Total Hemoglobin Research Articles

Combination of Remimazolam, Remifentanil Anesthesia, and Enteral Nutrition Support Restores Vital Signs and Nutritional Status of Patients Undergoing Intravascular Interventional Therapy for Intracranial Aneurysms

Ninety-eight patients from our hospital were included in the study from March 2022 to March 2023. The patients were divided into two groups: 49 patients received propofol + remifentanil in the control group and 49 patients received remimazolam + remifentanil in the observation group. Postoperatively, the control group accepted parenteral nutrition support, while the observation group accepted enteral nutrition support. The observation group experienced a longer duration of consciousness loss but shorter times for consciousness recovery and trachea extubation than the control group. Although both groups experienced elevated mean blood pressure, heart rate, norepinephrine, angiotensin II, and plasma cortisol levels during tracheal intubation and extraction, the observation group showed differences compared to the control group. No statistical significance was discovered in the incidence of postoperative adverse reactions between the two groups (P = 0.29). Furthermore, tumor necrosis factor-α and interleukin-6 levels were lower in the observation group than in the control group, while total protein, albumin, and hemoglobin levels were higher. Overall, remimazolam combined with remifentanil demonstrated superiority over propofol combined with remifentanil in the perioperative period for patients undergoing intravascular interventional therapy for intracranial aneurysms.

Effects of dietary Andrographis paniculata extract on growth, haematological, immune responses, immune-related genes expression of ornamental goldfish (Carassius auratus) and its susceptibility to Aeromonas hydrophila infection

In the present study, goldfish (Carassius auratus) were fed diets supplemented with different levels of methanolic crude extracts of Andrographis paniculata to assess their efficacy against Aeromonas hydrophila. The A. paniculata extract showed antibacterial activity against A. hydrophila at different concentrations and was characterised by FTIR and GC-MS analysis. The fishes (C. auratus) were divided into three groups, the control fishes were fed with a basel diet, the DI and DII group fishes were fed with a basel diet mixed with 0.1% and 1% of methanolic crude extracts of A. paniculata, respectively for 4 weeks. Then, haematological and immunological parameters were examined in each experimental and control group after the 2nd and 4th week. Finally, all group fish were challenged with A. hydrophila at the end of the 4th week, and their cytokine genes expression were investigated. The results showed that even at low concentrations (50 μg) of A. paniculata leaf extracts showed a potent antibacterial effect against A. hydrophila. GC-MS analysis revealed that the methanol precipitation contains Benzylamine, 2-hydroxy-N,N-DI-[2-aminoethyl]-, 18-Nonadecen-1-OL, and andrographolide. Similarly, FTIR analysis revealed aliphatic primary amine, conjugated ketone and alcohols, which are known antimicrobials. The extracts also changed the growth, haematological and immunological parameters of treated fishes by significantly increased the total RBC counts and haemoglobin level, along with the phagocytic, total immunoglobulin and myeloperoxidase activities when compared to the BD group. Moreover, fish fed with 1% of A. paniculata extract showed a higher survival rate (80%) against A. hydrophila. Furthermore, 1% of A. paniculata extract dietary was significantly up-regulated pro-anti-inflammatory cytokine gene expression, compared with the BD group. In conclusion, dietary A. paniculata extract supplementation beneficial for C. auratus, as it assesses their efficacy against A. hydrophila.

Rate of Cardiotoxicity in Childhood Acute Lymphoblastic Leukemia Treated with Daunorubicin Using Echocardiography and Troponin I

Background and Aim: Acute lymphoblastic leukemia (ALL) is the commonest malignancy in childhood. Childhood ALL Survivors have a lifelong increased risk for cardiovascular morbidity and mortality compared to the general population, mainly caused by chemotherapy with daunorubicin. The aim of the study is to detect the rate of daunorubicin induced cardiotoxicity in children with acute lymphoblastic leukemia during induction phase chemotherapy. Meterials & Methods : This prospective observational study was conducted in the department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU) on 40 newly diagnosed patients of ALL aged between 1 to17.9 years who got daunorubicin during induction. Complete blood count and echocardiography were done and troponin I was measured in all patients before and after completion of induction period. Result: Of the 40 patients, 8 patients (20%) had developed cardiotoxicity evidenced by reduction of left ventricular ejection fraction (LVEF) in echocardiography. Baseline LVEF was 68.80±5.98% which was then reduced to 65.32±7.07% after induction phase of chemotherapy (p=0.023). No significant alteration of troponin I was seen (P= 0.581) between baseline and after completion of induction. Total WBC count and hemoglobin had a significant difference (P<0.05) between baseline and after induction period. Male patients had a greater risk of developing cardiotoxicity than females but statistically was not significant (P=0.643). There was no significant association between age of the patients and cardiotoxicity (P=0.112).Cardiotoxicity was seen higher in patient with initial high WBC count (p=0.039). Echocardiography also reveled increased tendency of mitral regurgitation and left ventricular hypertrophy after induction phase chemotherapy. Conclusion: This study showed the rate of cardiotoxicity was 20% in ALL patients treated with daunorubicin. It also found that LVEF was decreased during therapy.Echocardiography can be used to detect early cardiotoxicity induced by daunorubicin. University Heart Journal 2023; 19(1): 20-25

Noninvasive hemoglobin monitoring for maintaining hemoglobin concentration within the target range during major noncardiac surgery: A randomized controlled trial

Study objectiveThe effect of noninvasive CO-oximetry hemoglobin (SpHb) monitoring on the clinical outcomes of patients undergoing surgery remains unclear. This trial aimed to evaluate whether SpHb monitoring helps maintain hemoglobin levels within a predefined target range during major noncardiac surgeries with a potential risk of intraoperative hemorrhage. DesignA single-center, prospective, randomized controlled trial. SettingUniversity hospital. PatientsOne hundred and thirty patients undergoing elective noncardiac surgery with a potential risk of hemorrhage. InterventionsPatients were randomly allocated to undergo either SpHb-guided management (SpHb group) or usual care (control group). MeasurementsThe primary outcome was the rate of deviation of the total hemoglobin concentration (determined from laboratory testing) from a pre-specified target range (8–14 g/dL). This was defined as the number of laboratory tests revealing such deviations divided by the total number of laboratory tests performed during the surgery. Main resultsThe primary outcome occurred significantly less frequently in the SpHb group as compared to that in the control group (15/555 [2.7%]) vs. 68/598 [11.4%]; relative risk, 0.24; 95% confidence interval, 0.13–0.41; P < 0.001). Fewer point-of-care blood tests were performed in the SpHb group than in the control group (median [interquartile range], 2 [1–4] vs. 4 [2–5]; P < 0.001). There were no significant intergroup differences in the number of patients who received red blood cell transfusions during surgery (SpHb vs. control, 33.8% vs. 46.2%; P = 0.201). The incidence of unnecessary red blood cell preparation (>2 units) was lower in the SpHb group than in the control group (3.1% vs. 16.9%; P = 0.024). ConclusionsCompared with routine care, SpHb-guided management resulted in significantly lower rates of hemoglobin deviation outside the target range intraoperatively in patients undergoing major noncardiac surgeries with a potential risk of hemorrhage. Clinical trial registrationClinicalTrials.gov (identifier: NCT03816514).

