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Abstract: Etavopivat is an investigational, once daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: 1 single-dose, 2 multiple ascending doses, and 1 open-label (OL). In the OL cohort, 15 patients (median age 33.0 years [range, 17-55]) received 400 mg etavopivat once daily for 12 weeks; 14 patients completed treatment. Consistent with the mechanism of PKR activation, increases in adenosine triphosphate and decreases in 2,3-diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in hemoglobin (Hb; mean maximal increase 1.6 g/dL [range, 0.8-2.8]), with >1 g/dL increase in 11 (73%) patients during treatment. In addition, the oxygen tension at which Hb is 50% saturated was reduced (P = .0007) with a concomitant shift in point of sickling (P = .0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, and lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n = 7) in the OL cohort. In this, to our knowledge, the first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well tolerated, resulting in rapid and sustained increases in Hb, improved red blood cell physiology, and decreased hemolysis. This trial was registered at www.ClinicalTrials.gov as #NCT03815695., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Vaso-occlusive crises (VOCs) cause debilitating pain and are a common cause of emergency department (ED) visits, for people with sickle cell disease (SCD). Strategies for achieving optimal pain control vary widely despite evidence-based guidelines. We tested existing guidelines and hypothesized that a patient-specific pain protocol (PSP) written by their SCD provider may be more effective than weight-based (WB) dosing of parenteral opiate medication, in relieving pain., Methods: This study was a prospective, randomized controlled trial comparing a PSP versus WB protocol for patients presenting with VOCs to six EDs. Patients were randomized to a PSP or WB protocol prior to an ED visit. The SCD provider wrote their protocol and placed it in the electronic health record for future ED visits with VOC exclusion criteria that included preexisting PSP excluding parenteral opioid analgesia or outpatient use of buprenorphine or methadone or highly suspected for COVID-19. Pain intensity scores, side effects, and safety were obtained every 30 min for up to 6 h post-ED bed placement. The primary outcome was change in pain intensity score from placement in an ED space to disposition or 6 h., Results: A total of 328 subjects were randomized; 104 participants enrolled (ED visit, target n = 230) with complete data for 96 visits. The study was unable to reach the target sample size and stopped early due to the impact of COVID-19. We found no significant differences between groups in the primary outcome; patients randomized to a PSP had a shorter ED length of stay (p = 0.008), and the prevalence of side effects was low in both groups. Subjects in both groups experienced both a clinically meaningful and a statistically significant decrease in pain (27 mm on a 0- to 100-mm scale)., Conclusions: We found a shorter ED length of stay for patients assigned to a PSP. Patients in both groups experienced good pain relief without significant side effects., (© 2023 Society for Academic Emergency Medicine.)

Hydroxyurea (HU) is an effective but underused disease-modifying therapy for patients with sickle cell anaemia (SCA). EMBRACE SCD, a sickle cell disease treatment demonstration project, aimed to improve access to HU by increasing prescription (Rx) rates by at least 10% from baseline in children with SCA.The Model for Improvement was used as the quality improvement framework. HU Rx was assessed from clinical databases in three paediatric haematology centres. Children aged 9 months-18 years with SCA not on chronic transfusions were eligible for HU treatment. The health belief model was the conceptual framework to discuss with patients and promote HU acceptance. A visual aid showing erythrocytes under the effect of HU and the American Society of Hematology HU brochure were used as educational tools. At least 6 months after offering HU, a Barrier Assessment Questionnaire was given to assess reasons for HU acceptance and refusals. If HU was declined, the providers discussed with family again. We conducted chart audits to find missed opportunities to prescribe HU as one plan-do-study-act cycle.At initial measurement, 50.2% of 524 eligible patients had HU prescribed. During the testing and initial implementation phase, the mean performance after 10 data points was 53%. After 2 years, the mean performance was 59%, achieving an 11% increase in mean performance and a 29% increase from initial to the last measurement (64.8% HU Rx). During a 15-month period, 32.1% (N=168) of the eligible patients who were offered HU completed the barrier questionnaire with 19% (N=32) refusing HU, mostly based on not perceiving enough severity of their children's SCA or fearing side effects.Reviewing patient charts for missed opportunity of offering HU with feedback and evaluating the reasons of declining HU via a questionnaire were key components in increasing HU Rx in our population., Competing Interests: Competing interests: ELJC and IO report employment by Forma Therapeutics, now part of Novo Nordisk. IO also reports funding by Patient-Centered Outcomes Research Institute (PCORI) for another study., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Emerging adults with sickle cell disease (EASCD) experience significant challenges transitioning from pediatric to adult care. Acute care utilization increases, quality of life (QOL) declines, with an increased risk of mortality. Currently, there are no practice standards to guide emerging adults through the transition process. We are creating a structured transition education (STE) based program for EASCD by customizing the Six Core Elements (6 CE) of Health Care Transition model and are evaluating the effectiveness of adding peer mentoring (PM)., Methods: The Sickle Cell Trevor Thompson Transition Project (ST3P-UP) is an ongoing multi-site, cluster randomized clinical trial with a target enrollment of 537 EASCD aged 16 to 25 years in pediatric care. Each site (n = 14) comprises a pediatric clinic, adult clinic, and a sickle cell disease (SCD) community-based organization (CBO). Sites are randomized 1:1 to either STE or STE + PM. EASCDs are followed prospectively for 24 months. Rapid cycle plan-do-study-act quality improvement (QI) methods are used to implement the STE. The primary objective is to compare the effectiveness of STE + PM versus STE only at decreasing the number of acute care visits per year over 24 months. The secondary objectives are to compare overall healthcare utilization and patient-reported QOL outcomes at 24 months., Conclusion: We aim to demonstrate the feasibility of using a QI approach to implement 6 CE-based practice standards at 14 disparate SCD clinical programs to guide EASCD through the transition process. We hypothesize that adding PM to the STE program will improve acute care reliance, QOL, and satisfaction with transition outcomes., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: I.O. received grant funding from HRSA, CDC; and previously served as a consultant for Novartis, Global Blood Therapeutics, Forma Therapeutics, Cyclerion, Emmaus, Cheisi, and Acceleron. P.D. received grant funding from CHL-Bhering, Takeda, UPMC, UT Memphis, NIH, Forma, and Novartis; and serves as a NMDP study monitor and Forma advisory board member. The remaining authors have no relevant interests to declare., (Copyright © 2023. Published by Elsevier Inc.)

