Racial differences in brain health at midlife and the potential mediating role of cardiorespiratory fitness and cardiometabolic risk

Blacks are at a higher risk for adverse brain-related outcomes, including stroke and dementia. Due to associations of vascular risk factors with brain health, differences in brain health may result from a greater burden of vascular risk factors in blacks, especially in midlife. However, relationships between vascular risk factors and midlife racial disparities in brain health have been underexplored. The overall objective of this dissertation is to improve our understanding of racial disparities in brain health outcomes and test for potential mediators of any observed racial differences. This objective was addressed through three studies. Since cerebral small vessel disease is a major cause of both stroke and dementia, our first study aimed to examine whether blacks exhibit more subclinical markers of cerebral small vessel disease than whites. We found that blacks appear to be at a greater risk for developing white matter hyperintensities, but relationships with other markers of brain health remain unclear. Major limitations in the current literature include: 1) a lack of representation by younger age groups, 2) limited geographic representation, 3) few study samples, and 4) the lack of reporting diverse markers for brain health. The second study investigated racial differences in brain health among a middle-aged population. After adjustment for demographics, blacks exhibited significantly lower gray matter volume, smaller hippocampus, less cortical surface area, and a thinner cerebral cortex than whites (all p’s<0.05). No differences in cerebral blood flow were found. The third study examined whether cardiorespiratory fitness (CRF) and/or cardiometabolic risk (CMR) mediate the relationship between race and brain health. We found that CRF and CMR partially mediated the association of race with cortical surface area and gray matter volume. Overall, the findings of these three complementary studies are of public health relevance given by revealing that brain health disparities exist in an otherwise healthy midlife population and by examining potential mediators for these disparities. Future work is needed to better understand these disparities. Researchers should investigate other potential pathways, examine younger populations and observe changes in brain health overtime

External validation of the Garvan nomograms for predicting absolute fracture risk: The Tromso study

Background: Absolute risk estimation is a preferred approach for assessing fracture risk and treatment decision making. This study aimed to evaluate and validate the predictive performance of the Garvan Fracture Risk Calculator in a Norwegian cohort. Methods: The analysis included 1637 women and 1355 aged 60+ years from the Tromsø study. All incident fragility fractures between 2001 and 2009 were registered. The predicted probabilities of non-vertebral osteoporotic and hip fractures were determined using models with and without BMD. The discrimination and calibration of the models were assessed.Reclassification analysis was used to compare the models performance. Results: The incidence of osteoporotic and hip fracture was 31.5 and 8.6 per 1000 population in women, respectively; in men the corresponding incidence was 12.2 and 5.1. The predicted 5-year and 10-year probability of fractures was consistently higher in the fracture group than the non-fracture group for all models. The 10-year predicted probabilities of hip fracture in those with fracture was 2.8 (women) to 3.1 times (men) higher than those without fracture. There was a close agreement between predicted and observed risk in both sexes and up to the fifth quintile. Among those in the highest quintile of risk, the models over-estimated the risk of fracture. Models with BMD performed better than models with body weight in correct classification of risk in individuals with and without fracture. The overall net decrease in reclassification of the model with weight compared to the model with BMD was 10.6% (p = 0.008) in women and 17.2% (p = 0.001) in men for osteoporotic fractures, and 13.3% (p = 0.07) in women and 17.5% (p = 0.09) in men for hip fracture. Conclusions: The Garvan Fracture Risk Calculator is valid and clinically useful in identifying individuals at high risk of fracture. The models with BMD performed better than those with body weight in fracture risk prediction

Coordination of sustainable financing for evidence-based youth mental health treatments: Protocol for development and evaluation of the fiscal mapping process

