthcare Journal of Medicine

Background

We present a rare case of Sweet syndrome with underlying monoclonal gammopathy of unknown significance (MGUS) which initially presented as upper respiratory tract infection.

Case Presentation

A 52-year-old woman presented with a complaint of sore throat for 6 days, productive cough and fever for 5 days, and red, pruritic, circular, tender rashes on face, arms and trunk for 2 days. There was a past history of similar self-limiting rashes presenting intermittently for 1.5 years. She also reported to be taking tablet ibuprofen, as required for the past 1-2 years, for cervical spondylosis. On integumentary examination, widespread, red, tender, annular …

A Complex Case Of A Large Fibroid Uterus Compressing The Inferior Vena Cava Causing Recurrent Deep Vein Thrombosis And Pulmonary Embolisms, Jessica Gil, Jessica Klingensmith, Lauren Hendrix, Patrick J. Stocker, Olugbenga Oyesanmi

HCA Healthcare Journal of Medicine

Background

Uterine fibroids have been found to increase the risk for venous thromboembolism. There have been other case reports linking large uterine fibroids, pulmonary embolisms, and deep vein thrombosis (DVT) together due to compression of blood vessels and increased venous stasis. This case report will discuss a case of a large fibroid uterus compressing the inferior vena cava causing a patient with few risk factors to have recurrent DVTs and pulmonary embolisms.

Case Presentation

The patient was a 35-year-old woman who presented with repeated unprovoked thrombosis episodes. The patient had a full workup after the first episode of DVT and …

May Thurner Syndrome: Can We Stent It And Forget It ?, Sahej Arora, Asmaa Ahmed, Hafsa Jawaid, Aakriti Jain, Stephen Silver

Advances in Clinical Medical Research and Healthcare Delivery

Background: May-Thurner Syndrome (MTS) is a cause of venous obstruction and acute Deep Vein Thrombosis (DVT) in young females, due to extrinsic venous compression of left ilio-caval venous territory. It generally presents with unilateral lower limb swelling and DVT and long-term management requires endovascular stenting with anticoagulation. Little data is available on long term post-interventional outcomes. Case: A 73-year-old female with MTS, who underwent endovascular stenting of left external and common iliac vein 11 months ago, presented with recurrent symptoms. She had completed almost a year of oral anticoagulation with Eliquis approximately 45 days before presentation. She was found to …

Radiologic Findings Of A Mediastinal Mass With Pleural Fluid Cytologic Analysis: A Case Report Of Recurrent Mantle-Cell Lymphoma, Mark Cwajna, Zaain Ahmad, Evan Basha, Emily Maggioncalda, Shehbaz Ahmad, Joel Thompson

Advances in Clinical Medical Research and Healthcare Delivery

This case report details a 69-year-old male who presented with a right-sided pleural effusion and a mediastinal mass that was ultimately identified as recurrent mantle-cell lymphoma, occurring over 20 years after his initial diagnosis. Imaging findings discussed include chest radiograph and chest, abdomen and pelvis computed tomography depicting the mass compressing on various neighboring structures.

Successful Multimodal Interventional Management Of Extensive Portal Venous System Thrombosis In A Patient With A Hypercoagulable State, Dillon Woody, Jedediah Bondy, Donnette Dabydeen, Korinne Diss, Amanda Neider Neider

Advances in Clinical Medical Research and Healthcare Delivery

We present a case of extensive mesenteric and portal vein thrombosis in a 59-year-old male with a history of multiple thrombotic events and hypercoagulable conditions. The patient presented with abdominal pain, nausea, vomiting, and black stools, leading to the discovery of thrombosis in the portal vein, splenic vein, and superior mesenteric vein (SMV) with associated bowel ischemia. The goal of treatment was to prevent mesenteric ischemia, maintain portal vein patency, and preserve options for potential liver transplantation. The case was managed through a combination of ultrasound-guided paracentesis, portal and SMV venography, mechanical thrombectomy using the AngioJet device, and continuous thrombolytic …

Cns And Retinal Radiologic Findings Of A Young Patient With Heterozygous Prothrombin G20210a Gene Mutation, Justina Kasteri, Timothy Ehmann, Bryan Scott

Advances in Clinical Medical Research and Healthcare Delivery

Stroke is one of the leading causes of death and acquired long-term disability in the world.¹ In United States stroke is the 5^th leading cause of death with a mortality rate of 49.1 deaths per 100,000 people.² Strokes can be ischemic or hemorrhagic in origin, of which 85% are ischemic strokes. Approximately 10--15% of ischemic strokes occur in patients 18-50 years of age, and inherited thrombophilia may be a contributing factor through induction of a hypercoagulable state. Prothrombin G20210A mutation has an overall prevalence of approximately 2% of the general population, with an association between young patients …