The international Sickle Cell World Assessment Survey (SWAY) reported a high impact of sickle cell disease (SCD) on patients' daily lives globally. In this study, we analyzed whether the reported burden differed between patients from the USA (n = 384) and other high-income (HI; n = 820) or low- to middle-income (LMI; n = 941) countries. We assessed symptoms and complications, incidence/management of vaso-occlusive crises (VOCs), treatment utilization/satisfaction, and the impact of SCD on education/employment. Certain symptoms (bone aches, insomnia, and joint stiffness) and complications (swollen/painful fingers/toes, gallstones, vision problems, blood clots, and asthma) were reported proportionally more by patients in the USA than in the HI/LMI countries. Self-reported VOCs were more common (mean [SD]: 7.1 [5.7] vs. 5.5 [8.9] and 4.4 [4.6] in the previous 12 months) and were managed more often by hospitalization (52% vs. 24% and 32%) in the USA than the HI and LMI countries. A higher proportion of patients from the USA than the HI/LMI countries reported a negative impact of SCD on their employment/schooling. Although high overall satisfaction with current treatments was reported globally, most patients indicated a strong desire for alternative pain medications. There are likely several reasons for the relatively high patient-reported burden in the USA group compared with the HI/LMI countries, including an older population and differences in newborn screening programs and pediatric/adult transition of care. It is clear that there is an urgent need for improved understanding and management of SCD globally, not just in the USA., (© 2022 Novartis Pharmaceuticals. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Health systems and providers across America are increasingly employing telehealth technologies to better serve medically underserved low-income, minority, and rural populations at the highest risk for health disparities. The Patient-Centered Outcomes Research Institute (PCORI) has invested US $386 million in comparative effectiveness research in telehealth, yet little is known about the key early lessons garnered from this research regarding the best practices in using telehealth to address disparities., Objective: This paper describes preliminary lessons from the body of research using study findings and case studies drawn from PCORI seminal patient-centered outcomes research (PCOR) initiatives. The primary purpose was to identify common barriers and facilitators to implementing telehealth technologies in populations at risk for disparities., Methods: A systematic scoping review of telehealth studies addressing disparities was performed. It was guided by the Arksey and O'Malley Scoping Review Framework and focused on PCORI's active portfolio of telehealth studies and key PCOR identified by study investigators. We drew on this broad literature using illustrative examples from early PCOR experience and published literature to assess barriers and facilitators to implementing telehealth in populations at risk for disparities, using the active implementation framework to extract data. Major themes regarding how telehealth interventions can overcome barriers to telehealth adoption and implementation were identified through this review using an iterative Delphi process to achieve consensus among the PCORI investigators participating in the study., Results: PCORI has funded 89 comparative effectiveness studies in telehealth, of which 41 assessed the use of telehealth to improve outcomes for populations at risk for health disparities. These 41 studies employed various overlapping modalities including mobile devices (29/41, 71%), web-based interventions (30/41, 73%), real-time videoconferencing (15/41, 37%), remote patient monitoring (8/41, 20%), and store-and-forward (ie, asynchronous electronic transmission) interventions (4/41, 10%). The studies targeted one or more of PCORI's priority populations, including racial and ethnic minorities (31/41, 41%), people living in rural areas, and those with low income/low socioeconomic status, low health literacy, or disabilities. Major themes identified across these studies included the importance of patient-centered design, cultural tailoring of telehealth solutions, delivering telehealth through trusted intermediaries, partnering with payers to expand telehealth reimbursement, and ensuring confidential sharing of private information., Conclusions: Early PCOR evidence suggests that the most effective health system- and provider-level telehealth implementation solutions to address disparities employ patient-centered and culturally tailored telehealth solutions whose development is actively guided by the patients themselves to meet the needs of specific communities and populations. Further, this evidence shows that the best practices in telehealth implementation include delivery of telehealth through trusted intermediaries, close partnership with payers to facilitate reimbursement and sustainability, and safeguards to ensure patient-guided confidential sharing of personal health information., (©James E Bailey, Cathy Gurgol, Eric Pan, Shirilyn Njie, Susan Emmett, Justin Gatwood, Lynne Gauthier, Lisa G Rosas, Shannon M Kearney, Samantha Kleindienst Robler, Raymona H Lawrence, Karen L Margolis, Ifeyinwa Osunkwo, Denise Wilfley, Vallabh O Shah. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.12.2021.)

