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People are increasingly eager to know more about themselves through technology. To date, technology has primarily provided information on our physiology. Yet, with advances in wearable technology and artificial intelligence, the current advent of consumer neurotechnology will enable users to measure their cognitive activity. We see an opportunity for research in Human-Computer Interaction (HCI) in the development of these devices. Neurotechnology offers new insights into user experiences and facilitates the development of novel methods in HCI. Researchers will be able to create innovative interactive systems based on the ability to measure cognitive activity at scale in real-world settings. In this paper, we contribute a vision of how neurotechnology will transform HCI research and practice. We discuss how neurotechnology prompts a discussion about ethics, privacy, and trust. This trend highlights HCI’s crucial role in ensuring that neurotechnology is developed and utilised in ways that truly benefit people.

Morphological subtypes of autism spectrum disorder (ASD) may differ in their genetic bases. Chan et al. develop a method for calculating a patient-level, genome-wide rare variant score and find significant differences in rare and common variant associations between dysmorphic and nondysmorphic ASD groups.

Abstract Background Vocal cord palsy after cervical mediastinoscopy is usually reported at less than 1%. However, its incidence might be underestimated and no follow-up studies are available. Our study aimed to evaluate the incidence of voice changes after cervical mediastinoscopy and report on long-term outcomes, including quality of life, after at least one-year follow-up. Methods A retrospective cohort study was performed, considering all patients who underwent cervical mediastinoscopy in our center between January 2011 and April 2016. Patients with pre-existing voice changes, voice changes only after pulmonary resection and patients who underwent neoadjuvant chemo(radio)therapy were excluded. Voice changes with full recovery within 14 days were attributed to intubation-related causes. Follow-up questionnaires, including the standardized Voice Handicap Index, were sent to patients with documented voice changes. Results Of 270 patients who were included for final analysis, 17 (6.3%) experienced voice changes after cervical mediastinoscopy, which persisted > 2 years in 4 patients (1.5%), causing mild to moderate disabilities in daily living. Twelve patients (out of 17, 71%) were referred for otolaryngology consultation, and paresis of the left vocal cord suggesting recurrent laryngeal nerve injury was confirmed in 10 (3.7% of our total study group). Additionally, 83% of the patients who were referred for otolaryngology consultation received voice treatment. Recovery rate after vocal exercises therapy and injection laryngoplasty was respectively 71% and 33%. Conclusions Voice changes after cervical mediastinoscopy is an underreported complication, with an incidence of at least 6.3% in our retrospective study, with persisting complaints in at least 1.5% of patients, leading to mild to moderate disabilities in daily living. These findings highlight the need for appropriate patient education for this underestimated complication, as well as the exploration of possible preventive measures.

Abstract Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10−7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7–58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

Abstract Investigating the determinants of the reproductive biology of fishes is an essential component of fisheries research. Tilapia breeding patterns were investigated to determine the impact of non‐native Oreochromis niloticus on the native congeneric Oreochromis macrochir in the upper Kabompo River in the Northwest of Zambia using the gonadosomatic index and the sex ratios. Oreochromis niloticus was the most abundant fish caught (221, 63.5%) than O. macrochir (127, 36.5%). Results showed that the overall gonadosomatic index means of O. macrochir in both sections were similar. Oreochromis macrochir bred in December and February–March, with no reproduction in June. However, O. niloticus in the invaded section indicated all year reproduction through reduced spawning in May–June, with increased spawning activity in February–March. The sex ratio (females: males) was 1:1.3 and 1:1.7 for O. niloticus and O. macrochir, respectively, and both significantly deviated from the sex ratio of 1:1 (ꭓ2 = 8.42 and 9.37, p

Abstract Invasive alien species have been revealed to drastically alter the structure of native communities; however, there is scarce information on whether taxonomic and functional spaces occupied by native species are equally filled by exotic species. We investigated the diversity of native species to understand the impact of exotic Oreochromis niloticus in the upper Kabompo River, northwest of Zambia using taxonomic and functional diversity indices. To achieve this, two tests were performed (Test 1, compared natives in invaded and uninvaded sections; Test 2, compared natives in invaded section). A total of 17 species were collected for functional diversity computation, out of which fourteen (14) functional trait measurements linked to feeding, locomotion, and life history strategy were taken. Findings revealed that taxonomic and functional diversity values changed with invasion in both tests. Taxonomic diversity was 15% more in invaded than uninvaded sections in Test 1 and was not consistent across sampling points of invaded section in Test 2. Invaded areas were taxonomically less diverse, but functionally diverse in both tests. The analysis of similarity and nonmetric multidimensional scaling revealed no difference in Bray–Curtis similarity assemblages in both tests. Our findings revealed that exotic species more often occupy unfilled gaps in the communities often occupied by the native species; this is achieved by occupying functional spaces. Overall, changes in taxonomic and functional diversity of native species documented here partially confirmed impacts of O. niloticus invasion. Therefore, we recommend a multifaceted approach to assess cumulative impacts of invasion on native species.

