International comparison of quality indicators in United States, Icelandic and Canadian nursing facilities.
To discuss the results of a comparison using minimum data set (MDS)-based quality indicators (QIs) for residents in nursing facilities in three countries (Iceland; Ontario, Canada; and Missouri, United States) together with implications regarding nursing practices and resident outcomes in these countries. Data were extracted from databases in each country for four consecutive quarterly periods during 1997 and 1998. All facilities investigated had the required consecutive quarterly data. Analytical techniques were matched to measure resident outcomes using the same MDS-based QIs in the three countries. Similarities among the three countries included the use of nine or more multiple medications, weight loss, urinary tract infection, dehydration, and behavioural symptoms that affect others. Differences among the three countries included bowel and bladder incontinence, indwelling catheter use, fecal impaction, tube feeding use, development of pressure ulcers, bedridden residents, physical restraint use, depression without receiving antidepressant therapy, residents with depression, use of anti-anxiety or hypnotic drugs, use of anti-psychotic drugs in the absence of psychotic and related conditions, residents spending little or no time in activities, and falls. Comparisons highlighted differences in clinical practices among countries, which may account for differences in resident outcomes. Learning from each other's best practices can improve the quality of care for older people in nursing homes in many countries.


Biodiversity inventories in high gear: DNA barcoding facilitates a rapid biotic survey of a temperate nature reserve.
Comprehensive biotic surveys, or 'all taxon biodiversity inventories' (ATBI), have traditionally been limited in scale or scope due to the complications surrounding specimen sorting and species identification. To circumvent these issues, several ATBI projects have successfully integrated DNA barcoding into their identification procedures and witnessed acceleration in their surveys and subsequent increase in project scope and scale. The Biodiversity Institute of Ontario partnered with the rare Charitable Research Reserve and delegates of the 6th International Barcode of Life Conference to complete its own rapid, barcode-assisted ATBI of an established land trust in Cambridge, Ontario, Canada. The existing species inventory for the rare Charitable Research Reserve was rapidly expanded by integrating a DNA barcoding workflow with two surveying strategies - a comprehensive sampling scheme over four months, followed by a one-day bioblitz involving international taxonomic experts. The two surveys resulted in 25,287 and 3,502 specimens barcoded, respectively, as well as 127 human observations. This barcoded material, all vouchered at the Biodiversity Institute of Ontario collection, covers 14 phyla, 29 classes, 117 orders, and 531 families of animals, plants, fungi, and lichens. Overall, the ATBI documented 1,102 new species records for the nature reserve, expanding the existing long-term inventory by 49%. In addition, 2,793 distinct Barcode Index Numbers (BINs) were assigned to genus or higher level taxonomy, and represent additional species that will be added once their taxonomy is resolved. For the 3,502 specimens, the collection, sequence analysis, taxonomic assignment, data release and manuscript submission by 100+ co-authors all occurred in less than one week. This demonstrates the speed at which barcode-assisted inventories can be completed and the utility that barcoding provides in minimizing and guiding valuable taxonomic specialist time. The final product is more than a comprehensive biotic inventory - it is also a rich dataset of fine-scale occurrence and sequence data, all archived and cross-linked in the major biodiversity data repositories. This model of rapid generation and dissemination of essential biodiversity data could be followed to conduct regional assessments of biodiversity status and change, and potentially be employed for evaluating progress towards the Aichi Targets of the Strategic Plan for Biodiversity 2011-2020.


Choroidal venous pulsations at an arterio-venous crossing in polypoidal choroidal vasculopathy.
It has been reported that pulsations in abnormal vessels are observed on indocyanine green (ICG) angiography in half of patients with polypoidal choroidal vasculopathy (PCV), although the mechanism of the pulsation is unknown. In this study, we report a case of PCV showing venous pulsations at an arterio-venous (A-V) crossing, and discuss a possible mechanism of polypoidal vessel formation and pulsations in PCV. A 66-year-old female presented with a reddish-orange elevated lesion and serous retinal detachment in the macula of her left eye, and was diagnosed as PCV. She was treated with photodynamic therapy (PDT), and followed-up through routine examinations, including ICG angiography. ICG angiography at presentation showed a branching vascular network and choroidal venules with dye leakage (polypoidal vessels) in the left eye. Pulsations, supposedly of venous origin, were observed at an A-V crossing in the abnormal vessels. Within 3 months after PDT, the polypoidal vessel ceased to leak and the pulsations vanished. The reddish-orange lesion gradually decreased in size with complete disappearance of retinal detachment. This study suggests that an unusual compression at an A-V crossing may make a venule polypoidal, and fluctuations of blood flow and pressure in the venule may cause pulsatile movements of the vessel wall.


Seaweed Secondary Metabolites In Vitro and In Vivo Anticancer Activity.
Isolation, finding or discovery of novel anticancer agents is very important for cancer treatment, and seaweeds are one of the largest producers of chemically active metabolites with valuable cytotoxic properties, and therefore can be used as new chemotherapeutic agents or source of inspiration to develop new ones. Identification of the more potent and selective anticancer components isolated from brown, green and red seaweeds, as well as studies of their mode of action is very attractive and constitute a small but relevant progress for pharmacological applications. Several researchers have carried out in vitro and in vivo studies in various cell lines and have disclosed the active metabolites among the terpenoids, including carotenoids, polyphenols and alkaloids that can be found in seaweeds. In this review the type of metabolites and their cytotoxic or antiproliferative effects will be discussed additionally their mode of action, structure-activity relationship and selectivity will also be revealed. The diterpene dictyolactone, the sterol cholest-5-en-3β,7α-diol and the halogenated monoterpene halomon are among the reported compounds, the ones that present sub-micromolar cytotoxicity. Additionally, one dimeric sesquiterpene of the cyclolaurane-type, three bromophenols and one halogenated monoterpene should be emphasized because they exhibit half maximal inhibitory concentration (IC50) values between 1⁻5 µM against several cell lines.


Costs of conservative management of early-stage prostate cancer compared to radical prostatectomy-a claims data analysis.
Due to widespread PSA testing incidence rates of localized prostate cancer increase but curative treatment is often not required. Overtreatment imposes a substantial economic burden on health care systems. We compared the direct medical costs of conservative management and radical therapy for the management of early-stage prostate cancer in routine care. An observational study design is chosen based on claims data of a German statutory health insurance fund for the years 2008-2011. Three hundred fifty-three age-matched men diagnosed with prostate cancer and treated with conservative management and radical prostatectomy, are included. Individuals with diagnoses of metastases or treatment of advanced prostate cancer are excluded. In an excess cost approach direct medical costs are considered from an insured community perspective for in- and outpatient care, pharmaceuticals, physiotherapy, and assistive technologies. Generalized linear models adjust for comorbidity by Charlson comorbidity score and recycled predictions method calculates per capita costs per treatment strategy. After follow-up of 2.5 years per capita costs of conservative management are €6611 lower than costs of prostatectomy ([-9734;-3547], p < 0.0001). Complications increase costs of assistive technologies by 30% (p = 0.0182), but do not influence any other costs. Results are robust to cost outliers and incidence of prostate cancer diagnosis. The short time horizon does not allow assessing long-term consequences of conservative management. At a time horizon of 2.5 years, conservative management is preferable to radical prostatectomy in terms of costs. Claims data analysis is limited in the selection of comparable treatment groups, as clinical information is scarce and bias due to non-randomization can only be partly mitigated by matching and confounder adjustment.


