Presence Of Immature Cells Research Articles

Morphological abnormalities of peripheral blood cells among patients with COVID-19 disease

PurposeThe hematological changes in COVID-19 patients continue to receive great attention, especially in the field of public health. To our knowledge, coronavirus disease may be identified based on the severity of illness, and the study of peripheral blood smears may offer important information to facilitate the identification. Thus, we evaluated the morphological abnormalities (atypical and immature lymphocytes, lymphocytes with micronuclei, various nuclear abnormalities among erythrocytes) and quantitative changes in peripheral blood cells among 48 individuals with COVID-19 disease. MethodsThe present study is a retrospective analysis of 48 individuals, including 24 hospitalized patients diagnosed with COVID-19 disease. The blood smears of all patients were subjected to a hematological examination to identify various morphological abnormalities in white and red blood cells. In addition, a micronucleus test was conducted to assess the incidence of chromosomal damage in lymphocytes. Furthermore, the complete blood count (CBC) was performed to evaluate changes in peripheral blood cells, particularly the differential total leukocyte count, which could indicate the immune response against viral infection in COVID-19 patients. ResultsThe findings of the hematological study conducted on patients diagnosed with COVID-19 disease revealed neutrophilia, eosinophilia, mild monocytosis, decreased hematocrit level, elevated erythrocyte sedimentation rate (ESR), and immature leukocytes. It was observed that patients who were infected with coronavirus demonstrated mild thrombocytopenia. Furthermore, the micronucleus test indicated the presence of immature cells with micronuclei among lymphocytes and numerous nuclear abnormalities in red blood cells. These results help to shed light on the hematological changes that occur in COVID-19 patients, and could potentially contribute to the development of more effective treatments for the disease. ConclusionsThe examination of complete blood counts (CBCs) in conjunction with peripheral blood smears offers a potential means of identifying the impact of SARS-CoV-2 infection on the hematopoietic and immune systems, thereby providing early indications of inflammation. Based on a study, it has been suggested that SARS-CoV-2 may affect red and white blood cells causing morphological alterations thereby establishing a corresponding relationship with disease severity.

Imaging Techniques and Clinical Application of the Marrow-Blood Barrier in Hematological Malignancies.

The pathways through which mature blood cells in the bone marrow (BM) enter the blood stream and exit the BM, hematopoietic stem cells in the peripheral blood return to the BM, and other substances exit the BM are referred to as the marrow-blood barrier (MBB). This barrier plays an important role in the restrictive sequestration of blood cells, the release of mature blood cells, and the entry and exit of particulate matter. In some blood diseases and tumors, the presence of immature cells in the blood suggests that the MBB is damaged, mainly manifesting as increased permeability, especially in angiogenesis. Some imaging methods have been used to monitor the integrity and permeability of the MBB, such as DCE-MRI, IVIM, ASL, BOLD-MRI, and microfluidic devices, which contribute to understanding the process of related diseases and developing appropriate treatment options. In this review, we briefly introduce the theory of MBB imaging modalities along with their clinical applications.

Applying different morphometric intestinal mucosa methods and the correlation with broilers performance under Eimeria challenge

The intestinal wall has on its surface, protrusions called villi that are responsible for the absorption of nutrients. Commonly, these structures have their dimensions measured to related more area surface with better absorption. However, the measurement of these villi neglects the inflammation and the presence of immature cells that increase the surface area but affect negatively the absorption and compromise the animal performance. The measurements of villi/crypt are traditional tools in animal research; however, they may overlook alterations that impact the mucosal functionality. This study aimed to compare the morphometry of the intestinal villi/crypt with the I See Inside (ISI) scoring methodology, exploring their correlation with zootechnical performance. Therefore, broilers were grouped as nonchallenged (NC) and challenged with Eimeria (CH) and jejunum samples were collected at 22 d for histological analysis. The same villi were submitted to the ISI methodology, which is based on the scoring of 8 parameters related to the inflammatory process, and the measurements of villus height (VH), villus width (VW), crypt depth (CD), crypt width (CW), VH:CD ratio and villi absorptive surface (VAS). The CH group presented higher ISI total score, VW, CD, CW and lower VH, VH:CD, and VAS in comparison to the NC group. While the villi/crypt morphometry did not exhibit correlations with performance, the presence of Eimeria oocysts and the ISI total score was positively correlated (P < 0.05) with the feed conversion ratio (FCR), demonstrating a statistical interaction between high ISI scores and worse performance. In conclusion, a larger villus is not related to better intestinal functionality when this enlargement is unleashed by the immune processes occurring inside. The scoring system that evaluates the type of alteration observed has a direct impact on the animal's zootechnical performance which is not observed with the single metric surface evaluation.