This paper examines switch reference (SR) in A’ingae, an understudied isolate language from Amazonian Ecuador. We present a theoretically informed survey of SR, identifying three distinct uses of switch reference: in clause chaining, adverbial clauses, and so-called ‘bridging’ clause linkage. We describe the syntactic and semantic properties of each use in detail, the first such description for A’ingae, showing that the three constructions differ in important ways. While leaving a full syntactic analysis to future work, we argue that these disparate properties preclude a syntactic account that unifies these three constructions to the exclusion of other environments without SR. Conversely, while a full semantic account is also left to future work, we suggest that a unified semantic account in terms of discourse coherence principles appears more promising. In particular, we propose that switch reference in A’ingae occurs in all and only the constructions that are semantically restricted to non-structuring coordinating coherence relations in the sense of Segmented Discourse Representation Theory.

In this work, a strain-based degradation model was implemented and validated to better understand the dynamic interactions between the bioresorbable vascular scaffold (BVS) and the artery during the degradation process. Integrating the strain-modulated degradation equation into commercial finite element codes allows a better control and visualization of local mechanical parameters. Both strut thinning and discontinuity of the stent struts within an artery were captured and visualized. The predicted results in terms of mass loss and fracture locations were validated by the documented experimental observations. In addition, results suggested that the heterogeneous degradation of the stent depends on its strain distribution following deployment. Degradation is faster at the locations with higher strains and resulted in the strut thinning and discontinuity, which contributes to the continuous mass loss, and the reduced contact force between the BVS and artery. A nonlinear relationship between the maximum principal strain of the stent and the fracture time was obtained, which could be transformed to predict the degradation process of the BVS in different mechanical environments. The developed computational model provided more insights into the degradation process, which could complement the discrete experimental data for improving the design and clinical management of the BVS.

Abstract Background The severity and frequency of drought has increased around the globe, creating challenges in ensuring food security for a growing world population. As a consequence, improving water use efficiency by crops has become an important objective for crop improvement. Some wild crop relatives have adapted to extreme osmotic stresses and can provide valuable insights into traits and genetic signatures that can guide efforts to improve crop tolerance to water deficits. Eutrema salsugineum, a close relative of many cruciferous crops, is a halophytic plant and extremophyte model for abiotic stress research. Results Using comparative transcriptomics, we show that two E. salsugineum ecotypes display significantly different transcriptional responses towards a two-stage drought treatment. Even before visibly wilting, water deficit led to the differential expression of almost 1,100 genes for an ecotype from the semi-arid, sub-arctic Yukon, Canada, but only 63 genes for an ecotype from the semi-tropical, monsoonal, Shandong, China. After recovery and a second drought treatment, about 5,000 differentially expressed genes were detected in Shandong plants versus 1,900 genes in Yukon plants. Only 13 genes displayed similar drought-responsive patterns for both ecotypes. We detected 1,007 long non-protein coding RNAs (lncRNAs), 8% were only expressed in stress-treated plants, a surprising outcome given the documented association between lncRNA expression and stress. Co-expression network analysis of the transcriptomes identified eight gene clusters where at least half of the genes in each cluster were differentially expressed. While many gene clusters were correlated to drought treatments, only a single cluster significantly correlated to drought exposure in both ecotypes. Conclusion Extensive, ecotype-specific transcriptional reprogramming with drought was unexpected given that both ecotypes are adapted to saline habitats providing persistent exposure to osmotic stress. This ecotype-specific response would have escaped notice had we used a single exposure to water deficit. Finally, the apparent capacity to improve tolerance and growth after a drought episode represents an important adaptive trait for a plant that thrives under semi-arid Yukon conditions, and may be similarly advantageous for crop species experiencing stresses attributed to climate change.

