EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma.
Squamous cell carcinoma (SCC) and malignant pleural mesothelioma (MPM) are thoracic malignancies with very poor prognosis and limited treatment options. It is an established fact that most of the solid tumors have overexpression of EPHA2 receptor tyrosine kinase. EPHA2 is known to exhibit opposing roles towards cancer progression. It functions in inhibiting cancer survival and migration via a ligand and tyrosine kinase dependent signaling (Y772). Whereas it is known to promote tumor progression and cell migration through a ligand-independent signaling (S897). We analyzed the expression profile and mutational status of the ephrin receptor A2 (EPHA2) in SCC and MPM cell lines and primary patient specimens. The EPHA2 receptor was found to be either overexpressed, mutated or amplified in SCC and MPM. In particular, the EPHA2 mutants A859D and T647M were interesting to explore, A859D Y772 dead mutant exhibited lower levels of phosphorylation at Y772 compared to T647M mutant. Molecular Dynamics simulations studies suggested that differential changes in conformation might form the structural basis for differences in the level of EPHA2 activation. Consequently, A859D mutant cells exhibited increased proliferation as well as cell migration compared to controls and T647M mutant. Kinomics analysis demonstrated that the STAT3 and PDGF pathways were upregulated whereas signaling through CBL was suppressed. Considered together, the present work has uncovered the oncogenic characteristics of EPHA2 mutations in SSC and MPM reinstating the dynamics of different roles of EPHA2 in cancer. This study also suggests that a combination of doxazosin and other EPHA2 inhibitors directed to inhibit the pertinent signaling components may be a novel therapeutic strategy for MPM and Non-small cell lung cancer patients who have either EPHA2 or CBL alterations.


Interactions between silica particles in the presence of multivalent coions.
Forces between charged silica particles in solutions of multivalent coions are measured with colloidal probe technique based on atomic force microscopy. The concentration of 1 : z electrolytes is systematically varied to understand the behavior of electrostatic interactions and double-layer properties in these systems. Although the coions are multivalent the Derjaguin, Landau, Verwey, and Overbeek (DLVO) theory perfectly describes the measured force profiles. The diffuse-layer potentials and regulation properties are extracted from the forces profiles by using the DLVO theory. The dependencies of the diffuse-layer potential and regulation parameter shift to lower concentration with increasing coion valence when plotted as a function of concentration of 1 : z salt. Interestingly, these profiles collapse to a master curve if plotted as a function of monovalent counterion concentration.


IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors.
Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction. Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the challenges facing direct kinase inhibition in cancer. MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1), assemble pathway kinases to affect signal transmission, and disrupting scaffold function therefore offers an orthogonal approach to MAPK cascade inhibition. Consistent with this, we found a requirement for IQGAP1 in RAS-driven tumorigenesis in mouse and human tissue. In addition, the ERK1/2-binding IQGAP1 WW domain peptide disrupted IQGAP1-ERK1/2 interactions, inhibited RAS- and RAF-driven tumorigenesis, bypassed acquired resistance to the BRAF inhibitor vemurafenib (PLX-4032) and acted as a systemically deliverable therapeutic to significantly increase the lifespan of tumor-bearing mice. Scaffold-kinase interaction blockade acts by a mechanism distinct from direct kinase inhibition and may be a strategy to target overactive oncogenic kinase cascades in cancer.


Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial.
Accumulation of iron in excess of physiologic requirements has been implicated in risk of cardiovascular disease because of increased iron-catalyzed free radical-mediated oxidative stress. To test the hypothesis that reducing body iron stores through phlebotomy will influence clinical outcomes in a cohort of patients with symptomatic peripheral arterial disease (PAD). Multicenter, randomized, controlled, single-blinded clinical trial based on the Iron (Fe) and Atherosclerosis Study (FeAST) (VA Cooperative Study #410) and conducted between May 1, 1999, and April 30, 2005, within the Department of Veterans Affairs Cooperative Studies Program and enrolling 1277 patients with symptomatic but stable PAD. Those with conditions likely to cause acute-phase increase of the ferritin level or with a diagnosis of visceral malignancy within the preceding 5 years were excluded. Analysis was by intent-to-treat. Patients were assigned to a control group (n = 641) or to a group undergoing reduction of iron stores by phlebotomy with removal of defined volumes of blood at 6-month intervals (avoiding iron deficiency) (n = 636), stratified by hospital, age, and baseline smoking status, diagnosis of diabetes mellitus, ratio of high-density to low-density lipoprotein cholesterol level, and ferritin level. The primary end point was all-cause mortality; the secondary end point was death plus nonfatal myocardial infarction and stroke. There were no significant differences between treatment groups for the primary or secondary study end points. All-cause deaths occurred in 148 patients (23%) in the control group and in 125 (20%) in the iron-reduction group (hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.67-1.08; P = .17). Death plus nonfatal myocardial infarction and stroke occurred in 205 patients (32%) in the control group and in 180 (28%) in the iron-reduction group (HR, 0.88; 95% CI, 0.72-1.07; P = .20). Reduction of body iron stores in patients with symptomatic PAD did not significantly decrease all-cause mortality or death plus nonfatal myocardial infarction and stroke. Clinicaltrials.gov Identifier: NCT00032357.


The effect of soil properties on the toxicity and bioaccumulation of Ag nanoparticles and Ag ions in Enchytraeus crypticus.
Standard natural Lufa soils (2.2, 2.3 and 5M) with different organic carbon contents (0.67-1.61%) and pHCaCl2 (5.5-7.3) were spiked with ionic Ag (AgNO3) and polyvinyl pyrrolidone (AgNP-PVP) and citrate (AgNP-Cit) coated Ag nanoparticles (NPs). Enchytraeus crypticus were exposed for 21 days to assess effects on survival and reproduction. Soil, pore water and animals were analyzed for Ag. AgNP-Cit had a strong increasing effect on soil pH, leading to high enchytraeid mortality at concentrations higher than 60-100mg Ag/kg dry soil which made it impossible to determine the influence of soil properties on its toxicity. LC50s were lower for AgNO3 than for AgNP-PVP (92-112 and 335-425mg Ag/kg dry soil, respectively) and were not affected by soil properties. AgNO3 and AgNP-PVP had comparable reproductive toxicity with EC50s of 26.9-75.2 and 28.2-92.3mg Ag/kg dry soil, respectively; toxicity linearly increased with decreasing organic carbon content of the soils but did not show a clear effect of soil pH. Ag uptake in the enchytraeids was higher at higher organic carbon content, but could not explain differences in toxicity between soils. This study indicates that the bioavailability of both ionic and nanoparticulate Ag is mainly affected by soil organic carbon, with little effect of soil pH.


Association of Breastfeeding and Child IQ Score at Age 5 Years.
To evaluate whether breastfeeding and its duration are associated with a reduced risk of low IQ scores or other neurodevelopmental problems. We conducted a secondary analysis of two parallel multicenter, double-blinded randomized controlled trials in which participants with a singleton pregnancy and either subclinical hypothyroidism or hypothyroxinemia were treated with thyroxine or placebo. Our primary outcome was a low IQ score (less than 85 on the WPPSI-III [Wechsler Preschool and Primary Scale of Intelligence III] at age 5 years). Secondary outcomes included performance measures on other validated neurodevelopmental tests. Univariable and multivariable analyses were performed to evaluate the association between breastfeeding and neurodevelopmental outcomes. Stepwise backward proceeding linear and logistic regression models were used to develop the final adjusted models. Of the 772 participants studied, 614 (80%) reported breastfeeding. Of these, 31% reported breastfeeding for less than 4 months, 19% for 4-6 months, 11% for 7-9 months, 15% for 10-12 months and 23% for more than 12 months. IQ scores were available for 756 children; mean age-5 scores were higher with any breastfeeding (96.7±15.1) than without (91.2±15.0, mean difference 5.5, 95% CI 2.8-8.2), and low IQ scores were less frequent with any breastfeeding (21.5%) than with no breastfeeding (36.2%, odds ratio 0.48, 95% CI 0.33-0.71). In adjusted analyses, breastfeeding remained associated with reduced odds of low IQ score (adjusted odds ratio [aOR] 0.62, 95% CI 0.41-0.93), and each additional month of breastfeeding was associated with lower odds of a low IQ scores (aOR 0.97, 95% CI 0.939-0.996). No significant associations between breastfeeding and other neurodevelopmental outcomes were identified in adjusted analyses. Breastfeeding and its duration are associated with lower odds of low IQ score at age 5 years.


Influence of perineal swellings on behavior and stress reaction in levonorgestrel implanted Macaca sylvanus females.
Contraceptives are common tools in controlling the reproductive physiology in primates. Levonorgestrel, a synthetic gestagen, can usually enable contraception and does not suppress the extension of perineal swellings. This study investigated the effects on intra-sexual behavior and fecal cortisol excretion rates in different swollen Barbary macaque females (N =24) during the non-reproductive phase of the year. The study was conducted on a semi-free population at Affenberg Salem (Germany). The results showed that females with reduced swellings received more aggressive encounters than females with enlarged perinea; whereas, at the same time the latter individuals have increased their active grooming interactions paralleled with decreased fecal cortisol excretion rates. No correlations were found between the perineal swelling size and the dominance rank, age, or implantation time of the females. This report shows that the rate of perineal swelling expression can modulate intra-sexual behavior and stress reactivity in levonorgestrel implanted Barbary macaque females. We conclude that large perineal swellings represent an influencing key factor in Barbary macaque females' social interactions, irrespective of whether these signals are shown naturally or induced biochemically.


