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REVIEW | doi:10.20944/preprints202305.1725.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Molecular biology; infectious diseases; clinical diagnostic; early detection; prognosis
Online: 25 May 2023 (03:34:18 CEST)
Antibiotic therapy is a cornerstone of modern medicine, yet the development of antibiotic re-sistance threatens to render these therapies ineffective. The gut microbiota, a complex ecosystem of microorganisms residing in the gastrointestinal tract, plays a critical role in modulating anti-biotic efficacy and resistance. This review delves into the intricate relationship between gut mi-crobiota, antibiotic therapy, and resistance, and discusses the potential applications of gut mi-crobiota research in guiding personalized antibiotic therapy and resistance mitigation strategies. Recent advancements in metagenomics, metatranscriptomics, and metabolomics have demon-strated the potential for tailored antibiotic regimens that minimize collateral damage to com-mensal bacteria and reduce the risk of resistance. Adjuvant therapies such as probiotics, prebi-otics, and synbiotics have shown promise in restoring gut microbial balance and mitigating the adverse effects of antibiotic therapy. We address the challenges associated with this emerging field including the need for standardized methodologies, ethical considerations, and interdisci-plinary collaboration. With continued interdisciplinary collaboration and the implementation of standardized methodologies, gut microbiota research can contribute to the global fight against antibiotic resistance and improve patient outcomes.
Mon, 22 May 2023
REVIEW | doi:10.20944/preprints202304.0843.v2
Subject: Medicine And Pharmacology, Hematology Keywords: CLL, Zanubrutinib, BTK inhibitors, efficacy, safety, chronic lymphocytic leukemia
Online: 22 May 2023 (16:15:16 CEST)
Ibrutinib, a first-in-class Bruton’s Tyrosine Kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated, and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by significant off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients with an acceptable safety profile. More recently, data from the phase III ALPINE trial which directly compared zanu with ibrutinib has demonstrated that zanu’s advantages are both an improved safety profile and enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and newly released German CLL algorithm, suggest that zanu may replace first-generation BTKi as one of the preferred therapeutic options for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile.
ARTICLE | doi:10.20944/preprints202305.1500.v1
Subject: Medicine And Pharmacology, Hematology Keywords: diffuse large B-cell lymphoma; relapsed; refractory; autologous stem cell transplantation
Online: 22 May 2023 (10:29:20 CEST)
Treating relapsed and refractory diffuse large B-cell lymphoma is still challenging for clinicians, but the available CAR-T and bispecific antibodies revolutionized therapy. Autologous stem cell transplantation was the most effective treatment modality previously. The authors report data from a single center over ten years. The retrospective study included 116 patients. There were 53 relapsed, 39 primary refractory cases, 19 had CNS involvement, and 5 received primary consolidation transplants. The median duration of follow-up was 46 months. The median event-free survival was 75 months, and the median overall survival was 105 months for all cases. Five-year overall survival was 59%, and event-free survival was 54%. Pretreatment prognostic factors at diagnosis had no effect on the outcome of transplantation. The authors found no difference between survival in relapsed or refractory cases, and the number of salvage lines or the germinal center / activated B-cell type also did not influence the results. Complete metabolic response before transplant confirmed by 18FDG PET/CT strongly affected survival. The pretransplant creatinine and CRP levels significantly influenced the long-term outcome. The number of stem cells infused did not affect survival, but engraftment within nine days did result in better survival. These data support the finding that the response to salvage therapy did select a better prognostic group who may still benefit from autologous transplantation.
ARTICLE | doi:10.20944/preprints202305.1477.v1
Subject: Medicine And Pharmacology, Hematology Keywords: myelofibrosis; ruxolitinib; severity of symptoms; adherence to therapy
Online: 22 May 2023 (08:52:13 CEST)
We aimed to explore symptoms severity and adherence to therapy for patients with myelofibrosis treated with ruxolitinib in Bulgaria. It is a prospective, non-interventional study performed at the Specialized hospital for active treatment of hematological diseases in Sofia during 2022 - 2023. Date of diagnosis, demographic characteristics, clinical indicators, ruxolitinib dose, and other data points were collected. Clinical indicators were assessed at baseline, in the middle and at the end of observation. Severity of symptoms was measured with MPN-SAF TSS and adherence to therapy with the Morisky 4 questionnaire 6 times during the observation. The mean age of diagnosis was 58.5 years, with the average duration of disease of 3 years. Pa-tients’ laboratory results were within physiological ranges, with spleen size experiencing a con-stant decrease. The average value for the severity of the symptoms per MPN-SAF TSS results decreased significantly, indicating better disease control. The average adherence to therapy did not change and remained high at around 9 points, except for one patient. In conclusion the treatment of myelofibrosis patients with ruxolitinib decreased symptoms se-verity and spleen size. Patients were adherent to the therapy over the observed period but as treatment duration increases the risk of adherence decreasing.
Fri, 19 May 2023
ARTICLE | doi:10.20944/preprints202305.1382.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Fetal hemoglobin; pregnancy; glycosylated hemoglobin; HbA1C; β-HCG
Online: 19 May 2023 (05:17:09 CEST)
It is believed that fetal hemoglobin (HbF) expression in adults is largely genetically regulated. The increased expression of HbF in pregnancy has been reported in a small number of articles. Different mechanisms have been proposed, but the description of HbF expression during pregnancy remains unclear. The objectives of this study were to document HbF expression during peri and postpartum periods, confirm its maternal origin, and assess clinical and biochemical parameters potentially associated with HbF modulation. In this observational prospective study, 345 pregnant women were followed. At baseline, 169 had HbF expression (≥1% of total hemoglobin) and 176 did not have HbF expression. Women were followed at the obstetric clinic during their pregnancy. Clinical and biochemical parameters were measured at each visit. Analyses were made to determine which parameters had a significant correlation to HbF expression. Results show that HbF expression of ≥ 1% during peri and postpartum periods in pregnant women without influencing comorbidities is at its highest peak during the first trimester. In all women, it was proven that HbF was of maternal origin. A significant positive correlation between HbF expression, β-HCG, and HbA1C was present. A significant negative association between HbF expression and total hemoglobin was found. HbF expression induction during pregnancy is probably associated with increase in β-HCG and HbA1C, and decrease of total hemoglobin, which could temporarily reactivate the fetal erythropoietic system.
Wed, 17 May 2023
REVIEW | doi:10.20944/preprints202305.1213.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Hodgkin lymphoma; tumor microenvironment; tumor associated macrophages; CD169+ macrophages; immune evasion; immunosuppression
Online: 17 May 2023 (09:37:22 CEST)
Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed-Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T-cells (CD4 helper, CD8 cytotoxic and regulatory), and tumor-associated macrophages (TAMs) but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through production of various cytokines and/or aberrant expression of immune checkpoint molecules, in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency.
Fri, 12 May 2023
ARTICLE | doi:10.20944/preprints202305.0887.v1
Subject: Medicine And Pharmacology, Hematology Keywords: transglutaminase 2; cancer; ATO
Online: 12 May 2023 (05:04:48 CEST)
Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signaling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukemia cells and that these responses were enhanced when TG2 was deleted. The combined ATRA+ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of cellular oxidative stress response, and proteolytic activity of calpain, resulting in TG2 degradation and reduced survival of WT leukemia cells. We further showed that upon ATO treatment, the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line, and primary peripheral blood mononuclear cells, thereby sensitizing these cell types to apoptotic signals.
Wed, 10 May 2023
ARTICLE | doi:10.20944/preprints202305.0700.v1
Subject: Medicine And Pharmacology, Hematology Keywords: allogeneic hematopoietic stem cell transplantation; autoimmune limbic encephalitis; cyclo-phosphamide; regulatory T cells; CD25; Foxp3; IL-6; fever; acute graft-versus-host disease; cyto-kine-release syndrome
Online: 10 May 2023 (07:46:24 CEST)
Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hem-atopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflam-matory biomarkers, and reconstitution of various T cell populations. Of 35 patients, four devel-oped LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.
Thu, 4 May 2023
ARTICLE | doi:10.20944/preprints202302.0320.v2
Subject: Medicine And Pharmacology, Hematology Keywords: non-invasive; point-of-care testing; blood values; Radial arterial blood; blood gas; transcutaneous; algorithm
Online: 4 May 2023 (03:07:48 CEST)
The purpose of this work was to evaluate a novel methodology developed by Digital Blood Corporation (DBC) to calculate critical blood values using four non-invasive measured values as input. The values obtained using a point-of-care testing (POCT) device were utilized for comparison and reference. Radial arterial blood was collected for the POCT comparator analysis using the Abbott i-STAT® device. The non-invasive methodology from DBC requires four parameters to be directly measured: temperature, hemoglobin, pO2, and pCO2. Subsequently, sodium, potassium, chloride, ionized calcium, total carbon dioxide, pH, bicarbonate, and oxygen saturation are calculated using an algorithm. The agreement between the POCT and DBC’s methodology was analyzed using Bland-Altman difference plots. For a second data set, pO2 and pCO2 values collected with the POCT were used as input for DBC’s algorithm to test its robustness. Data from 37 healthy ambulatory individuals, mean age: 42.4 + 13 years; range: 18-64 years, were included in the primary analysis. In the case of the non-invasive gained four input values the greatest variation between POCT and DBC’s approach was observed for pO2 and consequently for algorithm values that depend upon pO2 precision. Replacing transcutaneous pO2 and pCO2 with POCT values demonstrates the principal ability of DBC’s algorithm to predict the additional 8 blood values in sufficient agreement with a standard POCT device in healthy patients. The algorithm developed by DBC appears to be robust in the case of healthy patients but does need the four measured input values with preciseness comparable to a POCT device to give reliable and clinically relevant results. The present study thus serves as a proof of concept to facilitate future study and further development of this methodology into a non-invasive device.
