Disparities in electronic health record portal access and use among patients with cancer.

BACKGROUND: Electronic health record-linked portals may improve health-care quality for patients with cancer. Barriers to portal access and use undermine interventions that rely on portals to reduce cancer care disparities. This study examined portal access and persistence of portal use and associations with patient and structural factors before the implementation of 3 portal-based interventions within the Improving the Management of symPtoms during And following Cancer Treatment (IMPACT) Consortium. METHODS: Portal use data were extracted from electronic health records for the 12 months preceding intervention implementation. Sociodemographic factors, mode of accessing portals (web vs mobile), and number of clinical encounters before intervention implementation were also extracted. Rurality was derived using rural-urban commuting area codes. Broadband access was estimated using the 2015-2019 American Community Survey. Multiple logistic regression models tested the associations of these factors with portal access (ever accessed or never accessed) and persistence of portal use (accessed the portal ≤20 weeks vs ≥21 weeks in the 35-week study period). RESULTS: Of 28 942 eligible patients, 10 061 (35%) never accessed the portal. Male sex, membership in a racial and ethnic minority group, rural dwelling, not working, and limited broadband access were associated with lower odds of portal access. Younger age and more clinical encounters were associated with higher odds of portal access. Of those with portal access, 25% were persistent users. Using multiple modalities for portal access, being middle-aged, and having more clinical encounters were associated with persistent portal use. CONCLUSION: Patient and structural factors affect portal access and use and may exacerbate disparities in electronic health record-based cancer symptom surveillance and management.

Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome.

Background Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains understudied in Vascular Ehlers-Danlos syndrome. Methods and Results Subjects with a pathogenic COL3A1 variant diagnosed at age <50 years were included from 2 institutions and the GenTAC Registry (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). Height-adjusted vertebral artery tortuosity index (VTI-h) using magnetic resonance or computed tomography angiography was calculated. Associations between VTI-h and outcomes of (1) cardiovascular events (arterial dissection/rupture, aneurysm requiring intervention, stroke), or (2) hollow organ collapse/rupture at age <50 years were evaluated using receiver operator curve analysis (using outcome by age 30 years) and mixed-effects Poisson regression for incidence rate ratios. Of 65 subjects (54% male), median VTI-h was 12 (interquartile range, 8-16). Variants were missense in 46%, splice site in 31%, and null/gene deletion in 14%. Thirty-two subjects (49%) had 59 events, including 28 dissections, 5 arterial ruptures, 4 aneurysms requiring intervention, 4 strokes, 11 hollow organ ruptures, and 7 pneumothoraces. Receiver operator curve analysis suggested optimal discrimination at VTI-h ≥15.5 for cardiovascular events (sensitivity 70%, specificity 76%) and no association with noncardiovascular events (area under the curve, 0.49 [95% CI, 0.22-0.78]). By multivariable analysis, older age was associated with increased cardiovascular event rate while VTI-h ≥15.5 was not (incidence rate ratios, 1.79 [95% CI, 0.76-4.24], P=0.185). However, VTI-h ≥15.5 was associated with events among those with high-risk variants <40 years (incidence rate ratios, 4.14 [95% CI, 1.13-15.10], P=0.032), suggesting effect modification by genotype and age. Conclusions Increased arterial tortuosity is associated with a higher incidence rate of cardiovascular events in Vascular Ehlers-Danlos syndrome. Vertebral tortuosity index may be a useful biomarker for prognosis when evaluated in conjunction with genotype and age.

Examining Mental Health, Education, Employment, and Pain in Sickle Cell Disease.

