Citations

While genetic research (GR) is fueling discoveries in fields like precision medicine, there is a growing concern that underrepresentation of racial and ethnic populations in GR will limit access to its benefits and subsequently worsen health disparities. This study aimed to understand GR perceptions among members from underrepresented communities by studying discourse and language use in focus group discussions. Nine focus groups were conducted with adults from three populations: African American, Hispanic/Latino, and Native American; 53 women and 15 men participated. Data were analyzed using methods of discourse and content analysis. Discourse analysis highlighted how conceptualization of science and family—rooted in historical experiences—can influence views on GR risks and benefits to self and others. The use of focus group discourse in particular provided an opportunity for group sense making around the science and ethics of GR. Content analysis highlighted differences between the language use of focus group moderators, who spoke about scientific discovery and research oversight, and that of participants, whose talk highlighted ancestral bloodline, personal risk, and ethical concerns. The findings can inform efforts to bolster GR participation, including recruitment and educational campaigns. However, they also challenge researchers to consider areas of discordance between their own and community members’ conceptualization of the risks and benefits of GR participation, including the notion of future and family benefit.

Background Past research has shown how fires, heat and hot substances are important causes of health loss globally. Detailed estimates of the morbidity and mortality from these injuries could help drive preventative measures and improved access to care. Methods We used the Global Burden of Disease 2017 framework to produce three main results. First, we produced results on incidence, prevalence, years lived with disability, deaths, years of life lost and disability-adjusted life years from 1990 to 2017 for 195 countries and territories. Second, we analysed these results to measure mortality-to-incidence ratios by location. Third, we reported the measures above in terms of the cause of fire, heat and hot substances and the types of bodily injuries that result. Results Globally, there were 8 991 468 (7 481 218 to 10 740 897) new fire, heat and hot substance injuries in 2017 with 120 632 (101 630 to 129 383) deaths. At the global level, the age-standardised mortality caused by fire, heat and hot substances significantly declined from 1990 to 2017, but regionally there was variability in age-standardised incidence with some regions experiencing an increase (eg, Southern Latin America) and others experiencing a significant decrease (eg, High-income North America). Conclusions The incidence and mortality of injuries that result from fire, heat and hot substances affect every region of the world but are most concentrated in middle and lower income areas. More resources should be invested in measuring these injuries as well as in improving infrastructure, advancing safety measures and ensuring access to care.