Sat, 29 April 2023
REVIEW | doi:10.20944/preprints202304.1236.v1
Subject: Medicine And Pharmacology, Hematology Keywords: FLT3 mutations; resistant/relapsed acute myeloid leukemia; tyrosine kinase inhibitors; gilteritinib
Online: 29 April 2023 (10:55:21 CEST)
The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction into the clinics of tyrosine kinase inhibitors (TKI) such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a 2nd generation TKI with deeper single-agent activity than 1st generation drugs against both FLT3-ITD and TKD mutations, in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3-mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences confirmed the positive results in the R/R AML setting. Finally, gilterinib based combinations currently under investigation with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance) will be analyzed in detail in the review.
Fri, 28 April 2023
REVIEW | doi:10.20944/preprints202304.1161.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Multiple myeloma; belantamab mafodotin; antibody-drug-conjugate.
Online: 28 April 2023 (10:12:31 CEST)
Despite the recent approval of novel immunotherapies, as immunomodulatory drug, proteasome inhibitors and anti-CD38 monoclonal antibodies, Multiple Myeloma (MM) remains incurable and the acquisition of triple-refractoriness leads to really dismal outcomes, in even earlier lines of therapy. More recently, innovative therapeutic strategies targeting B cell maturation antigen (BCMA), highly expressed on the plasma cell surface, are drawing different future landscapes in terms of effectiveness and outcomes. Belantamab Mafodotin, a first-in-class anti-BCMA antibody drug conjugates, demonstrated good efficacy and safety profile in triple-refractory patients in the phase 2 DREAMM-2 trial and it was approved for the treatment of MM triple-exposed patients with >4 prior lines of therapy. Here, starting from Belantamab Mafodotin clinical trials also exploring combination studies and different schedules in order to improve its efficacy and toxicity, we focused on real life experiences all over the world, which have confirmed clinical trial data and encourage further Belantamab Mafodotin investigations
Mon, 24 April 2023
REVIEW | doi:10.20944/preprints202304.0843.v1
Subject: Medicine And Pharmacology, Hematology Keywords: CLL; Zanubrutinib; BTK inhibitors; efficacy; safety; chronic lymphocytic leukemia
Online: 24 April 2023 (09:43:47 CEST)
Ibrutinib, a first-in-class Bruton’s Tyrosine Kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated, relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by significant off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab in treatment-naive CLL patients with an acceptable safety profile. More recently, data from the phase III ALPINE trial which directly compared zanu with ibrutinib has demonstrated that zanu’s advantages are both an improved safety profile and enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated National Comprehensive Cancer Network (NCCN) and newly released German CLL practice guidelines, suggest that zanu may replace first-generation BTKi as the preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favourable toxicity profile.
Thu, 20 April 2023
COMMUNICATION | doi:10.20944/preprints202304.0616.v1
Subject: Medicine And Pharmacology, Hematology Keywords: CP-CML; Accelerated Phase (AP); Blast Phase (BP); CD26+LSCs
Online: 20 April 2023 (07:31:53 CEST)
In Chronic Myeloid Leukemia (CML) patients, CD34+/CD38-/CD26+ cell population represents a “CML specific” Leukemia Stem Cell (LSC) compartment. Indeed, preliminary studies showed that the expression of CD26 discriminates bone marrow CML Leukemic Stem Cells (LSCs) from nor-mal Hematopoietic Stem Cells (HSCs) or from LSCs of other myeloid neoplasms. We were first to demonstrate that at diagnosis CD34+/CD38-/CD26+ cells are easily measurable also in Peripheral Blood (PB) and that residual circulating CD26+LSCs persist, with a fluctuating trend, in most pa-tients in optimal response during treatment with Tyrosine Kinase Inhibitors (TKIs) and even after successful TKI discontinuation. These data corroborate and confirm the possibility of using flow-cytometry CD26+ evaluation as an important diagnostic tool that, combined with molecular biology and cytogenetic, could provide a rapid diagnosis of Chronic Phase (CP) CML starting from a simple PB sample. Yet, few data are available regarding the behavior of CD26+LSCs during Accelerated Phase (AP) or Blast Phase (BP) CML and the role, if any, this peculiar staminal cell compartment may play in disease progression. In the present study we compared the presence and phenotypic characteristics of circulating CD26+LSCs in CP CML patients at diagnosis, during AP and in cases of progression to lymphoid BP, inquiring a possible role of these cells during dis-ease evolution.
Tue, 18 April 2023
REVIEW | doi:10.20944/preprints202304.0482.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Acute Myeloid Leukemia, cellular therapies, chimeric antigen T cells, T cell receptor T cells, CAR-NK cells, RNAseq
Online: 18 April 2023 (04:22:46 CEST)
Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed-refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything, considering only around 30% of patients show a response but with consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T and CAR-NK therapies; approaches to tailor the microenvironment and target neoantigens; and allogeneic approaches.
Thu, 23 March 2023
ARTICLE | doi:10.20944/preprints202303.0415.v1
Subject: Medicine And Pharmacology, Hematology Keywords: spacetime theorems; naturalism; abiogenesis; panspermia; process structuralism; Cambrian explosion; amino acids; homochirality; hand of God dilemma
Online: 23 March 2023 (13:40:22 CET)
The more than thirty spacetime theorems developed over the past five decades establish that the universe and its spacetime dimensions have emerged from a cause/Causal Agent beyond the cosmos. Thus, to infer that this cause/Causal Agent may have intervened in the origin and history of Earth and Earth’s life resides well within the bounds of reason. Meanwhile, proponents of each of the three prevailing naturalistic models for the origin and history of Earth’s life have marshalled arguments and evidence that effectively undermine and refute the other two models. A biblical perspective and approach to Earth’s life can help resolve this impasse. While a superficial and pervasive appeal to divine intervention thwarts scientific advance, so does a rigid adherence to naturalism. A productive way forward is to identify which models (or parts of models), whether naturalistic, theistic, or a combination, most effectively narrow, rather than widen, knowledge gaps, minimize anomalies, offer the most comprehensive and detailed explanation of the data, and prove most successful in predicting scientific discoveries.
Tue, 21 March 2023
REVIEW | doi:10.20944/preprints202303.0371.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Nuclei isolation; Next-generation sequencing; Cell-type specific isolation; Epigenetics; Transcriptomics; Single cell sequencing; Single nucleus sequencing
Online: 21 March 2023 (06:40:11 CET)
In the last decade, we have witnessed an upsurge in nuclei-based studies, particularly coupled with next-generation sequencing. Such studies aim at understanding the molecular states that exist in heterogeneous cell populations by applying increasingly more affordable sequencing approaches, in addition to optimized methodologies developed to isolate and select nuclei. Although these powerful new methods promise unprecedented insights, it is important to understand and critically consider the associated challenges. Here, we provide a comprehensive overview of the rise of nuclei-based studies and elaborate on their advantages and disadvantages. Improved designs and appropriate use of the various experimental strategies will result in acquiring biologically accurate and meaningful information.
Mon, 27 February 2023
ARTICLE | doi:10.20944/preprints202302.0469.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Long COVID; Laboratory Markers; Haematological Tests
Online: 27 February 2023 (09:53:40 CET)
Long COVID affects a significant number of people after acute coronavirus disease 2019 (COVID-19), and haematological changes can persist in the COVID-19 phase. This study aimed to evaluate these haematological laboratory markers, linking them to clinical findings and long-term outcomes in patients with long COVID. This cross-sectional study selected participants from a ‘long COVID’ clinical care programme in the Amazon region. Clinical data and baseline demographics were obtained, and blood samples were collected for quantification of erythrogram-, leukogram-, and plateletgram-related markers. Long COVID was reported for up to 985 days. Patients hospitalised in the acute phase had higher mean red/white cell, platelet, and plateletcrit levels and red cell distribution width. In addition, haematimetric parameters were higher in shorter periods of long COVID. Patients presenting with more than six concomitant long COVID symptoms had a higher white blood cell count, shorter prothrombin time (PT), and increased PT activity. Within up to 985 days of long COVID, our results suggest a probable benign compensation for erythrogram-related markers. Increased levels of leukogram-related markers and increased coagulation activity were observed in the worse long COVID groups, also indicating an exacerbated response after the acute disturbance, which is uncertain and requires further investigation.
ARTICLE | doi:10.20944/preprints202302.0467.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Diagnostic; Iron deficiency; Polycythemia; Polycythemia vera; Secondary polycythemia
Online: 27 February 2023 (09:36:45 CET)
Several observations have shown that patients with polycythemia have iron deficiency. Our objectives were to report the prevalence of iron deficiency, to evaluate the diagnostic performance of serum ferritin in polycythemia vera and to describe the mechanisms of this association. This is a retrospective descriptive and analytical study carried out in the internal medicine department of the Henri Mondor Hospital, Aurillac, France. The study involved 114 patients with polycythemia, followed in the department from January 1, 2010 to December 31, 2021. To evaluate the diagnostic performance, the JAK2 mutation was considered as the gold standard of diagnosis. Thirty-three patients had polycythemia vera and 76 patients had secondary polycythemia. The mean age of the patients was 61.79 years (±15.44) with a sex ratio of 4.43. The overall prevalence of iron deficiency was 21.05%. The prevalence was 53% in polycythemia vera group and 1.32% in secondary polycythemia group. The risk of iron deficiency was high in polycythemia vera (OR=115; 95% CI [14.4-918.2], p<0.000). The sensitivity and specificity of serum ferritin were 52.63% and 100% respectively. Assessment of iron deficiency should be part of the initial evaluation of polycythemia. The presence of iron deficiency is specific for polycythemia vera.
