Background: Sickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0–6; ≤4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency. Findings: Among 7743 participants followed for a median of 7•1 years, 85 of 583 participants with SCT (14•6%) developed incident cognitive impairment compared to 902 of 7160 (12•6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1•18 (95% CI: 0•93, 1•51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p N 0•11). Interpretation: In this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function. FUNDING: National Institutes of Health, American Society of Hematology. Abstract source Full text

Background: People with sickle cell disease (SCD) have a life expectancy of <50 years, so understanding their end-of-life care is critical. Objective: We aimed to determine where individuals with SCD were dying and their patterns of care in the year preceding death to highlight end-of-life research priorities and possible opportunities for intervention. Design: Using the California SCD Data Collection Program database (containing administrative data, vital records, and Medicaid claims), we examined people with SCD who died between 2006 and 2015 (cases) at age <80 years and examined their hospital and emergency department (ED) utilization in their last year of life. Comparators included living controls with SCD matched 1:1 based on age, analysis year, insurance, and income. Results: We identified 486 people with SCD (cases) who died at a median age of 45 years (SD: 16 years). Most died in the hospital (63%) and ED (15%). In their last year of life, people with SCD were hospitalized for an average of 42 days (SD: 49 days) over five admissions. Inpatient admissions and ED visits were stable throughout the year until the month before death when acute care utilization sharply increased. In their last year of life, cases had more hospitalizations than controls, but similar ED utilization. Conclusions: People with SCD are dying acutely at a young age and most die in the hospital and the ED. Since clinicians caring for people with SCD currently cannot predict which acute events may be life-threatening, a comprehensive palliative approach to people with SCD must extend beyond chronic pain management and psychosocial support to include advance care planning. Abstract source

Background/Aims: We surveyed sickle cell disease (SCD) patients who transitioned from pediatric care at Texas Children's Hematology Center (TCHC) to adult care to determine the characteristics of patients with an adult SCD provider, continuation rates of pre-transition therapies, and patient perceptions of the transition process. Methods: A cross-sectional study was conducted by telephone survey of 44 young adults with SCD, aged 19-29 years, who transitioned from TCHC to adult care within the last 15 years. Results: Findings of the 23-item questionnaire revealed that transitioned patients with current adult providers (68.2%) were more likely to have seen a provider within 6 months of transition (p = 0.023) and to have been on hydroxyurea and/or monthly blood transfusions pre-transition (p = 0.021) than transitioned patients without a provider; 83% of patients on pre-transition hydroxyurea reported continuing hydroxyurea after transition. Transition challenges included inadequate preparation, difficulty finding knowledgeable adult providers, and lack of healthcare insurance/coverage. Conclusion: Transition to adult providers is predicted by establishing care with an adult SCD provider within 6 months of transition and being on pre-transition disease-modifying therapy. Transition may be improved if pediatric hematology centers assist and verify adult provider contact within 6 months of transition and engage patients of all disease severity during transition. Abstract source

Adolescents with sickle cell disease (SCD), a chronic condition primarily impacting African Americans, experience challenges graduating high school. Understanding demographic, educational, and community-level correlates of disease is critical to creating effective interventions for these youths. This study aimed to examine 1) educational attainment for adolescents with SCD, 2) neighborhood correlates of their education, and 3) feasibility of a pilot to increase General Education Diploma (GED) class enrollment. Findings suggest demographic characteristics influence educational attainment. Improving educational attainment in adolescents with SCD requires understanding risk beyond disease severity. Identifying risk and protective neighborhood-level factors can inform interventions to improve educational attainment. Feasibility of programming to increase GED enrollment should be further investigated. Abstract source

Objectives: Sickle cell disease (SCD) is a serious illness with disabling acute and chronic pain that needs better therapies, but insufficient patient participation in research is a major impediment to advancing SCD pain management. The purpose of this article is to discuss the challenges of conducting an SCD study and approaches to successfully overcoming those challenges. Design: In repeated-measures, longitudinal study designed to characterize SCD pain phenotypes, we recruited 311 adults of African ancestry. Adults with SCD completed 4 study visits 6 months apart, and age- and gender-matched healthy controls completed 1 visit. Results: We recruited and completed measures on 186 patients with SCD and 125 healthy controls. We retained 151 patients with SCD with data at 4 time points over 18 months and 125 healthy controls (1 time point) but encountered many challenges in recruitment and study visit completion. Enrollment delays often arose from patients' difficulty in taking time from their complicated lives and frequent pain episodes. Once scheduled, participants with SCD cancelled 49% of visits often because of pain; controls canceled 30% of their scheduled visits. To facilitate recruitment and retention, we implemented a number of strategies that were invaluable in our success. Conclusion: Patients' struggles with illness, chronic pain, and their life situations resulted in many challenges to recruitment and completion of study visits. Important to overcoming challenges was gaining the trust of patients with SCD and a participant-centered approach. Early identification of potential problems allowed strategies to be instituted proactively, leading to success. Abstract source

