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BACKGROUND: Acquisition of HIV primary drug-resistant (PDR) infection can lead to poor virologic and clinical outcomes in individuals and hampers public health efforts in epidemic control. Monitoring PDR in HIV-positive blood donors can be used to inform nationwide trends in the spread of drug-resistant HIV strains. METHODS: We conducted a cross-sectional study using genetic sequence analysis to assess HIV pol sequences, PDR, and risk factors for infection using audio computer-assisted structured interviews (ACASI) in four large blood centers in Brazil from 2007 to 2017. RESULTS: Of 716 HIV-positive blood donors, 504 (70.4%) were successfully sequenced. HIV clade B (73.2%) was the most prevalent subtype, followed by a mix of non-B (21.2%) sub-types. A two-fold increase (from 4% to 8%) in recombinants prevalence was observed during the study period. Sixty-four (12.7%) presented PDR. Overall, HIV PDR prevalence remained stable during the study period. Drug resistance mutations for non-nucleoside reverse transcriptase inhibitors were found in 39 (7.7%) donors, while for nucleoside reverse transcriptase inhibitors were found in 26 (5.1%), and for protease inhibitors in 24 (4.8%) of HIV-infected donors. We did not find statistically significant differences in demographics, behavioral risk factors, or HIV genotypes when comparing volunteers with and without PDR. CONCLUSION: The HIV PDR rate among donors remained stable during the study period. HIV-positive blood donors can be an informative population to monitor primary HIV resistance and ultimately may help to increase the knowledge and awareness of HIV risk factors and PDR.

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.

BACKGROUND AND OBJECTIVES: Incidence in first-time and repeat blood donors is an important measure of transfusion-transmitted HIV infection (TT-HIV) risk. This study assessed HIV incidence over time at four large blood centers in Brazil. MATERIALS AND METHODS: Donations were screened and confirmed using serological assays for HIV from 2007 – 2016, and additionally screened by nucleic acid testing from 2011 forward. Limiting antigen (LAg) avidity testing was conducted on HIV seroreactive samples from first-time donors to classify whether an infection was recently acquired. We calculated incidence in first-time donors using the mean duration of recent infection and in repeat donors using classical methods. Time and demographic trends were assessed using Poisson regression. RESULTS: Over the 10-year period, HIV incidence in first-time donors was highest in Recife (45.1/100,000 person–years (10(5) py)) followed by São Paulo (32.2/10(5) py) and then Belo Horizonte (23.3/10(5) py), and in repeat donors was highest in Recife (33.2/10(5) py), Belo Horizonte (27.5/10(5) py) and São Paulo (17.0/10(5) py). Results from Rio de Janeiro were available from 2013 to 2016 with incidence in first time donors of 35.9/10(5) py and repeat donors from 2011 to 2016 of 29.2/10(5) py. Incidence varied by other donor demographics. When incidence was considered in 2-year intervals, no significant trend was evident. Overall residual risk of TT-HIV was 5.46 and 7.41 per million units of pRBC and FFP transfused, respectively. CONCLUSION: HIV incidence in both first-time and repeat donors varied by region in Brazil. Clear secular trends were not evident.

ObjectivesSickle 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.MethodsThe 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.ResultsRespondents 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.ConclusionsA 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.

BACKGROUND Patients with sickle cell disease (SCD) often require red blood cell (RBC) transfusion for clinical complications, so may be exposed to transfusion-transmitted infections (TTIs). The prevalence of markers for human immunodeficiency virus (HIV), hepatitis C virus (HCV) and B (HBV), human T-cell lymphotropic virus (HTLV-1/2), Chagas disease, and syphilis in an SCD cohort in Brazil were studied. STUDY DESIGN AND METHODS Clinical history, interview data, blood samples, and medical chart review data were collected during cohort enrollment from November 2013 to May 2015. Serologic markers of infection were assessed. Standard measures of statistical association were calculated, and multivariable models were developed for the most prevalent infections to identify associated factors. RESULTS Infection markers were evident in 5.2% (144/2779) of the enrolled cohort. Anti-HCV was detected in 69 (2.5%), syphilis antibodies in 34 (1.2%), anti-HTLV-1/2 in 17 (0.6%), HBV surface antigen in 13 (0.5%), Chagas disease antibodies in 13 (0.5%), and anti-HIV in 8 (0.3%) of participants. Factors associated with increased odds of being anti-HCV reactive were older age, illegal drug use, increasing number of RBCs, more than three pain crises in the previous year, and geographic location. Syphilis was associated with older age, females, and smoking history. CONCLUSION HCV infection was more common in older patients who may have received RBCs before testing was performed on donations, suggesting possible historic transfusion transmission. The cohort showed decreasing rates of infections and a reduction in transfusion transmission markers in younger patients compared to historical literature except for syphilis, indicating contemporary reduced risk of TTI.