Informational masking and auditory attention.
Informational masking is broadly defined as a degradation of auditory detection or discrimination of a signal embedded in a context of other similar sounds; it is not related to energetic masking caused by physical interactions between signal and masker. In this paper, we report a systematic release from informational masking of a target tone in a nine-tone rapid auditory sequence as the target is increasingly isolated in frequency or intensity from the remaining sequence components. Improved target-tone frequency difference limens as isolation increases are interpreted as a reflection of increasingly focused auditory attention. The change from diffuse to highly focused attention is gradual over the frequency and intensity ranges examined, with each 1-dB increment in target intensity relative to the remaining components producing performance improvements equivalent to those produced by a 2% increase in frequency isolation. The results are modeled as bands of attention in the frequency and intensity domains. For attention directed by frequency isolation, there is a strong correspondence with auditory filters predicted by the power spectrum model of masking. These data also support the existence of an attention band of intensity, with a bandwidth of about 5-7 dB at the moderate levels used in this experiment.


Well-being and affective style: neural substrates and biobehavioural correlates.
One of the most salient features of emotion is the pronounced variability among individuals in their reactions to emotional incentives and in their dispositional mood. Collectively, these individual differences have been described as affective style. Recent research has begun to dissect the constituents of affective style. The search for these components is guided by the neural systems that instantiate emotion and emotion regulation. In this article, this body of research and theory is applied specifically to positive affect and well-being. The central substrates and peripheral biological correlates of well-being are described. A resilient affective style is associated with high levels of left prefrontal activation, effective modulation of activation in the amygdala and fast recovery in response to negative and stressful events. In peripheral biology, these central patterns are associated with lower levels of basal cortisol and with higher levels of antibody titres to influenza vaccine. The article concludes with a consideration of whether these patterns of central and peripheral biology can be modified by training and shifted toward a more salubrious direction.


Pulse oximetry in discharge decision-making: a survey of emergency physicians.
Our primary objective was to describe the pulse oximetry discharge thresholds used by general and pediatric emergency physicians for well-appearing children with bronchiolitis and pneumonia, and to assess the related practice variability. This mail-in survey was conducted in August and September 2001 and included the 281 active members of the Pediatric Emergency Medicine Section of the American College of Emergency Physicians. The survey consisted of 2 case scenarios of previously healthy, well-appearing children: a 2-year-old with pneumonia and a 10-month-old with bronchiolitis. Respondents were asked about their years of experience, teaching load, percentage of children in their practice, whether they currently have a written departmental guideline at their institution, and the lowest pulse oximetry reading that they would accept and still discharge the patient directly home. One hundred and eighty-two (65%) physicians answered the survey and met the inclusion criteria. The respondents' median oximetry value and interquartile range (IQR) for the pneumonia and bronchiolitis cases were 93% (92%-94%) and 94% (92%-94%) respectively. With the exception of the 3 physicians practising >1000 metres above sea level, the responses by subgroups were similar. There does not yet exist a safe, clinically validated pulse oximetry discharge threshold. Emergency physicians from this study sample have a modest degree of practice variability in a self-reported pulse oximetry discharge threshold. Emergency physicians may use this data to compare their own practice with that reported by this group.


The relationship between adiponectin, ageing and renal function in a bi-ethnic sample.
Ageing is associated with elevated adiponectin levels. Our aim was to assess whether age-related increase in adiponectin is associated with a decrease in renal function. The study comprised African (N=277) and Caucasian (N=326) men and women. Adiponectin levels, estimated creatinine clearance rate and obesity indices were determined. African men revealed significantly higher adiponectin levels compared to Caucasian men (p<0.01), reflecting the lower adiposity levels of the African men. No difference in obesity measures (p=0.92) and adiponectin levels (p=0.27) was observed between African and Caucasian women. A significant increase in adiponectin levels with ageing was observed in both African men and women (p<0.01). To the contrary, progressive ageing seems not to be significantly related to elevated adiponectin levels within Caucasians. Renal impairment decreased significantly within all of the groups (p<0.01). Single regression analyses performed in all specified groups revealed significant associations between adiponectin and estimated creatinine clearance, however a multiple regression model revealed that insulin resistance had the strongest association with adiponectin within all the groups. In conclusion, age-related rise in adiponectin levels observed in Africans may not be due to renal impairment.


The poplar Phi class glutathione transferase: expression, activity and structure of GSTF1.
Glutathione transferases (GSTs) constitute a superfamily of enzymes with essential roles in cellular detoxification and secondary metabolism in plants as in other organisms. Several plant GSTs, including those of the Phi class (GSTFs), require a conserved catalytic serine residue to perform glutathione (GSH)-conjugation reactions. Genomic analyses revealed that terrestrial plants have around ten GSTFs, eight in the Populus trichocarpa genome, but their physiological functions and substrates are mostly unknown. Transcript expression analyses showed a predominant expression of all genes both in reproductive (female flowers, fruits, floral buds) and vegetative organs (leaves, petioles). Here, we show that the recombinant poplar GSTF1 (PttGSTF1) possesses peroxidase activity toward cumene hydroperoxide and GSH-conjugation activity toward model substrates such as 2,4-dinitrochlorobenzene, benzyl and phenetyl isothiocyanate, 4-nitrophenyl butyrate and 4-hydroxy-2-nonenal but interestingly not on previously identified GSTF-class substrates. In accordance with analytical gel filtration data, crystal structure of PttGSTF1 showed a canonical dimeric organization with bound GSH or 2-(N-morpholino)ethanesulfonic acid molecules. The structure of these protein-substrate complexes allowed delineating the residues contributing to both the G and H sites that form the active site cavity. In sum, the presence of GSTF1 transcripts and proteins in most poplar organs especially those rich in secondary metabolites such as flowers and fruits, together with its GSH-conjugation activity and its documented stress-responsive expression suggest that its function is associated with the catalytic transformation of metabolites and/or peroxide removal rather than with ligandin properties as previously reported for other GSTFs.


Instantaneous venous return curves in an intact canine preparation.
The relationship between right atrial pressure (Pra) and venous return describes a venous return curve. Because changes in venous return and right ventricular stroke volume (SVRV) are similar during small tidal volume (VT) breathing, we compared the relationship of SVRV and Pra during positive-pressure ventilation (VT less than 10 ml/kg) in 17 pentobarbital-anesthetized, closed-chest, canine preparations. The SVRV-Pra relationship describes a straight line with a negative slope and a positive mean systemic pressure (Pms)-zero flow intercept (instantaneous Pms). Instantaneous Pms is similar to ventricular fibrillation-induced (stop-flow) Pms (8.1 +/- 0.8 vs. 8.4 +/- 0.7 mmHg, mean +/- SE). With volume infusion, both instantaneous and stop-flow Pms increase to a similar degree (R = 0.9014, P less than 0.001). The effect of opening an arteriovenous fistula is time dependent and variable between dogs, but by 30 s it is associated with an increase in instantaneous Pms (5.2 +/- 3.2 mmHg). Vascular compliance determined by adding and removing blood from the intravascular space displays a curvilinear hysteresis. The instantaneous venous return curve is affected by intravascular blood volume, vasomotor tone, and resistance to venous return. The relationship between SVRV and Pra during small VT breathing define instantaneous venous return curves similar to those described using right-heart bypass preparations.


The influence of immigrant status and concentration on psychiatric disorder in Canada: a multi-level analysis.
Many studies have reported an increased incidence of psychiatric disorder (particularly psychotic disorders) among first generation adult immigrants, along with an increasing risk for ethnic minorities living in low-minority concentration neighborhoods. These studies have depended mostly on European case-based databases. In contrast, North American studies have suggested a lower risk for psychiatric disorder in immigrants, although the effect of neighborhood immigrant concentration has not been studied extensively. Using multi-level modeling to disaggregate individual from area-level influences, this study examines the influence of first generation immigrant status at the individual level, immigrant concentration at the neighborhood-level and their combined effect on 12-month prevalence of mood, anxiety and substance-dependence disorders and lifetime prevalence of psychotic disorder, among Canadians. Individual-level data came from the Canadian Community Health Survey (CCHS) 1.2, a cross-sectional study of psychiatric disorder among Canadians over the age of 15 years; the sample for analysis was n=35,708. The CCHS data were linked with neighborhood-level data from the Canadian Census 2001 for multi-level logistic regression. Immigrant status was associated with a lower prevalence of psychiatric disorder, with an added protective effect for immigrants living in neighborhoods with higher immigrant concentrations. Immigrant concentration was not associated with elevated prevalence of psychiatric disorder among non-immigrants. The finding of lower 12-month prevalence of psychiatric disorder in Canadian immigrants, with further lessening as the neighborhood immigrant concentration increases, reflects a model of person-environment fit, highlighting the importance of studying individual risk factors within environmental contexts.


Shape and refractive powers in corneal topography.
To compare the relative advantages and disadvantages of four different representations of corneal power--identified as instantaneous, axial, position, and refractive--based on curvature, slope, coordinate position, and focal properties, respectively. The four types of corneal power were evaluated by examining their interrelationship for 12 hypothetical corneal shapes chosen to represent the general characteristics of regular, irregular, and surgically altered corneas. There is only a limited association between refractive power and the other three powers, which are based on shape properties. For corneal shapes represented by ellipsoids of low eccentricity (e), refractive power increased as a function of the distance from the reference axis, whereas axial and instantaneous powers were either constant (for e = 0) or decreased, with instantaneous power having the largest decrease. Refractive power decreased for elliptical corneal shapes with eccentricities greater than the reciprocal of the index of refraction, although always decreasing less than the axial or instantaneous power. For various corneal shapes formed by segments of circles (or a polynomial) with large differences in instantaneous power, the refractive power was more closely associated with axial than instantaneous or position powers. The Purkinje image measurements from videokeratograpy are most closely related to the slope-based axial power because it is slope that determines the direction of reflected rays forming the corneal image. Because of this direct connection, axial power is less sensitive to noise than is refractive, instantaneous, or position power. Present videokeratographs that report axial power provide an approximation of refractive power, but if an exact refractive power is needed it can be calculated easily. Instantaneous power provides the most sensitive measure of local curvature changes, such as those occurring in keratoconus or refractive surgery. There are unique practical applications for each of the four powers.