BackgroundPublic health organizations have begun to use social media to increase awareness of health harm and positively improve health behavior. Little is known about effective strategies to disseminate health education messages digitally and ultimately achieve optimal audience engagement. ObjectiveThis study aims to assess the difference in audience engagement with identical antismoking health messages on three social media sites (Twitter, Facebook, and Instagram) and with a referring link to a tobacco prevention website cited in these messages. We hypothesized that health messages might not receive the same user engagement on these media, although these messages were identical and distributed at the same time. MethodsWe measured the effect of health promotion messages on the risk of smoking among users of three social media sites (Twitter, Facebook, and Instagram) and disseminated 1275 health messages between April 19 and July 12, 2017 (85 days). The identical messages were distributed at the same time and as organic (unpaid) and advertised (paid) messages, each including a link to an educational website with more information about the topic. Outcome measures included message engagement (ie, the click-through rate [CTR] of the social media messages) and educational website engagement (ie, the CTR on the educational website [wCTR]). To analyze the data and model relationships, we used mixed effects negative binomial regression, z-statistic, and the Hosmer-Lemeshow goodness-of-fit test. ResultsComparisons between social media sites showed that CTRs for identical antitobacco health messages differed significantly across social media (P

The Canadian beaver (Castor canadensis) is the largest indigenous rodent in North America. We report a draft annotated assembly of the beaver genome, the first for a large rodent and the first mammalian genome assembled directly from uncorrected and moderate coverage (< 30 ×) long reads generated by single-molecule sequencing. The genome size is 2.7 Gb estimated by k-mer analysis. We assembled the beaver genome using the new Canu assembler optimized for noisy reads. The resulting assembly was refined using Pilon supported by short reads (80 ×) and checked for accuracy by congruency against an independent short read assembly. We scaffolded the assembly using the exon–gene models derived from 9805 full-length open reading frames (FL-ORFs) constructed from the beaver leukocyte and muscle transcriptomes. The final assembly comprised 22,515 contigs with an N50 of 278,680 bp and an N50-scaffold of 317,558 bp. Maximum contig and scaffold lengths were 3.3 and 4.2 Mb, respectively, with a combined scaffold length representing 92% of the estimated genome size. The completeness and accuracy of the scaffold assembly was demonstrated by the precise exon placement for 91.1% of the 9805 assembled FL-ORFs and 83.1% of the BUSCO (Benchmarking Universal Single-Copy Orthologs) gene set used to assess the quality of genome assemblies. Well-represented were genes involved in dentition and enamel deposition, defining characteristics of rodents with which the beaver is well-endowed. The study provides insights for genome assembly and an important genomics resource for Castoridae and rodent evolutionary biology.

The advent of long-read sequencing offers a new assessment method of detecting genomic structural variation (SV) in numerous rare genetic diseases. For autism spectrum disorders (ASD) cases where pathogenic variants fail to be found in the protein-coding genic regions along chromosomes, we proposed a scalable workflow to characterize the risk factor of SVs impacting non-coding elements of the genome. We applied whole-genome sequencing on an Emirati family having three children with ASD using long and short-read sequencing technology. A series of analytical pipelines were established to identify a set of SVs with high sensitivity and specificity. At 15-fold coverage, we observed that long-read sequencing technology (987 variants) detected a significantly higher number of SVs when compared to variants detected using short-read technology (509 variants) (p-value < 1.1020 × 10−57). Further comparison showed 97.9% of long-read sequencing variants were spanning within the 1–100 kb size range (p-value < 9.080 × 10−67) and impacting over 5000 genes. Moreover, long-read variants detected 604 non-coding RNAs (p-value < 9.02 × 10−9), comprising 58% microRNA, 31.9% lncRNA, and 9.1% snoRNA. Even at low coverage, long-read sequencing has shown to be a reliable technology in detecting SVs impacting complex elements of the genome.

β-decay spectroscopy of nuclei far from stability can provide powerful insight into a broad variety of topics in nuclear science, ranging from exotic nuclear structure phenomena, stellar nucleosynthesis processes, and applied topics such as quantifying “decay heat” discrepancies for advanced nuclear fuel cycles. Neutronrich nuclei approaching the drip-line are difficult to access experimentally, leaving many key examples largely under studied. The CARIBU radioactive beam facility at Argonne National Laboratory exploits spontaneous fission of 252Cf in production of such beams. The X-Array and SATURN decay station have been commissioned to perform detailed decay spectroscopy of low-energy CARIBU beams. An extended science campaign was started during 2015; with projects investigating nuclear shape changes, collective octupole vibrations, β-delayed neutron emission, and decay-scheme properties which could explain the reactor antineutrino puzzle. In this article we review the current status of the setup, update on the first results and recent hardware upgrades, and look forward to future possibilities.