Mon, 20 February 2023
ARTICLE | doi:10.20944/preprints202302.0320.v1
Subject: Medicine And Pharmacology, Hematology Keywords: non-invasive; point-of-care testing; blood values; Radial arterial blood; blood gas; transcutaneous; algorithm
Online: 20 February 2023 (06:07:08 CET)
There are several point-of-care testing (POCT) devices for measuring critical laboratory values, but real-time utility can be cumbersome considering need for blood draws, multiple cartridges, and potential for delays in obtaining results. Digital Blood Corporation (DBC) developed an algorithm for non-invasive, real-time measurement of multiple values. The objective of this study was to compare the values obtained using a POCT device with the DBC’s non-invasive methodology and to evaluate the robustness of the algorithm. After Institutional Review Board approval, a pilot and feasibility study was conducted in healthy ambulatory individuals aged 18-64 years. Radial arterial blood was collected for the POCT comparator analysis using the Abbott i-STAT® device. The four parameters directly measured for DBC’s algorithm included temperature, hemoglobin, and partial pressures of oxygen and carbon dioxide (pO2 and pCO2, respectively). Using these values, the algorithm calculated sodium, potassium, chloride, ionized calcium (iCa), total carbon dioxide (TCO2), pH, bicarbonate, and oxygen saturation (SO2). Bland-Altman difference plot were calculated for analyzing the agreement between the Abbott i-STAT® device and DBC’s non-invasive methodology. For a second set of data, pO2 and pCO2 values collected using the Abbott i-STAT® device were used as input for DBC’s algorithm to test robustness of the algorithm. Data from 37 participants (mean age: 42.4 + 13 years; range: 18-64 years) were included in the primary analysis. Mean difference was less than 5% for sodium, chloride, pH, SO2, and bicarbonate; 6-10% for hemoglobin, TCO2 and pCO2; and greater than 10% for iCA, potassium, and pO2. The greatest variation between POCT and DBC’s approach was observed for pO2. Algorithm values that depend upon pO2 precision obtained from the TINA TCM4 radiometer are expected to show greatest deviation. Replacing transcutaneous pO2 and pCO2 values from the TINA TCM4 instrument with Abbott i-STAT values demonstrates the robustness of DBC’s algorithm and its ability to predict blood values comparable to the POC device in healthy patients. This pilot study serves as a proof of concept to trigger future study and further development of the DBC’s non-invasive device in critical care settings and test the usability of the device via quantitative and qualitative measures with different healthcare providers (e.g., pharmacists, nurses, paramedics). The broader clinical significance especially among critically ill adults and children remains to be determined.
Fri, 17 February 2023
ARTICLE | doi:10.20944/preprints202302.0311.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Monozygotic twins (MTs); morphology; hemodynamics; environmental and genetic factors; neurovascular diseases; cerebral aneurysms (CAs)
Online: 17 February 2023 (13:01:18 CET)
The contribution of genetic and environmental factors to the pathophysiology of cerebral aneurysms in monozygotic twins is under-reported and presents ambiguous arguments. The morphology and hemodynamics of neurovascular arteries in a pair of monozygotic twins (MTs) were investigated to reveal the underlying mechanisms. Four arterial models were reconstructed for the twin A-right brain and left brain, twin B-left brain, and B-left brain without anterior cerebral arteries based on preclinical scanned information. Subsequently, the dimensions, configurations and outlined curves of the three-perspective geometries were compared between the MTs. Adopting an in-vitro validated numerical cerebral aneurysm model, hemodynamic patterns were investigated and compared in the MT models, respectively. Morphological comparisons of the MTs show the size and shape of cerebral arteries exist significant differences, despite of the expected genetic similarities. These differences can be attributed to variations during embryological development and external environmental influences. Qualitatively and generally, numerical results indicate the MTs have some hemodynamic similarities (e.g., time-averaged pressure (TAP) distributions (~13400 Pa), and oscillatory shear index (0~0.49), but present significant differences in specific local arteries due to morphological variances. Specifically, the difference in the volumetric blood flow rate in corresponding arteries between the MTs is from 16% (smallest) in anterior choroidal artery (AChA) to 221% (largest) in the ophthalmic artery (OphA), varying with specific compared arteries. Also, the registered hemodynamic indicators, such as the maximum time-averaged wall shear stress (TWSS) (53.6 Pa vs. 37.8 Pa), and different local OSI distributions were observed between the MTs. The findings revealed that morphological variations in MTs could be generated by embryological and environmental factors, thus assuming they share the identical morphology in cardiovascular and neurovascular systems may lead to significant misevaluations in hemodynamics quantifications and further lesions.
Tue, 20 December 2022
ARTICLE | doi:10.20944/preprints202212.0368.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Betulinic acid; bovine serum albumin; doxorubicin; drug delivery system; lung cancer; synergistic effect.
Online: 20 December 2022 (10:40:12 CET)
Nanosized drug delivery systems (DDS) have been studied as a novel strategy against cancer due to their potential to simultaneously decrease drug inactivation and systemic toxicity and increase passive and/or active drug accumulation within the tumor(s). Triterpenes are plant-derived compounds with interesting therapeutic properties. Betulinic acid (BeA) is a pentacyclic triterpene which has great cytotoxic activity against different cancer types. Herein, we developed a nanosized protein-based DDS of bovine serum albumin (BSA) as the drug carrier combining two compounds: doxorubicin (Dox) and the triterpene BeA using an oil-water-like micro-emulsion method. Spectrophotometric assays were performed to determine protein and drug concentrations in the DDS. The biophysical properties of these DDS were characterized using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy confirming nanoparticle (NP) formation and drug loading into the protein structure, respectively. The encapsulation efficiency was 77% for Dox and 18% for BeA. More than 50% of both drugs were released within 24 h, at pH 6.8, while less drug was released at pH 7.4 in this time period. Co-incubation viability assays of Dox and BeA alone for 24 h demonstrated synergistic cytotoxic activity in the low μM range against the non-small cell lung carcinoma (NSCLC) A549 cells. Viability assays of the BSA(Dox+BeA) DDS demonstrated a higher synergistic cytotoxic activity than the two drugs with no carrier. Moreover, confocal microscopy analysis confirmed cellular internalization of the DDS and nucleus accumulation of the Dox. We determined the mechanism of action of the BSA(Dox+BeA) DDS, confirming S-phase cell cycle arrest, DNA damage, caspase cascade activation, and downregulation of the epidermal growth factor receptor (EGFR) expression. This DDS has the potential to synergistically maximize the therapeutic effect of Dox and diminish chemoresistance induced by EGFR expression using a natural triterpene against NSCLC.
Thu, 8 December 2022
ARTICLE | doi:10.20944/preprints202212.0152.v1
Subject: Medicine And Pharmacology, Hematology Keywords: chronic limb-threatening ischemia; outcome; sex; age; limb salvage
Online: 8 December 2022 (09:39:30 CET)
Background: Identifying sex-related differences/variables associated with 30-day/1-year mortality in patients with chronic limb-threatening ischemia (CLTI). Methods: Multicenter/retrospective/observational study. Database sent to all-the-Italian vascular surgeries to collect all-the¬-patients operated for CLTI in 2019. Acute lower-limb ischemia and neuropathic-diabetic foot not included. Follow-up: 1-year. Data on demographics/comorbidities, treatments/outcome, and 30-day/1-year mortality investigated. Results: Information on 2399 cases (69.8% men) from 36/143 (25.2%) centers. Median (IQR) age: 73 (66-80) and 79 (71-85) yrs for men/women, respectively (p<.0001). Women more over-75 (63.2%vs40.1%, p=.0001). More men smokers (73.7%vs42.2%, p<.0001), on hemodialysis (10.1%vs6.7%, p=.006), affected by diabetes (61.9%vs52.8%, p<.0001), dyslipidemia (69.3%vs61.3%, p<.0001), hypertension (91.8%vs88.5%, p=.011), coronaropathy (43.9%vs29.4%, p<.0001), bronchopneumopathy (37.1%vs25.6%, p<.0001), underwent more open/hybrid surgeries (37.9%vs28.8%, p<.0001), and minor amputations (22%vs13.7%, p<.0001). More women underwent endovascular revascularizations (61.6%vs55.2%, p=.004), major amputations (9.6%vs6.9%, p=.024), and obtained limb-salvage if with limited gangrene (50.8%vs44.9%, p=.017). Age >75 (HR3.63, p=.003) associated with 30-day mortality. Age >75 (HR2.14, p<.0001), nephropathy (HR1.54, p<.0001), coronaropathy (HR1.26, p=.036), infection/necrosis of the foot (dry, HR1.42, p=.040; wet, HR2.04, p<.0001) associated with 1-year mortality. No sex-linked difference in mortality statistics. Conclusion: Women exhibit fewer comorbidities, but are struck by CLTI when over-75, a factor associated with short/mid-term mortality, explaining why mortality doesn’t statistically differ between the sexes.