Addition of multiple limiting resources reduces grassland diversity.
Niche dimensionality provides a general theoretical explanation for biodiversity-more niches, defined by more limiting factors, allow for more ways that species can coexist. Because plant species compete for the same set of limiting resources, theory predicts that addition of a limiting resource eliminates potential trade-offs, reducing the number of species that can coexist. Multiple nutrient limitation of plant production is common and therefore fertilization may reduce diversity by reducing the number or dimensionality of belowground limiting factors. At the same time, nutrient addition, by increasing biomass, should ultimately shift competition from belowground nutrients towards a one-dimensional competitive trade-off for light. Here we show that plant species diversity decreased when a greater number of limiting nutrients were added across 45 grassland sites from a multi-continent experimental network. The number of added nutrients predicted diversity loss, even after controlling for effects of plant biomass, and even where biomass production was not nutrient-limited. We found that elevated resource supply reduced niche dimensionality and diversity and increased both productivity and compositional turnover. Our results point to the importance of understanding dimensionality in ecological systems that are undergoing diversity loss in response to multiple global change factors.


Genomic analysis of three Bifidobacterium species isolated from the calf gastrointestinal tract.
Ruminant animals contribute significantly to the global value of agriculture and rely on a complex microbial community for efficient digestion. However, little is known of how this microbial-host relationship develops and is maintained. To begin to address this, we have determined the ability of three Bifidobacterium species isolated from the faeces of newborn calves to grow on carbohydrates typical of a newborn ruminant diet. Genome sequences have been determined for these bacteria with analysis of the genomes providing insights into the host association and identification of several genes that may mediate interactions with the ruminant gastrointestinal tract. The present study provides a starting point from which we can define the role of potential beneficial microbes in the nutrition of young ruminants and begin to influence the interactions between the microbiota and the host. The differences observed in genomic content hint at niche partitioning among the bifidobacterial species analysed and the different strategies they employ to successfully adapt to this habitat.


Modeling enamel matrix secretion in mammalian teeth.
The most mineralized tissue of the mammalian body is tooth enamel. Especially in species with thick enamel, three-dimensional (3D) tomography data has shown that the distribution of enamel varies across the occlusal surface of the tooth crown. Differences in enamel thickness among species and within the tooth crown have been used to examine taxonomic affiliations, life history, and functional properties of teeth. Before becoming fully mineralized, enamel matrix is secreted on the top of a dentine template, and it remains to be explored how matrix thickness is spatially regulated. To provide a predictive framework to examine enamel distribution, we introduce a computational model of enamel matrix secretion that maps the dentine topography to the enamel surface topography. Starting from empirical enamel-dentine junctions, enamel matrix deposition is modeled as a diffusion-limited free boundary problem. Using laboratory microCT and synchrotron tomographic data of pig molars that have markedly different dentine and enamel surface topographies, we show how diffusion-limited matrix deposition accounts for both the process of matrix secretion and the final enamel distribution. Simulations reveal how concave and convex dentine features have distinct effects on enamel surface, thereby explaining why the enamel surface is not a straightforward extrapolation of the dentine template. Human and orangutan molar simulations show that even subtle variation in dentine topography can be mapped to the enamel surface features. Mechanistic models of extracellular matrix deposition can be used to predict occlusal morphologies of teeth.


Empathy Between Physician Assistant Students and Standardized Patients: Evidence of an Inflation Bias.
Empathic communication with patients is an essential component of quality primary care. This study examines the ability of physician assistant (PA) students to communicate empathically in clinical interviews with standardized patients. In their first year of training, PA students conducted 3 clinical interviews with standardized patients over a 6-month period in 2014, during the second half of their didactic year. Each interview was evaluated for empathy by 4 individuals: the students themselves, their standardized patients, their clinical instructors, and third-party observers. Students consistently rated their empathic abilities more favorably than did patients, clinical instructors, or observers, with mean differences ranging from 0.56 to 1.92 and averaging 1.09 on a 9-point scale. Students' evaluations were most dissimilar from those of patients (difference M = 1.12) and most similar to those of observers (difference M = 1.06). The assessments of all 4 raters varied over time: students rated themselves as significantly more empathic in April (time 2) than in July (time 3) of their didactic year. Patients rated students as significantly less empathic in January of the didactic year (time 1) than at time 2 and as significantly more empathic at time 2 than time 3. Instructors rated students as significantly less empathic at time 1 than at either time 2 or time 3. Finally, observers rated students as significantly more empathic at time 1 than at either time 2 or time 3. PA students consistently overestimate their empathic abilities during their first year of training. Given the importance of empathy in clinical care, increased didactic efforts focused on developing and conveying empathy may be warranted in PA education.


Characterizing the normal proteome of human ciliary body.
The ciliary body is the circumferential muscular tissue located just behind the iris in the anterior chamber of the eye. It plays a pivotal role in the production of aqueous humor, maintenance of the lens zonules and accommodation by changing the shape of the crystalline lens. The ciliary body is the major target of drugs against glaucoma as its inhibition leads to a drop in intraocular pressure. A molecular study of the ciliary body could provide a better understanding about the pathophysiological processes that occur in glaucoma. Thus far, no large-scale proteomic investigation has been reported for the human ciliary body. In this study, we have carried out an in-depth LC-MS/MS-based proteomic analysis of normal human ciliary body and have identified 2,815 proteins. We identified a number of proteins that were previously not described in the ciliary body including importin 5 (IPO5), atlastin-2 (ATL2), B-cell receptor associated protein 29 (BCAP29), basigin (BSG), calpain-1 (CAPN1), copine 6 (CPNE6), fibulin 1 (FBLN1) and galectin 1 (LGALS1). We compared the plasma proteome with the ciliary body proteome and found that the large majority of proteins in the ciliary body were also detectable in the plasma while 896 proteins were unique to the ciliary body. We also classified proteins using pathway enrichment analysis and found most of proteins associated with ubiquitin pathway, EIF2 signaling, glycolysis and gluconeogenesis. More than 95% of the identified proteins have not been previously described in the ciliary body proteome. This is the largest catalogue of proteins reported thus far in the ciliary body that should provide new insights into our understanding of the factors involved in maintaining the secretion of aqueous humor. The identification of these proteins will aid in understanding various eye diseases of the anterior segment such as glaucoma and presbyopia.


Temporal impact of the vascular wilt pathogen Verticillium dahliae on tomato root proteome.
The soil-borne fungus Verticillium dahliae is the causal agent of wilting disease and affects a wide range of plant species worldwide. Here, we report on the time-resolved analysis of the tomato root proteome in response to fungal colonization. Tomato (Solanum lycopersicum cv. Hildares) was inoculated with V. dahliae at the two-leaf stage and roots were harvested at 7, 14 and 21 days post inoculation (dpi). In order to identify proteins related to the fungal spread at the different time points, a subsequent proteome analysis by two-dimensional differential gel electrophoresis (2D-DIGE) was conducted on samples from three independent experiments. Hierarchical clustering and k-means clustering of identified proteins distinguished early and late responses to fungal colonization. The results underline that plant defense and adaptation responses are timely coordinated. Proteins involved in oxidative stress were down-regulated at 7 dpi but induced 21 dpi indicating versatile reactive oxygen species signaling interacting with salicylic acid defence signaling at that stage of infection. Drought-stress proteins were induced at 21 dpi, reflecting the beginning of wilting symptoms. Notably, two proteins involved in energy-generating pathways were induced throughout all sampling dates and may reflect the increase in metabolic activity to maintain root growth and, concurrently, activate defense responses. Mounting of defense responses requires a substantial flux of carbon and nitrogen from primary to secondary metabolites. In-depth understanding of these key metabolic pathways required for growth and defense responses, especially at proteome level, will allow the development of breeding strategies for crops where Verticillium tolerance is absent. Our data show early and late responses of tomato root proteins towards pathogen infection and identify primary metabolism enzymes affected by V. dahliae. Those proteins represent candidates for plant improvement.


Noise-induced hearing loss in a longitudinal study of Norwegian railway workers.
The aim of this study was to analyse longitudinal data to assess the risk of noise-induced hearing loss (NIHL) in Norwegian railway workers. Longitudinal. A major Norwegian railway company. We examined data from the first and last audiograms for the period 1991-2014, from 9640 railway workers with varying occupational noise exposure and with an average observation period of 10 years. The course of hearing acuity in seven groups of railway workers (train drivers, conductors, bus drivers, traffic controllers, train maintenance workers, track maintenance workers and others) were compared with each other and with ISO standards (ISO 1999). The change in hearing threshold during the observation period was 2-3 dB in the 0.5-4 kHz range and 6-7 dB in the 3-6 kHz range adjusted for age and sex, for all occupational groups, which is slightly less than expected (8 dB) according to ISO 1999. The risk of NIHL in Norwegian railway workers during the period 1991-2014 has been negligible.