Antibiotic prophylaxis is a mainstay in sickle cell disease management. However, adherence is estimated at only 66%. This study aimed to develop and validate a Sickle Cell Antibiotic Adherence Level Evaluation (SCAALE) to promote systematic and detailed adherence evaluation. Methods: A 28-item questionnaire was created, covering seven adherence areas. General Adherence Ratings from the parent and one health care provider and medication possession ratios were obtained as validation measures. Results: Internal consistency was very good to excellent for the total SCAALE (α=0.89) and four of the seven subscales. Correlations between SCAALE scores and validation measures were strong for the total SCAALE and five of the seven subscales. Conclusion: The SCAALE provides a detailed, quantitative, multidimensional, and global measurement of adherence and can promote clinical care and research. Abstract source

Despite being described in the medical literature over a hundred years ago, sickle cell disease continues to be associated with significant morbidity and mortality secondary to end-organ damage resulting from ischemia, chronic inflammation, iron overload and endothelial dysfunction. Unfortunately, current therapies for sickle cell disease remain limited, and the only current curative treatment is allogeneic bone marrow transplant, which is associated with significant risks. Impaired nitric oxide bioavailability has been documented in patients with sickle cell disease and has been implicated in the pathophysiology of pulmonary vascular complications and other vasomotor defects, suggesting that therapies aimed at restoring nitric oxide balance may be promising in this patient population. Therapeutic strategies to restore nitric oxide balance in prior clinical trials have included direct inhalation of nitric oxide gas and its donors, amplification of nitric oxide effects through inhibition of cyclic guanosine monophosphate hydrolysis, and oral supplementation with substrates of nitric oxide synthesis. While preclinical trials of nitric oxide-based therapies for the treatment of pulmonary vascular complications in sickle cell disease have been promising, early clinical trials in this patient population have been limited, largely due to the increased risk of painful vasoocclusive crises, which might be attributable to the known dual nociceptive effects of nitric oxide. Further preclinical and clinical trials are warranted to investigate the therapeutic benefits of nitric oxide-based therapies in the treatment of specific complications of sickle cell disease, including pulmonary and systemic hypertension and chronic kidney disease. Abstract source

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This issue titled "Changing the Conversation for Sickle Cell Disease and Reshaping its Future" contains abstracts and poster presentations related to sickle cell disease research. The issue was published in the Journal of Sickle Cell Disease and Hemoglobinopathies by the Foundation for Sickle Cell Disease Research (FSCDR). FSCDR is a non-profit organization focused on reshaping the future of Sickle Cell Disease by putting on the end to the pain and suffering that millions of individuals have had to endure for generations. Managing sickle cell disease is a balancing act involving pain management, and preventing other complications that may be life-threatening.    Abstract source

Hemolysis is a fundamental feature of sickle cell anemia that contributes to its pathophysiology and phenotypic variability. Decompartmentalized hemoglobin, arginase 1, asymmetric dimethylarginine, and adenine nucleotides are all products of hemolysis that promote vasomotor dysfunction, proliferative vasculopathy, and a multitude of clinical complications of pulmonary and systemic vasculopathy, including pulmonary hypertension, leg ulcers, priapism, chronic kidney disease, and large-artery ischemic stroke. Nitric oxide (NO) is inactivated by cell-free hemoglobin in a dioxygenation reaction that also oxidizes hemoglobin to methemoglobin, a non-oxygen-binding form of hemoglobin that readily loses heme. Circulating hemoglobin and heme represent erythrocytic danger-associated molecular pattern (eDAMP) molecules, which activate the innate immune system and endothelium to an inflammatory, proadhesive state that promotes sickle vaso-occlusion and acute lung injury in murine models of sickle cell disease. Intravascular hemolysis can impair NO bioavailability and cause oxidative stress, altering redox balance and amplifying physiological processes that govern blood flow, hemostasis, inflammation, and angiogenesis. These pathological responses promote regional vasoconstriction and subsequent blood vessel remodeling. Thus, intravascular hemolysis represents an intrinsic mechanism for human vascular disease that manifests clinical complications in sickle cell disease and other chronic hereditary or acquired hemolytic anemias. Abstract source Full text