Positive Effect of Danhong Assisted by Information Motivation Behavioral-Based Progressive Rehabilitation Nursing on Nutritional Recovery of Patients with Coronary Heart Disease After Percutaneous Coronary Intervention

This study aimed to analyze the influence of Danhong injection, assisted by information-motivation-behavioral skills model-based progressive rehabilitation nursing, on the nutritional status of coronary heart disease patients after percutaneous coronary intervention. A total of 107 coronary heart disease patients were randomly divided into a control group and the research group, comprising 53 and 54 patients, respectively. The control group received routine nursing, while the research group underwent information-motivation-behavioral skills model-based progressive rehabilitation nursing for comparative analysis. We found that the cardiac function and exercise endurance of the research group were improved compared to the control group after nursing, and the hemodynamics was better (P &lt; 0.05). Moreover, although both groups’ average daily energy and protein intakes did not meet the target requirements, the research group exhibited better performance than the control group (P &lt; 0.05). Furthermore, elevated postoperative total protein, hemoglobin, and albumin levels were observed in the research group (P &lt; 0.05). Regarding dietary compliance, the research group exhibited higher compliance and a lower incidence of adverse reactions (P &lt; 0.05). These findings indicated that Danhong injection, assisted by information-motivation-behavioral skills model-based progressive rehabilitation nursing, effectively promotes the nutritional recovery of coronary heart disease patients following percutaneous coronary intervention, thereby enhancing the patient’s health and prognosis.

APS calculator: a data-driven tool for setting outcome-based analytical performance specifications for measurement uncertainty using specific clinical requirements and population data.

According to ISO 15189:2022, analytical performance specifications (APS) should relate to intended clinical use and impact on patient care. Therefore, we aimed to develop a web application for laboratory professionals to calculate APS based on a simulation of the impact of measurement uncertainty (MU) on the outcome using the chosen decision limits, agreement thresholds, and data of the population of interest. We developed the "APS Calculator" allowing users to upload and select data of concern, specify decision limits and agreement thresholds, and conduct simulations to determine APS for MU. The simulation involved categorizing original measurand concentrations, generating measured (simulated) results by introducing different degrees of MU, and recategorizing measured concentrations based on clinical decision limits and acceptable clinical misclassification rates. The agreements between original and simulated result categories were assessed, and values that met or exceeded user-specified agreement thresholds that set goals for the between-category agreement were considered acceptable. The application generates contour plots of agreement rates and corresponding MU values. We tested the application using National Health and Nutrition Examination Survey data, with decision limits from relevant guidelines. We determined APS for MU of six measurands (blood total hemoglobin, plasma fasting glucose, serum total and high-density lipoprotein cholesterol, triglycerides, and total folate) to demonstrate the potential of the application to generate APS. The developed data-driven web application offers a flexible tool for laboratory professionals to calculate APS for MU using their chosen decision limits and agreement thresholds, and the data of the population of interest.

Abstract 14659: Muscle Oxygenation Responses to Acute Exercise and Cellular Biomarkers of Vascular Health in Veterans With Chronic Kidney Disease

Introduction: Increased susceptibility of endothelial dysfunction and skeletal muscle impairments suggest peripheral limitations as an explanation for diminished aerobic capacity in chronic kidney disease (CKD) patients. However, data on peripheral limitations in CKD patients is limited. Hypothesis: We hypothesized CKD patients would experience reduced muscle oxygenation responses to acute exercise and cellular evidence of declines in vascular health compared to those without CKD. Methods: Sixteen male Veterans (CKD: n=9, age 74±6 yrs, eGFR, 41.7±10 mL/min/1.73 m 2 ; non-CKD controls (CON): n=7, age, 67±8 yrs, eGFR, 75±10.6 mL/min/1.73 m 2 ) completed treadmill cardiopulmonary exercise testing via the Modified Bruce protocol. Oxygenation responses were obtained from the medial gastrocnemius using near-infrared spectroscopy. Blood samples were collected at rest and analyzed for colony-forming units (CFU), flow-cytometry of mononuclear cells (MNCs) focusing on endothelial lineage cells and gene expression of MNCs. Effect sizes between groups were determined using Hedge’s g (g). Results: At peak exercise, oxygen consumption (VO 2peak 19±5 vs 25.8±5.2 ml/kg/min -1 , g=1.2), heart rate (HR peak 132±21 vs 160±9 bpm, g=1.6), oxygen extraction (Δ[HHb] 14.8±10.8 vs 24.9±6.8 a.u., g=1.0), and change in total hemoglobin concentration (Δ[tHb] 8.9±5.1 vs 22.5±12.8 a.u., g=1.4) were lower in CKD compared to CON. At an exercise intensity of 3.4 METs, Δ[HHb] and Δ[tHb] were 42% and 54% lower (8.0±7.8 vs 13.8±8.8 a.u., g=0.6 and 4.9±4.1 vs 10.7±4.5 a.u., g=1.2) in CKD vs CON, despite no differences in oxygen consumption or heart rate. CD34 + 184 expression was 47% lower in CKD vs CON (0.2±0.04 vs 0.38±0.48 %, g=0.5). CFU was significantly inversely correlated with body mass index and waist circumference (r=-0.67, p=0.034; r=-0.65, p=0.041). Conclusions: Preliminary data from this ongoing study suggest oxygen extraction and capillary blood volume expansion are impaired during exercise in CKD patients when compared to those without CKD. CD34 + 184 expression was lower in CKD patients versus those without CKD, indicating poor hematopoietic stem cell migratory function in the CKD group. In addition, an inverse association between CFU and body habitus was observed.

