Individualized Learning Plan (ILP) Is an Effective Tool in Assessing Achievement of Otology-related Subcompetency Milestones.
To investigate the individualized learning plan (ILP) as a tool in assessment of residents' milestone achievements as they pertain to Otology subcompetencies: Chronic Ear Disease, Pediatric Otitis Media, and Hearing Loss. Prospective study. Twenty otolaryngology residents were instructed to use an ILP and identify six milestones from three otology-related subcompetencies to focus on during the course of a 3-month rotation. They were also asked to plan out specific activities which would help them achieve these milestones, to specify whether or not they successfully achieved them, by what instructional or learning methods and to identify any barriers. The completed ILPs were reviewed by a faculty member. The effectiveness of the ILP was assessed by response compliance rate, corroboration of self-reported milestone achievement with faculty evaluations and the ability to set attainable milestones. There was 95% compliance in using an ILP to achieve milestones. Self-reported milestone scores corresponded to the faculty evaluations in a large majority (89.6%) of patients, and tended to be underestimated by the residents. Out of 114 total milestones identified, 44 (38.6%) were not achieved, with particular overestimation in the use of independent study as a learning method. The ILP is an effective tool in measuring residents' achievement of otology-related milestones, and could possibly be used to supplement or replace faculty assessment. The ILP provides valuable information on barriers to achieving milestones and informs trainees on how to set attainable goals as they pertain to patient care and medical knowledge in otology.


Use of noseclips in pulmonary function tests.
Spirometry was performed on 136 male industrial workers experienced in undergoing pulmonary function testing for the purpose of studying the effects of the use of noseclips on forced vital capacity (FVC) maneuvers. A cross-over design was employed with each subject serving as his own reference. Forced expiratory volume in 1 second (FEV1) and FVC measurements were recorded adhering closely to the guidelines set down by the American Thoracic Society. Assuming that a 30-ml difference in FVC and FEV1 is not important, we conclude that these measurements are not significantly affected by the use of noseclips. However, trial order was found to affect the outcome. The FVC and FEV1 values on the first trial were consistently lower than those on the second regardless of noseclip use. Many subjects experienced discomfort from noseclips and their use is not recommended for routine purposes.


Molecular Insights from Conformational Ensembles via Machine Learning.
Biomolecular simulations are intrinsically high dimensional and generate noisy data sets of ever-increasing size. Extracting important features from the data is crucial for understanding the biophysical properties of molecular processes, but remains a big challenge. Machine learning (ML) provides powerful dimensionality reduction tools. However, such methods are often criticized as resembling black boxes with limited human-interpretable insight. We use methods from supervised and unsupervised ML to efficiently create interpretable maps of important features from molecular simulations. We benchmark the performance of several methods, including neural networks, random forests, and principal component analysis, using a toy model with properties reminiscent of macromolecular behavior. We then analyze three diverse biological processes: conformational changes within the soluble protein calmodulin, ligand binding to a G protein-coupled receptor, and activation of an ion channel voltage-sensor domain, unraveling features critical for signal transduction, ligand binding, and voltage sensing. This work demonstrates the usefulness of ML in understanding biomolecular states and demystifying complex simulations.


The effect of bovine lactoferrin and lactoferricin B on the ability of feline calicivirus (a norovirus surrogate) and poliovirus to infect cell cultures.
To characterize the effect of bovine lactoferrin and lactoferricin B against feline calicivirus (FCV), a norovirus surrogate and poliovirus (PV), as models for enteric viruses. Crandell-Reese feline kidney (CRFK) cells were used for the propagation of FCV and monkey embryo kidney (MEK) cells for PV. The assays included visual assessment of cell lines for cytopathic effects and determination of the percentage cell death using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium] dye reduction assay. Incubation of bovine lactoferrin with CRFK cells either prior to or together with FCV inoculation substantially reduced FCV infection. In contrast, the interference of lactoferrin with the infection of cells with PV was demonstrated only when lactoferrin was present with cell lines and virus for the entire assay period. Using indirect immunofluorescence, lactoferrin was detected on the surface of both CRFK and MEK cells, suggesting that the interference of viral infection may be attributed to lactoferrin binding to the surfaces of susceptible cells, thereby preventing the attachment of the virus particles. Lactoferricin B, a cationic antimicrobial peptide derived from the N-terminal domain of bovine lactoferrin, reduced FCV but not PV infection. Lactoferrin was shown to interfere with the infection of cells for both FCV and PV. However, lactoferricin B showed no interference of infection with PV and interference with infection for FCV required the presence of lactoferricin B together with the cell line and virus. An in vitro basis is provided for the effects of bovine lactoferrin and lactoferricin B in moderating food-borne infections of enteric viruses.


3D Imaging of Retinal Pigment Epithelial Cells in the Living Human Retina.
Dysfunction of the retinal pigment epithelium (RPE) underlies numerous retinal pathologies, but biomarkers sensitive to RPE change at the cellular level are limited. In this study, we used adaptive optics optical coherence tomography (AO-OCT) in conjunction with organelle motility as a novel contrast mechanism to visualize RPE cells and characterize their 3-dimensional (3D) reflectance profile. Using the Indiana AO-OCT imaging system (λc = 790 nm), volumes were acquired in the macula of six normal subjects (25-61 years). Volumes were registered in 3D with subcellular accuracy, layers segmented, and RPE and photoreceptor en face images extracted and averaged. Voronoi and two-dimensional (2D) power spectra analyses were applied to the images to quantify RPE and cone packing and cone-to-RPE ratio. Adaptive optics OCT revealed two distinct reflectance patterns at the depth of the RPE. One is characterized by the RPE interface with rod photoreceptor tips, the second by the RPE cell nuclei and surrounding organelles, likely melanin. Increasing cell contrast by averaging proved critical for observing the RPE cell mosaic, successful in all subjects and retinal eccentricities imaged. Retinal pigment epithelium mosaic packing and cell thickness generally agreed with that of histology and in vivo studies using other imaging modalities. We have presented, to our knowledge, the first detailed characterization of the 3D reflectance profile of individual RPE cells and their relation to cones and rods in the living human retina. Success in younger and older eyes establishes a path for testing aging effects in larger populations. Because the technology is based on OCT, our measurements will aid in interpreting clinical OCT images.


Quantitative Characterization of Molecular-Stream Separation.
Molecular-stream separation (MSS), for example, by free flow electrophoresis or continuous annular chromatography, has great potential for applications that require continuous downstream separation such continuous flow synthesis. Despite its potential, MSS still needs to be greatly advanced, which requires currently lacking tools for quantitative characterization of streams in MSS. We developed and introduce here an analytical toolbox for this task. The first tool is a method to convolute 3D raw MSS data into a 2D "angulagram" via signal integration over the whole separation zone using a polar coordinate system. The second tool is three quantitative parameters characterizing stream width, linearity, and deflection, which are determined from an angulagram. The third tool is the analysis of the three parameters in relation to physicochemical characteristics of MSS which reveals deficiencies and guides improvements in MSS devices and methods. Examples of toolbox application to validation of previously published MSS data are provided.


Bacterial Human Virulence Genes across Diverse Habitats As Assessed by In silico Analysis of Environmental Metagenomes.
The occurrence and distribution of clinically relevant bacterial virulence genes across natural (non-human) environments is not well understood. We aimed to investigate the occurrence of homologs to bacterial human virulence genes in a variety of ecological niches to better understand the role of natural environments in the evolution of bacterial virulence. Twenty four bacterial virulence genes were analyzed in 46 diverse environmental metagenomic datasets, representing various soils, seawater, freshwater, marine sediments, hot springs, the deep-sea, hypersaline mats, microbialites, gutless worms and glacial ice. Homologs to 16 bacterial human virulence genes, involved in urinary tract infections, gastrointestinal diseases, skin diseases, and wound and systemic infections, showed global ubiquity. A principal component analysis did not demonstrate clear trends across the metagenomes with respect to occurrence and frequency of observed gene homologs. Full-length (>95%) homologs of several virulence genes were identified, and translated sequences of the environmental and clinical genes were up to 50-100% identical. Furthermore, phylogenetic analyses indicated deep branching positions of some of the environmental gene homologs, suggesting that they represent ancient lineages in the phylogeny of the clinical genes. Fifteen virulence gene homologs were detected in metatranscriptomes, providing evidence of environmental expression. The ubiquitous presence and transcription of the virulence gene homologs in non-human environments point to an important ecological role of the genes for the activity and survival of environmental bacteria. Furthermore, the high degree of sequence conservation between several of the environmental and clinical genes suggests common ancestral origins.