Sickle cell disease (SCD) is associated with significant morbidity, and allogeneic hematopoietic stem cell transplantation (HSCT) remains the primary curative treatment. Recently, the Brazilian Ministry of Health released a regulation that required the publically funded healthcare system to pay for HSCT for SCD patients with defined indications. We used an existing 2794-member SCD cohort established during 2013 to 2015 to characterize candidates for HSCT and estimate the number of possible donors. Of 2064 patients with SC anemia (SCA), 152 of 974 children (16%) and 279 of 1090 adults (26%) had at least 1 HSCT indication. The most common indication for transplant was stroke (n = 239) followed by avascular necrosis (n = 96), priapism (n = 82), cerebrovascular disease (n = 55),2 vaso-occlusive episodes (n = 38), alloantibodies and chronic transfusion therapy (n = 18), and2 acute chest syndrome episodes (n = 11). Increasing age, number of transfusions, abnormal transcranial Doppler, retinopathy, dactylitis, and use of hydroxyurea were more frequent in the 152 children with an indication for HSCT compared with 822 without (P.001). Of 152 children and 279 adults meeting the eligibility definition, 77 (50%) and 204 (73%), respectively, had at least 1 non-SCD full sibling who could potentially serve as a donor. In conclusion, in a large cohort of SCA patients, 16% of children and 26% of adults had at least 1 indication for HSCT; these indications were associated with the severity of the disease. This study provides clinical data necessary for estimating the costs and infrastructure that would be required to implement HSCT in a public healthcare system.

Background Genetic diversity in the RH genes among sickle cell disease (SCD) patients is well described but not yet extensively explored in populations of racially diverse origin. Transfusion support is complicated in patients who develop unexpected Rh antibodies. Our goal was to describe RH variation in a large cohort of Brazilian SCD patients exhibiting unexpected Rh antibodies (antibodies against RH antigens to which the patient is phenotypically positive) and to evaluate the impact of using the patient's RH genotype to guide transfusion support. Study design and methods Patients within the Recipient Epidemiology and Evaluation Donor Study (REDS)-III Brazil SCD cohort with unexpected Rh antibodies were selected for study. RHD and RHCE exons and flanking introns were sequenced by targeted next-generation sequencing. Results Fifty-four patients with 64 unexplained Rh antibodies were studied. The majority could not be definitively classified as auto- or alloantibodies using serologic methods. The most common altered RH were RHD*DIIIa and RHD*DAR (RHD locus) and RHCE*ce48C, RHCE*ce733G, and RHCE*ceS (RHCE locus). In 53.1% of the cases (34/64), patients demonstrated only conventional alleles encoding the target antigen: five of 12 anti-D (41.7%), 10 of 12 anti-C (83.3%), 18 of 38 anti-e (47.4%), and one of one anti-E (100%). Conclusion RHD variation in this SCD cohort differs from that reported for African Americans, with increased prevalence of RHD*DAR and underrepresentation of the DAU cluster. Many unexplained Rh antibodies were found in patients with conventional RH allele(s) only. RH genotyping was useful to guide transfusion to determine which patients could potentially benefit from receiving RH genotyped donor units.

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.

Approximately 3,500 children with Sickle Cell Disease (SCD) are born in Brazil each year, but the burden of SCD morbidity is not fully characterised. A large, multi-centre cohort was established to characterise clinical outcomes in the Brazilian SCD population and create the infrastructure to perform genotype-phenotype association studies. Eligible patients were randomly selected from participating sites and recruited at routine visits. A biorepository of blood samples was created and comprehensive demographic and clinical outcome data were entered in a centralized electronic database. Peripheral blood genome-wide single nucleotide polymorphism (SNP) genotyping was performed using a customized Transfusion Medicine (TM) Array. A total of 2795 participants at six Brazilian sites were enrolled between 2013 and 2015. The cohort included slight predominance of children