Tue, 6 December 2022
ARTICLE | doi:10.20944/preprints202212.0087.v1
Subject: Medicine And Pharmacology, Hematology Keywords: low T3 syndrome, oxidative stress, sepsis, septic shock, thyroid hormone, type 3 deiodinase
Online: 6 December 2022 (02:18:24 CET)
Background: Low T3 syndrome occurs frequently in patients with sepsis. Type 3 deiodinase (Dio3) is present in immune cells but there is no description of its presence in this patients. Here we aimed to determine the prognostic impact of thyroid hormones levels (TH) measured on ICU admission on mortality and on evolution to chronic critical illness (CCI) and the presence of D3 in white cells. Methods: Prospective cohort study with a follow-up for 28 days or deceased. Results: Low T3 levels at admission were present in 86.5% of the patients. Dio3 was 55% induced in immune cells. The cut-off value of 60 pg/mL for T3 displayed a sensitivity and specificity of 81% and 64% for predicting death, odds ratio of 4.89. Lower T3 yielded an area under the receiver operating characteristic curve of 0.76 and 0.75 for mortality and evolution to CCI, respectively, thus displaying better performance than commonly used prognostic scores. Conclusions: We advance in the pathophysiology of low T3 showing induced D3 in immune cells during sepsis. Low T3 levels independently predicted a progression to CCI and mortality within 28 days in sepsis and septic shock.
Sat, 1 October 2022
ARTICLE | doi:10.20944/preprints202210.0002.v1
Subject: Medicine And Pharmacology, Hematology Keywords: antithrombin; recombinant thrombomodulin; SOFA score; JAAM DIC score; PMX-DHP
Online: 1 October 2022 (07:09:59 CEST)
Backgroud. To improve mortality in patients with sepsis and septic shock, anticoagulant and acute blood purification therapies are performed depends on their severity of organ failure including coagulopathy. Therapeutic approach is required in clinical settings. Material and Methods. We evaluated anticoagulant and acute blood purification therapy in 2,007 patients with sepsis-induced disseminated intravascular coagulation (DIC) in a post-marketing survey examining plasma-derived antithrombin (AT) concentrate. Results. The 28-day mortality rate was 24.2%; before AT administration, there was a significant difference in proportion to the severity of the Sequential Organ Failure Assessment (SOFA) score (p<0.001). The median SOFA score was 9. In patients with SOFA scores >9, the mortality rate was lower in AT combined therapy with recombinant thrombomodulin (rTM) than in AT monotherapy if their JAAM DIC score was >6 (28.5% and 40.0%, respectively; p =0.031). In multiple logistic regression analysis, endotoxin adsorbed polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) before AT administration was correlated with reduced 28-day mortality (odds ratios: 2.071; 95% confidence intervals 1.374–3.121, p=0.001). Conclusions. To improve mortality in patients with sepsis, if patients with endotoxin-induced septic shock, PMX-DHP would undergo, and further development to DIC, AT concentrate administer, followed by rTM if their SOFA and JAAM DIC scores are >9 and 6, respectively. Further prospective study is needed.
Tue, 20 September 2022
ARTICLE | doi:10.20944/preprints202209.0299.v1
Subject: Medicine And Pharmacology, Hematology Keywords: leprosy; ABO/Rh blood group; Clinical; Angola
Online: 20 September 2022 (09:28:22 CEST)
Introduction: Leprosy, caused by Mycobacterium leprae is one of the oldest infectious diseases in human history and its eradication is linked to poverty control, lack of basic sanitation, the fragility of health, and education services. Objective: To evaluate the frequency of blood groups (ABO/Rh) and the sociodemographic and clinical profile of Angolan patients with Leprosy treated at the Anti-Tuberculosis and Leprosy Dispensary in Luanda, the capital city of Angola. Methodology: A descriptive, introspective, cross-sectional study with a quantitative approach was carried out with 102 patients of Luanda, in the second half of 2021. Results: Of the 102 patients included in the study, the majority belonged to the ORh+ group (51.9%), followed by the BRh+ group (27.4%) and ARh+ (18.6%), most were under 51 years of age ( 87.3%), with low education (54.9%), coming from urban areas (44.1%). As for clinical conditions, most had a multibacillary infection (93.1%), diagnosed mainly by smear microscopy (75.5%) without other infection (79.4%), some of them with complications (28.4%) and individuals with non-O blood group showed changes in the blood count. Conclusion: Leprosy seems to be common in ORh+ individuals, it continues to affect especially those residing in areas of population agglomerations and with low education, presenting itself as a multibacillary infection, where changes in the blood count are greater in non-O individuals.
Thu, 8 September 2022
ARTICLE | doi:10.20944/preprints202209.0114.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Blood Transfusion; Knowledge; Attitude; Practice; Healthcare Providers
Online: 8 September 2022 (03:02:03 CEST)
Introduction: Blood transfusion involves the transfer of blood from donors to patients. A blood transfusion is carried out every 2 seconds in the US. It is made up of about 29000 units of red blood cells and is transfused every day in the US. When blood transfusion is done correctly, it can result in the saving of lives and the improvement of healthcare. However, it may also lead to immediate, late, delayed, and chronic complications. No previous studies have been conducted in Qatar to address this issue. Methods: This is a cross-sectional study intended to determine the knowledge, attitude, and practice toward blood transfusion among healthcare providers at Hamad Medical Corporation (HMC), which is the principal healthcare provider in Qatar. Participants between 18 and 25 years of age were selected for the research study. A 10-item online questionnaire that people can fill out on their own will be used to get the data needed for the analysis and meet the study's goals. Results: the analysis has indicated that facing negative reactions after blood transfusion and being worried about getting affected by any infection have a small positive association, with the specific values coming in at r = 0.317, p = 0.000. Fever after blood transfusion and feeling like refusing blood transfusion have a significant and moderate positive correlation, with the specific values coming in at r = 0.630 and p = 0.000. Conclusion: The findings of this study have helped us figure out how healthcare providers feel, what they know, and what they do during a blood transfusion.
Wed, 10 August 2022
ARTICLE | doi:10.20944/preprints202208.0193.v1
Subject: Medicine And Pharmacology, Hematology Keywords: liver; Neuropilin-1; Toll-like receptors; COVID-19
Online: 10 August 2022 (05:05:04 CEST)
Purpose: The study aimed to investigate if there were any links between liver function biomarkers and immunoglobulins levels in serum, and Toll-like receptors (TLRs) and neuropilin-1 (NRP1) in COVID-19 patients. The study also aimed to assess the accuracy—sensitivity, specificity, and area under the curve (AUC) by the receiver operator curve (ROC) analysis for immunoglobulins levels and TLRs expressions. Patients and Methods: This study included 150 patients (100 patients with confirmed COVID-19 and 50 healthy volunteers as a control group). Patients with COVID-19 were subdivided into two groups according to the severity of symptoms (moderate and severe, with 50 patients each). Serum C-reactive protein (CRP), alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), albumin, lactate dehydrogenase (LDH), immunoglobulin (Ig) G, and IgM levels were estimated. TLRs (TLR2 and TLR4) and NRP1 gene expression in blood samples were investigated using quantitative real-time polymerase chain reaction (qRT-PCR). ROC analysis was also applied to determine the accuracy of various detected parameters in predicting the possibility of COVID-19 infection. Results: In COVID-19 patients, serum parameters related to liver function, except serum albumin, CRP, IgG, IgM, and TLR2, TLR4, and NRP1 mRNA expression levels, significantly elevated compared to controls. Severe COVID-19 patients exhibited significantly higher liver enzymes (ALT, AST and LDH), CRP, and TLR2 mRNA expression levels and lower albumin levels than the moderate group. In the moderate and severe groups, ALT, CRP, TLR2, and TLR4 had a significant positive correlation with IgM levels. ALT, AST, LDH, CRP, TLR2, and TLR4 showed a significant positive correlation with IgG levels in both groups. In both the moderate and severe groups, NRP1 expression was found to be significantly correlated with CRP, IgG, IgM, TLR2, and TLR4. In contrast, serum albumin levels exhibited a significant negative correlation with IgG and IgM levels only in the severe group, but they showed a significant negative correlation with TLR2, TLR4, and NRP1 expression in both moderate and severe groups. Serum ALT and AST activities were positively correlated with NRP1 expression in the moderate group but not in the severe group and as well as TLR2 and TLR4 expression in both the moderate and severe groups. ROC analysis indicated that AUC was higher than 0.800 for serum IgM level and TLR4 gene expression in moderate COVID-19 group. Conclusions: The increased liver function biomarkers in serum and NRP1 expression are closely correlated with sustained activations in humoral and innate immune responses during COVID-19 infection. As a result, TLR2, TLR4, and NRP1 could be targets for limiting COVID-19 infection and impairment effects on liver function. Moreover, detection of IgM level in serum and TLR4 expression in blood have a good accuracy in predicting the possibility of infection with COVID-19 in moderate cases.
Wed, 3 August 2022
ARTICLE | doi:10.20944/preprints202204.0058.v2
Subject: Medicine And Pharmacology, Hematology Keywords: Digital reference object; Perivascular spaces; Spatio-temporal imaging artefacts; Perivascular space enhancement; Cerebral small vessel disease
Online: 3 August 2022 (11:12:43 CEST)
Growing interest surrounds the assessment of perivascular spaces (PVS) on magnetic resonance imaging (MRI) and their validation as a clinical biomarker of adverse brain health. Nonetheless, the limits of validity of current state-of-the-art segmentation methods are still unclear. Here, we propose an open-source three-dimensional computational framework comprising 3D digital reference objects and evaluate the performance of three PVS filtering methods under various spatiotemporal imaging considerations (including sampling, motion artefacts, and Rician noise). Specifically, we study the performance of the Frangi, Jerman and RORPO filters in enhancing PVS-like structures to facilitate segmentation. Our findings were three-fold. First, as long as voxels are isotropic, RORPO outperforms the other two filters, regardless of imaging quality. Unlike the Frangi and Jerman filters, RORPO’s performance does not deteriorate as PVS volume increases. Second, the performance of all “vesselness” filters is heavily influenced by imaging quality, with sampling and motion artefacts being the most damaging for these types of analyses. Third, none of the filters can distinguish PVS from other hyperintense structures (e.g. white matter hyperintensities, stroke lesions, or lacunes) effectively, the area under precision-recall curve dropped substantially (Frangi: from 94.21 [IQR 91.60, 96.16] to 43.76 [IQR 25.19, 63.38]; Jerman: from 94.51 [IQR 91.90, 95.37] to 58.00 [IQR 35.68, 64.87]; RORPO: from 98.72 [IQR 95.37, 98.96] to 71.87 [IQR 57.21, 76.63] without and with other hyperintense structures, respectively). The use of our computational model enables comparing segmentation methods and identifying their advantages and disadvantages, thereby providing means for testing and optimising pipelines for ongoing and future studies.
