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John Sunwoo,1 Patjanaporn Chalacheva,1 Maha Khaleel,2 Payal Shah,2 Richard Sposto,3 Roberta M Kato,4 Jon Detterich,5 Lonnie K Zeltzer,6 John C Wood,1,5 Thomas D Coates,2 Michael CK Khoo1 1Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA; 2Hematology Section, Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 3Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 4Division of Pediatric Pulmonology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 5Division of Pediatric Cardiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 6Pediatric Pain and Palliative Care Program, Department of Pediatrics, Division of Hematology-Oncology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA Purpose: The purpose of this work was to noninvasively detect and quantify microvascular blood flow changes in response to externally applied pain in humans. The responsiveness of the microvasculature to pain stimulation might serve as an objective biomarker in diseases associated with altered pain perception and dysregulated vascular functions. The availability of such a biomarker may be useful as a tool for predicting outcome and response to treatments, particularly in diseases like sickle cell anemia where clinical manifestations are directly linked to microvascular perfusion. We, therefore, developed a method to distinguish the blood flow response due to the test stimulus from the blood flow measurement that also includes concurrent flow changes from unknown origins.Subjects and methods: We measured the microvascular blood flow response in 24 healthy subjects in response to a train of randomly spaced and scaled heat pulses on the anterior forearm. The fingertip microvascular perfusion was measured using laser Doppler flowmetry. The cross-correlation between the heat pulses and the blood flow response was computed and tested for significance against the null distribution obtained from the baseline recording using bootstrapping method.Results: We estimated correlation coefficients, response time, response significance, and the magnitude of vasoreactivity from microvascular blood flow responses. Based on these pain response indices, we identified strong responders and subjects who did not show significant responses.Conclusion: The cross-correlation of a random pattern of painful stimuli with directly measured microvascular flow can detect vasoconstriction responses in a noisy blood flow signal, determine the time between stimulus and response, and quantify the magnitude of this response. This approach provided an objective measurement of vascular response to pain that may be an inherent characteristic of individual human subjects, and may also be related to the severity of vascular disorders. Keywords: objective quantification of pain, randomized heat pulse train, laser Doppler flowmetry, cross-correlation, bootstrap test, vasoreactivity

Ravi R Bhatt,1 Sarah R Martin,1 Subhadra Evans,2 Kirsten Lung,1 Thomas D Coates,3,4 Lonnie K Zeltzer,1 Jennie C Tsao1 1UCLA Pediatric Pain and Palliative Care Program, Division of Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 2School of Psychology, Deakin University, Geelong, VIC, Australia; 3Department of Pediatrics, Keck School of Medicine, University of Southern California, 4Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Los Angeles, CA, USA Background: Vaso-occlusive pain crises (VOCs) are the “hallmark” of sickle-cell disease (SCD) and can lead to sympathetic nervous system dysfunction. Increased sympathetic nervous system activation during VOCs and/or pain can result in vasoconstriction, which may increase the risk for subsequent VOCs and pain. Hypnosis is a neuromodulatory intervention that may attenuate vascular and pain responsiveness. Due to the lack of laboratory-controlled pain studies in patients with SCD and healthy controls, the specific effects of hypnosis on acute pain-associated vascular responses are unknown. The current study assessed the effects of hypnosis on peripheral blood flow, pain threshold, tolerance, and intensity in adults with and without SCD. Subjects and methods: Fourteen patients with SCD and 14 healthy controls were included. Participants underwent three laboratory pain tasks before and during a 30-minute hypnosis session. Peripheral blood flow, pain threshold, tolerance, and intensity before and during hypnosis were examined. Results: A single 30-minute hypnosis session decreased pain intensity by a moderate amount in patients with SCD. Pain threshold and tolerance increased following hypnosis in the control group, but not in patients with SCD. Patients with SCD exhibited lower baseline peripheral blood flow and a greater increase in blood flow following hypnosis than controls. Conclusion: Given that peripheral vasoconstriction plays a role in the development of VOC, current findings provide support for further laboratory and clinical investigations of the effects of cognitive–behavioral neuromodulatory interventions on pain responses and peripheral vascular flow in patients with SCD. Current results suggest that hypnosis may increase peripheral vasodilation during both the anticipation and experience of pain in patients with SCD. These findings indicate a need for further examination of the effects of hypnosis on pain and vascular responses utilizing a randomized controlled trial design. Further evidence may help determine unique effects of hypnosis and potential benefits of integrating cognitive–behavioral neuromodulatory interventions into SCD treatment. Keywords: sickle-cell disease, pain, hypnosis, blood

