Exploring multilocus associations of inflammation genes and colorectal cancer risk using hapConstructor

<p>Abstract</p> <p>Background</p> <p>In candidate-gene association studies of single nucleotide polymorphisms (SNPs), multilocus analyses are frequently of high dimensionality when considering haplotypes or haplotype pairs (diplotypes) and differing modes of expression. Often, while candidate genes are selected based on their biological involvement in a given pathway, little is known about the functionality of SNPs to guide association studies. Investigators face the challenge of exploring multiple SNP models to elucidate which variants, independently or in combination, might be associated with a disease of interest. A data mining module, hapConstructor (freely-available in Genie software) performs systematic construction and association testing of multilocus genotype data in a Monte Carlo framework. Our objective was to assess its utility to guide statistical analyses of haplotypes within a candidate region (or combined genotypes across candidate genes) beyond that offered by a standard logistic regression approach.</p> <p>Methods</p> <p>We applied the hapConstructor method to a multilocus investigation of candidate genes involved in pro-inflammatory cytokine IL6 production, <it>IKBKB</it>, <it>IL6</it>, and <it>NFKB1 </it>(16 SNPs total) hypothesized to operate together to alter colorectal cancer risk. Data come from two U.S. multicenter studies, one of colon cancer (1,556 cases and 1,956 matched controls) and one of rectal cancer (754 cases and 959 matched controls).</p> <p>Results</p> <p>HapConstrcutor enabled us to identify important associations that were further analyzed in logistic regression models to simultaneously adjust for confounders. The most significant finding (nominal <it>P </it>= 0.0004; false discovery rate <it>q </it>= 0.037) was a combined genotype association across <it>IKBKB </it>SNP rs5029748 (1 or 2 variant alleles), <it>IL6 </it>rs1800797 (1 or 2 variant alleles), and <it>NFKB1 </it>rs4648110 (2 variant alleles) which conferred an ~80% decreased risk of colon cancer.</p> <p>Conclusions</p> <p>Strengths of hapConstructor were: systematic identification of multiple loci within and across genes important in CRC risk; false discovery rate assessment; and efficient guidance of subsequent logistic regression analyses.</p

Remarkable muscles, remarkable locomotion in desert-dwelling wildebeest

Large mammals that live in arid and/or desert environments can cope with seasonal and local variations in rainfall, food and climate1 by moving long distances, often without reliable water or food en route. The capacity of an animal for this long-distance travel is substantially dependent on the rate of energy utilization and thus heat production during locomotion—the cost of transport2,3,4. The terrestrial cost of transport is much higher than for flying (7.5 times) and swimming (20 times)4. Terrestrial migrants are usually large1,2,3 with anatomical specializations for economical locomotion5,6,7,8,9, because the cost of transport reduces with increasing size and limb length5,6,7. Here we used GPS-tracking collars10 with movement and environmental sensors to show that blue wildebeest (Connochaetes taurinus, 220 kg) that live in a hot arid environment in Northern Botswana walked up to 80 km over five days without drinking. They predominantly travelled during the day and locomotion appeared to be unaffected by temperature and humidity, although some behavioural thermoregulation was apparent. We measured power and efficiency of work production (mechanical work and heat production) during cyclic contractions of intact muscle biopsies from the forelimb flexor carpi ulnaris of wildebeest and domestic cows (Bos taurus, 760 kg), a comparable but relatively sedentary ruminant. The energetic costs of isometric contraction (activation and force generation) in wildebeest and cows were similar to published values for smaller mammals. Wildebeest muscle was substantially more efficient (62.6%) than the same muscle from much larger cows (41.8%) and comparable measurements that were obtained from smaller mammals (mouse (34%)11 and rabbit (27%)). We used the direct energetic measurements on intact muscle fibres to model the contribution of high working efficiency of wildebeest muscle to minimizing thermoregulatory challenges during their long migrations under hot arid conditions

The chicken or the egg? Exploring bi-directional associations between Newcastle disease vaccination and village chicken flock size in rural Tanzania