Broadband infrared vibrational nano-spectroscopy using thermal blackbody radiation.
Infrared vibrational nano-spectroscopy based on scattering scanning near-field optical microscopy (s-SNOM) provides intrinsic chemical specificity with nanometer spatial resolution. Here we use incoherent infrared radiation from a 1400 K thermal blackbody emitter for broadband infrared (IR) nano-spectroscopy. With optimized interferometric heterodyne signal amplification we achieve few-monolayer sensitivity in phonon polariton spectroscopy and attomolar molecular vibrational spectroscopy. Near-field localization and nanoscale spatial resolution is demonstrated in imaging flakes of hexagonal boron nitride (hBN) and determination of its phonon polariton dispersion relation. The signal-to-noise ratio calculations and analysis for different samples and illumination sources provide a reference for irradiance requirements and the attainable near-field signal levels in s-SNOM in general. The use of a thermal emitter as an IR source thus opens s-SNOM for routine chemical FTIR nano-spectroscopy.


The influence of previous robotic experience in the initial learning curve of laparoscopic radical prostatectomy.
This study analyzed the impact of the experience with Robotic-Assisted Laparoscopic Prostatectomy (RALP) on the initial experience with Laparoscopic Radical Prostatectomy (LRP) by examining perioperative results and early outcomes of 110 patients. LRPs were performed by two ro-botic fellowship trained surgeons with daily practice in RALP. 110 LRP were performed to treat aleatory selected patients. The patients were divided into 4 groups for prospective analyses. A transperitoneal approach that simulates the RALP technique was used. The median operative time was 163 minutes (110-240), and this time significantly decreased through case 40, when the time plateaued (p=0.0007). The median blood loss was 250mL. No patients required blood transfusion. There were no life-threatening complications or deaths. Minor complications were uniformly distributed along the series (P=0.6401). The overall positive surgical margins (PSM) rate was 28.2% (20% in pT2 and 43.6% in pT3). PSM was in the prostate apex in 61.3% of cases. At the 12-month follow-up, 88% of men were continent (0-1 pad). The present study shows that there are multiple learning curves for LRP. The shallowest learning curve was seen for the operative time. Surgeons transitioning between the RALP and LRP techniques were considered competent based on the low perioperative complication rate, absence of major complications, and lack of blood transfusions. This study shows that a learning curve still exists and that there are factors that must be considered by surgeons transitioning between the two techniques.


The high burden of injuries in South Africa.
To estimate the magnitude and characteristics of the injury burden in South Africa within a global context. The Actuarial Society of South Africa demographic and AIDS model (ASSA 2002) - calibrated to survey, census and adjusted vital registration data - was used to calculate the total number of deaths in 2000. Causes of death were determined from the National Injury Mortality Surveillance System profile. Injury death rates and years of life lost (YLL) were estimated using the Global Burden of Disease methodology. National years lived with disability (YLDs) were calculated by applying a ratio between YLLs and YLDs found in a local injury data source, the Cape Metropole Study. Mortality and disability-adjusted life years' (DALYs) rates were compared with African and global estimates. Interpersonal violence dominated the South African injury profile with age-standardized mortality rates at seven times the global rate. Injuries were the second-leading cause of loss of healthy life, accounting for 14.3% of all DALYs in South Africa in 2000. Road traffic injuries (RTIs) are the leading cause of injury in most regions of the world but South Africa has exceedingly high numbers - double the global rate. Injuries are an important public health issue in South Africa. Social and economic determinants of violence, many a legacy of apartheid policies, must be addressed to reduce inequalities in society and build community cohesion. Multisectoral interventions to reduce traffic injuries are also needed. We highlight this heavy burden to stress the need for effective prevention programmes.


The dynamics of polymerized carbon nanotubes in semiconductor polymer electronics and electro-mechanical sensing.
Polymerized carbon nanotubes (CNTs) are promising materials for polymer-based electronics and electro-mechanical sensors. The advantage of having a polymer nanolayer on CNTs widens the scope for functionalizing it in various ways for polymer electronic devices. However, in this paper, we show for the first time experimentally that, due to a resistive polymer layer having carbon nanoparticle inclusions and polymerized carbon nanotubes, an interesting dynamics can be exploited. We first show analytically that the relative change in the resistance of a single isolated semiconductive nanotube is directly proportional to the axial and torsional dynamic strains, when the strains are small, whereas, in polymerized CNTs, the viscoelasticity of the polymer and its effective electrical polarization give rise to nonlinear effects as a function of frequency and bias voltage. A simplified formula is derived to account for these effects and validated in the light of experimental results. CNT-polymer-based channels have been fabricated on a PZT substrate. Strain sensing performance of such a one-dimensional channel structure is reported. For a single frequency modulated sine pulse as input, which is common in elastic and acoustic wave-based diagnostics, imaging, microwave devices, energy harvesting, etc, the performance of the fabricated channel has been found to be promising.


Structural basis for catalysis by the mono- and dimetalated forms of the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase.
Biosynthesis of lysine and meso-diaminopimelic acid in bacteria provides essential components for protein synthesis and construction of the bacterial peptidoglycan cell wall. The dapE operon enzymes synthesize both meso-diaminopimelic acid and lysine and, therefore, represent potential targets for novel antibacterials. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase functions in a late step of the pathway and converts N-succinyl-L,L-diaminopimelic acid to L,L-diaminopimelic acid and succinate. Deletion of the dapE gene is lethal to Helicobacter pylori and Mycobacterium smegmatis, indicating that DapE's are essential for cell growth and proliferation. Since there are no similar pathways in humans, inhibitors that target DapE may have selective toxicity against only bacteria. A major limitation in developing antimicrobial agents that target DapE has been the lack of structural information. Herein, we report the high-resolution X-ray crystal structures of the DapE from Haemophilus influenzae with one and two zinc ions bound in the active site, respectively. These two forms show different activity. Based on these newly determined structures, we propose a revised catalytic mechanism of peptide bond cleavage by DapE enzymes. These structures provide important insight into catalytic mechanism of DapE enzymes as well as a structural foundation that is critical for the rational design of DapE inhibitors.