Ear protection against water-borne infection: an objective evaluation.
Eight different ear plug materials were tested, in 5 ears each, in artificial shallow underwater conditions for 30 minutes, in order to determine their efficacy in sealing the ear canals to avoid water-borne infections in ear canals and open middle ears. Most of the plugs tested would meet everyday requirements for protection, but the polymeric foam plugs, treated with petroleum jelly, and moldable plastic materials were most effective in protecting both the middle ear and the ear canal skin.


Routine Pouchoscopy Prior to Ileostomy Takedown May Not Be Necessary in Patients with Chronic Ulcerative Colitis.
Creation of a J pouch is the gold standard surgical intervention in the treatment of chronic ulcerative colitis (UC). Pouchoscopy prior to ileostomy takedown is commonly performed. We describe the frequency, indication, and findings on pouchoscopy, and determine if pouchoscopy affects rates of complications after takedown. All UC or indeterminate inflammatory bowel disease patients with a J pouch were retrospectively evaluated from January 1994 to December 2014. Cases were defined as having routine (asymptomatic) pouchoscopy after pouch creation but before ileostomy takedown. Controls were defined as having no pouchoscopy or pouchoscopy on the same day as that of takedown. The study included 178 patients (81.5% cases, 18.5% controls). Fifty two percent of pouchoscopies were reported as normal. Common abnormal endoscopy findings included stricture (35%), pouchitis (7%), and cuffitis (0.7%). Length of stay during takedown hospitalization was shorter for cases than controls (3 vs. 5 days; p = 0.001), but neither short- nor long-term complications were statistically different between cases and controls. Abnormalities on pouchoscopy were not predictive for short-term complications (p = 0.73) or long-term complications (p = 0.55). Routine pouchoscopy did not delay takedown surgery in any of the included patients. Routine pouchoscopy may not be necessary prior to ileostomy takedown; its greatest utility is in patients with suspected pouch complications.


Extending the reach of public health genomics: what should be the agenda for public health in an era of genome-based and "personalized" medicine?
The decade following the completion of the Human Genome Project has been marked by divergent claims about the utility of genomics for improving population health. On the one hand, genomics is viewed as the harbinger of a brave new world in which novel treatments rectify known causes of disease. On the other hand, genomics may have little practical relevance to the principal causes or remedies of diseases which are predominantly social or environmental in origin, particularly in low- and middle-income countries. Those supportive of a role for public health genomics argue that increasing knowledge of genomics and molecular pathology could unlock effective diagnostic techniques and treatments, and better target public health interventions. To resolve some of these tensions, an international multidisciplinary meeting was held in May 2010 in Ickworth, United Kingdom, with the aim of setting an agenda for the development of public health in an era of genome-based and "personalized" medicine. A number of key themes emerged, suggesting a need to reconfigure both the focus for existing genomic research and the stage at which funding is targeted, so that priority is given to areas of greatest potential health impact and that translation from basic science to implementation is given greater emphasis. To support these developments, there should be an immediate, sustained and systematic effort to provide an evidence base. These deliberations formed the basis for six key recommendations, which could guide the practice of public health in an era of genomics and personalized medicine.


Hybrid median filter background estimator for correcting distortions in microtiter plate data.
Microtiter plate (MTP) assays often exhibit distortions, such as caused by edge-dependent drying and robotic fluid handling variation. Distortions vary by assay system but can have both systematic patterns (predictable from plate to plate) and random (sporadic and unpredictable) components. Random errors can be especially difficult to resolve by assay optimization alone, and postassay algorithms reported to date have smoothing effects that often blunt hits. We implemented a 5 x 5 bidirectional hybrid median filter (HMF) as a local background estimator to scale each data point to the MTP global background median and compared it with a recently described Discrete Fourier Transform (DFT) technique for correcting errors on computationally and experimentally generated MTP datasets. Experimental data were generated from a 384-well format fluorescent bioassay using cells engineered to express eGFP and DsRED. MTP arrays were produced with and without control treatments used to simulate hits in random wells. The HMF demonstrated the greatest improvements in MTP coefficients of variation and dynamic range (defined by the ratio of average hit amplitude to standard deviation, SD) for all synthetic and experimental MTPs examined. After HMF application to a MTP of eGFP signal from mouse insulinoma (MIN6) cells obtained by a plate-reader, the assay coefficient of variation (CV) decreased from 8.0% in the raw dataset to 5.1% and the hit amplitudes were reduced by only 1% while the DFT method increased the CV by 36.0% and reduced the hit amplitude by 21%. Thus, our results show that the bidirectional HMF provides superior corrections of MTP data distortions while at the same time preserving hit amplitudes and improving dynamic range. The software to perform hybrid median filter MTP corrections is available at http://bccg.burnham.org/HTS/HMF_Download_Page.aspx, password is pbushway.


Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review.
Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. This comprehensive literature review considers the evidence for and against an association between glucose or lipid dysregulation and eight separate second-generation antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole. This review also includes an assessment of the potential contributory role of treatment-induced weight gain in conferring risk for hyperglycaemia and dyslipidaemia during treatment with different antipsychotic medications. Substantial evidence from a variety of human populations, including some recent confirmatory evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. Comparison of mean weight changes and relative percentages of patients experiencing specific levels of weight increase from controlled, randomised clinical trials indicates that weight gain liability varies significantly across the different second generation antipsychotic agents. Clozapine and olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Risperidone, quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced diabetes mellitus and dyslipidaemia during risperidone treatment, despite a comparable volume of published data. A similarly smaller and inconsistent signal suggests limited if any increased risk of diabetes or dyslipidaemia during quetiapine treatment, but this is based on less published data than is available for risperidone. The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison to olanzapine. With increasing data from clinical trials but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism. In general, the rank order of risk observed for the second-generation antipsychotic medications suggests that the differing weight gain liability of atypical agents contributes to the differing relative risk of insulin resistance, dyslipidaemia and hyperglycaemia. This would be consistent with effects observed in nonpsychiatric samples, where risk for adverse metabolic changes tends to increase with increasing adiposity. From this perspective, a possible increase in risk would be predicted to occur in association with any treatment that produces increases in weight and adiposity. However, case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment. Pending further testing from preclinical and clinical studies, limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The results of studies in this area are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of type 2 diabetes mellitus and cardiovascular disease in populations that are often treated with second-generation antipsychotic medications.


HIV outbreaks among people who inject drugs in Europe, North America, and Israel.
During 2011-16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks.


Factors controlling the uptake of yeast copper/zinc superoxide dismutase into mitochondria.
We have previously shown that a fraction of yeast copper/zinc-superoxide dismutase (SOD1) and its copper chaperone CCS localize to the intermembrane space of mitochondria. In the present study, we have focused on the mechanism by which SOD1 is partitioned between cytosolic and mitochondrial pools. Using in vitro mitochondrial import assays, we show that only a very immature form of the SOD1 polypeptide that is apo for both copper and zinc can efficiently enter the mitochondria. Moreover, a conserved disulfide in SOD1 that is essential for activity must be reduced to facilitate mitochondrial uptake of SOD1. Once inside the mitochondria, SOD1 is converted to an active holo enzyme through the same post-translational modifications seen with cytosolic SOD1. The presence of high levels of CCS in the mitochondrial intermembrane space results in enhanced mitochondrial accumulation of SOD1, and this apparently involves CCS-mediated retention of SOD1 within mitochondria. This retention of SOD1 is not dependent on copper loading of the enzyme but does require protein-protein interactions at the heterodimerization interface of SOD1 and CCS as well as conserved cysteine residues in both molecules. A model for how CCS-mediated post-translational modification of SOD1 controls its partitioning between the mitochondria and cytosol will be presented.