BackgroundMuch concern has been raised over pro-eating disorder (pro-ED) website communities, but little quantitative research has been conducted on these websites and their users. ObjectiveTo examine associations between levels of pro-ED website usage, disordered eating behaviors, and quality of life. MethodsWe conducted a cross-sectional, Internet-based survey of adult pro-ED website users. Main outcomes were Eating Disorder Examination Questionnaire (EDE-Q) and Eating Disorder Quality of Life (EDQOL) scores. ResultsWe included responses from 1291 participants; 1254 (97.13%) participants were female. Participants had an average age of 22.0 years and a mean body mass index of 22.1 kg/m2; 24.83% (296/1192) were underweight; 20.89% (249/1192) were overweight or obese. Over 70% of participants had purged, binged, or used laxatives to control their weight; only 12.91% (163/1263) were in treatment. Mean EDE-Q scores were above the 90th percentile and mean EDQOL scores were in the severely impaired range. When compared with moderate and light usage, heavy pro-ED website usage was associated with higher EDE-Q global (4.89 vs 4.56 for medium and 4.0 for light usage, P < .001) and EDQOL total scores (1.64 vs 1.45 for medium and 1.25 for light usage, P < .001), and more extreme weight loss behaviors and harmful post-website usage activities. In a multivariate model, the level of pro-ED website usage remained a significant predictor of EDE-Q scores. ConclusionsPro-ED website visitors reported many disordered eating behaviors, although few had been treated. Heavy users reported poorer quality of life and more disordered eating behaviors.

Abstract A World Food Preservation Center (WFPC) is proposed in response to a pending civilization-threatening food shortage and our limited ability to adequately increase food production. Some estimates put losses of food in developing countries after it is produced and before it is consumed at 50%. These losses are particularly threatening to individuals and farmers who are living in the midst of food insecurity. Although numerous organizations have attempted to address this problem worldwide, the magnitude of the effort has not come close to the enormity of the problem. Most of these programs are also short-term and require continuous input by postharvest specialists from developed countries in order to be sustainable. A critical need exists for a substantial and sustainable worldwide program that can significantly reduce losses and waste of food in developing countries. The World Food Preservation Center proposed here meets this need by educating young scientists in developing countries about low-input, appropriate technologies for preserving food postharvest. It also conducts research on postharvest technologies especially suited for application in developing countries such as biological control, solar refrigeration, and coordinated transport and marketing schemes that support and sustain the local production of food commodities.

Abstract Background Triticum monococcum L., an A genome diploid einkorn wheat, was the first domesticated crop. As a diploid, it is attractive genetic model for the study of gene structure and function of wheat-specific traits. Diploid wheat is currently not amenable to reverse genetics approaches such as insertion mutagenesis and post-transcriptional gene silencing strategies. However, TILLING offers a powerful functional genetics approach for wheat gene analysis. Results We developed a TILLING population of 1,532 M2 families using EMS as a mutagen. A total of 67 mutants were obtained for the four genes studied. Waxy gene mutation frequencies are known to be 1/17.6 - 34.4 kb DNA in polyploid wheat TILLING populations. The T. monococcum diploid wheat TILLING population had a mutation frequency of 1/90 kb for the same gene. Lignin biosynthesis pathway genes- COMT1, HCT2, and 4CL1 had mutation frequencies of 1/86 kb, 1/92 kb and 1/100 kb, respectively. The overall mutation frequency of the diploid wheat TILLING population was 1/92 kb. Conclusion The mutation frequency of a diploid wheat TILLING population was found to be higher than that reported for other diploid grasses. The rate, however, is lower than tetraploid and hexaploid wheat TILLING populations because of the higher tolerance of polyploids to mutations. Unlike polyploid wheat, most mutants in diploid wheat have a phenotype amenable to forward and reverse genetic analysis and establish diploid wheat as an attractive model to study gene function in wheat. We estimate that a TILLING population of 5, 520 will be needed to get a non-sense mutation for every wheat gene of interest with 95% probability.

