A Neighborhood-Wide Association Study (NWAS): Example of prostate cancer aggressiveness

by Shannon M. Lynch, Nandita Mitra, Michelle Ross, Craig Newcomb, Karl Dailey, Tara Jackson, Charnita M. Zeigler-Johnson, Harold Riethman, Charles C. Branas, Timothy R. Rebbeck

Purpose

Cancer results from complex interactions of multiple variables at the biologic, individual, and social levels. Compared to other levels, social effects that occur geospatially in neighborhoods are not as well-studied, and empiric methods to assess these effects are limited. We propose a novel Neighborhood-Wide Association Study(NWAS), analogous to genome-wide association studies(GWAS), that utilizes high-dimensional computing approaches from biology to comprehensively and empirically identify neighborhood factors associated with disease.

Methods

Pennsylvania Cancer Registry data were linked to U.S. Census data. In a successively more stringent multiphase approach, we evaluated the association between neighborhood (n = 14,663 census variables) and prostate cancer aggressiveness(PCA) with n = 6,416 aggressive (Stage≥3/Gleason grade≥7 cases) vs. n = 70,670 non-aggressive (Stage Results

We identified 17 new neighborhood variables associated with PCA. These variables represented income, housing, employment, immigration, access to care, and social support. The top hits or most significant variables related to transportation (OR = 1.05;CI = 1.001–1.09) and poverty (OR = 1.07;CI = 1.01–1.12).

Conclusions

This study introduces the application of high-dimensional, computational methods to large-scale, publically-available geospatial data. Although NWAS requires further testing, it is hypothesis-generating and addresses gaps in geospatial analysis related to empiric assessment. Further, NWAS could have broad implications for many diseases and future precision medicine studies focused on multilevel risk factors of disease.

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Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States

by Michael H. Le, Pardha Devaki, Nghiem B. Ha, Dae Won Jun, Helen S. Te, Ramsey C. Cheung, Mindie H. Nguyen

In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition Examination Survey (NHANES) 1988–1994. Our goal was to determine the NAFLD prevalence in the recent 1999–2012 NHANES, risk factors for advanced fibrosis (stage 3–4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93–5.08, p

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Stationarity of the inter-event power-law distributions

by Yerali Gandica, João Carvalho, Fernando Sampaio dos Aidos, Renaud Lambiotte, Timoteo Carletti

A number of human activities exhibit a bursty pattern, namely periods of very high activity that are followed by rest periods. Records of these processes generate time series of events whose inter-event times follow a probability distribution that displays a fat tail. The grounds for such phenomenon are not yet clearly understood. In the present work we use the freely available Wikipedia’s editing records to unravel some features of this phenomenon. We show that even though the probability to start editing is conditioned by the circadian 24 hour cycle, the conditional probability for the time interval between successive edits at a given time of the day is independent from the latter. We confirm our findings with the activity of posting on the social network Twitter. Our results suggest that there is an intrinsic humankind scheduling pattern: after overcoming the encumbrance of starting an activity, there is a robust distribution of new related actions, which does not depend on the time of day at which the activity started.

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Caudwell Xtreme Everest: A prospective study of the effects of environmental hypoxia on cognitive functioning

by Konstadina Griva, Jan Stygall, Mark H. Wilson, Daniel Martin, Denny Levett, Kay Mitchell, Monty Mythen, Hugh E. Montgomery, Mike P. Grocott, Golnar Aref-Adib, Mark Edsell, Tracie Plant, Chris Imray, Debbie Cooke, Jane Harrington, Maryam Khosravi, Stanton P. Newman, for the Caudwell Xtreme Everest Research Group

Background

The neuropsychological consequences of exposure to environmental hypobaric hypoxia (EHH) remain unclear. We thus investigated them in a large group of healthy volunteers who trekked to Mount Everest base camp (5,300 m).

Methods

A neuropsychological (NP) test battery assessing memory, language, attention, and executive function was administered to 198 participants (age 44.5±13.7 years; 60% male). These were studied at baseline (sea level), 3,500 m (Namche Bazaar), 5,300 m (Everest Base Camp) and on return to 1,300 m (Kathmandu) (attrition rate 23.7%). A comparable control group (n = 25; age 44.5±14.1 years; 60% male) for comparison with trekkers was tested at/or near sea level over an equivalent timeframe so as to account for learning effects associated with repeat testing. The Reliable Change Index (RCI) was used to calculate changes in cognition and neuropsychological function during and after exposure to EHH relative to controls.