Newcastle disease (ND) is a viral disease of poultry with global importance, responsible for the loss of a potential source of household nutrition and economic livelihood in many low-income food-deficit countries. Periodic outbreaks of this endemic disease result in high mortality amongst free-ranging chicken flocks and may serve as a disincentive for rural households to invest time or resources in poultry-keeping. Sustainable ND control can be achieved through vaccination using a thermotolerant vaccine administered via eyedrop by trained "community vaccinators". This article evaluates the uptake and outcomes of fee-for-service ND vaccination programs in eight rural villages in the semi-arid central zone of Tanzania. It represents part of an interdisciplinary program seeking to address chronic undernutrition in children through improvements to existing poultry and crop systems. Newcastle disease vaccination uptake was found to vary substantially across communities and seasons, with a significantly higher level of vaccination amongst households participating in a longitudinal study of children's growth compared with non-participating households (p = 0.009). Two multivariable model analyses were used to explore associations between vaccination and chicken numbers, allowing for clustered data and socioeconomic and cultural variation amongst the population. Results demonstrated that both (a) households that undertook ND vaccination had a significantly larger chicken flock size in the period between that vaccination campaign and the next compared with those that did not vaccinate (p = 0.018); and (b) households with larger chicken flocks at the time of vaccination were significantly more likely to participate in vaccination programs (p < 0.001). Additionally, households vaccinating in all three vaccination campaigns held over 12 months were identified to have significantly larger chicken flocks at the end of this period (p < 0.001). Opportunities to understand causality and complexity through quantitative analyses are limited, and there is a role for qualitative approaches to explore decisions made by poultry-keeping households and the motivations, challenges and priorities of community vaccinators. Evidence of a bi-directional relationship, however, whereby vaccination leads to greater chicken numbers, and larger flocks are more likely to be vaccinated, offers useful insights into the efficacy of fee-for-service animal health programs. This article concludes that attention should be focused on ways of supporting the participation of vulnerable households in ND vaccination campaigns, and encouraging regular vaccination throughout the year, as a pathway to strengthen food security, promote resilience and contribute to improved human nutrition

Predictive police patrolling to target hotspots and cover response demand

This is an Open Access Article. It is published by Springer under the Creative Commons Attribution 4.0 Unported Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/Police forces are constantly competing to provide adequate service whilst faced with major funding cuts. The funding cuts result in limited resources hence methods of improving resource efficiency are vital to public safety. One area where improving the efficiency could drastically improve service is the planning of patrol routes for incident response officers. Current methods of patrolling lack direction and do not consider response demand. Police patrols have the potential to deter crime when directed to the right areas. Patrols also have the ability to position officers with access to high demand areas by pre-empting where response demand will arise. The algorithm developed in this work directs patrol routes in real-time by targeting high crime areas whilst maximising demand coverage. Methods used include kernel density estimation for hotspot identification and maximum coverage location problems for positioning. These methods result in more effective daily patrolling which reduces response times and accurately targets problem areas. Though applied in this instance to daily patrol operations, the methodology could help to reduce the need for disaster relief operations whilst also positioning proactively to allow quick response when disaster relief operations are required

Little evidence for an epidemic of myopia in Australian primary school children over the last 30 years

BACKGROUND: Recently reported prevalences of myopia in primary school children vary greatly in different regions of the world. This study aimed to estimate the prevalence of refractive errors in an unselected urban population of young primary school children in eastern Sydney, Australia, between 1998 and 2004, for comparison with our previously published data gathered using the same protocols and other Australian studies over the last 30 years. METHODS: Right eye refractive data from non-cycloplegic retinoscopy was analysed for 1,936 children aged 4 to 12 years who underwent a full eye examination whilst on a vision science excursion to the Vision Education Centre Clinic at the University of New South Wales. Myopia was defined as spherical equivalents equal to or less than -0.50 D, and hyperopia as spherical equivalents greater than +0.50 D. RESULTS: The mean spherical equivalent decreased significantly (p < 0.0001) with age from +0.73 ± 0.1D (SE) at age 4 to +0.21 ± 0.11D at age 12 years. The proportion of children across all ages with myopia of -0.50D or more was 8.4%, ranging from 2.3% of 4 year olds to 14.7% of 12 year olds. Hyperopia greater than +0.50D was present in 38.4%. A 3-way ANOVA for cohort, age and gender of both the current and our previous data showed a significant main effect for age (p < 0.0001) but not for cohort (p = 0.134) or gender (p = 0.61). CONCLUSIONS: Comparison of our new data with our early 1990s data and that from studies of over 8,000 Australian non-clinical rural and urban children in the 1970's and 1980's provided no evidence for the rapidly increasing prevalence of myopia described elsewhere in the world. In fact, the prevalence of myopia in Australian children continues to be significantly lower than that reported in Asia and North America despite changing demographics. This raises the issue of whether these results are a reflection of Australia's stable educational system and lifestyle over the last 30 years