Thu, 30 June 2022
REVIEW | doi:10.20944/preprints202206.0424.v1
Subject: Medicine And Pharmacology, Hematology Keywords: SARS-COV-2; COVID-19; TTP; refractory; thrombotic microangiopathies
Online: 30 June 2022 (09:06:54 CEST)
Introduction: The proliferation of literature regarding COVID-19 pandemic has served to highlight a wide spectrum of disease manifestations and complications like thrombotic microangiopathies. Our review with a brief case presentation highlights the increasing recognition of TTP in COVID-19 and describes its salient characteristics. Methods: We screened the available literature in Pubmed, EMBASE and Cochrane database from inception till April 2022 of articles mentioning COVID-19 associated TTP in English Language. Results: From 404 records, we included 8 articles mentioning data of 11 patients in our review. TTP was predominantly reported in females (72%) with a mean age of 48.2 years (SD 15.1). Dyspnea was the most common symptom in 1/3rd of patients (36.6%). Neurological symptoms were reported in 27.3% of cases. The time to diagnosis of TTP was 10 days (SD: 5.8) from onset of Covid-19. All 11 cases underwent plasma exchange (PLEX), with a mean of 12 sessions per patient, whereas six cases received Rituximab (54.5%), and three received Caplacizumab (27.3%). One patient died from the illness. Conclusion: This review of available literature highlights the atypical and refractory nature of COVID-19 associated TTP. It required longer sessions of PLEX with half of the patients receiving at least one immunosuppressant.
Thu, 16 June 2022
ARTICLE | doi:10.20944/preprints202206.0230.v1
Subject: Medicine And Pharmacology, Hematology Keywords: COVID-19; carotid stenosis; abdominal aortic aneurysm; chronic limb-threatening ischemia; amputation; deep venous thrombosis
Online: 16 June 2022 (04:40:54 CEST)
Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study conducted through cross-sectional survey. Each received a 13-point questionnaire, investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs 2019 (9161 patients): post-EVAR surveillance, treatment for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased [1484 (16.2%) vs 1014 (14.3%), p=0.0009; 1401 (15.29%) vs 959 (13.52%), p=0.0006; and 1558 (17.01%) vs 934 (13.17%), p<0.0001, respectively]; while revascularization or major amputations for chronic limb-threatening ischemia, and urgent revascularization for symptomatic carotid stenosis significantly increased [1204 (16.98%) vs 1245 (13.59%), p<0.0001; 355 (5.01%) vs 358 (3.91%), p=0.0007; and 153 (2.16%) vs 140 (1.53%), p=0.0009, respectively]. Conclusions: The suspension of elective activities during the COVID-19 pandemic caused a significant reduction in asymptomatic carotid stenosis revascularization, treatment for Rutherford 3 peripheral arterial disease, post-EVAR surveillance. Contestually, we observed a significant increase in urgent revascularization for symptomatic carotid stenosis, and revascularization or major amputations for chronic limb-threatening ischemia.
Thu, 7 April 2022
ARTICLE | doi:10.20944/preprints202204.0058.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Digital reference object; Perivascular spaces; Spatio-temporal imaging artefacts; Perivascular space enhancement; Cerebral small vessel disease
Online: 7 April 2022 (11:27:03 CEST)
Growing interest surrounds the assessment of perivascular spaces (PVS) on magnetic resonance imaging (MRI) and their validation as a clinical biomarker of adverse brain health. Nonetheless, the limits of validity of current state-of-the-art segmentation methods is still unclear. Here, we propose an open-source computational model generating three-dimensional digital reference objects to evaluate enhancement performance in relation to PVS characteristics and spatiotemporal imaging considerations (including sampling, motion artefacts, and Rician noise). With it, we study the performance of the Frangi, Jerman and RORPO filters in enhancing PVS-like structures to facilitate segmentation. Our findings were three-fold. First, as long as voxels are isotropic, RORPO outperforms all other filters, regardless of imaging quality. Unlike the Frangi and Jerman filters, RORPO’s performance does not deteriorate as PVS volume increases. Second, the performance of all “vesselness” enhancement filters is heavily influenced by imaging quality, with sampling and motion artefacts being the most damaging for these types of analyses. Third, none of the filters can distinguish PVS from other hyperintense structures (e.g. white matter hyperintensities, stroke lesions, or lacunes) effectively, the area under the precision-recall curve dropped substantially (Frangi: from 94.21 [IQR 91.60, 96.16] to 43.76 [IQR 25.19, 63.38]; Jerman: from 94.51 [IQR 91.90, 95.37] to 58.00 [IQR 35.68, 64.87]; RORPO: from 98.72 [IQR 95.37, 98.96] to 71.87 [IQR 57.21, 76.63] without and with other hyperintense structures, respectively). The use of our computational model enables comparing segmentation methods and identifying their advantages and disadvantages, thereby providing means for testing and optimising pipelines for ongoing and future studies.
Fri, 14 January 2022
REVIEW | doi:10.20944/preprints202201.0208.v1
Subject: Medicine And Pharmacology, Hematology Keywords: End of Life; Advance Directives; Advance Care Planning; Intensive Care, Medical Oncology; malignant hemopathy
Online: 14 January 2022 (11:34:51 CET)
Patients living with cancer often experience serious adverse events due to their condition or its treatments. Those events may lead to a critical care unit admission or even result in death. One of the most important but challenging part of care is to build a caring plan according to the patient’s wishes, meeting his goals and values. Advance directives (ADs) allow everyone to give their preferences in advance regarding life sustaining treatments, continuation, and withdrawal or withholding of treatments in case one is not able to speak his mind anymore. While the absence of ADs is associated with a greater probability of receiving unwanted intensive care around the end of his life, their existence correlates with the respect of the patient’s desires and his greater satisfaction. Although progress has been made to promote ADs’ completion, they are still scarcely used among cancer patients in many countries. Several limitations to their acceptation and use can be detected. Efforts should be made to provide tailored solutions for the identified hindrances. This narrative review aims to depict the situation of ADs in the oncology context, and to highlight the future areas of improvement.
Tue, 11 January 2022
ARTICLE | doi:10.20944/preprints202112.0207.v2
Subject: Medicine And Pharmacology, Hematology Keywords: Hematological parameters; biochemical parameters; reference ranges; sickle cell disease; Tanzania; steady-state.
Online: 11 January 2022 (12:54:23 CET)
Hematological and biochemical reference values in sickle cell disease (SCD) are crucial for patient management and evaluation of interventions. This study was conducted at Muhimbili National Hospital (MNH) in Dar es Salaam, to establish laboratory reference ranges in SCD at steady-state. Patients were grouped into five age groups with respects to their sex. Aggregate functions were used to handle repeated measures within the indi-vidual level in each age group. A nonparametric approach was used to smooth the curves and a parametric approach was used to determine SCD normal ranges. Comparison between males and females and against the general population was documented. Data from 4,422 patients collected from 2004-2015 were analyzed. The majority of the patients (35.41%) were children aged between 5-11 years. There were no significant differences (p≥0.05) in mean corpuscular hemoglobin concentration (MCHC), lymphocytes, basophils and bilirubin direct observed between males and females. Significant differences (p<0.05) were observed in all selected parameters across age groups except neutrophils and MCHC in adults, as well as platelets and alkaline phosphatase in infants when SCD estimates were compared to the general population. Laboratory reference ranges in SCD at steady-state were different from those of the general population and varied with sex and age. The established reference ranges for SCD at steady-state will be a helpful in the management and monitoring of the progress of SCD.
Mon, 13 December 2021
ARTICLE | doi:10.20944/preprints202112.0207.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Hematological parameters; biochemical parameters; reference ranges; sickle cell disease; Tanzania; steady-state.
Online: 13 December 2021 (13:33:11 CET)
Hematological and biochemical reference values in sickle cell disease (SCD) are crucial for patient management and evaluation of interventions. This study was conducted at Mu-himbili National Hospital (MNH) in Dar es Salaam, to establish laboratory reference ranges in SCD at steady-state. Patients were grouped into five age groups with respects to their sex. Aggregate functions were used to handle repeated measures within the indi-vidual level in each age group. A nonparametric approach was used to smooth the curves and a parametric approach was used to determine SCD normal ranges. Comparison between males and females and against the general population was documented. Data from 4,422 patients collected from 2004-2015 were analyzed. The majority of the patients (35.41%) were children aged between 5-11 years. There were no significant differences (p≥0.05) in mean corpuscular hemoglobin concentration (MCHC), lymphocytes, basophils and bilirubin direct observed between males and females. Significant differences (p<0.05) were observed in all selected parameters across age groups except neutrophils and MCHC in adults, as well as platelets and alkaline phosphatase in infants when SCD estimates were compared to the general population. Laboratory reference ranges in SCD at steady-state were different from those of the general population and varied with sex and age. The established reference ranges for SCD at steady-state will be a helpful in the management and monitoring of the progress of SCD.