Transient Myeloproliferative Syndrome associated with Down syndrome and Fetal Hydrops: Case Report

BACKGROUND: Transient myeloproliferative Syndrome can be defined as an abnormal proliferation of immature leukemic cells. It presents in newborns with Down syndrome or trisomy 21 mosaicism, as an uncontrolled proliferation of blasts in the megakaryocytic lineage; it resolves spontaneously during the first three months of life. One of the characteristic manifestations is Non-Immune Fetal Hydrops. CASE REPORT: Premature newborn patient adequate for gestational age, born by C-Section due to ultrasound diagnosis of NIHF. At birth, we evidenced phenotypic characteristics of Down syndrome; in addition, the clinical picture and physical examination (respiratory distress, bradycardia, hypotension, prolonged capillary refill, hypotonia, and thrombocytopenia) supported the diagnostic suspicion of neonatal sepsis. The initial management of the patient in the intensive care unit included: mechanical ventilation, vasopressor support, surfactant administration, intravenous antibiotic therapy, furosemide, fentanyl and midazolam, albumin, and vitamin k. EVOLUTION: During his hospital stay, the patient developed acute kidney injury. In addition, we detected leukocytosis and presence of immature cells, anemia and thrombocytopenia, with diagnostic suspicion of congenital leukemia versus MTS, confirmed by flow cytometry. Subsequently, the patient presented elevated bilirubin, with jaundice and subsequent multifactorial cholestasis. The patient was hospitalized for 48 days and after the resolution of the mentioned pathologies, he was discharged. At the follow up, 15 days after discharge, normalization of leucocyte, red blood cell and platelet values confirmed the TMS diagnosis. CONCLUSION: In this case report, the patient developed MTS in relation to Down syndrome and had a complicated clinical course due to all the complications derived from his prematurity, his congenital disease, and the presence of hydrops fetalis and other manifestations of MTS. In the present case, there were criteria of severity, poor prognosis and high risk of mortality, which advantageously do not affect his current clinical condition, but require continuous and strict clinical surveillance. Multidisciplinary management, a high index of suspicion, timely attention to the multiple manifestations and complications, and proper follow-up allowed for a favorable evolution and greater survival in this patient.

Prognostic Significance of Plasmablastic Plasma Cells in the Era of Novel Agents in Multiple Myeloma