Sixteen patients diagnosed with mild-to-moderate Alzheimer's disease were assessed at two time points, pre- and post-treatment with Aricept, an acetylcholine esterase inhibitor. Abattery of standardised neuropsychological tests was administered in addition to recording dose tolerance and maintenance. All patients significantly improved their scores on tests measuring visual memory, visuo-spatial skills, and auditory verbal memory after an interval of approximately 16 weeks. These findings support those of past studies that found an overall increase in cognitive functioning. However, these findings are unique in finding significant improvement in specific measures of visual memory and visuo-spatial functioning. [ABSTRACT FROM AUTHOR]

Background: Children treated for cancer are at risk for adverse effects of iron due to transfusions administered during prolonged marrow suppression, which may increase exposure to toxic forms of iron, extrahepatic iron accumulation, and long-term organ damage., Objective: This study aimed to characterize the severity and organ distribution of clinically significant, multisystem iron overload (IO) in an at-risk cohort of pediatric cancer patients., Methods: This was a retrospective, cross-sectional study of childhood cancer patients who underwent a magnetic resonance imaging (MRI) due to clinical concern for IO. Data regarding cancer type and treatment, transfusion history, MRI and laboratory results, and treatment for IO were collected. Severity of IO was analyzed by non-parametric tests with respect to clinical characteristics., Results: Of the 103 patients, 98% of whom had a Cancer Intensity Treatment Rating (ITR-3) of 3 or higher, 53% (54/102) had moderate or greater hepatic siderosis, 80% (77/96) had pancreatic siderosis, 4% (3/80) had cardiac siderosis, and 45% (13/29) had pituitary siderosis and/or volume loss. Pancreatic iron was associated with both cardiac (p = .0043) and pituitary iron (p = .0101). In the 73 off-therapy patients, ferritin levels were lower (p = .0008) with higher correlation with liver iron concentration (LIC) (p = .0016) than on-therapy patients. Fifty-eight subjects were treated for IO., Conclusion: In this heavily treated cohort of pediatric cancer patients, more than 80% had extrahepatic iron loading, which occurs with significant exposure to toxic forms of iron related to decreased marrow activity in setting of transfusions. Further studies should examine the effects of exposure to reactive iron on long-term outcomes and potential strategies for management., (© 2024 Wiley Periodicals LLC.)

Abstract: Chronically transfused patients with sickle cell disease typically do not exhibit iron-mediated extrahepatic toxicity. However, we demonstrate that the pituitary gland is vulnerable to iron deposition, and it occurs regardless of other extrahepatic involvement. Severe pituitary siderosis is associated with early organ dysfunction., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Prior to the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, non-invasive monitoring of organ specific iron loading in humans and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment., (Copyright © 2024 American Society of Hematology.)

Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in human-wildlife interactions along gradients of human influence., (© 2024. The Author(s).)

