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BackgroundSickle Cell Disease (SCD) is a progressive genetic disease that causes organ damage and reduces longevity. Hydroxyurea is an underutilized evidence-based medication that reduces complications and improves survival in SCD. In a multi-site clinical trial, part of the NIH-funded Sickle Cell Disease Implementation Consortium (SCDIC), we evaluate the implementation of a multi-level and multi-component mobile health (mHealth) patient and provider intervention to target the determinants and context of low hydroxyurea use. Given the complexity of the intervention and contextual variability in its implementation, we combined different behavioral and implementation theories, models, and frameworks to facilitate the evaluation of the intervention implementation. In this report, we describe engagement with stakeholders, planning of the implementation process, and final analytical plan to evaluate the implementation outcomes.MethodsDuring 19 meetings, a 16-member multidisciplinary SCDIC implementation team created, conceived, and implemented a project that utilized Intervention Mapping to guide designing an intervention and its evaluation plan. The process included five steps: (1) needs assessment of low hydroxyurea utilization, (2) conceptual framework development, (3) intervention design process, (4) selection of models and frameworks, and (5) designing evaluation of the intervention implementation.ResultsBehavioral theories guided the needs assessment and the design of the multi-level mHealth intervention. In designing the evaluation approach, we combined two implementation frameworks to best account for the contextual complexity at the organizational, provider, and patient levels: (1) the Consolidated Framework for Implementation Research (CFIR) that details barriers and facilitators to implementing the mHealth intervention at multiple levels (users, organization, intervention characteristics, broader community), and (2) the Technology Acceptance Model (TAM), a conceptual model specific for explaining the intent to use new information technology (including mHealth). The Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) framework was used to measure the outcomes.DiscussionOur research project can serve as a case study of a potential approach to combining different models/frameworks to help organize and plan the evaluation of interventions to increase medication adherence. The description of our process may serve as a blueprint for future studies developing and testing new strategies to foster evidence-based treatments for individuals living with SCD.

Objective: Sickle cell disease (SCD) is associated with complications during pregnancy and can negatively influence maternal outcomes. Our study aimed to determine the prevalence and predictors of maternal morbidity among participants enrolled in an eight-site SCD Implementation Consortium (SCDIC) registry., Methods: We conducted a cross-sectional analysis of female registry participants, aged 15-45 years, with a confirmed diagnosis of SCD. Participants completed a survey of self-reported pregnancies and outcomes., Results: Seven hundred and thirty-eight individuals had at least one pregnancy event, with 1076 live births. Twenty percent reported a pregnancy loss or fetal demise. Of the 1076 live births, 75% involved at least one complication. The most prevalent complications were pain crises (61.1%) and pregnancy requiring blood transfusion(s) (33.0%). Multiparous individuals with a prior occurrence of a complication in a previous pregnancy had higher odds of recurrence of the same complication in subsequent pregnancies (i.e., previous acute crisis was associated with subsequent acute pain events odds ratio [OR]: 3.13; 95% confidence interval [CI]: 2.06-4.76) and prior transfusion requiring another transfusion (OR: 3.22; 95% CI: 2.01-5.16)., Conclusion: Individuals reported a high prevalence of pregnancy loss and maternal complications. Our findings underscore the importance of preconception counseling and early initiation of perinatal care in SCD., (© 2024 International Federation of Gynecology and Obstetrics.)

Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested 2 mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU Toolbox) in a multi-center, non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week preintervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSβ0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; P < 0.001) and sustained (39.7% to 51.4%, P < 0.001). Mean HbF increased (10.95% to 12.78%; P = 0.03). Self-reported pain frequency reduced (3.54 to 3.35 events/year; P = 0.041). InCharge Health was used ≥1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with ≥1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, P = 0.0045) and weeks 25-36 (1.25 events/patient, P = 0.0015). PDC increased with app use (P < 0.001), with the greatest effect in those with private insurance (P = 0.0078), older subjects (P = 0.033), and those with lower pain interference (P = 0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, 4 unreported), only 11.2% used HU Toolbox ≥1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence can potentially improve adherence and provide clinical benefits. A definitive randomized study is warranted. This trial was registered at www.clinicaltrials.gov as #NCT04080167., (© 2023 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: This study aimed to capture the implementation process of the ALIGN Study, (An individualized Pain Plan with Patient and Provider Access for Emergency Department care of Sickle Cell Disease). ALIGN aimed to embed Individualized Pain Plans in the electronic health record (E-IPP) and provide access to the plan for both adult patients with sickle cell disease (SCD) and emergency department providers when a person with SCD comes to the emergency department in vaso-occlusive crises., Methods: Semi-structured interviews were conducted with research teams from the 8 participating sites from the ALIGN study. Seventeen participants (principal investigators and study coordinators) shared their perspectives about the implementation of ALIGN in their sites. Data were analyzed in three phases using open coding steps adapted from grounded theory and qualitative content analysis., Results: A total of seven overarching themes were identified: (1) the E-IPP structure (location and upkeep) and collaboration with the informatics team, (2) the role of ED champion, (3) the role of research coordinators, (4) research team communication, and communication between research team and clinical team, (5) challenges with the study protocol, (6) provider feedback: addressing over-utilizers, patient mistrust, and the positive feedback about the intervention, and (7) COVID-19 and its effects on study implementation., Conclusions: Findings from this study contribute to learning how to implement E-IPPs for adult patients with SCD in ED. The study findings highlight the importance of early engagement with different team members, a champion from the emergency department, study coordinators with different skills and enhancement of communication and trust among team members. Further recommendations are outlined for hospitals aiming to implement E-IPP for patients with SCD in ED., (© 2023. The Author(s).)

The onset of erythropoiesis is under strict developmental control, with direct and indirect inputs influencing its derivation from the hematopoietic stem cell. A major regulator of this transition is KLF1/EKLF, a zinc finger transcription factor that plays a global role in all aspects of erythropoiesis. Here, we have identified a short, conserved enhancer element in KLF1 intron 1 that is important for establishing optimal levels of KLF1 in mouse and human cells. Chromatin accessibility of this site exhibits cell-type specificity and is under developmental control during the differentiation of human CD34+ cells towards the erythroid lineage. This site binds GATA1, SMAD1, TAL1, and ETV6. In vivo editing of this region in cell lines and primary cells reduces KLF1 expression quantitatively. However, we find that, similar to observations seen in pedigrees of families with KLF1 mutations, downstream effects are variable, suggesting that the global architecture of the site is buffered towards keeping the KLF1 genetic region in an active state. We propose that modification of intron 1 in both alleles is not equivalent to complete loss of function of one allele., (© 2023. The Author(s).)

Background: Sickle Cell Disease (SCD) is a progressive genetic disease that causes organ damage and reduces longevity. Hydroxyurea is an underutilized evidence-based medication that reduces complications and improves survival in SCD. In a multi-site clinical trial, part of the NIH-funded Sickle Cell Disease Implementation Consortium (SCDIC), we evaluate the implementation of a multi-level and multi-component mobile health (mHealth) patient and provider intervention to target the determinants and context of low hydroxyurea use. Given the complexity of the intervention and contextual variability in its implementation, we combined different behavioral and implementation theories, models, and frameworks to facilitate the evaluation of the intervention implementation. In this report, we describe engagement with stakeholders, planning of the implementation process, and final analytical plan to evaluate the implementation outcomes., Methods: During 19 meetings, a 16-member multidisciplinary SCDIC implementation team created, conceived, and implemented a project that utilized Intervention Mapping to guide designing an intervention and its evaluation plan. The process included five steps: (1) needs assessment of low hydroxyurea utilization, (2) conceptual framework development, (3) intervention design process, (4) selection of models and frameworks, and (5) designing evaluation of the intervention implementation., Results: Behavioral theories guided the needs assessment and the design of the multi-level mHealth intervention. In designing the evaluation approach, we combined two implementation frameworks to best account for the contextual complexity at the organizational, provider, and patient levels: (1) the Consolidated Framework for Implementation Research (CFIR) that details barriers and facilitators to implementing the mHealth intervention at multiple levels (users, organization, intervention characteristics, broader community), and (2) the Technology Acceptance Model (TAM), a conceptual model specific for explaining the intent to use new information technology (including mHealth). The Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) framework was used to measure the outcomes., Discussion: Our research project can serve as a case study of a potential approach to combining different models/frameworks to help organize and plan the evaluation of interventions to increase medication adherence. The description of our process may serve as a blueprint for future studies developing and testing new strategies to foster evidence-based treatments for individuals living with SCD., Competing Interests: JSH receives consultancy fees from Forma Therapeutics, CVS Health, and Global Blood Therapeutics., (© 2023 Hankins, Potter, Fernandez, Melvin, DiMartino, Jacobs, Bosworth, King, Simon, Glassberg, Kutlar, Gordeuk, Shah, Baumann, Klesges and the Sickle Cell Disease Implementation Consortium.)