Purpose: To compare the incidence of oversedation between oral and parenteral diphenhydramine therapy for treatment of opioid-induced pruritus in patients with sickle cell disease vaso-occlusive crisis (SCD VOC). Methods: This retrospective, single-center, cohort study included patients greater than or equal to 18 years old with sickle cell disease admitted for vaso-occlusive crisis who received either intravenous or oral diphenhydramine for opioid-induced pruritus. Patients were identified through ICD-9 and ICD-10 codes from June 1, 2016 through July 1, 2017. Rates of oversedation were compared between the 2 formulations. Secondary endpoints included length of stay, amount and duration of diphenhydramine, rate of acute chest and indication for IV therapy. Results: Fifty unique patients were included in the analysis representing 121 admissions. Seven patients received both formulations on separate admissions and were included in both groups. Twenty-nine percent of patients in the IV diphenhydramine group experienced oversedation (12/42) versus 13% in the oral diphenhydramine group (2/15, P  = .312). The average number of admissions was significantly higher in the IV versus oral group (2.45 vs 1.20; P  = .005) with average and median length of stay also significantly higher in the IV versus oral group (30.57, 16.0 vs 10.67, 10.0; P  = .003). Conclusion: While there was no statistically significant difference in the rates of oversedation with use of IV versus oral diphenhydramine formulations, patients with SCD VOC who received IV diphenhydramine had more frequent admissions and a longer length of stay. Clinicians may consider oral diphenhydramine preferentially in appropriate patients over IV administration., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Measuring the effectiveness of transitional care interventions has historically relied on health care utilization as the primary outcome. Although the Care Transitions Measure was the first outcome measure specifically developed for transitional care, its applicability beyond the hospital-to-home transition is limited. There is a need for patient-centered outcome measures (PCOMs) to be developed for transitional care settings (ie, TC-PCOMs) to ensure that outcomes are both meaningful to patients and relevant to the particular care transition. The overall objective of this paper is to describe the opportunities and challenges of integrating TC-PCOMs into research and practice., Methods and Results: This narrative review was conducted by members of the Patient-Centered Outcomes Research Institute (PCORI) Transitional Care Evidence to Action Network. We define TC-PCOMs as outcomes that matter to patients because they account for their individual experiences, concerns, preferences, needs, and values during the transition period. The cardinal features of TC-PCOMs should be that they are developed following direct input from patients and stakeholders and reflect their lived experience during the transition in question. Although few TC-PCOMs are currently available, existing patient-reported outcome measures could be adapted to become TC-PCOMs if they incorporated input from patients and stakeholders and are validated for the relevant care transition., Conclusion: Establishing validated TC-PCOMs is crucial for measuring the responsiveness of transitional care interventions and optimizing care that is meaningful to patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Sickle cell disease (SCD) is a genetic disorder, characterized by hemolytic anemia and vaso-occlusive crises (VOCs). Data on the global SCD impact on quality of life (QoL) from the patient viewpoint are limited. The international Sickle Cell World Assessment Survey (SWAY) aimed to provide insights into patient-reported impact of SCD on QoL. This cross-sectional survey of SCD patients enrolled by healthcare professionals and advocacy groups assessed disease impact on daily life, education and work, symptoms, treatment goals, and disease management. Opinions were captured using a Likert scale of 1-7 for some questions; 5-7 indicated "high severity/impact." Two thousand one hundred and forty five patients (mean age 24.7 years [standard deviation (SD) = 13.1], 39% ≤18 years, 52% female) were surveyed from 16 countries (six geographical regions). A substantial proportion of patients reported that SCD caused a high negative impact on emotions (60%) and school achievement (51%) and a reduction in work hours (53%). A mean of 5.3 VOCs (SD = 6.8) was reported over the 12 months prior to survey (median 3.0 [interquartile range 2.0-6.0]); 24% were managed at home and 76% required healthcare services. Other than VOCs, fatigue was the most commonly reported symptom in the month before survey (65%), graded "high severity" by 67% of patients. Depression and anxiety were reported by 39% and 38% of patients, respectively. The most common patient treatment goal was improving QoL (55%). Findings from SWAY reaffirm that SCD confers a significant burden on patients, epitomized by the high impact on patients' QoL and emotional wellbeing, and the high prevalence of self-reported VOCs and other symptoms., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Chronic pain in sickle cell disease (SCD) refers to pain present on most days lasting over six months. It can start during childhood and the prevalence increases with age. By adulthood, over 55% of patients experience pain on over 50% of days; 29% reporting pain on 95% of days. The true prevalence of chronic pain in SCD is likely underappreciated as it is mostly managed at home. Patients with chronic pain and SCD frequently seek acute care for exacerbation of underlying chronic pain difficult to distinguish from their usual acute vaso-occlusive crises. When treating chronic pain in SCD, the challenge is distinguishing between non-SCD related etiologies versus chronic pain resulting from SCD pathophysiological processes. This distinction is important to delineate as it will drive appropriate management strategies. Chronic pain in SCD has profound consequences for the patient; is often associated with comorbid psychiatric illnesses (depression and anxiety), not dissimilar from other chronic pain syndromes. They may also experience challenges with sleep hygiene, various somatic symptoms, and chronic fatigue that impair quality of life. How best to treat chronic pain in SCD is not definitively established. Both acute and chronic pain in SCD is typically treated with opioids. Emerging data suggests that chronic opioid therapy (COT) is a suboptimal treatment strategy for chronic pain. This review will discuss the complexity of managing chronic pain in SCD; pain that may be dependent or independent of the underlying SCD diagnosis. We will also describe alternative treatment approaches to high-dose COT., Competing Interests: Conflict-of-interest disclosure: I.O. has consulted for Novartis, Pfizer, Cyclerion, Forma Therapeutics, Acceleron Pharma, MagellanRx; been on the speakers' bureau for Novartis, Terumo, and Global Blood Therapeutics; been on the advisory board for Novartis, Pfizer, Acceleron, Cyclerion, and Global Blood Therapeutics; received grants from Health Resources and Services Administration, Patient Centered Outcomes Research Institute, NC State Dept. of Health and Human Services, and Data and Safety Monitoring Boards; has membership for Micella Biopharma ASH Guidelines Panel and the National Academies of Sciences, Engineering, and Medicine SCD study committee; and is the Hematology News board editor-in-chief. E.S. is on the advisory board for FORMA therapeutics and has received Health Resources and Services Administration funding. H.F.O. declares no competing financial interests., (© 2020 by The American Society of Hematology.)