Bioactive lysophospholipids: role in regulation of aqueous humor outflow and intraocular pressure in the context of pathobiology and therapy of glaucoma.
Homeostasis of aqueous humor (AH) outflow and intraocular pressure (IOP) is essential for normal vision. Impaired AH outflow through the trabecular meshwork (TM) and a resultant elevation in IOP are common changes in primary open-angle glaucoma (POAG), which is the most prevalent form of glaucoma. Although elevated IOP has been recognized as a definitive risk factor for POAG and lowering elevated IOP remains a mainstay for glaucoma treatment, little is known about the molecular mechanisms, especially external cues and intracellular pathways, involved in the regulation of AH outflow in both normal and glaucomatous eyes. In addition, despite the recognition that increased resistance to AH outflow via the conventional pathway consisting of TM and Schlemm's canal is the main cause for elevated IOP, there are no clinically approved drugs that target the conventional pathway to lower IOP in glaucoma patients. The aim of this article is to briefly review published work on the importance of bioactive lysophospholipids (eg, lysophosphatidic acid and sphingosine-1-phosphate), their receptors, metabolism, signaling, and role in the regulation of AH outflow via the TM and IOP, and to discuss pharmacological targeting of key proteins in the lysophospholipid signaling pathways to lower IOP in glaucoma patients.


An emergency department-based nurse discharge coordinator for elder patients: does it make a difference?
To evaluate the impact of an emergency department (ED)-based nurse discharge plan coordinator (NDPC) on unscheduled return visits within 14 days of discharge, satisfaction with discharge recommendations, adherence with discharge instructions, and perception of well-being of elder patients discharged from the ED. Patients aged 75 years and older discharged from the ED of the Sir Mortimer B. Davis-Jewish General Hospital were recruited in a pre/post study. During the pre (control) phase, study patients (n = 905) received standard discharge care. Patients in the post (intervention) phase (n = 819) received the intervention of an ED-based NDPC. The intervention included patient education, coordination of appointments, patient education, telephone follow-up, and access to the NDPC for up to seven days following discharge. Patients in the two groups were similar with respect to gender and age. However, the patients managed by the ED NDPC appeared to be, at baseline, less autonomous, frailer, and sicker. The unadjusted relative risk for unscheduled return visits within 14 days of discharge was 0.79 (95% confidence interval [95% CI] = 0.62 to 1.02). A relative risk reduction of 27% (95% CI = 0% to 44%) for unscheduled return visits was observed for up to eight days postdischarge, and a relative risk reduction of 19% (95% CI = -2% to 36%) for unscheduled return visits was observed for up to 14 days postdischarge. Significant increases in satisfaction with the clarity of discharge information and perceived well-being were also noted. An ED-based NDPC, dedicated specifically to the discharge planning care of elder patients, reduces the proportion of unscheduled ED return visits and facilitates the transition from ED back home and into the community health care network.


Mouthpart conduit sizes of fluid-feeding insects determine the ability to feed from pores.
Fluid-feeding insects, such as butterflies, moths and flies (20% of all animal species), are faced with the common selection pressure of having to remove and feed on trace amounts of fluids from porous surfaces. Insects able to acquire fluids that are confined to pores during drought conditions would have an adaptive advantage and increased fitness over other individuals. Here, we performed feeding trials using solutions with magnetic nanoparticles to show that butterflies and flies have mouthparts adapted to pull liquids from porous surfaces using capillary action as the governing principle. In addition, the ability to feed on the liquids collected from pores depends on a relationship between the diameter of the mouthpart conduits and substrate pore size diameter; insects with mouthpart conduit diameters larger than the pores cannot successfully feed, thus there is a limiting substrate pore size from which each species can acquire liquids for fluid uptake. Given that natural selection independently favoured mouthpart architectures that support these methods of fluid uptake (Diptera and Lepidoptera share a common ancestor 280 Ma that had chewing mouthparts), we suggest that the convergence of this mechanism advocates this as an optimal strategy for pulling trace amounts of fluids from porous surfaces.


Methylome of human skeletal muscle after acute & chronic resistance exercise training, detraining & retraining.
DNA methylation is an important epigenetic modification that can regulate gene expression following environmental encounters without changes to the genetic code. Using Infinium MethylationEPIC BeadChip Arrays (850,000 CpG sites) we analysed for the first time, DNA isolated from untrained human skeletal muscle biopsies (vastus lateralis) at baseline (rest) and immediately following an acute (single) bout of resistance exercise. In the same participants, we also analysed the methylome following a period of muscle growth (hypertrophy) evoked via chronic (repeated bouts-3 sessions/wk) resistance exercise (RE) (training) over 7-weeks, followed by complete exercise cessation for 7-weeks returning muscle back to baseline levels (detraining), and finally followed by a subsequent 7-week period of RE-induced hypertrophy (retraining). These valuable methylome data sets described in the present manuscript and deposited in an open-access repository can now be shared and re-used to enable the identification of epigenetically regulated genes/networks that are modified after acute anabolic stimuli and hypertrophy, and further investigate the phenomenon of epigenetic memory in skeletal muscle.


Kit ligand has a critical role in mouse yolk sac and aorta-gonad-mesonephros hematopoiesis.
Few studies report on the in vivo requirement for hematopoietic niche factors in the mammalian embryo. Here, we comprehensively analyze the requirement for Kit ligand (Kitl) in the yolk sac and aorta-gonad-mesonephros (AGM) niche. In-depth analysis of loss-of-function and transgenic reporter mouse models show that Kitl-deficient embryos harbor decreased numbers of yolk sac erythro-myeloid progenitor (EMP) cells, resulting from a proliferation defect following their initial emergence. This EMP defect causes a dramatic decrease in fetal liver erythroid cells prior to the onset of hematopoietic stem cell (HSC)-derived erythropoiesis, and a reduction in tissue-resident macrophages. Pre-HSCs in the AGM require Kitl for survival and maturation, but not proliferation. Although Kitl is expressed widely in all embryonic hematopoietic niches, conditional deletion in endothelial cells recapitulates germline loss-of-function phenotypes in AGM and yolk sac, with phenotypic HSCs but not EMPs remaining dependent on endothelial Kitl upon migration to the fetal liver. In conclusion, our data establish Kitl as a critical regulator in the in vivoAGM and yolk sac endothelial niche.


Charge Transport Limitations in Self-Assembled TiO2 Photoanodes for Dye-Sensitized Solar Cells.
Solid-state dye-sensitized solar cells offer the possibility of high-power conversion efficiencies due to theoretically lower fundamental losses in dye regeneration. Despite continuous progress, limitations in charge diffusion through the mesoporous photoanode still constrain the device thickness and hence result in reduced light absorption with the most common sensitizers. Here we examine block copolymer-assembled photoanodes with similar surface area and morphology but a large variation in crystal size. We observe that the crystal size has a profound effect on the electron transport, which is not explicable by considering solely the ratio between free and trapped electrons. Our results are consistent with the long-range mobility of conduction band electrons being strongly influenced by grain boundaries. Therefore, maximizing the crystal size while maintaining high enough surface area will be an important route forward.