Incidence Of Cytogenetic Abnormalities Detected By Fish Analysis In Multiple Myeloma Cases: A Seven-Year Study From A Cytogenetic Laboratory In King Chulalongkorn Memorial Hospital, Thailand (2018–2024), Montakarn Tansatit, Nutcharee Jongpornchai, Suwannee Songchart, Kittipornpan Krajokpap, Hudadini Da-Oh

Chulalongkorn Medical Journal

Background: Multiple myeloma (MM) is a genetically heterogeneous plasma cell malignancy with cytogenetic abnormalities influencing prognosis and treatment outcomes. Fluorescence in situ hybridization (FISH) is crucial for detecting clinically significant abnormalities, including IGH translocations and deletions (e.g., del(17p)), particularly in non-dividing plasma cells. However, cost and accessibility challenges limit comprehensive testing in resource-constrained settings like Thailand. Objectives: To investigate the incidence of cytogenetic abnormalities detected by FISH in MM cases over seven years in a Thai population, highlighting regional trends and barriers to comprehensive testing. Methods: A retrospective analysis was conducted on 360 bone marrow samples from MM patients between …

Complications And Management Of Idiopathic Multicentric Castleman Disease, Kavanya Feustel, Jacob W. Keeling, Olivia Makos, Dmitriy Scherbak

HCA Healthcare Journal of Medicine

Background

The pathophysiology of idiopathic multicentric Castleman disease (iMCD) is poorly understood compared to the other subtypes of MCD, which has contributed to limited treatment options and poor prognosis for iMCD patients. The pathogenesis of iMCD is thought to be mediated in part by dysregulation of interleukin (IL)-6.

Case Presentation

We present a case report of a 39-year-old Caucasian man with siltuximab-refractory iMCD. He presented with severe lower extremity lymphedema and wounds. His disease progressed through standard-of-care siltuximab. Due to his severe disease-related morbidity, he contracted recurrent infections, often complicated by sepsis. Ultimately, he required a left lower extremity amputation. …

Immune Thrombocytopenic Purpura Association With Epstein-Barr Virus, Amer Aldamouk, Bachr Masri, Ali Khan, Pulkita Uppal

Graduate Medical Education Research Journal

Immune thrombocytopenia (ITP), also referred to as idiopathic thrombocytopenic purpura, is an acquired form of thrombocytopenia caused by antibodies directed against platelet glycoproteins, particularly anti-GpIIb/IIIa antibodies. Epstein-Barr virus (EBV), a herpes virus infecting a large majority of the population before adulthood, has been implicated in various immune-mediated disorders, including ITP. In this report, we present a case of a young adult female with a history of thrombocytopenia who was found to have severe thrombocytopenia attributed to chronic EBV infection. Despite initial treatment with corticosteroids and intravenous immunoglobulin (IVIG), the patient's condition necessitated second-line therapies, including rituximab and thrombopoietin receptor agonists. …

Cars And Trucks: Driving A Paradigm Shift In Hematologic Malignancies, Christine Charek, Tia Solh

Lynchburg Journal of Medical Science

Hematologic malignancies account for a significant number of annual cancer diagnoses and deaths across the globe. Historically, the prognosis for relapsed and/or refractory disease after standard therapies, such as chemotherapy and/or radiation, was poor. Chimeric antigen receptor (CAR) T-cell therapy offers an additional treatment option. While promising, this type of immunotherapy also comes with potentially severe side effects, toxicities, and limitations. A better understanding of the development, administration, and management of patients undergoing treatment can provide the general clinician with the knowledge to assist within a multidisciplinary team to ultimately improve patient outcomes.

A Challenging Case Of Pyruvate Kinase Deficiency Complicated By Hemophagocytic Lymphohistiocytosis, Christopher Pope, Farah Ashraf, Jacqueline White, Akhilesh Sivakumar, Eric Behling, Tulin Budak-Alpdogan

Cooper Rowan Medical Journal

Pyruvate kinase deficiency (PKD) is an autosomal recessive disorder and the most common cause of chronic hemolytic anemia secondary to red blood cell (RBC) enzyme defects. Treatment is mainly supportive including splenectomy and transfusions. Mitapivat, an oral allosteric activator of defective pyruvate kinase, was approved by the FDA in February 2022 for treatment of adults with PKD. However, because Mitapivat undergoes liver metabolism, patients must have stable liver profiles prior to initiation of therapy. We present a case of PKD complicated by hemophagocytic lymphohistiocytosis (HLH). We initiated steroid therapy for his HLH with the intent to subsequently start Mitapivat. We …