Attendance at professional conferences is an important component of career development, because conferences are a major forum for presenting new research, interacting with colleagues and networking. An extensive literature documents differences in the professional experiences of women and men, including experiences at professional conferences. We hypothesized that women are less likely than men to ask questions at conferences, thus forgoing opportunities for professional development. To address this issue, we analyzed the question-asking behavior of women and men at the 2019 Annual Meeting and Exposition of the American Society of Hematology. In all, 112 sessions (55% of those eligible) were randomly chosen for coding, yielding data on 577 presentations. Although approximately 50% of moderators and speakers were women, the proportion of questions asked by women was significantly lower compared with the estimated proportion of women attending the conference (23% vs 39%; P < .0001). Women were more likely to ask questions if another woman asked the first question or if the session topic was red cells. These results suggest that although women are represented equally as moderators and speakers, they are less likely to engage in the postpresentation discourse by asking questions. Encouraging women to speak up in professional situations and providing training on question-asking skills can help address this gender gap that potentially contributes to disparities in professional visibility and career advancement for women in hematology.

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management., Competing Interests: Conflict of interest statement: IO has received research funding from Health Resources and Services Administration, North Carolina Division of Public Health, and Patient-Centered Outcomes Research Institute; served as a consultant for Cyclerion Therapeutics Inc., Global Blood Therapeutics, Novartis Pharmaceuticals Corp., and Pfizer Inc; participated on advisory boards for Acceleron Biopharma, Forma Therapeutics, Global Blood Therapeutics, Novartis Pharmaceuticals Corp., and Pfizer Inc; participated on the speakers’ bureau for Global Blood Therapeutics, Novartis Pharmaceutics Corp., and Terumo Medical Corporation; and is a member of the Data and Safety Monitoring Board for Micelle BioPharma Inc.; currently serves as Editor in Chief of Hematology News. DM has received research funding from bluebird bio and Global Blood Therapeutics, and served as a consultant for Global Blood Therapeutics, Novartis Pharmaceuticals Corp., and Pfizer Inc. JK has received research funding from Health Resources and Services Administration, Center for Disease Control, and National Institute of Health as well as from bluebird bio and Novartis Pharmaceuticals Corp.; served as a consultant for bluebird bio, Imara Inc., Modus Therapeutics, Novartis Pharmaceuticals Corp., Agios, Beam Therapeutics, and Sanofi; and received honoraria from Bluebird Bio, Global Blood Therapeutics and Terumo Medical Corporation., (© The Author(s), 2020.)

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. It is a medically and socially complex, multisystem illness that affects individuals throughout the lifespan. Given improvements in care, most children with SCD survive into adulthood. However, access to adult sickle cell care is poor in many parts of the United States, resulting in increased acute care utilization, disjointed care delivery, and early mortality for patients. A dearth of nonmalignant hematology providers, the lack of a national SCD registry, and the absence of a centralized infrastructure to facilitate comparative quality assessment compounds these issues. As part of a workshop designed to train health care professionals in the skills necessary to establish clinical centers focused on the management of adults living with SCD, we defined an SCD center, elucidated required elements of a comprehensive adult SCD center, and discussed different models of care. There are also important economic impacts of these centers at an institutional and health system level. As more clinicians are trained in providing adult-focused SCD care, center designation will enhance the ability to undertake quality improvement and compare outcomes between SCD centers. Activities will include an assessment of the clinical effectiveness of expanded access to care, the implementation of SCD guidelines, and the efficacy of newly approved targeted medications. Details of this effort are provided., (© 2020 by The American Society of Hematology.)

Background: Sickle cell disease (SCD) is a genetic chronic haemolytic and pro-inflammatory disorder. With increased catabolism and deficits in energy and nutrient intake, individuals with SCD suffer multiple macro- and micro-nutritional deficiencies, including vitamin D deficiency. This is an update of a previous review., Objectives: To investigate the effects of vitamin D supplementation in children and adults with SCD and to compare different dose regimens. To determine the effects of vitamin D supplementation on general health (e.g. growth status and health-related quality of life), on musculoskeletal health (including bone mineral density, pain crises, bone fracture and muscle health), on respiratory health (including lung function, acute chest syndrome, acute exacerbation of asthma and respiratory infections) and the safety of vitamin D supplementation., Search Methods: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 March 2020. We also searched database such as PubMed, clinical trial registries and the reference lists of relevant articles and reviews. Date of last search: 14 January 2020., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing oral administration of any form of vitamin D supplementation at any dose and for any duration to another type or dose of vitamin D or placebo or no supplementation in people with SCD, of all ages, gender, and phenotypes., Data Collection and Analysis: Two authors independently extracted the data and assessed the risk of bias of the included studies. They used the GRADE guidelines to assess the quality of the evidence., Main Results: Vitamin D versus placebo One double-blind RCT (n = 39) compared oral vitamin D3 (cholecalciferol) supplementation (20 participants) to placebo (19 participants) for six weeks. Only 25 participants completed the full six months of follow-up. The study had a high risk of bias due to incomplete outcome data, but a low risk of bias for randomisation, allocation concealment, blinding (of participants, personnel and outcome assessors) and selective outcome reporting; and an unclear risk of other biases. Vitamin D supplementation probably led to higher serum 25(OH)D levels at eight weeks, mean difference (MD) 29.79 (95% confidence interval (CI) 26.63 to 32.95); at 16 weeks, MD 12.67 (95% CI 10.43 to 14.90); and at 24 weeks, MD 15.52 (95% CI 13.50 to 17.54) (moderate-quality evidence). There was little or no difference in adverse events (tingling of lips or hands) between the vitamin D and placebo groups, risk ratio 3.16 (95% CI 0.14 to 72.84) (low-quality evidence). Vitamin D supplementation probably caused fewer pain days compared to the placebo group at eight weeks, MD -10.00 (95% CI -16.47 to -3.53) (low-quality evidence), but probably led to a lower (worse) health-related quality of life score (change from baseline in physical functioning PedsQL scores); at both 16 weeks, MD -12.56 (95% CI -16.44 to -8.69) and 24 weeks, MD -12.59 (95% CI -17.43 to -7.76), although this may not be the case at eight weeks (low-quality evidence). Vitamin D supplementation regimens compared Two double-blind RCTs (83 participants) compared different regimens of vitamin D. One RCT (n = 62) compared oral vitamin D3 7000 IU/day to 4000 IU/day for 12 weeks, while the second RCT (n = 21) compared oral vitamin D3 100,000 IU/month to 12,000 IU/month for 24 months. Both RCTs had low risk of bias for blinding (of participants, personnel and outcome assessors) and incomplete outcome data, but the risk of selective outcome reporting bias was high. The bias from randomisation and allocation concealment was low in one study but not in the second. There was an unclear risk of other biases. When comparing oral vitamin D 100,000 IU/month to 12,000 IU/month, the higher dose may have resulted in higher serum 25(OH)D levels at one year, MD 16.40 (95% CI 12.59 to 20.21) and at two years, MD 18.96 (95% CI 15.20 to 22.72) (low-quality evidence). There was little or no difference in adverse events between doses (low-quality evidence). There were more episodes of acute chest syndrome in the high-dose group, at one year, MD 0.27 (95% CI 0.02 to 0.52) but there was little or no difference at two years, MD 0.09 (95% CI -0.04 to 0.22) (moderate-quality evidence). At one year and two years there was also little or no difference between the doses in the presence of pain (moderate-quality evidence) or forced expiratory volume in one second % predicted. However, the high-dose group had lower values for % predicted forced vital capacity at both one and two years, MD -7.20% predicted (95% CI -14.15 to -0.25) and MD -7.10% predicted (95% CI -14.03 to -0.17), respectively. There were little or no differences between dose regimens in the muscle health of either hand or the dominant hand. The study comparing oral vitamin D3 7000 IU/day to 4000 IU/day (21 participants) did not provide data for analysis, but median serum 25(OH)D levels were reported to be lower in the low-dose group at both six and 12 weeks. At 12 weeks the median serum parathyroid hormone level was lower in the high-dose group., Authors' Conclusions: We included three RCTs of varying quality. We consider that the current evidence presented in this review is not of sufficient quality to guide clinical practice. Until further evidence becomes available, clinicians should consider the relevant existing guidelines for vitamin D supplementation and dietary reference intakes for calcium and vitamin D. Well-designed RCTs of parallel design, are required to determine the effects and the safety of vitamin D supplementation as well as to assess the relative benefits of different doses in children and adults with SCD., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Prevention and management of end-organ disease represent major challenges facing providers of children and adults with sickle cell disease (SCD). Uncertainty and variability in the screening, diagnosis, and management of cardiopulmonary and renal complications in SCD lead to varying outcomes for affected individuals., Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD., Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews up to September 2017. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment., Results: The panel agreed on 10 recommendations for screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Recommendations related to anticoagulation duration for adults with SCD and venous thromboembolism were also developed., Conclusions: Most recommendations were conditional due to a paucity of direct, high-quality evidence for outcomes of interest. Future research was identified, including the need for prospective studies to better understand the natural history of cardiopulmonary and renal disease, their relationship to patient-important outcomes, and optimal management., (© 2019 by The American Society of Hematology.)