A recent evidence gaps assessment of the clinical, health-related quality of life, and economic burden associated with α-thalassemia is lacking. We conducted a systematic literature review (SLR) following the methodological and reporting requirements of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Handbook for Systematic Reviews, using available literature over the past decade. This SLR identified a considerable evidence gap with regard to understanding the current burden of α-thalassemia as evident from paucity of studies published in the past 10 years. The limited data available still indicate that patients with α-thalassemia experience substantial morbidity and quality of life/economic burden that is generally comparable to patients with β-thalassemia., Competing Interests: Khaled M. Musallam has been or is a consultant for Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and received research funding from Agios Pharmaceuticals and Pharmacosmos. Vip Viprakasit is supported by the Department of Research Development, Faculty of Medicine Siriraj Hospital. He received research grants from Agios, GPO (Thailand), Bristol Myers Squibb and Silence for clinical research studies. Louise Lombard, Keely Gilroy, and Amey Rane are employees of and own stock in Agios Pharmaceuticals. Thomas D. Coates provides advisory support to Agios Pharmaceuticals, Bristol Myers Squibb, and Chiesi. Lydia Vinals and Maria Rizzo are employees of Cytel Inc. Candice Tam was employed by Cytel Inc during the conduct of this work., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation., Methods: We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences., Results: Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation., Conclusions: Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss., Impact: Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency., Competing Interests: Declaration of competing interest K.M.M. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. M.D.C. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma, and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. T.D.C. provides advisory support to Agios Pharma, Bristol Meyers Squibb, and Chiesi. K.H.M.K. reports consultancy fees from Agios Pharmaceuticals, Alexion Pharmaceuticals, Bristol Myers Squibb, Forma Therapeutics, Pfizer, NovoNordisk, and Vertex Pharmaceuticals; honoraria from Agios Pharmaceuticals and Bristol Myers Squibb; membership on an advisory committee for Bioverativ/Sanofi/Sangamo; and research funding from Agios Pharmaceuticals and Pfizer. H.A-S. reports consultancy fees from Novartis, Forma Therapeutics, Agios Pharmaceuticals, argenx, Moderna, Pharmacosmos, and Sobi; and research funding from Agios Pharmaceuticals, Amgen, Sobi, Novartis, and Vaderis Therapeutics. S.S. reports consultancy fees from Agios Pharmaceuticals, bluebird bio, Fulcrum Therapeutics, Chiesi, Celgene Corp (Bristol Myers Squibb), and Vertex; honoraria for CME activities from Plexus, CCO, and Physicians' Education Resource; advisory board travel from Agios Pharmaceuticals, Celgene Corp (Bristol Myers Squibb), and bluebird bio; research funding from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, and Forma Therapeutics; and serving on a clinical trial steering committee for CRISPR/Vertex CTX001 for thalassemia. V.V. reports consultancy fees from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Novartis, Vifor Pharma, Pharmacosmos, IONIS Pharmaceuticals, Inc., and DisperSol Technologies, LLC; and research funding from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Novartis, Vifor Pharma, Pharmacosmos, IONIS Pharmaceuticals, Inc., DisperSol Technologies, LLC, and The Government Pharmaceutical Organization (GPO). A.T.T. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Vifor Pharma, and Pharmacosmos; and research funding from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Vifor Pharma, and Pharmacosmos., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Splenic iron decreased whereas liver iron was stable during luspatercept therapy in some individuals with thalassemia. This suggests a reduction of ineffective erythropoiesis changes the organ distribution of iron and demonstrates that liver iron concentration alone may not accurately reflect total body iron content. This article describes data from subjects enrolled in BELIEVE (NCT02604433) and BEYOND (NCT03342404)., (© 2023 by The American Society of Hematology.)

Significance: Sickle cell disease (SCD), characterized by painful vaso-occlusive crises, is associated with cognitive decline. However, objective quantification of cognitive decline in SCD remains a challenge, and the associated hemodynamics are unknown., Aim: To address this, we utilized functional near-infrared spectroscopy (fNIRS) to measure prefrontal cortex (PFC) oxygenation responses to N -back working memory tasks in SCD patients and compared them with healthy controls., Approach: We quantified the PFC oxygenation rate as an index of cognitive activity in each group and compared them. In half of the participants, a Stroop test was administered before they started N -back to elevate their baseline stress level., Results: In SCD compared to healthy controls, we found that (1) under a high baseline stress level, there were significantly greater oxygenation responses during the 2-back task, further elevated with histories of stroke; (2) there was a marginally slower N -back response time, and it was even slower with a history of stroke; and (3) the task accuracy was not different., Conclusions: Additional requirements for processing time, PFC resources, and PFC oxygenation in SCD patients offer an important basis for understanding their cognitive decline and highlight the potential of fNIRS for evaluating cognitive functions., (© 2023 The Authors.)