Introduction Emerging literature suggests body mass index (BMI) may be increasing in individuals with sickle cell disease (SCD), a condition historically associated with underweight status. However, the current prevalence of overweight and obese adults with SCD remains unclear in a country where high BMI is prevalent in the general population. We present an epidemiological analysis of the prevalence of overweight and obese individuals in a large representative sample of adult SCD patients, identifying associations between BMI, sociodemographic and clinical characteristics. Methods Using the Sickle Cell Disease Consortium (SCDIC) registry, we compiled a detailed clinical and demographical from a non-random sample of adults, aged 20-45 years. The SCDIC collects data from eight academic centers providing comprehensive care throughout the U.S. Adult participants were excluded from the analysis if they were under 20 years of age, pregnant at the time of enrollment, or were without medical records or patient enrollment surveys. Sociodemographic information and patient-reported outcomes, including pain frequency and severity, SCD complications, and hydroxyurea use, were collected at the time of enrollment. Non-SCD medical conditions and anthropometric measurements were abstracted from medical records. We stratified BMI, measured in kilograms per meters squared (kg/m2) following CDC criteria: underweight (30 kg/m2). An epidemiological analysis was performed of BMI in those with SCD. Bivariate analyses were conducted using Chi-square test, t-test, and ANOVA; non-parametric tests were used when appropriate. Data were analyzed using SAS 9.4 (SAS Institute; Cary, NC). Results In total, 1,664 adults met the inclusion criteria for this cross-sectional analysis of SCDIC registry data. The median BMI for the entire sample was 23.9 kg/m² (IQR: 21.1-28). The majority of participants were African American (99.1%), female (56.6%), and had an HbSS genotype (69.6%). The prevalence of an obese BMI (17.5%) was greater than underweight BMI (6.4%) among the entire cohort (Table 1). When compared to under/normal weight participants, those who were overweight/obese were older (median age 31.2 versus 29.3 years; p Conclusion To date, this is the largest analysis of adult BMI among individuals with SCD in the U.S. Among the eight SCDIC sites spanning from the Northeast to Southwest U.S., the prevalence of underweight BMI was less than that of overweight or obese BMI status, challenging previous understandings of weight status and further aligning with the growing rates of overweight and obesity in the general U.S. population. Significant associations between high BMI and hypertension, age, and pain intensity highlight an opportunity for further research to understand the impact of increasing BMI on SCD outcomes and non-SCD comorbidities. Figure 1 Figure 1. Disclosures Ibemere: bluebird bio Insights Council: Consultancy, Honoraria; Ugali Youth: Consultancy, Membership on an entity's Board of Directors or advisory committees. King: Health Resources and Services Administration: Research Funding; National Cancer Institute: Research Funding; Global Blood Therapeutics: Research Funding; National Heart, Lung, and Blood Institute: Research Funding. Hankins: Global Blood Therapeutics: Consultancy; UpToDate: Consultancy; Bluebird Bio: Consultancy; Vindico Medical Education: Consultancy. Tanabe: CSL Behring: Consultancy. Shah: Emmaus: Consultancy; GLG: Consultancy; Alexion: Speakers Bureau; Guidepoint Global: Consultancy; Bluebird Bio: Consultancy; CSL Behring: Consultancy; Novartis: Research Funding, Speakers Bureau; GBT: Consultancy, Research Funding, Speakers Bureau.

Background Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL. Objectives This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data. Methods QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity. Results In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL. Conclusions In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity.

Background Red blood cell (RBC) transfusions are used in sickle cell disease (SCD) to treat acute complications or as chronic transfusion therapy (CTT) to prevent severe manifestations. The objectives of this study were to describe blood utilization and adverse events (AEs) associated with RBCs in the Brazilian SCD population and compare characteristics of patients treated or not with CTT. Study design and methods A SCD cohort was established at six Brazilian centers. Medical and blood bank records were abstracted for clinical and transfusion history. Two controls not treated with CTT matched on center, SCD genotype, sex, and age were selected for each CTT case within the cohort to compare characteristics between the two groups. Results Most of the 2794-member cohort had received a transfusion (75.0% of children and 89.2% of adults) with 29.2% of patients receiving transfusion in the prior year. There were 170 (10.6%) children and 115 (9.2%) adults treated with CTT. Children not treated with CTT were more likely to have pain and acute chest hospitalizations in the prior year (25.3% vs. 11.9%, p = 0.0003; and 22.0% vs. 10.7%, p = 0.002, respectively). Both iron overload and alloimmunization were more common in CTT cases compared to controls (65.6% vs. 17.0% and 36.2% vs. 15.9%, respectively). A higher proportion of adults treated with CTT demonstrated oxygen saturation of greater than 95% compared to controls not treated (51.1% vs. 39.2%), while there was no difference in oxygenation between children treated or not. Of 4501 transfusion episodes, 28 (0.62%) AEs were reported. There was no difference in AEs associated with transfusions for acute indications versus CTT. Conclusion Red blood cell transfusion was common in Brazilian SCD patients, with utilization driven by CTT. Transfusion reactions were not common; however, alloimmunization and iron overload were frequent among those on CTT, highlighting the need for novel clinical strategies to mitigate these risks.

