Subjective and objective measures of dryness symptoms in primary Sjögren's syndrome: capturing the discrepancy

Objective: To develop a novel method for capturing the discrepancy between objective tests and subjective dryness symptoms (a sensitivity scale) and to explore predictors of dryness sensitivity. Methods: Archive data from the UK Primary Sjögren's Syndrome Registry (n = 688) were used. Patients were classified on a scale from −5 (stoical) to +5 (sensitive) depending on the degree of discrepancy between their objective and subjective symptoms classes. Sensitivity scores were correlated with demographic variables, disease-related factors, and symptoms of pain, fatigue, anxiety, and depression. Results: Patients were on average relatively stoical for both types of dryness symptoms (mean ± SD ocular dryness −0.42 ± 2.2 and −1.24 ± 1.6 oral dryness). Twenty-seven percent of patients were classified as sensitive to ocular dryness and 9% to oral dryness. Hierarchical regression analyses identified the strongest predictor of ocular dryness sensitivity to be self-reported pain and that of oral dryness sensitivity to be self-reported fatigue. Conclusion: Ocular and oral dryness sensitivity can be classified on a continuous scale. The 2 symptom types are predicted by different variables. A large number of factors remain to be explored that may impact symptom sensitivity in primary Sjögrenʼs syndrome, and the proposed method could be used to identify relatively sensitive and stoical patients for future studies

Current understanding in climbing psychophysiology research

The sport of rock climbing places a significant physiological and psychological load on participants. Psychophysiological analysis provides a unique insight into affective states arising from the demands of climbing, and the impact that they have on performance. This review provides an overview of climbing psychophysiology research completed to date. To summarise, an on-sight lead ascent of a route elicits the greatest psychophysiological response in climbers; whilst, a red-point top-rope ascent produces the least. The affects of climbing stimuli on an individual’s performance appear to be conditional on their experience. In general, experienced climbers show superior performance and are less anxious than their less practiced counterparts, with significantly lower cognitive and somatic anxiety, increased self-confidence and lower values of the steroid stress hormone cortisol. It is likely that the experience-stressor-performance relationship is due to advanced climbers’ greater understanding of the risks associated with the sport, their habituation to the stressors gained through practice and their ability to perform well with higher levels of anxiety. This review outlines pertinent psychological climbing stimuli, summarise current methodologies and presents a detailed review of climbing psychophysiology research. It also concludes with suggestions for improving the depth and breadth of future research, including the need for the refinement of existing measures

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families

How non-native English-speaking staff are evaluated in linguistically diverse organizations: A sociolinguistic perspective

The aim of this paper is to examine the effects of evaluations of non-native speaking staff?s spoken English in international business settings. We adopt a sociolinguistic perspective on power and inequalities in linguistically diverse organizations in an Anglophone environment. The interpretive qualitative study draws on 54 interviews with non-native English-speaking staff in 19 UK business schools. We analyze, along the dimensions of status, solidarity and dynamism, the ways in which non-native speakers, on the basis of their spoken English, are evaluated by themselves and by listeners. We show how such evaluations refer to issues beyond the speaker?s linguistic fluency, and have consequences for her or his actions. The study contributes to the literature on language and power in international business through offering fine-grained insights into and elucidating how the interconnected evaluative processes impact the formation and perpetuation of organizational power relations and inequalities. It also puts forward implications for managing the officially monolingual, yet linguistically diverse organizations