Tue, 30 November 2021
ARTICLE | doi:10.20944/preprints202111.0578.v1
Subject: Medicine And Pharmacology, Hematology Keywords: DPI; Mitochondria; Leukaemia; Oxidative stress; OxPhos; Ara-C
Online: 30 November 2021 (21:37:18 CET)
Acute myeloid leukaemia (AML) is characterized by the accumulation of undifferentiated blast cells in the bone marrow and blood. In most AMLs, relapse frequently occurs due to resistance to chemotherapy. Compelling research results indicate that drug resistance in cancer cells is highly dependent on the intracellular levels of reactive oxygen species (ROS). Modulating ROS levels is therefore a valuable strategy to overcome the chemotherapy resistance of leukemic cells. In this study, we evaluated the efficiency of diphenyleneiodonium (DPI), a well-known inhibitor of ROS production, in targeting AML cells. Results showed that although inhibiting cytoplasmic ROS production, DPI triggered an increase in the mitochondrial ROS levels caused by the disruption of the mitochondrial respiratory chain. We also demonstrated that DPI blocks the mitochondrial oxidative respiration (OxPhos) in a dose-dependent manner and that AML cells with high OxPhos status were highly sensitive to treatment with DPI, which synergizes with the chemotherapeutic agent cytarabine (Ara-C). Thus, our results suggest that targeting mitochondrial function by DPI might be exploited to target AML cells with high OxPhos status.
Tue, 23 November 2021
ARTICLE | doi:10.20944/preprints202111.0438.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Systemic Sclerosis; Raynaud’s phenomenon; ultrasound; microvascular imaging; blood flow
Online: 23 November 2021 (16:15:51 CET)
Systemic sclerosis is an autoimmune disease characterized by organ fibrosis and vasculopathy. Almost all patients suffer from Raynaud’s phenomenon (RP). Currently, several imaging techniques are available; nailfold video capillaroscopy (NVC) is the most widely available, but flow quantification is not possible with NVC. Novel imaging techniques are of interest in this population. We performed a single-center feasibility study using Micro Vascular Imaging (MVI) as a novel imaging technique for flow quantification of small fingertip vessels. We compared a group of 20 healthy controls (HCs) with 20 Systemic Sclerosis (SSc) patients. In HCs, flow measurements assessed with MVI were statistically significantly higher in individual fingers and combined for all fingers (p<0.0001). As a cut-off value to discriminate HCs from SSc, a peak systolic (PS) flow velocity of <6.9 cm/s and an end-diastolic (ED) flow velocity of <2.68 cm/s was determined. Test characteristics for PS flow velocity showed moderate sensitivity (0.69, 95% CI 0.58-0.78) but high specificity (0.88, 95% CI 0.79-0.93). Similar test characteristics for ED flow velocity were obtained. The optimal cut-off point was estimated at <2.68 cm/s, sensitivity was moderate (0.65, 95% CI 0.53-0.75), specificity was 0.80 (95% CI 0.70-0.87). Here, we present the first study on the use of MVI to assess blood flow in the fingertips with high specificity in SSc patients. Future studies need to investigate correlations with the risk for organ complications, such as digital ulcers or pulmonary arterial hypertension.
Thu, 18 November 2021
ARTICLE | doi:10.20944/preprints202111.0320.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Arteriogenesis; Arterial structure; extracellular matrix; peripheral arterial disease; collateral circulation
Online: 18 November 2021 (10:59:12 CET)
When a large artery becomes occluded, hemodynamic changes stimulate remodeling of arterial networks to form collateral arteries in a process termed arteriogenesis. However, the structural changes necessary for collateral remodeling have not been defined. We hypothesize that decon-struction of the extracellular matrix is essential to the remodeling of smaller arteries into effective collaterals. Using multiphoton microscopy, we analyzed collagen and elastin structure in maturing collateral arteries isolated from ischemic rat hindlimbs. Collateral arteries harvested at different timepoints showed progressive diameter expansion associated with striking rearrangement of in-ternal elastic lamina (IEL) into a loose fibrous mesh, a pattern persisting at 8 weeks. Despite a 2.5-fold increase in luminal diameter, total elastin content remained unchanged in collaterals compared with control arteries. Among the collateral midzones, baseline elastic fiber content is low. Outward remodeling of these vessels with a 10-20 fold diameter increase was associated with fractures of the elastic fibers and evidence of increased wall tension as demonstrated by straight-ening of the adventitial collagen. Inhibition of lysyl oxidase (LOX) function with β-aminopropionitrile resulted in severe fragmentation or complete loss of continuity of the IEL in developing collaterals. Collateral artery development is associated with permanent redistribution of existing elastic fibers to accommodate diameter growth. We found no evidence of new elastic fiber formation. Stabilization of the arterial wall during outward remodeling is necessary and dependent on LOX activity.
Wed, 27 October 2021
ARTICLE | doi:10.20944/preprints202110.0404.v1
Subject: Medicine And Pharmacology, Hematology Keywords: pathogen reduction; blood safety; platelet transfusion; INTERCEPT; plasma
Online: 27 October 2021 (12:27:33 CEST)
(1) Background: We reviewed the logistics of the implementation of pathogen inactivation (PI) using the INTERCEPT Blood System™ for platelets and the experience with routine use and clinical outcomes in the patient population at the Sírio-Libanês Hospital of São Paulo, Brazil. (2) Methods: Platelet concentrate (PC), including pathogen reduced (PR-PC) production, inventory management, discard rates, blood utilization, and clinical outcomes were analyzed over the 40 months before and after PI implementation. Age distribution and wastage rates were compared over the 10 months before and after approval for PR-PC to be stored for up to 7 days. (3) Results: A 100% PR-PC inventory was achieved by increasing double apheresis collections and production of double doses using pools of two single apheresis units. Discard rates decreased from 6% to 3% after PI implementation and further decreased to 1.2% after 7-day storage extension for PR-PCs. The blood utilization remained stable, with no increase in component utilization. A significant decrease in adverse transfusion events was observed after the PI implementation. (4) Conclusion: Our experience demonstrates the feasibility for Brazilian blood centers to achieve a 100% PR-PC inventory. All patients at our hospital received PR-PC and showed no increase in blood component utilization and decreased rates of adverse transfusion reactions.
Thu, 14 October 2021
REVIEW | doi:10.20944/preprints202108.0448.v2
Subject: Medicine And Pharmacology, Hematology Keywords: stroke; cellular senescence; coagulation; adhesion
Online: 14 October 2021 (15:21:58 CEST)
The most important predictors for outcomes after ischemic stroke, that is, for health deterioration and death, are chronological age and stroke severity; gender, genetics and lifestyle / environmental factors also play a role. Of all these, only the latter can be influenced after the event, even though recurrent stroke may be prevented by antiaggregant/anticoagulant therapy, angioplasty of high-grade stenoses, and treatment of cardiovascular risk factors. Moreover, blood cell composition and protein biomarkers such as C-reactive protein or interleukins in serum are frequently considered as biomarkers of outcome. We surveyed protein biomarkers that were reported to be predictive for outcome after ischemic stroke, specifically considering biomarkers that predict long-term outcome (≥3 months) and that are measured over the first days following the event. We classified the protein biomarkers as immune‑inflammatory, coagulation-related, and adhesion-related biomarkers. Some of these biomarkers are closely related to cellular senescence and, in particular, to the inflammatory processes that can be triggered by senescent cells. Moreover, the processes that underlie inflammation, hypercoagulation and cellular senescence connect stroke to cancer, and biomarkers of cancer-associated thromboembolism, as well as of sarcopenia, overlap strongly with the biomarkers discussed here. Finally, we demonstrate that most of the outcome-predicting protein biomarkers form a close-meshed functional interaction network, suggesting that the outcome after stroke is partially determined by an interplay of molecular processes relating to inflammation, coagulation, cell adhesion and cellular senescence.
Tue, 7 September 2021
REVIEW | doi:10.20944/preprints202109.0127.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Zingiber officinale; 6-Shogaol; 6-gingerol; hematopoiesis; hepcidin; anaemia
Online: 7 September 2021 (12:08:59 CEST)
Myelodysplastic syndrome (MDS) evolves due to genomic instability, dysregulated signalling pathway and overproduction of inflammatory markers. Reactive oxygen species contribute to the inflammatory response, which causes gene damage, cellular remodelling and fibrosis. MDS can be a debilitating condition, and management options in patients with MDS aim to improve cytopenias, delay disease progression, and enhance quality of life. High serum ferritin levels, a source of iron for reactive oxygen species production, correlate with a higher risk of progression to acute myeloid leukaemia, and iron overload is compounded by blood transfusions given to improve anaemia. 6-shogaol is a natural phenolic compound formed when ginger is exposed to heat and/or acidic conditions, and it has been shown to possess anti-tumour activity against leukaemia cell lines and antioxidant effects. This narrative review assessed the potential benefits of this phytochemical in lower-risk MDS patients through examining the current evidence on the pharmacological and therapeutic properties of ginger and 6-shogaol.
