Marlene Peters-Lawrence

Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis: A Randomized Controlled Trial

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) patients and familys 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.

Severe painful vaso-occlusive crises and mortality in a contemporary adult sickle cell anemia cohort study.

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/

A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease

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.

Vasculopathy, inflammation, and blood flow in leg ulcers of patients with sickle cell anemia

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. Am. J. Heamtol. 89:1–6, 2014.

Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial

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).

The Communication, Awareness, Relationships and Empowerment (C.A.R.E.) Model: An Effective Tool for Engaging Urban Communities in Community-Based Participatory Research

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.

Digital Food Records in Community-Based Interventions: Mixed-Methods Pilot Study

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)

Examining relationships between perceptions and objective assessments of neighborhood environment and sedentary time: Data from the Washington, D.C. Cardiovascular Health and Needs Assessment

Sedentary time (ST) and neighborhood environment (NE) are predictors of cardiovascular (CV) health. However, little is known about STs 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.