BACKGROUND: Sustained delivery of evidence-based treatments (EBTs) is essential to addressing the public health and economic impacts of youth mental health problems, but is complicated by the limited and fragmented funding available to youth mental health service agencies (hereafter, service agencies ). Strategic planning tools are needed that can guide these service agencies in their coordination of sustainable funding for EBTs. This protocol describes a mixed-methods research project designed to (1) develop and (2) evaluate our novel fiscal mapping process that guides strategic planning efforts to finance the sustainment of EBTs in youth mental health services. METHOD: Participants will be 48 expert stakeholder participants, including representatives from ten service agencies and their partners from funding agencies (various public and private sources) and intermediary organizations (which provide guidance and support on the delivery of specific EBTs). Aim 1 is to develop the fiscal mapping process: a multi-step, structured tool that guides service agencies in selecting the optimal combination of strategies for financing their EBT sustainment efforts. We will adapt the fiscal mapping process from an established intervention mapping process and will incorporate an existing compilation of 23 financing strategies. We will then engage participants in a modified Delphi exercise to achieve consensus on the fiscal mapping process steps and gather information that can inform the selection of strategies. Aim 2 is to evaluate preliminary impacts of the fiscal mapping process on service agencies\u27 EBT sustainment capacities (i.e., structures and processes that support sustainment) and outcomes (e.g., intentions to sustain). The ten agencies will pilot test the fiscal mapping process. We will evaluate how the fiscal mapping process impacts EBT sustainment capacities and outcomes using a comparative case study approach, incorporating data from focus groups and document review. After pilot testing, the stakeholder participants will conceptualize the process and outcomes of fiscal mapping in a participatory modeling exercise to help inform future use and evaluation of the tool. DISCUSSION: This project will generate the fiscal mapping process, which will facilitate the coordination of an array of financing strategies to sustain EBTs in community youth mental health services. This tool will promote the sustainment of youth-focused EBTs

Ancient Nursery Area for the Extinct Giant Shark Megalodon from the Miocene of Panama

BACKGROUND: As we know from modern species, nursery areas are essential shark habitats for vulnerable young. Nurseries are typically highly productive, shallow-water habitats that are characterized by the presence of juveniles and neonates. It has been suggested that in these areas, sharks can find ample food resources and protection from predators. Based on the fossil record, we know that the extinct Carcharocles megalodon was the biggest shark that ever lived. Previous proposed paleo-nursery areas for this species were based on the anecdotal presence of juvenile fossil teeth accompanied by fossil marine mammals. We now present the first definitive evidence of ancient nurseries for C. megalodon from the late Miocene of Panama, about 10 million years ago. METHODOLOGY/PRINCIPAL FINDINGS: We collected and measured fossil shark teeth of C. megalodon, within the highly productive, shallow marine Gatun Formation from the Miocene of Panama. Surprisingly, and in contrast to other fossil accumulations, the majority of the teeth from Gatun are very small. Here we compare the tooth sizes from the Gatun with specimens from different, but analogous localities. In addition we calculate the total length of the individuals found in Gatun. These comparisons and estimates suggest that the small size of Gatun's C. megalodon is neither related to a small population of this species nor the tooth position within the jaw. Thus, the individuals from Gatun were mostly juveniles and neonates, with estimated body lengths between 2 and 10.5 meters. CONCLUSIONS/SIGNIFICANCE: We propose that the Miocene Gatun Formation represents the first documented paleo-nursery area for C. megalodon from the Neotropics, and one of the few recorded in the fossil record for an extinct selachian. We therefore show that sharks have used nursery areas at least for 10 millions of years as an adaptive strategy during their life histories

Association of Functional Polymorphism rs2231142 (Q141K) in the ABCG2 Gene With Serum Uric Acid and Gout in 4 US Populations

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008–2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10−67, P = 3.98 × 10−5, P = 6.97 × 10−9, and P = 5.33 × 10−4 in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10−10, P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10−80) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10−12). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout

Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

The synthesis of inactive enzyme precursors, also known as “zymogens,” serves as a mechanism for regulating the execution of selected catalytic activities in a desirable time and/or site. Zymogens are usually activated by proteolytic cleavage. Many viruses encode proteases that execute key proteolytic steps of the viral life cycle. Here, we describe a proof of concept for a therapeutic approach to fighting viral infections through eradication of virally infected cells exclusively, thus limiting virus production and spread. Using the hepatitis C virus (HCV) as a model, we designed two HCV NS3 protease-activated “zymogenized” chimeric toxins (which we denote “zymoxins”). In these recombinant constructs, the bacterial and plant toxins diphtheria toxin A (DTA) and Ricin A chain (RTA), respectively, were fused to rationally designed inhibitor peptides/domains via an HCV NS3 protease-cleavable linker. The above toxins were then fused to the binding and translocation domains of Pseudomonas exotoxin A in order to enable translocation into the mammalian cells cytoplasm. We show that these toxins exhibit NS3 cleavage dependent increase in enzymatic activity upon NS3 protease cleavage in vitro. Moreover, a higher level of cytotoxicity was observed when zymoxins were applied to NS3 expressing cells or to HCV infected cells, demonstrating a potential therapeutic window. The increase in toxin activity correlated with NS3 protease activity in the treated cells, thus the therapeutic window was larger in cells expressing recombinant NS3 than in HCV infected cells. This suggests that the “zymoxin” approach may be most appropriate for application to life-threatening acute infections where much higher levels of the activating protease would be expected

Donation after circulatory death is associated with increased fibrosis on 1‐year post‐transplant kidney allograft surveillance biopsy

AimThe use of kidneys donated after circulatory death (DCD) provides an invaluable expansion of the organ supply for transplantation. Here, we investigated the effect of DCD on fibrotic changes on 1 1‐year post 1‐transplant surveillance kidney allograft biopsy.MethodsRecipients of a deceased donor kidney transplant between 2013 and 2017 at a single institution, who survived 1 year and underwent surveillance biopsy, were included in the analysis (n = 333: 87 DCD kidneys, 246 kidneys donated after brain death [DBD]). Banff scores for interstitial fibrosis and tubular atrophy were summed as IFTA and compared between the groups.ResultsDCD and DBD groups were comparable for baseline characteristics. Delayed graft function was 39% in DCD versus 19% in DBD, P = .0002. Patient and graft survival were comparable for DCD and DBD cohorts. IFTA scores were higher in DCD compared to DBD (2.43±..13 vs. 2.01±..08, P = .0054). On multivariate analysis, the odds of IFTA > 2 in the DCD group was 2.5× higher (95%CI: 1.354.63) than in the DBD group. Within the DCD group, kidneys with IFTA > 2 had inferior 5‐year graft survival (P = .037).ConclusionCompared to DBD kidneys, DCD kidneys developed a greater degree of fibrotic changes on 1‐year post‐transplant surveillance biopsy, which affected graft longevity within the DCD cohort.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170896/1/ctr14399.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170896/2/ctr14399_am.pd

Coexisting Sedges in Northern Wisconsin Forests are Functionally Similar and May be Distantly Related in Evolutionary History

Color poster with text, charts, and images.Organisms coexist either by having similar functional traits that match habitat requirements or by having non-similar traits to reduce competition. A classic study showed that coexisting oak trees in Florida tend to be functionally similar and phylogenetically diverse, meaning certain functional traits associated with habitat filtering evolved. We are investigating whether the hyperdiverse plant genus Carex (sedges) shows similar ecological filtering and convergent evolution.University of Wisconsin--Eau Claire Office of Research and Sponsored Program

Functional Community Assembly is Increasingly Deterministic at Larger Spatial Grain Sizes

Color poster with text and graphs.Community assembly is the result of ecological selection processes, dispersal processes, and random drift processes. Selection processes can cause coexisting species to be more similar or more different in traits, depending on the strength of environmental filtering or the strength of competition. Scale in terms of the spatial extent can influence how trait similarity differs from random drift. For example, a grassland could have higher than expected trait diversity by having tall, medium and short species in most samples. But if the scale is expanded to include forests with tall trees, then the grassland plants may have lower than expected trait diversity. Scale also includes the sample scale or grain size. We sampled forest vegetation Northern Wisconsin at three grain sizes (0.1 m2, 1 m2, and 10 m2) to investigate how grain size and spatial extent influence our conclusions about community assembly.University of Wisconsin--Eau Claire Office of Research and Sponsored Program