Abstract Background Despite important implications for the budgets, statistical power and generalisability of research findings, detailed reports of recruitment and retention in randomised controlled trials (RCTs) are rare. The NOURISH RCT evaluated a community-based intervention for first-time mothers that promoted protective infant feeding practices as a primary prevention strategy for childhood obesity. The aim of this paper is to provide a detailed description and evaluation of the recruitment and retention strategies used. Methods A two stage recruitment process designed to provide a consecutive sampling framework was used. First- time mothers delivering healthy term infants were initially approached in postnatal wards of the major maternity services in two Australian cities for consent to later contact (Stage 1). When infants were approximately four months old mothers were re-contacted by mail for enrolment (Stage 2), baseline measurements (Time 1) and subsequent random allocation to the intervention or control condition. Outcomes were assessed at infant ages 14 months (Time 2) and 24 months (Time 3). Results At Stage 1, 86% of eligible mothers were approached and of these women, 76% consented to later contact. At Stage 2, 3% had become ineligible and 76% could be recontacted. Of the latter, 44% consented to full enrolment and were allocated. This represented 21% of mothers screened as eligible at Stage 1. Retention at Time 3 was 78%. Mothers who did not consent or discontinued the study were younger and less likely to have a university education. Conclusions The consent and retention rates of our sample of first time mothers are comparable with or better than other similar studies. The recruitment strategy used allowed for detailed information from non-consenters to be collected; thus selection bias could be estimated. Recommendations for future studies include being able to contact participants via mobile phone (particularly text messaging), offering home visits to reduce participant burden and considering the use of financial incentives to support participant retention. Trial registration Australian and New Zealand Clinical Trials Registry Number ACTRN12608000056392

Abstract Background Health ministries and providers are rapidly scaling up insecticide-treated nets (ITN) distribution to control malaria, yet possession and proper use typically remain below targeted levels. In Malawi, health facilities (HFs) are currently the principal points of ITN distribution, making it important to understand how access to these ITN sources affects ownership, possession, and use. The authors evaluated the association between proximity to HFs and ITN possession or use among Malawian children six to 59 months of age. Methods A household malaria survey undertaken in eight districts of Malawi during 2007 was used to characterize ITN possession and use. The location of each respondent's household was geocoded as was those of Ministry of Health (MoH) HFs and other health centres. Euclidean distance from each household to the nearest HF was calculated. Patterns of net possession and use were determined through descriptive methods. The authors then analysed the significance of distance and ITN possession/use through standard statistical tests, including logistic regression. Results Median distance to HFs was greater among households that did not possess ITNs and did not use an ITN the previous evening. Descriptive statistical methods confirmed a pattern of decreasing ITN possession and use with increasing distance from HFs. Logistic regression showed the same statistically significant association of distance to HFs, even when controlling for age and gender of the child, ratio of nets to children in household, community net possession and use, and household material wealth. Conclusions Strategies that exclusively distribute ITNs through HFs are likely to be less effective in increasing possession and use in communities that are more distant from those health services. Health providers should look towards community-based distribution services that take ITNs directly to community members to more effectively scale up ITN possession and regular use aimed at protecting children from malaria.

Abstract Background Identification of high-risk malaria foci can help enhance surveillance or control activities in regions where they are most needed. Associations between malaria risk and land-use/land-cover are well-recognized, but these environmental characteristics are closely interrelated with the land's topography (e.g., hills, valleys, elevation), which also influences malaria risk strongly. Parsing the individual contributions of land-cover/land-use variables to malaria risk requires examining these associations in the context of their topographic landscape. This study examined whether environmental factors like land-cover, land-use, and urban density improved malaria risk prediction based solely on the topographically-determined context, as measured by the topographic wetness index. Methods The topographic wetness index, an estimate of predicted water accumulation in a defined area, was generated from a digital terrain model of the landscape surrounding households in two neighbouring western Kenyan highland communities. Variables determined to best encompass the variance in this topographic wetness surface were calculated at a household level. Land-cover/land-use information was extracted from a high-resolution satellite image using an object-based classification method. Topographic and land-cover variables were used individually and in combination to predict household-level malaria in the communities through an iterative split-sample model fitting and testing procedure. Models with only topographic variables were compared to those with additional predictive factors related to land-cover/land-use to investigate whether these environmental factors improved prediction of malaria based on the shape of the land alone. Results Variables related to topographic wetness proved most useful in predicting the households of individuals contracting malaria in this region of rugged terrain. Other variables related to human modification of the environment also demonstrated clear associations with household malaria. However, these land-cover/land-use variables failed to produce unambiguous improvements in statistical predictive models controlling for important topographic factors, with none improving prediction of household-level malaria more than 75% of the time. Conclusions Topographic wetness values in this region of highly varied terrain more accurately predicted houses at greater risk of malaria than did consideration of land-cover/land-use characteristics. As such, those planning control or local elimination strategies in similar highland regions may use topographic and geographic characteristics to effectively identify high-receptivity regions that may require enhanced vigilance.

