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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.
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Anemia Falciforme/complicações , Úlcera da Perna/etiologia , Úlcera da Perna/patologia , Pele/irrigação sanguínea , Adulto , Biópsia , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/patologia , Úlcera da Perna/diagnóstico , Masculino , Microcirculação , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Fatores de Risco , TermografiaRESUMO
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 = 10) and with pulmonary hypertension (n = 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 = 49) versus normal (n = 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P < 0.005), four trans-acting (P < 2.1 × 10(-7)) and one cis-acting (P = 0.6 × 10(-4)) 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.
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Anemia Falciforme/genética , Anemia Falciforme/fisiopatologia , N-Acetilgalactosaminiltransferases/genética , Receptor A2B de Adenosina/genética , Insuficiência da Valva Tricúspide/genética , Insuficiência da Valva Tricúspide/fisiopatologia , Adulto , Anemia Falciforme/diagnóstico por imagem , Cateterismo Cardíaco , Estudos de Coortes , Ecocardiografia Doppler/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Masculino , Análise em Microsséries/métodos , Polimorfismo de Nucleotídeo Único/genética , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Reprodutibilidade dos Testes , Máquina de Vetores de Suporte , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
CONTEXT: Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). OBJECTIVE: To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo. MAIN OUTCOME MEASURES: The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home. RESULTS: There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. CONCLUSION: Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00094887.
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Anemia Falciforme/complicações , Fatores Relaxantes Dependentes do Endotélio/administração & dosagem , Óxido Nítrico/administração & dosagem , Dor/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Medição da Dor , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Sickle cell disease (SCD) is a genetic disorder predominantly affecting people of African descent and is associated with significant morbidity and mortality. To improve SCD outcomes, the National Heart Lung and Blood Institute funded eight centers to participate in the SCD Implementation Consortium. Sites were required to each recruit 300 individuals with SCD, over 20 months. We aim to describe recruitment strategies and challenges encountered. Participants aged 15-45 years with confirmed diagnosis of SCD were eligible. Descriptive statistics were used to analyze the effectiveness of each recruitment strategy. A total of 2432 participants were recruited. Majority (95.3%) were African American. Successful strategies were recruitment from clinics (68.1%) and affiliated sites (15.6%). Recruitment at community events, emergency departments and pain centers had the lowest yield. Challenges included saturation of strategies and time constraints. Effective recruitment of participants in multi-site studies requires multiple strategies to achieve adequate sample sizes.
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Anemia Falciforme , Negro ou Afro-Americano , Serviço Hospitalar de Emergência , Humanos , Sistema de RegistrosRESUMO
Sedentary time (ST) and neighborhood environment (NE) are predictors of cardiovascular (CV) health. However, little is known about ST's relationship with NE. We examined associations of perceived and objective NE with ST in the predominantly African American faith-based population of the Washington, D.C. CV Health and Needs Assessment. After using community-based research principles, participants reported NE perceptions, including sidewalks, recreational areas, and crime presence. Factor analysis was conducted to explore pertinent constructs; factor sums were created and combined as Total Perception Score (TPS) (higher score = more favorable perception). Objective NE was assessed using Google Maps and the Active Neighborhood Checklist (ANC). ST was self-reported. Linear regression determined relationships between TPS and ST, and ANC scores and ST, for 1) overall population, 2) lower median-income D.C. areas, and 3) higher median-income DC and Maryland areas. For the sample (N = 98.9% African-American, 78% female), lower median-income areas had significantly lower mean TPS and ANC scores than higher median-income areas (p < 0.001). Three factors (neighborhood violence, physical/social environment, and social cohesion) were associated with overall NE perception. Among those in lower median-income areas, there was a negative association between TPS and ST that remained after covariate adjustment; this was not observed in higher median-income areas. There was no association between ANC scores and ST. Poorer NE perception is associated with greater ST for those in lower income areas, while objective environment is not related to ST. Multi-level interventions are needed to improve NE perceptions in lower-median income areas, reduce ST, and improve CV health.
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BACKGROUND: A pressing need exists to understand and optimize the use of dietary assessment tools that can be used in community-based participatory research (CBPR) interventions. A digital food record, which uses a mobile device to capture the dietary intake through text and photography inputs, is a particularly promising mobile assessment method. However, little is understood about the acceptability and feasibility of digital food records in CBPR and how to best tailor dietary assessment tools to the needs of a community. OBJECTIVE: The objective of our study was to evaluate the acceptability and feasibility of digital food records among church-based populations in resource-limited wards of Washington, DC, USA, using a mixed-methods approach. METHODS: This community-based pilot study was conducted as part of the Washington, DC Cardiovascular Health and Needs Assessment. Participants (n=17) received a mobile device (iPod Touch) to photodocument their dietary intake for a 3-day digital food record using a mobile app, FitNinja (Vibrent Health). The acceptability of the digital food record was explored through the thematic analysis of verbatim transcripts from a moderated focus group (n=8). In addition, the feasibility was evaluated by the percentage of participants complying with instructions (ie, capturing both before and after meal photos for at least 2 meals/day for 3 days). RESULTS: Qualitative themes identified were related to (1) the feasibility and acceptability of the mobile device and app, including issues in recording the dietary information and difficulty with photodocumentation; (2) suggestions for additional support and training experiences; and (3) comparisons with other mobile apps. Overall, the participants accepted the digital food record by demonstrating satisfaction with the tool and intent to continue the use (eg, participants recorded an average of 5.2, SD 7, consecutive days). Furthermore, of the 17 participants, 15 photodocumented at least 1 meal during the study period and 3 fully complied with the digital food record instructions. CONCLUSIONS: This study demonstrated digital food records as an acceptable tool in CBPR and identified contributors and barriers to the feasibility of digital food records for future research. Engaging community members in the implementation of novel assessment methods allows for the tailoring of technology to the needs of the community and optimizing community-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01927783; https://www.clinicaltrials.gov/ct2/show/NCT01927783 (Archived by WebCite at http://www.webcitation.org/70WzaFWb6).
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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.
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Pesquisa Participativa Baseada na Comunidade/métodos , Educação em Saúde , Telemedicina , População Urbana , Negro ou Afro-Americano , Conscientização , Comunicação , District of Columbia , Exercício Físico , Feminino , Humanos , Masculino , Poder PsicológicoRESUMO
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/m2. 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.
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Acelerometria , Exercício Físico , Monitores de Aptidão Física , Avaliação das Necessidades , Cooperação do Paciente , Tecnologia sem Fio , Índice de Massa Corporal , Cristianismo , District of Columbia , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade , Pobreza , Telemedicina , Populações VulneráveisRESUMO
BACKGROUND: Resource-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. OBJECTIVE: The 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. METHODS: To 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. RESULTS: Study 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. CONCLUSIONS: PA-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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01927783; https://clinicaltrials.gov/ct2/show/NCT01927783 (Archived by WebCite at http://www.webcitation.org/6f8wL117u).
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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).
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BACKGROUND: Frequent 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. METHODS: Two 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. RESULTS: Higher 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. CONCLUSIONS: Severe 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 REGISTRATION: ClinicalTrials.gov NCT00011648 http://clinicaltrials.gov/
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Anemia Falciforme/mortalidade , Anemia Falciforme/fisiopatologia , Adulto , Anemia Falciforme/metabolismo , HDL-Colesterol/metabolismo , Feminino , Ferritinas/metabolismo , Hematócrito , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
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.