PROLONGED SITTING WITH OR WITHOUT HIGH GLYCEMIC INDEX MEAL AND THE ACUTE EFFECTS ON CEREBROVASCULAR FUNCTION IN HEALTHY ADULTS

The study purpose was to determine if prolonged (3-hr) sitting (a) resulted in a decreased total brain blood flow (QBF) and executive function, and (b) whether this decrease is exacerbated by a high glycemic index meal (HGI). Subjects (n=18) participated in a HGI and low glycemic index (LGI) condition. Doppler Ultrasound was used to measure QBF using the equation: [(ICA blood flow + VA blood flow) x 2 (ml min-1)]. Executive function was assessed using the Stroop Task and Trail Making using the Trail Making Test – Part B. QBF decreased during sitting, as shown through the LGI condition, but increased in HGI, with a condition effect (P=0.04). No differences were observed in the Stroop and Trail Making tests. Future studies are needed that measure total brain blood flow, cerebral blood flow velocity, perfusion and autoregulation simultaneously to help further understand the effects of prolonged sitting on cerebrovascular function.Master of Art

Acute changes in carotid-femoral pulse-wave velocity are tracked by heart-femoral-pulse-wave velocity

Background: Carotid-femoral pulse-wave velocity (cfPWV) is the reference standard measure of central arterial stiffness. However, it requires assessment of the carotid artery, which is technically challenging, and subject-level factors, including carotid artery plaque, may confound measurements. A promising alternative that overcomes these limitations is heart-femoral PWV (hfPWV), but it is not known to what extent changes in cfPWV and hfPWV are associated. Objectives: To determine, (1) the strength of the association between hfPWV and cfPWV; and (2) whether change in hfPWV is associated with change in cfPWV when central arterial stiffness is perturbed. Methods: Twenty young, healthy adults (24.0 [SD: 3.1] years, 45% female) were recruited. hfPWV and cfPWV were determined using Doppler ultrasound at baseline and following a mechanical perturbation in arterial stiffness (120mmHg thigh occlusion). Agreement between the two measurements was determined using mixed-effects regression models and Bland-Altman analysis. Results: There was, (1) strong (ICC >0.7) agreement between hfPWV and cfPWV (ICC= 0.82, 95%CI: 0.69,0.90), and, (2) very strong (ICC >0.9) agreement between change in hfPWV and cfPWV (ICC = 0.92, 95%CI: 0.86,0.96). cfPWV was significantly greater than hfPWV at baseline and during thigh occlusion (both P <0.001). Inspection of the Bland-Altman plot, comparing cfPWV and corrected hfPWV, revealed no measurement magnitude bias. Discussion: The current findings indicate that hfPWV and cfPWV are strongly associated, and that change in cfPWV is very strongly associated with change in hfPWV. hfPWV may be a simple alternative to cfPWV in the identification of cardiovascular risk in clinical and epidemiological settings

Validity and reliability of lower-limb pulse-wave velocity assessments using an oscillometric technique

There is a growing interest in the deleterious effects of sedentary behaviour on lower-limb arterial health. To permit further investigation, including in larger epidemiological studies, there is a need to identify lower-limb arterial health assessment tools that are valid and reliable, yet simple to administer. Purpose: This study sought to determine the validity and between-day reliability of femoral-ankle pulse-wave velocity (faPWV) measures obtained using an oscillometric-based device (SphygmocCor XCEL) in supine and seated positions. Doppler ultrasound (US) was used as the criterion. Methods: A total of 47 healthy adults were recruited for validity (n=32) and reliability (n=15) analyses. Validity was determined by measuring faPWV in seated and supine positions using the XCEL and US devices, in a randomised order. Between-day reliability was determined by measuring seated and supine faPWV using the XCEL on 3 different mornings, separated by a maximum of 7 days. Results: The validity criteria (absolute standard error of estimate [aSEE] <1.0 m/s) was met in the supine (aSEE = 0.8 m/s, 95% CI: 0.4-1.0), but not the seated (aSEE = 1.2 m/s, 95 % CI: 1.1, 1.2) position. Intras-class correlation coefficient estimates revealed the XCEL demonstrated good reliability in the supine position (ICC=0.83, 95% CI: 0.65, 0.93), but poor reliability in the seated position (ICC = 0.29, 95% CI: 0.23, 0.63). Conclusions: The oscillometric XCEL device can be used to determine lower-limb PWV with acceptable validity and reliability in the conventionally recommended supine position, but not the seated position

Effects of acute prolonged sitting on cerebral perfusion and executive function in young adults: a randomized cross-over trial