Police districting problem: literature review and annotated bibliography

The police districting problem concerns the efficient and effective design of patrol sectors in terms of performance attributes. Effectiveness is particularly important as it directly influences the ability of police agencies to stop and prevent crime. However, in this problem, a homogeneous distribution of workload is also desirable to guarantee fairness to the police agents and an increase in their satisfaction. This chapter provides a systematic review of the literature related to the police districting problem, whose history dates back to almost 50 years ago. Contributions are categorized in terms of attributes and solution methodology adopted. Also, an annotated bibliography that presents the most relevant elements of each research is given

The Method for Assigning Priority Levels (MAPLe): A new decision-support system for allocating home care resources

<p>Abstract</p> <p>Background</p> <p>Home care plays a vital role in many health care systems, but there is evidence that appropriate targeting strategies must be used to allocate limited home care resources effectively. The aim of the present study was to develop and validate a methodology for prioritizing access to community and facility-based services for home care clients.</p> <p>Methods</p> <p>Canadian and international data based on the Resident Assessment Instrument – Home Care (RAI-HC) were analyzed to identify predictors for nursing home placement, caregiver distress and for being rated as requiring alternative placement to improve outlook.</p> <p>Results</p> <p>The Method for Assigning Priority Levels (MAPLe) algorithm was a strong predictor of all three outcomes in the derivation sample. The algorithm was validated with additional data from five other countries, three other provinces, and an Ontario sample obtained after the use of the RAI-HC was mandated.</p> <p>Conclusion</p> <p>The MAPLe algorithm provides a psychometrically sound decision-support tool that may be used to inform choices related to allocation of home care resources and prioritization of clients needing community or facility-based services.</p

Loss of ubiquitin E2 Ube2w rescues hypersensitivity of Rnf4 mutant cells to DNA damage

SUMO and ubiquitin play important roles in the response of cells to DNA damage. These pathways are linked by the SUMO Targeted ubiquitin Ligase Rnf4 that catalyses transfer of ubiquitin from a ubiquitin loaded E2 conjugating enzyme to a polySUMO modified substrate. Rnf4 can functionally interact with multiple E2s, including Ube2w, in vitro. Chicken cells lacking Rnf4 are hypersensitive to hyroxyurea, DNA alkylating drugs and DNA crosslinking agents, but this sensitivity is suppressed by simultaneous depletion of Ube2w. Cells depleted of Ube2w alone are not hypersensitive to the same DNA damaging agents. Similar results were also obtained in human cells. These data indicate that Ube2w does not have an essential role in the DNA damage response, but is deleterious in the absence of Rnf4. Thus, although Rnf4 and Ube2w functionally interact in vitro, our genetic experiments indicate that in response to DNA damage Ube2w and Rnf4 function in distinct pathways

The publics' understanding of daily caloric recommendations and their perceptions of calorie posting in chain restaurants

<p>Abstract</p> <p>Background</p> <p>Calorie posting in chain restaurants has received increasing attention as a policy lever to reduce energy intake. Little research has assessed consumer understanding of overall daily energy requirements or perceived effectiveness of calorie posting.</p> <p>Methods</p> <p>A phone survey was conducted from May 1 through 17, 2009 with 663 randomly selected, nationally-representative adults aged 18 and older, including an oversample of Blacks and Hispanics in the United States. To examine differences in responses by race and ethnicity (White, Black, and Hispanic) and gender, we compared responses by conducting chi-squared tests for differences in proportions.</p> <p>Results</p> <p>We found that most Americans were knowledgeable about energy requirements for moderately active men (78%) and women (69%), but underestimated energy requirements for inactive adults (60%). Whites had significantly higher caloric literacy and confidence about their caloric knowledge than Blacks and Hispanics (p < 0.05). As compared to their counterparts, Blacks, Hispanics and women reported a significantly higher likelihood of eating at a chain restaurant and of selecting lower calorie foods where caloric information was posted. Most Americans favored the government requiring chain restaurants to post calorie information on menus at the point of purchase (68%). Support for government mandated calorie posting in chain restaurants was significantly higher among Blacks, Hispanics and women as compared to their counterparts. The public was divided about the mode of caloric information that would best help them make a lower calorie decision; a third favored number of calories (35%) which is the current standard mode of presenting caloric information in chain restaurants, a third favored a physical activity equivalent (26%), and a third favored percentage of total energy intake (39%).</p> <p>Conclusion</p> <p>Mandating calorie posting in chain restaurants may be a useful policy tool for promoting energy balance, particularly among Blacks, Hispanics and women who have higher obesity risk.</p