Importance: Pain related to sickle cell disease (SCD) is complex and associated with social determinants of health. Emotional and stress-related effects of SCD impact daily quality of life and the frequency and severity of pain. Objective: To explore the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with SCD. Design, Setting, and Participants: This is a cross-sectional analysis of patient registry data collected at baseline (2017-2018) from patients treated at 8 sites of the US Sickle Cell Disease Implementation Consortium. Data analysis was performed from September 2020 to March 2022. Main Outcomes and Measures: Electronic medical record abstraction and a participant survey provided demographic data, mental health diagnosis, and Adult Sickle Cell Quality of Life Measurement Information System pain scores. Multivariable regression was used to examine the associations of education, employment, and mental health with the main outcomes (pain frequency and pain severity). Results: The study enrolled a total of 2264 participants aged 15 to 45 years (mean [SD] age, 27.9 [7.9] years; 1272 female participants [56.2%]) with SCD. Nearly one-half of the participant sample reported taking daily pain medication (1057 participants [47.0%]) and/or hydroxyurea use (1091 participants [49.2%]), 627 participants (28.0%) received regular blood transfusion, 457 (20.0%) had a depression diagnosis confirmed by medical record abstraction, 1789 (79.8%) reported severe pain (rated most recent pain crises as ≥7 out of 10), and 1078 (47.8%) reported more than 4 pain episodes in the prior 12 months. The mean (SD) pain frequency and severity t scores for the sample were 48.6 (11.4) and 50.3 (10.1), respectively. Educational attainment and income were not associated with increased pain frequency or severity. Unemployment (ß, 2.13; 95% CI, 0.99 to 3.23; P < .001) and female sex (ß, 1.78; 95% CI, 0.80 to 2.76; P < .001) were associated with increased pain frequency. Age younger than 18 years was inversely associated with pain frequency (ß, -5.72; 95% CI, -7.72 to -3.72; P < .001) and pain severity (ß, 5.10; 95% CI, -6.70 to -3.51; P < .001). Depression was associated with increased pain frequency (ß, 2.18; 95% CI, 1.04 to 3.31; P < .001) but not pain severity. Hydroxyurea use was associated with increased pain severity (ß, 1.36; 95% CI, 0.47 to 2.24; P = .003), and daily use of pain medication was associated with both increased pain frequency (ß, 6.29; 95% CI, 5.28 to 7.31; P < .001) and pain severity (ß, 2.87; 95% CI, 1.95 to 3.80; P < .001). Conclusions and Relevance: These findings suggest that employment status, sex, age, and depression are associated with pain frequency among patients with SCD. Depression screening for these patients is warranted, especially among those experiencing higher pain frequency and severity. Comprehensive treatment and pain reduction must consider the full experiences of patients with SCD, including impacts on mental health.

Infertility and treatment-seeking practices among females and males with sickle cell disease in the Sickle Cell Disease Implementation Consortium registry.

OBJECTIVE: To describe the prevalence of infertility and infertility treatment seeking among people enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry and identify sociodemographic and clinical correlates of infertility. DESIGN: Cross-sectional. PARTICIPANTS: The study population included 2108 women and men (≥18 years of age) enrolled in the SCDIC registry who completed the fertility questionnaire. RESULTS: All participants who completed the infertility-specific questions were included in the analysis (1224 females; 884 males). Of these, 16.9% of males and 23.7% of females reported infertility, in contrast to rates in the general population (12% of males; 11% of females). Only 22.8% of this subgroup had sought a fertility consultation; of these, 41% received infertility testing and 58% received advice, yet only a few received specific treatment: ovulation medication (19.1%), fallopian tubal surgery (4.8%), other female treatment (17.5%), varicocelectomy (8.1%), or other male treatment (10.8%). Increasing age, employment status, and interaction between gender and single marital status are associated with reported infertility. We did not observe differences between groups relative to sickle cell disease (SCD) genotype, a broad category of self-reported hydroxyurea use any time during life, type of medical insurance, income, or education. CONCLUSION: To our knowledge, this is the first study to examine self-reported identification of and treatment for infertility among a large sample of people with SCD. These findings suggest that (a) infertility occurs at a higher rate, but fertility care treatment seeking is less frequent than in the general public; and (b) sociodemographic and clinical differences between individuals who report experiencing infertility and those who do not did not emerge in this study.

Characterising the prevalence of overweight and obese status among adults with sickle cell disease.