Differences in peripheral microcirculatory blood flow regulation in chronic kidney disease based on wavelet analysis of resting near-infrared spectroscopy

Vascular impairment is closely related to increased mortality in chronic kidney disease (CKD). The objective of this study was to assess impairments in the regulation of peripheral microvascular perfusion in patients with CKD based on time-frequency spectral analysis of resting near-infrared spectroscopy (NIRS) signals. Total hemoglobin (tHb) concentration and tissue saturation index (TSI) signals were collected using NIRS for a continuous 5 mins at 10 Hz from the forearm of 55 participants (34 CKD including 5 with end-stage renal disease, and 21 age-matched control). Continuous wavelet transform-based spectral analysis was used to quantify the spectral amplitude within five pre-defined frequency intervals (I, 0.0095–0.021 Hz; II, 0.021–0.052 Hz; III, 0.052–0.145 Hz; IV, 0.145–0.6 Hz and V, 0.6–2.0 Hz), representing endothelial, neurogenic, myogenic, respiratory and heartbeat activity, respectively. CKD patients showed lower tHb average spectral amplitude within the neurogenic frequency interval compared with controls (p = 0.014), consistent with an increased sympathetic outflow observed in CKD. CKD patients also showed lower TSI average spectral amplitude within the endothelial frequency interval compared with controls (p = 0.046), consistent with a reduced endothelial function in CKD. These findings demonstrate the potential of wavelet analysis of NIRS to provide complementary information on peripheral microvascular regulation in CKD.

Exploring Near Infrared Spectroscopy As a Tool for Monitoring Tissue Hemodynamics for Patients with Sickle Cell Disease

Sickle cell disease (SCD) is a genetic disorder that has higher prevalence in people of African ancestry. In the United States, SCD affects about 100,000 people and 1 in 365 African Americans. Sickled red blood cells (RBCs) have a shorter life span and are rigid, causing chronic hemolytic anemia and vaso-occlusive crises. There is a need for accessible diagnostic and monitoring technologies to characterize hemodynamic health, especially for patients with SCD. Near infrared spectroscopy (NIRS) is a noninvasive optical technique that uses light in the near infrared range (650 - 900 nm) to gain information from tissue absorption and light scattering. The purpose of this study is to show that NIRS is sensitive to differences in tissue hemodynamics between patients with SCD and healthy population. We enrolled adults (age ≥ 18 years) of African descent who were not recently transfused under protocol NCT05604547. Baseline hemodynamics and day-to-day variability were quantified in 10 SCD patients with HbSS (six male, four female) and six healthy, ethnically matched participants (four male, two female). We assessed participants with affixed transmission speckle analysis (ATSA) and a dual system frequency domain-NIRS (FD-NIRS) with diffuse correlation spectroscopy (DCS) device to measure blood flow and hemoglobin concentration. Participants underwent a respiratory challenge, three sets of breath holds, with the optical probe on their forehead. Then, the participants underwent a vascular occlusion challenge, a three-minute brachial blood pressure cuff occlusion at 200 mmHg, with the optical probe on their forearm. We also measured skin and adipose tissue thickness (SATT) of the forearm site with ultrasound. Two of the healthy control participants were excluded from the skeletal muscle analysis due to SATT &amp;gt; 8 mm. A Mann-Whitney significance test was used to evaluate the results. From these measurements, we acquired the concentration of oxygenated (O 2Hb), deoxygenated (HHb), and total hemoglobin (tHb); blood flow index (BFi); and tissue oxygen saturation (StO 2) for cerebral and skeletal muscle. The cerebral StO 2 in the SCD cohort was lower than the control group, 55.5 ± 7.4% versus 66.9 ± 2.5% (p = 0.003), respectively. Skeletal muscle StO 2 in the SCD cohort was lower than that in control, 59.2 ± 5.8% versus 66.4 ± 6.7%, respectively, but the difference was not significant (p = 0.19). The muscle O 2Hb in the SCD cohort was lower compared to control: 32.7 ± 6.5 µM versus 51.0 ± 9.2 µM (p = 0.01), respectively. The muscle tHb had a similar trend, with the SCD cohort measuring 55.8 ± 12.0 µM and the control group measuring 76.5 ± 9.0 µM (p = 0.03). The SCD cohort was also found to have lower overall muscle BFi, averaging 5.37 x 10 -9 ± 3.47 x 10 -9 cm/s, whereas the control group had an average of 1.90 x 10 -8 ± 1.33 x 10 -8 cm/s (p = 0.004). We also calculated hemodynamic markers, such as components of the occlusion recovery. The post-occlusion O 2Hb recovery slope for the SCD cohort was 0.31 ± 0.19 µM/s compared with control group at 1.56 ± 0.75 µM/s (p = 0.004). The goal of this study is to compare baseline vascular hemodynamics between patients with SCD and ethnically matched healthy controls. This study is ongoing and preliminary data analysis suggests impaired cardiovascular health in SCD subjects. The cerebral StO 2, muscle O 2Hb, and tHb in the SCD cohort is hypothesized to be a result of the reduced ability of sickled RBC to carry oxygen. There was a significant difference in the cerebral StO 2 but not in the skeletal muscle StO 2, suggesting that there are more dynamic changes seen in the brain than the muscle. This is consistent with previous work using commercial, continuous-wave NIRS systems for a SCD cohort (Barriteau et al. 2022) that also reported significantly lower cerebral StO 2 and lower trending, but not significant, muscle StO 2 values.The post-occlusion O 2Hb recovery upslope is hypothesized to be slower for the SCD cohort due to reduced endothelial function. We plan to assess repeatability of intra-individual NIRS parameters and to compare the non-invasive hemodynamic metrics to clinical markers, such as blood Hb and echocardiogram. These preliminary results indicate that NIRS is sensitive to changes in hemodynamic variations between SCD patients and healthy controls and, therefore, has the potential to serve as a point-of-care technology for individualized clinical management for patients with SCD.

