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Background Our objective was to determine associations of occupational exposures with cardiac structure and function in Hispanic/Latino adults. Methods and Results Employed participants were included (n=782; 52% women, mean age 52.9 years). Occupational exposures to burning wood, vehicle exhaust, solvents, pesticides, and metals at the current and longest‐held job were assessed by questionnaire. Survey multivariable linear regression analyses were used to model the relationship of each self‐reported exposure with echocardiographic measures of cardiac structure and function. Exposure to burning wood at the current job was associated with decreased left ventricular (LV) ejection fraction (−3.1%; standard error [SE], 1.0 [ P =0.002]). When the analysis was restricted to exposure at the longest‐held job, occupational exposure to burning wood was associated with increased LV diastolic volume (6.7 mL; SE, 1.6 [ P P P =0.0009]), and decreased right ventricular fractional area change (−0.02; SE, 0.004 [ P P P =0.04]), increased stroke volume (3.6 mL; SE, 1.6 [ P =0.03]), and increased LV mass indexed to BSA (9.2 g/m 2 ; SE, 3.8 [ P =0.01]) or height (4.4 g/m 2.7 ; SE, 1.9 [ P =0.02]). Conclusions Occupational exposures to burning wood, vehicle exhaust, pesticides, and metals were associated with abnormal parameters of LV and right ventricular systolic function. Reducing exposures to toxic chemicals and particulates in the workplace is a potential opportunity to prevent cardiovascular disease in populations at risk.

Introduction The BMT-CTN 1204 study for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (NCT01998633) (RICHI) was a single arm study testing safety and efficacy of reduced intensity conditioning (RIC) with alemtuzumab (1mg/kg), fludarabine (150 mg/m2) and melphalan (140 mg/m2). Survival was favorable compared to historical studies, but patients experienced high rates of mixed chimerism (MC) and ultimate secondary graft failure (GF). Mechanisms for GF are not known. Expansion of recipient T cells and interferon-gamma pathway activation have been proposed as drivers for GF. However, high peri-transplant alemtuzumab levels have been associated with higher risk of MC and eventual secondary GF, suggesting an inverse relationship between GF and immune activation in the context of RIC. In order to elucidate mechanisms of GF for patients on the RICHI study, we systematically evaluated cytokine patterns and alemtuzumab levels and their association with durable engraftment. Methods Serial blood samples were collected, processed, and stored for consenting patients at day -14 (window: day -28 to -14), day -7 (+/- 1 day), day -1 (+/- 1), day +1 (+1 to +3), day +14 (+/- 2), day +28 (+/- 2), day +42 (+/- 3), day +70 (+/- 10), and day +100 (+/- 10). Alemtuzumab levels were measured using a flow cytometric assay as previously described. Comprehensive cytokine analysis was performed for over 100 analytes using the MagPix platform. Primary GF was defined as donor chimerism Results Thirty-three patients were included in this study with HLH (n=25), CAEBV (n=3), CGD (n=2), HIGM (n=2), and IPEX (n=1). All patients received bone marrow grafts and 27 (82%) patients had unrelated donors. Twenty-one grafts were 8/8 or 6/6 HLA-matched (64%) and 12 grafts were 7/8 HLA-matched (36%). Among all patients, 1 patient (3%) developed primary GF, 22 (67%) developed mixed chimerism (MC), and 11 patients (33%) developed secondary GF. Survival with sustained engraftment without DLI or second HCT was 40.0%. We first evaluated peripheral blood levels of 100+ cytokines. Analysis revealed significant differences between patients with and without GF as shown in Figure 1A. Notably, on day +14 and +28, patients with secondary GF had significantly lower CXCL9 levels than those without GF. We then estimated the cumulative incidence (CI) of secondary GF among patients with CXCL9 levels above and below the day +14 median level of 2394pg/mL. The CI of secondary GF in patients with a day +14 CXCL9 level ≤2394pg/mL was 73.6% vs 0% in patients with a level >2394pg/mL (p=0.002). The CI of secondary GF in patients with a day +28 CXCL9 level ≤2867pg/mL (day +28 median) was 64.3%, vs 0% in patients with levels >2867pg/mL (p=0.004). We then sought to correlate CXCL9 levels with alemtuzumab exposure, as high alemtuzumab levels would result in more efficient T cell depletion of donor grafts that could lead to lower CXCL9 levels. Indeed, CXCL9 levels inversely correlated with day 0 alemtuzumab levels. Patients with day 0 alemtuzumab levels >0.32µg/mL had lower CXCL9 levels compared to patients with levels ≤0.32µg/mL (Figure 1B). Finally, we examined the impact of alemtuzumab levels on MC and secondary GF. Patients with day 0 alemtuzumab levels ≤0.32µg/mL had a lower CI of MC compared to patients with levels >0.32µg/mL, 14.3% vs 90.9%, respectively (p=0.03). The CI of secondary GF was 0% in patients with day 0 alemtuzumab levels ≤0.32µg/mL compared to 54.3% in patients with levels >0.32µg/mL (p=0.08). Conclusions This study demonstrates a strong relationship between alemtuzumab levels and durable engraftment. Further, interferon gamma activity, as reflected by CXCL9, inversely correlates with peri-transplant alemtuzumab levels in this prospective cohort treated with RIC. Our findings support the paradigm that higher alemtuzumab levels drive efficient T cell depletion of the stem cell product which increases the risk of MC and secondary GF, suggesting that donor T cells promote engraftment via a graft versus hematopoiesis function. Precision alemtuzumab dosing strategies may offer an opportunity to improve outcomes for patients who undergo RIC HCT. Figure 1 Figure 1. Disclosures Pulsipher: Adaptive: Research Funding; Equillium: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Honoraria. Bollard: Neximmune: Current equity holder in publicly-traded company; Catamaran Bio: Membership on an entity's Board of Directors or advisory committees; Cabaletta Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Repertoire Immune Medicines: Current equity holder in publicly-traded company; ROCHE: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kean: Regeneron: Research Funding; Bristol Myers Squibb: Patents & Royalties: From clinical trial data, Research Funding; Bluebird Bio: Research Funding; Gilead: Research Funding; Vertex: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy. Jordan: Sobi: Consultancy. Allen: Sobi: Consultancy. OffLabel Disclosure: Alemtuzumab, humanized monoclonal antibody against CD52, used as part of allogeneic HCT conditioning

Environmental exposures in low- and middle-income countries lie at the intersection of increased economic development and the rising public health burden of cardiovascular disease. Increasing evidence suggests an association of exposure to ambient air pollution, household air pollution from biomass fuel, lead, arsenic, and cadmium with multiple cardiovascular disease outcomes, including hypertension, coronary heart disease, stroke, and cardiovascular mortality. Although populations in low- and middle-income countries are disproportionately exposed to environmental pollution, evidence linking these exposures to cardiovascular disease is derived from populations in high-income countries. More research is needed to further characterize the extent of environmental exposures.

We developed a haploidentical transplantation protocol with post-transplant cyclophosphamide (CY) for in vivo T-cell depletion using a novel adapted-dosing schedule (25 mg/kg on days +3 and +4) for Fanconi Anemia. With median follow-up of 3 years (range, 37 days to 6.2 years), all six patients engrafted. Two patients with multiple co-morbidities and late referrals to transplant died from sepsis (n=2) and chronic graft-versus-host disease (GVHD) (n=1). Four patients without pre-existing co-morbidities and early transplant referrals are alive with 100% donor chimerism and excellent performance status. We conclude that modulated-dosing post-transplant CY is effective in vivo T-cell depletion to promote full donor engraftment in patients with Fanconi anemia.

Introduction Congenital dyserythropoietic anemias (CDA) are a rare group of hereditary disorders characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. While some CDA patients respond to interferon α therapy (type I CDA) or splenectomy (type II CDA), others are dependent on chronic red cell transfusions lifelong. Hematopoietic cell transplant (HCT), remains the only curative option for this disease. In 39 patients reviewed by the European Society for Blood and Marrow Transplant (EBMT), graft rejection (GR) was 12% (1-23%), the 3-year overall survival (OS) and event free survival (EFS) were 71% (55-87%) and 45% (45-63%) respectively1. A trend towards higher incidence of GR and severe (Grade III-IV) acute graft versus host disease (GvHD) was observed in patients with iron overload and unrelated donor HCT but these risk factors were not statistically significant1. We report the outcomes in 17 children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) centers. Methods Clinical information on transplant and associated outcomes were collected retrospectively after IRB approval using a common questionnaire. Data were analyzed using descriptive statistics. Comparisons between groups were made using Fisher's exact tests. Survival estimates and corresponding 95% confidence intervals were performed using the Kaplan-Meier method. Results Seventeen patients (11 males) with CDA were eligible by diagnosis and underwent HCT from 2002-2019. The median age at diagnosis was 0.7 (range: 0.2 - 14) years. A majority (n=12) of patients had CDA type II while the remainder either had CDA type I (n=2) or were unknown (n=3). Twelve (71%) patients had evidence of iron overload by biopsy or imaging and 11 received pre-HCT chelation. Three of the 12 patients had liver fibrosis confirmed by biopsy. Thirteen patients had splenomegaly and four underwent splenectomy prior to HCT. Three patients received pre-HCT immunosuppressive therapy (PTIS). Median age at the time of HCT was 5.5 (range: 0.7 - 15) years. The median interval between diagnosis and HCT was 3.8 (range 0 - 12.3) years. Most patients received myeloablative busulfan-based conditioning (n=12); however, 5 patients received nonmyeloablative (n=1) or reduced intensity (n=4) fludarabine-based conditioning regimens. Donor sources included HLA matched sibling (n=3), matched unrelated (n=9), haploidentical (n=1) and mismatched unrelated (n=4) donors. Graft source was bone marrow in all but 2 patients who received umbilical cord blood. The median total nucleated cell (TNC) dose for bone marrow grafts was 6.0 (range: 3.4- 20.6) x 108/kg. Cord blood recipients received a TNC dose of 3.8 x 107 and 4.8 x 107/kg. Five (29%) patients developed acute GvHD grade II-IV, with one patient with grade III-IV acute GvHD (5.8%). Post-HCT complications included veno-occlusive disease (n=3), acute kidney injury (n=1), congestive cardiac failure (n=1), thrombotic microangiopathy (n=1), CMV viremia requiring therapy (n=2), mucormycosis (n=1), streptococcal pneumonia (n=1), recurrent clostridium difficle colitis (n=1), and parvovirus infection (n=1). Four patients developed chronic GvHD (23.5%; 2 limited and 2 extensive). Characteristics and outcomes of the four patients (23.5%) who developed GR are shown in Table 1. With a median follow-up of 3.4 (range: 0.08 - 14) years; fourteen patients are alive. Three patients died from respiratory failure due to adenovirus, congestive cardiac failure and extensive chronic GvHD post 2nd HCT. The 2-year OS, EFS and GvHD-free-rejection-free survival of the entire cohort (95% confidence interval) were 87% (72-100%), 64% (44 -92%), and 58% (39- 88%), respectively (Figure 1). Due to limited sample size, we did not find any patient or HCT-related factors that were associated with GR, OS or GvHD. Conclusion HCT can be curative for patients with CDA. The incidence of GR and GvHD in our CDA cohort was comparable to the recent EBMT report1. Strategies such as aggressive chelation, use of PTIS and perhaps early HCT in the presence of a suitable donor before co-morbidities occur are needed to improve engraftment without increasing risk for toxicities and mortality. Not unexpectedly we observed considerable morbidities in patients who had GR and required a 2nd HCT. Disclosures Pulsipher: Novartis: Honoraria; Bellicum: Honoraria; Jasper: Honoraria; Mesoblast: Honoraria; Miltenyi: Honoraria, Research Funding; Adaptive: Research Funding.

Background The complex interaction between pulmonary function, cardiac function and adverse cardiovascular events has only been partially described. We sought to describe the association between pulmonary function with left heart structure and function, all-cause mortality and incident cardiovascular hospitalization. Methods This study is a retrospective analysis of patients evaluated in a single tertiary care medical center. We used multivariable linear regression analyses to examine the relationship between FVC and FEV1 with left ventricular ejection fraction (LVEF), left ventricular internal dimension in systole and diastole (LVIDS, LVIDD) and left atrial diameter, adjusting for baseline characteristics, right ventricular function and lung hyperinflation. We also used Cox proportional hazards models to examine the relationship between FVC and FEV1 with all-cause mortality and cardiac hospitalization. Results A total of 1807 patients were included in this analysis with a median age of 61 years and 50% were female. Decreased FVC and FEV1 were both associated with decreased LVEF. In individuals with FVC less than 2.75 L, decreased FVC was associated with increased all-cause mortality after adjusting for left and right heart echocardiographic variables (hazard ratio [HR] 0.49, 95% CI 0.29, 0.82, respectively). Decreased FVC was associated with increased cardiac hospitalization after adjusting for left heart size (HR 0.80, 95% CI 0.67, 0.96), even in patients with normal LVEF (HR 0.75, 95% CI 0.57, 0.97). Conclusion In a tertiary care center reduced pulmonary function was associated with adverse cardiovascular events, a relationship that is not fully explained by left heart remodeling or right heart dysfunction.

ObjectiveWe assessed the hypothesis that metabolic syndrome is associated with adverse changes in cardiac structure and function in participants of the Echocardiographic Study of Latinos (Echo-SOL).MethodsNon-diabetic Echo-SOL participants were included in this cross-sectional analysis. Metabolic syndrome was defined according to the American Heart Association/National Heart, Lung, and Blood Institute 2009 Joint Scientific Statement. Survey multivariable linear regression analyses using sampling weights were used adjusting for multiple potential confounding variables. Additional analysis was stratified according to the presence/absence of obesity (body mass index (BMI) ≥25 kg/m2) and the presence/absence of metabolic syndrome.ResultsWithin Echo-SOL, 1260 individuals met inclusion criteria (59% female; mean age 55.2 years). Compared with individuals without metabolic syndrome, those with metabolic syndrome had lower medial and lateral E′ velocities (−0.4 cm/s, (SE 0.1), p=0.0002; −0.5 cm/s (0.2), p=0.02, respectively), greater E/E′ (0.5(0.2), p=0.01) and worse two-chamber left ventricular longitudinal strain (0.9%(0.3), p=0.009), after adjusting for potential confounding variables. Increased left ventricular mass index (9.8 g/m2 (1.9), p2 (1.7), p2) and metabolic syndrome had worse left ventricular global longitudinal strain (2.1%(0.7), p=0.002) and reduced left ventricular ejection fraction (−3.5%(1.4), p=0.007) compared with normal-weight individuals without metabolic syndrome.ConclusionsIn a sample of US Hispanics/Latinos metabolic syndrome was associated with worse left ventricular systolic and diastolic function. Adverse changes in left ventricular size and function were observed in obese individuals with and without metabolic syndrome but decreased left ventricular function was also present in normal-weight individuals with metabolic syndrome.

ObjectiveTo describe the relationship of household secondhand smoke (SHS) exposure and cardiac structure and function.MethodsParticipants (n=1069; 68 % female; age 45–74 years) without history of tobacco use, coronary artery disease or severe valvular disease were included. Past childhood (starting at age ResultsSHS exposure in childhood only was associated with reduced E/A velocity ratio (β=−0.06 (SE 0.02), p=0.008). SHS exposure in adolescence/adult only was associated with increased left ventricular ejection fraction (LVEF) (1.2 (0.6), p=0.04), left atrial volume index (1.7 (0.8), p=0.04) and decreased isovolumic relaxation time (−0.003 (0.002), p=0.03). SHS exposure in childhood and adolescence/adult was associated with worse left ventricular global longitudinal strain (LVGLS) (two-chamber) (0.8 (0.4), p= 0.049). Compared with individuals who do not live with a tobacco smoker, individuals who currently live with at least one tobacco smoker had reduced LVEF (−1.4 (0.6), p=0.02), LVGLS (average) (0.9 (0.40), p=0.03), medial E′ velocity (−0.5 (0.2), p=0.01), E/A ratio (−0.09 (0.03), p=0.003) and right ventricular fractional area change (−0.02 (0.01), p=0.01) with increased isovolumic relaxation time (0.006 (0.003), p=0.04).ConclusionsPast and current household exposure to SHS was associated with abnormalities in cardiac systolic and diastolic function. Reducing household SHS exposure may be an opportunity for cardiac dysfunction prevention to reduce the risk of future clinical heart failure.

Prokineticins are involved in many physiological processes including circadian rhythms, neurogenesis, angiogenesis, and cancer. Recently, they have been found to play a role in regulating food intake. Historically, proteins that increase feeding behavior in mammals decrease reproductive behavior to prevent pregnancy and lactation when food is scarce. In the current study, prokineticin-2 (PK2) had pronounced effects on reproductive and ingestive behaviors when given to female Syrian hamsters. Administration of PK2 prevented ingestive behaviors induced by food restriction, such as the amount of time spent with food and eating. Hamsters given PK2 preferred to engage in reproductive behaviors, including spending time with a male and lordosis. Furthermore, analysis of blood plasma revealed that changes to behavior persisted despite similar levels of des-acyl ghrelin (DAG) and reduced glucose concentrations in the blood. Additionally, administering 10 mg/kg of acyl ghrelin (AG) to a different cohort of animals significantly decreased the amount of time females spent with a potential mating partner, increased the amount of time females spent with food, decreased the duration of lordosis, and increased the duration of eating. Results from the current study support the need for further research investigating the reproductive and ingestive roles of PK2 and ghrelin.