Background Aortic dissection (AoD) is a serious complication of thoracic aortic aneurysm (TAA). Relative risk for AoD in relation to TAA etiology, incidence, and pattern after prophylactic TAA surgery are poorly understood. Objectives This study sought to determine the incidence, pattern, and relative risk for AoD among patients with genetically associated TAA. Methods The population included adult GenTAC participants without AoD at baseline. Standardized core laboratory tests classified TAA etiology and measured aortic size. Follow-up was performed for AoD. Results Bicuspid aortic valve (BAV) (39%) and Marfan syndrome (MFS) (22%) were the leading diagnoses in the studied GenTAC participants (n = 1,991). AoD occurred in 1.6% over 3.6 ± 2.0 years; 61% of AoD occurred in patients with MFS. Cumulative AoD incidence was 6-fold higher among patients with MFS (4.5%) versus others (0.7%; p Conclusions Among patients with genetically associated TAA, MFS augments risk for AoD even after TAA grafting. Although increased aortic size is a risk factor for subsequent AoD, events typically occur below established thresholds for prophylactic TAA repair.

Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, 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 academic and 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. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p Conclusion Key differences in SCD presentation and occurrence of complications exist among males and females. Females had higher rates of depression and anxiety while males had more chronic end-organ complications that are life threatening. Our findings emphasize the need for stratification of data analysis by sex in future SCD studies. Disclosures Hankins: Global Blood Therapeutics: Consultancy, Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; Novartis: Research Funding. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy. King:Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company; RiverVest: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees. Glassberg:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy. Shah:Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau.

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

Vertebral artery tortuosity has been associated with adverse events in Marfan and Loeys-Dietz syndromes, but has not been assessed in Vascular Ehlers-Danlos syndrome (VEDS). Subjects

Background The C-C chemokine receptor Type 5 (CCR5) is a key receptor for human immunodeficiency virus type 1 (HIV-1) entry into T-cells and a variant allele, CCR5 delta-32, is associated with decreased viral replication and disease progression. Active HIV-1 replication is highly associated with accelerated rates of hepatic fibrosis. We postulated that CCR5 plays a role in the development of hepatic fibrosis and evaluated the longitudinal effect of natural or drug-induced CCR5 mutation and blockade on biomarkers of liver fibrosis in HIV-1 patients. Methods To accomplish this goal, we examined 2 distinct cohorts. First, we evaluated fibrosis markers in the Multicenter Hemophilia Cohort Studies (MHCS), which included subjects with HIV and hepatitis C virus (HCV) coinfection with the CCR5 delta-32 allele. We also evaluated an HIV-1 infected cohort that was treated with a dual CCR5/CCR2 antagonist, cenicriviroc. The enhanced liver fibrosis (ELF) index was validated against liver histology obtained from HCV/HIV and HCV patients and demonstrated strong correlation with fibrosis stage. Results In both the MHCS patients and patients treated with cenicriviroc, CCR5 mutation or blockade was associated with a significant decrease in the ELF index. Among the patients with the delta-32 allele, the ELF index rate significantly decreased in sequential samples as compared to CCR5 wild-type patients (P = .043). This was not observed in control subjects treated with efavirenz nor with a lower dose of 100 mg cenicriviroc. Conclusion These findings suggest that hepatic fibrosis in HIV-1 infected patients can be modulated by the mutation of CCR5 and/or use of CCR5/CCR2 blockade agents. Clinical Trials Registration NCT01338883.