Background:Plasmablastic (PB) feature has long been identified as poor prognosis in multiple myeloma (MM), although most data was reported in the era of conventional therapy. Furthermore, PB feature does not belong to the R-ISS scoring system in part due to lack of data since the emergence of novel therapy based regimens.Methods: We have performeda retrospective multicenter analysisof all MMdiagnosed in the network area of the Poitiers academic hospital since 2005 to identify MM with PB features. PB was defined as presence of immature cells, any percentage, characterized with high proliferative index rate, centrally reviewed in Poitiers hematology laboratory by 3 hematologists.Results: 65 MM with PB were identified, of which 53,8% were in first-line therapy. Adverse cytogenetic (IMWG) was reported in 6 patients, del17p x3, t(4;14) x2, and one with both. However, 33,8% were ISS 3, and 23,1% R-ISS 3. Presence of extramedullary disease (EMD) was reported in 40%. As a whole, ORR with any triplet-based treatment containing always a proteasome inhibitor and IMiDs or alkylator was 49,2%, with 29,2% VGPR and 4,6% CR. The median PFS and OS were 6,9 and 14,9 months as a whole, respectively, and independently of diagnosis or relapse settings. We noticed that one regimen appeared to fare much better than the other, namely VRd (bortezomib, lenalidomide and dexamethasone), with a median PFS at 36,1 months [CI95%: 0-99] vs 5,5 [0,59-10,4] otherwise; p=0,014. Similarly, ASCT was associated with longer PFS and OS, 21,4 months [12,8-30,1] vs 2,83 [0-5,7], p=0,003; and 50,4 months ([29,9-70,7] vs 6,27 [1,1-11,4] p=0,001 respectively. We were not able to demonstrate that use of anthracyclines was able to control the PB clone, although it was one of our initial hypothesis. Univariate and multivariate analysis for poor OS identified acute renal failure at disease entry, presence of EMD, of del(17p), and high LDH, markers strongly associated to PB presence. We found that the % of PB correlated to poor prognosis on a linear fashion.Conclusion: This study confirms the poor prognosis of PB feature in MM even in the era of novel agents. A triplet-based association PI + IMId + dex is warranted possibly consolidated by ASCT when possible. The role of the new anti CD38 monoclonal antibody has yet to be confirmed in this population. DisclosuresSonneveld:Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding. Leleu:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Automatic Segmentation of Leukocytes for the Detection of Leukemia Using a New Computing Algorithm

Hematological disorders refer to the diseases caused with the changes in blood cells or blood system such as Leukemia, Anemia, Malaria and Azotemia. Leukocytes are the cells of immune system derived in the bone marrow as hematopoietic stem cell. The presence of immature cells changes the granularity and geometry of leukocytes. Detection of white blood cells plays an important role in the diagnosis of diseases like leukemia. Features such as nucleus and cytoplasm area, average color co-ordinates and number of pixels in the nuclear perimeter are used. Accurate classification of human blood cells plays a decisive role in the diagnosis and treatment of diseases. Hematological disorders refer to the diseases caused with the changes in blood cells or blood system such as Leukemia, Anemia, Malaria and Azotemia. This paper explores the techniques used in the automatic segmentation of leukocytes using a new computing technique.

Protocolo diagnóstico de la leucocitosis con formas celulares anómalas

IntroductionIt is important to evaluate the leukocytosis in relation to the absolute range of different types of white blood cells, also assessing the presence of abnormal cellular forms. Therefore, detection of leukocytosis requires a quick scrutiny of automated differential formula and other parameters of blood count, and the study of smear conducting a manual recount of blood leukocyte formula. NeutrophiliaIn neutrofilias with anomalous forms we can find myelemia or left shift (infections or chronic myeloid leukemia) or a leukoerythroblastic syndrome (myelofibrosis or solid tumor infiltration). LymphocytosisIf what prevails is a lymphocytosis with atypical forms, the most important diagnostic groups are mononucleósicos syndromes and lymphoid neoplasms (B or T), both precursor cells and mature lymphocytes. MonocytosisOn the contrary, we must rule out the presence of immature cells in peripheral blood before monocitosis and leukocytosis associated with cytopenias (acute myeloid leukemia or chronic myelomonocytic leukemia).

Anemia in Kassala Area Eastern Sudan

ObjectiveThe objective of this study was to determine the types and the ways of diagnosis of anemia at Kassala region, Sudan.MethodsIn this study we examined and investigate 210 patients with anemia.Full blood cell count including peripheral picture, blood film for malaria, urine analysis and stool examination were done for every patient.Bone marrow aspiration was done for patients with splenomegaly with or without pancytopenia and or presence of immature cells in the peripheral blood. Serum iron and serum ferritin, for confirmation of iron deficiency were measured in some patients.ResultsOut of all patients, 45(21%) had chronic illness, 42(20%) had history of repeated attacks of malaria and 3(18%) patients had nutritional anemia.Sixty three (30%) patients presented with severe anemia, 32(15%) with mild anemia and 115(55%) with moderate anemia. Eighty patients presented with enlarge spleen. 26 (33%) out of the latter group had features of hypersplenism.ConclusionCommon causes of anemia in this area were chronic illness, followed by nutritional and repeated malaria infection. Splenomegaly and hypersplenism are common. We recommended that full blood count, peripheral blood picture and estimation of serum iron andserum ferritin should be performed for every anaemic patient. Blood film for malaria should be done for every anaemic patient and negative films should be repeated by immunochromatography test for plasmodium falciparum and vivax.Keywords: Splenomegaly, hypersplenism, immunochromatography, malaria.