Safety and Efficacy of RM-001 (Autologous HBG1/2 Promoter-modified CD34+ Hematopoietic Stem and Progenitor Cells) in Patients with Transfusion-Dependent β-Thalassemia

Background: Reactivating fetal globin (HbF) is a promising treatment for β-hemoglobinopathies. Natural mutations in the promoter region of γ-globin genes ( HBG1/2) that disrupt the binding of the transcriptional repressors BCL11A could lead to a lifelong persistence of fetal γ-globin expression. Using gene editing to mimic these mutations should reactivate γ-globin in patients with transfusion-dependent β-thalassemia (TDT) and ameliorate the symptoms of patients. RM-001 is a novel cell therapy that uses non-viral, ex vivo CRISPR-Cas9 gene editing in autologous hematopoietic stem and progenitor cells (HSPCs) at the promoter of the γ-globin genes ( HBG1/2) to disrupt the binding site of BCL11A. Aims: ChiCTR2100053406 and ChiCTR2100052858 are ongoing multi-center, first-in-human studies of RM-001 for TDT. Here, we present available safety and efficacy results from 7 patients that have been dosed with RM-001. Methods: Patients (6-35 y of age) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/y or ≥10 units/y in the previous 2ys were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF and plerixafor. CD34+ cells were edited with CRISPR-Cas9 using a guide RNA specific for the binding site of BCL11A on the HBG1/2 promoter. Prior to RM-001 product infusion (day 0), patients received myeloablative conditioning with Busulfan from day-7 to day-3. Patients were monitored for stem cell engraftment/hematopoietic recovery, adverse events (AEs), Hb production, HbF and F-cell expression, and pRBC transfusion requirements. Bone marrow cells were obtained at 3, 6, 12 and 24 months after RM-001 infusion to measure the on-target allelic editing frequency using next-generation sequencing. Results: Data presented here for 7 TDT patients have been treated with RM-001. As of July 31, 2023, patients were followed up from 1 to 20 months and 5 of them have been followed up more than 15 months. Six patients have β 0/β 0 genotype (CD17/CD41-42, n=1; CD41-42/CD41-42, n=5) and the other has β 0/β + genotype (CD41-42/IVS-II-654). In addition to β-thalassemia (CD41-42/CD41-42), two patients also carry a Southeast Asian deletion of α-globin genes (– SEA/αα). Patients had received a mean of 55.8 units/y pRBC transfusions (range: 39-79.6 units/y). All patients received a single dose of RM-001 cells, and achieved both neutrophil and platelet engraftments 2 to 3 weeks after RM-001 infusion (neutrophil: day 11-19, platelet: day 10-22). All patients ceased pRBC transfusions within 1 month after RM-001 infusion and remained transfusion-free through the reported period (Figure). For the 6 patients that have been followed up more than 6 months, HbF reached 9g/dL at 4 month post-RM-001 infusion and continuously maintained over this level through the reported period. From 6 month post-RM-001 infusion, hemoglobin in all patients consists of HbF (97.6%-99.8%) and HbA2 only, including the fifth patient who has a β0/β+ genotype (99.5% HbF). Five participants have remained transfusion independent more than 15 months and the mean HbF in the first 4 patients was 11g/dL(10.9-11.3 g/dL) at 18 month post-RM-001 infusion. The safety profile was generally consistent with busulfan myeloablation and autologous hematopoietic stem cell transplantation. No RM-001 related SAE report. Summary/Conclusion: This updated data reported here from 7 patients with TDT infused with RM-001 demonstrated clinically meaningful increases in total hemoglobin (Hb) and HbF levels. All patients stopped receiving pRBC transfusions within 1 month after RM-001 infusion and remained transfusion-free through the time of this analysis. The safety profile of RM-001 is generally consistent with myeloablative conditioning and autologous hematopoietic stem cell transplantation. These results strongly support continued investigation of RM-001 as a potential cure for patients with TDT. Data will be updated for the presentation. Submitted on behalf of the RM-001 Investigators.

A Phase 1b Double-Blind, Placebo-Controlled Study of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Non-Dialysis Dependent Chronic Kidney Disease and Anemia

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) and anemia. Elevations in hepcidin contribute to the onset, maintenance, and severity of anemia. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin (HJV), a co-receptor in the bone morphogenetic protein-signaling pathway regulating hepcidin expression. In a healthy volunteer study, DISC-0974 demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously (SC), and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count. In a rat model of anemia in CKD, DISC-0974 decreased hepcidin, increased serum iron, and normalized hemoglobin (Wu et al., ASH 2022). DISC-0974-103 is a Phase 1b, double-blind, placebo-controlled, single-ascending dose study (NCT05745883) to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with NDD-CKD and anemia. Eligible participants include patients over 18 years of age with NDD-CKD, stages 2-5, hemoglobin (Hgb) &amp;lt;10.5 g/dL in women and &amp;lt;11.0 g/dL in men, serum ferritin ≥100 μg/L, and transferrin saturation (TSAT) ≤30%. Major exclusionary criteria include: concomitant treatment with therapeutic oral iron, intravenous iron, erythropoietin-stimulating agents, or blood transfusions; splenectomy; and nutritional, genetic, infectious, or autoimmune causes of anemia. Approximately 32 participants will be enrolled. On Day 1, participants will receive a single dose of DISC-0974 SC with evaluations for safety, PK, and PD through 57 days of follow-up. Dose escalation is planned across 4 cohorts consisting of 8 participants each, randomized 3:1 active treatment to placebo, treated at single doses of 28, 40, 60, and 90 mg SC DISC-0974. Safety Review Committee assessments are planned to gate escalation decisions. Primary endpoints include adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include changes in serum hepcidin-25, iron, TSAT, ferritin, Hgb, and other hematology biomarkers. Enrollment is currently ongoing, and available study results will be presented at the meeting.

AsCas12a Gene Editing of HBG1/2 Promoters with EDIT-301 Results in Rapid and Sustained Normalization of Hemoglobin and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