Background: Biomarkers that reflect progression of dilatation of the aorta in patients with aortic conditions are needed as surrogate tools to assist in monitoring the condition in a non-invasive manner in combination with imaging procedures but are yet to be established. This study aimed to establish clinically useful biomarkers for aortic conditions in patients enrolled in the Genetically-Triggered Thoracic Aortic Conditions (GenTAC) registry. Methods: Plasma samples of 159 patients enrolled in the GenTAC registry were assessed for circulating biomarkers (interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP1), tissue inhibitor of metalloproteinase-2 (TIMP-2) and transforming growth factor-β1 (TGF β1)] by enzyme-linked immunosorbent assay. Primary diagnosis and aortic image data were compared with the measured values. Results: IL-6 showed significant positive correlations with aortic dimensions at each segment of the aorta, the correlation becoming stronger as it shifts to distal (ascending aorta R=0.26 p=0.004, proximal arch R=0.35 p

Background Unicuspid aortic valve (UAV) is a rare disorder, often difficult to distinguish from bicuspid aortic valve (BAV). BAV and UAV share valve pathology such as the presence of a raphe, leaflet fusion, aortic stenosis, aortic regurgitation, and/or ascending aortic dilatation, but a comprehensive echocardiographic comparison of patients with UAV and BAV has not been previously performed. Methods We investigated UAV and BAV patients at an early stage of disease included in GenTAC, a national registry of genetically related aortic aneurysms and associated cardiac conditions. Clinical and echocardiographic data from the GenTAC Registry were compared between 17 patients with UAV and 17 matched-controls with BAV. Results Baseline characteristics including demographics, clinical findings including family history of BAV and aortic aneurysm/coarctation, and echocardiographic variables were similar between BAV and UAV patients; aortic stenosis was more common and more severe in patients with UAV. This was evidenced by higher mean and peak gradient, smaller aortic valve area, and more advanced valvular degeneration (all P

SUMMARY Objective: Describe the characteristics of persons with epilepsy (PWEs) and caregivers that have or have not heard of sudden unexpected death in epilepsy (SUDEP) prior to completing a survey through the Internet or in the clinical setting. Methods: An online survey for adult PWEs and caregivers was solicited by e-mail and newsletter to Epilepsy Therapy Project members. A similar survey was implemented in a clinic setting of a community hospital. The survey asked about seizure characteristics, epilepsy management, fear of death, and familiarity with the term SUDEP. Respondents that never heard of SUDEP read a definition and responded to questions about their initial reactions. Results: Surveys from 1,392 PWEs and 611 caregivers recruited through an epilepsy Website and a clinic demonstrated that Internet respondents were much more likely to have heard about SUDEP than the clinic population (71.1% vs. 38.8%; p < 0.001), and caregivers of PWEs were more likely to have heard about SUDEP than PWEs (76.2% vs. 65.2%; p < 0.001). Prior awareness was related to an increased level of education, more severe and longer duration of epilepsy, and having an epileptologist as the primary care provider. Although most PWEs and caregivers reported feelings of fear, anxiety, and sadness after first hearing of SUDEP, they wanted to discuss it with their doctor. Persons with epilepsy, and especially their caregivers, often worry that the PWEs may die of epilepsy or seizures. This worry escalated with knowledge of SUDEP and increased epilepsy severity. Approximately half of PWEs and caregivers believed that knowledge about SUDEP would influence their epilepsy management. Significance: Our results may help epilepsy care providers determine when to facilitate a discussion about epilepsy-related mortality and SUDEP among patients and caregivers, and to educate those at high risk about the importance of seizure control as well as reduce fears about death in patients with well-controlled and nonconvulsive epilepsies.

Background Biomarkers that reflect progression of dilatation of the aorta in patients with aortic conditions are needed as surrogate tools to assist in monitoring the condition in a non-invasive manner in combination with imaging procedures. This study aimed to investigate whether biomarkers are associated with aortic dimensions in patients enrolled in the Genetically-Triggered Thoracic Aortic Conditions (GenTAC) registry. Methods Plasma samples of 159 patients enrolled in the GenTAC registry were assessed for circulating biomarkers [interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue inhibitor of metalloproteinase-2 (TIMP-2) and transforming growth factor-β1 (TGFβ1)]. Association of circulating biomarker levels with aortic dimensions was investigated. Results IL-6 showed significant positive correlations with aortic dimensions at each segment of the aorta, with the correlation increasing in more distal aortic regions (ascending aorta, R = 0.26, p = 0.004; proximal arch, R = 0.35, p