Assaying the granulocyte-macrophage colony-stimulating factor (GM-CSF) as a mitogen of immature cells in fetal blood cultures

Based on the presence of immature cells in fetal blood, and in an attempt to shorten the cytogenetic reporting time, three simultaneous one-day culture regimes were established in 23 fetal blood samples: (a) the standard phytohemagglutinin (PHA)-stimulated lymphocytes culture, (b) a culture using the granulocyte-macrophage colony-stimulating factor (GM-CSF) as an alternative mitogen, and (c) an unstimulated culture. Diagnostic success rates achieved by these three methods were as follows: 43 per cent (95 per cent CI: 23-64) (GM-CSF), 30 per cent (95 per cent CI: 12-49) (PHA) and 9 per cent (unstimulated). These three regimes were also assayed in three-day cultures giving 100 per cent diagnostic success rate for the PHA and GM-CSF, and 62 per cent (95 per cent CI: 41-83) for the unstimulated. A moderate correlation was found between the initial concentration of cultured erythroblasts and the metaphase count in one-day GM-CSF-stimulated (r=0.43, p=0.01) and unstimulated (r=0.35, p=0.05) cultures, suggesting that erythroblasts may be in part responsible for the mitotic index observed in these two regime cultures. In conclusion, our experience suggests that immature cells in fetal blood may be successfully cultured for diagnostic purposes.

Assaying the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) as a mitogen of immature cells in fetal blood cultures

Based on the presence of immature cells in fetal blood, and in an attempt to shorten the cytogenetic reporting time, three simultaneous one-day culture regimes were established in 23 fetal blood samples: (a) the standard phytohemagglutinin (PHA)-stimulated lymphocytes culture, (b) a culture using the granulocyte-macrophage colony-stimulating factor (GM-CSF) as an alternative mitogen, and (c) an unstimulated culture. Diagnostic success rates achieved by these three methods were as follows: 43 per cent (95 per cent CI: 23–64) (GM-CSF), 30 per cent (95 per cent CI: 12–49) (PHA) and 9 per cent (unstimulated). These three regimes were also assayed in three-day cultures giving 100 per cent diagnostic success rate for the PHA and GM-CSF, and 62 per cent (95 per cent CI: 41–83) for the unstimulated. A moderate correlation was found between the initial concentration of cultured erythroblasts and the metaphase count in one-day GM-CSF-stimulated (r=0·43, p=0·01) and unstimulated (r=0·35, p=0·05) cultures, suggesting that erythroblasts may be in part responsible for the mitotic index observed in these two regime cultures. In conclusion, our experience suggests that immature cells in fetal blood may be successfully cultured for diagnostic purposes. Copyright © 1999 John Wiley & Sons, Ltd.

Erythromelalgia: Review of clinical characteristics and pathophysiology

Erythromelalgia is characterized by burning discomfort, warmth, and dermal erythema of the feet and/or the hands. Lowering the involved part and exposure to heat worsen symptoms, whereas elevation or cooling of the extremity relieves the discomfort. Several different subtypes of erythromelalgia have been documented and include an adult-onset form secondary to myeloproliferative syndrome-related thrombocytosis and an early-onset form that appears in childhood or adolescence and is idiopathic. A disturbed platelet function affecting the microvasculature has been implicated in thrombocythemia-related erythromelalgia. Importantly, manifestations of erythromelalgia often precede the onset of the myeloproliferative disease by several years. Therefore, the blood cell count should be monitored periodically in all adult patients with erythromelalgia. An abnormal hemoglobin, white blood cell, or platelet count or the presence of immature cells in the differential should prompt the physician to initiate a diagnostic evaluation for an underlying hematologic disorder. The symptoms of adults with erythromelalgia are markedly relieved after treatment with a single daily dose of acetylsalicylic acid. In contrast, childhood erythromelalgia appears without an underlying disorder, may be familial, and is resistant to treatment with aspirin.