We introduce McDAPS, an interactive software for assessing autonomic imbalance from non-invasive multi-channel physiological recordings. McDAPS provides a graphical user interface for data visualization, beat-to-beat processing and interactive analyses. The software extracts beat-to-beat RR interval systolic blood pressure, diastolic blood pressure, the pulse amplitude of photoplethysmogram and the pulse-to-pulse interval. The analysis modules include stationary and time-varying power spectral analyses, moving-correlation analysis and univariate analyses. Analyses can also be performed in batch mode if multiple datasets have to be processed in the same way. The program exports results in standard CSV format. McDAPS runs in MATLAB, and is supported on MS Windows and MAC OS systems. The MATLAB source code is available at https://github.com/thuptimd/McDAPS.git., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Purpose: Congenital anemias, including sickle cell anemia and thalassemia, are associated with cerebral tissue hypoxia and heightened stroke risks. Recent works in sickle cell disease mouse models have suggested that hyperoxia respiratory challenges can identify regions of the brain having chronic tissue hypoxia. Therefore, this work investigated differences in hyperoxic response and regional cerebral oxygenation between anemic and healthy subjects., Methods: A cohort of 38 sickle cell disease subjects (age 22 ± 8 years, female 39%), 25 non-sickle anemic subjects (age 25 ± 11 years, female 52%), and 31 healthy controls (age 25 ± 10 years, female 68%) were examined. A hyperoxic gas challenge was performed with concurrent acquisition of blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS). In addition to hyperoxia-induced changes in BOLD and NIRS, global measurements of cerebral blood flow, oxygen delivery, and cerebral metabolic rate of oxygen were obtained and compared between the three groups., Results: Regional BOLD changes were not able to identify brain regions of flow limitation in chronically anemic patients. Higher blood oxygen content and tissue oxygenation were observed during hyperoxia gas challenge. Both control and anemic groups demonstrated lower blood flow, oxygen delivery, and metabolic rate compared to baseline, but the oxygen metabolism in anemic subjects were abnormally low during hyperoxic exposure., Conclusion: These results indicated that hyperoxic respiratory challenge could not be used to identify chronically ischemic brain. Furthermore, the low hyperoxia-induced metabolic rate suggested potential negative effects of prolonged oxygen therapy and required further studies to evaluate the risk for hyperoxia-induced oxygen toxicity and cerebral dysfunction., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Patients with transfusion-dependent β-thalassaemia require lifelong, regular red blood cell transfusions for survival; however, frequent blood transfusions are associated with an increased risk of iron overload, transfusion-transmitted disease and alloimmunization, as well as reduced quality of life. Luspatercept, an erythroid maturation agent that promotes late-stage erythroid maturation independently of erythropoietin, has demonstrated efficacy in reducing transfusion burden in patients with transfusion-dependent β-thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion-dependent patients with β-thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers., (© 2022 Wiley Periodicals LLC.)