Detection of isolated tumor cells in neuroblastoma by immunohistochemical analysis in bone marrow biopsy specimens: improved detection with use of beta-catenin.
Evaluation of the bone marrow is a critical component of accurate staging and surveillance for recurrent disease in neuroblastoma. The value of routine immunohistochemical analysis of otherwise histologically negative bone marrow biopsy specimens has not been adequately evaluated. By using synaptophysin, chromogranin, and beta-catenin, immunohistochemical analysis performed on otherwise histologically negative bone marrow specimens identified isolated tumor cells (ITCs) in 9.1%, 5.0%, and 10.0% of 220 biopsy specimens, respectively. Overall survival, as estimated by the Kaplan-Meier method, was not significantly different between patients with and without ITCs (P = .357). Of the immunohistochemical markers evaluated, beta-catenin showed the greatest sensitivity for identifying ITCs in the bone marrow and showed reactivity in primary tumor samples. We found that the presence of ITCs identified by immunohistochemical analysis may predict the persistence of disease but does not show significant overall survival differences. We also identified beta-catenin as a sensitive immunohistochemical marker of primary and metastatic neuroblastoma.


The treatment of severe atopic dermatitis in childhood with narrowband ultraviolet B phototherapy.
There is a lack of data regarding the use of narrowband ultraviolet B (NB-UVB) phototherapy in children with atopic dermatitis (AD). Many centres use this mode of treatment for children with AD; however, there have only been two previous studies observing the effect of NB-UVB in children with AD. We undertook a retrospective review of children with severe eczema who had undergone NB-UVB consecutively in our department between 1999 and 2005. All children with AD who had undergone NB-UVB consecutively in our department between 1999 and 2005 were identified from the phototherapy database. Their clinical notes were reviewed for information on age, sex, skin type, minimal erythema dose (MED), adjuvant therapy, previous therapy, adverse effects, number of exposures, cumulative dose, response to treatment and length of remission. In total, 50 children (83%) completed more than 10 exposures of NB-UVB. Complete clearance or minimal residual activity was achieved in 20 children (40%). A good improvement was achieved in a further 10 children (23%), and a moderate improvement in 13 (26%). Children with MEDs > 390 mJ/cm2 were more likely to clear, and this was found to be statistically significant (P = 0.02). Overall, the treatment was well tolerated and the median length of remission was 3 months. NB-UVB is an effective treatment for children with severe AD. Children with MEDs > 390 mJ/cm2 are more likely to clear. Further studies are needed to evaluate the efficacy of NB-UVB and long-term safety in treating children with severe AD.


Clustered star formation and the origin of stellar masses.
Star clusters are ubiquitous in galaxies of all types and at all stages of their evolution. We also observe them to be forming in a wide variety of environments, ranging from nearby giant molecular clouds to the supergiant molecular clouds found in starburst and merging galaxies. The typical star in our galaxy and probably in others formed as a member of a star cluster, so star formation is an intrinsically clustered and not an isolated phenomenon. The greatest challenge regarding clustered star formation is to understand why stars have a mass spectrum that appears to be universal. This review examines the observations and models that have been proposed to explain these fundamental issues in stellar formation.


Toxicity of Herbicide Mixtures to Tropical Freshwater Microalgae Using a Multispecies Test.
Agriculture within the Great Barrier Reef catchment area has contributed to pesticide contamination of adjacent freshwater ecosystems that flow into the Great Barrier Reef World Heritage Area. A novel multispecies toxicity test was used to assess the toxicity of diuron and hexazinone, 2 herbicides commonly detected within the Great Barrier Reef catchment area, to a community of 3 tropical freshwater microalgae: Monoraphidium arcuatum, Nannochloropsis-like sp., and Pediastrum duplex. Diuron was the most toxic herbicide, with 10% inhibition concentration (IC10) values of 4.3, 7.1, and 29 µg/L for P. duplex, M. arcuatum, and Nannochloropsis-like sp., respectively, followed by hexazinone, with IC10 values of 15, 18, and 450 µg/L, respectively Toxicity testing on 2 commercial formulations (Barrage, 13.2% hexazinone and 48.6% diuron; Diurex, 90% diuron) showed that additives in the commercial formulations did not significantly increase the toxicity of diuron. Direct toxicity assessments were carried out on water samples from the herbicide-contaminated Sandy Creek, which discharges to the Great Barrier Reef lagoon, and a clean reference site, Tully Gorge in the Tully River. Toxicity was observed in several Sandy Creek samples. Artificial herbicide mixtures were assessed in synthetic soft water and natural freshwaters, with toxic responses being observed at environmentally relevant concentrations. The present study successfully applied a novel multispecies tropical microalgal toxicity test, indicating that it is an effective tool for the assessment of herbicide toxicity in both natural and synthetic freshwaters. Environ Toxicol Chem 2021;40:473-486. © 2020 SETAC.


Hospitalization for Influenza A Versus B.
The extent to which influenza A and B infection differs remains uncertain. Using active surveillance data from the Canadian Immunization Monitoring Program Active at 12 pediatric hospitals, we compared clinical characteristics and outcomes of children ≤16 years admitted with laboratory-confirmed influenza B or seasonal influenza A. We also examined factors associated with ICU admission in children hospitalized with influenza B. Over 8 nonpandemic influenza seasons (2004-2013), we identified 1510 influenza B and 2645 influenza A cases; median ages were 3.9 and 2.0 years, respectively (P < .0001). Compared with influenza A patients, influenza B patients were more likely to have a vaccine-indicated condition (odds ratio [OR] = 1.30; 95% confidence interval [CI] = 1.14-1.47). Symptoms more often associated with influenza B were headache, abdominal pain, and myalgia (P < .0001 for all symptoms after adjustment for age and health status). The proportion of deaths attributable to influenza was significantly greater for influenza B (1.1%) than influenza A (0.4%); adjusted for age and health status, OR was 2.65 (95% CI = 1.18-5.94). A similar adjusted OR was obtained for all-cause mortality (OR = 2.95; 95% CI = 1.34-6.49). Among healthy children with influenza B, age ≥10 years (relative to <6 months) was associated with the greatest odds of ICU admission (OR = 5.79; 95% CI = 1.91-17.57). Mortality associated with pediatric influenza B infection was greater than that of influenza A. Among healthy children hosptialized with influenza B, those 10 years and older had a significant risk of ICU admission.


New visual feedback device improves performance of chest compressions by professionals in simulated cardiac arrest.
Quality of external chest compression (ECC) is a key component of Basic Life Support. Different approaches to improve rescuers' performance have been evaluated, but few attempts have been made to invent simple devices to improve performance. This study evaluates a new visual feedback system for ECC for healthcare professionals. Ninety-three healthcare professionals volunteered (14 emergency medical technicians, 45 paramedics, 34 physicians; age 32+/-7.2 (range 21-61); 72% male) in this randomized cross-over study. All subjects were tested on a manikin (Skillreporter ResusciAnne, Laerdal, Stavanger, Norway) in identical mock cardiac arrest scenario and asked to perform 2 min of continuous ECC (secured airway): Group A (n=46): ECC with device first, followed by ECC without device a minimum of 45 min later; group B (n=47): vice versa. Primary endpoints: mean compression rate 90-120 min(-1); mean compression depth 38-51 mm. Data were analyzed using repeated measure logistic regression model for binary categorized endpoints and repeated measure ANOVA test for continuous endpoints. Correct compression depth was achieved by 45.2% of subjects (95%-CI: 30.5-64.9 mm) without vs. 73.1% (95%-CI: 40.3-57.4 mm) with device (p<0.001); correct compression rate was achieved by 62.4% (95%-CI: 78-147.8 min(-1)) without vs. 94.6% (95%-CI: 87.3-126.6 min(-1)) with device (p<0.001). Overall, 85% of the subjects thought the feedback system was helpful and 80.6% would use it if available. The new visual feedback device significantly improved ECC performance (compression rate and depth) by healthcare professionals in simulated cardiac arrest. Most participants found the device easy to use.


Cardiovascular risk and attitudes to lifestyle: what do patients think?
To examine the relation between subjects' level of cardiovascular risk and their beliefs about the harmfulness of their smoking habit, current diet, and level of exercise, together with their stated desire to modify such behaviour. Self administered postal health and life-style questionnaire followed by a structured health check conducted by a nurse. Five general practices in Luton and Dunstable, Bedfordshire. 5803 people aged 35-64 years enrolled in the OXCHECK trial who attended for a health check before 1 March 1992. Perceived risk to health of lifestyle behaviours, desire to modify behaviour, and a reported serious attempt to modify behaviour in the preceding year. A high proportion of smokers and those who were physically inactive perceived their behaviour to be harmful (1020; (76%; 95% confidence interval 74% to 79%) and 350 (74%; 70% to 78%) respectively) and wished to modify it (1212 (79%; 77% to 81%) and 375 (74%; 71% to 78%) respectively). In contrast, only 289 (45%; 41% to 48%) of obese people and 188 (14%; 12% to 16%) of people with a high dietary fat intake perceived their current diet to be harmful. The more cardiovascular risk factors present, the more likely subjects were to perceive a health risk attached to their diet and lack of exercise (p < 0.01 in both cases) and to want to improve their diet. Awareness of the health risk from smoking and motivation to stop is high. Further efforts are required, however, to educate the public about the risks associated with a high dietary fat intake. Although the health risks of inactivity were widely recognised, motivation to take more exercise needs to be increased.


Impact of a recruitment campaign on students' applications to medical school.
Medical schools might benefit if they have information about the activities that may help them to increase the number of applicants with superior academic qualifications. The study was carried out at the Split University School of Medicine, Croatia. Medical school applicants were surveyed in 2007 and 2009. Promotional activities consisted of presentations on medical education covering six general high-schools in 2008, and a presentation on regional television, aired in 2008 and 2009 shortly before the admission term. The survey response rate was 79% (299/379). The number of applicants in 2009 increased by 37% and the percentage of applicants from general high schools increased by 10%, in relation to 2007. The percentage of students with the best grades in all four years of high school was 42% in the both surveys. Presumed quality was a major influencing factor for choosing Split University Medical School. However, the medical school in the Croatian capital remained the first choice for students. Only a few applicants stated that the medical schools' promotional campaigns influenced their decision about where to study; 9.7% and 1.5%, respectively. Presentations in elected general high schools and a television campaign should be further explored as possible activities that regional schools may use to recruit potential applicants.


Comparison of anti-siphon devices-how do they affect CSF dynamics in supine and upright posture?
Three different types of anti-siphon devices (ASDs) have been developed to counteract siphoning-induced overdrainage in upright posture. However, it is not known how the different ASDs affect CSF dynamics under the complex pressure environment seen in clinic due to postural changes. We investigated which ASDs can avoid overdrainage in upright posture best without leading to CSF accumulation. Three shunts each of the types Codman Hakim with SiphonGuard (flow-regulated), Miethke miniNAV with proSA (gravitational), and Medtronic Delta (membrane controlled) were tested. The shunts were compared on a novel in vitro setup that actively emulates the physiology of a shunted patient. This testing method allows determining the CSF drainage rates, resulting CSF volume, and intracranial pressure in the supine, sitting, and standing posture. The flow-regulated ASDs avoided increased drainage by closing their primary flow path when drainage exceeded 1.39 ± 0.42 mL/min. However, with intraperitoneal pressure increased in standing posture, we observed reopening of the ASD in 3 out of 18 experiment repetitions. The adjustable gravitational ASDs allow independent opening pressures in horizontal and vertical orientation, but they did not provide constant drainage in upright posture (0.37 ± 0.03 mL/min and 0.26 ± 0.03 mL/min in sitting and standing posture, respectively). Consequently, adaptation to the individual patient is critical. The membrane-controlled ASDs stopped drainage in upright posture. This eliminates the risk of overdrainage, but leads to CSF accumulation up to the volume observed without shunting when the patient is upright. While all tested ASDs reduced overdrainage, their actual performance will depend on a patient's specific needs because of the large variation in the way the ASDs influence CSF dynamics: while the flow-regulated shunts provide continuous drainage in upright posture, the gravitational ASDs allow and require additional adaptation, and the membrane-controlled ASDs show robust siphon prevention by a total stop of drainage.


Fundamental diffraction limitations in a paraxial 4-f imaging system with coherent and incoherent illumination.
In the usual model of an imaging system, only the effects of the aperture stop are considered in determining diffraction-limited system performance. In fact, diffraction at other stops--those associated with different lens elements, for example--can also affect system performance and cause the imaging to be space variant, even in the absence of vignetting in the conventional ray optics sense. For the 4-f imaging system investigated in this paper, the severity of the space variance depends on the relative sizes of the two lens stops and the aperture stops. If the diameters of the lenses are equal, the aperture of the first lens has a greater effect on system performance than does that of the second.


Genome-wide analysis of attention deficit hyperactivity disorder in Norway.
Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but it has been difficult to identify genes underlying this disorder. This study aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci. Participants were recruited through Norwegian medical and birth registries as well as the general population. Presence of ADHD was defined according to DSM-IV criteria. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD. In total, 1.358 individuals (478 cases and 880 controls) and 598.384 autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs9949006 in the ENSG00000263745 gene (OR=1.51, 95% CI 1.28-1.79, p=1.38E-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs1393072, OR=1.46, 95% CI = 1.21-1.77, p=9.95E-05) and TPH2 (rs17110690, OR = 1.38, 95% CI = 1.14-1.66, p=8.31E-04). This study confirms the complexity and heterogeneity of ADHD etiology. Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder.


Prevalence and risk factors of problematic Internet use: a cross-national comparison of Japanese and Chinese university students.
The aim of the present study was to compare risk factors for problematic Internet use (PIU) among Japanese and Chinese university students. A sample of 267 Japanese and 236 Chinese first year university students responded to questionnaires on the severity of PIU, depression, self-image/image of others, and perceived parental child-rearing styles. The results indicated that Japanese participants were more likely to demonstrate PIU than their Chinese counterparts. Compared to Chinese students, Japanese students reported more negative self-image, lower parental care, greater overcontrol, and higher depression scores. The PIU group had a higher depression score compared to the normal Internet use group. Compared with the non-PIU group, the PIU group consisted of more male and Japanese participants. Further, they tended to have more negative self-images, saw their mothers to be less caring, and perceived their mothers and fathers as more overcontrolling. PIU is strongly associated with depression, negative self-image, and parental relations. Finally, mediation analysis revealed that such national differences in PIU between Japanese and Chinese were clarified in depression and perceived mother's care. This cross-national study indicated that depression and perceived mother's care were both significant risk factors that were associated with the national difference in PIU between Japanese and Chinese participants.


Short-chain fatty acids induce colonic mucosal injury in rats with various postnatal ages.
Short chain fatty acids (SCFAs) may play a role in the pathogenesis of neonatal necrotizing enterocolitis. To evaluate the injurious effect of SCFAs on the colonic mucosa of rats at various postnatal developmental stages, we studied a total of 170 newborn Sprague-Dawley rats at postnatal ages days 3, 9, and 23. A 1.8-F silastic catheter or umbilical catheter was inserted rectally deep into the proximal colon of the rats. Rats from each of the three postnatal age groups were randomly divided to receive one of the following distinct SCFA solutions: acetic acid, butyric acid, propionic acid, or a mixture of above SCFAs solutions. An additional subgroup of rats from each of the age groups received normal saline as a control. The concentration of each SCFA solution was 300 mM, and the pH of all solutions was adjusted to 4.0. The volume of administered solution was 0.1 mL/10 g of body weight. After 24 h, all rats were killed and the daily weight change was recorded and proximal colon was collected for histologic examination. A histologic injury score was used to quantify the severity of mucosal injury. The severity of mucosal injury induced by luminal SCFAs administration decreased as the rats matured; by postnatal day 23, the injury caused by SCFAs was minimal. Thus, the severity of the colonic mucosal injury induced by luminal SCFAs is maturation dependent; the immature state of the mucosal defense in early postnatal age in newborn rat may explain its greater vulnerability to luminal SCFAs.


Effects of food supplementation on the physiological ecology of female Western diamond-backed rattlesnakes (Crotalus atrox).
Food availability is an important factor in the life histories of organisms because it is often limiting and thus can affect growth, mass change, reproduction, and behaviors such as thermoregulation, locomotion, and mating. Experimental studies in natural settings allow researchers to examine the effects of food on these parameters while animals are free to behave naturally. The wide variation among organisms in energy demands and among environmental food resources suggest that responses to changes in food availability may vary among organisms. Since most supplemental feeding field experiments have been conducted on species with high energy demands, we conducted a supplemental feeding study on free-ranging, female Western diamond-backed rattlesnakes (Crotalus atrox), a species with low energy demands and infrequent reproductive investment. Snakes were offered thawed rodents 1-4 times per week. Over two active seasons, we collected data on surface activity, home range size, growth, mass change, and reproduction of supplementally fed and control snakes. Fed and control snakes did not differ in surface activity levels (proportion of time encountered above versus below ground) or home range size. Fed snakes grew and gained mass faster, and had a dramatically higher occurrence of reproduction than control snakes. Also, fed snakes were in better body condition following reproduction than snakes that were not fed. However, litter characteristics such as offspring number and size were not increased by feeding, suggesting that these characteristics may be fixed. These data experimentally demonstrate that food availability can directly impact some life history traits (i.e., growth and reproduction for C. atrox), but not others (i.e., surface activity and home range size for C. atrox). The relationship between food availability and life history traits is affected in a complex way by ecological traits and physiological constraints, and thus interspecific variation in this relationship is likely to be high.


Monitoring macromolecular complexes involved in the chaperonin-assisted protein folding cycle by mass spectrometry.
We have used native mass spectrometry to analyze macromolecular complexes involved in the chaperonin-assisted refolding of gp23, the major capsid protein of bacteriophage T4. Adapting the instrumental methods allowed us to monitor all intermediate complexes involved in the chaperonin folding cycle. We found that GroEL can bind up to two unfolded gp23 substrate molecules. Notably, when GroEL is in complex with the cochaperonin gp31, it binds exclusively one gp23. We also demonstrated that the folding and assembly of gp23 into 336-kDa hexamers by GroEL-gp31 can be monitored directly by electrospray ionization mass spectrometry (ESI-MS). These data reinforce the great potential of ESI-MS as a technique to investigate structure-function relationships of protein assemblies in general and the chaperonin-protein folding machinery in particular. A major advantage of native mass spectrometry is that, given sufficient resolution, it allows the analysis at the picomole level of sensitivity of heterogeneous protein complexes with molecular masses up to several million daltons.


Magnetic resonance and applanation tonometry for noninvasive determination of left ventricular load and ventricular vascular coupling in the time and frequency domain.
Cardiac magnetic resonance (CMR) is potentially more useful than Doppler ultrasound for quantifying ascending aortic flow velocity in the presence of complex flow patterns. Our aim was to characterize flow velocity wave patterns in the ascending aorta with age and their use with central (carotid) pressure waves to estimate ascending aortic impedance as left ventricular (LV) load and interpret vascular/ventricular interaction. Ascending aortic flow velocity was measured noninvasively, using velocity-encoded CMR, in 50 healthy individuals (21-70 years) by averaging flow velocities across the aortic cross-section. Pressure waves were measured noninvasively by carotid tonometry as a surrogate of aortic pressure. Impedance was determined in modulus and phase from corresponding harmonics of pressure and flow velocity waves. With increasing age, ascending aortic peak flow velocity decreased from 67 ± 18 cm/s in younger persons (≤50 years) to 48 ± 13 cm/s in older persons (>50 years) (P < 0.0001), largely attributable to increase in aortic diameter 2.5 ± 0.3 cm for third decade to 3.3 ± 0.2 cm for seventh decade (P < 0.001). With ageing, carotid pressure augmentation index increased (r = 0.52, P < 0.001), as expected from increased aortic stiffness, whereas ascending aortic flow pressure augmentation index decreased during the mid-to-late systolic period (r = 0.26, P < 0.001), attributable to progressive impairment in LV contractility. Ascending aortic impedance spectra showed ageing changes seen in previous invasive studies and as predicted from modelling. CMR provides noninvasive measures of LV pulsatile load in time and frequency domain, with expected differences between young and older persons. This conforms with and extends the new American Heart Association recommendations for LV afterload and vascular/ventricular interaction.


Using a similarity measure for credible classification.
This paper concerns classification by Boolean functions. We investigate the classification accuracy obtained by standard classification techniques on unseen points (elements of the domain, {0, 1}(n), for some n) that are similar, in particular senses, to the points that have been observed as training observations. Explicitly, we use a new measure of how similar a point x in {0, 1}(n) is to a set of such points to restrict the domain of points on which we offer a classification. For points sufficiently dissimilar, no classification is given. We report on experimental results which indicate that the classification accuracies obtained on the resulting restricted domains are better than those obtained without restriction. These experiments involve a number of standard data-sets and classification techniques. We also compare the classification accuracies with those obtained by restricting the domain on which classification is given by using the Hamming distance.


Cellular perception and misperception: Internal models for decision-making shaped by evolutionary experience.
Cells live in dynamic environments that necessitate perpetual adaptation. Since cells have limited resources to monitor external inputs, they are required to maximize the information content of perceived signals. This challenge is not unique to microscopic life: Animals use senses to perceive inputs and adequately respond. Research showed that sensory-perception is actively shaped by learning and expectation allowing internal cognitive models to "fill in the blanks" in face of limited information. We propose that cells employ analogous strategies and use internal models shaped through the long process of evolutionary adaptation. Given this perspective, we postulate that cells are prone to "misperceptions," analogous to visual illusions, leading them to incorrectly decode patterns of inputs that lie outside of their evolutionary experience. Mapping cellular misperception can serve as a fundamental approach for dissecting regulatory networks and could be harnessed to modulate cell behavior, a potentially new avenue for therapy.


Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.
Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification). Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993. Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048). Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.


Bilateral blockade of NMDA receptors in anterior thalamus by dizocilpine (MK-801) injures pyramidal neurons in rat retrosplenial cortex.
Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine, phencyclidine (PCP) and dizocilpine (MK-801), produce psychosis in people. In rodents they produce cytoplasmic vacuoles in injured retrosplenial cortical neurons that express HSP70 heat shock protein. This study examined possible circuits and receptors that mediate this neuronal injury. Bilateral, but not unilateral, injection of dizocilpine (5, 10, 15, 20 microg/microL per side) into the anterior thalamus induced HSP70 protein in pyramidal neurons in deep layer III of rat retrosplenial cortex 24 h later. In contrast, bilateral dizocilpine injections (5, 10, 15, 20 microg/microL per side) into the retrosplenial cortex or into the diagonal band of Broca did not induce HSP70. Bilateral injections of muscimol (0.1, 1, 10 microg/microL per side), a GABAA (gamma-aminobutyric acid) agonist, into the anterior thalamus blocked HSP70 induction in the retrosplenial cortex produced by systemic dizocilpine (1 mg/kg). Bilateral thalamic injections of baclofen (0.1, 1, 10 microg/microL per side), a GABAB agonist, were ineffective. Anterograde tracer studies confirmed that neurons in the anterior thalamus project to superficial layer III of the retrosplenial cortex where the dendrites of HSP70-immunostained neurons in deep layer III reside. Bilateral blockade of NMDA receptors on GABA neurons in the reticular nuclei of the thalamus is proposed to decrease GABA neuronal firing, decrease GABA release and decrease activation of GABAA receptors. This activates thalamic projection neurons that damage retrosplenial cortical neurons presumably via unblocked cortical glutamate alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and kainate receptors. The increases of blood flow that occur in the thalamus and retrosplenial cortex of people that have psychosis produced by NMDA antagonists could be related to thalamic excitation of the retrosplenial cortex produced by these drugs.


Serological divergence of Dobrava and Saaremaa hantaviruses: evidence for two distinct serotypes.
In order to investigate the serological relationship of Dobrava hantavirus (DOBV, originating from Slovenia) and the Dobrava-like Saaremaa virus (SAAV, recently discovered in Estonia) we analysed 37 human serum samples, 24 from Estonia and 13 from the Balkans, by focus reduction neutralization test (FRNT). Most of the Estonian sera (19), including all sera from Saaremaa island (12), reacted with higher FRNT end-point titres to the local SAAV; the majority of them (15 and 11, respectively), with at least fourfold or higher titres to SAAV than to DOBV. In contrast, out of the 13 sera collected in Slovenia, Bosnia-Herzegovina and Greece, only one reacted more strongly with SAAV (with a twofold higher titre), while 10 of these sera reacted more strongly with the local DOBV (9/10 with fourfold or higher titres). These results indicate that DOBV and SAAV define unique hantavirus serotypes.


Multiple Discharges of Treated Municipal Wastewater Have a Small Effect on the Quantities of Numerous Antibiotic Resistance Determinants in the Upper Mississippi River.
This study evaluated multiple discharges of treated wastewater on the quantities of antibiotic resistance genes (ARGs) in the Upper Mississippi River. Surface water and treated wastewater samples were collected along the Mississippi River during three different periods of 4 days during the summer of 2012, and quantitative real-time PCR (qPCR) was used to enumerate several ARGs and related targets. Even though the wastewater effluents contained 75- to 831-fold higher levels of ARGs than the river water, the quantities of ARGs in the Mississippi River did not increase with downstream distance. Plasmids from the incompatibility group A/C were detected at low levels in the wastewater effluents but not in the river water; synthetic DNA containing an ampicillin resistance gene (bla) from cloning vectors was not detected in either the wastewater effluent or river samples. A simple 1D model suggested that the primary reason for the small impact of the wastewater discharges on ARG levels was the large flow rate of the Mississippi River compared to that of the wastewater discharges. Furthermore, this model generally overpredicted the ARG levels in the Mississippi River, suggesting that substantial loss mechanisms (e.g., decay or deposition) were occurring in the river.


First-Year GPA and Academic Service Use Among College Students With and Without ADHD.
Objective: ADHD is a chronic neurodevelopmental disorder that typically results in persistent academic difficulties over time. Although most colleges offer support services, students often do not use the available services or those to which they are entitled. The present study examined predictors of academic performance among college students with and without ADHD. In addition, the rate, predictors, and outcomes of academic service use were explored. Methods: A series of multivariate analyses of variance (MANOVAs) and regression analyses were conducted using SPSS v. 21 ® software. Results: First year college students with ADHD earned significantly lower grade point averages (GPAs) relative to students without ADHD. Additionally, ADHD combined with other disorders, but not ADHD alone, predicted higher rates of service use relative to students without ADHD. Finally, the findings suggest that typically available academic services are not independently related to GPA among first-year college students with or without ADHD. Conclusion: This study replicates previous work demonstrating significantly lower GPAs among a rigorously defined sample of students with ADHD relative to students without ADHD. Second, this study indicates that traditional predictors of college success may be less meaningful for students with ADHD relative to those without ADHD. Finally, additional research needs to be conducted regarding the use and effectiveness of academic services on college campuses.


New insights into Legionella pneumophila biofilm regulation by c-di-GMP signaling.
The waterborne pathogen Legionella pneumophila grows as a biofilm, freely or inside amoebae. Cyclic-di-GMP (c-di-GMP), a bacterial second messenger frequently implicated in biofilm formation, is synthesized and degraded by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), respectively. To characterize the c-di-GMP-metabolizing enzymes involved in L. pneumophila biofilm regulation, the consequences on biofilm formation and the c-di-GMP concentration of each corresponding gene inactivation were assessed in the Lens strain. The results showed that one DGC and two PDEs enhance different aspects of biofilm formation, while two proteins with dual activity (DGC/PDE) inhibit biofilm growth. Surprisingly, only two mutants exhibited a change in global c-di-GMP concentration. This study highlights that specific c-di-GMP pathways control L. pneumophila biofilm formation, most likely via temporary and/or local modulation of c-di-GMP concentration. Furthermore, Lpl1054 DGC is required to enable the formation a dense biofilm in response to nitric oxide, a signal for biofilm dispersion in many other species.