Objectives: Sickle cell disease (SCD) leads to chronic and acute complications that require specialised care to manage symptoms and optimise clinical results. The National Heart Lung and Blood Institute (NHLBI) evidence-based guidelines assist providers in caring for individuals with SCD, but adoption of these guidelines by providers has not been optimal. The objective of this study was to identify barriers to treating individuals with SCD., Methods: The SCD Implementation Consortium aimed to investigate the perception and level of comfort of providers regarding evidence-based care by surveying providers in the regions of six clinical centres across the USA, focusing on non-emergency care from the providers' perspective., Results: Respondents included 105 providers delivering clinical care for individuals with SCD. Areas of practice were most frequently paediatrics (24%) or haematology/SCD specialist (24%). The majority (77%) reported that they were comfortable managing acute pain episodes while 63% expressed comfort with managing chronic pain. Haematologists and SCD specialists showed higher comfort levels prescribing opioids (100% vs 67%, p=0.004) and managing care with hydroxyurea (90% vs 51%, p=0.005) compared with non-haematology providers. Approximately 33% of providers were unaware of the 2014 NHLBI guidelines. Nearly 63% of providers felt patients' medical needs were addressed while only 22% felt their mental health needs were met., Conclusions: A substantial number of providers did not know about NHLBI's SCD care guidelines. Barriers to providing care for patients with SCD were influenced by providers' specialty, training and practice setting. Increasing provider knowledge could improve hydroxyurea utilisation, pain management and mental health support., Competing Interests: Competing interests: JSH receives research funding support from Global Blood Therapeutics and is received consultancy fees from Bluebird Bio, Forma Therapeutics, and Global Blood Therapeutics; JG receives research funding support from Pfizer; AK owns stock in Magenta Therapeutics., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Sex-based clinical outcome differences in sickle cell disease (SCD) remain largely unknown despite evidence that female sex is associated with an increased lifespan. To better characterize sex-based differences in SCD, we assessed pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry., Methods: The SCDIC consists of eight comprehensive SCD centers and one data coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Eligibility criteria included: 15 to 45 years of age and a confirmed diagnosis of SCD. Self-report surveys were completed and data were also abstracted from the participants' medical records., Results: A total of 2,124 participants were included (mean age: 27.8 years; 56% female). The majority had hemoglobin SS SCD genotype. Females had worse reports of pain severity (mean (SD) T-score 51.6 (9.6) vs 49.3 (10), p<0.001), more vaso-occlusive episodes (p = 0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9% vs. 25.5, p = 0.03). On multivariable analysis, males had higher odds of acute chest syndrome (odds ratio (OR) 1.4, p = 0.002), cardiovascular (OR 1.70, p<0.001) and musculoskeletal (OR 1.33, p = 0.0034) complications and lower odds of depression (OR 0.77, p = 0.0381). Females had higher fetal hemoglobin levels with and without hydroxyurea use (9.6% vs 8.5%, p = 0.03 and 3% vs 2.2%, p = 0.0005, respectively)., Conclusion: Our data suggests that sex differences in clinical outcomes do occur among individuals with SCD. Future research needs to explore the mechanisms underlying these differences., Competing Interests: Jane S. Hankins receives consultancy fees from Forma Therapeutics, Global Blood Therapeutics and bluebird bio. All other authors have declared that no competing interests exist.