Background: In patients with non-transfusion-dependent β-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent β-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent β-thalassaemia., Methods: We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of β-thalassaemia or haemoglobin E/β-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent β-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing., Findings: Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study., Interpretation: Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent β-thalassaemia, for whom effective approved treatment options are scarce., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests ATT reports receiving consulting fees from Agios Pharmaceuticals; and research funding and consulting fees from Celgene/Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis Pharmaceuticals, and Vifor Pharma. MDC reports receiving advisory board fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Novo Nordisk, Sanofi Genzyme, Silence Therapeutics, and Vifor Pharma. AK reports receiving advisory board fees and consulting fees from Agios Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor Pharma; and research support, paid to his institution, from Celgene/Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb, Chiesi Farmaceutuici, CRISPR Therapeutics/Vertex, and Novartis; and personal fees from Bristol Myers Squibb. SP reports receiving grant support, paid to his institution, from Novartis, and personal fees from bluebird bio and Celgene. AGP reports receiving grant support, paid to his institution, from Acceleron Pharma and Celgene, and advisory board fees from Celgene. AF reports advisory board fees from Celgene and grant support, paid to his institution, from bluebird bio and Novartis. JBP reports receiving advisory board fees from bluebird bio, Bristol Myers Squibb, Silence Therapeutics, and Vifor Pharma. TDC reports receiving consultancy fees from Agios Pharmaceuticals, bluebird bio, Bristol Myers Squibb/Celgene, Chiesi Farmaceutici, and Vifor Pharma. GLF reports receiving consulting fees and grant support, paid to his institution, from Agios Pharmaceuticals, Bristol Myers Squibb, and Novartis; and advisory board fees from Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb and Novartis. AA Thompson reports receiving grant support from Baxalta, Biomarin, bluebird bio, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Editas Medicine, and Novartis; and consulting fees from bluebird bio, Celgene/Bristol Myers Squibb, and CRISPR Therapeutics/Vertex; fees for leadership of fiduciary role in a committee or advocacy group from Global Blood Therapeutics; previous employment (last 12 months) at Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; and current employment at Children's Hospital of Philadelphia, Philadelphia, PA, USA. IT reports receiving honoraria from Celgene. KMM reports receiving consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Novartis, and Vifor Pharma. JTB reports ending employment at Acceleron Pharma in the last 12 months and owning stock in Acceleron Pharma, and Bristol Myers Squibb. OE, W-LK, and DM report being employed by Bristol Myers Squibb. ACG, JL-B, AY, and JKS report being employed by and owning stock in Bristol Myers Squibb. TZ reports ending employment at Bristol Myers Squibb in the last 24 months and owning stock in Bristol Myers Squibb. EV and VV report no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Liver iron concentration (LIC) measured by MRI has become the clinical reference standard for managing iron overload in chronically transfused patients. Transverse relaxivity (R 2 or R 2 * ) measurements are converted to LIC units using empirically derived calibration curves., Hypothesis: That flip angle (FA) error due to B 1 + spatial heterogeneity causes significant LIC quantitation error. B 1 + scale (b 1 , [FA actual /FA specified ]) variation is a major problem at 3 T which could reduce the accuracy of transverse relaxivity measurements., Study Type: Prospective., Population: Forty-seven subjects with chronic transfusional iron overload undergoing clinically indicated LIC assessment., Field Strength/sequence: 5 T/3 T dual-repetition time B 1 + mapping sequence ASSESSMENT: We quantified the average/standard deviation b 1 in the right and left lobes of the liver from B 1 + maps acquired at 1.5 T and 3 T. The impact of b 1 variation on spin echo LIC estimates was determined using a Monte Carlo model., Statistical Tests: Mean, median, and standard deviation in whole liver and right and left lobes; two-sided t-test between whole-liver b 1 means., Results: Average b 1 within the liver was 99.3% ± 12.3% at 1.5 T versus 69.6% ± 14.6% at 3 T and was independent of iron burden (P < 0.05). Monte Carlo simulations demonstrated that b 1 systematically increased R 2 estimates at lower LIC (<~25 mg/g at 1.5 T, <~15 mg/g at 3 T) but flattened or even inverted the R 2 -LIC relationship at higher LIC (≥~25 mg/g to 1.5 T, ≥~15 mg/g to 3 T); changes in the R 2 -LIC relationship were symmetric with respect to over and under excitation and were similar at 1.5 T and 3 T (for the same R 2 value). The R 2 * -LIC relationship was independent of b 1 ., Conclusion: Spin echo R 2 measurement of LIC at 3 T is error-prone without correction for b 1 errors. The impact of b 1 error on current 1.5 T spin echo-based techniques for LIC quantification is large enough to introduce measurable intersubject variability but the in vivo effect size needs a dedicated validation study., Technical Efficacy Stage: 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