Background: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are hereditary blood disorders caused by mutations in the β-globin gene. Clinical evidence has demonstrated that increased fetal hemoglobin (HbF, α2γ2) can reduce or eliminate SCD and TDT complications. EDIT-301, an investigational gene-edited autologous hematopoietic stem cell medicine, has a unique genomic modification that mimics naturally occurring mutations of hereditary persistence of fetal hemoglobin in the γ-globin gene ( HBG1/2) promoters. These mutations reactivate γ-globin expression and increase HbF production. EDIT-301 is manufactured with a highly efficient and specific, proprietary gene editing nuclease, AsCas12a. In preclinical studies, edited CD34 + cells from patients with SCD or TDT increased HbF production in red blood cells (RBCs) sufficient for a therapeutic effect, including reduced sickling (SCD) and improved erythropoiesis (TDT). Aim: RUBY (NCT04853576) and EdiThal (NCT05444894) are Phase I/II, multicenter, open-label, single-arm studies evaluating the safety, efficacy, and tolerability of EDIT-301 in patients with severe SCD and TDT, respectively. As of June 28, 2023, 7 SCD patients and 2 TDT patients have received EDIT-301 treatment. Preliminary clinical efficacy and safety data are reported. Methods: Patients aged 18-50 years with severe SCD (defined as ≥2 severe vaso-occlusive events [VOEs] per year in the 2 years prior to informed consent [IC]) and patients aged 18-35 years with TDT (defined as at least 100 mL/kg/year or 10 U/year of packed RBC transfusions in the 2 years prior to IC) were eligible to enroll in RUBY and EdiThal, respectively. Autologous CD34 + hematopoietic stem and progenitor cells collected by apheresis after plerixafor (RUBY) or plerixafor + filgrastim (EdiThal) mobilization were edited at the HBG1/2 promoters with AsCas12a. After myeloablative conditioning with busulfan, patients received a single infusion of EDIT-301 (a minimum of 3 × 10 6 CD34 + cells/kg), and were monitored for engraftment, total hemoglobin (Hb), HbF, mean HbF concentration/F-cell (MCH-F/F-cell), percentage of F-cells, markers of hemolysis, transfusion requirement, VOEs (SCD only), and adverse events (AEs) for 24 months. Results: Based on a data cut of June 28, 2023, Patients 1-4 with SCD were 12-, 9-, 4-, and 4-months post-EDIT-301 infusion, respectively. Patients 5-7 with SCD were &amp;lt;1-month post-EDIT-301 infusion. Patients 1-2 with TDT were 3- and &amp;lt;1-months post-EDIT-301 infusion, respectively. Neutrophil and platelet engraftment were achieved after a mean (range) of 25 (23-29) and 27 (19-37) days in Patients 1-4 with SCD and on Day 23 and 26 in Patient 1 with TDT, respectively. There were no VOEs in SCD patients post-EDIT-301 infusion, compared with a mean (range) of 4.2 (3.0-5.5) VOEs/year in the 2 years before enrollment (n=6). Following EDIT-301 infusion, Hb levels rapidly increased to 14.2 (12.4-15.7) g/dL by Month 4 (n=4), reaching the normal physiological range, from a mean (range) of 10.5 (8.5-11.9) g/dL at baseline (n=5). By Month 4, the mean (range) HbF concentration was 6.8 (5.7-7.6) g/dL and HbF was &amp;gt;40% (n=4); Patients 3 and 4 had &amp;gt;50% HbF. Percentage of F-cells and MCH-F/F-cell also increased. Key markers of hemolysis improved or normalized in all patients with SCD. Patient 1 with TDT had a HbF concentration of 7.2 g/dL by Month 3, stopped receiving RBC transfusions 20 days after EDIT-301 infusion, and remained transfusion free through the 3-month period. Patient 2 with TDT also showed early improvements. The safety profile of EDIT-301 in both SCD and TDT was consistent with myeloablative conditioning with busulfan. No serious AEs were reported after EDIT-301 infusion. Conclusion: These data demonstrated successful engraftment, a rapid and sustained normalization of Hb as early as 4 months after infusion, an increase in HbF and percentage of F-cells, resolution of VOEs (SCD) and transfusion independence (TDT). In addition, there were improvements in key markers of hemolysis (SCD) and a favorable safety profile in EDIT-301-treated patients. EDIT-301 treatment showed promising results for the first clinical use of AsCas12a in both SCD and TDT patients after gene editing of the γ-globin gene ( HBG1/2) promoters. These findings support further investigation of EDIT-301 in the RUBY and EdiThal trials. Updated data with additional outcomes will be presented.

The Importance of Screening for Food Insecurity in Children with Sickle Cell Anemia: An Ancillary Study to the Severe Acute Malnutrition Feasibility Trial in Nigeria

Introduction Household food insecurity-lacking access to, or having uncertain access to, food that meets a person's dietary needs-is a longstanding problem in Nigeria that has continued to worsen in recent years. One of its most severe consequences is malnutrition, particularly affecting children due to their high nutrient demand coupled with higher energy expenditure. Even in high-income countries, such as the United States, many children with sickle cell anemia have lower weights and heights than their healthy peers. Due to their elevated nutrient requirements, children with sickle cell anemia may be at an even greater risk of malnutrition when faced with limited access to adequate food. The relationship between childhood food insecurity and malnutrition has been previously studied in younger children in Nigeria, but rarely in older children, and to our knowledge, never in older children with sickle cell anemia. We tested the hypothesis that there is a direct association between increased food insecurity and more severe malnutrition (lower body mass index [BMI] z-score) in older children with sickle cell anemia in Nigeria. Methods This was a planned analysis of the data of children enrolled in a feasibility trial for managing severe acute malnutrition in older children with sickle cell anemia in Nigeria (SAMS trial; #NCT03634488). In this study, children 5-12 years old with sickle cell anemia and uncomplicated severe acute malnutrition (BMI z-score &amp;lt;-3.0) were randomly assigned to receive either supplemental ready-to-use therapeutic food (RUTF) only or RUTF combined with moderate fixed-dose hydroxyurea therapy for 12 weeks. Baseline anthropometric data were obtained for each participant. Upon enrollment in the trial, the participants' caregivers completed the US Household Food Security Survey Module (HFSSM). Using the eight questions in the childhood portion of this standardized survey, we categorized the participants into three food security statuses: food security (0-1), low food security (2-4), and very low food security (5-8). Childhood food security scores were also measured as a continuous variable on a scale of 0-8, with higher scores indicating greater food insecurity. We constructed a linear regression model to estimate the association between childhood food insecurity and baseline BMI z-score. Results Data were collected between August 2021 and May 2022. The median age of the 108 participants in the study was 10.3 years (IQR 8.8-11.5). Most participants had low (55%) or very low (34%) food security. BMI z-score was not associated with categorical food security status (p=0.108). However, higher food insecurity as a continuous variable was associated with a lower BMI z-score (Pearson correlation -0.23, p=0.015; Figure 1). In a multivariable linear regression with sex, age at study entry, total hemoglobin, employment status, and head of household educational status, the childhood food insecurity score was negatively associated with the BMI z-score (Beta coefficient = -.05, p=0.047). Conclusions Our study reveals a high prevalence of food insecurity among older children with sickle cell anemia in Nigeria. Moreover, children experiencing higher food insecurity also exhibited more severe malnutrition, as evidenced by their lower BMI z-scores. Based on these results, we have started implementing food insecurity assessment as routine medical care in children with sickle cell anemia at multiple clinics in northern Nigeria. Children experiencing higher levels of food insecurity are referred to nutritional counseling, where they receive guidance on locally available nutrient-dense foods and preparation strategies. Figure 1.The predicted baseline body mass index z-score with 95% confidence intervals based on childhood food insecurity scores from a linear regression model of the participants in the SAMS trial.