Individuals with sickle cell disease (SCD) have historically been considered underweight. Despite increasing body mass index (BMI) in the general population, the prevalence of overweight and obese status remains unclear in the adult SCD population. Our primary aim was to determine the prevalence of overweight and obese status and to identify associations between BMI, demographic, and clinical characteristics. We conducted an analysis of abstracted electronic health record data and patient-reported outcomes from the Sickle Cell Disease Implementation Consortium registry; individuals aged 20-45 years were included. The median (interquartile range) BMI for the 1664 adults in this analysis was 23.9 (21.1-28) kg/m2 . In this cohort, 42.9% had a BMI of >25 kg/m2 (Centers for Disease Control and Prevention definition of overweight/obese). In multivariable analysis, higher odds of being overweight or obese were associated with female gender, older age, college education, private insurance, and hypertension diagnosis. Higher odds of a BMI of >25 kg/m2 were observed in individuals with HbSC or HbSß+ thalassaemia regardless of hydroxycarbamide (hydroxyurea) exposure (odds ratio [OR] 3.4, p < 0.0001) and HbSS or HbSß0 thalassaemia exposed to hydroxycarbamide (OR 1.6, p = 0.0003) compared to those with HbSS or HbSß0 thalassaemia with no hydroxycarbamide exposure. These data highlight the importance of early identification, prevention, and intervention for increasing BMI to reduce obesity-related complications that may impact SCD-related complications.

An evaluation of patient-reported outcomes in sickle cell disease within a conceptual model.

PURPOSE: To examine the relations between patient-reported outcomes (PROs) within a conceptual model for adults with sickle cell disease (SCD) ages 18 - 45 years enrolled in the multi-site Sickle Cell Disease Implementation Consortium (SCDIC) registry. We hypothesized that patient and SCD-related factors, particularly pain, and barriers to care would independently contribute to functioning as measured using PRO domains. METHODS: Participants (N = 2054) completed a 48-item survey including socio-demographics and PRO measures, e.g., social functioning, pain impact, emotional distress, and cognitive functioning. Participants reported on lifetime SCD complications, pain episode frequency and severity, and barriers to healthcare. RESULTS: Higher pain frequency was associated with higher odds of worse outcomes in all PRO domains, controlling for age, gender and site (OR range 1.02-1.10, 95% CI range [1.004-1.12]). Reported history of treatment for depression was associated with 5 of 7 PRO measures (OR range 1.58-3.28 95% CI range [1.18-4.32]). Fewer individual barriers to care and fewer SCD complications were associated with better outcomes in the emotion domain (OR range 0.46-0.64, 95% CI range [0.34-0.86]). CONCLUSIONS: Study results highlight the importance of the biopsychosocial model to enhance understanding of the needs of this complex population, and to design multi-dimensional approaches for providing more effective interventions to improve outcomes.

Identifying barriers to evidence-based care for sickle cell disease: results from the Sickle Cell Disease Implementation Consortium cross-sectional survey of healthcare providers in the USA.

OBJECTIVES: Sickle 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. METHODS: The 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. RESULTS: Respondents 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. CONCLUSIONS: A 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.

Sex-based differences in the manifestations and complications of sickle cell disease: Report from the Sickle Cell Disease Implementation Consortium.

INTRODUCTION: Sex-based clinical outcome differences in sickle cell disease (SCD) remain largely unknown despite evidence that female sex is associated with an increased lifespan. To better characterize sex-based differences in SCD, we assessed 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 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. Eligibility criteria included: 15 to 45 years of age and a confirmed diagnosis of SCD. Self-report surveys were completed and data were also abstracted from the participants' medical records. RESULTS: A total of 2,124 participants were included (mean age: 27.8 years; 56% female). The majority had hemoglobin SS SCD genotype. Females had worse reports of pain severity (mean (SD) T-score 51.6 (9.6) vs 49.3 (10), p<0.001), more vaso-occlusive episodes (p = 0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9% vs. 25.5, p = 0.03). On multivariable analysis, males had higher odds of acute chest syndrome (odds ratio (OR) 1.4, p = 0.002), cardiovascular (OR 1.70, p<0.001) and musculoskeletal (OR 1.33, p = 0.0034) complications and lower odds of depression (OR 0.77, p = 0.0381). Females had higher fetal hemoglobin levels with and without hydroxyurea use (9.6% vs 8.5%, p = 0.03 and 3% vs 2.2%, p = 0.0005, respectively). CONCLUSION: Our data suggests that sex differences in clinical outcomes do occur among individuals with SCD. Future research needs to explore the mechanisms underlying these differences.

HIV primary drug resistance and associated HIV risk factors among HIV positive blood donors in Brazil from 2007 to 2017.

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 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 twofold 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, behavioural 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.

Effective Recruitment Strategies for a Sickle Cell Patient Registry Across Sites from the Sickle Cell Disease Implementation Consortium (SCDIC).

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.

10-year analysis of human immunodeficiency virus incidence in first-time and repeat donors in Brazil.

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 centres in Brazil. MATERIALS AND METHODS: Donations were screened and confirmed using serological assays for HIV from 2007 to 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 (105 py)) followed by São Paulo (32·2/105 py) and then Belo Horizonte (23·3/105 py), and in repeat donors was highest in Recife (33·2/105 py), Belo Horizonte (27·5/105 py) and São Paulo (17·0/105 py). Results from Rio de Janeiro were available from 2013 to 2016 with incidence in first-time donors of 35·9/105 py and repeat donors from 2011 to 2016 of 29·2/105 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.

A Survey-Based Needs Assessment of Barriers to Optimal Sickle Cell Disease Care in the Emergency Department.

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.

Blood utilization and characteristics of patients treated with chronic transfusion therapy in a large cohort of Brazilian patients with sickle cell disease.

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.

Prevalence of serologic markers of transfusion and sexually transmitted infections and their correlation with clinical features in a large cohort of Brazilian patients with sickle cell disease.

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.

Diversity of RH and transfusion support in Brazilian sickle cell disease patients with unexplained Rh antibodies.

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.

Identification and Characterization of Hematopoietic Stem Cell Transplant Candidates in a Sickle Cell Disease Cohort.

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), and >2 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.

Circulating interleukin-6 (IL-6) levels are associated with aortic dimensions in genetic aortic conditions.

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-ß1 (TGFß1)]. 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<0.0001; transverse arch, R = 0.30, p = 0.0005; mid-descending thoracic aorta, R = 0.40, p<0.0001; thoracoabdominal aorta, R = 0.38, p<0.0001; suprarenal abdominal aorta, R = 0.42, p<0.0001; and infrarenal aorta, R = 0.43, p<0.0001). TIMP-1 showed a significant correlation albeit weaker than IL-6, and also showed increasing correlation towards the distal areas of the aorta. CONCLUSIONS: Circulating IL-6 and TIMP-1 were associated with aortic dimensions in patients with aortopathies enrolled in the GenTAC cohort.

Improvement in Hepatic Fibrosis Biomarkers Associated With Chemokine Receptor Inactivation Through Mutation or Therapeutic Blockade.

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.

Clinical and genetic ancestry profile of a large multi-centre sickle cell disease cohort in Brazil.

Approximately 3500 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 <18 years (55·9%) and females (53·0%). Haemoglobin (Hb) SS was the most common SCD genotype (70·7%), followed by HbSC (23%), Sß0 (3·0%) and Sß+ (2·9%). SNP data from the TM Array were analysed to evaluate the genetic ancestry of the cohort and revealed significant admixture among the population. Demographics and clinical complications, stratified by age and SCD genotype, are summarized and future studies in this cohort are discussed.

Bicuspid and unicuspid aortic valves: Different phenotypes of the same disease? Insight from the GenTAC Registry.

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 < .05). There were no significant differences in aortic dimensions, with a similar pattern of enlargement of the ascending aorta. CONCLUSIONS: The similar baseline characteristics with more accelerated aortic valve degeneration and stenosis suggest that UAV represents an extreme in the spectrum of BAV syndromes. Therefore, it is reasonable to consider application of recommendations for the management of patients with BAV to those with the rarer UAV.