Abstract Abstract 3655 Background Primary central nervous system lymphoma (PCNSL) is an aggressive lymphoma with devastating prognosis. High-dose methotrexate (HD-MTX) in combination with HD-cytarabine builds the backbone of current treatments. Elderly patients constitute 45% of cases, exhibit poor outcome and frequent iatrogenic toxicity. However, research efforts to optimize therapy in this subgroup have been neglected. On this background, we conducted a systematic review (SR) and individual patient data meta-analysis (IPDMA) to provide comprehensive evidence-based management strategy for elderly patients with PCNSL. Patients and Methods SR: We searched MEDLINE and EMBASE without language restriction. Eligibility criteria were prospective/retrospective observational studies or randomized trials (RCT) (all N>=10) that exclusively focused on first-line therapy/outcomes in immunocompetent PCNSL patients ≥60 years. Eligible studies were evaluated for methodological quality and reporting of the following baseline characteristics: Age, performance status (PS), involvement of deep brain structures (IDB), serum LDH at baseline, cerebro-spinal fluid (CSF) protein concentration elevation, neurotoxicity (as reported), specific co-morbidity indices, and functional status. For the IPDMA, investigators of eligible studies were asked to provide individual patient data. Minimal eligibility criteria: Age at baseline, details about first-line therapy, and follow-up information. If no data were available, studies were included in the SR, but not in the IPDMA. To maximize statistical power and generalizability, published/unpublished data from other international collaborators were included. Impact of different first-line treatments on overall survival (OS) was investigated using time dependent mixed effects multivariable Cox regression models (age and PS as fixed effects, study/database as random effect). Results SR: We identified 13 eligible studies including 583 patients in total, median age 68–76, published from 1996–2011. Design of studies: prospective (3 multicenter [1 RCT]; 2 single center), retrospective (4 multicenter and single-center, respectively). Accrual of the RCT was recently finished, but publication is pending. From published studies, information about age and therapy was given throughout, for clinical performance in 77%, for LDH and CSF protein in 15%, and IDB in 38%. Functional status was reported in only one study. From the identified 13 studies, 261 individual patient data were available for our IPDMA and pooled with 408 patients from other databases; altogether 669 patients diagnosed from 1977–2011. Preliminary results IPDMA: 50% were male, median age 68 (60–70 [N=431], 70–80 [N=211], >80 [N=22]); median KPS was 60% (10–100%). Therapy regimens widely varied. Overall response to first-line treatment was 65% (45% CR, 19% PR). After a median follow-up of 23 months (1–171), 44% were still alive, with a 3-year OS of 32% [95%CI, 29–37%]. Grouping by time of diagnosis revealed improvement for patients diagnosed after 1997 (N=462) (P<0.001). In multivariate analysis, MTX-based poly-chemotherapy (CT) (N=474) was associated with improved OS (Hazard ratio [HR] 0.69, 95% CI 0.52–0.91) compared to non-MTX regimens (N=195); this was consistent among patients who received consolidating WBRT (HR 0.33, 95% CI 0.01–0.66) and those who did not (HR 0.46, 95% CI 0.23–0.89). In patients who received any MTX-based poly-CT, addition of CHOP-like components (N=90) was not associated with improved OS (HR 0.98, 95% 0.65–1.48). Although any WBRT showed an overall trend for superior OS, it was associated with a 4-fold risk increase for neurotoxicity (Odds Ratio 4.21, 95% CI 2.23–8.21). Further results of treatment patterns and explorative comparisons will be presented at the meeting. Conclusion This international meta-analysis revealed widely varying treatment approaches and demonstrates that prognosis for elderly PCNSL patients is still poor. However, improvement over the last decades was observed. MTX-based poly-CT was associated with better outcome compared to non-MTX containing approaches. The addition of CHOP-like regimens to HD-MTX did not improve outcome. WBRT was associated with better outcome, but also clearly increased risk of neurotoxicity. Prospective trials designed ad hoc for elderly PCNSL patients are promptly needed. Disclosures: No relevant conflicts of interest to declare.

While the triple tracer isotope dilution method has enabled accurate estimation of carbohydrate turnover after a mixed meal, use of the simple carbohydrate glucose as the carbohydrate source limits its translational applicability to everyday meals that typically contain complex carbohydrates. Hence, utilizing the natural enrichment of [13C]polysaccharide in commercially available grains, we devised a novel tracer method to measure postprandial complex carbohydrate turnover and indices of insulin action and β-cell function and compared the parameters to those obtained after a simple carbohydrate containing mixed meal. We studied healthy volunteers after either rice ( n = 8) or sorghum ( n = 8) and glucose ( n = 16) containing mixed meals and modified the triple tracer technique to calculate carbohydrate turnover. All meals were matched for calories and macronutrient composition. Rates of meal glucose appearance (2,658 ± 736 vs. 4,487 ± 909 μM·kg−1·2 h−1), endogenous glucose production (−835 ± 283 vs. −1,123 ± 323 μM·kg−1·2 h−1) and glucose disappearance (1,829 ± 807 vs. 3,606 ± 839 μM·kg−1·2 h−1) differed ( P < 0.01) between complex and simple carbohydrate containing meals, respectively. Interestingly, there were significant increase in indices of insulin sensitivity (32.5 ± 3.5 vs. 25.6 ± 3.2 10−5(dl·kg−1·min−2)/pM, P = 0.006) and β-cell responsivity (disposition index: 1,817 ± 234 vs. 1,236 ± 159 10−14(dl·kg−1·min−2)/pM, P < 0.005) with complex than simple carbohydrate meals. We present a novel triple tracer approach to estimate postprandial turnover of complex carbohydrate containing mixed meals. We also report higher insulin sensitivity and β-cell responsivity with complex than with simple carbohydrates in mixed meals of identical calorie and macronutrient compositions in healthy adults.