Objective To compare all-cause and cause-specific mortality among 3 distinct groups: within-country, rural-to-urban migrants, and rural and urban dwellers in a longitudinal cohort in Peru. Methods The PERU MIGRANT Study, a longitudinal cohort study, used an age-stratified and sex-stratified random sample of urban dwellers in a shanty town community in the capital city of Peru, rural dwellers in the Andes, and migrants from the Andes to the shanty town community. Participants underwent a questionnaire and anthropomorphic measurements at a baseline evaluation in 2007–2008 and at a follow-up visit in 2012–2013. Mortality was determined by death certificate or family interview. Results Of the 989 participants evaluated at baseline, 928 (94%) were evaluated at follow-up (mean age 48 years; 53% female). The mean follow-up time was 5.1 years, totalling 4732.8 person-years. In a multivariable survival model, and relative to urban dwellers, rural participants had lower all-cause mortality (HR=0.27; 95% CI 0.07 to 0.98), and both the rural (HR=0.07; 95% CI 0.01 to 0.87) and migrant (HR=0.13; 95% CI 0.02 to 0.81) groups had lower cardiovascular mortality. Conclusions Cardiovascular mortality of migrants remains similar to that of the rural group, suggesting that rural-to-urban migrants do not appear to catch up with urban mortality in spite of having a more urban cardiovascular risk factor profile.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for pediatric patients with hematologic malignancies. Historically, matched sibling donors (MSD) have been the preferred donor source given ease of availability and lower rates of graft-versus-host-disease (GVHD). However, only 30% of patients have a MSD and relapse rates are high after MSD HSCT, raising the question of best donor choice. As conditioning regimens evolve, GVHD management improves and supportive care advances, it is important to evaluate the role of donor source on short and long-term clinical outcomes to inform donor selection. We performed a single-center retrospective analysis comparing post-HSCT outcomes in a cohort of pediatric patients undergoing MSD, matched unrelated donor (MUD), and umbilical cord blood (CB) transplants from 2006 to 2018. Methods: A retrospective analysis was performed on an IRB-approved protocol through Fred Hutchinson Cancer Research Center. 232 patients were included who received MSD (n=56), MUD (n=89) or CB (n=87) transplants. Of note, 24 CB patients received expanded CB cells in addition to unmanipulated unit(s). GVHD prophylaxis in all patients consisted of a calcineurin inhibitor and MMF or methotrexate. The vast majority received a high-intensity conditioning regimen (86%, 96%, and 82% respectively for MSD, MUD and CB). Overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method. Probabilities of non-relapse mortality (NRM), relapse, and acute GVHD were evaluated using cumulative incidence (CI) estimates with appropriate competing risks. The Cox regression model was used for adjusted analysis for age, year of transplant, sex, CMV status, MRD status, disease risk, and conditioning regimen. Results: Patient/treatment/donor demographics are shown in Table 1. Median follow-up was 2.6, 3.7 and 3.1 years for MSD, MUD and CB respectively. Patient diagnosis, disease risk, gender, age, and CMV serology were balanced between groups. CI of engraftment was similar as well, with only one graft failure in the MUD group (Fig 1). Median time to platelet recovery was significantly faster in MUD and MSD groups as compared to the CB group (p Conclusions: Our data demonstrate no difference in unadjusted OS between MSD, MUD and CB recipients. Importantly, despite this equivalence, 5-year DFS was significantly better in the CB v. MSD group, reflecting the lower relapse rate observed in CB patients and seen previously by us and others. CB continues to be viewed as an "alternative" donor for HSCT due to the low stem cell dose in a CB graft resulting in delayed neutrophil recovery, primary graft failure and increased NRM. However, this was not observed herein, supporting the use of CB for pediatric HSCT perhaps especially in patients at high risk of post-transplant relapse. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Bleakley:HighPass Biotherapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Despite the Institute of Medicine report on racial and ethnic disparities in health care outcomes that was published more than 10 years ago, disparities in health outcomes including cardiovascular disease outcomes persist. The recent literature on racial and ethnic disparities in cardiovascular disease outcomes incorporates geospatial-mapping analyses in order to shed light on the ways in which disparities vary by location, highlighting variability in access to health care. In addition the problem of access to health care, the quality of the health care that is available to minority communities has also been scrutinized, underscoring the potential of quality improvement interventions to reduce existing disparities in cardiovascular outcomes. Targeted interventions to expand health education, expand access to primary and tertiary care and improve the quality of the health care received by racial and ethnic minorities could reduce disparities in cardiovascular outcomes.