Age-dependent distribution of Plasmodium falciparum gametocytes quantified by Pfs25 real-time QT-NASBA in a cross-sectional study in Burkina Faso.
Sexual stages of Plasmodium falciparum play a key role in the transmission of malaria. Studies on gametocytes are generally based on microscopic detection, but more sensitive detection methods for P. falciparum gametocytes frequently detect sub-patent gametocytes. We used Pfs25 mRNA quantitative-nucleic acid sequence-based amplification (QT-NASBA) to quantify gametocytes in 412 samples from a cross-sectional study in Burkina Faso, covering all age groups, to determine age-related patterns in gametocyte carriage and gametocyte density. The more sensitive QT-NASBA technique gave estimates of gametocyte prevalence 3.3-fold higher than microscopy (70.1% versus 21.4%, respectively). Prevalence of gametocytes significantly decreased with age. Our data suggest that asexual parasite densities are primarily responsible for the age-related decrease of gametocyte prevalence, possibly because of developing asexual stage immunity. Gametocyte densities decrease also with age, primarily because of decreasing asexual parasite densities; only a small but significant age effect on gametocyte density may be caused by developing sexual stage-specific immunity.


TRAF6-deficient mice display hypohidrotic ectodermal dysplasia.
Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adapter protein that links signals from members of the TNFR superfamily and Toll/IL-1 receptor family to activation of transcription factors NFkappaB and AP-1. Analysis of TRAF6-deficient mice revealed that TRAF6 is essential for normal bone formation and establishment of immune and inflammatory systems. Here we report that TRAF6 deficiency results in defective development of epidermal appendixes, including guard hair follicles, sweat glands, sebaceous glands of back skin, and modified sebaceous glands such as meibomian glands, anal glands, and preputial glands. Except the sebaceous gland impairment, these abnormal phenotypes are identical to those observed in Tabby (Ta), downless (dl), and crinkled (cr) mice, which are models of hypohidrotic (anhidrotic) ectodermal dysplasia in human. beta-catenin and mucosal addressin cell adhesion molecule-1, an early marker of developing guard-hair follicles is absent in the skin of TRAF6-deficient embryos. Thus, TRAF6 is essential for development of epidermal appendixes. TRAF6 does not associate with the cytoplasmic tail of the dl protein (DL)/ectodysplasin receptor (EDAR) receptor, which, when mutated, results in hypohidrotic (anhidrotic) ectodermal dysplasia. However, TRAF6 associates with X-linked ectodysplasin-A2 receptor (XEDAR) and TNFR super family expressed on the mouse embryo (TROY/toxicity and JNK inducer (TAJ), which are EDAR-related members of the TNFR superfamily that are expressed at high level in epidermal appendixes. Furthermore, TRAF6 is essential for the XEDAR-mediated NFkappaB activation. Our results suggest that TRAF6 may transduce signals emanating from XEDAR or TROY/TAJ that are associated with development of epidermal appendixes.


Validation of a near-infrared probe for detection of thin intracranial white matter structures.
The authors have developed an intracranial near-infrared (NIR) probe that analyzes the scattering of light emitted from its tip to measure the optical properties of cerebral tissue. Despite its success in distinguishing graymatter from white matter in humans during stereotactic surgery, the limits of this instrument's resolution remain unclear. In this study, the authors determined the spatial resolution of this new probe by using a rodent model supplemented with phantom measurements and computer simulation. A phantom consisting of Intralipid and gelatin was constructed to resemble a layer of white matter overlying a layer of gray matter. Near-infrared measurements were obtained as the probe was inserted through the gray-white matter transition. A computer simulation of NIR measurements through a gray-white matter transition was also performed using Monte Carlo techniques. The NIR probe was then used to study 19 tracks from the cortical surface through the corpus callosum in an in vivo rodent preparation. The animals were killed and histological sections through the tracks were obtained. Data from the phantom models and computer simulations showed that the NIR probe samples a volume of tissue extending 1 to 1.5 mm in front of the probe tip (this distance is termed the "lookthrough" distance). Measurements obtained from an NIR probe passing through a thin layer of white matter consisted of an initial segment of increasing values, a maximum (peak) value, and a trailing segment of decreasing values. The length of the initial segment is the lookthrough distance, the position of the peak indicates the location of the superficial white matter boundary, and the length of the trailing segment is the thickness of the layer. These considerations were confirmed in experiments with rodents. All tracks passed through the corpus callosum, which was demonstrated as a broad peak on each NIR graph. The position of the dorsal boundary of the corpus callosum and its width (based on histological measurements) correlated well with the peak of the NIR curve and its trailing segment, respectively. The initial segments correlated well with estimates of the lookthrough distance. Five of the tracks transected the smaller anterior commissure (diameter 0.2 mm), producing a narrow NIR peak at the correct depth. Data in this study confirm that the NIR probe can reliably detect and measure the thickness of layers of white matter as thin as 0.2 mm. Such resolution should be adequate to detect larger structures of interest encountered during stereotactic surgery in humans.


Evaluation of deep convolutional neural networks for in situ hybridization gene expression image representation.
High resolution in situ hybridization (ISH) images of the brain capture spatial gene expression at cellular resolution. These spatial profiles are key to understanding brain organization at the molecular level. Previously, manual qualitative scoring and informatics pipelines have been applied to ISH images to determine expression intensity and pattern. To better capture the complex patterns of gene expression in the human cerebral cortex, we applied a machine learning approach. We propose gene re-identification as a contrastive learning task to compute representations of ISH images. We train our model on an ISH dataset of ~1,000 genes obtained from postmortem samples from 42 individuals. This model reaches a gene re-identification rate of 38.3%, a 13x improvement over random chance. We find that the learned embeddings predict expression intensity and pattern. To test generalization, we generated embeddings in a second dataset that assayed the expression of 78 genes in 53 individuals. In this set of images, 60.2% of genes are re-identified, suggesting the model is robust. Importantly, this dataset assayed expression in individuals diagnosed with schizophrenia. Gene and donor-specific embeddings from the model predict schizophrenia diagnosis at levels similar to that reached with demographic information. Mutations in the most discriminative gene, Sodium Voltage-Gated Channel Beta Subunit 4 (SCN4B), may help understand cardiovascular associations with schizophrenia and its treatment. We have publicly released our source code, embeddings, and models to spur further application to spatial transcriptomics. In summary, we propose and evaluate gene re-identification as a machine learning task to represent ISH gene expression images.