Results

Overall, attention, verbal ability and executive function declined in those exposed to EHH when the performance of the control group was taken into account (RCI .05 to -.95) with decline persisting at descent. Memory and psychomotor function showed decline at highest ascent only (RCI -.08 to -.56). However, there was inter-individual variability in response: whilst NP performance declined in most, this improved in some trekkers. Cognitive decline was greater amongst older people (r = .42; p Conclusions

After correcting for learning effects, attention, verbal abilities and executive functioning declined with exposure to EHH. There was considerable individual variability in the response of brain function to sustained hypoxia with some participants not showing any effects of hypoxia. This might have implications for those facing sustained hypoxia as a result of any disease.

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Most women recover from psychological distress after postoperative complications following implant or DIEP flap breast reconstruction: A prospective long-term follow-up study

by Reinier Timman, Jessica P. Gopie, J. Nick Brinkman, Annelies Kleijne, Caroline Seynaeve, Marian B. E. Menke-Pluymers, Moniek M. ter Kuile, Aad Tibben, Marc A. M. Mureau

Background

Substantial complication rates after postmastectomy breast reconstruction (BR) in breast cancer patients have been reported. Few studies have reported on the resulting psychological distress (PD) and satisfaction with the aesthetic result in relation to postoperative complications after completion of implant or DIEP flap BR. The present study investigated whether women were able to recover from complication related distress in the long term.

Methods

PD was prospectively measured using questionnaires regarding anxiety, depression and cancer distress. Eligible patients completed questionnaires before BR (T0, n = 144), after one month (T1, n = 139) and after completion of BR, approximately 21 months after initial reconstructive surgery (T2, n = 119). Satisfaction with the aesthetic result was assessed 21 months after BR. Data concerning complications, subsequent additional surgery and total reconstruction failure up to T2 were collected from the medical records. Analyses were performed using multi-level regression analyses correcting for age.

Results

One or more complications occurred in 61 patients (42%) and 50 women required subsequent surgery (35%). In time, mean PD significantly declined towards baseline scores independent of complications. However, a total reconstruction failure (n = 10) was significantly associated with a large temporary increase in depression scores. After additional surgery due to complications patients were less satisfied with aesthetic outcome, although patient satisfaction was independent of PD.

Conclusions

PD outcomes generally declined to normal levels after completion of the entire BR course. Patients experiencing a total reconstruction failure reported more depression after this loss, but in the long term recovered to the same level as women without complications. These findings indicate that women generally can cope efficiently with these serious adverse events, even if they were less satisfied with the aesthetic result.

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Association of eNOS and Cav-1 gene polymorphisms with susceptibility risk of large artery atherosclerotic stroke

by Hann-Yeh Shyu, Ming-Hua Chen, Yi-Hsien Hsieh, Jia-Ching Shieh, Ling-Rong Yen, Hsiao-Wei Wang, Chun-Wen Cheng

Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin-1 (Cav-1), which supports normal functioning of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case-control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09–2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16–2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06–2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trendtrend eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan.

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Gonadotropin-releasing hormone receptor (Gnrhr) gene knock out: Normal growth and development of sensory, motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice

by Ellen R. Busby, Nancy M. Sherwood

Gonadotropin-releasing hormone (GnRH) is important in the control of reproduction, but its actions in non-reproductive processes are less well known. In this study we examined the effect of disrupting the GnRH receptor in mice to determine if growth, metabolism or behaviors that are not associated with reproduction were affected. To minimize the effects of other hormones such as FSH, LH and sex steroids, the neonatal-prepubertal period of 2 to 28 days of age was selected. The study shows that regardless of sex or phenotype in the Gnrhr gene knockout line, there was no significant difference in the daily development of motor control, sensory detection or spatial orientation among the wildtype, heterozygous or null mice. This included a series of behavioral tests for touch, vision, hearing, spatial orientation, locomotory behavior and muscle strength. Neither the daily body weight nor the final weight on day 28 of the kidney, liver and thymus relative to body weight varied significantly in any group. However by day 28, metabolic changes in the GnRH null females compared with wildtype females showed a significant reduction in inguinal fat pad weight normalized to body weight; this was accompanied by an increase in glucose compared with wildtype females shown by Student-Newman-Keuls Multiple Comparison test and Student’s unpaired t tests. Our studies show that the GnRH-GnRHR system is not essential for growth or motor/sensory/orientation behavior during the first month of life prior to puberty onset. The lack of the GnRH-GnRHR axis, however, did affect females resulting in reduced subcutaneous inguinal fat pad weight and increased glucose with possible insulin resistance; the loss of the normal rise of estradiol at postnatal days 15–28 may account for the altered metabolism in the prepubertal female pups.

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