BackgroundFrequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort.MethodsTwo hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation.ResultsHigher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p < 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p < 0.0001) were also independent risk factors for mortality. ConclusionsSevere painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies.Trial RegistrationClinicalTrials.gov NCT00011648 http://clinicaltrials.gov/

Chronic leg ulcers are frequent and debilitating complications of sickle cell anemia. Inadequate blood supply has been postulated to be an important factor in their occurrence and delayed healing. Little is known about their microcirculatory and histopathological changes. We evaluated the microcirculation of lower extremity ulcers with laser speckle contrast imaging and infrared thermography and obtained clinical and laboratory characteristics in 18 adults with sickle cell anemia and chronic leg ulcers. Skin biopsies were obtained in four subjects. Subjects had markers of severe disease, anemia, high degree of hemolysis, inflammation, and thrombophilia. The highest blood flow was present in the ulcer bed, progressively less in the immediate periwound area, and an unaffected control skin area in the same extremity. Microscopic examination showed evidence of venostasis, inflammation, and vasculopathy. Blood vessels were increased in number, had activated endothelium and evidence of thrombosis/recanalization. High blood flow may be due to chronic inflammation, cutaneous vasodilatation, venostasis, and in situ thrombosis. These changes in skin microcirculation are similar to chronic venous ulcers in the non-sickle cell disease (SCD) population, thus suggesting that leg ulcers may be another end-organ complication with endothelial dysfunction that appears in patients with SCD at a younger age and with higher frequency than in the general population.

BackgroundResource-limited communities in Washington, D.C. have high rates of obesity-related cardiovascular disease in addition to inadequate physical activity (PA) facilities and limited Internet access. Engaging community members in the design and implementation of studies to address these health disparities is essential to the success of community-based PA interventions.ObjectiveThe objective of the study was to use qualitative and quantitative methods to evaluate the feasibility and acceptability of PA-monitoring wristbands and Web-based technology by predominantly African American, church-based populations in resource-limited Washington, D.C. neighborhoods.MethodsTo address cardiovascular health in at-risk populations in Washington, D.C., we joined community leaders to establish a community advisory board, the D.C. Cardiovascular Health and Obesity Collaborative (D.C. CHOC). As their first initiative, the Washington, D.C. Cardiovascular Health and Needs Assessment intends to evaluate cardiovascular health, social determinants of health, and PA-monitoring technologies. At the recommendation of D.C. CHOC members, we conducted a focus group and piloted the proposed PA-monitoring system with community members representing churches that would be targeted by the Cardiovascular Health and Needs Assessment. Participants (n=8) agreed to wear a PA-monitoring wristband for two weeks and to log cardiovascular health factors on a secure Internet account. Wristbands collected accelerometer-based data that participants uploaded to a wireless hub at their church. Participants agreed to return after two weeks to participate in a moderated focus group to share experiences using this technology. Feasibility was measured by Internet account usage, wristband utilization, and objective PA data. Acceptability was evaluated through thematic analysis of verbatim focus group transcripts.ResultsStudy participants (5 males, 3 females) were African American and age 28-70 years. Participant wristbands recorded data on 10.1±1.6 days. Two participants logged cardiovascular health factors on the website. Focus group transcripts revealed that participants felt positively about incorporating the device into their church-based populations, given improvements were made to device training, hub accessibility, and device feedback.ConclusionsPA-monitoring wristbands for objectively measuring PA appear to be a feasible and acceptable technology in Washington, D.C., resource-limited communities. User preferences include immediate device feedback, hands-on device training, explicit instructions, improved central hub accessibility, and designation of a church member as a trained point-of-contact. When implementing technology-based interventions in resource-limited communities, engaging the targeted community may aid in early identification of issues, suggestions, and preferences.ClinicalTrialTrial Registration: ClinicalTrials.gov NCT01927783; https://clinicaltrials.gov/ct2/show/NCT01927783 (Archived by WebCite at http://www.webcitation.org/6f8wL117u)

Background The NHLBI-sponsored Sickle Cell Disease Clinical Research Network (SCDCRN) conducted a multi-center, acute intervention randomized clinical trial of two methods of Patient Controlled Analgesia for acute pain. This trial was terminated early due to low enrollment. We analyzed the perceived barriers and recruitment difficulties as reported by the coordinators and principal investigators. Methods Participating sites completed a missed eligibility log of subjects admitted in pain crisis throughout the study and a survey at the end of the trial. The survey covered site-specific factors, policies, and procedures in study implementation, recruitment strategies, and eligibility factors. The New England Research Institutes (NERI) collected de-identified surveys from 31 respondents at 29 of 31 participating sites. Results From December 2009 to June 2010, 1116 patient encounters for SCD and pain occurred at participating institutions: 38 subjects were enrolled (14 pediatric and 24 adults) and 34 completed the trial, below the projected 278 subjects. Fourteen sites enrolled subjects and seventeen did not. Recruitment barriers included insufficient staff, subject ineligibility or in too much pain to consent, competing protocols, and concerns regarding pain control. Recruitment methods were referrals from urgent care, SCD clinics and in house databases. No use of media or outside physicians was reported. Conclusion We identified multiple barriers to patient accrual including short duration of enrollment period, protocol design, complex dosing schedule, requirement for staff availability during week-end and after hours, multiple departments’ involvement, protocol acceptance, eligibility criteria, competing protocols, and limited staff. Each of these areas should be targeted for intervention in order to plan and conduct successful future clinical trials.