Recent studies have shown that individuals with sickle cell disease (SCD) exhibit greater vasoconstriction responses to physical autonomic stressors, such as heat pain and cold pain than normal individuals, but this is not the case for mental stress (MTS). We sought to determine whether this anomalous finding for MTS is related to inter-group differences in baseline cardiac and vascular autonomic function. Fifteen subjects with SCD and 15 healthy volunteers participated in three MTS tasks: N-back, Stroop, and pain anticipation (PA). R-R interval (RRI), arterial blood pressure and finger photoplethysmogram (PPG) were continuously monitored before and during these MTS tasks. The magnitude of vasoconstriction was quantified using change in PPG amplitude (PPGa) from the baseline period. To represent basal autonomic function, we assessed both cardiac and vascular arms of the baroreflex during the baseline period. Cardiac baroreflex sensitivity (BRSc) was estimated by applying both the "sequence" and "spectral" techniques to beat-to-beat measurements of systolic blood pressure and RRIs. The vascular baroreflex sensitivity (BRSv) was quantified using the same approaches, modified for application to beat-to-beat diastolic blood pressure and PPGa measurements. Baseline BRSc was not different between SCD and non-SCD subjects, was not correlated with BRSv, and was not associated with the vasoconstriction responses to MTS tasks. BRSv in both groups was correlated with mean PPGa, and since both baseline PPGa and BRSv were lower in SCD, these results suggested that the SCD subjects were in a basal state of higher sympathetically mediated vascular tone. In both groups, baseline BRSv was positively correlated with the vasoconstriction responses to N-back, Stroop, and PA. After adjusting for differences in BRSv within and between groups, we found no difference in the vasoconstriction responses to all three mental tasks between SCD and non-SCD subjects. The implications of these findings are significant in subjects with SCD since vasoconstriction reduces microvascular flow and prolongs capillary transit time, increasing the likelihood for vaso-occlusive crisis (VOC) to be triggered by exposure to stressful events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thuptimdang, Shah, Khaleel, Sunwoo, Veluswamy, Kato, Coates and Khoo.)

Sickle cell anemia (SCA) is characterized by decreased red blood cell (RBC) deformability due to polymerization of deoxygenated hemoglobin, leading to abnormal mechanical properties of RBC, increased cellular adhesion, and microcirculatory obstruction. Prior work has demonstrated that NO• influences RBC hydration and deformability and is produced at a basal rate that increases under shear stress in normal RBC. Nevertheless, the origin and physiological relevance of nitric oxide (NO•) production and scavenging in RBC remains unclear. We aimed to assess the basal and shear-mediated production of NO• in RBC from SCA patients and control (CTRL) subjects. RBCs loaded with a fluorescent NO• detector, DAF-FM (4-Amino-5-methylamino- 2',7'-difluorofluorescein diacetate), were imaged in microflow channels over 30-min without shear stress, followed by a 30-min period under 0.5Pa shear stress. We utilized non-specific nitric oxide synthase (NOS) blockade and carbon monoxide (CO) saturation of hemoglobin to assess the contribution of NOS and hemoglobin, respectively, to NO• production. Quantification of DAF-FM fluorescence intensity in individual RBC showed an increase in NO• in SCA RBC at the start of the basal period; however, both SCA and CTRL RBC increased NO• by a similar quantity under shear. A subpopulation of sickle-shaped RBC exhibited lower basal NO• production compared to discoid RBC from SCA group, and under shear became more circular in the direction of shear when compared to discoid RBC from SCA and CTRL, which elongated. Both CO and NOS inhibition caused a decrease in basal NO• production. Shear-mediated NO• production was decreased by CO in all RBC, but was decreased by NOS blockade only in SCA. In conclusion, total NO• production is increased and shear-mediated NO• production is preserved in SCA RBC in a NOS-dependent manner. Sickle shaped RBC with inclusions have higher NO• production and they become more circular rather than elongated with shear., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Cerebral T 2 oximetry is a non-invasive imaging method to measure blood T 2 and cerebral venous oxygenation. Measured T 2 values are converted to oximetry estimates using carefully validated and potentially disease-specific calibrations. In sickle cell disease, red blood cells have abnormal cell shape and membrane properties that alter T 2 oximetry calibration relationships in clinically meaningful ways. Previous in vitro works by two independent groups established potentially competing calibration models., Methods: This study analyzed pooled datasets from these two studies to establish a unified and more robust sickle-specific calibration to serve as a reference standard in the field., Results: Even though the combined calibration did not demonstrate statistical superiority compared to previous models, the calibration was unbiased compared to blood-gas co-oximetry and yielded limits of agreement of (-10.1%, 11.6%) in non-transfused subjects with sickle cell disease. In transfused patients, this study proposed a simple correction method based on individual hemoglobin S percentage that demonstrated reduced bias in saturation measurement compared to previous uncorrected sickle calibrations., Conclusion: The combined calibration is based on a larger range of hematocrit, providing greater confidence in the hematocrit-dependent model parameters, and yielded unbiased estimates to blood-gas co-oximetry measurements from both sites. Additionally, this work also demonstrated the need to correct for transfusion in T 2 oximetry measurements for hyper-transfused sickle cell disease patients and proposes a correction method based on patient-specific hemoglobin S concentration., (© 2021 International Society for Magnetic Resonance in Medicine.)