Towards a biological basis for predicting nutrient partitioning: the dairy cow as an example.
Prediction of nutrient partitioning is a long-standing problem of animal nutrition that has still not been solved. Another substantial problem for nutritional science is how to incorporate genetic differences into nutritional models. These two problems are linked as their biological basis lies in the relative priorities of different life functions (growth, reproduction, health, etc.) and how they change both through time and in response to genetic selection. This paper presents recent developments in describing this biological basis and evidence in support of the concepts involved as they relate to nutrient partitioning. There is ample evidence that at different stages of the reproductive cycle various metabolic pathways, such as lipolysis and lipogenesis, are up or down regulated. The net result of such changes is that nutrients are channelled to differing extents to different organs, life functions and end-products. This occurs not as a homeostatic function of changing nutritional environment but rather as a homeorhetic function caused by the changing expression of genes for processes such as milk production through time. In other words, the animal has genetic drives and there is an aspect of nutrient partitioning that is genetically driven. Evidence for genetic drives other than milk production is available and is discussed. Genetic drives for other life functions than just milk imply that nutrient partitioning will change through lactation and according to genotype - i.e. it cannot be predicted from feed properties alone. Progress in describing genetic drives and homeorhetic controls is reviewed. There is currently a lack of good genetic measures of physiological parameters. The unprecedented level of detail and amounts of data generated by the advent of microarray biotechnology and the fields of genomics, proteomics, etc. should in the long-term provide the necessary information to make the link between genetic drives and metabolism. However, gene expression, protein synthesis etc, have all been shown to be environmentally sensitive. Thus, a major challenge in realising the potential afforded by this new technology is to be able to be able to distinguish genetically driven and environmentally driven effects on expression. To do this we need a better understanding of the basis for the interactions between genotypes and environments. The biological limitations of traditional evaluation of genotype × environment interactions and plasticity are discussed and the benefits of considering these in terms of trade-offs between life functions is put forward. Trade-offs place partitioning explicitly at the centre of the resource allocation problem and allow consideration of the effects of management and selection on multiple traits and on nutrient partitioning.


Control of human energy expenditure by cytochrome c oxidase subunit IV-2.
Resting metabolic rate (RMR) in humans shows pronounced individual variations, but the underlying molecular mechanism remains elusive. Cytochrome c oxidase (COX) plays a key role in control of metabolic rate, and recent studies of the subunit 4 isoform 2 (COX IV-2) indicate involvement in the cellular response to hypoxia and oxidative stress. We evaluated whether the COX subunit IV isoform composition may explain the pronounced individual variations in resting metabolic rate (RMR). RMR was determined in healthy humans by indirect calorimetry and correlated to levels of COX IV-2 and COX IV-1 in vastus lateralis. Overexpression and knock down of the COX IV isoforms were performed in primary myotubes followed by evaluation of the cell respiration and production of reactive oxygen species. Here we show that COX IV-2 protein is constitutively expressed in human skeletal muscle and strongly correlated to RMR. Primary human myotubes overexpressing COX IV-2 displayed markedly (>60%) lower respiration, reduced (>50%) cellular H2O2 production, higher resistance toward both oxidative stress, and severe hypoxia compared with control cells. These results suggest an important role of isoform COX IV-2 in the control of energy expenditure, hypoxic tolerance, and mitochondrial ROS homeostasis in humans.


Feature integration within and across visual streams occurs at different visual processing stages.
Direction repulsion is a perceptual illusion in which the directions of two superimposed surfaces are repulsed away from the real directions of motion. The repulsion is reduced when the surfaces differ in dorsal stream features such as speed. We have previously shown that segmenting the surfaces by color, a ventral stream feature, did not affect repulsion but instead reduced the time needed to process both surfaces. The current study investigated whether segmenting two superimposed surfaces by a feature coprocessed with direction in the dorsal stream (i.e., speed) would also reduce processing time. We found that increasing the speed of one or both surfaces reduced direction repulsion. Since color segmentation does not affect direction repulsion, these results suggest that motion processing integrates speed and direction prior to forming an object representation that includes ventral stream features such as color. Like our previous results for differences in color, differences in speed also decreased processing time. Therefore, the reduction in processing time derives from a later processing stage where both ventral and dorsal features bound into the object representations can reduce the time needed for decision making when those features differentiate the superimposed surfaces from each other.


Development of a dyadic sleep intervention for Alzheimer's disease patients and their caregivers.
This study aimed to refine a behavioral sleep intervention program targeting patients with Alzheimer's disease and their caregivers. In this case series, key components of the sleep program were built upon previous intervention studies of patients with cognitive impairment/dementia. The intervention consisted of five weekly sessions covering sleep hygiene, sleep compression, stimulus control, daily walking/light exposure, relaxation/mindfulness, and caregiver training to manage patients' behavioral problems. The materials and structure were iteratively refined based on feedback from caregivers and sleep educators. Sleep diaries were used to evaluate sleep outcomes. Five out of six enrolled dyads completed the sessions. Several revisions were made during testing: the last session was changed from telephone to in-person; some components (e.g., sleep scheduling, mindfulness) were rearranged within or across sessions; sleep educator guidelines for sleep scheduling, light exposure, and walking were revised. After the fifth dyad, no additional issues were identified by the caregiver or the sleep educator. Four patients and three caregivers had improved sleep at the last session. The iterative refinement process was successful in finalizing the intervention program, with evidence of sleep improvements. Formal pilot testing of the program will provide further information on feasibility and effectiveness.IMPLICATIONS FOR REHABILITATIONOur dyadic behavioral sleep program can be tailored to various types of sleep problems among patients with Alzheimer's disease and their family caregivers, with the goal of improving daytime function by reducing sleep disturbances at night.Caregiver training and participation of both members of the dyad in sleep management may benefit the patients' sleep and other health outcomes, reduce caregiver stress and burden, and ultimately delay or prevent institutionalization of Alzheimer's disease patients.


Social Participation and the Prevention of Decline in Effectance among Community-Dwelling Elderly: A Population-Based Cohort Study.
We examined the association between a decline in effectance and social participation (SP) from the perspective of the number and the type of SP in a prospective cohort study. Included in this analysis were community-dwelling elderly aged ≥ 65 without dependency on the basic activities of daily living and reporting a perfect baseline effectance score (n = 4,588; mean age 72.8 ± 5.7). SP was categorized into 5 types: neighborhood associations, hobby groups, local event groups, senior citizen clubs, and volunteer groups. Effectance was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence. Using logistic regression analysis, odds ratio (OR) and a 95% confidence interval (CI) for a decline in effectance were calculated. Age, family, BMI, pensions, medical history, medications, alcohol, smoking, cognitive function, depression, social support, ADL, and IADL were used as covariates. During the 3-year follow-up, 17.8% of eligible participants reported a decline in effectance. After adjustment for covariates, participation in various groups was associated with the preservation of effectance for both genders. Regarding the type of SP, among females, participation in neighborhood associations (OR: 0.62, 95%CI: 0.48-0.81), hobby groups (0.58, 0.43-0.77), local event groups (0.63, 0.47-0.86), and volunteer groups (0.53, 0.35-0.82) was inversely associated with a decline in effectance. Among males, the beneficial effect was more likely limited to hobby groups (0.59, 0.43-0.81) and volunteer groups (0.57, 0.39-0.83). Our results suggest that participation in a variety of social groups is effective for maintenance of older people's effectance, while the beneficial effect of each type of SP on effectance is stronger for females than for males. Recommending community-dwelling elderly to participate in social groups appropriate for their gender may be effective for successful aging.


The NMR structure and dynamics of the two-domain tick carboxypeptidase inhibitor reveal flexibility in its free form and stiffness upon binding to human carboxypeptidase B.
The structure of the tick carboxypeptidase inhibitor (TCI) and its backbone dynamics, free and in complex with human carboxypeptidase B, have been determined by NMR spectroscopy. Although free TCI has the same overall fold as that observed in the crystal structures of its complexes with metallocarboxypeptidase types A and B, there are structural differences at the linker between the two domains. The linker residues have greater flexibility than the globular domains, and the C-terminal residues are highly flexible in free TCI. Upon formation of a complex with carboxypeptidase B, TCI becomes more rigid, especially at the level of the linker and at the C-terminus, which is inserted into the active site groove of the carboxypeptidase. Solvent exchange rates of the backbone amide protons also show a strong reduction of the local TCI dynamics and a stabilization of its structure upon complex formation. The findings are consistent with a recognition mechanism that primarily involves the C-terminal domain, which adjusts its conformation and that of the linker, thus facilitating complex stabilization by further interactions between the N-terminal domain and an exosite of the carboxypeptidase. This adaptability enables TCI to tune its global conformation for proper interaction with distinct types of carboxypeptidases by a mechanism of induced fit. Our results provide new information about the structure-function relationship and stability of a molecule with potential biomedical applications in thrombolytic therapy. Furthermore, the plasticity of TCI makes it an ideal scaffold for developing stronger and/or more specific inhibitors directed toward modulating the activity of metallocarboxypeptidases.