While household air pollution from biomass fuel combustion has been linked to cardiovascular disease, the effects on cardiac structure and function have not been well described. We sought to determine the association between biomass fuel smoke exposure and cardiac structure and function by transthoracic echocardiography. We identified a random sample of urban and rural residents living in the high-altitude region of Puno, Peru. Daily biomass fuel use was self-reported. Participants underwent transthoracic echocardiography. Multivariable linear regression was used to examine the relationship of biomass fuel use with echocardiographic measures of cardiac structure and function, adjusting for age, sex, height, body mass index, diabetes, physical activity, and tobacco use. One hundred and eighty-seven participants (80 biomass fuel users and 107 non-users) were included in this analysis (mean age 59 years, 58% women). After adjustment, daily exposure to biomass fuel smoke was associated with increased left ventricular internal diastolic diameter (P=.004), left atrial diameter (P=.03), left atrial area (four-chamber) (P=.004) and (two-chamber) (P=.03), septal E' (P=.006), and lateral E' (P=.04). Exposure to biomass fuel smoke was also associated with worse global longitudinal strain in the two-chamber view (P=.01). Daily biomass fuel use was associated with increased left ventricular size and decreased left ventricular systolic function by global longitudinal strain.

For decades, it has remained challenging to achieve long-term engraftment and correction of blood counts using gene-modified hematopoietic stem cells for Fanconi anemia. Toward this goal, our group conducted preclinical studies using a safety modified lentiviral vector encoding full-length cDNA for FANCA in normal and affected patient hematopoietic progenitor cells, and in a mutant mouse model that supported the IND for a gene therapy clinical trial for Fanconi anemia, complementation group A (NCT01331018). These studies led us to incorporate methods such as addition of N-acetylcysteine and hypoxic incubation during transduction. Because of the low stem cell numbers of Fanconi patients and initial difficulty with using plerixafor off-label for mobilization, we began our study with bone marrow as the source of stem cells. Due to concerns regarding secondary cancers, no conditioning was administered prior to infusion of gene-modified cells. The US Food and Drug Administration approved adult patients initially, but later permitted pediatric patient enrollment with a minimum age of 4 years. The primary objective of our phase I trial was safety. Secondary objectives included in vitro correction of mitomycin C (MMC) sensitivity, procurement of sufficient cell numbers, and ultimately, long-term correction of blood counts in recipients. Eligibility included absolute neutrophil count ≥0.5, hemoglobin ≥8, platelet count ≥20,000, lack of matched family donor, adequate organ function, and not meeting criteria for diagnosis of MDS. Our three enrolled patients were ages 22, 10, and 5 years. All demonstrated defects in the FANCA gene, with two patients sequenced and one patient diagnosed by complementation. Due to in-process learning and the later addition of plerixafor mobilization to the protocol, three different laboratory procedures were used to prepare the gene-modified product for each patient. Cell products were CD34+ selected bone marrow, bone marrow mononuclear cells depleted of red cells by hetastarch, and G-CSF and plerixafor mobilized cells depleted of red blood cells and cells bearing lineage markers, respectively. Transduction efficiencies were 17.7, 42.7 and 26.3% of colony forming cells (CFC) in 0 nM MMC, and 80, 100, and 100% of CFC in 10 nM MMC. Growth of hematopoietic colonies in MMC indicated functional correction of the FANCA defect. The 1st patient received 6.1×10e4, the 2nd 2.9×10e5, and the 3rd 4.3×10e6 CD34+ cells/kg. Serious adverse events included cytopenias in all patients, and hospital admission for fever due to viral upper respiratory infection in one patient. The patients remain alive at 46, 38, and 12 months after receipt of gene-modified cells. Due to worsening cytopenias, the third patient underwent hematopoietic cell transplant from an unrelated donor 10 months after infusion of gene-modified cells. To date, he has done well with transplant, and no indication that prior gene therapy impacted the outcome. The blood counts for the first 2 patients who have not undergone allogeneic transplant remain stable at 1,111 and 1,077 days post infusion compared to the first blood counts when they arrived at our center. For the 1st patient, vector was detectable in white blood cells (WBC) up to 21 days, in the 2nd up to 582 days, and the 3rd up to 81 days post infusion. Thus, in these patients, despite dramatic improvement in cell dose during the study, there was lack of persistence in detection of gene-modified WBCs beyond 1.5 years. A number of factors may have contributed, including lack of conditioning, in vitro cell manipulation including cytokine exposure, inability to transduce primitive hematopoietic stem cells, and paucity of long-term repopulating cells at the ages of the patients, suggesting earlier collection may be beneficial. This study is now closed to enrollment. Valuable information gained as a result of this study will contribute to future clinical gene therapy trials. Current work focuses on how to evaluate stem cell fitness prior to attempting gene therapy, minimizing manipulation required for gene correction and/or in vivo genetic correction and non-chemotherapy-based conditioning to facilitate engraftment. We would like to personally thank each patient and their families for participating in this study, as we could not have learned these lessons without their support. Disclosures Becker: GlycoMimetics: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; BMS: Research Funding; CVS Caremark: Consultancy; Trovagene: Research Funding; Rocket Pharmaceuticals: Research Funding; Novartis: Research Funding; Pfizer: Consultancy; JW Pharmaceuticals: Research Funding. Adair:Miltenyi Biotec: Honoraria; RX Partners: Honoraria; Rocket Pharmaceuticals: Patents & Royalties: PCT/US2017/037967 and PCT/US2018/029983. Kiem:Rocket Pharmaceuticals: Consultancy; Homology Medicine: Consultancy; Magenta: Consultancy.