MO-D-BRB-02: The Radiological Physics Center's Quality Audit Program: Where Can We Improve?
To analyze the findings of the Radiological Physics Center's (RPC) QA audits of institutions participating in NCI sponsored clinical trials. The RPC has developed an extensive Quality Assurance (QA) program over the past 44 years. This program includes on-site dosimetry reviews where measurements on therapy machines are made, records are reviewed and personnel are interviewed. The program's remote audit tools include mailed dosimeters (OSLD/TLD) to verify output calibration, comparison of dosimetry data with RPC 'standard' data, evaluation of benchmark and patient calculations to verify the treatment planning algorithms, review of institution's QA procedures and records, and use of anthropomorphic phantoms to verify tumor dose delivery. The RPC endeavors to assist institutions in finding the origins of any detected discrepancies, and to resolve them. Ninety percent of institutions receiving dosimetry recommendations has remained level for the past 5 years. The most frequent recommendations were for not performing TG-40 QA tests, wedge factors, small field size output factors and off-axis factors. Since TG-51 was published, the number of beam calibrations audited during visits with ion chambers, that met the RPC's ±3% criterion, decreased initially but has risen to pre-TG-51 levels. The OSLD/TLD program shows that only ∼3% of the beams are outside our ±5% criteria, but these discrepancies are distributed over 12-20% of the institutions. The percent of institutions with ï,3 l beam outside the RPC's criteria is approximately the same whether OSLD/TLD or ion chambers were used. The first time passing rate for the anthropomorphic phantoms is increasing with time. The prostate phantom has the highest pass rate while the spine phantom has the lowest. Numerous dosimetry errors continue to be discovered by the RPC's QA program and the RPC continues to play an important role in helping institutions resolve these errors. This work was supported by PHS grants CA10953 and CA081647 awarded by NCI.


Accuracy of Self-reported Colonic Polyps: Results from the Prostate, Lung, Colorectal, and Ovarian Screening Trial Study of Colonoscopy Utilization.
Colonoscopy follow-up recommendations depend on the presence or absence of polyps, and if found, their number, size, and histology. Patients may be responsible for conveying results between primary and specialty care or providing medical information to family members; thus, accurate reporting is critical. This analysis assessed the accuracy of self-reported colonoscopy findings. 3,986 participants from the Study of Colonoscopy Utilization, an ancillary study nested within the Prostate, Lung, Colorectal, and Ovarian Screening Trial, were included. Self-reports of polyp and adenoma were compared to medical records, and measures of sensitivity and specificity were calculated. Correlates of accurate self-report of polyp were assessed using logistic regression and weighted to account for study sampling. The sensitivity and specificity of self-reported polyp findings were 88% and 85%, respectively, and for adenoma 11% and 99%, respectively. Among participants with a polyp, older age was associated with lower likelihood while polyp severity and non-white race were associated with increased likelihood of accurate recall. Among participants without a polyp, having multiple colonoscopies was associated with lower likelihood while family history of colorectal cancer was associated with increased likelihood of accurate recall. Among both groups, longer time since colonoscopy was associated with lower likelihood of accurate recall. Participants recalled with reasonable accuracy whether they had a prior polyp; however, recall of histology, specifically adenoma, was much less accurate. Identification of strategies to increase accurate self-report of colonic polyps are needed, particularly for patient-provider communications and patient reporting of results to family members.


Early spread of the 2009 influenza A(H1N1) pandemic in the United Kingdom--use of local syndromic data, May-August 2009.
Following the confirmation of the first two cases of pandemic influenza on 27 April 2009 in the United Kingdom (UK), syndromic surveillance data from the Health Protection Agency (HPA)/QSurveillance and HPA/NHS Direct systems were used to monitor the possible spread of pandemic influenza at local level during the first phase of the outbreak. During the early weeks, syndromic indicators sensitive to influenza activity monitored through the two schemes remained low and the majority of cases were travel-related. The first evidence of community spread was seen in the West Midlands region following a school-based outbreak in central Birmingham. During the first phase several Primary Care Trusts had periods of exceptional influenza activity two to three weeks ahead of the rest of the region. Community transmission in London began slightly later than in the West Midlands but the rates of influenza-like illness recorded by general practitioners (GPs) were ultimately higher. Influenza activity in the West Midlands and London regions peaked a week before the remainder of the UK. Data from the HPA/NHS Direct and HPA/QSurveillance systems were mapped at local level and used alongside laboratory data and local intelligence to assist in the identification of hotspots, to direct limited public health resources and to monitor the progression of the outbreak. This work has demonstrated the utility of local syndromic surveillance data in the detection of increased transmission and in the epidemiological investigation of the pandemic and has prompted future spatio-temporal work.


[Multiple tumors in endometrial cancer].
Out of 1220 (100%) cases of endometrial carcinomas, registered at the Klinik Bad Trissl during a period of 20 years (1968-1988), over 127 cases (10.4%) of double and triple malignomas were found. 86 cases (7.0%) are correlated with a second primary breast cancer, 41 (3.4%) with other primary malignomas. 14 cases (1.1%) show triple malignomas. 8 precancerous cases (0.7%) were included in the survey. Contrary to medical literature the survey reveals a different distribution of neoplasms among the affected organs. Four fifths of the tumour combinations were located in the female genital tract including the breast. Therefore the early detection of potential secondary malignomas should be included in the aftercare of endometrial cancer.


Pharmacological treatment of chronic pain - the need for CHANGE.
Although chronic pain affects around 20% of adults in Europe and the USA, there is substantial evidence that it is inadequately treated. In June 2009, an international group of pain specialists met in Brussels to identify the reasons for this and to achieve consensus on strategies for improving pain management. Literature on chronic pain management was reviewed, and information presented to and discussed by a panel of experts. It was agreed that guidelines are not universally accepted by those involved in pain management, and pain treatment seems to be driven mainly by tradition and personal experience. Other factors include poor communication between patients and physicians, the side effects of analgesic drugs, and limited individualisation of therapy. Difficulty in maintaining the balance between adequate pain relief and acceptable tolerability, particularly with strong opioids, can lead to the establishment of a 'vicious circle' that alternates between lack of efficacy and unpleasant side effects, prompting discontinuation of treatment. The medical community's understanding of the physiological differences between nociceptive pain and neuropathic pain, which is often more severe and difficult to treat, could be improved. Increasing physicians' knowledge of the pharmacological options available to manage these different pain mechanisms offers the promise of better treatment decisions and more widespread adoption of a multi-mechanistic approach; this could involve loosely combining two substances from different drug classes, or administering an analgesic with two different mechanisms of action. In some circumstances, a single compound capable of addressing both nociceptive and neuropathic pain is desirable. To improve patient outcomes, a thorough understanding of pain mechanisms, sensitisation and multi-mechanistic management is required. Universal, user-friendly educational tools are therefore required to familiarise physicians with these topics, and also to improve communication between physicians and their pain patients, so that realistic expectations of treatment can be established.