A Phase 1b Trial of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Myelofibrosis and Anemia

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic elevations in hepcidin contribute to the onset and severity of anemia. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Preclinical studies have shown that DISC-0974 suppresses hepcidin and increases serum iron. A healthy volunteer study has demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously, and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count. In this Phase 1b/2a, open-label, multiple-ascending dose study (NCT05320198), we are assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with MF and anemia. Eligible participants include patients over 18 years of age with intermediate-2 or higher-risk MF and anemia. MF is required to be confirmed using the World Health Organization 2016 criteria. Anemia is defined per protocol as Hgb &amp;lt; 10 g/dL or transfusion dependence, as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). A stable dose of hydroxyurea and/or Janus kinase (JAK) inhibitor is allowed on trial. Major exclusion criteria include: liver iron concentration ≥ 7 mg/g dry weight; splenectomy; nutritional, genetic, infectious, or autoimmune causes of anemia. Dose escalation is based on a Bayesian optimal interval design with accelerated titration. Safety Review Committee assessments gate escalation decisions. Dosing occurs monthly for a total of 6 doses. Primary endpoints include safety and tolerability assessments of adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include anemia response as defined by the IWG-MRT, transfusion response as defined by a decrease of 50% in transfusion requirement over any 8-week period, standard PK parameters and PD metrics including serum hepcidin-25, iron, transferrin saturation, ferritin, and hematology biomarkers. All data are summarized using descriptive statistics. Initial data show a dose-related increase in pharmacokinetic parameters. DISC-0974 treatment led to dose-dependent reductions in serum hepcidin-25 and increases in serum iron levels. There have been no serious AEs or AEs leading to study withdrawal. Most AEs were mild, transient, and unrelated to DISC-0974. As of August 1, 2023, enrollment and dose escalation are ongoing. Safety, PK, and PD data from at least the first two cohorts will be presented.

Dynamic Modelling for Cancer-Associated Venous Thromboembolism

Background: Cancer-associated venous thromboembolism (VTE) is an important source of morbidity and mortality. Current risk prediction models for thrombosis are handicapped by static applicability (i.e. one-time evaluation prior to the first cycle of chemotherapy). We hypothesized that event forecasting using time series modelling could account for important changes in clinical state, variations in treatment and aspects of cancer progression over time. Methods: The cohort consisted of adult patients with a solid tumor enrolled in the MSK-IMPACT study between 2014 and 2019. VTE was defined as any symptomatic or asymptomatic pulmonary embolus or lower extremity deep vein thrombosis. We derived time series mixed-effects logistic regression models in order to predict cancer-associated VTE events using baseline patient characteristics (cancer type, time from diagnosis and age) along with time-dependent covariates including total white blood cell count, hemoglobin, platelet count, albumin, creatinine and parenteral chemotherapy type. Time-periods of one month were used and models were fitted to predict the presence or absence of a VTE episode in the following period (time = t+1) based on predictor values in the current period (time = t). The laboratory test result ascribed to a given period could be either the last value in the interval or the mean of all interval-specific values (both approaches tested). Missing laboratory results were imputed using the previously known value when available. Differences in laboratory values between periods t-1 and t were included as predictors in the initial model along with indicators of missingness (see Figure for flow of information between time-period cells). We hypothesized that absence of laboratory testing for a time-period would be a marker of stable medical state and hence associated with a lower risk of VTE. A previously defined training set comprising 80% of the cohort was used and different modelling approaches were evaluated using 5-fold cross-validation. The final selected model was evaluated in a separate dedicated validation set including the remaining 20% of the cohort. Results: The original cohort included 35,391 patients, from which 26,075 individuals with no cancer-associated VTE episode before observation start and sufficient laboratory test information could be included in the analysis, comprising 276,579 months of observation and 1,463 VTE events. The initial logistic regression model including all available predictors was fitted on the training set, revealing associations between predictors and VTE risk largely consistent with data reported by other groups (see Table). After adjusting for multiple comparisons, significant predictors of cancer-associated VTE identified included albumin, cell count result missingness (decreased risk for missing value), treatment with a platinum analogue (increased risk), hemoglobin, white blood cell count, breast cancer (decreased risk) and high-grade glioma (increased risk). Based on model metrics and prior knowledge from published literature, the set of covariates selected for inclusion in the final model consisted of cell counts along with the corresponding missingness indicator, platelet count change over time, albumin and chemotherapy types. The c-index for the final model using 5-fold cross-validation in the training set was 0.77 (95% CI = 0.75-0.80), compared to 0.77 (95% CI = 0.74-0.79) in the validation set. The latter corresponded to a specificity of 0.83 (95% CI = 0.79-0.86) when fixing sensitivity at 50%. Conclusions: A simple mixed-effects logistic regression time series model demonstrated promising potential to estimate the risk of cancer-associated VTE on a dynamic basis using routine laboratory test results and chemotherapy prescription data widely available in most electronic health record systems. Validation of this dynamic VTE risk model has the potential to optimize outpatient thromboprophylaxis during periods of high thrombotic risk.

Efficacy and Safety of Brl-101, CRISPR-Cas9-Mediated Gene Editing of the BCL11A Enhancer in Transfusion-Dependent β-Thalassemia