Can Anemia Be A Prognostic Indicator To Scope For Gastroesophageal Junction Adenocarcinoma?, Ryan Tam, Neha Narayanan, Evan Basha, Joel Thompson

Advances in Clinical Medical Research and Healthcare Delivery

Gastroesophageal junction adenocarcinoma is a rapidly progressive disease that has a poor prognosis with a 5-year survival rate of 20%. It commonly presents with major symptoms of dysphagia and weight loss in addition to a long-standing history of reflux. As of now, screening for esophageal adenocarcinoma (EAC) is dependent on identifying risk factors which include a family history of Barrett’s esophagus and esophageal adenocarcinoma or patients with gastroesophageal reflux disease and at least one other risk factory for EAC such as age greater than 50 years, obesity or central adiposity, history of smoking, or male gender. Here, we present a …

Mystery Of Maha: Hypertension’S Twist Over Cancer’S Shadow, Andrew Takla, Gabriel Vachon, John Hix, Nagesh Jadhav

Advances in Clinical Medical Research and Healthcare Delivery

Microangiopathic hemolytic anemia (MAHA) refers to nonimmune hemolysis resulting from the intravascular fragmentation of red blood cells. The etiology of such disorders can range from primary thrombotic microangiopathic syndromes (TMA) to various systemic conditions, posing a diagnostic challenge. Prompt identification requires a sharp clinical assessment to improve outcomes.

Iron Deficiency—More Than Just Anemia: A Literature Review, Arianna S Moss, Zahra Pakbaz

Journal of Community Hospital Internal Medicine Perspectives

Iron deficiency (ID) is a global public health concern, as it can be a prodrome of gastrointestinal (GI) malignancies, exacerbate chronic conditions, and lead to an overall decreased quality of life. Despite being the most prevalent nutritional deficiency, it remains underdiagnosed by many healthcare professionals. Misconceptions regarding the clinical and laboratory manifestations of ID lead to delayed or missed diagnoses, contributing to poor patient outcomes. Though anemia is a commonly known consequence of ID, there are additional consequences that remain underrecognized by the medical community, including vague signs and symptoms, such as fatigue, depression, and abnormalities in white blood cell …

Tattoos As A Risk Factor For Malignant Lymphoma, Michael Escobar, Hajirah Farah, Anna Zhao, Hafsah Umerani, Rubab Imtiaz

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Nielsen C, Jerkeman M, Jöud AS. Tattoos as a risk factor for malignant lymphoma: a population-based case-control study. EClinicalMedicine. 2024;72:102649. Published 2024 May 21. https://doi.org/10.1016/j.eclinm.2024.102649

for a teenage patient contemplating getting a tattoo.

Evolution Of Btk Inhibitors, Dena Mathew

Lynchburg Journal of Medical Science

The purpose of this clinical review evaluates the evolution of bruton’s tyrosine kinase (BTK) inhibitors in becoming the standard of care in treating chronic lymphocytic leukemia (CLL). The first-generation BTK inhibitor ibrutinib has demonstrated superior efficacy over traditional chemotherapy in several randomized clinical trials in terms of progression free survival (PFS). However, due to cardiovascular toxicities of atrial fibrillation (afib), hypertension (HTN), and bleeding, have led to drug discontinuation. Second-generation BTK inhibitors, acalabrutinib and zanubrutinib have demonstrated reduced rates in cardiovascular toxicities due to improved BTK receptor selectivity, as seen in three head-to-head ibrutinib clinical trials. The emergence of BTK …

Hemophagocytic Lymphohistiocytosis In A Critically Ill Patient: A Case Report Of A Potentially Fatal Entity, Ali Khreisat, Inna Mikaella Sta Maria, Giovi Grasso-Knight, Meghan Mansour

HCA Healthcare Journal of Medicine

Background

Hemophagocytic lymphohistiocytosis (HLH) is a non-neoplastic proliferation and macrophage activation that induces cytokine-mediated bone marrow suppression and features of intense phagocytosis in the bone marrow and liver, leading to multi-organ dysfunction and ultimate failure. The diagnosis of HLH in an intensive care setting is challenging, and it is associated with high morbidity and mortality. HLH-94 is the standard protocol for treatment, consisting of dexamethasone and chemotherapy like etoposide.