Detection of important abnormalities of the differential count using the Coulter STKR blood counter.

An assessment of the three part differential provided by the Coulter STKR blood counter showed good correlation when compared with an 800 cell manual differential. Satisfactory flagging of eosinophilia, basophilia, and the presence of immature cells was found. The use of variables derived from the STKR in conjunction with interpretive reporting and user-defined flagging enabled this department to reduce considerably the numbers of films requiring manual differential counts.

Lack of TdT and immunoglobulin and T-cell receptor gene rearrangements in Hodgkin's disease.

To study the pathogenesis of Hodgkin's disease (HD), which today remains obscure, we have undertaken a combined experimental approach: determination of TdT and molecular analysis of rearrangements of immunoglobulin heavy chain (IgH), T-cell receptor (TCR) beta chain and the T-cell rearranging gamma (TRG) genes. TdT determination indicate would the presence of immature cells that are not detected in the normal lymphnode; molecular analysis of the rearrangements of these genes would reveal the presence of even a small monoclonal population of both T and B lineages in the lymphnodes. We believe that the combination of these two types of analysis can indicate whether an expanding lymphoid clone is responsible for this disease. TdT determination was negative in all 41 cases tested. Gene rearrangements were studied in 10 cases for IgH and TCR beta genes and in 5 cases for the TRG gene. No abnormal band beside the germ-line ones was detected in any of our cases, ruling out the presence of a minor neoplastic population. We can explain these results in at least three ways: first, the neoplastic population could represent less than 1% of the total, thus escaping detection by current techniques; second, the neoplastic population is not lymphoid in nature or is composed of mature cells that do not rearrange Ig and TCR genes and therefore belongs to a true non-B, non-T lineage; third, the pathogenesis of HD is completely different from that of non-Hodgkin's lymphomas (NHL) and does not involve the clonal expansion of a cell frozen at a particular maturative stage as is thought to happen in most NHL.

In situ immunologic phenotyping of mycosis fungoides

In situ immunologic phenotyping of the cutaneous lymphoid infiltrates of five cases of mycosis fungoides (MF) was performed. This was done by the immunoperoxidase technic using monoclonal antibodies directed against normally expressed by mature peripheral T cells and T cells subsets. A significant proportion of the infiltrates reacted with peripheral T cell antibodies. In addition, "helper" predominance was demonstrated. However, cells reacting positively with "suppressor" antibodies were also demonstrated in three cases, indicating immunologic heterogeneity of the infiltrates. The presence of a significant component of the infiltrates yielding an equivocal or negative reaction with the mature T cell antibodies, especially in the infiltrates of one case which had a fatal outcome, suggests further heterogeneity with the presence of immature cells. Future investigation with monoclonal antibodies directed against immature T cell differentiation antigens will be of interest.

Differential radiosensitivity of neurons and neuroglia of the hippocampus in the adult rabbit.

Adult rabbits were subjected to 4.5 Gy of whole-blody or brain alone gamma-irradiation, and their hippocampus was examined with the light and electron microscope. Pycnotic cells were found at the base of the granular layer of the dentate gyrus in the so-called subgranular zone, as soon as 3 h after irradiation, and were cleared up by active phagocytosis after 48 h. Some of these cells appeared as undifferentiated, whereas others were differentiating granule cells, and possibly immature neuroglia. The extent of cell necrosis was contingent upon the age of the animal, the oldest animal studied (27 months) showing only sparse lesion of that type. Astrocytes and microglia were responsible for the phagocytosis of dead cells. Another type of lesion was found in the nuclei of the mature granule cells and consisted of light spots which appeared 1 h after the irradiation and disappeared almost completely after 48 h. Pyramidal cells did not show any of these two lesions. It is concluded that the laterations in the electrical activity of pyrimidal cells, following irradiation, are at least partly due to lesions affecting the dentate gyrus. Radionecrosis in the subgranular zone is related to the presence of immature cells in this region.