Sickle cell disease (SCD) is associated with pain and decreased health-related quality of life (HRQOL). Coping strategies influence pain but have not been evaluated as mediating the relation between pain and HRQOL in pediatric SCD. The current study examined whether pain-related coping mediates the association between pain and HRQOL in children and adolescents with SCD. In total, 104 children and adolescents 8 to 18 years of age (Mage=12.93 y) with SCD attending outpatient clinics completed pain intensity, HRQOL, and pain-related coping measures. Multiple mediation analyses were used to examine whether pain-related coping mediated the pain and HRQOL relation and whether types of coping (ie, approach, emotion-focused avoidance, problem-focused avoidance) were independent mediators. Total indirect effects for models examining physical and psychosocial HRQOL were not significant. After controlling for covariates, emotion-focused avoidance significantly mediated the association between pain and physical HRQOL (effect: -0.023; bootstrapped SE: 0.018; 95% confidence interval: -0.0751, -0.0003) but not the pain and psychosocial HRQOL relation. Approach and problem-focused avoidance were not significant mediators. Coping with pain in pediatric SCD is an important avenue for clinical intervention and additional research. Among children with SCD reporting high pain intensity, interventions should emphasize negative impacts of emotion-focused avoidance coping and integrate other empirically supported coping strategies to improve HRQOL.

Background: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain., Methods: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle β 0 -thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period., Results: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group., Conclusions: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