Hepatitis C virus (HCV) is a blood-borne infection readily transmitted by transfusion. Persons with hemophilia were at very high risk of acquiring HCV, but the chronology and correlates of HCV incidence in the US hemophilia population remain unknown. The authors used multiple data sources and new statistical methods to reconstruct HCV incidence in White males with hemophilia A from 1940 through 1990. HCV incidence was approximately 1%/year until 1950 but 2-3%/year by 1955. With mild hemophilia, HCV incidence increased in the 1960s, reaching a plateau of approximately 8%/year from 1969 to 1980. With moderate and severe hemophilia, HCV incidence increased steeply to peaks of 11.7%/year in 1970 and 17.2%/year in 1968, respectively. Overall, HCV incidence declined after 1970, steeply after 1984, to nearly zero by 1990. With improving and increasing use of plasma derivatives, the size of the hemophilia population increased 86% during these 50 years. Study results imply that these life-saving treatments also carried an increasing risk of HCV, particularly before clotting factor concentrates were licensed in the 1970s. They also suggest that multiple synergistic interventions since 1970, particularly donor deferral, screening for hepatitis B and human immunodeficiency virus, and viral inactivation of clotting factor concentrates, were needed to reduce transfusion of HCV prior to its discovery.

Background: Immune perturbation likely affects the development of Kaposi sarcoma (KS) among people infected with the KS-associated herpesvirus (KSHV). We tested whether KSHV-seropositive individuals or cases of classic KS (cKS), which typically originates in the leg, had differing delayed-type hypersensitivity (DTH) in the forearm or leg. Methods: Mantoux DTH with three antigens (Candida, tetanus, PPD) was performed on the forearm and leg of 15 cKS cases, 14 KSHV-positives without KS, and 15 KSHV-negative controls. The diameters of induration responses were compared by group and body site. Results: Leg DTH was greater than forearm DTH among controls (mean difference 5.6 mm, P=0.0004), whereas this was not observed in cKS cases (−2.2 mm, P=0.32) or KSHV-positives (0.5 mm, P=0.56). Leg-minus-forearm DTH difference was greater in controls compared with cKS cases (P=0.004) and KSHV-positives (P=0.002). Leg-plus-forearm DTH was similar in controls (mean 28.2 mm) and cKS cases (24.5 mm, P=0.60), but it was reduced in KSHV-positives (11.8 mm, P=0.02), particularly in the leg (P=0.004) and marginally in the forearm (P=0.07). Conclusion: KS cases had weaker DTH only in the leg, whereas both body sites appeared weaker in KSHV-positives without KS. Both systemic and regional immune alterations may influence the development of this malignancy.

Background Kaposi sarcoma (KS), a malignancy of dermal endothelial cells that is caused by human herpesvirus 8 (HHV8) infection, is sensitive to perturbations of immunity. Nicotine might be effective against KS because of its immunologic and vascular effects and because smoking is associated with a low risk of KS. Objective and study design We conducted a masked, randomized phase 2 clinical trial of transdermal nicotine and placebo patches to assess the safety and efficacy of nicotine against classic KS (cKS). Subjects and methods Three cKS lesions, predominantly nodules, in each of 24 non-smoking patients were randomly assigned to 15 weeks continuous treatment with nicotine patch (escalated to 7 mg), identical masked placebo patch or no patch. Changes in lesion area and elevation from baseline through six follow-up visits, by direct measurement and by two independent readers using digital photographs of the lesions, were compared using non-parametric and regression methods. Changes in longitudinal levels of HHV8 antibodies and DNA in blood cells were similarly assessed. Results There were no systemic or serious adverse events, and compliance was good. One patient resumed smoking and discontinued patches, and two patients withdrew at week 12 for unrelated indications. Six (29%) of the remaining 21 suspended use of patches to relieve local skin irritation; four of these six completed the trial at reduced dose. Treatment assignment was not associated with significant or consistent changes in cKS lesion area or elevation, HHV8 viral load or antibodies. Conclusion Transdermal nicotine and placebo patches caused no serious toxicities but had no demonstrable effect on nodular cKS lesions or HHV8 levels.