Case Presentation

We present the case of a 73-year-old woman who had a prolonged hospitalization for vomiting, diarrhea, and dehydration. Her conditions were complicated by acute refractory pancytopenia on the 12th …

Hemophagocytic Lymphohistiocytosis Due To Ehrlichiosis: A Case Series, Ajay Iyer, Mattias D'Anna, Shruti Verma, Thomas Pritchard, Vladimir Begilman, Himal Bajracharya, Kaveh Naemi

HCA Healthcare Journal of Medicine

Background

Hemophagocytic lymphohistiocytosis (HLH) is an immunologic syndrome characterized by excessive inflammation and tissue injury due to uncontrolled activation of the phagocytic system. The underlying mechanism is a lack of downregulation of activated macrophages and lymphocytes by natural killer and T cells. Unfortunately, the diagnosis is often delayed or missed due to the rarity of the disease, decreased awareness, and clinical picture variability. Ehrlichiosis is becoming a more prevalent tick-borne illness in endemic regions and a relatively uncommon but increasingly considered cause of HLH.

Case Presentation

We describe the cases of 2 patients diagnosed with secondary HLH as per the …

Investigating The Effects Of Nosocomial Clostridioides Difficile Infection Among Acute Leukemia Patients: Insights From The 2020 National Inpatient Sample, Zubair Hassan Bodla, Mariam Hashmi, Fatima Niaz, Umer Farooq, Muhammad Jahanzeb Khalil, Farhan Khalid, Kipson Charles, Christopher L. Bray

HCA Healthcare Journal of Medicine

Background

Rising nosocomial Clostridioides difficile infections pose high risks, especially for immunocompromised leukemia patients, necessitating targeted research to enhance patient care and outcomes.

The objective of this study was to investigate the impact of nosocomial Clostridioides difficile infections (CDI) on patients hospitalized with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Methods

Our study was a retrospective analysis of adult patients hospitalized with a primary diagnosis of ALL or AML, using the Nationwide Inpatient Sample (NIS) database for 2020. Primary outcomes included the incidence of nosocomial CDI and all-cause inpatient mortality. Secondary outcomes included hospital length of stay, resource …

Navigating Rarity: A Case Report On Primary Splenic Lymphoma, Santosh Pv Rai, Skand Rastogi, Anshuman Senapati, Jyoti Kini, Salama Yasmeen

Manipal Journal of Medical Sciences

Primary Splenic Lymphoma (PSL) is a rare condition, which complicates its understanding and definition. The rarity of PSL has led to varied definitions: some consider it primary only if splenomegaly is predominant, while others include spleen involvement with hilar lymph nodes. Documentation on PSL is sparse in Indian literature. This case report of a 48-year-old woman, presenting with fever, weight loss, and left hypochondrium pain, and diagnosed with PSL through CECT abdomen and USG-guided biopsy, contributes to better understanding of the condition.

The Revised Cdc Chronic Pain Guidelines And Payer Opioid Analgesic Policies In Michigan, Victoria Tutag Lehr, Cynthia L. Arfken

Michigan Journal of Public Health

Abstract

The 2016 publication of A Guideline for Prescribing Opioids for Chronic Pain by the Centers for Disease Control and Prevention motivated commercial and Medicaid payers to restrict their opioid prescribing policies including the imposition of hard limits on opioid daily dosages and duration. One result of these policies was an increase in abrupt opioid discontinuation and rapid tapering events for patients receiving long-term opioid therapy. Responding to this misapplication of the 2016 guideline, the 2022 revised guidelines emphasized individualized opioid therapy and exclusion of certain chronic diseases. However, it is not known if the payers changed their policies to …

How Did Dat Happen? A Coombs Negative Delayed Hemolytic Transfusion Reaction In A Patient With Myelodysplastic Syndrome: A Case Report, Aniket Vijay Rao Dr, Aditya Sanjeevi, Daniel Jose Idoate, Nagesh Jadhav, Basil Verghese, Himal Kharel

Advances in Clinical Medical Research and Healthcare Delivery

Delayed hemolytic transfusion reactions (DHTRs) present significant challenges in diagnosis and management despite advancements in pre-transfusion testing. We report a case of a 76-year-old female with myelodysplastic syndrome (MDS) who developed severe hemolytic anemia following a seemingly compatible blood transfusion and appropriate pretransfusion testing. Evaluation revealed characteristics consistent with DHTR. Diagnostic uncertainty arose due to a negative Direct Antiglobulin Test (DAT) in the setting of a concomitant Vitamin B-12 deficiency. She was supported with prednisone and B12 supplementation. We discuss challenges in diagnosis, including the limitation of DAT, and propose strategies for comprehensive antibody identification. The case underscores the importance …