Little is known about recruitment methods for racial/ethnic minority populations from resource-limited areas for community-based health and needs assessments, particularly assessments that incorporate mobile health (mHealth) technology for characterizing physical activity and dietary intake. We examined whether the Communication, Awareness, Relationships and Empowerment (C.A.R.E.) model could reduce challenges recruiting and retaining participants from faith-based organizations in predominantly African American Washington, D.C. communities for a community-based assessment. Employing C.A.R.E. model elements, our diverse research team developed partnerships with churches, health organizations, academic institutions and governmental agencies. Through these partnerships, we cultivated a visible presence at community events, provided cardiovascular health education and remained accessible throughout the research process. Additionally, these relationships led to the creation of a community advisory board (CAB), which influenced the study’s design, implementation, and dissemination. Over thirteen months, 159 individuals were recruited for the study, 99 completed the initial assessment, and 81 used mHealth technology to self-monitor physical activity over 30 days. The culturally and historically sensitive C.A.R.E. model strategically engaged CAB members and study participants. It was essential for success in recruitment and retention of an at-risk, African American population and may be an effective model for researchers hoping to engage racial/ethnic minority populations living in urban communities.

Wearable mobile health (mHealth) technologies offer approaches for targeting physical activity (PA) in resource-limited, community-based interventions. We sought to explore user characteristics of PA tracking, wearable technology among a community-based population within a health and needs assessment. In 2014-2015, we conducted the Washington, D.C., Cardiovascular Health and Needs Assessment in predominantly African-American churches among communities with higher obesity rates and lower household incomes. Participants received a mHealth PA monitor and wirelessly uploaded PA data weekly to church data collection hubs. Participants (n = 99) were 59 ± 12 years, 79% female, and 99% African-American, with a mean body mass index of 33 ± 7 kg/m. Eighty-one percent of participants uploaded PA data to the hub and were termed "PA device users." Though PA device users were more likely to report lower household incomes, no differences existed between device users and non-users for device ownership or technology fluency. Findings suggest that mHealth systems with a wearable device and data collection hub may feasibly target PA in resource-limited communities.

Rationale: An increased tricuspid regurgitation jet velocity (TRV . 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). Objectives: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. Methods: Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms. Measurements and Main Results: Genome-wide gene and miRNA expression profiles were correlated against TRV, yielding 631 transcripts and 12 miRNAs. Support vector machine analysis identified a 10-gene signature including GALNT13 (encoding polypeptide N-acetylgalactosaminyltransferase 13) that discriminates patients with and without increased TRV with 100% accuracy. This finding was then validated in a cohort of patients with SCD without (n ¼ 10) and with pulmonary hypertension (n ¼ 10, 90% accuracy). Increased TRV-related miRNAs revealed strong in silico binding predictions of miR-301a to GALNT13 corroborated by microarray analyses demonstrating an inverse correlation between their expression. A genetic association study comparing patients with an elevated (n ¼ 49) versus normal (n ¼ 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P , 0.005), four trans-acting (P , 2.1 3 10 27) and one cis-acting (P ¼ 0.6 3 10 24 ) expression quantitative trait locus upstream of the adenosine-A2B receptor gene (ADORA2B). Conclusions: These studies validate the clinical usefulness of genomic signatures as potential biomarkers and highlight ADORA2B and GALNT13 as potential candidate genes in SCD-associated elevated TRV.

Summary Background Well-tolerated and effective treatments are needed for chronic leg ulcers in sickle cell anaemia. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects. We aimed to assess the safety, tolerability, and pharmacokinetics of topical sodium nitrite in patients with sickle cell disease and chronic leg ulcers. Methods We enrolled adult patients from an ambulatory clinic at the National Institutes of Health (Bethesda, MD, USA) with sickle cell anaemia with leg ulcers (with a surface area of 2.5–100 cm2) persisting for at least 4 weeks into a safety and tolerability phase 1 dose-escalation trial of topical sodium nitrite. Increasing concentrations of sodium nitrite cream were applied twice weekly for 4 weeks to one ulcer per patient at five dose levels (0.5%, 1%, 1.5%, 1.8%, and 2%). The primary endpoints were safety and tolerability, with secondary endpoints of pharmacokinetics, blood flow, and wound healing. Pain relief was analysed post hoc. Endpoints were analysed over time for the whole study population and according to dose level. This study is registered with ClinicalTrials.gov, number NCT01316796. Findings Between April 4, 2011, and March 19, 2013, we enrolled 18 adult patients with sickle cell anaemia and leg ulcers into our trial. We assigned three patients into each cohort, and each cohort was treated with a different concentration of sodium nitrite cream (cohort 1: 0.5%, cohort 2: 1.0%, cohort 3: 1.5%, and cohort 4: 2.0%). Patients were not enrolled into the next cohort dose until we were able to establish that no dose-limiting toxicities were observed. An additional six patients were enrolled to cohort 3a: 1.8%, after two patients in cohort 4 had asymptomatic drops in diastolic blood pressure. No grade 3–4 adverse events were observed, and there were no serious adverse events or dose-limiting side-effects. Pharmacokinetic analysis showed that systemic absorption of sodium nitrite was very low. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging (p=0.0002), corroborated by increased peri-wound skin temperature by infrared thermography (p=0.0119). We recorded a dose-dependent decrease in leg ulcer size (p=0.0012) and pain (p<0.0001). Ulcers healed completely in three patients who received the highest concentrations of topical sodium nitrite (the 1.8% and 2% cream). In our post-hoc analysis of pain, brief pain inventory scores improved in pain severity (p=0.0048) and pain interference (p=0.0013). Interpretation Our results indicate that topical sodium nitrite 2% cream is suitable for additional clinical trials in adults with sickle cell anaemia to promote healing of leg ulcers. Funding National Heart, Lung and Blood Institute Division of Intramural Research (National Institutes of Health).