We sought to determine the incidence, prevalence, and life expectancy of Aicardi syndrome from 408 cases compiled from multiple international sources. Last known age ranged from less than 1 month to 42 years. The incidence rates per live births for the United States and The Netherlands were 1 per 105 000 and 1 per 93 000, respectively. The prevalence in the United States is greater than 853 cases, and the worldwide estimate is several thousand. Forty-five cases were deceased (age range, 1 month to 33 years), and the risk of death peaked at age 16. The probability of survival at 27 years of age was 0.62 (95% CI, 0.47-0.77). The risk of death by age follows other congenital neurological disorders with a wide range in severity of functional disability. The longer life expectancy found in our study hints at a higher functioning capacity in Aicardi syndrome and may inform counseling to families.

Objective: To identify correlates of spontaneous hepatitis C virus (HCV) clearance among people with human immunodeficiency virus (HIV) co-infection. Design: Baseline (2001–2004) analysis of a cohort study of people with hemophilia. Methods: Detailed questionnaire data were used to identify dates of primary HCV and HIV infections and to categorize sex; race; alcohol use; interferon treatment; hepatitis B virus (HBV) status; and HIV/AIDS history, treatment and current status. Spontaneous HCV clearance was defined as nondetection of HCV RNA by polymerase chain reaction assay in paired annual plasma, excluding those treated with interferon. Chi-squared, Fisher exact test, and logistic regression were used to identify correlates of clearance. Results: Among 478 HIV-infected participants, 61 (12.8%) had cleared HCV. Among the 31 participants with chronic HBV (as well as HIV), 16 (51.6%) had cleared HCV. With chronic HBV, HCV clearance was increased 11.2-fold (95% confidence interval, 5.1–24.8), after adjusting for sex, race, and hemophilia severity. Excluding the participants with chronic HBV, the prevalence of HCV clearance was 10.1%; and it was significantly reduced among males (9.7%, P = 0.05), blacks (1.6%, P = 0.01), and participants with severe hemophilia (8.2%, P = 0.02). HCV clearance was not associated with HIV RNA detection in plasma, CD4 cell count, anti-HIV therapy, AIDS history, ages at or years of HIV or HCV infection, or alcohol consumption. Conclusions: HCV clearance is unambiguously and markedly increased with chronic HBV infection among HIV co-infected people.

Background & Aims: Hemophilic siblings provide a unique population to explore the natural history of chronic hepatitis C. Methods: From 3993 hemophilic patients with hepatitis C, 257 sibling pairs, of which both members had evidence of hepatitis C infection, were studied to evaluate the genetic contribution to spontaneous and treatment-induced clearance of hepatitis C infection and progression of liver disease. Familial aggregation was assessed by comparing observed probabilities of concordance for these disease characteristics within sibling pairs to those expected for randomly paired hemophilic subjects. Additional measures of familial aggregation, heritability, and sibling relative risk were also calculated. Results: Among human immunodeficiency virus-negative subjects, concordance for spontaneous viral clearance was 2-fold higher in siblings compared with randomly paired subjects (8.8% vs 4.3%, respectively, P = .04). Similarly, the concordance rate for treatment-related viral clearance was over twice that among sibling pairs than among randomly paired hemophiliacs (31.3% vs 13.3%, respectively, P = ns). Heritability estimates for spontaneous and treatment-induced viral clearance were 0.24 ± 0.14 ( P = .04) and 0.43 ± 0.42 ( P = .10), respectively. The sibling relative risks for these respective characteristics were 1.6 and 1.7. Concordance for advanced liver disease was higher among siblings but did not reach statistical significance (4.0% vs 2.3%, respectively, P = ns). The heritability estimate was 0.29 ± 0.13 ( P = .02). Conclusions: Concordance rates and heritability estimates for spontaneous and treatment-related viral clearance indicate that genetic factors have a modest influence on the outcome of hepatitis C, although shared environmental factors cannot be excluded. Investigations to map candidate disease-susceptibility genes associated with these characteristics must be approached with caution.