Background: Sickle cell disease is a genetic chronic haemolytic and pro-inflammatory disorder. The clinical manifestations of sickle cell disease result from the presence of mutations on the beta globin genes that generate an abnormal haemoglobin product (called haemoglobin S) within the red blood cell. Sickle cell disease can lead to many complications such as acute chest syndrome, stroke, acute and chronic bone complications (including painful vaso-occlusive crisis, osteomyelitis, osteonecrosis and osteoporosis). With increased catabolism and deficits in energy and nutrient intake, individuals with sickle cell disease suffer multiple macro- and micro-nutritional deficiencies, including vitamin D deficiency. Since vitamin D maintains calcium homeostasis and is essential for bone mineralisation, its deficiency may worsen musculoskeletal health problems encountered in sickle cell disease. Therefore, there is a need to review the effects and the safety of vitamin D supplementation in sickle cell disease., Objectives: To investigate the hypothesis that vitamin D supplementation increases serum 25-hydroxyvitamin D level in children and adults with sickle cell disease.To determine the effects of vitamin D supplementation on general health such as growth status and health-related quality of life; on musculoskeletal health including bone mineral density, pain crises, bone fracture and muscle health; on respiratory health which includes lung function tests, acute chest syndrome, acute exacerbation of asthma and respiratory infections; and the safety of vitamin D supplementation in children and adults with sickle cell disease., Search Methods: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched database such as PubMed, clinical trial registries and the reference lists of relevant articles and reviews.Date of last search: 15 December 2016., Selection Criteria: Randomised controlled studies and quasi-randomised controlled studies (controlled clinical studies) comparing oral administration of any form of vitamin D supplementation to another type of vitamin D or placebo or no supplementation at any dose and for any duration, in people with sickle cell disease, of all ages, gender, and phenotypes including sickle cell anaemia, haemoglobin sickle cell disease and sickle beta-thalassaemia diseases., Data Collection and Analysis: Two authors independently extracted the data and assessed the risk of bias of the included study. They used the GRADE guidelines to assess the quality of the evidence., Main Results: One double-blind randomised controlled study including 46 people with sickle cell disease (HbSS, HbSC, HbSβ+thal and HbSβ0thal) was eligible for inclusion in this review. Of the 46 enrolled participants, seven withdrew before randomisation leaving 39 participants who were randomised. Only 25 participants completed the full six months of follow up. Participants were randomised to receive oral vitamin D3 (cholecalciferol) (n = 20) or placebo (n = 19) for six weeks and were followed up to six months. Two participants from the treatment group have missing values of baseline serum 25-hydroxyvitamin D, therefore the number of samples analysed was 37 (vitamin D n = 18, placebo n = 19).The included study had a high risk of bias with regards to incomplete outcome data (high dropout rate in the placebo group), but a low risk of bias for other domains such as random sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, selective outcome reporting; and an unclear risk of other biases.Compared to the placebo group, the vitamin D group had significantly higher serum 25-hydroxyvitamin D (25(OH)D) levels at eight weeks, mean difference 29.79 (95% confidence interval 26.63 to 32.95); at 16 weeks, mean difference 12.67 (95% confidence interval 10.43 to 14.90); and at 24 weeks, mean difference 15.52 (95% confidence interval 13.50 to 17.54). We determined the quality of the evidence for this outcome to be moderate. There was no significant difference of adverse events (tingling of lips or hands) between the vitamin D and placebo groups, risk ratio 3.16 (95% confidence interval 0.14 to 72.84), but the quality of the evidence was low. Regarding the frequency of pain, the vitamin D group had significantly fewer pain days compared to the placebo group, mean difference -10.00 (95% confidence interval -16.47 to -3.53), but again the quality of the evidence was low. Furthermore, the review included physical functioning PedsQL scores which was reported as absolute change from baseline. The vitamin D group had a lower (worse) health-related quality of life score than the placebo group but this was not significant at eight weeks, mean difference -2.02 (95% confidence interval -6.34 to 2.30). However, the difference was significant at both 16 weeks, mean difference -12.56 (95% confidence interval -16.44 to -8.69) and 24 weeks, mean difference -12.59 (95% confidence interval -17.43 to -7.76). We determined the quality of evidence for this outcome to be low., Authors' Conclusions: We included only one low-quality clinical study which had a high risk of bias with regards to incomplete outcome data. Therefore, we consider that the evidence is not of sufficient quality to guide clinical practice. Until further evidence becomes available, clinicians should consider the relevant existing guidelines for vitamin D supplementation (e.g. the Endocrine Society Clinical Practice Guidelines) and dietary reference intakes for calcium and vitamin D (e.g. from the USA Institute of Medicine). Evidence of vitamin D supplementation in sickle cell disease from high quality studies is needed. Well-designed, randomised, placebo-controlled studies of parallel design, are required to determine the effects and the safety of vitamin D supplementation in children and adults with sickle cell disease.

'Paradoxical' embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2-19 years) with SCA + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45·6% vs. 23·6%, P < 0·001). The odds ratio for potential RLS in the SCA + stroke group was 2·7 (95% confidence interval: 1·6-4·6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA., Competing Interests: of Conflicts of Interest WO is on the Novartis Speaker’s Bureau, JAP reports research funding from the NIH and ASH. The other authors have nothing to disclose., (© 2016 John Wiley & Sons Ltd.)

Background: Osteoporosis is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis represents an important cause of morbidity in people with beta-thalassaemia and its pathogenesis is multifactorial. Factors include bone marrow expansion due to ineffective erythropoiesis, resulting in reduced trabecular bone tissue with cortical thinning; endocrine dysfunction secondary to excessive iron loading, leading to increased bone turnover; and lastly, a predisposition to physical inactivity due to disease complications with a subsequent reduction in optimal bone mineralization.A number of therapeutic strategies have been applied to treat osteoporosis in people with beta-thalassaemia, which include bisphosphonates, with or without, hormone replacement therapy. There are various forms of bisphosphonates, such as clodronate, pamidronate, alendronate and zoledronic acid. Other treatments include calcitonin, calcium, zinc supplementation, hydroxyurea and hormone replacement therapy for preventing hypogonadism., Objectives: To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 04 February 2016., Selection Criteria: Randomised, placebo-controlled trials in people with thalassaemia with a bone mineral density z score of less than -2 standard deviations for: children less than 15 years old; adult males (15 to 50 years old); and all pre-menopausal females above 15 years and a bone mineral density t score of less than -2.5 standard deviations for post-menopausal females and males above 50 years old., Data Collection and Analysis: Two review authors assessed the eligibility and risk of bias of the included trials, extracted and analysed data and completed the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate., Main Results: Four trials (with 211 participants) were included; three trials investigated the effect of bisphosphonate therapies and one trial investigated the effect of zinc supplementation. Only one trial was judged to be of good quality (low risk of bias); the remaining trials had a high or unclear risk of bias in at least one key domain.One trial (data not available for analysis) assessing the effect of neridronate (118 participants) reported significant increases in favour of the bisphosphonate group for bone mineral density at the lumbar spine and hip at both six and 12 months. For the femoral neck, a significant difference was noted at 12 months only. A further trial (25 participants) assessed the effect of alendronate and clodronate and found that after two years, bone mineral density increased significantly in the alendronate and clodronate groups as compared to placebo at the lumbar spine, mean difference 0.14 g/cm(2) (95% confidence interval 0.05 to 0.22) and at the femoral neck, mean difference 0.40 g/cm(2) (95% confidence interval 0.22 to 0.57). One 12-month trial (26 participants) assessed the effects of different doses of pamidronate (30 mg versus 60 mg) and found a significant difference in bone mineral density in favour of the 60 mg dose at the lumbar spine and forearm, mean difference 0.43 g/cm(2) (95% CI 0.10 to 0.76), mean difference 0.87 g/cm(2) (95% CI 0.23 to 1.51), respectively, but not at the femoral neck.In a zinc sulphate supplementation trial (42 participants), bone mineral density increased significantly compared to placebo at the lumbar spine after 12 months (37 participants), mean difference 0.15 g/cm(2) (95% confidence interval 0.10 to 0.20) and after 18 months (32 participants), mean difference 0.34 g/cm(2) (95% confidence interval 0.28 to 0.40). The same was true for bone mineral density at the hip after 12 months, mean difference 0.15 g/cm(2) (95% confidence interval 0.11 to 0.19) and after 18 months, mean difference 0.26 g/cm(2) (95% confidence interval 0.21 to 0.31).Fractures were not observed in one trial and not reported in three trials. There were no major adverse effects reported in two of the bisphosphonate trials; in the neridronate trial there was a reduction noted in the use of analgesic drugs and in the reported back pain score in favour of bisphosphonate treatment. Adverse effects were not reported in the trial of different doses of pamidronate or the zinc supplementation trial., Authors' Conclusions: There is evidence to indicate an increase in bone mineral density at the femoral neck, lumbar spine and forearm after administration of bisphosphonates and at the lumbar spine and hip after zinc sulphate supplementation. The authors recommend that further long-term randomised control trials on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia and osteoporosis are undertaken.