Study Objective: Guided by an implementation science framework, this needs assessment identifies institutional-, provider-, and patient-level barriers to care of sickle cell disease (SCD) in the emergency department (ED) to inform future interventions conducted by the multicenter Sickle Cell Disease Implementation Consortium., Methods: The consortium developed and implemented a validated needs assessment survey administered to a cross-sectional convenience sample of patients with SCD and ED providers caring for them. In total, 516 adolescents and adults with SCD and 243 ED providers from 7 and 5 regions of the United States, respectively, responded to the ED care delivery for SCD survey., Results: Survey results demonstrated that 84.5% of respondents with SCD have an outpatient provider who treats many patients with SCD. In the ED, 54.3% reported not receiving care fast enough and 46.0% believed physicians did not care about them and believed similarly of nurses (34.9%). Consequently, 48.6% of respondents were "never" or "sometimes" satisfied with their ED care. Of surveyed ED providers, 75.1% were unaware of the National Heart, Lung, and Blood Institute recommendations for vaso-occlusive crises, yet 98.1% were confident in their knowledge about caring for patients with SCD. ED providers identified the following factors as barriers to care administration: opioid epidemic (62.1%), patient behavior (60.9%), crowding (58.0%), concern about addiction (47.3%), and implicit bias (37.0%)., Conclusion: The results underscore that many patients with SCD are dissatisfied with their ED care and highlight challenges to optimal care on the practice, provider, and patient levels. Exploring these differences may facilitate improvements in ED care., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Sickle cell disease (SCD) is an autosomal recessive blood disorder affecting approximately 100,000 Americans and 3.1 million people globally. The scarcity of relevant knowledge and experience with rare diseases creates a unique need for cooperation and infrastructure to overcome challenges in translating basic research advances into clinical advances. Despite registry initiatives in SCD, the unavailability of descriptions of the selection process and copies of final data collection tools, coupled with incomplete representation of the SCD population hampers further research progress. This manuscript describes the SCDIC (Sickle Cell Disease Implementation Consortium) Registry development and makes the SCDIC Registry baseline and first follow-up data collection forms available for other SCD research efforts., Results: Study data on 2400 enrolled patients across eight sites was stored and managed using Research Electronic Data Capture (REDCap). Standardized data collection instruments, recruitment and enrollment were refined through consensus of consortium sites. Data points included measures taken from a variety of validated sources (PHENX, PROMIS and others). Surveys were directly administered by research staff and longitudinal follow-up was coordinated through the DCC. Appended registry forms track medical records, event-related patient invalidation, pregnancy, lab reporting, cardiopulmonary and renal functions., Conclusions: The SCDIC Registry strives to provide an accurate, updated characterization of the adult and adolescent SCD population as well as standardized, validated data collecting tools to guide evidence-based research and practice.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality. Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1 ) acute chest syndrome, 2 ) lower airways disease and pulmonary function, 3 ) sleep-disordered breathing and hypoxia, and 4 ) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus. Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation. Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

Pain is the leading cause of emergency department (ED) visits for individuals living with sickle cell disease (SCD). The care that is delivered in the ED is often cited by patients with SCD as the area of health care in greatest need of improvement. In 2014, the National Heart, Lung, and Blood Institute released guidelines for the care of SCD, including recommendations for the management of acute sickle cell pain in the ED. These guidelines provide a framework to understand the elements of ideal emergency sickle cell pain care; however, they do not provide guidance on barriers and facilitators to achieving these ideals in the complex system of the ED. Presented in this article are 4 tenets of implementing guideline-adherent emergency sickle cell care gleaned from the available literature and continuous quality improvement efforts at our institution. These include: (1) strategies to reduce negative provider attitudes toward patients with SCD; (2) strategies to reduce time-to-first-dose of analgesic medication; (3) strategies to improve ED pain care beyond the first dose of medication; and (4) strategies to improve ED patient safety. Application of the principles discussed within can improve patient and provider satisfaction, quality, and safety., Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests., (© 2016 by The American Society of Hematology. All rights reserved.)

Purpose of Review: The purpose of this article is to provide a comprehensive review of wheezing in sickle cell disease (SCD), including epidemiology, pathophysiology, associations between wheezing and SCD morbidity and finally the clinical approach to evaluation and management of individuals with SCD who wheeze., Recent Findings: Wheezing is common in SCD and in some individuals represents an intrinsic component of SCD-related lung disease rather than asthma. Emerging data suggest that, regardless of the cause, individuals with SCD and with recurrent wheezing are at increased risk for subsequent morbidity and premature mortality. We believe individuals who acutely wheeze and have respiratory symptoms should be managed with a beta agonist and short-term treatment of oral steroids, typically less than 3 days to attenuate rebound vaso-occlusive disease. For those who wheeze and have a history or examination associated with atopy, we consider asthma treatment and monitoring per National Heart, Lung and Blood Institute asthma guidelines., Summary: Wheezing in SCD should be treated aggressively both in the acute setting and with controller medications. Prospective SCD-specific clinical trials will be necessary to address whether anti-inflammatory asthma therapies (leukotriene antagonists, inhaled corticosteroids) can safely mitigate the sequelae of wheezing in SCD.