Exposure to acute prolonged sitting reportedly leads to decreased cerebral blood flow. However, it is unclear whether this exposure translates to decreased cerebral perfusion and executive function, or whether simple strategies to break-up sitting can maintain cerebral perfusion and executive function. This study sought to answer two questions: in young, healthy adults (i) does prolonged (3 h) sitting lead to decreased cerebral perfusion and executive function? and (ii) does breaking-up prolonged sitting, using intermittent calf raise exercises, prevent changes in cerebral perfusion and executive function? Twenty young, healthy participants (21.7 [2.5] y, 70% F, 25.5 [6.1] kg/m2) were randomized to: 3 h sitting with 10 calf raises every 10 min (CALF), and 3 h sitting without calf intermittent calf raises (CON). Prefrontal cortex perfusion was assessed using near-infrared spectroscopy to monitor total hemoglobin (tHB) concentration and tissue saturation index (TSI, oxygenated hemoglobin). Executive function was assessed using the Stroop Word and Color Tasks. Following 3 h sitting, tHb was significantly lower in CALF vs. CON (-2.1 μM, 95% CI: -3.1, -1.1). TSI was not significantly different between conditions (P = .667). Word (1.6 ms, 95% CI: 0.7, 2.5) and Color (1.3 ms, 95% CI: -0.2, 2.8) completion times were longer (worse) for CALF compared to CON. In conclusion, calf raises decreased both cerebral perfusion and executive function. Simple strategies, such as fidgeting or calf raises, which have been reported to preserve vascular function in the legs, appear not to be sufficient enough to benefit cerebral perfusion or executive function

Undergoing Transformation to the Patient Centered Medical Home in Safety Net Health Centers: Perspectives from the Front Lines

Objectives—Safety Net Health Centers (SNHCs), which include Federally Qualified Health Centers (FQHCs) provide primary care for underserved, minority and low income patients. SNHCs across the country are in the process of adopting the Patient Centered Medical Home (PCMH) model, based on promising early implementation data from demonstration projects. However, previous demonstration projects have not focused on the safety net and we know little about PCMH transformation in SNHCs. Design—This qualitative study characterizes early PCMH adoption experiences at SNHCs. Setting and Participants—We interviewed 98 staff,(administrators, providers, and clinical staff) at 20 of 65 SNHCs, from five states, who were participating in the first of a five-year PCMH collaborative, the Safety Net Medical Home Initiative. Main Measures—We conducted 30-45 minute, semi-structured telephone interviews. Interview questions addressed benefits anticipated, obstacles encountered, and lessons learned in transition to PCMH. Results—Anticipated benefits for participating in the PCMH included improved staff satisfaction and patient care and outcomes. Obstacles included staff resistance and lack of financial support for PCMH functions. Lessons learned included involving a range of staff, anticipating resistance, and using data as frequent feedback. Conclusions—SNHCs encounter unique challenges to PCMH implementation, including staff turnover and providing care for patients with complex needs. Staff resistance and turnover may be ameliorated through improved healthcare delivery strategies associated with the PCMH. Creating predictable and continuous funding streams may be more fundamental challenges to PCMH transformation

Using near-term forecasts and uncertainty partitioning to improve predictions of low-frequency cyanobacterial events

Near-term ecological forecasts provide resource managers advance notice of changes in ecosystem services, such as fisheries stocks, timber yields, or water and air quality. Importantly, ecological forecasts can identify where uncertainty enters the forecasting system, which is necessary to refine and improve forecast skill and guide interpretation of forecast results. Uncertainty partitioning identifies the relative contributions to total forecast variance (uncertainty) introduced by different sources, including specification of the model structure, errors in driver data, and estimation of initial state conditions. Uncertainty partitioning could be particularly useful in improving forecasts of high-density cyanobacterial events, which are difficult to predict and present a persistent challenge for lake managers. Cyanobacteria can produce toxic or unsightly surface scums and advance warning of these events could help managers mitigate water quality issues. Here, we calibrate fourteen Bayesian state-space models to evaluate different hypotheses about cyanobacterial growth using data from eight summers of weekly cyanobacteria density samples in an oligotrophic (low nutrient) lake that experiences sporadic surface scums of the toxin-producing cyanobacterium, Gloeotrichia echinulata. We identify dominant sources of uncertainty for near-term (one-week to four-week) forecasts of G. echinulata densities over two years. Water temperature was an important predictor in calibration and at the four-week forecast horizon. However, no environmental covariates improved over a simple autoregressive (AR) model at the one-week horizon. Even the best fit models exhibited large variance in forecasted cyanobacterial densities and often did not capture rare peak density occurrences, indicating that significant explanatory variables in calibration are not always effective for near-term forecasting of low-frequency events. Uncertainty partitioning revealed that model process specification and initial conditions uncertainty dominated forecasts at both time horizons. These findings suggest that observed densities result from both growth and movement of G. echinulata, and that imperfect observations as well as spatial misalignment of environmental data and cyanobacteria observations affect forecast skill. Future research efforts should prioritize long-term studies to refine process understanding and increased sampling frequency and replication to better define initial conditions. Our results emphasize the importance of ecological forecasting principles and uncertainty partitioning to refine and understand predictive capacity across ecosystems.Accepted manuscrip

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe