Inference of disease associations with unmeasured genetic variants by combining results from genome-wide association studies with linkage disequilibrium patterns in a reference data set

Results from whole-genome association studies of many common diseases are now available. Increasingly, these are being incorporated into meta-analyses to increase the power to detect weak associations with measured single-nucleotide polymorphisms (SNPs). Imputation of genotypes at unmeasured loci has been widely applied using patterns of linkage disequilibrium (LD) observed in the HapMap panels, but there is a need for alternative methods that can utilize the pooled effect estimates from meta-analyses and explore possible associations with SNPs and haplotypes that are not included in HapMap

Scorpion Biodiversity and Interslope Divergence at “Evolution Canyon”, Lower Nahal Oren Microsite, Mt. Carmel, Israel

BACKGROUND: Local natural laboratories, designated by us as the "Evolution Canyon" model, are excellent tools to study regional and global ecological dynamics across life. They present abiotic and biotic contrasts locally, permitting the pursuit of observations and experiments across diverse taxa sharing sharp microecological subdivisions. Higher solar radiation received by the "African savannah-like" south-facing slopes (AS) in canyons north of the equator than by the opposite "European maquis-like" north-facing slopes (ES) is associated with higher abiotic stress. Scorpions are a suitable taxon to study interslope biodiversity differences, associated with the differences in abiotic factors (climate, drought), due to their ability to adapt to dry environments. METHODOLOGY/PRINCIPAL FINDINGS: Scorpions were studied by the turning stone method and by UV light methods. The pattern observed in scorpions was contrasted with similar patterns in several other taxa at the same place. As expected, the AS proved to be significantly more speciose regarding scorpions, paralleling the interslope patterns in taxa such as lizards and snakes, butterflies (Rhopalocera), beetles (families Tenebrionidae, Dermestidae, Chrysomelidae), and grasshoppers (Orthoptera). CONCLUSIONS/SIGNIFICANCE: Our results support an earlier conclusion stating that the homogenizing effects of migration and stochasticity are not able to eliminate the interslope intra- and interspecific differences in biodiversity despite an interslope distance of only 100 m at the "EC" valley bottom. In our opinion, the interslope microclimate selection, driven mainly by differences in insolance, could be the primary factor responsible for the observed interslope pattern

A Systematic Review and Evidence Synthesis of Non-Medical Triage, Self-Referral and Direct Access Services for Patients with Musculoskeletal Pain.

Introduction The demand for musculoskeletal (MSK) care is rising, and is a growing challenge for general practice. Direct access to physiotherapy and other healthcare services may offer appropriate care for MSK pain patients but there is uncertainty regarding the effectiveness or efficiency of this approach in practice. This study aimed to review the evidence regarding characteristics, outcomes, barriers and facilitators of MSK triage and direct access services. Methods A comprehensive search of eight databases (including MEDLINE, EMBASE, and Cochrane library) up to February 2018 was conducted to identify studies (trials, cohorts and qualitative evidence) on direct access services for MSK in primary care settings. Using predefined inclusion and exclusion criteria, titles, abstracts, and subsequent full texts were independently screened by reviewers. Methodological quality of eligible studies was assessed using the mixed methods appraisal tool, and extracted data regarding study characteristics and results were independently reviewed. A narrative synthesis and grading of evidence was undertaken. Approaches to MSK triage and direct access were profiled along with their respective outcomes of care relating to patient-oriented and socioeconomic outcomes. Barriers and facilitators of each model of direct access services were also highlighted. Results 9010 unique citations were screened, of which 26 studies were eligible. Three approaches (open access, combination and service pathway models) to MSK triage and direct access shared similar goals but were heterogeneous in application. MSK patients using direct access showed largely similar characteristics (age, sex and duration of symptoms) compared to GP-led care, although they were often younger, slightly more educated and with better socio-economic status than patients seen through GP-led care. Although many studies showed limitations in design or methods, outcomes of care (patient oriented outcomes of pain, and disability) did not show large differences between direct access and GP-led care. In most studies direct access patients were reported to have lower healthcare utilisation (fewer physiotherapy or GP consultations, analgesics or muscle relaxants prescriptions, or imaging procedures) and less time off work compared to GP-led care. Discussion This study provides insight into the current state of evidence regarding MSK triage and direct access services and highlights potential implications for future research, healthcare services planning, resource utilisation and organising care for MSK patients in primary care. There is consistent, although limited, evidence to suggest that MSK triage and direct access services lead to comparable clinical outcomes with lower healthcare consumption, and can help to manage GP workload. However, due to the paucity of strong empirical data from methodologically robust studies, a scale up and widespread roll out of direct access services cannot as yet be assumed to result in long term health and socio-economic gains

Conglobation in the Pill Bug, Armadillidium vulgare, as a Water Conservation Mechanism

Water balance of the terrestrial isopod, Armadillidium vulgare, was investigated during conglobation (rolling-up behavior). Water loss and metabolic rates were measured at 18 ± 1°C in dry air using flow-through respirometry. Water-loss rates decreased 34.8% when specimens were in their conglobated form, while CO2 release decreased by 37.1%. Water loss was also measured gravimetrically at humidities ranging from 6 to 75 %RH. Conglobation was associated with a decrease in water-loss rates up to 53 %RH, but no significant differences were observed at higher humidities. Our findings suggest that conglobation behavior may help to conserve water, in addition to its demonstrated role in protection from predation

Validation of the modified Fresno Test: assessing physical therapists' evidence based practice knowledge and skills

<p>Abstract</p> <p>Background</p> <p>Health care educators need valid and reliable tools to assess evidence based practice (EBP) knowledge and skills. Such instruments have yet to be developed for use among physical therapists. The Fresno Test (FT) has been validated only among general practitioners and occupational therapists and does not assess integration of research evidence with patient perspectives and clinical expertise. The purpose of this study was to develop and validate a modified FT to assess EBP knowledge and skills relevant to physical therapist (PT) practice.</p> <p>Methods</p> <p>The FT was modified to include PT-specific content and two new questions to assess integration of patient perspectives and clinical expertise with research evidence. An expert panel reviewed the test for content validity. A cross-sectional cohort representing three training levels (EBP-novice students, EBP-trained students, EBP-expert faculty) completed the test. Two blinded raters, not involved in test development, independently scored each test. Construct validity was assessed through analysis of variance for linear trends among known groups. Inter and intra-rater reliability, internal consistency, item discrimination index, item total correlation, and difficulty were analyzed.</p> <p>Results</p> <p>Among 108 participants (31 EBP-novice students, 50 EBP-trained students, and 27 EBP-expert faculty), there was a statistically significant (p < 0.0001) difference in total score corresponding to training level. Total score reliability and psychometric properties of items modified for discipline-specific content were excellent [inter-rater (ICC (2,1)] = 0.91); intra-rater (ICC (2,1)] = 0.95, 0.96)]. Cronbach's α was 0.78. Of the two new items, only one had strong psychometric properties.</p> <p>Conclusions</p> <p>The 13-item modified FT presented here is a valid, reliable assessment of physical therapists' EBP knowledge and skills. One new item assesses integration of patient perspective as part of the EBP model. Educators and researchers may use the 13-item modified FT to evaluate PT EBP curricula and physical therapists' EBP knowledge and skills.</p

The Pheromone of the Cave Cricket, Hadenoecus cumberlandicus, Causes Cricket Aggregation but Does Not Attract the Co-Distributed Predatory Spider, Meta ovalis

Food input by the cave cricket, Hadenoecus cumberlandicus Hubble & Norton (Orthoptera: Rhaphidophoridae), is vital to the cave community, making this cricket a true keystone species. Bioassays conducted on cave walls and in the laboratory show that clustering in H. cumberlandicus is guided by a pheromone, presumably excreta. This aggregation pheromone was demonstrated by using filter paper discs that had previous adult H. cumberlandicus exposure, resulting in > 70% response by either nymphs or adults, prompting attraction (thus, active component is a volatile), followed by reduced mobility (arrestment) on treated surfaces. Adults were similarly responsive to pheromone from nymphs, agreeing with mixed stage composition of clusters in the cave. Effects of [0.001M – 0.1M] uric acid (insect excreta's principle component) on H. cumberlandicus behavior were inconsistent. This pheromone is not a host cue (kairomone) and is not used as a repellent (allomone) as noted through lack of responses to natural H. cumberlandicus pheromone and uric acid concentrations by a co-occurring predatory cave orb weaver spider, Meta ovalis Gertsch (Araneae: Tetragnathidae). This pheromone is not serving as a sex pheromone because nymphs were affected by it and because this population of H. cumberlandicus is parthenogenic. The conclusion of this study is that the biological value of the aggregation pheromone is to concentrate H. cumberlandicus in sheltered sites in the cave conducive for minimizing water stress. Rather than signaling H. cumberlandicus presence and quality, the reduced mobility expressed as a result of contacting this pheromone conceivably may act as a defense tactic (antipredator behavior) against M. ovalis, which shares this favored habitat site

The bashful and the boastful : prestigious leaders and social change in Mesolithic Societies