Study Objective: We determine whether emergency provider attitudes and demographics are associated with adherence to national guidelines for the management of acute sickle cell disease pain., Methods: We conducted a cross-sectional survey of emergency providers at the 2011 annual American College of Emergency Physicians Scientific Assembly, using a validated instrument to assess provider attitudes and self-reported analgesic practices toward patients with sickle cell disease. Multivariable, relative risk regressions were used to identify factors associated with adherence to guidelines., Results: There were 722 eligible participants, with a 93% complete response rate. Most providers self-reported adherence to the cornerstones of sickle cell disease pain management, including parenteral opioids (90%) and redosing opioids within 30 minutes if analgesia is inadequate (85%). Self-reported adherence was lower for other recommendations, including use of patient-controlled analgesia, acetaminophen, non-steroidal anti-inflammatory drugs and hypotonic fluids for euvolemic patients. Emergency providers in the highest quartile of negative attitudes were 20% less likely to redose opioids within 30 minutes for inadequate analgesia (risk ratio 0.8; 95% confidence interval [CI] 0.7 to 0.9). High-volume providers (those who treat more than 1 sickle cell disease patient per week), were less likely to redose opioids within 30 minutes for inadequate analgesia (risk ratio 0.9; 95% CI 0.8 to 0.9). Pediatric providers were 6.6 times more likely to use patient-controlled analgesia for analgesia (95% CI 2.6 to 16.6)., Conclusion: The majority of emergency providers report that they adhere to national guidelines about use of opioids for sickle cell disease-related acute pain episodes. Other recommendations have less penetration. Negative attitudes toward individuals with sickle cell disease are associated with lower adherence to guidelines., (Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

To assess the associations between a doctor diagnosis of asthma and wheezing (independent of a diagnosis of asthma) with sickle cell disease (SCD) morbidity, we conducted a retrospective review of Emergency Department (ED) visits to the Mount Sinai Medical Center for SCD between 1 January 2007 and 1 January 2011. Outcomes were ED visits for pain and acute chest syndrome. The cohort included 262 individuals, median age 23·8 years, (range: 6 months to 67·5 years). At least one episode of wheezing recorded on a physical examination was present in 18·7% (49 of 262). Asthma and wheezing did not overlap completely, 53·1% of patients with wheezing did not carry a diagnosis of asthma. Wheezing was associated with a 118% increase in ED visits for pain (95% confidence interval [CI]: 56-205%) and a 158% increase in ED visits for acute chest syndrome (95% CI: 11-498%). A diagnosis of asthma was associated with a 44% increase in ED utilization for pain (95% CI: 2-104%) and no increase in ED utilization for acute chest syndrome (rate ratio 1·00, 95%CI 0·41-2·47). In conclusion, asthma and wheezing are independent risk factors for increased painful episodes in individuals with SCD. Only wheezing was associated with more acute chest syndrome., (© 2012 Blackwell Publishing Ltd.)

Objectives: The objective was to identify clinical, social, and environmental risk factors for increased emergency department (ED) use in children with sickle cell disease (SCD)., Methods: This study was a secondary analysis of ED utilization data from the international multicenter Silent Cerebral Infarct Transfusion (SIT) trial. Between December 2004 and June 2010, baseline demographic, clinical, and laboratory data were collected from children with SCD participating in the trial. The primary outcome was the frequency of ED visits for pain. A secondary outcome was the frequency of ED visits for acute chest syndrome., Results: The sample included 985 children from the United States, Canada, England, and France, for a total of 2,955 patient-years of data. There were 0.74 ED visits for pain per patient-year. A past medical history of asthma was associated with an increased risk of ED utilization for both pain (rate ratio [RR] = 1.28, 95% confidence interval [CI] = 1.04 to 1.58) and acute chest syndrome (RR = 1.60, 95% CI = 1.03 to 2.49). Exposure to environmental tobacco smoke in the home was associated with 73% more ED visits for acute chest syndrome (RR = 1.73, 95% CI = 1.09 to 2.74). Each $10,000 increase in household income was associated with 5% fewer ED visits for pain (RR = 0.95, 95% CI = 0.91 to 1.00, p = 0.05). The association between low income and ED utilization was not significantly different in the United States versus countries with universal health care (p = 0.51)., Conclusions: Asthma and exposure to environmental tobacco smoke are potentially modifiable risk factors for greater ED use in children with SCD. Low income is associated with greater ED use for SCD pain in countries with and without universal health care., (© 2012 by the Society for Academic Emergency Medicine.)