Quantitative genetic variation in Daphnia: temporal changes in genetic architecture.
Nonadditive genetic variation and genetic disequilibrium are two important factors that influence the evolutionary trajectory of natural populations. We assayed quantitative genetic variation in a temporary-pond-dwelling population of Daphnia pulex over a full season to examine the role of nonadditive genetic variation and genetic disequilibrium in determining the short-term evolutionary trajectory of a cyclic parthenogen. Quantitative traits were influenced by three factors: (1) clonal selection significantly changed the population mean phenotype during the course of the growing season; (2) sexual reproduction and recombination led to significant changes in life-history trait means and the levels of expressed genetic variation, implying the presence of substantial nonadditive genetic variation and genetic disequilibrium; and (3) Egg-bank effects were found to be an important component of the realized year-to-year change. Additionally, we examined the impact of genetic disequilibria induced by clonal selection on the genetic (co)variance structure with a common principal components model. Clonal selection caused significant changes in the (co)variance structure that were eliminated by a single bout of random mating, suggesting that a build-up of disequilibria was the primary source of changes in the (co)variance structure. The results of this study highlight the complexity of natural selection operating on populations that undergo alternating phases of sexual and asexual reproduction.


MET Inhibition in Clear Cell Renal Cell Carcinoma.
Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms such as activation of the MET pathway have been described. Dual MET/VEGFR2 inhibitors have recently shown clinical benefit but limited preclinical data evaluates their effects in ccRCC. An interrogation of the Cancer Genome Atlas (TCGA) dataset was performed to evaluate oncogenic alterations in the MET/VEGFR2 pathway. We evaluated the in vitro effects of Cabozantinib, a dual MET/VEGFR2 inhibitor, using a panel of ccRCC cell lines. Drug effects of cell viability and proliferation, migration, cell scatter, anchorage independent growth, and downstream MET/VEGFR2 signaling pathways were assessed. Twelve percent of TCGA cases had possible MET/HGF oncogenic alterations with co-occurrence noted (p<0.001). MET/HGF altered cases had worse overall survival (p=0.044). Cabozantinib was a potent inhibitor of MET and VEGFR2 in vitro in our cell line panel. PI3K, MAPK and mTOR pathways were also suppressed by cabozantinib, however the effects on cell viability in vitro were modest. At nanomolar concentrations of cabozantinib, HGF-stimulated migration, invasion, cellular scattering and soft agar colony formation were inhibited. We provide further preclinical rationale for dual MET/VEGFR2 inhibition in ccRCC. While the MET pathway is implicated in VEGFR resistance, dual inhibitors may have direct anti-tumor effects in a patient subset with evidence of MET pathway involvement. Cabozantinib is a potent dual MET/VEGFR2 inhibitor, significantly inhibits cell migration and invasion in vitro and likely has anti-angiogenic effects similar to other VEGFR tyrosine kinase inhibitors. Future work involving in vivo models will be useful to better define mechanisms of potential anti-tumor activity.


Complications after Radiofrequency Ablation for Hepatocellular Carcinoma: A Multicenter Study Involving 9,411 Japanese Patients.
Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is considered a safe and minimally invasive procedure. We previously reported that the mortality and complication rates for RFA were 0.038% (5/13,283 patients) and 3.54% (579 complications/16,346 procedures), respectively, from 1999 to 2010 (previous period). In this study, we investigated the clinical criteria for RFA and the mortality and complication rates from 2011 to 2015 (recent period). Data were collected from 25 centers by using a questionnaire developed by the Chugoku-Shikoku Society for Local Ablation Therapy of HCC. The criteria for RFA, RFA modification, use of image-guidance modalities, mortality, and complications during the previous and recent periods were compared. We evaluated 11,298 procedures for 9,411 patients, including those that involved new devices (bipolar RFA and internally adjustable electrode system). The criterion of hepatic function for RFA increased from a Child-Pugh score ≤8 during the previous period to ≤9 during the recent period. The criteria regarding the tumor location and other risk factors have been expanded recently because of the increased use of several modifications of the RFA procedure and image-guidance modalities. The mortality rate was 0.064% (6/9,411 patients), and the complication rate was 2.92% (330 complications/11,298 procedures). There was no difference in mortality rates between the 2 periods (p = 0.38), but the complication rates was significantly lower during the recent period (p = 0.038). Our findings confirmed that RFA, including the use of new devices, is a low-risk procedure for HCC, despite the expansion of the criteria for RFA during the recent period.


Atypical Herpes simplex keratitis (HSK) presenting as a perforated corneal ulcer with a large infiltrate in a contact lens wearer: multinucleated giant cells in the Giemsa smear offered a clue to the diagnosis.
To report a case of atypical herpes simplex keratitis initially diagnosed as bacterial keratitis, in a contact lens wearer. Case report of an 18-year-old woman using contact lenses who presented with pain, redness and gradual decrease in vision in the right eye. Examination revealed a paracentral large stromal infiltrate with a central 2-mm perforation. Corneal and conjunctival scrapings were collected for microbiological investigations. Corneal tissue was obtained following penetrating keratoplasty. Corneal scraping revealed no microorganisms. Giemsa stained smear showed multinucleated giant cells. Conjunctival, corneal scrapings and tissue were positive for herpes simplex virus - 1 (HSV) antigen. Corneal tissue was positive for HSV DNA by PCR. Atypical HSV keratitis can occur in contact lens wearers. A simple investigation like Giemsa stain may offer a clue to the diagnosis.


Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found that treatment with atorvastatin 80 mg per day reduced the risk of stroke and cardiovascular events in patients with a recent transient ischemic attack (TIA) or stroke. We hypothesized this benefit would be greatest in the subgroup of patients with carotid stenosis. The SPARCL trial randomized patients with TIA or stroke within 1 to 6 months without known coronary heart disease (CHD) and low-density lipoprotein cholesterol 100 to 190 mg/dL to treatment with atorvastatin 80 mg per day or placebo. Investigators identified subjects as having carotid stenosis not requiring revascularization at the time of randomization. Of the total SPARCL population, 1007 were documented as having carotid stenosis at baseline, 3271 did not, and the status of 453 was unknown. We found no heterogeneity in the treatment effect for the SPARCL primary (fatal and nonfatal stroke) and secondary end points between the group with and without carotid stenosis. The group with carotid artery stenosis had greater benefit when all cerebro- and cardiovascular events were combined. In the group with carotid artery stenosis, treatment with atorvastatin was associated with a 33% reduction in the risk of any stroke (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.47, 0.94; P=0.02), and a 43% reduction in risk of major coronary events (HR 0.57, 95% CI 0.32, 1.00; P=0.05). Later carotid revascularization was reduced by 56% (HR 0.44, 95% CI 0.24, 0.79; P=0.006) in the group randomized to atorvastatin. Consistent with the overall results of the SPARCL intention to treat population, intense lipid lowering with atorvastatin reduced the risk of cerebro- and cardiovascular events in patients with and without carotid stenosis. The carotid stenosis group may have greater benefit.