Accuracy of 64-slice computed tomography for the preoperative detection of coronary artery disease in patients with chronic aortic regurgitation.
We studied the diagnostic accuracy of 64-slice computed tomography for the diagnosis of significant coronary artery disease (CAD) compared with conventional coronary angiography (CA) in patients with chronic aortic regurgitation (AR) referred for elective aortic valve surgery. Fifty consecutive patients with chronic AR (38 men, mean age 54 +/- 14 years) scheduled for valve surgery underwent 64-slice computed tomographic (CT) coronary angiography and CA. Significant stenosis was defined as a luminal diameter decrease >50%. Mean heart rate during CT scanning was 65.5 +/- 7.4 beats/min. Mean Agatston score was 136 +/- 278 (range 0 to 1207); prevalence of significant CAD in the study population was 26% (13 of 50 patients). Thirteen of 742 segments (1.8%) in 3 patients were considered nondiagnostic with computed tomography because of motion artifacts (n = 9) or calcium (n = 4). In a patient-based analysis taking nonevaluative segments as falsely positive, sensitivity, specificity, and positive and negative predictive values of computed tomography were 100%, 95%, 87%, and 100%, respectively. Preoperative CA could have been avoided in 70% of patients (35 of 50), CA would have been performed to confirm the CT diagnosis in 26% (13 of 50), and unnecessary CA would have been performed in 4% (2 of 50) on the basis of false-positive CT ratings. In conclusion, 64-slice CT coronary angiography provides high diagnostic accuracy for diagnosing significant CAD in patients with chronic AR and may be used as a filter test before valve surgery to decide whether CA should be performed.


Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome.
The 26S proteasome is a 2.5 MDa molecular machine that executes the degradation of substrates of the ubiquitin-proteasome pathway. The molecular architecture of the 26S proteasome was recently established by cryo-EM approaches. For a detailed understanding of the sequence of events from the initial binding of polyubiquitylated substrates to the translocation into the proteolytic core complex, it is necessary to move beyond static structures and characterize the conformational landscape of the 26S proteasome. To this end we have subjected a large cryo-EM dataset acquired in the presence of ATP and ATP-γS to a deep classification procedure, which deconvolutes coexisting conformational states. Highly variable regions, such as the density assigned to the largest subunit, Rpn1, are now well resolved and rendered interpretable. Our analysis reveals the existence of three major conformations: in addition to the previously described ATP-hydrolyzing (ATPh) and ATP-γS conformations, an intermediate state has been found. Its AAA-ATPase module adopts essentially the same topology that is observed in the ATPh conformation, whereas the lid is more similar to the ATP-γS bound state. Based on the conformational ensemble of the 26S proteasome in solution, we propose a mechanistic model for substrate recognition, commitment, deubiquitylation, and translocation into the core particle.


The small molecular weight, gamma-carboxyglutamic acid-containing protein of rabbit bone tissue.
The major gamma-carboxyglutamic acid-containing protein of rabbit cortical bone isolated and purified from near-neutral (pH 7.5) EDTA-extracts by DEAE-cellulose and Sephadex G 75 column chromatography had a molecular weight of about 5600 based on integral amino-acid composition; this was confirmed by high-performance liquid chromatography. The purified protein had high glutamic acid and aspartic-acid contents, two to three residues of gamma-carboxyglutamic acid per molecule and zero levels of serine, threonine, methionine, histidine and tryptophan. Equilibrium dialysis indicated that the protein has a weak affinity for calcium ions with a formation constant of 1515 M-1 at I 0.15, pH 7.5, 25 degrees C with a binding capacity of 2 mol calcium per mole protein.


Expedient synthesis of a phenanthro-imidazo-pyridine fused heteropolynuclear framework via CDC coupling: a new class of luminophores.
We herein report the design and synthesis of a group of fused phenanthro-imidazo[1,2-a]pyridine derivatives as a new class of luminescent materials through a Pd(ii) catalyzed intramolecular CDC (cross dehydrogenative coupling) reaction. This method thus unlocked a convenient & expedient way for the synthesis of a new molecular framework containing π-extended fused heteropolycycles. The heteropolycycles showed very good fluorescence properties both in solid and solution phases which were further utilized in live cell imaging. These kinds of molecules have potential to be used as therapeutic probes and also their solid state luminescence properties can be further utilized for making optoelectronic devices.


Stereoelectroencephalography: surgical methodology, safety, and stereotactic application accuracy in 500 procedures.
Stereoelectroencephalography (SEEG) methodology, originally developed by Talairach and Bancaud, is progressively gaining popularity for the presurgical invasive evaluation of drug-resistant epilepsies. To describe recent SEEG methodological implementations carried out in our center, to evaluate safety, and to analyze in vivo application accuracy in a consecutive series of 500 procedures with a total of 6496 implanted electrodes. Four hundred nineteen procedures were performed with the traditional 2-step surgical workflow, which was modified for the subsequent 81 procedures. The new workflow entailed acquisition of brain 3-dimensional angiography and magnetic resonance imaging in frameless and markerless conditions, advanced multimodal planning, and robot-assisted implantation. Quantitative analysis for in vivo entry point and target point localization error was performed on a sub--data set of 118 procedures (1567 electrodes). The methodology allowed successful implantation in all cases. Major complication rate was 12 of 500 (2.4%), including 1 death for indirect morbidity. Median entry point localization error was 1.43 mm (interquartile range, 0.91-2.21 mm) with the traditional workflow and 0.78 mm (interquartile range, 0.49-1.08 mm) with the new one (P < 2.2 × 10). Median target point localization errors were 2.69 mm (interquartile range, 1.89-3.67 mm) and 1.77 mm (interquartile range, 1.25-2.51 mm; P < 2.2 × 10), respectively. SEEG is a safe and accurate procedure for the invasive assessment of the epileptogenic zone. Traditional Talairach methodology, implemented by multimodal planning and robot-assisted surgery, allows direct electrical recording from superficial and deep-seated brain structures, providing essential information in the most complex cases of drug-resistant epilepsy.


Procalcitonin Identifies Cell Injury, Not Bacterial Infection, in Acute Liver Failure.
Because acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF. Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls. Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups-non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL. While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.


Needle-Free Injection of Vesicular Phospholipid Gels-A Novel Approach to Overcome an Administration Hurdle for Semisolid Depot Systems.
Vesicular phospholipid gels (VPGs) are depot formulations for the sustained release of drugs which are characterized by a high amount of phospholipids in the formulation. They consist of physiological excipients only and therefore display high biocompatibility. Their manufacture is simple, cheap, solvent free, and ideal for the processing of proteins and peptides because of the low stress on the molecule, for example, by elevated temperatures. One major hurdle of VPGs is their high viscosity which makes them hard to almost impossible to inject with conventional, thin needles used for subcutaneous administration. However, so far no data are published to overcome this administration challenge. In the present study, needle-free injection was investigated and successfully applied as a technology for the easy and elegant administration of VPGs. VPGs with different phospholipid content were injected with a Biojector 2000 into gelatin blocks and full thickness pig skin postmortem as in vitro models and the injection depth was determined after injection. The release behavior was tested after shearing the VPG with the device to evaluate the effect of shearing on the drug release from the formulation. No differences were observed when compared to an ejection with needle and syringe.


The influence of construct scale on the composition and functional properties of cartilaginous tissues engineered using bone marrow-derived mesenchymal stem cells.
Engineering cartilaginous tissue of a scale necessary to treat defects observed clinically is a well-documented challenge in the field of cartilage tissue engineering. The objective of this study was to determine how the composition and mechanical properties of cartilaginous tissues that are engineered by using bone marrow-derived mesenchymal stem cells (MSCs) depend on the scale of the construct. Porcine bone marrow-derived MSCs were encapsulated in agarose hydrogels, and constructs of different cylindrical geometries (Ø4×1.5 mm; Ø5×3 mm; Ø6×4.5 mm; Ø8×4.5 mm) were fabricated and maintained in a chemically defined serum-free medium supplemented with transforming growth factor-β3 for 42 days. Total sulfated glycosaminoglycan (sGAG) accumulation by day 42 increased from 0.14% w/w to 0.88% w/w as the construct geometry increased from Ø4×1.5 to Ø8×4.5 mm, with collagen accumulation increasing from 0.31% w/w to 1.62% w/w. This led to an increase in the dynamic modulus from 90.81 to 327.51 kPa as the engineered tissue increased in scale from Ø4×1.5 to Ø8×4.5 mm. By decreasing the external oxygen tension from 20% to 5%, it was possible to achieve these higher levels of mechanical functionality in the smaller engineered tissues. Constructs were then sectioned into smaller subregions to quantify the spatial accumulation of extracellular matrix components, and a model of oxygen diffusion and consumption was used to predict spatial gradients in oxygen concentration throughout the construct. sGAG accumulation was always highest in regions where oxygen concentration was predicted to be lowest. In addition, as the size of the engineered construct increased, different regions of the construct preferentially supported either sGAG or collagen accumulation, thus suggesting that gradients in regulatory factors other than oxygen were playing a role in determining levels of collagen synthesis. The identification of such factors and the means to control their spatial concentration within developing tissues represents a central challenge in engineering large cartilaginous grafts.


Agreement of histopathological findings of preoperative uterine curettage and hysterectomy specimens: impact of time factor and hormonal therapy.
To study the agreement of preoperative curettage and definitive histology after hysterectomy as well as the correlation of time factor and hormonal therapy to this agreement. This retrospective study was done in the Departments of Obstetrics and Gynecology and Pathology, Faculty of Medicine, Mansoura University, Egypt. Pathology reports of patients exposed to dilatation and curettage followed by hysterectomy during the period from May, 2004 to April, 2011 were reviewed. We reviewed 83 cases who fulfilled the inclusion criteria. There were non-significant differences between findings of D&C and hysterectomy specimens (P = 0.42). The concordance rate between D&C and hysterectomy was 79.5%. One case of endometrial carcinoma (1.2%), one case of simple endometrial hyperplasia, one case of atrophic endometrium, and two cases of endometrial polyp were diagnosed only after hysterectomy (4.8%). Furthermore, histologic examination of hysterectomy specimens confirmed only 8 of 13 cases (61.5%) of endometrial hyperplasia with atypia. No significant correlation of time factor and hormonal therapy to the agreement between findings of D&C and hysterectomy specimens (P = 0.58 & 0.19 respectively). There was no significant difference between preoperative endometrial histology and hysterectomy specimens (P = 0.41).This agreement had not been significantly affected by time interval and hormonal therapy. Future researches with larger number of cases are needed to confirm or disagree with our findings.


T cell response to Epstein-Barr virus transactivators in chronic rheumatoid arthritis.
Rheumatoid arthritis is a multistep disorder associated with autoimmune features of yet unknown etiology. Implication of viruses such as Epstein-Barr virus (EBV) in rheumatoid arthritis pathogenesis has been suspected on the basis of several indirect observations, but thus far, a direct link between EBV and rheumatoid arthritis has not been provided. Here we show that a large fraction of T cells infiltrating affected joints from a patient with chronic rheumatoid arthritis recognizes two EBV transactivators (BZLF1 and BMLF1) in a major histocompatibility complex-restricted fashion. Responses to these EBV antigens by synovial lymphocytes from several other chronic rheumatoid arthritis patients were readily detectable. Thus these results suggest a direct contribution of EBV to chronic rheumatoid arthritis pathogenesis. They also demonstrate for the first time the occurrence of T cell responses against EBV transactivating factors, which might be central in the control of virus reactivation.


The Influence of the CTIP Polymorphism, Q418P, on Homologous Recombination and Predisposition to Radiation-Induced Tumorigenesis (mainly rAML) in Mice.
Exposure to ionizing radiation increases the incidence of acute myeloid leukemia (AML), which has been diagnosed in Japanese atomic bombing survivors, as well as patients treated with radiotherapy. The genetic basis for susceptibility to radiation-induced AML is not well characterized. We previously identified a candidate murine gene for susceptibility to radiation-induced AML (rAML): C-terminal binding protein (CTBP)-interacting protein (CTIP)/retinoblastoma binding protein 8 (RBBP8). This gene is essential for embryonic development, double-strand break (DSB) resection in homologous recombination (HR) and tumor suppression. In the 129S2/SvHsd mouse strain, a nonsynonymous single nucleotide polymorphism (nsSNP) in Ctip, Q418P, has been identified. We investigated the role of Q418P in radiation-induced carcinogenesis and its effect on CTIP function in HR. After whole-body exposure to 3 Gy of X rays, 11 out of 113 (9.7%) 129S2/SvHsd mice developed rAML. Furthermore, 129S2/SvHsd mouse embryonic fibroblasts (MEFs) showed lower levels of recruitment of HR factors, Rad51 and replication protein A (RPA) to radiation-induced foci, compared to CBA/H and C57BL/6 MEFs, isolated from rAML-sensitive and resistant strains, respectively. Mitomycin C and alpha particles induced lower levels of sister chromatid exchanges in 129S2/SvHsd cells compared to CBA/H and C57BL/6. Our data demonstrate that Q418P nsSNP influences the efficiency of CTIP function in HR repair of DNA DSBs in vitro and in vivo, and appears to affect susceptibility to rAML.


Disclosure in times of ART: a relational analysis of social practices.
The reach of HIV counseling and testing has grown rapidly since the 2000s, particularly since 2007 when provider-initiated counseling and testing was implemented alongside voluntary counseling and testing and testing for the prevention of mother-to-child transmission. Nevertheless, we still know little about the attendant practices of disclosing HIV-positive status. Persistently high rates of non-disclosure raise difficult ethical, public health and human rights issues. The articles in this special issue show that disclosure practices in Africa not only follow the public health rationality but are shaped by fears of stigma that favor secrecy. They show how practices of disclosure are embedded in social relationships. More specifically, they present disclosure practices at the intersection of five social spaces: international norms, national legislation and public health recommendations; household and family settings; couples' relationships; parental relationships; and relationships between health workers and PLWHA. The authors describe how people pursue strategies of disclosure in one or more of these social spaces, which sometimes allows them to avoid barriers (for instance when they choose to disclose only partially to certain 'significant others' in the household). One important finding is that counselors often do not support PLWHA to disclose their HIV status. Counselors themselves may be influenced by divergent logics and experience conflicts in values; they may also lack sufficient knowledge and skills to discuss sensitive issues based on rapidly changing medical data and public health recommendations.


Effect of ozone on bronchial mucosal inflammation in asthmatic and healthy subjects.
Epidemiological studies suggestthat asthmatics are more affected by ozone than healthy people. This study tested three hypotheses (1) that short-term exposure to ozone induces inflammatory cell increases and up-regulation of vascular adhesion molecules in airway lavages and bronchial tissue 6 h after ozone exposure in healthy subjects; (2) these responses are exaggerated in subjects with mild allergic asthma; (3) ozone exacerbates pre-existent allergic airways inflammation. We exposed 15 mild asthmatic and 15 healthy subjects to 0.2 ppm of ozone or filtered air for 2 h on two separate occasions. Airway lavages and bronchial biopsies were obtained 6 h post-challenge. We found that ozone induced similar increases in bronchial wash neutrophils in both groups, although the neutrophil increase in the asthmatic group was on top of an elevated baseline. In healthy subjects, ozone exposure increased the expression of the vascular endothelial adhesion molecules P-selectin and ICAM- 1, as well as increasing tissue neutrophil and mast cell numbers. The asthmatics showed allergic airways inflammation at baseline but ozone did not aggravate this at the investigated time point. At 6 h post-ozone-exposure, we found no evidence that mild asthmatics were more responsive than healthy to ozone in terms of exaggerated neutrophil recruitment or exacerbation of pre-existing allergic inflammation. Further work is needed to assess the possibility of a difference in time kinetics between healthy and asthmatic subjects in their response to ozone.


Two novel variants on 13q22.1 are associated with risk of esophageal squamous cell carcinoma.
Chromosome 13q22.1 has previously been identified to be a susceptibility locus for pancreatic cancer in Chinese and European ancestry populations. This pleiotropy study aimed to identify novel variants in this region associated with susceptibility to different types of human cancer. To fine-map the 13q22.1 region, imputation analyses were conducted on the basis of the GWAS data of 2,031 esophageal squamous cell cancer (ESCC) cases and 2,044 controls and 5,930 SNPs (625 directly genotyped and 5,305 well imputed). Promising associations were then examined in ESCC (4,146 cases and 4,135 controls), gastric cardia cancer (1,894 cases and 1,912 controls), noncardia gastric cancer (1,007 cases and 2,243 controls), and colorectal cancer (1,111 cases and 1,138 controls). Fine mapping and biochemical analyses were further performed to elucidate the potential function of novel variants. Two novel variants, rs1924966 and rs115797771, were associated with ESCC risk (P = 1.37 × 10(-10) and P = 2.32 × 10(-10), respectively) and were also associated with risk of gastric cardia cancer (P = 0.0003 and P = 0.0018, respectively) but not gastric cancer and colorectal cancer. Fine-mapping revealed another SNP, rs58090485, in strong linkage disequilibrium with rs115797771 (r(2) = 0.94). Functional analysis showed that this SNP disturbs a transcriptional repressor binding to the promoter region of KLF5, which might result in high constitutional expression of KLF5. These results demonstrate that variants mapped on 13q22.1 are associated with the risk of different types of cancer. 13q22.1 might serve as a biomarker for the identification of individuals at risk for ESCC and gastric cardia cancer.


Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies.
It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.


A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations.
We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years. Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing. Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001). We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.


Are rises in Electro-Magnetic Field in the human environment, interacting with multiple environmental pollutions, the tripping point for increases in neurological deaths in the Western World?
Whilst humans evolved in the earth's Electro-Magnetic-Field (EMF) and sun-light, both being essential to life but too much sun and we burn. What happens if background EMF rise to critical levels, coinciding with increasing environmental pollutants? Two of the authors can look back over 50 clinical years and appreciate the profound changes in human morbidity across a range of disparate conditions - autoimmune diseases, asthma, earlier cancer incidence and reduced male sperm counts. In particular have been increased autism, dyslexia, Attention Deficit Hyperactivity Disorder and neurological diseases, such as Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Parkinson's Disease, Early Onset Dementia, Multiple System Atrophy and Progressive Supranuclear Palsy. What might have caused these changes-whilst genetic factors are taken as given, multiple environmental pollutants are associated with neurological disease although the mechanisms are unclear. The pace of increased neurological deaths far exceeds any Gompertzian explanation - that because people are living longer they are more likely to develop more age-related problems such as neurological disease. Using WHO global mortality categories of Neurological Disease Deaths (NDD) and Alzheimer's and Dementia deaths (Alz), updated June 2018, together they constitute Total Neurological Mortality (TNM), to calculate mortality rates per million for people aged 55-74 and for the over-75's in twenty-one Western countries. Recent increases in American people aged over-75's rose 49% from 1989 to 2015 but US neurological deaths increased five-fold. In 1989 based on Age-Standardised-Deaths-Rates America USA was 17th at 324 pm but rising to 539 pm became second highest. Different environmental/occupational factors have been found to be associated with neuro-degenerative diseases, including background EMF. We briefly explore how levels of EMF interact upon the human body, which can be described as a natural antennae and provide new evidence that builds upon earlier research to propose the following hypothesis. Based upon recent and new evidence we hypothesise that a major contribution for the relative sudden upsurge in neurological morbidity in the Western world (1989-2015), is because of increased background EMF that has become the tipping point-impacting upon any genetic predisposition, increasing multiple-interactive pollutants, such as rises in petro-chemicals, hormone disrupting chemicals, industrial, agricultural and domestic chemicals. The unprecedented neurological death rates, all within just twenty-five years, demand a re-examination of long-term EMF safety related to the increasing background EMF on human health. We do not wish to 'stop the modern world', only make it safer.


Oxalic acid is an elicitor of plant programmed cell death during Sclerotinia sclerotiorum disease development.
Accumulating evidence supports the idea that necrotrophic plant pathogens interact with their hosts by controlling cell death. Sclerotinia sclerotiorum is a necrotrophic ascomycete fungus with a broad host range (>400 species). Previously, we established that oxalic acid (OA) is an important pathogenicity determinant of this fungus. In this report, we describe a mechanism by which oxalate contributes to the pathogenic success of this fungus; namely, that OA induces a programmed cell death (PCD) response in plant tissue that is required for disease development. This response exhibits features associated with mammalian apoptosis, including DNA laddering and TUNEL reactive cells. Fungal mutants deficient in OA production are nonpathogenic, and apoptotic-like characteristics are not observed following plant inoculation. The induction of PCD by OA is independent of the pH-reducing abilities of this organic acid, which is required for sclerotial development. Moreover, oxalate also induces increased reactive oxygen species (ROS) levels in the plant, which correlate to PCD. When ROS induction is inhibited, apoptotic-like cell death induced by OA does not occur. Taken together, we show that Sclerotinia spp.-secreted OA is an elicitor of PCD in plants and is responsible for induction of apoptotic-like features in the plant during disease development. This PCD is essential for fungal pathogenicity and involves ROS. Thus, OA appears to function by triggering in the plant pathways responsible for PCD. Further, OA secretion by Sclerotinia spp. is not directly toxic but, more subtly, may function as a signaling molecule.


Sympathetic nervous system effects in the hands following a grade III postero-anterior rotatory mobilisation technique applied to T4: a randomised, placebo-controlled trial.
Joint mobilisation to the T4 vertebra has been advocated as a treatment for T4 syndrome. To date no controlled studies have investigated the effects of thoracic spinal manual therapy (SMT) applied to T4 on sympathetic activity in the hands. This study investigated whether a grade III postero-anterior rotatory joint mobilisation technique applied to the T4 vertebra at a frequency of 0.5 Hz had demonstrably greater effects than a validated placebo intervention on skin conductance (SC) in the hands of healthy subjects. A power analysis calculation was performed and using a double blind, placebo-controlled, independent groups design, 36 healthy subjects (18-35 years) were randomly assigned to two groups (placebo intervention or treatment intervention). A BioPac unit recorded continuous SC measures before, during and after each experimental intervention. An exit questionnaire was used to validate the expectancy effects of the placebo intervention. Results demonstrated a significant difference between groups in SC in the right hand during the post-treatment rest period (F = 4.888, p = 0.034); with the treatment intervention being sympathoexcitatory in nature. A trend towards a significant difference between groups was also demonstrated in the left hand during the rest period (F = 4.072, p = 0.052). This study provides preliminary evidence that joint mobilisation applied to the T4 vertebra at a frequency of 0.5 Hz can produce sympathoexcitatory effects in the hand. Further research is recommended in a patient population.


Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.
Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).


Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans.
Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric hypoxia with or without breathing oxygen-enriched air to ensure systemic normoxemia. With 9 h of hypoxia, arterial EPO increased (from 6.0±2.2 to 22.0±6.0 mU/ml, n=11, P<0.0001) and jugular venous EPO displayed a similar response (to 22.2±6.0 mU/ml, n=11). Thus, the arterio-jugular venous EPO difference was unaffected by hypoxia and also in cerebrospinal fluid EPO remained stable following hypoxic exposure (0.33±0.15 mU/ml, n=9 in normoxia vs. 0.41±0.20 mU/ml, n=9 in hypoxia, P=0.40). No change in plasma EPO was observed when only skin was exposed to hypobaric hypoxia (n=8). Thus, neither dermal oxygen exposure nor cerebral EPO production appears to be important for the systemic EPO response to acute hypoxia in healthy humans.


Strategies for large-scale targeted metabolomics quantification by liquid chromatography-mass spectrometry.
Advances in liquid chromatography-mass spectrometry (LC-MS) instruments and analytical strategies have brought about great progress in targeted metabolomics analysis. This methodology is now capable of performing precise targeted measurement of dozens or hundreds of metabolites in complex biological samples. Classic targeted quantification assay using the multiple reaction monitoring (MRM) mode has been the foundation of high-quality metabolite quantitation. However, utilization of this strategy in biological studies has been limited by its relatively low metabolite coverage and throughput capacity. A number of methods for large-scale targeted metabolomics assay which have been developed overcome these limitations. These strategies have enabled extended metabolite coverage which is defined as targeting of large numbers of metabolites, while maintaining reliable quantification performance. These recently developed techniques thus bridge the gap between traditional targeted metabolite quantification and untargeted metabolomics profiling, and have proven to be powerful tools for metabolomics study. Although the LC-MRM-MS strategy has been used widely in large-scale metabolomics quantification analysis due to its fast scan speed and ideal analytic stability, there are still drawbacks which are due to the low resolution of the triple quadrupole instruments used for MRM assays. New approaches have been developed to expand the options for large-scale targeted metabolomics study, using high-resolution instruments such as parallel reaction monitoring (PRM). MRM and PRM-based techniques are now attractive strategies for quantitative metabolomics analysis and high-throughput biomarker discovery. Here we provide an overview of the major developments in LC-MS-based strategies for large-scale targeted metabolomics quantification in biological samples. The advantages of LC-MRM/PRM-MS based analytical strategies which may be used in multiplexed and high throughput quantitation for a wide range of metabolites are highlighted. In particular, PRM and MRM strategies are compared, and we summarize the work flow commonly used for large-scale targeted metabolomics analysis including sample preparation, LC separation and data analysis, as well as recent applications in biological studies.


Input impedance of the lower abdominal aorta in chronically instrumented fetal sheep.
Five fetal sheep (gestational age, 118 to 125 days) were instrumented to measure impedances of the lower abdominal aorta. Four days after surgery, flow and pressure pulses were recorded during control conditions and during infusion of norepinephrine (0.3 to 3 micrograms.min-1.kg-1 body weight) or angiotensin II (0.2 to 3 micrograms.min-1.kg-1). The protocol was repeated after injection of hexamethonium (10 mg.kg-1). Moduli and phases of impedances for the first ten harmonics were calculated by fast Fourier transformation. During control, input resistance was 4300 +/- 940 dyne.s.cm-5 (mean +/- SD) at a mean blood flow of 13.3 +/- 2.4 cm3.s-1 and pressure of 54,960 +/- 6980 dyne.cm-2. Moduli fell to 50% of input resistance between 2 and 3 Hz and, declining continuously, reached a minimum of 20% near 10 to 12 Hz, then increased slightly to 30% at about 30 Hz. At the first three harmonics, flow was always leading pressure. Infusion of angiotensin or norepinephrine increased impedance moduli significantly. Resistance increase was largest with angiotensin (19,800 +/- 11,370 dyne.s.cm-5), but no difference was detectable between angiotensin and norepinephrine when related to the same increase of input resistance. The position of the minimum seemed to be unchanged at high resistance values, but relative impedance moduli were smaller than during control, and low-frequency phases were significantly more negative. An analog of inertance, compliance, and resistance to steady flow was used to simulate impedances, and the effect of resistance increases on flow waveforms in the fetal abdominal aorta was calculated.(ABSTRACT TRUNCATED AT 250 WORDS)


Ionic changes in the mitotic apparatus at the metaphase/anaphase transition.
We have employed a series of permeant, nontoxic, fluorescent probes to detect changes in ionic conditions within the mitotic apparatus of living endosperm cells of Haemanthus during the transition from metaphase to anaphase. Fluorescence emission intensity measurements from the spindle for chlorotetracycline (CTC) decline before the onset of anaphase, indicating a reduction in the amount of membrane-associated Ca2+ and suggesting an efflux of Ca2+ from membrane compartments into the spindle. Subsequent to the onset of anaphase, we observe increases in fluorescence with both 8-anilino-1-naphthalene sulfonate (ANS) and 3,3'-dipentyl 2,2'-dioxacarbocyanine (diO-C5(3)), sensitive to cationic and anionic charges at membrane surfaces, respectively. The increases with ANS and diO-C5(3) suggest that redistributions of ions within the spindle accompany anaphase motion. During the metaphase/anaphase transition, spindle membrane content remains constant, as evidenced by unchanging fluorescence with the hydrophobic probe, N-phenyl-1-naphthylamine (NPN). Shifts in emission intensity from the nonspindle cytoplasm or from the spindle poles do not accompany the changes in fluorescence we observe in the spindle, suggesting that any ionic fluxes responsible for the changes in fluorescence are restricted to the spindle domain.


Confocal Fluorescence Microscopy Platform Suitable for Rapid Evaluation of Small Fragments of Tissue in Surgical Pathology Practice.
Rapid advances in the fields of biophotonics, computer science, and instrumentation have allowed for high-resolution imaging of biologic tissues. To evaluate the quality of images from an optimized confocal fluorescence microscopy (CFM) platform for rapid evaluation of small fragments of tissue, compared with hematoxylin-eosin staining. Tissue fragments (up to 1.0 × 0.3 cm) were stained with 0.6 mM acridine orange for 60 seconds and imaged using a CFM platform at 488-nm and 785-nm wavelength. The imaged tissues were then fixed in formalin and processed to generate hematoxylin-eosin-stained tissue sections. The quality of CFM images was scored on a scale of 0 to 3 on the basis of the percentage of the CFM images with recognizable tissue architecture (0, 0%; 1, <20%; 2, 20%-50%; 3, >50%). The diagnoses made using CFM images were compared with those made using histopathologic analysis of the hematoxylin-eosin-stained tissue sections. We imaged 118 tissue fragments obtained from 40 breast, 23 lung, 39 kidney, and 16 liver surgical excision specimens. We acquired CFM images in 2 to 3 minutes; 95.8% (113 of 118) of images showed a quality score of 3, and 4.2% (5 of 118) had a score of 2. We achieved a sensitivity of 95.5%, specificity of 97.3%, positive predictive value of 95.5%, and negative predictive value of 97.3%. Our results demonstrate the suitability of the CFM platform for rapid and accurate evaluation of small tissue fragments in surgical pathology practice.


Modified diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score including deep white matter lesions predicts symptomatic intracerebral hemorrhage following intravenous thrombolysis.
The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used for the assessment of early ischemic changes (EICs) before thrombolysis. However, for symptomatic intracerebral hemorrhage (sICH) following intravenous recombinant tissue plasminogen activator (rt-PA), the prediction abilities of CT-ASPECTS, diffusion-weighted imaging (DWI)-ASPECTS, and DWI-ASPECTS including EICs in deep white matter (DWI-ASPECTS + W) are unclear. We investigated associations between each score and sICH following intravenous rt-PA. Data from consecutive patients who received intravenous rt-PA for acute ischemic stroke from 2005 to 2015 in four hospitals were retrospectively screened. We included data from patients who had undergone both CT and magnetic resonance imaging before thrombolysis and without evidence of posterior circulation stroke. We analyzed the ability of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W to predict sICH, accompanied by an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 within the initial 36 h. Of 455 patients (273 men, median 75 years old), sICH occurred in 15 patients (3.3%). Receiver operating characteristics curve analysis showed that the optimal cut-offs of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W for predicting sICH were ≤ 9 (sensitivity 60.0%, specificity 59.8%, c-statistic 0.625), ≤ 6 (sensitivity 53.3%, specificity 80.9%, c-statistic 0.718), and ≤ 8 (sensitivity 86.7%, specificity 55.9%, c-statistic 0.756), respectively. A DWI-ASPECTS + W of ≤ 8 was independently associated with sICH (odds ratio 5.21, 95% confidence interval 1.30-35.31) after adjustment for pretreatment with antithrombotic agents, pretreatment NIHSS score, and large artery occlusions. DWI-ASPECTS + W predicted sICH in patients with acute anterior circulation stroke receiving intravenous rt-PA.


Clinical Trials Eligibility of Patients With Malignant Pleural Mesothelioma: Use of Novel Therapies and Outcomes.
Studies of bevacizumab and pembrolizumab in the treatment of malignant pleural mesothelioma suggest anticancer efficacy; clinical trial populations are not reflective of real-world patients. We aimed to determine the proportion of real-world patients who would be eligible for trials, identify patients who participated in clinical trials, and examine treatment and outcome data. Consecutive patients with unresectable malignant pleural mesothelioma seen at our center from January 2012 to July 2018 were assessed with regards to their eligibility for Mesothelioma Avastin Cisplatin Study (MAPS) and KEYNOTE-028 clinical trials. Prognostic information, treatment use, and overall survival (OS) data were also collected. A total of 133 patients were included: 50% and 37%, respectively, did not meet trial eligibility for MAPS or KEYNOTE-028, most commonly owing to age ≥75 (23%), Eastern Cooperative Oncology Group performance status of ≥2 (21%), concomitant medication (21%), or comorbidity (12%). MAPS eligibility did not correlate with use of bevacizumab (P = .30) or improved OS (P = .87). Eligibility for KEYNOTE-028 correlated with pembrolizumab use (P < .001), but not improved OS (P = .21). Patients who received an investigational anticancer therapy on any clinical trial had improved OS: 32.4 (95% CI, 23.9-40.9) months versus 20.5 (95% CI, 15.8-25.3) months (P = .01). Only ≤63% of our patients were eligible for these trials, highlighting the differences between real-world patients and the highly select trial population. Our patients who participated in clinical trials had superior OS, further emphasizing the selection bias in the trial population.


What your leader expects of you.
The success of an executive team depends heavily on the relationships the boss has with his or her direct reports. Yet the leadership literature has had little to say about what is expected in those relationships-on either side. Larry Bossidy, formerly the chairman and CEO of Honeywell, and before that of AlliedSignal, shares what he calls "the CEO compact," detailing the behaviors a leader should look for in subordinates and what they should be able to expect in return. A CEO's best people, he says, know when a situation calls for them to get involved. They generate ideas-remembering that some of the best ones may sound crazy at first. They are willing to collaborate, putting the long-term good of the company above short-term goals of their divisions. They step up to lead initiatives, even if the outcome is uncertain. They develop leaders among their people, especially through direct involvement in performance appraisals. They stay current on world events and anticipate how those events may affect the company and its competition. They drive their own growth by exposing themselves to new people and ideas and by accepting demanding assignments. And they sustain these behaviors in bad times as well as good. On the other side of the compact, the boss should provide clarity of direction; set goals and objectives; give frequent, specific, and immediate feedback; be decisive and timely; demonstrate honesty and candor; and offer an equitable compensation plan. Executives who aren't lucky enough to have such a boss can create a compact with their own subordinates, Bossidy says, and demonstrate by example. The result will be to improve team and company performance and accelerate individual growth.


Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines.
Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D2 [PGD2]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C4, LTD4, and LTE4, are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD2, IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. Human ILC2s expressed the LT receptor CysLT1, levels of which were increased in atopic subjects. CysLTs, particularly LTE4, induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE4 enhanced the effect of PGD2, IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE4 was inhibited by montelukast, a CysLT1 antagonist. Interestingly, addition of IL-2 to LTE4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CysLTs, particularly LTE4, are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators.


Beyond Beer's Law: Why the Index of Refraction Depends (Almost) Linearly on Concentration.
Beer's empiric law states that absorbance is linearly proportional to the concentration. Based on electromagnetic theory, an approximately linear dependence can only be confirmed for comparably weak oscillators. For stronger oscillators the proportionality constant, the molar attenuation coefficient, is modulated by the inverse index of refraction, which is itself a function of concentration. For comparably weak oscillators, the index of refraction function depends, like absorbance, linearly on concentration. For stronger oscillators, this linearity is lost, except at wavenumbers considerably lower than the oscillator position. In these transparency regions, linearity between the change of the index of refraction and concentration is preserved to a high degree. This can be shown with help of the Kramers-Kronig relations which connect the integrated absorbance to the index of refraction change at lower wavenumbers than the corresponding band. This finding builds the foundation not only for refractive index sensing, but also for new interferometric approaches in IR spectroscopy, which allow measuring the complex index of refraction function.


Mindfulness-based cognitive therapy for recurrent major depression: A 'best buy' for health care?
While mindfulness-based cognitive therapy is effective in reducing depressive relapse/recurrence, relatively little is known about its health economic properties. We describe the health economic properties of mindfulness-based cognitive therapy in relation to its impact on depressive relapse/recurrence over 2 years of follow-up. Non-depressed adults with a history of three or more major depressive episodes were randomised to mindfulness-based cognitive therapy + depressive relapse active monitoring (n = 101) or control (depressive relapse active monitoring alone) (n = 102) and followed up for 2 years. Structured self-report instruments for service use and absenteeism provided cost data items for health economic analyses. Treatment utility, expressed as disability-adjusted life years, was calculated by adjusting the number of days an individual was depressed by the relevant International Classification of Diseases 12-month severity of depression disability weight from the Global Burden of Disease 2010. Intention-to-treat analysis assessed the incremental cost-utility ratios of the interventions across mental health care, all of health-care and whole-of-society perspectives. Per protocol and site of usual care subgroup analyses were also conducted. Probabilistic uncertainty analysis was completed using cost-utility acceptability curves. Mindfulness-based cognitive therapy participants had significantly less major depressive episode days compared to controls, as supported by the differential distributions of major depressive episode days (modelled as Poisson, p < 0.001). Average major depressive episode days were consistently less in the mindfulness-based cognitive therapy group compared to controls, e.g., 31 and 55 days, respectively. From a whole-of-society perspective, analyses of patients receiving usual care from all sectors of the health-care system demonstrated dominance (reduced costs, demonstrable health gains). From a mental health-care perspective, the incremental gain per disability-adjusted life year for mindfulness-based cognitive therapy was AUD83,744 net benefit, with an overall annual cost saving of AUD143,511 for people in specialist care. Mindfulness-based cognitive therapy demonstrated very good health economic properties lending weight to the consideration of mindfulness-based cognitive therapy provision as a good buy within health-care delivery.


Demographic history and rare allele sharing among human populations.
High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2-4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.


International optimism: Correlates and consequences of dispositional optimism across 61 countries.
The current exploratory study sought to examine dispositional optimism, or the general expectation for positive outcomes, around the world. Dispositional optimism and possible correlates were assessed across 61 countries (N = 15,185; mean age = 21.92; 77% female). Mean-level differences in optimism were computed along with their relationships with individual and country-level variables. Worldwide, mean optimism levels were above the midpoint of the scale. Perhaps surprisingly, country-level optimism was negatively related to gross domestic product per capita, population density, and democratic norms and positively related to income inequality and perceived corruption. However, country-level optimism was positively related to projected economic improvement. Individual-level optimism was positively related to individual well-being within every country, although this relationship was less strong in countries with challenging economic and social circumstances. While individuals around the world are generally optimistic, societal characteristics appear to affect the degree to which their optimism is associated with psychological well-being, sometimes in seemingly anomalous ways.


Why do humans get acne? A hypothesis.
Acne is a disease unique to humans and is associated with sebaceous glands that are found at high density on the scalp, forehead and face. Despite being a near universal problem in adolescence, the reason why such troublesome sebaceous glands exist at all is not well understood. Some interesting theories have been postulated including roles for skin maintenance, immunological function and perhaps even pheromones, but pre-pubertal skin which has sebaceous glands that are largely inactive, is healthy. Dystocia, obstructed labour, is unique to humans and no other animal has as much trouble giving birth. This is thought to reflect the relatively large human foetal head and proportionally small maternal pelvis. Noting the high density of sebaceous glands on the face, chest and back; these are exactly the same structures that pose the greatest obstruction during childbirth. Sebaceous glands develop after the fourth month of gestation and are large and well-developed at birth. Sebum production is also relatively high at birth. Having extra lubrication at these sites would help make the baby more slippery for birth conferring a selective advantage to successful delivery, as does the presence of the vernix caseosa, a white creamy substance, unique to humans that coats new-born infants. It is proposed that the sebaceous glands that cause acne are present on the face and forehead as they confer a selective advantage by 'lubricating' the widest parts of the new born baby to ease the passage of childbirth. Later in life, sebaceous glands may be inappropriately and pathologically primed, driven by a combination of hormones, diet and lifestyle to create acne.


Electronic structure of Cu(3)N films studied by soft x-ray spectroscopy.
Soft x-ray emission spectroscopy was used to characterize the electronic structure of seven copper nitride films, one synthesized with atomic layer deposition (ALD) and six grown with chemical vapor deposition (CVD) at different preparation temperatures. Interpretation of the x-ray emission spectra was supported by calculations of the electronic structure for bulk pure Cu(3)N and Cu(3)N with: an excess of Cu atoms, oxygen or carbon impurities, and N vacancies. The calculations are shown to describe the experimental spectra quite well. Analysis of the x-ray spectra suggests that films grown in copper rich environments and above a cut-off temperature of approximately 360 °C have a growing fraction of copper enriched areas, while films prepared below this temperature do not have these areas with excess copper.


"Knife before wife": an exploratory study of gender and the UK medical profession.
The paper aims to explore the increasing feminisation of the medical profession and career progression of women in the medical profession. Furthermore, the paper explores the implications of gender segregation in the medical profession for health service provision. The paper presents an overview of studies in this area and draws upon primary, empirical research with medical practitioners and medical students. However, unlike most other studies the sample includes male and female participants. The research involved elite interviews and self-completion questionnaires in order to provide perspectives of both male and female medical practitioners and medical students. The findings are consistent with those of other studies; that gender discrimination and segregation is still prevalent in the medical profession. But there are significant differences in perceptions between the genders. Moreover, it is concluded that the gendered career structure and organisational culture of the health sector and medical profession create a role conflict between personal and professional lives. The current difficulties in reconciling this role conflict create barriers to the career progression of women in the medical profession. Further research in this area could include a longitudinal study of medical students and the impact of changes in the design of medical training and career structures to assess whether these changes enable female career progression in the medical profession. Further analysis is needed of gendered practices and career development in specific specialist areas, and the role of the medical profession, NHS and Royal Colleges should play in addressing gender and career progression in medicine. Gender segregation (vertical and horizontal) in the medical profession will have implications for the attraction, retention and increased shortages of practitioners in hospital and surgical specialities with the resultant economic and health provision inefficiencies. The paper provides a review of literature in this area, thereby providing a longitudinal perspective of gender and the medical profession. Moreover, the research sample includes both male and female medical practitioners and medical students, which provides perspectives from both genders and from those who have experience within the medical profession and from those beginning their career in the medical profession. The research will be of value to the medical profession, the NHS and Royal Colleges of Medicine.


Optimization of output power in hollow-waveguide lasers.
We present an approximate analysis of the nonlinear operation of the hollow-waveguide laser, including gain saturation and longitudinal- as well as transverse-field distribution of the laser mode. The model presented is general and can be applied to the study of an arbitrary configuration of the waveguide laser. The laser characteristics obtained reveal that the optimal position of the output mirror (which provides maximal power efficiency of the laser system with the other parameters constant) depends on the output-power level and the mirror-reflectivity coefficient. Moreover, it has been shown that when an addition device is introduced into the cavity, the power efficiency also depends on which end of the laser the light power is extracted from.