Reference equations for lung function screening of healthy never-smoking adults aged 18-80 years.
The need for updated spirometric reference values to be used on European populations is widely acknowledged, especially for subjects aged >70 yrs. Their reference values are generally based on extrapolations. The aim of the present study was to calculate reference values for lung function screening of healthy, never-smoking adults aged 18-80 yrs and to compare them with the most widely used reference equations. Results of screening spirometry of 8,684 healthy, never-smoking adults were used to calculate mean values and fifth percentiles of lung function variables. The European Community of Coal and Steel (ECCS) reference equations underestimate forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). For example, in 50-yr-old males (height 175 cm), lower limits of normal for FEV(1) are underestimated by 198 mL, and for FVC by 210 mL. In 50-yr-old females (height 165 cm), lower limits of normal for FEV(1) are underestimated by 191 mL, and for FVC by 270 mL. The decline of FVC in elderly subjects is steeper than predicted by the ECCS. Reference equations derived from spirometry data locally collected in a practical setting by well-trained personnel might be more appropriate for everyday use than generally used equations based on data from scientific studies in the distant past.


Impingement of infrapatellar fat pad (Hoffa's disease): results of high-portal arthroscopic resection.
We performed a retrospective cohort study with prospective data collection to assess clinical and functional outcomes of painful impingement of the infrapatellar fat pad (Hoffa's disease) treated with high-portal arthroscopic resection. Hoffa's disease as an isolated lesion was confirmed by arthroscopy in 34 patients with recalcitrant anterior knee pain. The visualization portals were made high in the soft spot above the level of the lower pole of the patella. Patients were treated by resection of the affected part of the fat pad and assessed via the Lysholm knee and Tegner activity level scales preoperatively and at 3 months and at 1 year postoperatively, as well as at the conclusion of this study. The mean age of the patients was 38 years (range, 19 to 62 years). The mean duration of symptoms before surgery was 10 months (range, 1 to 22 months). Twelve patients had one or more previous failed arthroscopies at other centers. The mean follow-up period was 68 months (range, 49 to 95 months). The mean improvement in Lysholm score was 44.76, 55.58, and 53.97 at 3 months, at 1 year, and at the latest follow-up, respectively. On the basis of the Tegner activity level, all but 4 patients returned to their preinjury status. A statistically significant negative correlation was found between duration of symptoms and gain in Lysholm score after surgery (Pearson r = -0.58). Three types of lesion were identified. After resection, patients with acute lesions (type 1) had a quicker return to their previous level of activity according to the Tegner scale as compared with patients with chronic lesions (types 2 and 3) (P = .05 and .03, respectively). Patients with Hoffa's disease without any other concomitant pathology can expect resolution or long-term improvement in their symptoms and function after arthroscopic resection. Level IV, therapeutic case series.


Pain Assessment and Management After a Knowledge Translation Booster Intervention.
Inadequate pain treatment leaves hospitalized children vulnerable to immediate and long-term sequelae. A multidimensional knowledge translation intervention (ie, the Evidence-based Practice for Improving Quality [EPIQ]) improved pain assessment, management, and intensity outcomes in 16 units at 8 Canadian pediatric hospitals. The sustained effectiveness of EPIQ over time is unknown, however. The goals of this study were to determine the following: (1) sustainability of the impact of EPIQ on pain assessment, management, and intensity outcomes 12, 24, and 36 months after EPIQ; (2) effectiveness of a pain practice change booster (Booster) intervention to sustain EPIQ outcomes over time; and (3) influence of context on sustainability. A prospective, repeated measures, cluster randomized controlled trial was undertaken in the 16 EPIQ units, 12 months after EPIQ completion, to determine the effectiveness of a practice change booster (Booster) to sustain EPIQ outcomes. Generalized estimating equation models examined outcomes controlling for child and unit contextual factors. Outcomes achieved during EPIQ were sustained in the use of any pain assessment measure (P = .01) and a validated pain assessment measure in the EPIQ units (P = .02) up to 36 months after EPIQ. Statistically significant improvements in pain management practices persisted in EPIQ units; results varied across time. There were no significant differences in outcomes after implementation of the Booster between the Booster and Nonbooster groups. Improved pain assessment and management practices were sustained after EPIQ; however, the Booster did not seem to provide additional impact.


BDNF polymorphisms are linked to poorer working memory performance, reduced cerebellar and hippocampal volumes and differences in prefrontal cortex in a Swedish elderly population.
Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking. 367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF. The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes. The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly.


Exploring structure and function of sensory cortex with 7T MRI.
In this paper, we present an overview of 7T magnetic resonance imaging (MRI) studies of the detailed function and anatomy of sensory areas of the human brain. We discuss the motivation for the studies, with particular emphasis on increasing the spatial resolution of functional MRI (fMRI) using reduced field-of-view (FOV) data acquisitions. MRI at ultra-high-field (UHF) - defined here as 7T and above - has several advantages over lower field strengths. The intrinsic signal-to-noise ratio (SNR) of images is higher at UHF, and coupled with the increased blood-oxygen-level-dependent (BOLD) signal change, this results in increased BOLD contrast-to-noise ratio (CNR), which can be exploited to improve spatial resolution or detect weaker signals. Additionally, the BOLD signal from the intra-vascular (IV) compartment is relatively diminished compared to lower field strengths. Together, these properties make 7T functional MRI an attractive proposition for high spatial specificity measures. But with the advantages come some challenges. For example, increased vulnerability to susceptibility-induced geometric distortions and signal loss in EPI acquisitions tend to be much larger. Some of these technical issues can be addressed with currently available tools and will be discussed. We highlight the key methodological considerations for high resolution functional and structural imaging at 7 T. We then present recent data using the high spatial resolution available at UHF in studies of the visual and somatosensory cortex to highlight promising developments in this area.


Access and use of health services by chronically mentally ill Medicaid beneficiaries.
This article has two objectives: to quantify the access and utilization of services received by chronically mentally ill Medicaid recipients, and to compare service utilization and access under prepayment and fee-for-service (FFS) payment. The study setting is Hennepin County (Minneapolis), Minnesota, where 35 percent of Medicaid recipients were randomly assigned to receive services from prepaid plans. An algorithm was developed to identify recipients with chronic mental illness, resulting in 739 study participants, split approximately evenly between prepayment and FFS Medicaid. Data were collected through in-person surveys at baseline, and after 1 year. We found slight improvements in the majority of access measures studied and no significant decreases in the use of inpatient or outpatient services for enrollees in prepaid health plans. The results support efforts to expand the use of prepaid health plans to meet the needs of non-institutionalized chronically mentally ill Medicaid beneficiaries.


[Studies on the active constituents of Momordica charantia L].
Five compounds were isolated from the seeds of Momordica charantia. This paper reports their structure determination by spectral (IR, UV, HNMR, CNMR, and MS) and chemical methods. The structures of I, II, III, IV and V were elucidated as vacine, mycose, 3-O-(beta-D-glucopyranosyl)-24 beta-ethyl-5 alpha-cholesta-7, trans-22E, 25 (27)-trien-3 beta-ol, momorcharaside A and momorcharaside B respectively. Mycose was the first time found in this plant and compound III was the first time found in the genus Momordica. IV and V were new compounds. IV exhibited obvious inhibition of DNA and RNA syntheses in S 180 tumor cells in preliminary pharmacological studies.


Prominent radiative contributions from multiply-excited states in laser-produced tin plasma for nanolithography.
Extreme ultraviolet (EUV) lithography is currently entering high-volume manufacturing to enable the continued miniaturization of semiconductor devices. The required EUV light, at 13.5 nm wavelength, is produced in a hot and dense laser-driven tin plasma. The atomic origins of this light are demonstrably poorly understood. Here we calculate detailed tin opacity spectra using the Los Alamos atomic physics suite ATOMIC and validate these calculations with experimental comparisons. Our key finding is that EUV light largely originates from transitions between multiply-excited states, and not from the singly-excited states decaying to the ground state as is the current paradigm. Moreover, we find that transitions between these multiply-excited states also contribute in the same narrow window around 13.5 nm as those originating from singly-excited states, and this striking property holds over a wide range of charge states. We thus reveal the doubly magic behavior of tin and the origins of the EUV light.


Increased cytosolic sodium and reduced Na,K-ATPase activity in transgenic rats.
The transgenic rat TGR(mRen2)27 is a new monogenetic model in hypertension research that develops fulminant hypertension after the mouse Ren-2d renin gene has been integrated into its genome. To evaluate the molecular mechanism of development of hypertension in this animal model, we measured cytosolic free sodium concentration in intact lymphocytes from seven transgenic rats and eight age-matched normotensive Sprague-Dawley rats using the novel sodium-sensitive fluorescent dye sodium-binding benzofuranisophthalate. Resting cytosolic sodium was significantly higher in transgenic rats compared with Sprague-Dawley rats (31.7 +/- 2.2 versus 18.2 +/- 0.4 mmol/L, mean +/- SEM, P < .001). Inhibition of Na,K-ATPase by 0.5 mmol/L ouabain for 5 minutes significantly increased lymphocytic cytosolic sodium in Sprague-Dawley rats to 36.5 +/- 3.4 mmol/L (P < .001 compared with resting value), whereas no significant change could be observed in transgenic rats (35.4 +/- 0.6 mmol/L), indicating that Na,K-ATPase is less responsive in transgenic rats. The Na,K-ATPase activity from erythrocytes was measured with an enzyme-linked assay. Na,K-ATPase activity was significantly reduced in transgenic rats compared with Sprague-Dawley rats (4.0 +/- 0.3 versus 8.1 +/- 0.6 U/L, P < .001). We concluded that reduced Na,K-ATPase activity leads to elevated cytosolic sodium in this model of genetic hypertension.