Anemia is the most common blood disorder in the world. In patients with chronic anemia, such as sickle cell disease or major thalassemia, cerebral blood flow increases to compensate for decreased oxygen content. However, the effects of chronic anemia on oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO 2 ) are less well understood. In this study, we examined 47 sickle-cell anemia subjects (age 21.7 ± 7.1, female 45%), 27 non-sickle anemic subjects (age 25.0 ± 10.4, female 52%) and 44 healthy controls (age 26.4 ± 10.6, female 71%) using MRI metrics of brain oxygenation and flow. Phase contrast MRI was used to measure resting cerebral blood flow, while T 2 -relaxation-under-spin-tagging (TRUST) MRI with disease appropriate calibrations were used to measure OEF and CMRO 2 . We observed that patients with sickle cell disease and other chronic anemias have decreased OEF and CMRO 2 (respectively 27.4 ± 4.1% and 3.39 ± 0.71 ml O 2 /100 g/min in sickle cell disease, 30.8 ± 5.2% and 3.53 ± 0.64 ml O 2 /100 g/min in other anemias) compared to controls (36.7 ± 6.0% and 4.00 ± 0.65 ml O 2 /100 g/min). Impaired CMRO 2 was proportional to the degree of anemia severity. We further demonstrate striking concordance of the present work with pooled historical data from patients having broad etiologies for their anemia. The reduced cerebral oxygen extraction and metabolism are consistent with emerging data demonstrating increased non-nutritive flow, or physiological shunting, in sickle cell disease patients., (© 2021 Wiley Periodicals LLC.)

Transient increases in peripheral vasoconstriction frequently occur in obstructive sleep apnea and periodic leg movement disorder, both of which are common in sickle cell disease (SCD). These events reduce microvascular blood flow and increase the likelihood of triggering painful vaso-occlusive crises (VOC) that are the hallmark of SCD. We recently reported a significant association between the magnitude of vasoconstriction, inferred from the finger photoplethysmogram (PPG) during sleep, and the frequency of future VOC in 212 children with SCD. In this study, we present an improved predictive model of VOC frequency by employing a two-level stacking machine learning (ML) model that incorporates detailed features extracted from the PPG signals in the same database. The first level contains seven different base ML algorithms predicting each subject's pain category based on the input PPG characteristics and other clinical information, while the second level is a meta model which uses the inputs to the first-level model along with the outputs of the base models to produce the final prediction. Model performance in predicting future VOC was significantly higher than in predicting VOC prior to each sleep study (F1-score of 0.43 vs 0.35, p-value < 0.0001), consistent with our hypothesis of a causal relationship between vasoconstriction and future pain incidence, rather than past pain leading to greater propensity for vasoconstriction. The model also performed much better than our previous conventional statistical model (F1=0.33), as well as all other algorithms that used only the base-models for predicting VOC without the second tier meta model. The modest F1 score of the present predictive model was due in part to the relatively small database with substantial imbalance (176:36) between low-pain and high-pain subjects, as well as other factors not captured by the sleep data alone. This report represents the first attempt ever to use noninvasive finger PPG measurements during sleep and a ML-based approach to predict increased propensity for VOC crises in SCD. The promising results suggest the future possibility of embedding an improved version of this model in a low-cost wearable system to assist clinicians in managing long-term therapy for SCD patients.