Abstract Background Metalloproteinase inhibitors can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Matrix metalloproteinase-9 (MMP-9) has been implicated, but it is not clear if other MMPs are also involved, including matrilysin/MMP-7 – an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression. Results Here we report that MMP-7-deficient (mmp7-/-) mice on the C57Bl/6 background are resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG). Brain sections from MOG-primed mmp7-/-mice did not show signs of immune cell infiltration of the CNS, but MOG-primed wild-type mice showed extensive vascular cuffing and mononuclear cell infiltration 15 days after vaccination. At the peak of EAE wild-type mice had MMP-7 immuno-reactive cells in vascular cuffs that also expressed the macrophage markers Iba-1 and Gr-1, as well as tomato lectin. MOG-specific proliferation of splenocytes, lymphocytes, CD4+ and CD8+ cells were reduced in cells isolated from MOG-primed mmp7-/- mice, compared with MOG-primed wild-type mice. However, the adoptive transfer of splenocytes and lymphocytes from MOG-primed mmp7-/- mice induced EAE in naïve wild-type recipients, but not naïve mmp7-/- recipients. Finally, we found that recombinant MMP-7 increased permeability between endothelial cells in an in vitro blood-brain barrier model. Conclusion Our findings suggest that MMP-7 may facilitate immune cell access or re-stimulation in perivascular areas, which are critical events in EAE and multiple sclerosis, and provide a new therapeutic target to treat this disorder.

Abstract Background Malaria is an important public-health problem in the archipelago of Vanuatu and climate has been hypothesized as important influence on transmission risk. Beginning in 1988, a major intervention using insecticide-treated bed nets (ITNs) was implemented in the country in an attempt to reduce Plasmodium transmission. To date, no study has addressed the impact of ITN intervention in Vanuatu, how it may have modified the burden of disease, and whether there were any changes in malaria incidence that might be related to climatic drivers. Methods and findings Monthly time series (January 1983 through December 1999) of confirmed Plasmodium falciparum and Plasmodium vivax infections in the archipelago were analysed. During this 17 year period, malaria dynamics underwent a major regime shift around May 1991, following the introduction of bed nets as a control strategy in the country. By February of 1994 disease incidence from both parasites was reduced by at least 50%, when at most 20% of the population at risk was covered by ITNs. Seasonal cycles, as expected, were strongly correlated with temperature patterns, while inter-annual cycles were associated with changes in precipitation. Following the bed net intervention, the influence of environmental drivers of malaria dynamics was reduced by 30–80% for climatic forces, and 33–54% for other factors. A time lag of about five months was observed for the qualitative change ("regime shift") between the two parasites, the change occurring first for P. falciparum. The latter might be explained by interspecific interactions between the two parasites within the human hosts and their distinct biology, since P. vivax can relapse after a primary infection. Conclusion The Vanuatu ITN programme represents an excellent example of implementing an infectious disease control programme. The distribution was undertaken to cover a large, local proportion (~80%) of people in villages where malaria was present. The successful coverage was possible because of the strategy for distribution of ITNs by prioritizing the free distribution to groups with restricted means for their acquisition, making the access to this resource equitable across the population. These results emphasize the need to implement infectious disease control programmes focusing on the most vulnerable populations.

Abstract Background Urban malaria is likely to become increasingly important as a consequence of the growing proportion of Africans living in cities. A novel sampling strategy was developed for urban areas to generate a sample simultaneously representative of population and inhabited environments. Such a strategy should facilitate analysis of important epidemiological relationships in this ecological context. Methods Census maps and summary data for Kisumu, Kenya, were used to create a pseudo-sampling frame using the geographic coordinates of census-sampled structures. For every enumeration area (EA) designated as urban by the census (n = 535), a sample of structures equal to one-tenth the number of households was selected. In EAs designated as rural (n = 32), a geographically random sample totalling one-tenth the number of households was selected from a grid of points at 100 m intervals. The selected samples were cross-referenced to a geographic information system, and coordinates transferred to handheld global positioning units. Interviewers found the closest eligible household to the sampling point and interviewed the caregiver of a child aged < 10 years. The demographics of the selected sample were compared with results from the Kenya Demographic and Health Survey to assess sample validity. Results were also compared among urban and rural EAs. Results 4,336 interviews were completed in 473 of the 567 study area EAs from June 2002 through February 2003. EAs without completed interviews were randomly distributed, and non-response was approximately 2%. Mean distance from the assigned sampling point to the completed interview was 74.6 m, and was significantly less in urban than rural EAs, even when controlling for number of households. The selected sample had significantly more children and females of childbearing age than the general population, and fewer older individuals. Conclusion This method selected a sample that was simultaneously population-representative and inclusive of important environmental variation. The use of a pseudo-sampling frame and pre-programmed handheld GPS units is more efficient and may yield a more complete sample than traditional methods, and is less expensive than complete population enumeration.