Functional richness and ecosystem services: bird predation on arthropods in tropical agroecosystems.
In agroecosystems, biodiversity correlates with ecosystem function, yet mechanisms driving these relationships are often unknown. Examining traits and functional classifications of organisms providing ecosystem functions may provide insight into the mechanisms. Birds are important predators of insects, including pests. However, biological simplification of agroforests may decrease provisioning of this pest removal service by reducing bird taxonomic and functional diversity. A recent meta-analysis of bird exclosure studies from a range of agroecosystems in Central America concluded that higher bird richness is associated with significantly greater arthropod removal, yet the mechanism remains unclear. We conducted a meta-analysis of the same data to examine whether birds demonstrate functional complementarity in tropical agroforests. We classified birds according to relevant traits (body mass, foraging strategy, foraging Strata, and diet) and then examined how design of functional classification, including trait selection, classification methods, and the functional diversity metric used affect the suitability of different classifications as predictors of ecosystem services. We determined that vegetation characteristics are not likely drivers of arthropod removal by birds. For some functional classifications, functional richness positively correlated with arthropod removal, indicating that species complementarity may be an important mechanism behind this ecosystem function. The predictive ability of functional classifications increased with the number of traits included in the classification. For the two best classifications examined, functional group richness was a better predictor of arthropod reduction than other metrics of functional diversity (FD and Rao's Q). However, no functional classification predicted arthropod removal better than simple species richness; thus other factors may be important. Our analysis indicates that the sampling effect may also play a role, as one species and two functional groups were responsible for disproportionate effects of arthropod removal.


Classification of a Hypervirulent Aeromonas hydrophila Pathotype Responsible for Epidemic Outbreaks in Warm-Water Fishes.
Lineages of hypervirulent Aeromonas hydrophila (vAh) are the cause of persistent outbreaks of motile Aeromonas septicemia in warm-water fishes worldwide. Over the last decade, this virulent lineage of A. hydrophila has resulted in annual losses of millions of tons of farmed carp and catfish in the People's Republic of China and the United States (US). Multiple lines of evidence indicate US catfish and Asian carp isolates of A. hydrophila affiliated with sequence type 251 (ST251) share a recent common ancestor. To address the genomic context for the putative intercontinental transfer and subsequent geographic spread of this pathogen, we conducted a core genome phylogenetic analysis on 61 Aeromonas spp. genomes, of which 40 were affiliated with A. hydrophila, with 26 identified as epidemic strains. Phylogenetic analyses indicate all ST251 strains form a coherent lineage affiliated with A. hydrophila. Within this lineage, conserved genetic loci unique to A. hydrophila were identified, with some genes present in consistently higher copy numbers than in non-epidemic A. hydrophila isolates. In addition, results from analyses of representative ST251 isolates support the conclusion that multiple lineages are present within US vAh isolated from Mississippi, whereas vAh isolated from Alabama appear clonal. This is the first report of genomic heterogeneity within US vAh isolates, with some Mississippi isolates showing closer affiliation with the Asian grass carp isolate ZC1 than other vAh isolated in the US. To evaluate the biological significance of the identified heterogeneity, comparative disease challenges were conducted with representatives of different vAh genotypes. These studies revealed that isolate ZC1 yielded significantly lower mortality in channel catfish, relative to Alabama and Mississippi vAh isolates. Like other Asian vAh isolates, the ZC1 lineage contains all core genes for a complete type VI secretion system (T6SS). In contrast, more virulent US isolates retain only remnants of the T6SS (clpB, hcp, vgrG, and vasH) which may have functional implications. Collectively, these results characterize a hypervirulent A. hydrophila pathotype that affects farmed fish on multiple continents.


Does single blind peer review hinder newcomers?
Several fields of research are characterized by the coexistence of two different peer review modes to select quality contributions for scientific venues, namely double blind (DBR) and single blind (SBR) peer review. In the first, the identities of both authors and reviewers are not known to each other, whereas in the latter the authors' identities are visible since the start of the review process. The need to adopt either one of these modes has been object of scholarly debate, which has mostly focused on issues of fairness. Past work reported that SBR is potentially associated with biases related to the gender, nationality, and language of the authors, as well as the prestige and type of their institutions. Nevertheless, evidence is lacking on whether revealing the identities of the authors favors reputed authors and hinder newcomers, a bias with potentially important consequences in terms of knowledge production. Accordingly, we investigate whether and to what extent SBR, compared to a DBR, relates to a higher ration of reputed scholars, at the expense of newcomers. This relation is pivotal for science, as past research provided evidence that newcomers support renovation and advances in a research field by introducing new and heterodox ideas and approaches, whereas inbreeding have serious detrimental effects on innovation and creativity. Our study explores the mentioned issues in the field of computer science, by exploiting a database that encompasses 21,535 research papers authored by 47,201 individuals and published in 71 among the 80 most impactful computer science conferences in 2014 and 2015. We found evidence that-other characteristics of the conferences taken in consideration-SBR indeed relates to a lower ration of contributions from newcomers to the venue and particularly newcomers that are otherwise experienced of publishing in other computer science conferences, suggesting the possible existence of ingroup-outgroup behaviors that may harm knowledge advancement in the long run.


The distribution of Notch receptors and their ligands during articular cartilage development.
We examined the distribution of Notch family members and their ligands during the development of articular cartilage and the growth plate. Notch 1 was expressed by the chondrocytes of the developing articular surface but became increasingly restricted to the deeper layers after birth whilst expression of this family member was restricted to hypertrophic chondrocytes in the growth plate. Notch 2 and 4, Delta and Jagged 2 showed a broadly similar distribution, being present throughout the articular cartilage during development and becoming increasingly restricted to deeper layers with age. Hypertrophic chondrocytes within the growth plate also expressed Notch 2 and 4, Delta and Jagged 2 (which was also expressed in prehypertrophs). Notch 3 and Jagged 1 were absent from developing articular cartilage but were present in deeper layers at later time points (> 1 month) and both receptor and ligand were expressed in hypertrophic chondrocytes at all ages examined. These results highlight the complex Notch signalling interactions that result in the formation of the heterogeneous articular cartilage and allow for the co-ordinated ossification and elongation of the growth plate. Mechanisms by which these processes are controlled are discussed in light of recent advances in the understanding of Notch signalling pathways.


The moderator effect that wasn't there: statistical problems in ambivalence research.
Ambivalence researchers often collapse separate measures of positivity and negativity into a single numerical index of ambivalence and refer to it as objective, operative, or potential ambivalence. The authors argue that this univariate approach to ambivalence models undermines the validity of subsequent statistical analyses because it confounds the effects of the index and its components. To remedy this situation, they demonstrate how the assumptions underlying the indices derived from the conflicting reactions model and similarity-intensity model can be tested using a multivariate approach to ambivalence models. On the basis of computer simulations and reanalyses of published moderator effects, the authors show that the frequently reported moderating influence of ambivalence on attitude effects may be a statistical artifact resulting from unmodeled correlations of positivity and negativity with attitude and the dependent variable. On the basis of extensive power analyses, they conclude that it may be extremely difficult to detect moderator effects of ambivalence in observational data. Therefore, they encourage ambivalence researchers to take an experimental approach to study design and a multivariate approach to data analysis.


Teaching statistics to medical students using problem-based learning: the Australian experience.
Problem-based learning (PBL) is gaining popularity as a teaching method in UK medical schools, but statistics and research methods are not being included in this teaching. There are great disadvantages in omitting statistics and research methods from the main teaching. PBL is well established in Australian medical schools. The Australian experience in teaching statistics and research methods in curricula based on problem-based learning may provide guidance for other countries, such as the UK, where this method is being introduced. All Australian medical schools using PBL were visited, with two exceptions. Teachers of statistics and medical education specialists were interviewed. For schools which were not visited, information was obtained by email. No Australian medical school taught statistics and research methods in a totally integrated way, as part of general PBL teaching. In some schools, statistical material was integrated but taught separately, using different tutors. In one school, PBL was used only for 'public health' related subjects. In some, a parallel course using more traditional techniques was given alongside the PBL teaching of other material. This model was less successful than the others. There are several difficulties in implementing an integrated approach. However, not integrating is detrimental to statistics and research methods teaching, which is of particular concern in the age of evidence-based medicine. Some possible ways forward are suggested.


Eye gaze performance for children with severe physical impairments using gaze-based assistive technology-A longitudinal study.
Gaze-based assistive technology (gaze-based AT) has the potential to provide children affected by severe physical impairments with opportunities for communication and activities. This study aimed to examine changes in eye gaze performance over time (time on task and accuracy) in children with severe physical impairments, without speaking ability, using gaze-based AT. A longitudinal study with a before and after design was conducted on 10 children (aged 1-15 years) with severe physical impairments, who were beginners to gaze-based AT at baseline. Thereafter, all children used the gaze-based AT in daily activities over the course of the study. Compass computer software was used to measure time on task and accuracy with eye selection of targets on screen, and tests were performed with the children at baseline, after 5 months, 9-11 months, and after 15-20 months. Findings showed that the children improved in time on task after 5 months and became more accurate in selecting targets after 15-20 months. This study indicates that these children with severe physical impairments, who were unable to speak, could improve in eye gaze performance. However, the children needed time to practice on a long-term basis to acquire skills needed to develop fast and accurate eye gaze performance.


Solitons in geometric potentials.
We show that the geometrically induced potential existing in undulated slab waveguides dramatically affects the properties of solitons. In particular, whereas solitons residing in the potential maxima do not feature power thresholds and are stable, their counterparts residing in the potential minima are unstable and may exhibit a power threshold for their existence. Additionally, the geometric potential is shown to support stable multipole solitons that cannot be supported by straight waveguides. Finally, the geometric potential results in the appearance of the effective barriers that prevent transverse soliton motion.