Individuals with sickle cell disease often experience acute and chronic bone pain due to occlusive events within the tissue vasculature that result in ischemia, necrosis, and organ degeneration. Macroscopically, sickle bone is identified in clinical radiographs by its reduced mineral density, widening of the marrow cavity, and thinning of the cortical bone due to the elevated erythroid hyperplasia accompanying the disease. However, the microstructural architecture of sickle bone and its role in mechanical functionality is largely unknown. This study utilized micro-CT and biomechanical testing to determine the relationship between the bone morphology, tissue mineral density, and trabecular and cortical microarchitecture of 10- and 21-week-old femurs from transgenic sickle male mice and littermates with sickle trait, as well as a wild-type control. While bone tissue mineral density did not vary among the genotypes at either age, variation in bone microstructure were observed. At 10 weeks, healthy and trait mice exhibited similar morphology within the cortical and trabecular bone, while sickle mice exhibited highly connected trabeculae. Within older femurs, sickle and trait specimens displayed significantly fewer trabeculae, and the remaining trabeculae had a more deteriorated geometry based on the structure model index. Thinning of the cortical region in sickle femurs contributed to the displayed flexibility with a significantly lower elastic modulus than the controls at both 10- and 21-weeks old. Wild-type and trait femurs generally demonstrated similar mechanical properties; however, trait femurs had a significantly higher modulus than sickle and wild-type control at 21-weeks. Overall, these data indicate that the progressive damage to the microvasculature caused by sickle cell disease, results in deleterious structural changes in the bone tissue׳s microarchitecture and mechanics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Sickle cell disease (SCD) is increasingly appreciated as an inflammatory condition associated with alterations in immune phenotype and function. In this cross-sectional study we performed a multiparameter analysis of 18 immune markers in 114 paediatric SCD patients divided by treatment group [those receiving hydroxycrabamide (HC, previously termed hydroxyurea), chronic transfusion (CT), or no disease-modifying therapy] and 29 age-matched African American healthy controls. We found global elevation of most immune cell counts in SCD patients receiving no disease-modifying therapy at steady state. Despite the decrease in percentage of haemoglobin S associated with CT therapy, the abnormal cellular immune phenotype persisted in patients on CT. In contrast, in both univariate and multivariate analysis, treatment with HC was associated with normalization of the vast majority of leucocyte populations. This study provides additional support for HC treatment in SCD, as it appears that HC decreases the abnormally elevated immune cell counts in patients with SCD., (© 2015 John Wiley & Sons Ltd.)

Background: Patients with sickle cell disease in the USA have been noted to have lower levels of vitamin D - measured as 25-hydroxyvitamin D (25(OH)D) - compared to controls. Average serum 25(OH)D levels are also substantially lower in African Americans than whites, while population distributions of 25(OH)D among Jamaicans of African descent and West Africans are the same as among USA whites. The purpose of this study was to examine whether adult patients with sickle cell disease living in tropical regions had reduced 25(OH)D relative to the general population., Methods: We analyzed serum 25(OH)D in stored samples collected from studies in Jamaica and West Africa of adult patients with sickle cell disease and adult population controls., Results: In samples of 20 Jamaicans and 50 West Africans with sickle cell disease mean values of 25(OH)D were 37% and 39% lower than controls, respectively. Metabolic abnormalities in the absorption and conversion pathways are possible causes for the consistent relative deficiency of 25(OH)D in sickle cell disease., Conclusions: Low 25(OH)D levels in tropical Africa where the burden of sickle cell disease is highest, deserve further investigation, and a randomized trial is warranted to address efficacy of supplementation.

Background: Prolonged hospitalizations for sickle cell disease painful episodes are not uncommon, as analgesic options are often suboptimal., Observations: Seven patients (15.4 ± 3.7 y, 6 females) were treated with epidural analgesia for refractory pain. The median duration of epidural catheter placement was 4 days (interquartile range, 3 to 6 d). Mean pain scores changed from 6.8 ± 2.7 to 4.8 ± 2.2, whereas mean daily parenteral opioid requirements changed from 79.7 ± 100.4 to 13.0 ± 13.1 mg of morphine equivalents., Conclusion: Continuous epidural analgesia is an alternative to continuing intravenous opioids in sickle cell disease patients with refractory pain, and may reduce opioid-related side effects and facilitate transition to oral analgesics.