Introduction: In β-thalassemia, imbalanced globin synthesis causes reduced red blood cell survival and ineffective erythropoiesis. Suppressed hepcidin levels increase ferroportin-mediated iron transport in enterocytes, causing increased iron absorption and potentially iron overload. Low hepcidin also stimulates ferroportin-mediated iron release from macrophages, increasing transferrin saturation (TSAT), potentially forming non-transferrin-bound iron, which can be toxic. Modulating the hepcidin-ferroportin axis is an attractive strategy to improve ineffective erythropoiesis and limit the potential tissue damage resulting from iron overload. There are no oral β-thalassemia treatments that consistently ameliorate anemia and prevent iron overload., Areas Covered: The preclinical and clinical development of vamifeport (VIT-2763), a novel ferroportin inhibitor, was reviewed. PubMed, EMBASE and ClinicalTrials.gov were searched using the search term 'VIT-2763'., Expert Opinion: Vamifeport is the first oral ferroportin inhibitor in clinical development. In healthy volunteers, vamifeport had comparable safety to placebo, was well tolerated and rapidly decreased iron levels and reduced TSAT, consistent with observations in preclinical models. Data from ongoing/planned Phase II studies are critical to define its potential in β-thalassemia and other conditions associated with iron overabsorption and/or ineffective erythropoiesis. If vamifeport potentially increases hemoglobin and reduces iron-related parameters, it could be a suitable treatment for non-transfusion-dependent and transfusion-dependent β-thalassemia.

Kidney iron deposition measured by R2* (magnetic resonance imaging) MRI is posited to result from tubular reabsorption of filtered haemoglobin due to intravascular haemolysis. In chronically transfused sickle cell disease (SCD), R2* is elevated and positively correlated with lactate dehydrogenase (LDH). To account for contributions to renal iron from systemic iron overload, we evaluated kidney R2*, urinary iron and haemolysis markers in 62 non-transfused SCD patients. On multivariate analysis, kidney R2* was associated with urinary iron and LDH (R 2  = 0·55, P < 0·0001). Our study confirms that kidney R2* is associated with intravascular haemolysis and raises important questions regarding the role of iron in SCD nephropathy., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α-globin protein from loss of up to four α-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two α-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α-globin gene deletions affect sickle red cell deformability, the α-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α-globin due to α-thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow-mediated dilation and microvascular post-occlusive reactive hyperemia in 27 human subjects (15 missing one or two α-globin genes and 12 healthy controls). Flow-mediated dilation was significantly higher in subjects with α-trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α-globin gene status. This may explain the beneficial effect of α-globin gene loss in sickle cell disease and suggests that α-globin gene status may play a role in other vascular diseases., (© 2020 Wiley Periodicals LLC.)

The basic model of SCD physiology states that vaso-occlusion occurs when hemoglobin S-containing red blood cells (RBC) undergo sickling before they escape the capillary into a larger vessel. We have shown that mental stress, pain and cold, and events reported by patients to trigger SCD vaso-occlusive crisis (VOC), cause rapid and significant decrease in blood flow, reducing the likelihood that RBC could transit the microvasculature before sickling occurs. However, the critical link between decrease in microvascular blood flow and the incidence of future sickle VOC has never been established experimentally in humans. Using data from centrally adjudicated, overnight polysomnograms (PSG), previously collected in a prospective multi-center cohort sleep study, we analyzed the beat-to-beat amplitudes of vasoconstriction reported by the fingertip photoplethysmogram in 212 children and adolescents with SCD and developed an algorithm that detects vasoconstriction events and quantifies the magnitude (M vasoc ), duration, and frequency of vasoconstriction that reflect the individual's inherent peripheral vasoreactivity. The propensity to vasoconstrict, quantified by median M vasoc , predicted the incidence rate of post-PSG severe acute vaso-occlusive pain events (P = .006) after accounting for age and hemoglobin. Indices of sleep-disordered breathing contributed to median M vasoc but did not predict future pain rate. Median M vasoc was not associated with vaso-occlusive pain events that occurred prior to each PSG. These results show that SCD individuals with high inherent propensity to vasoconstrict have more frequent severe acute pain events. Our empirical findings are consistent with the fundamental SCD hypothesis that decreased microvascular flow promotes microvascular occlusion., (© 2020 Wiley Periodicals LLC.)

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty-eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional-hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end-organ failure. On Cox proportional-hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S' results in a 91% increase, and 1 cm/s decrease in E' results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers., (© 2020 Wiley Periodicals LLC.)