Abstract Background Although sub-Saharan Africa (SSA) is rapidly urbanizing, the terms used to classify urban ecotypes are poorly defined in the context of malaria epidemiology. Lack of clear definitions may cause misclassification error, which likely decreases the accuracy of continent-wide estimates of malaria burden, limits the generalizability of urban malaria studies, and makes identification of high-risk areas for targeted interventions within cities more difficult. Accordingly, clustering techniques were applied to a set of urbanization- and malaria-related variables in Kisumu, Kenya, to produce a quantitative classification of the urban environment for malaria research. Methods Seven variables with a known or expected relationship with malaria in the context of urbanization were identified and measured at the census enumeration area (EA) level, using three sources: a) the results of a citywide knowledge, attitudes and practices (KAP) survey; b) a high-resolution multispectral satellite image; and c) national census data. Principal components analysis (PCA) was used to identify three factors explaining higher proportions of the combined variance than the original variables. A k-means clustering algorithm was applied to the EA-level factor scores to assign EAs to one of three categories: "urban," "peri-urban," or "semi-rural." The results were compared with classifications derived from two other approaches: a) administrative designation of urban/rural by the census or b) population density thresholds. Results Urban zones resulting from the clustering algorithm were more geographically coherent than those delineated by population density. Clustering distributed population more evenly among zones than either of the other methods and more accurately predicted variation in other variables related to urbanization, but not used for classification. Conclusion Effective urban malaria epidemiology and control would benefit from quantitative methods to identify and characterize urban areas. Cluster analysis techniques were used to classify Kisumu, Kenya, into levels of urbanization in a repeatable and unbiased manner, an approach that should permit more relevant comparisons among and within urban areas. To the extent that these divisions predict meaningful intra-urban differences in malaria epidemiology, they should inform targeted urban malaria interventions in cities across SSA.

Abstract Background Transmission of Plasmodium falciparum generally decreases with increasing elevation, in part because lower temperature slows the development of both parasites and mosquitoes. However, other aspects of the terrain, such as the shape of the land, may affect habitat suitability for Anopheles breeding and thus risk of malaria transmission. Understanding these local topographic effects may permit prediction of regions at high risk of malaria within the highlands at small spatial scales. Methods Hydrologic modelling techniques were adapted to predict the flow of water across the landscape surrounding households in two communities in the western Kenyan highlands. These surface analyses were used to generate indices describing predicted water accumulation in regions surrounding the study area. Households with and without malaria were compared for their proximity to regions of high and low predicted wetness. Predicted wetness and elevation variables were entered into bivariate and multivariate regression models to examine whether significant associations with malaria were observable at small spatial scales. Results On average, malaria case households (n = 423) were located 280 m closer to regions with very high wetness indices than non-malaria "control" households (n = 895) (t = 10.35, p < 0.0001). Distance to high wetness indices remained an independent predictor of risk after controlling for household elevation in multivariate regression (OR = 0.93 [95% confidence interval = 0.89–0.96] for a 100 m increase in distance). For every 10 m increase in household elevation, there was a 12% decrease in the odds of the house having a malaria case (OR = 0.88 [0.85–0.90]). However, after controlling for distance to regions of high predicted wetness and the community in which the house was located, this reduction in malaria risk was not statistically significant (OR = 0.98 [0.94–1.03]). Conclusion Proximity to terrain with high predicted water accumulation was significantly and consistently associated with increased household-level malaria incidence, even at small spatial scales with little variation in elevation variables. These results suggest that high wetness indices are not merely proxies for valley bottoms, and hydrologic flow models may prove valuable for predicting areas of high malaria risk in highland regions. Application in areas where malaria surveillance is limited could identify households at higher risk and help focus interventions.