Investigating sources of inaccuracy in wearable optical heart rate sensors.
As wearable technologies are being increasingly used for clinical research and healthcare, it is critical to understand their accuracy and determine how measurement errors may affect research conclusions and impact healthcare decision-making. Accuracy of wearable technologies has been a hotly debated topic in both the research and popular science literature. Currently, wearable technology companies are responsible for assessing and reporting the accuracy of their products, but little information about the evaluation method is made publicly available. Heart rate measurements from wearables are derived from photoplethysmography (PPG), an optical method for measuring changes in blood volume under the skin. Potential inaccuracies in PPG stem from three major areas, includes (1) diverse skin types, (2) motion artifacts, and (3) signal crossover. To date, no study has systematically explored the accuracy of wearables across the full range of skin tones. Here, we explored heart rate and PPG data from consumer- and research-grade wearables under multiple circumstances to test whether and to what extent these inaccuracies exist. We saw no statistically significant difference in accuracy across skin tones, but we saw significant differences between devices, and between activity types, notably, that absolute error during activity was, on average, 30% higher than during rest. Our conclusions indicate that different wearables are all reasonably accurate at resting and prolonged elevated heart rate, but that differences exist between devices in responding to changes in activity. This has implications for researchers, clinicians, and consumers in drawing study conclusions, combining study results, and making health-related decisions using these devices.


Barriers to accessing health care services: a qualitative study of migrant construction workers in a southwestern Indian city.
This study examined access to health care in an occupational context in an urban city of India. Many people migrate from rural areas to cities, often across Indian states, for employment prospects. The purpose of the study is to explore the barriers to accessing health care among a vulnerable group - internal migrants working in the construction sector in Manipal, Karnataka. Understanding the lay workers' accounts of access to health services can help to comprehend the diversity of factors that hinder access to health care. Individual semi-structured interviews involving 15 migrant construction workers were conducted. The study applied theory-guided content analysis to investigate access to health services among the construction workers. The adductive analysis combined deductive and inductive approaches with the aim of verifying the existing barrier theory in a vulnerable context and further developing the health care access barrier theory. This study's result is a revised version of the health care access barriers model, including the dimension of trust. Three known health care access barriers - financial, cognitive and structural, as well as the new barrier (distrust in public health care services), were identified among migrant construction workers in a city context in Karnataka, India. Further qualitative research on vulnerable groups would produce a more comprehensive account of access to health care. The socioeconomic status behind access to health care, as well as distrust in public health services, forms focal challenges for any policymaker hoping to improve health services to match people's needs.


WITHDRAWN: Methods of vascular occlusion for elective liver resections.
Vascular occlusion is used to reduce blood loss during liver resection surgery. There is considerable controversy regarding whether vascular occlusion should be used or not during elective liver resections. The method of vascular occlusion employed is also controversial. There is also considerable debate on the role of ischaemic preconditioning before vascular occlusion. To assess the advantages (decreased blood loss and peri-operative morbidity) and disadvantages (liver dysfunction from ischaemia) of vascular occlusion during liver resections. To compare the advantages (in decreasing blood loss or decreasing ischaemia-reperfusion injury) and disadvantages of different types of vascular occlusion versus total, continuous portal triad clamping. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until March 2007. We included randomised clinical trials comparing vascular occlusion versus no vascular occlusion during elective liver resections (irrespective of language or publication status). We also included randomised clinical trials comparing the different methods of vascular occlusion and those investigating the role of ischaemic preconditioning in liver resection. We collected the data on the characteristics of the trial, methodological quality of the trials, mortality, morbidity, blood loss, blood transfusion requirements, liver function tests, markers of neutrophil activation, operating time, and hospital stay. We analysed the data with both the fixed-effect and the random-effects models using RevMan Analysis. For each binary outcome we calculated the odds ratio (OR) with 95% confidence intervals (CI) based on intention-to-treat analysis. For continuous outcomes, we calculated the weighted mean difference (WMD) with 95% confidence intervals. We identified a total of 16 randomised trials. Five trials including 331 patients compared vascular occlusion (n = 166) versus no vascular occlusion (n = 165). Six trials including 521 patients compared different methods of vascular occlusion. Three trials including 210 patients compared ischaemic preconditioning before continuous portal triad clamping (n = 105) versus no ischaemic preconditioning (n = 105). Two trials including 127 patients compared ischaemic preconditioning before continuous portal triad clamping (n = 63) versus intermittent portal triad clamping (n = 64).The blood loss was significantly lower in vascular occlusion compared with no vascular occlusion. The liver enzymes were significantly elevated in the vascular occlusion group compared with no vascular occlusion. There was no difference in the mortality, liver failure, or other morbidities. Four of the five trials comparing vascular occlusion and no vascular occlusion used intermittent vascular occlusion. Trials comparing complete inflow and outflow occlusion to the liver, ie, hepatic vascular exclusion and portal triad clamping demonstrate significant detrimental haemodynamic changes in hepatic vascular exclusion compared to portal triad clamping. There was no significant difference in the number of units transfused and the number of patients needing transfusion. There was no difference in mortality, liver failure, or morbidity between total and selective methods of portal triad clamping. All four cases of mortality and liver failure in the comparison between the intermittent and continuous portal triad clamping occurred in the continuous portal triad clamping (statistically not significant). Intermittent portal triad clamping does not increase the total blood loss or operating time compared to continuous portal triad clamping.There was no statistically significant difference in the mortality, liver failure, morbidity, blood loss, or haemodynamic changes between ischaemic preconditioning versus no ischaemic preconditioning before continuous portal triad clamping. Liver enzymes used as markers of liver injury were significantly lower in the early post-operative period in the ischaemic preconditioning group. The intensive therapy unit stay and hospital stay were statistically significantly lower in the ischaemic preconditioning group than in the no ischaemic preconditioning group.There was no statistically significant difference in the mortality, liver failure, morbidity, intensive therapy unit stay, or hospital stay between ischaemic preconditioning before continuous portal triad clamping and intermittent portal triad clamping. The blood loss and transfusion requirements were lower in the ischaemic preconditioning group. Aspartate aminotransferase level was lower in the intermittent portal triad clamping group than the ischaemic preconditioning group on the third post-operative day. There was no difference in the peak aspartate aminotransferase levels or in the aspartate aminotransferase levels on first or sixth post-operative days of aspartate aminotransferase . Intermittent vascular occlusion seems safe in liver resection. However, it does not seem to decrease morbidity. Among the different methods of vascular occlusion, intermittent portal triad clamping has most evidence to support the clinical application. Hepatic vascular exclusion cannot be recommended routinely. Ischaemic preconditioning before continuous portal triad clamping may be of clinical benefit in reducing intensive therapy unit and hospital stay.


Performance on the Boston Naming Test in Bilinguals.
We examined performance on the Boston Naming Test (BNT) in older and younger adults who were monolingual English or French speakers, or bilingual speakers of English and French (n=215). Monolingual participants completed the task in their native language, and bilingual participants completed the task in English, French, and bilingual (either-language) administrations. Overall, younger and older monolingual French speakers performed worse than other groups; bilingual participants performed worst in the French administration and approximately two-thirds of bilingual participants performed better when responses were accepted in either language. Surprisingly, however, a subset of bilinguals performed worse when responses were accepted in either language as compared to their maximum score achieved in either English or French. This either-language disadvantage does not appear to be associated with the degree of balanced bilingualism, but instead appears to be related to overall naming abilities. Differential item analysis comparing language groups and the different administrations identified several items that displayed uniform and/or non-uniform differential item functioning (DIF). The BNT does not elicit equivalent performance in English and French, even when assessing naming performance in monolingual French speakers using the French version of the test. Scores were lower in French overall, and several items exhibited DIF. We recommend caution in interpreting performance on these items in bilingual speakers. Finally, not all bilinguals benefit from an either-language administration of the BNT.