Hydroxyurea (hydroxycarbamide, HU) is currently the only FDA-approved disease-modifying agent for individuals with sickle cell disease. Despite its efficacy in multicentered, randomized, placebo-controlled studies, HU remains highly underutilized among the sickle cell population. Several barriers to the use of HU have been identified including the need for frequent laboratory monitoring and physician visits. This study aimed to better assess the stability of patients' hematologic parameters when compliant with HU therapy to better determine the necessity of frequent routine laboratory monitoring. We conducted a retrospective review of 20 patients taking HU with record of good compliance. The within-subject coefficient of variation was computed as a measure of subject variability to better assess the stability of individual patients' blood counts to evaluate potential hematologic toxicity in subjects taking HU. Results demonstrated that during routine laboratory appointments, individuals' variability was very consistent; therefore assessment of significant change may be more accurately detected by individual symptomatology. Decreasing the stringency of the requirements for routine laboratory monitoring for patients on HU is unlikely to cause physicians to miss critical nadirs in absolute neutrophil count (or other laboratory values) and may lead to improved acceptance and use of this disease-modifying therapy in sickle cell disease.

Purpose of Review: To summarize the findings of the recent publications on sickle cell bone disease (SBD)., Recent Findings: Individuals with sickle cell disease (SCD) are living longer and develop progressive organ damage including SBD with age. Recent studies suggest alternative radiological diagnostics such as ultrasound and scintigraphy can detect and differentiate between different forms of SBD. MRI with or without diffusion-weighted sequences remains the gold standard. Case reports of cranio-orofacial SBD highlight the rarity of this presentation. Vitamin D deficiency is highly prevalent at all ages, but may not be an independent risk factor for avascular necrosis (AVN). Gene polymorphisms of the Annexin A gene may predict AVN in SCD. A recent study demonstrated reduced days with pain and improved physical activity quality of life following high-dose vitamin D therapy. The high rates of osteopenia and osteoporosis in SCD support the need for research addressing this rising public health problem. Lastly, results of total hip arthroplasty for AVN in SCD has improved significantly over time with the use of cementless prosthetic material and improved supportive care., Summary: SBD remains poorly studied. Prospective randomized studies targeting predictors, diagnostics, prevention, and treatment options for SBD are sorely needed.

The opioid medications codeine and hydrocodone, commonly prescribed in sickle cell disease (SCD), require metabolic conversion by cytochrome P450 2D6 (CYP2D6) to morphine and hydromorphone, respectively, to exert their analgesic effects. The CYP2D6 gene is highly polymorphic, with variant alleles that result in decreased, absent, or ultrarapid enzyme activity. Seventy-five children with SCD were tested for CYP2D6 polymorphisms, and metabolic phenotypes were inferred from the genotypes. The most common variant alleles were CYP2D6*2 (normal activity, 28.7%), CYP2D6*17 (reduced activity, 17.3%), CYP2D6*5 (gene deletion, 8.7%), and CYP2D6*4 (absent function, 8.0%). Normal/extensive metabolizer genotypes were found in 28/75 (37.5%), intermediate metabolism in 33/75 (44.0%), poor metabolism in 4/75 (5.3%), ultrarapid metabolism in 3/75 (4.0%), indeterminate in 6/75 (8.0%). Allele frequencies did not vary significantly among different hemoglobin genotypes. Identification of variant CYP2D6 genotypes may identify individuals with altered metabolism and therefore altered analgesic response to codeine and hydrocodone, thus providing a personalized medicine approach to treatment of pain in SCD. Further pharmacokinetic and pharmacodynamic studies are needed to define the relationship of CYP2D6 and other gene polymorphisms to individual opioid effect in SCD.

The prevalence of cerebrovascular events in sickle cell disease (SCD) can be as low as 10% by the age of 18 for overt cerebral infarction or strokes, up to 35% for silent cerebral infarction, and as high as 43/100 patient years for acute silent cerebral ischemic events. These events typically occur during childhood with a peak incidence between the age of 4 and 7 years. The cumulative risk of central nervous system events in SCD increases with age. Transcranial Doppler (TCD) ultrasonography is an established screening tool for detecting children with SCD at highest risk for stroke by measuring the flow velocity in the large intracranial vessels. Velocities are considered abnormal with readings >200 cm/s and chronic red cell transfusions are recommended to reduce further risk or progression. Red cell transfusions have reduced the rate of cerebrovascular accidents by 90%. We describe the case of 5 children with sickle cell anemia, whose antecedent screening TCD velocities were measured to be ≤70 cm/s in the study. All patients developed some form of cerebral insults, an overt cerebral infarctions, silent stroke or transient ischemic attack, and are now receiving chronic transfusion to prevent further progression. On the basis of these cases, low TCD velocities may identify another group of children at risk for cerebrovascular disease. We suggest TCD velocities <70 cm/s in major vessels (MCA, ACA, and ICA) be considered another type of "abnormal," prompting more sensitive evaluations (such as a brain MRI and MRA) for the presence of central nervous system disease, and, if negative, decrease intervals between subsequent TCD assessments.

We tested the hypothesis that extracellular haem is linked to the incidence of acute complications of sickle cell disease (SCD). Using multivariable regression analysis, higher plasma free haem, but not total plasma haem, was associated with increased odds of vaso-occlusive crisis (VOC) [P = 0·028, odds ratio (OR); 2·05, 95% Confidence Interval (CI) = 1·08-3·89] and acute chest syndrome (ACS) [P = 0·016, OR; 2·56, CI = 1·19, 5·47], after adjusting for age and gender in children with SCD. These findings suggest that haem and factors that influence its concentration in plasma may be informative of the risk of VOC and ACS in SCD patients., (© 2013 John Wiley & Sons Ltd.)

Background: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease., Purpose: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies., Methods: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint., Results: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation., Limitations: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers., Lessons Learned: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size., Conclusions: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were given a 6-week course of oral high-dose cholecalciferol (4000-100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82·5% and 52·5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects., (© 2012 Blackwell Publishing Ltd.)