The biology of inequalities in health: The LIFEPATH project

Socioeconomic differences in health have been consistently observed worldwide. Physical health deteriorates more rapidly with age among men and women with lower socioeconomic status (SES) than among those with higher SES. The biological processes underlying these differences are best understood by adopting a life course approach. In this paper we introduce the pan- European LIFEPATH project which uses multiple cohorts - including biomarker data - to investigate ageing as a phenomenon with two broad stages across life: build-up and decline. The ‘build-up’ stage, from conception and early intra-uterine life to late adolescence or early twenties, is characterised by rapid successions of developmentally and socially sensitive periods. The second stage, starting in early adulthood, is a period of ‘decline’ from maximum attained health to loss of function, overt disease and death. LIFEPATH adopts a study design that integrates social science and public health approaches with biology (including molecular epidemiology), using well-characterised population cohorts and omics measurements (particularly epigenomics). LIFEPATH includes information and biological samples from 17 cohorts, including several with extensive phenotyping and repeat biological samples, and a very large cohort (1 million individuals) without biological samples (WHIP, from Italy). The countries that are covered by the cohorts are France, Italy, Portugal, Ireland, UK, Finland, Switzerland and Australia. These cohorts are only a small proportion of all cohorts available in Europe, but we have chosen them for the combination of good measures of socioeconomic status, risk factors for non-communicable diseases (NCDs) and biomarkers already measured (or availability of blood samples for further testing). The majority of cohorts include ‘hard’ outcomes (diabetes, cancer, Cardiovascular Disease (CVD), total mortality), and the extensively phenotyped cohorts also include several measurements of the functional components of healthy ageing, including frailty, impaired vision, cognitive function, renal and brain function, osteoporosis, sleep disturbances and mental health. All age groups are represented with two birth cohorts, one cohort of adolescents and several cohorts encompassing young adults (age 18 and above). Furthermore, there is a strong representation of elderly subjects in seven cohorts. The specific objectives of the project are: (a) to show that healthy ageing is an achievable goal for society; (b) to improve the understanding of the mechanisms through which healthy ageing pathways diverge by SES, by investigating life course biological pathways using omic technologies; (c) to examine the consequences of the current economic recession on health and the biology of ageing (and the consequent increase in social inequalities); (d) to provide updated, relevant and innovative evidence for healthy ageing policies (particularly ‘health in all policies’) using both observational studies and an experimental approach based on a reanalysis of data from a ‘conditional cash transfer’ randomised experiment in New York and new data collected as part of an earned income tax credit randomised experiment in Atlanta and New York. To achieve these objectives, data are used from three categories of studies: 1. national census-based followup data to obtain mortality by socioeconomic status; 2. cohorts with intense phenotyping and repeat biological samples; 3. large cohorts with biological samples. With these objectives and methodologies, LIFEPATH seeks to provide updated, relevant and innovative evidence to underpin future policies and strategies for the promotion of healthy ageing, targeted disease prevention and clinical interventions that address the issue of social disparities in ageing and the social determinants of health. The present paper describes the design and some initial results of LIFEPATH as an example of the integration of social and biological sciences to provide evidence for public health policies

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Allostatic load and subsequent all-cause mortality: which biological markers drive the relationship? Findings from a UK birth cohort

The concept of allostatic load (AL) refers to the idea of a global physiological ‘wear and tear’ resulting from the adaptation to the environment through the stress response systems over the life span. The link between socioeconomic position (SEP) and mortality has now been established, and there is evidence that AL may capture the link between SEP and mortality. In order to quantitatively assess the role of AL on mortality, we use data from the 1958 British birth cohort including eleven year mortality in 8,113 adults. Specifically, we interrogate the hypothesis of a cumulative biological risk (allostatic load) reflecting 4 physiological systems potentially predicting future risk of death (N = 132). AL was defined using 14 biomarkers assayed in blood from a biosample collected at 44 years of age. Cox proportional hazard regression analysis revealed that higher allostatic load at 44 years old was a significant predictor of mortality 11 years later [HR = 3.56 (2.3 to 5.53)]. We found that this relationship was not solely related to early-life SEP, adverse childhood experiences and young adulthood health status, behaviours and SEP [HR = 2.57 (1.59 to 4.15)] . Regarding the ability of each physiological system and biomarkers to predict future death, our results suggest that the cumulative measure was advantageous compared to evaluating each physiological system sub-score and biomarker separately. Our findings add some evidence of a biological embodiment in response to stress which ultimately affects mortality

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)