The creation and maintenance of influential leaders and authorities is one of the key themes of archaeological and historical enquiry. However the social dynamics of authorities and leaders in the Mesolithic remains a largely unexplored area of study. The role and influence of authorities can be remarkably different in different situations yet they exist in all societies and in almost all social contexts from playgrounds to parliaments. Here we explore the literature on the dynamics of authority creation, maintenance and contestation in egalitarian societies, and discuss the implications for our interpretation and understanding of the formation of authorities and leaders and changing social relationships within the Mesolithic

A Long Baseline Neutrino Oscillation Experiment Using J-PARC Neutrino Beam and Hyper-Kamiokande

Document submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresHyper-Kamiokande will be a next generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of Hyper-Kamiokande is the study of $CP$ asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this document, the physics potential of a long baseline neutrino experiment using the Hyper-Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis has been updated from the previous Letter of Intent [K. Abe et al., arXiv:1109.3262 [hep-ex]], based on the experience gained from the ongoing T2K experiment. With a total exposure of 7.5 MW $\times$ 10$^7$ sec integrated proton beam power (corresponding to $1.56\times10^{22}$ protons on target with a 30 GeV proton beam) to a $2.5$-degree off-axis neutrino beam produced by the J-PARC proton synchrotron, it is expected that the $CP$ phase $\delta_{CP}$ can be determined to better than 19 degrees for all possible values of $\delta_{CP}$, and $CP$ violation can be established with a statistical significance of more than $3\,\sigma$ ($5\,\sigma$) for $76$ ($58$) of the $\delta_{CP}$ parameter space

CD103 Deficiency Prevents Graft-versus-Host Disease but Spares Graft-versus-Tumor Effects Mediated by Alloreactive CD8 T Cells

Graft-versus-host disease (GVHD) remains the main barrier to broader application of allogeneic hematopoietic stem cell transplantation (alloSCT) as a curative therapy for host malignancy. GVHD is mediated by allogeneic T cells directed against histocompatibility antigens expressed by host tissues. Based on previous studies, we postulated that the integrin CD103 is required for CD8-mediated GVHD, but not for graft-versus-tumor effects (GVT).We herein provide evidence in support of this hypothesis. To circumvent the potentially confounding influence of donor CD4 T cells, we developed an alloSCT model in which GVHD mortality is mediated by purified CD8 T cells. In this model, host-reactive CD8 T cells receive CD4 T cell help at the time of initial activation but not in the effector phase in which mature CD8 T effectors migrate into host tissues. We show that donor CD8 T cells from wild-type BALB/c mice primed to host alloantigens induce GVHD pathology and eliminate tumors of host origin in the absence of host CD4 T cells. Importantly, CD103 deficiency dramatically attenuated GVHD mortality, but had no detectable impact on the capacity to eliminate a tumor line of host origin. We provide evidence that CD103 is required for accumulation of donor CD8 T cells in the host intestinal epithelium but not in the tumor or host lymphoid compartments. Consistent with these data, CD103 was preferentially expressed by CD8 T cells infiltrating the host intestinal epithelium but not by those infiltrating the tumor, lamina propria, or lymphoid compartments. We further demonstrate that CD103 expression is not required for classic CD8 effector activities including cytokine production and cytotoxicity.These data indicate that CD103 deficiency inhibits GVHD pathology while sparing anti-tumor effects mediated by CD8 T cells, identifying CD103 blockade as an improved strategy for GVHD prophylaxis

The Composition of the Cuticular and Internal Free Fatty Acids and Alcohols from Lucilia sericata Males and Females

GC, GC–MS, and HPLC–LLSD analyses were used to identify and quantify cuticular and internal lipids in males and females of the blow-fly (Lucilia sericata). Sixteen free fatty acids, seven alcohols and cholesterol were identified and quantitatively determined in the cuticular lipids of L. sericata. Cuticular fatty acids ranged from C6 to C20 and included unsaturated entities such as 16:1n-9, 18:1n-9, 20:4n-3 and 20:5n-3. Cuticular alcohols (only saturated and even-numbered) ranged from C12 to C20 in males and C10 to C22 in females. Only one sterol was found in the cuticular lipids of both males and females. 23 free fatty acids, five alcohols and cholesterol were identified in the internal lipids. Internal fatty acids were present in large amounts—7.4 mg/g (female) and 10.1 mg/g (male). Only traces of internal alcohols (from C14 to C26 in males, from C14 to C22 in females) were found in L. sericata. Large amounts of internal cholesterol were identified in L. sericata males and females (0.49 and 0.97 mg/g of the insect body, respectively)