A case of severe repeated immunological reactions to intermittent rifampicin treatment

A case is reported in which a 36-year-old patient twice suffered a rapidly-developing severe reaction to intermittent rifampicin therapy. The symptoms were upper abdominal and back pain, nausea and shivering. Acute renal failure, thrombocytopenia, jaundice and haemolytic anaemia also developed. Aetiologically this was due to an immunopathological effect. This case was unusual in that all the previously observed reactions to rifampicin of an immunological aetiology occurred together, resulting in a marked leucocytosis with the presence of immature cells. It appears that the immediate administration of high-dose corticosteroids can favourably influence this condition. We consider that despite its greater risks daily treatment with rifampicin is to be preferred to discontinuous therapy because of its better tuberculostatic effect.

CONGENITAL LYMPHATIC LEUKEMIA

Leukemia occurring in infancy is quite uncommon. The clinical manifestations are the same as those in the adult, except for the acute fulminating course which the disease always runs. Cross 1 in 1944 was able to collect 23 cases of leukemia from a survey of the literature. Only 3 of these were of the lymphatic variety. Kelsey and Andersen 2 in 1939 reviewed the literature on leukemia occurring in the neonatal period. They were of the opinion that the following criteria should be present before one can call an early developing leukemia a congenital leukemia. Clinically, the symptoms should present themselves either at birth or within a few days after birth. There should be hepatomegaly, splenomegaly and enlarged lymph nodes. The peripheral blood should show leukocytosis with the presence of immature cells. The history should be free of any indication of syphilis, icterus gravis neonatorum or erythroblastosis. Histologically, there

Basal Metabolism in Experimental Anemias

Basal metabolic changes have been observed in various types of anemia and in different stages of the same anemia. A number of theories have been advanced to explain this phenomenon, among which may be mentioned the hematopoietic activity and the presence of immature cells in the blood. While immature erythrocytes do consume more oxygen than normal red blood cells, one can hardly expect them to appreciably influence the total metabolism since they constitute such a small fraction of the body mass. Bald-ridge and his associates seem to have shown, in their recent investigation, a reciprocal relationship between the oxygen consumption and the nitrogen balance in various blood diseases but they, too, do not doubt the part sometimes played by the circulating reticulocytes in raising the respiratory metabolism. The present study is planned to inquire into this particular question and to ascertain the behavior of the gaseous exchange in anemias produced by different methods. Young male adult albino rats of approximately the same age and weight (about 300 gm.) were used. Their normal oxygen consumption in the post-absorptive state was determined by repeated estimations according to the method of Davis and van Dyke. Anemia was produced in one group of the animals by intraperitoneal injection of phenylhydrazine hydrochloride, 10 mg. per 100 gm. of body weight. In another group the rats were bled from the tail, about 2 cc. daily. Throughout the experimental period the following data were collected by standard methods: Body weight, oxygen consumption, body temperature, red and white blood cell counts, hemoglobin content, hematocrit reading, morphology of stained blood-smear, differential count and reticulocyte count. If the animal survived through the experiment it was sacrificed and autopsied. All animals lost some weight in the course of the experiment, usually not exceeding 40 gm. The picture of the bone marrow is essentially the same in the 2 types of anemia, namely, marked hyperplasia involving both myelocytic and erythroblastic elements and nearly always some megaloblastic blood formation. In the first group only 4 animals were successfully studied, the majority succumbed too early to permit observation for a sufficiently long period. In them the phenylhydrazine produced a prompt drop of the red cell count and hemoglobin concentration. The reticulocyte count rose steadily, reached its maximum (varying between 45 and 50%) in from 5 to 8 days, and after being maintained at that level for about 2 days, declined slowly. Immediately following the injection of the drug the oxygen consumption showed a rise to from 10 to 30% above the control level but this rise only lasted for from 1 to 4 days. The peak of the reticulocyte curve lagged from 4 to 8 days behind the rise of metabolism. Leucocytosis and increase of the polymorphonuclear neutrophils accompanied the anemia.