Mon, 23 August 2021
REVIEW | doi:10.20944/preprints202108.0448.v1
Subject: Medicine And Pharmacology, Hematology Keywords: stroke; cellular senescence; coagulation; adhesion
Online: 23 August 2021 (14:01:30 CEST)
The most important predictors for outcomes after ischemic stroke, that is, for health deterioration and death, are chronological age and stroke severity; gender, genetics and environmental factors also play a role. Of all these, only the latter can be influenced after the event, even though recurrent stroke may be prevented by antiaggregant/anticoagulant therapy, angioplasty of high-grade stenoses, and treatment of cardiovascular risk factors. Moreover, blood cell composition and protein biomarkers such as C-reactive protein or interleukins in serum/plasma are frequently considered as biomarkers of outcome, and they are connected to underlying molecular mechanisms such as inflammation, hypercoagulation, and cellular senescence. We surveyed protein biomarkers that were reported to be predictive for outcome after ischemic stroke, specifically considering biomarkers that predict long-term outcome (≥3 months) and that are measured over the first days following the event. We classified the protein biomarkers as immune‑inflammatory, coagulation-related, and adhesion-related biomarkers. Some of these biomarkers are closely related to cellular senescence and, in particular, to the inflammatory processes that can be triggered by senescent cells. Moreover, the processes that underlie inflammation, hypercoagulation and cellular senescence connect stroke to cancer, and biomarkers of cancer-associated thromboembolism, as well as of sarcopenia, overlap strongly with the biomarkers discussed here. Finally, we demonstrate that many of the outcome-predicting protein biomarkers form a close-meshed functional interaction network, suggesting that the outcome after stroke is partially determined by an interplay of the molecular processes relating to inflammation, coagulation, cell adhesion and cellular senescence.
Thu, 8 July 2021
REVIEW | doi:10.20944/preprints202107.0203.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Polymorphism; genes; phase-II metabolism; glutathione; clopidogrel resistance
Online: 8 July 2021 (13:30:31 CEST)
Clopidogrel is one of the thienopyridine antiplatelet drugs commonly used as a prophylactic medication to prevent coagulation in vessels and cardiovascular events. The molecule of clopidogrel is metabolized in the liver via phase-I and phase-II metabolism pathways. The sulfenic acid clopidogrel metabolite undergoes phase-II metabolism through conjugation with glutathione by the glutathione-s-transferase (GST) to form a glutathione conjugate of clopidogrel (inactive metabolite). A glutaredoxin enzyme removes the glutathione conjugated with clopidogrel to form cis-thiol-clopidogrel. This review focused on the polymorphisms of genes related to phase-II metabolism during the clopidogrel bioactivation process. Overall, no well-controlled studies were done about the relationship between the clopidogrel bioactivation process and genes related to phase-II metabolism’s enzymes. Nevertheless, some polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK, and GLRX genes could be responsible for clopidogrel resistance due to low glutathione conjugate or glutaredoxin plasma levels. Studies needed to be concerned with the relationship between clopidogrel resistance and phase-II metabolism issues in the near future.
Mon, 14 September 2020
ARTICLE | doi:10.20944/preprints202009.0322.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Hemophilia A; Prophylaxis; Factor VIII; Platelets; Microvesicles; Calcium
Online: 14 September 2020 (16:12:08 CEST)
Aim: In the present work we have studied the role of platelets and microvesicles in patients with severe hemophilia A (HA) treated under the regimen of prophylaxis. We have analyzed whether the administration of coagulation factor FVIII modifies this hemorrhagic phenotype in a cohort of 16 patients with diagnosis of severe HA, who were on prophylactic treatment with recombinant FVIII. Methods: Blood tests were performed before (72h without FVIII, baseline sample) and after 15 minutes of FVIII infusion. As a control group, 15 healthy subjects were studied. Platelet aggregation was determined by closure time, optical aggregation, impedance aggregation and flow cytometry. We also studied the expression of the platelet activation markers P-selectin, CD63, platelet-tissue factor, formation of platelet-leukocyte aggregates and tissue factor exposure. The total number of platelet and endothelial microvesicles were also analyzed by flow cytometry, as well as platelet cytosolic Ca2+ mobilization. Results: We found no significant differences in platelet function in patients with severe HA in prophylactic treatment before and after FVIII infusion. After FVIII administration, patients presented fewer endothelial microvesicles, indicating that the treatment does not increase one of the possible thrombotic risk markers of these patients. The total amount of plasma microvesicles and the platelet microvesicles were decreased in patients with HA compared to the control group. Conclusions: Our results do not support any effect of FVIII on platelet function in patients with severe HA treated under the regime of prophylaxis.
Sun, 21 June 2020
ARTICLE | doi:10.20944/preprints202006.0275.v1
Subject: Medicine And Pharmacology, Hematology Keywords: SARS-CoV-2; COVID-19; real-time RT-PCR; COVID-19 symptoms; COVID-19 hematological findings; Bangladesh
Online: 21 June 2020 (14:47:03 CEST)
Objective: SARS-Cov-2 infection or COVID-19 is a global pandemic. From the time of identification to till, multiple clinical symptoms and parameters have been identified by the researchers of various countries and regions regarding the diagnosis and presentations of COVID-19 disease. In this manuscript, we investigated the primary symptoms and basic hematological presentations of SARS-CoV-2 infection among the Bangladeshi patients. Methodology: We have collected the disease history of mild to moderate degree of COVID-19 patients; hematological and biochemical on admission reports of moderate degree COVID-19 patients. All of them were tested positive for SARS-CoV-2 by RT-PCR in different institutes in Bangladesh. Results: According to this study though COVID-19 patients in Bangladesh commonly presented with fever, cough, fatigue, shortness of breath, and sore throat, but symptoms like myalgia, diarrhea, skin rash, headache, Abdominal pain/cramp, nausea, vomiting, restlessness, and a higher temperature of >1000F have a greater presentation rate and more frequent than other published studies. CRP and Prothrombin time was found to increase in all the patients. Serum ferritin, ESR, SGPT, and D-Dimer were found increased among 53.85%, 80.43, 44%, and 25% patients respectively. 17.39% of the patients had leukocytosis and neutrophilia. 28.26% of patients presented with lymphocytopenia. 62.52% of patients had mild erythrocytopenia. Conclusion: Despite some similarities, our study has evaluated a different expression in presenting symptoms in the case of COVID-19 patients in Bangladesh. CRP, Prothrombin time, serum ferritin, ESR, SGPT, D-Dimer, erythrocytopenia, and lymphocytopenia can be initial diagnostic hematological findings and assessment for prognosis COVID-19 disease. Also, gender variations have a different scenario of clinical and laboratory appearance in this region.
Sun, 7 June 2020
REVIEW | doi:10.20944/preprints202006.0062.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Covid19; DIC; coagulopathy; Sars Covid; blood coagulation disorder
Online: 7 June 2020 (07:41:24 CEST)
COVID-19 induces coagulopathy at the base of SIC (sepsis-induced coagulopathy) and it is an important cause of death in the patients. Cytokine storm causes imbalance in coagulation and fibrinolytic system. A combination of hypercoagulability state, decrease or inhibition of fibrinolytic and endothelialopathy causes thromboembolic events. Underlined disease with a high rate of mortality in COVID-19 like diabetes, hypertension and some conditions like aging and obesity are the main disorders with hemostatic disturbance and increase of coagulopathy. Therefore, it seems that the combination of COVID-19 infection and these risk factors increase the risk of thromboembolic all together.
Tue, 2 June 2020
ARTICLE | doi:10.20944/preprints202006.0001.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Copper; transfusion-dependent thalassemia; zinc; oxidative stress; antioxidants; biomarkers
Online: 2 June 2020 (09:21:13 CEST)
Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.Aim of the study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. Methods: This study recruited 60 children with TDT and 30 healthy children aged 3-12 years old.Results: Zinc was significantly higher in TDT children than in control children, whilst copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.
Sat, 29 February 2020
ARTICLE | doi:10.20944/preprints202002.0454.v1
Subject: Medicine And Pharmacology, Hematology Keywords: ABO blood groups; antigen; allele frequency; phenotype
Online: 29 February 2020 (08:26:18 CET)
Approximately 300 different types of blood groups are identified so far, the ABO and Rh antigens are still the clinically most significant and genetically most polymorphic of all human blood group systems to date. A total of 200 unrelated individuals from Uttar Pradesh were studied for the phenotype and allele frequency distribution of ABO and Rh (D) blood groups. In total 200 samples analyzed, phenotype B blood type has the highest frequency 36.5% (n=73), followed by O (34.5%; n=69), A (20.5%; n=41) and AB (8.5%; n=17). The O, A and B frequencies were 0.5849, 0.1571 and 0.2580 respectively. The overall phenotypic frequencies of ABO blood groups were B>O>A>AB. The variation in phenotypic frequencies between male and female might be due to small sample size of male sample. The allelic frequency of Rh-negative was 0.2.
Mon, 20 January 2020
Subject: Medicine And Pharmacology, Hematology Keywords: inherited platelet disorders; hereditary thrombocytopenias; blood smear; immunofluorescence; bleeding tendency
Online: 20 January 2020 (09:50:59 CET)
Inherited platelet disorders (IPDs) are rare diseases featured by low platelet count and/or defective platelet function. Patients have variable bleeding diathesis and sometimes additional features that can be congenital or acquired. Identification of an IPD is desirable to avoid misdiagnosis of immune thrombocytopenia and use of improper treatments. Diagnostic tools include platelet function studies and genetic testing. The latter can be challenging as the correlation of its outcomes with phenotype is not easy. The immune-morphological evaluation of blood smear (by light- and immunofluorescence microscopy) represents a reliable method to phenotype subjects with suspected IPD. It is relatively cheap, not excessively time-consuming, and applicable to shipped samples. In some forms, it can provide diagnosis by itself, as for MYH9-RD, or in addition to other first-line tests as aggregometry or flow cytometry. In regard to genetic testing, it can guide specific sequencing. Since only minimal amounts of blood are needed for preparation of blood smears, it can be used to further characterize thrombocytopenia in pediatric patients and even newborns. In principle it is based on visualizing alterations in the distribution of proteins, which result from specific genetic mutations, by using monoclonal antibodies. It can be applied to identify deficiencies in membrane proteins, disturbed distribution of cytoskeletal proteins, and alpha as well as delta granules. On the other hand mutations associated with impaired signal transduction are difficult to identify by immunofluorescence of blood smears. This review summarizes technical aspects and the main diagnostic patterns achievable by this method.