BACKGROUND: β-Thalassemia is an inherited hemolytic disease that is prevalent worldwide. Over 200 mutations in the HBB gene, which encodes adult hemoglobin (HbA), result in β-thalassemia. Hereditary persistence of fetal hemoglobin (HbF) can alleviate the symptoms of anemia. CRISPR-Cas9-mediated disruption of the BCL11A erythroid enhancer results in the reduction of BCL11A expression and the induction of fetal γ-globin, which is a practicable therapeutic strategy for treating transfusion-dependent β-thalassemia (TDT). METHODS: We obtained mobilized autologous CD34+ cells from 4 TDT patients sponsor initiated in phase I/II clinical trial (NCT05577312) and 6 TDT patients in investigator initiated clinical study（NCT04211480, NCT04205435）respectively. These cells were edited with CRISPR-Cas9 RNP at the +58 erythroid specific enhancer region of the BCL11A gene and then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, neutrophil and platelet engraftment. Efficacy assessments included proportion of transfusion-independent (TI) subjects, levels of total hemoglobin and HbF, and proportion of red blood cells expressing HbF in peripheral blood. TI was evaluated for elimination of transfusions starting 42 days after the last transfusion and Hb above 90 g/L. RESULTS: Between October 15, 2019 and November 20, 2022, 10 patients with TDT were enrolled and received BRL-101 with a median age of 12.4 years (6-26). Among all the treated patients, 5 patients were β 0/β 0 phenotype, 4 patients were β0/β+ phenotype and 1 patient were β +/β + phenotype. As of July 20, 2023, the median follow- up was 24.6 months (4.3-39.2 m) (Tab.1). All of 10 patients achieved TI. The median duration of TI was 22.1 months (1.3 - 37.2 m). The longest duration of TI was 37.2 months (Fig.1). The levels of HbF ranged from 2.3 to 140.7g/L and the levels of total hemoglobin ranged from 105.7 to 149 g/L (Fig.2). At 6 months after BRL-101 infusion, the proportion of HbF-expressing red blood cells in peripheral blood had reached 96.5%, and then continued to rise and remained around 98-99% (Fig.3). Treatment-related adverse events were typical of those associated with myeloablation and autologous stem-cell transplantation, mainly manifested as hematological toxicities (Tab.2, Tab.3). 3 patients experienced adverse events (AEs) grade ≥ 3 which related to BRL-101. 4 patients experienced serious AEs (SAEs), including decreased platelet count, shock, febrile infection, soft tissue infection, and veno-occlusive liver disease. Only decreased platelet count may related to BRL-101, the others were due to busulfan treatment. All the SAEs were resolved. No study drug-related withdrawals or deaths occurred during treatment. CONCLUSIONS: Whether genotype was β 0/β 0 or non-β 0/β 0, BRL-101 demonstrated clinically meaningful increases in total Hb and HbF which occurred early and have been maintained over time, the safety profile of BRL-101 is generally consistent with that of myeloablative conditioning and autologous hematopoietic stem cell transplant. The updated data with 10 patients reported here are consistent with previous reports and support continued investigation of BRL-101 as a potential functional cure for patients with TDT.

New Insights in Sickle Cell Disease Provided By Intravascular Hemolysis and Total Hb Mass Parameters

New biomarkers may provide a better understanding of the complex pathophysiology of sickle cell disease. Anemia is defined as a reduction in the blood concentration of hemoglobin ([Hb]) to &amp;lt; 12 g/dL in females and &amp;lt; 13 g/dL in males. [Hb] will depend not just on the total circulating quantity of hemoglobin (tHbmass), but also on plasma volume (PV) in which it is suspended. Exercise capacity correlates poorly with [Hb], in contrast to tHbmass, as shown by studies comparing elite athletes and sedentary individuals. Similarly, classic parameters of hemolysis (LDH, bilirubin, ASAT) are not very specific for erythrocytes and do not always reflect the intravascular component of hemolysis. Plasma hemoglobin and heme, released by hemoglobin oxidation, are specific biomarkers of RBC destruction in the circulation and have their own deleterious effects on vascular walls, NO bioavailability, and the inflammatory state. In this study, we aimed to analyze the contribution of these biomarkers to cardiac and vascular parameters. Method: We carried out a preliminary analysis of patients included in the HEMOPROVE trial (NCT05199766) a prospective open-label study designed to better understand the effects of Voxelotor. Patients had to be more than one month from a vaso-occlusive crisis, 3 months from a transfusion and on a stable dose of hydroxyurea (HU) for at least 3 months to be included. We extracted and analyzed data from patients who had a pre-treatment Hb mass measurement. Hb mass, plasma volume were determined using the validated oCOR method using medical device Detalo Clinical TM - CO Rebreather (IEC 60601-1 and IEC 62304 for medical devices). Only patients with a HbCO of less than 3% benefited from this measurement; plasma hemoglobin and plasma heme were measured using the technique developed by our team (BET 18P3417). Blood pressure and heart rate were measured during echocardiography. All values were collected within the same week of inclusion in the protocol. Correlations were performed using a Spearman test, paired data comparisons were made with a Wilcoxon test (Graphpad9, PRISM). Results: Fourteen patients were included for blood mass measurement. Median age was 38 years [34.7-50.7], sex ratio F/M was 7/7, 10/14 patients were treated with HU. Median [Hb] was 7.4g/dL [6.6-7.7], tHbmass was 522 g [352-704] corresponding to 8.1 g/kg [6.1-11.7]. [Hb] and tHbmass were strongly correlated (p=0.008, r=0.68), whereas it was weaker with tHbmass/kg (p=0.046, r=0.54). Interestingly, some patients with approximately the same [Hb] had widely varying tHbmass. These results can be explained by significant variability in plasma volume, which was increased in half the patients, with a median increase of +135% [100-215] and a median volume of 5656 ml [4140-6931]. The tHbMass (p=0.01; r=0.64), tHbMass/kg (p=0.05, r=0.52) and above all PV (p=0.004; r=0.73) correlated with the E/E' used to evaluate the left ventricle filing pressure, while there was no correlation with [Hb] (p=0.5). Interestingly, the cardiac index was inversely correlated with plasma Hemoglobin (p=0.003, r=-0.74) with no correlation with [Hb] (p=0.4) or LDH (p=0.90), while mean and diastolic blood pressure were negatively correlated with plasma Heme (respectively p=0.01; r=-0.65 and p=0.001; r=-0.77) with no correlation with [Hb] and LDH (p&amp;gt;0.4). Conclusions: Measurements of total hemoglobin mass and intravascular hemolysis parameters provide a better understanding of the diversity of manifestations that lie behind sickle cell anemia, underpinned by complex mechanisms.

Translating an HPFH-Mechanism into Oral Small Molecule Therapy for Beta-Hemoglobinopathies: Clinical Proof-of-Principle