Up to the late 1980s, hepatitis C virus (HCV) infected the majority of people with hemophilia (PWH) in the United States (US), via contaminated plasma clotting factor therapy. Approximately two-thirds of the HCV-infected PWH in the US also were infected with human immunodeficiency virus (HIV). The Second Multicenter Hemophilia Cohort Study (MHCS-II) investigated complications of HCV and HIV infections in people with hemophilia. From 2001 - 2005, data and specimens were collected from 2561 anti-HCV positive participants, including 763 who were co-infected with HIV. These data were analyzed for correlates of spontaneous HCV clearance. Results. Of the 763 HIV-positive, anti-HCV-positive participants, 285 were eliminated from the analysis because they had received interferon treatment to clear HCV, lacked HCV treatment data, or lacked sufficient specimens to determine HCV clearance status. Of the remaining 478 interferon-untreated participants, 61 (12.8%) had cleared HCV RNA from plasma. HCV had cleared in 8.6% of the 116 who were never infected with hepatitis B virus (HBV), 11.6% of 207 with resolved HBV infection, and 8.9% of 124 with missing HBV status (P≥ 0.41). In contrast, HCV had cleared in 16 (51.6%) of the 31 participants with chronic HBV surface antigen (HBsAg) in serum. Adjusted for gender and race, HCV clearance was increased 7.4-fold (95% CI 3.7 - 15.0) for those with chronic HBsAg. In the HBsAg negative group, HCV clearance was significantly lower among participants of African ancestry (1.6%, p=0.01) and was significantly lower in PWH with severe compared to mild or moderate coagulopathy (8.2% vs 15.9%, p=0.02). Clearance was unrelated to type of initial clotting factor replacement therapy, year of birth, year of primary HCV infection, age at primary HCV infection, age at HIV infection, and year of enrollment in the cohort. HCV clearance occurred in 2 (12.5%) of the 14 participants in whom primary HCV infection occurred after or within one year of HIV infection, compared to 9.1% when HCV infection occurred more than one year before HIV (p=0.65). HCV clearance was unrelated to CD4 count at cohort enrollment, history of immunologically or clinically defined AIDS, and detection of HIV RNA in plasma at cohort enrollment. HCV clearance tended to be higher among the 231 participants on HAART (12.6%) than in those on less intensive (9.1%), anomalous (6.7%) or no anti-HIV therapy (6.5%, Ptrend=0.07), although when restricted to non-African ancestry males, HIV therapy was not associated with clearance (Ptrend=0.26). Conclusion. Unlike in HIV-negative people with hemophilia, HCV clearance in the current study was unrelated to age at or year of primary HCV infection. We were unable to evaluate repeated exposure to and likely re-infection with HCV, although the lower clearance in patients with severe hemophilia, who would have been treated, and thus exposed more frequently, supports the hypothesis of lower clearance with re-infection. While reduced overall, spontaneous HCV clearance was markedly increased by the presence of chronic HBsAg carriage. These findings will increase our understanding of interactions between these viruses and may lead to improved approaches to treatment of co-infected patients.

Background Ecologic and in vitro studies suggest that exposures to plants or soil may influence risk of Kaposi sarcoma (KS). Methods In a population-based study of Sicily, we analyzed data on contact with 20 plants and residential exposure to 17 soils reported by 122 classic KS cases and 840 sex- and age-matched controls. With 88 KS-associated herpesvirus (KSHV) seropositive controls as the referent group, novel correlates of KS risk were sought, along with factors distinguishing seronegatives, in multinomial logistic regression models that included matching variables and known KS cofactors - smoking, cortisone use, and diabetes history. All plants were summed for cumulative exposure. Factor and cluster analyses were used to obtain scores and groups, respectively. Individual plants and soils in three levels of exposure with Ptrend ≤ 0.15 were retained in a backward elimination regression model. Results Adjusted for known cofactors, KS was not related to cumulative exposures to 20 plants [per quartile adjusted odds ratio (ORadj) 0.96, 95% confidence interval (CI) 0.73 - 1.25, Ptrend = 0.87], nor was it related to any factor scores or cluster of plants (P = 0.11 to 0.81). In the elimination regression model, KS risk was associated with five plants (Ptrend = 0.02 to 0.10) and with residential exposure to six soils (Ptrend = 0.01 to 0.13), including three soils (eutric regosol, chromic/pellic vertisol) used to cultivate durum wheat. None of the KS-associated plants and only one soil was also associated with KSHV serostatus. Diabetes was associated with KSHV seronegativity (ORadj 4.69, 95% CI 1.97 - 11.17), but the plant and soil associations had little effect on previous findings that KS risk was elevated for diabetics (ORadj 7.47, 95% CI 3.04 - 18.35) and lower for current and former smokers (ORadj 0.26 and 0.47, respectively, Ptrend = 0.05). Conclusions KS risk was associated with exposure to a few plants and soils, but these may merely be due to chance. Study of the effects of durum wheat, which was previously associated with cKS, may be warranted.