Abstract Background Used alone, the MAS5.0 algorithm for generating expression summaries has been criticized for high False Positive rates resulting from exaggerated variance at low intensities. Results Here we show, with replicated cell line data, that, when used alongside detection calls, MAS5 can be both selective and sensitive. A set of differentially expressed transcripts were identified that were found to be changing by MAS5, but unchanging by RMA and GCRMA. Subsequent analysis by real time PCR confirmed these changes. In addition, with the Latin square datasets often used to assess expression summary algorithms, filtered MAS5.0 was found to have performance approaching that of its peers. Conclusion When used alongside detection calls, MAS5 is a sensitive and selective algorithm for identifying differentially expressed genes.

Abstract Background Malaria epidemics in highland areas of East Africa have caused considerable morbidity and mortality in the past two decades. Knowledge of "hotspot" areas of high malaria incidence would allow for focused preventive interventions in resource-poor areas, particularly if the hotspot areas can be discerned during non-epidemic periods and predicted by ecological factors. Methods To address this issue, spatial distribution of malaria incidence and the relationship of ecological factors to malaria incidence were assessed in the highland area of Kipsamoite, Kenya, from 2001–2004. Results Clustering of disease in a single geographic "hotspot" area occurred in epidemic and non-epidemic years, with a 2.6 to 3.2-fold increased risk of malaria inside the hotspot, as compared to outside the area (P < 0.001, all 4 years). Altitude and proximity to the forest were independently associated with increased malaria risk in all years, including epidemic and non-epidemic years. Conclusion In this highland area, areas of high malaria risk are consistent in epidemic and non-epidemic years and are associated with specific ecological risk factors. Ongoing interventions in areas of ecological risk factors could be a cost-effective method of significantly reducing malaria incidence and blunting or preventing epidemics, even in the absence of malaria early warning systems. Further studies should be conducted to see if these findings hold true in varied highland settings.

Abstract Background Methods for analyzing space-time variation in risk in case-control studies typically ignore residential mobility. We develop an approach for analyzing case-control data for mobile individuals and apply it to study bladder cancer in 11 counties in southeastern Michigan. At this time data collection is incomplete and no inferences should be drawn – we analyze these data to demonstrate the novel methods. Global, local and focused clustering of residential histories for 219 cases and 437 controls is quantified using time-dependent nearest neighbor relationships. Business address histories for 268 industries that release known or suspected bladder cancer carcinogens are analyzed. A logistic model accounting for smoking, gender, age, race and education specifies the probability of being a case, and is incorporated into the cluster randomization procedures. Sensitivity of clustering to definition of the proximity metric is assessed for 1 to 75 k nearest neighbors. Results Global clustering is partly explained by the covariates but remains statistically significant at 12 of the 14 levels of k considered. After accounting for the covariates 26 Local clusters are found in Lapeer, Ingham, Oakland and Jackson counties, with the clusters in Ingham and Oakland counties appearing in 1950 and persisting to the present. Statistically significant focused clusters are found about the business address histories of 22 industries located in Oakland (19 clusters), Ingham (2) and Jackson (1) counties. Clusters in central and southeastern Oakland County appear in the 1930's and persist to the present day. Conclusion These methods provide a systematic approach for evaluating a series of increasingly realistic alternative hypotheses regarding the sources of excess risk. So long as selection of cases and controls is population-based and not geographically biased, these tools can provide insights into geographic risk factors that were not specifically assessed in the case-control study design.

Abstract Background Thyroid hormone plays a crucial role in the growth and function of the central nervous system. The purpose of the study was to examine the relationships between the status of subclinical thyroid conditions and cognition among adolescents in the United States. Methods Study sample included 1,327 adolescents 13 to 16 years old who participated in the Third National Health and Nutrition Examination Survey (NHANES III). Serum thyroxine (T4) and thyroid stimulating hormone (TSH) were measured and subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid groups were defined. Cognitive performance was assessed using the subscales of the Wide Range Achievement Test-Revised (WRAT-R) and the Wechsler Intelligence Scale for Children-Revised (WISC-R). The age-corrected scaled scores for arithmetic, reading, block design, and digit span were derived from the cognitive assessments. Results Subclinical hypothyroidism was found in 1.7% and subclinical hyperthyroidism was found in 2.3% of the adolescents. Cognitive assessment scores on average tended to be lower in adolescents with subclinical hyperthyroidism and higher in those with subclinical hypothyroidism than the score for the euthyroid group. Adolescents with subclinical hypothyroidism had significantly better scores in block design and reading than the euthyroid subjects even after adjustment for a number of variables including sex, age, and family income level. Conclusion Subclinical hypothyroidism was associated with better performance in some areas of cognitive functions while subclinical hyperthyroidism could be a potential risk factor.