Introduction: Hereditary persistence of fetal hemoglobin (HPFH) down-modulates co-inherited sickle cell disease (SCD) severity, encouraging characterization of HPFH-mechanisms for interventional reprise. One HPFH mechanism is polymorphisms in DNA methyltransferase 1( DNMT1) that decrease DNMT1 protein stability (Gong et al, Blood 2021), agreeing with biochemical observations that DNMT1 mediates repression of fetal hemoglobin (HbF) genes by BCL11A. Here we describe translation of this HPFH-mechanism into oral therapy for SCD patients at high-risk for early mortality (Steinberg et al, JAMA 2004) despite standard-treatments. Methods and Results: The small molecule decitabine (Dec) contains a pyrimidine ring modification that binds and depletes DNMT1 and a natural deoxyribose that incorporates into DNA without terminating chain synthesis: minimum biologically effective doses of Dec, to deplete DNMT1 without cytotoxicity, can thus be found (reviewed in Zavras et al, Clin Ca Res, 2021). Other key properties of Dec are tropism to hematopoietic precursors, driven by high expression in these cells of deoxycytidine kinase that phosphorylates Dec, and rapid catabolism in vivo by cytidine deaminase (CDA), that severely restricts Dec bioavailability and half-life. We therefore combined Dec with a CDA-inhibitor tetrahydrouridine (THU): dose and schedule of THU/Dec that depleted DNMT1 without cytotoxicity to hematopoietic precursors in vivo were identified in non-human primate studies and Phase 1 clinical trials (Molokie et al, PLoS Med 2017), and here we describe interim results from proof-of-principle study in patients with SCD ( Table 1). Study interventions were oral THU/Dec (~10/0.2 mg/kg) 1X/week with or without oral nicotinamide (vitamin B3) 1 g/day. B3 was studied because it is a direct precursor of NADH, a fundamental antioxidant currency and also a cofactor for epigenetic enzymes that channel hematopoiesis to erythropoiesis vs megakaryopoiesis, to potentially counter an expected side-effect of THU/Dec of increasing platelets. Randomization was to THU/Dec vs B3 for 12 weeks, followed by THU/Dec + B3 for 12 weeks, then option to extend therapy for a further 24 weeks. Standard clinical and laboratory parameters were measured. Six patients enrolled, were randomized equally to THU/Dec or B3, and opted to extend. Dose-limiting toxicities (DLTs), including neutropenia or thrombocytosis, did not occur ( Table 1). In the year preceding study-treatment, 15 vaso-occlusive crises (VOC) requiring hospitalization were documented ( Table 1). By comparison, during 52 weeks on-study (48 weeks on-therapy, 4 weeks follow-up), the grade 3/4 adverse events were VOC hospitalizations x3 (1 during follow-up without therapy, 1 during B3 alone, 1 during B3 + THU/Dec therapy), hyperkalemia x2, and non-cardiac chest pain x1 ( Table 1)(p=0.04, paired t-test 2-sided). THU/Dec dose (7.6/0.15 mg/kg) was below the Phase 1 identified minimum biologically effective dose window (8-12/0.16-0.25 mg/kg, protocol since amended to accommodate high body weights) in one patient (TDN04) who accordingly did not have HbF% or hemoglobin increases ( Fig.1). In the 5 other patients, HbF increases (pre-treatment to maximum) were: 9.4 to 17.3, 5.9 to 11, 3.4 to 9.3, 3.3 to 16.3 and 5.7 to 10 % ( Fig.1). There were corresponding improvements in hemolysis and coagulation pathway parameters (LDH, total bilirubin, D-Dimer), and total hemoglobin increased from 9.9 to 11.5, 8.7 to 10.6, 6.6 to 7.7, 5.7 to 7.1 and 8 to 9.7 g/dL respectively. TDN01 and 06, the two patients with lowest pre-treatment hemoglobin, requested and resumed THU/Dec post-study by Expanded Access. Conclusions: This is the longest-term treatment to date of oral THU/Dec to target DNMT1 in patients with SCD, with or without B3. Subjective and objective improvements were sustained without DLTs in high-risk patients who displayed known negative prediction markers for response to hydroxyurea (HbF% &amp;lt;7.5%, reticulocyte count &amp;lt;300 x10 9/L - Steinberg et al, Blood 1997). The safety and efficacy signals align with scientific target validation data, and together with accessibility, support relevance to SCD patient needs and goals worldwide, bearing in mind major study limitations of single-site enrollment and only 6 patients.

Transfusion Practice: Hemolysis Markers After In Vitro Infusion of Packed Red Blood Cells by the Gravitational Method in Peripheral Catheter.

The objective of this study was to compare hemolysis marker levels after in vitro infusion of red blood cells (RBCs) according to storage time, infusion rate, and peripheral intravenous catheter size. This is an experimental study with randomly administered RBCs in quintuplicate, according to storage time shorter than and longer than 14 days, as well as infusion rate (50 mL/h and 100 mL/h) using catheters with calibers of 14-, 18-, and 20-gauge. Aliquots were collected from RBCs (V1), after equipment and catheter (V2) free-flow filling and after controlled infusion through the catheter (V3). The hemolytic markers analyzed were degree of hemolysis (%), hematocrit (Ht) (%), total hemoglobin (THb) (g/dL), free hemoglobin (FHb) (g/dL), potassium (K) (mmol/L), and lactate dehydrogenase (LDH) (U/L), considering a probability of error ≤5%. Sixty experiments were performed with the analysis of 180 aliquots. When RBCs aged <14 days were used, all catheters tended to increase THb, FHb, and K; while >14 days, RBCs presented increased FHb and degree of hemolysis with catheters of 18-gauge and THb levels at 14-gauge. Among the conditions analyzed, only 20-gauge catheters (the smallest) did not influence changes in hemolysis markers, regardless of RBC storage time.

Evaluation of the pleth variability index, perfusion index, and other physiological parameters after COVID-19.

The aim of this study was to observe the changes in pleth variability index (PVI), perfusion index (PI) and other hemodynamic parameters in adult individuals who had had Coronavirus disease 2019 (COVID-19) and were currently living a normal life. A further aim was to draw attention to the fact that some hemodynamic changes after COVID-19 may cause long-term health problems. A total of 174 adult individuals who had had COVID-19 and were currently living a normal life and 56 healthy individuals with similar demographic characteristics who had not had COVID-19 were included in the study. The PI, PVI, oxygen saturation (SpO2), pulse rate (PR), total hemoglobin (Hgb), oxygen reserve index (ORI), and blood pressure values were measured by Masimo Radical 7. The data of individuals who had and did not have COVID-19 before were compared. The mean PVI (p = 0.008) and PI (p < 0.001) were significantly lower in people who had been exposed to COVID-19. Likewise, the mean of ORI, SpO2, and SpOC values was observed to be significantly lower in participants exposed to COVID-19 disease (p < 0.001, p < 0.001, and p = 0.006, respectively). The PVI had a positive correlation with body mass index (BMI) (r = 0.263, p < 0.001) and a negative correlation with SpO2 (r = -0.194, p = 0.003) and PR (r = 0.190, p = 0.004). The PVI, PI, and other physiological parameters could potentially be useful for monitoring COVID-19 patients and evaluating their response to therapy. We believe that people who have been exposed to COVID-19 may be more susceptible to other diseases; therefore, they should be subjected to regular clinical checks.