AbstractOmega-3 polyunsaturated fatty acids (n3-PUFA) are well recognized for their potent triglyceride-lowering effects, but the potential influence of these bioactive lipids on other biological processes, particularly in the context of healthy aging, remains unknown. With the goal of gaining new insight into some less well-characterized biological effects of n3-PUFAs in healthy older adults, we performed metabolomics of fasting peripheral blood plasma collected from 12 young adults and 12 older adults before and after an open-label intervention of n3-PUFA (3.9 g/day, 2.7 g eicosapentaenoic [EPA], 1.2 g docosahexaenoic [DHA]). Proton nuclear magnetic resonance (1H-NMR) based lipoprotein subclass analysis revealed the expected reduction in total triglyceride (TG), but also demonstrated that n3-PUFA supplementation reduced very low-density lipoprotein (VLDL) particle number, modestly increased high-density lipoprotein (HDL) cholesterol, and shifted the composition of HDL subclasses. Further metabolite profiling by 1H-NMR and mass spectrometry revealed pronounced changes in phospholipids, cholesterol esters, diglycerides, and triglycerides following n3-PUFA supplementation. Furthermore, significant changes in hydroxyproline, kynurenine, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) following n3-PUFA supplementation provide further insight into some less well-recognized biological effects of n3-PUFA supplementation, including possible effects on protein metabolism, the kynurenine pathway, and glucose metabolism.

Abstract Background: Late recurrence is characteristic of ER+ breast cancers. Despite an apparently effective adjuvant endocrine therapy, many breast cancers recur years after their initial endocrine treatment. Why some tumors recur early (&lt;3 years) and some recur later (&gt;5 years) is poorly understood. If systemic endocrine therapies killed all cells, recurrence would reflect only the appearance of new disease. Thus, we hypothesized that cells that survive and lie dormant may be driven, in part, by altered wiring of their cell death signaling. We, therefore, studied how cell death signaling is differentially wired in primary tumors that will recur early versus those that will recur later. Method: Genes involved in apoptosis, autophagy, ferroptosis, necrosis, and pyroptosis were identified from KEGG to initiate network feature analysis of gene expression data from public and our first in-house gene expression dataset. Data were collected from ER+ breast cancer pre-endocrine treatment samples with up to 20 years follow-up. Publicly available datasets used were GSE6532, GSE2034, GSE7390, GSE17705, GSE12093, and TCGA. We applied our Knowledge-fused Differential Dependency Network (KDDN) analysis tool to the public datasets; KDDN has provided powerful new insights into signaling in breast and other cancers. Common gene-gene interactions (edges) predicted in at least two different datasets were extracted from all KDDN analyses results. To strengthen the relevance of these features, predicted network edges that represent known protein-protein interactions (PPI) were identified from the STRING database, and these edges were noted in the signaling graphs. Final network graphs were constructed using the common edges from all overlaid networks. We conducted IPA analysis on all nodes in the final network and selected those incorporating network hubs. We took a similar approach to our second in-house dataset, which we used for independent testing. Here, patients were included if their tumor exhibited an initial reduction in volume of at least 40% by four months in response to neo-adjuvant Letrozole. Patients were then classified into two groups during follow-up of up to 3.7 years: i) initial tumor size reduction followed by continued response (expected to recur late); ii) initial reduction followed by tumor regrowth (expected to recur early). KDDN analysis was performed on pretreatment samples from these two groups and a network created annotated with PPI information. Results: MAPK8 and CYCS (Molecular Mechanisms of Cancer, p=1.58E-52), TNFRSF1A Neuroinflammation Signaling Pathway, p=1.26E-54), RELA, and NFKB1 (Colorectal Cancer Metastasis Signaling, p=7.94E-35), were identified as hubs. Hubs may be critical signaling components driving the differences between tumors that will become dormant and recur late. Connections between SLC25A6 and SQSTM1 (p = 0.008), BIRC2 and GABARAP (p = 0.021) in the early group, and AKT3 and IRS2 (p = 0.014) in the late group, were shared between the two final networks. With longer follow-up time on the second in-house dataset, we will better define the two groups and identify additional common phenotype specific gene-gene interactions. Citation Format: Clarke R, Dixon M, Jin L, Pearce D, Turnbull A, Selli C, Hu R, Zwart A, Wang Y, Xuan J, Sengupta S, Sims A, Liu MC. Local network topology differences between early and late recurrence in ER+ breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-17.

ABSTRACTBackground: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD.Objectives: The objective of this study was to generate and test a PD diagnostic criteria termed “clinically established early PD.”Methods: We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626‐patient validation study.Results: After documentation of parkinsonism, 18 individual exclusion criteria are assessed that preclude the diagnosis of “clinically established early PD.” Among 212 PD and 152 non‐PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity.Conclusions: We describe high‐specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society