The pathways by which environmental exposures contribute to the pathogenesis of cardiovascular disease are not well described. Our objective was to determine the association of toxic occupational exposures with cardiac structure and function as measured by transthoracic echocardiography in

Background. We studied women and their infants to evaluate risk factors for congenital transmission and cardiomyopathy in Trypanosoma cruzi–infected women. Methods. Women provided data and blood for serology and quantitative polymerase chain reaction (PCR). Infants of infected women had blood tested at 0 and 1 month by microscopy, PCR and immunoblot, and serology at 6 and 9 months. Women underwent electrocardiography (ECG). Results. Of 1696 women, 456 (26.9%) were infected; 31 (6.8%) transmitted T. cruzi to their infants. Women who transmitted had higher parasite loads than those who did not (median, 62.0 [interquartile range {IQR}, 25.8–204.8] vs 0.05 [IQR, 0–29.6]; P < .0001). Transmission was higher in twin than in singleton births (27.3% vs 6.4%; P = .04). Women who had not lived in infested houses transmitted more frequently (9.7% vs 4.6%; P = .04), were more likely to have positive results by PCR (65.5% vs 33.9%; P < .001), and had higher parasite loads than those who had lived in infested houses (median, 25.8 [IQR, 0–64.1] vs 0 [IQR, 0–12.3]; P < .001). Of 302 infected women, 28 (9.3%) had ECG abnormalities consistent with Chagas cardiomyopathy; risk was higher for older women (odds ratio [OR], 1.06 [95% confidence interval {CI}, 1.01–1.12] per year) and those with vector exposure (OR, 3.7 [95% CI, 1.4–10.2]). We observed a strong dose-response relationship between ECG abnormalities and reported years of living in an infested house. Conclusions. We hypothesize that repeated vector-borne infection sustains antigen exposure and the consequent inflammatory response at a higher chronic level, increasing cardiac morbidity, but possibly enabling exposed women to control parasitemia in the face of pregnancy-induced Th2 polarization.

Although cardiovascular disease (CVD) incidence and mortality are on the decline in high-income countries, globally, the burden of CVD continues to rise due to the increasing incidence of CVD in low- and middle-income countries (LMIC). Eighty percent of all CVD-related deaths occur in LMIC, yet the amount of global health spending on noncommunicable diseases prevention and treatment remains disproportionately low when compared to the global burden of these diseases [1]. In response to this alarming global trend in CVD and other non-communicable diseases, in 2011, a U.N. high-level meeting convened in order to highlight the impact of non-communicable diseases on public health and human development. Poverty exacerbates the epidemic of CVD in LMIC, and CVD in turn perpetuates social and economic inequality. CVD is inextricably linked to human development, and research aimed to reduce the burden of CVD in developing countries should be prioritized on the development agenda for LMIC.

Background: Household air pollution from biomass fuel use affects 3 billion people worldwide. There are few studies that examine the relationship between biomass fuel use and blood pressure. We sought to determine if daily biomass fuel use was associated with higher blood pressure and increased hypertension in Peru. Methods: We analyzed baseline information from an age- and sex-matched, population-based study in Puno, Peru. Daily biomass fuel use was self-reported. Hypertension was defined as a systolic blood pressure (SBP) ≥140 mmHg; diastolic blood pressure (DBP) ≥90 mmHg; or self-report of diagnosis and anti-hypertensive medications. We used linear and logistic multivariable regressions, adjusting for age, sex, daily cigarette use and body mass index, to examine the relationship between daily biomass fuel use with blood pressure and hypertension, respectively. Results: Data from 1004 individuals (mean age 55.3 years, 51.7% female) were included. There was evidence of an association between daily biomass fuel use and hypertension (adjusted OR = 2.1, 95%CI 1.2 to 3.5). Subjects who reported daily use of biomass fuels had 6.0 mmHg (95% CI 4.1 to 8.0) higher SBP and 4.8 mmHg (95%CI 3.5 to 6.0) higher DBP compared to those who did not use biomass fuels daily. In a secondary analysis, we used rural residence (vs. urban) as a proxy of biomass daily use and the relationship with hypertension and systolic blood pressure was similar: a higher odds of hypertension (adjusted OR = 2.1, 95%CI 1.3 to 3.6), and higher SBP (6.7mmHg, 95% CI 4.8 to 8.6) and DBP (5.5 mmHg, 95% CI 4.3 to 6.8) in rural vs. urban participants. Conclusion: Biomass fuel use is associated with increased odds of hypertension and higher blood pressure in Puno, Peru. Reducing exposure to air pollution from biomass fuel use represents a potential opportunity for cardiovascular prevention in rural communities worldwide. Longitudinal studies to evaluate the impact of reducing household air pollution are needed.