Fri, 25 October 2019
ARTICLE | doi:10.20944/preprints201910.0283.v1
Subject: Medicine And Pharmacology, Hematology Keywords: chronic inflammation; biomarker panels; leukocyte count; C-reactive protein; related syndromes and pathologies; risk assessment; screening programmes; ageing; elderly's health
Online: 25 October 2019 (04:16:43 CEST)
C-reactive protein (CRP) and leukocytes are blood biomarkers involved in "Inflamm-Aging", which is a risk factor for the onset and progression of age-related diseases. Studies show that higher serum concentrations of these biomarkers are associated with functional disability, increased risk of low muscle strength, decreased muscle mass and mortality in the elderly. The objective was to estimate the predictive power and discriminating criteria of C-reactive protein and leukocyte concentrations for the risk of adverse health factors in the elderly within 30 days after hospital discharge (HD). Prospective cohort study using exploratory methods and blood biomarkers with 135 older adults admitted to medical and surgical clinics at a government hospital. The elderly were monitored at home after 30 days of HD for adverse health factors (rehospitalization, falls, amount of medication consumed, disability in basic and instrumental activities of daily living and mortality). CRP> 2.4; ≥ 0.7 and> 24.7 mg / dL and leukocytes ≥ 6.410; ≥ 8.690 and> 8.310 mm³ were discriminant for rehospitalization, falls and mortality within 30 days after HD, respectively. The cut-off points described may be used as a reference in the screening of hospitalized elderly vulnerable to adverse health events after hospital discharge.
Tue, 20 August 2019
REVIEW | doi:10.20944/preprints201908.0199.v1
Subject: Medicine And Pharmacology, Hematology Keywords: polychlorinated dibenzo-p-dioxins (PCDDs); polychlorinated dibenzo-p-furans (PCDFs); human exposure; blood samples; dietary intake; risks
Online: 20 August 2019 (04:20:00 CEST)
Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) are environmental pollutants with a great persistence, capacity of bioaccumulation, and well known important toxic effects in humans and animals. Incinerators of hazardous, municipal and medical waste, chlorine bleaching of paper pulp, cement plants, and the traffic of motor vehicles are the most frequent emission sources of these compounds. The diet, followed at a great distance by inhalation, is generally the main way of human exposure to PCDD/Fs. Human biomonitoring is of a great importance to prevent potential adverse effects derived from exposure to chemicals such as PCDD/Fs. In relation to this, blood is among the most used biological monitors. In the current review, we have summarized the recent information (2000-2009) published in the scientific literature (databases: Scopus and PubMed) on the concentrations of PCDD/Fs in blood samples of non-occupationally exposed populations, as well as in some groups of occupationally exposed individuals. We have revised a number of studies conducted in various African American, Asian and European countries, and Australia. Unfortunately, the information is quite limited. No data are available for most countries over the world. Based on the results here reviewed –where available- the current health risks for the general populations do not seem to be of concern. Moreover, taking into account the important reductions observed in the levels of PCDD/Fs in foodstuffs, new decreases in the concentrations of PCDD/Fs in blood -and other biological tissues- are very probable in the immediate years.
Fri, 21 September 2018
REVIEW | doi:10.20944/preprints201809.0435.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Acute Myeloid Leukemia; FLT3; Tyrosine kinase inhibitors; resistance
Online: 21 September 2018 (10:28:34 CEST)
Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.
Mon, 23 July 2018
ARTICLE | doi:10.20944/preprints201807.0422.v1
Subject: Medicine And Pharmacology, Hematology Keywords: iron deficiency anemia; obestatin; ghrelin
Online: 23 July 2018 (12:34:21 CEST)
Ghrelin and obestatin, two antagonist peptide hormones, are purportedly involved in stimulating appetite and controlling energy balance in humans. Serum ghrelin level is also associated with iron deficiency anemia (IDA), but no study has yet been made of the obestatin level in patients with IDA, even though both hormones are a single gene product. Therefore, the purpose of this investigation is to see whether there is a link between IDA and these two hormones among other hematological parameters in patients with IDA. To measure ghrelin and obestatin, human saliva and serum were collected from 30 women with IDA, aged 31.7 ± 10.7 years, and 30 control women, aged 30.2 ± 8.0 years, with repeated collection of samples over a period of 1 week and 1 month. Saliva and serum ghrelin levels were measured by ELISA. Serum hemoglobin, ferritin, hematocrit and total iron-binding capacity (TIBC) values were determined with an Olympus AU2700. Saliva and serum ghrelin and obestatin levels were significantly lower in the IDA group compared with controls; these levels increased slightly above baseline with iron treatment, but remained below the control values. Furthermore, and as expected, serum hemoglobin, ferritin, and hematocrit levels were significantly increased with iron treatment, while total iron-binding capacity decreased compared to baseline concentrations. The findings suggest that IDA might be linked to imbalance of circulating (serum) and non-circulating (saliva) ghrelin and obestatin levels. Decreased ghrelin and obestatin might destroy iron homeostasis through its effect on intestinal absorption. Measuring these hormone levels might be useful for monitoring the response to iron treatment. Also, serum and saliva levels for both hormones were well correlated. Thus, using saliva in place of serum for monitoring the two hormones should minimize inconvenience and patient discomfort.
Thu, 21 September 2017
ARTICLE | doi:10.20944/preprints201709.0100.v1
Subject: Medicine And Pharmacology, Hematology Keywords: alpha; thalassemia; deletional; cut-off; number of genes; microcytic anemia; differential diagnosis
Online: 21 September 2017 (04:47:16 CEST)
Most of α-thalassemia cases are caused by deletions of the structural α-globin genes. The degree of microcytosis and hypochromia has been correlated with the number of affected α-globin genes, suggesting a promising role of hematologic parameters as predictive diagnostic tools. However, specific cut-off points for these parameters to discriminate between the different subtypes of α-thalassemia remain to be clearly defined. Six hematologic parameters (total number of erythrocytes, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and red cell distribution width) were evaluated in 174 cases of deletional α-thalassemia (92 heterozygous α+ thalassemia, 39 homozygous α+ thalassemia, 34 heterozygous α0 thalassemia and 9 cases of Hb H disease). A good correlation between the number of deleted alpha genes and MCV (r = -0.672, p<0.001), MCH (r = -0.788, p<0.001) and RDW (r = 0.633, p<0.001) was observed. The deletion of at least two alpha genes in adult individuals with microcytosis without iron deficiency and normal values of Hb A2 and Hb F should be discarded when MCH levels are lower than 23.15 pg. Furthermore, MCH <21.90 pg and/or MCV <70.80 fL are strongly suggestive of the presence of one α0 allele. Finally, an accurate presumptive diagnosis of Hb H disease can be made if both RDW ≥20% and MCH <18.45 pg are seen.
Thu, 4 May 2017
ARTICLE | doi:10.20944/preprints201705.0037.v1
Subject: Medicine And Pharmacology, Hematology Keywords: autologous; buffy coat; growth factor level; platelet-rich fibrin; thrombocyte concentrate
Online: 4 May 2017 (08:37:59 CEST)
Fibrin rich of platelets (PRF®) of Choukroun represents a new step in the therapeutic concept of platelet gel with a simplified processing and biochemical changes little artificial. A valid method of preparation of the PRF must effectively separate the plates by erythrocytes and concentrate without damaging or lysing the plates themselves. In this study the experimental design is to standardize the production of L-PRF in horse directing it to human production. Our hypothesis is that the L-PRF is easy to produce in the horse, without modifications of the human protocol, thus allowing a better standardization of the human protocol. A new device for the preparation and the standardization of L-PRF clots and membranes is the L-PRF Wound Box®. The optical microscopy, most cell bodies were highlighted concentrated in the proximal portion of each membrane, the last 1/4 was observed at the center; the distal part had only residual traces of cell bodies. The L-PRF will form constantly when the phases described above are strictly adhered to. The success of the art L-PRF depends entirely on the speed of blood collection and transfer in centrifuge within a minute and by a temperature of centrifugation and compression is higher than 21°C (between 21 and 30°C). Our experiments on the horse will no doubt be able to improve our understanding on wound healing, in particularly in chronic skin lesions therapy.
Tue, 4 October 2016
ARTICLE | doi:10.20944/preprints201610.0005.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Landfill, Waste, Socio-environmental impact, Hematologic diseases
Online: 4 October 2016 (09:03:17 CEST)
We are experiencing an unprecedented urbanization process that alongside with physical, social and economic developments is having a significant impact on population’s health. Due to higher apprehensions of pollution, violence and poverty, our modern cities no longer ensure a good quality of life so they become unhealthy environments. This study aims to measure the socio-environmental and hematologic profile of residents of Santo André’s landfill – “Bairro Espírito Santo” by using the contextualization of the studied area. The research method is Observational type and from Retrospective cohort and by convenience sampling in Santo André in the Greater ABC region. The study determined a socio environmental profile and the hematologic diseases screening related to a close location to the landfill. The disease manifests itself within a broad spectrum of symptoms that causes changes in blood count parameters. The full blood counts analysis was performed, indicating that the blood counts of residents living near the landfill led to positive hematological changes and diseases like Leukopenia, Anemia, Neutropenia and lymphocytosis were the most common changes. However it is considered that the proof of the relation of cause- effect to environmental exposures that may trigger chronic manifestations in humans requires specific studies that are often complicated.