Background: Pulmonary disease has been associated with poor cardiovascular outcomes including heart failure; yet, the relationship between measures of obstructive and restrictive lung disease as defined on pulmonary function testing (PFT) and left ventricular size and function remains unknown. The objective of this study is to determine the correlation between forced expiratory volume/1 sec (FEV1), forced vital capacity (FVC) and FEV1/FVC with left ventricular ejection fraction (LVEF), internal diastolic diameter (LVIDD), and internal systolic dimension (LVISD) as measured by transthoracic echocardiography (TTE). Methods: We selected patients who underwent both TTE and PFT within 7 days from January 2012 to April 2013. We examined for bivariate relationships by using Pearson’s correlation coefficient to determine associations between pre-bronchodilator FEV1, FVC and FEV1/FVC and the following TTE measures: LVEF,LVIDD, and LVISD. Multivariable regression analysis was used to adjust for age and sex. Results: We identified 2238 patients who had TTE and PFT within 7 days. After adjusting for age and sex, FEV1, FVC, and FEV1/FVC were positively correlated with LVEF and LVIDD. Every 100 cc reduction in FVC or 90 cc reduction in FEV1 was associated with a 5% decrease in LVEF (95% CI 0.079- 0.128, 0.068- 0.109). Moreover, a 200 cc reduction in FEV1 or 220 cc reduction in FVC was associated with a 1 cm decrease in LVIDD (95% CI 0.152- 0.247, 0.165- 0.282,). These correlations remained significant when percent predicted instead of absolute FEV1 and FVC were evaluated. Conclusion: Abnormal lung function is associated with reduced LV function without corresponding increases in ventricular size. These findings suggest that the association between pulmonary disease and heart failure may not depend on adverse ventricular remodeling and requires further study.

INTRODUCTION Management of malignant colorectal polyps is controversial. The options are resection or surveillance. Resection margin status is accepted as an independent predictor of adverse outcome. However, the rate of adverse outcome in polyps with a resection margin of METHODS A retrospective search of the pathology database was undertaken. All polyp cancers were included. A single histopathologist reviewed all of the included polyp cancers. Polyps were divided into three groups: clear resection margin, involved resection margin and unknown resection margin. Polyps were also analysed for tumour grade, morphology, Haggitt/Kikuchi level and lymphovascular invasion. Adverse outcome was defined as residual tumour at the polypectomy site and/or lymph node metastases in the surgical group and local or distant recurrence in the surveillance group. RESULTS Sixty-five polyps (34 male patients, mean age: 73 years, range: 50–94 years) were included. Forty-six had clear polyp resection margins; none had any adverse outcomes. Sixteen patients had involved polyp resection margins and twelve of these underwent surgery: seven had residual tumour and two of these patients had lymph node metastases. Four underwent surveillance, of whom two developed local recurrence. Three patients had resection margins on which the histopathologist was unable to comment. All patients with a clear resection margin had no adverse outcome regardless of other predictive factors. CONCLUSIONS Polyp cancers with clear resection margins, even those with

Cardiovascular disease is the leading cause of mortality in Cuba. Lifestyle risk factors for coronary heart disease (CHD) in Cubans have not been compared to risk factors in Cuban Americans. Articles spanning the last 20 years were reviewed. The data on Cuban Americans are largely based on the Hispanic Health and Nutrition Examination Survey (HHANES), 1982–1984, while more recent data on epidemiological trends in Cuba are available. The prevalence of obesity and type 2 diabetes mellitus remains greater in Cuban Americans than in Cubans. However, dietary preferences, low physical activity, and tobacco use are contributing to the rising rates of obesity, type 2 diabetes mellitus, and CHD in Cuba, putting Cubans at increased cardiovascular risk. Comprehensive national strategies for cardiovascular prevention that address these modifiable lifestyle risk factors are necessary to address the increasing threat to public health in Cuba.