Ultra-broadband one-to-two wavelength conversion using low-phase-mismatching four-wave mixing in silicon waveguides.
An ultra-broadband wavelength conversion is presented and experimentally demonstrated based on nondegenerate four-wave mixing in silicon waveguides. Two idlers can be generated and their wavelengths can be freely tuned by using two pumps where the first pump is set close to the signal and the second pump is wavelength tunable. Using this scheme, a small phase-mismatch and hence an ultra-broad conversion bandwidth is realized in spite of the waveguide dispersion profile. We show that the experimental demonstrations are consistent with the theoretical estimations. Total conversion bandwidth is estimated to reach >500 nm and it can provide a feasible approach to realize one-to-two wavelength conversion among different telecommunication bands between 1300 nm and 1800 nm.


Abnormal trafficking of endogenously expressed BMPR2 mutant allelic products in patients with heritable pulmonary arterial hypertension.
More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 (ΔEx2/+) mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 (ΔEx2/+) mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations.


Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol.
Young women presenting with breast cancer are more likely to have a genetic predisposition to the disease than breast cancer patients in general. A genetic predisposition is known to increase the risk of new primary breast (and other) cancers. It is unclear from the literature whether genetic status should be taken into consideration when planning adjuvant treatment in a young woman presenting with a first primary breast cancer. The primary aim of the POSH study is to establish whether genetic status influences the prognosis of primary breast cancer independently of known prognostic factors. The study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period. Power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforward.


Correction of axial and lateral chromatic aberration with false color filtering.
In this paper, we propose a chromatic aberration (CA) correction algorithm based on a false color filtering technique. In general, CA produces color distortions called color fringes near the contrasting edges of captured images, and these distortions cause false color artifacts. In the proposed method, a false color filtering technique is used to filter out the false color components from the chroma-signals of the input image. The filtering process is performed with the adaptive weights obtained from both the gradient and color differences, and the weights are designed to reduce the various types of color fringes regardless of the colors of the artifacts. Moreover, as preprocessors of the filtering process, a transient improvement (TI) technique is applied to enhance the slow transitions of the red and blue channels that are blurred by the CA. The TI process improves the filtering performance by narrowing the false color regions before the filtering process when severe color fringes (typically purple fringes) occur widely. Last, the CA-corrected chroma-signal is combined with the TI chroma-signal to avoid incorrect color adjustment. The experimental results show that the proposed method substantially reduces the CA artifacts and provides natural-looking replacement colors, while it avoids incorrect color adjustment.


Imaging approaches to measuring lysosomal calcium.
Endolysosomes are emerging as key players that generate as well as respond to intracellular Ca(2+) signals. The role of Ca(2+) in modulating acidic organelle function has long been recognized, but it is now emerging that acidic organelles also act as intracellular Ca(2+) stores; they actively sequester Ca(2+) in their lumina and release it to the cytosol upon activation of endolysosomal Ca(2+) channels. This local Ca(2+) signal is crucial for endolysosomal function and/or global Ca(2+) signaling. Importantly, defects in endolysosomal Ca(2+) are associated with disease. This chapter discusses several complimentary approaches to monitor endolysosomal Ca(2+), with particular emphasis on the inherent pitfalls that can plague the unwary.


Changes in alcohol use and relationship satisfaction in Norwegian couples during pregnancy.
Numerous studies have documented a profound reduction in alcohol use among pregnant women, whereas research on expectant fathers has been scarce. The aim of this study was to measure changes in alcohol consumption from before pregnancy to 17 weeks in gestation for mothers and fathers, differentiating between parents with and without any previous children, and to measure how level and change in alcohol consumption into early pregnancy was associated with relationship satisfaction. The data collection was conducted as part of the Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. This cohort now includes 108,000 children, 90,700 mothers and 71,500 fathers recruited from 1999 to 2008. The present study comprises 82 362 couples. Alcohol consumption was assessed using a questionnaire including items about usual drinking frequency, quantities, and number of occasions with heavy episodic drinking (HED). Relationship satisfaction was measured by five items scored on a Likert agreement scale. The findings indicate that both mothers and fathers reduce their drinking significantly during pregnancy. Reduction was apparent for all three measures of alcohol consumption. First-time fathers reduced their alcohol consumption more than experienced fathers, from initially higher levels. The gap between the fathers and their pregnant partner was greater for first-time parents compared to parents with previous children. Drinking pre-pregnancy and relationship satisfaction during pregnancy were weakly related within each partner, whereas no association across partners was observed. Both expectant mothers and fathers changed their alcohol consumption patterns when expecting a child. Almost all mothers stopped drinking, whereas fathers reduced their drinking to a considerable degree. Relationship satisfaction was only slightly related to their drinking patterns. The findings may have important policy implications, mainly with regard to developing alcohol preventive strategies.


How accurately can we predict the melting points of drug-like compounds?
This article contributes a highly accurate model for predicting the melting points (MPs) of medicinal chemistry compounds. The model was developed using the largest published data set, comprising more than 47k compounds. The distributions of MPs in drug-like and drug lead sets showed that >90% of molecules melt within [50,250]°C. The final model calculated an RMSE of less than 33 °C for molecules from this temperature interval, which is the most important for medicinal chemistry users. This performance was achieved using a consensus model that performed calculations to a significantly higher accuracy than the individual models. We found that compounds with reactive and unstable groups were overrepresented among outlying compounds. These compounds could decompose during storage or measurement, thus introducing experimental errors. While filtering the data by removing outliers generally increased the accuracy of individual models, it did not significantly affect the results of the consensus models. Three analyzed distance to models did not allow us to flag molecules, which had MP values fell outside the applicability domain of the model. We believe that this negative result and the public availability of data from this article will encourage future studies to develop better approaches to define the applicability domain of models. The final model, MP data, and identified reactive groups are available online at http://ochem.eu/article/55638.


Social oppression, psychological vulnerability, and unprotected intercourse among young Black men who have sex with men.
Young Black men who have sex with men (YBMSM) are at extraordinarily high risk for HIV infection. Given their dual minority identity, they experience multiple forms of social oppression-racism, homophobia, and poverty. This study tested a model for how these forces contribute to their sexual risk behavior. YBMSM (n = 1,289) from 2 Texas cities completed a 1-time assessment of sexual behaviors and psychosocial variables. Structural equation modeling was used to characterize relationships among variables. Experiences of racism, homophobia, and socioeconomic distress were all associated with unprotected anal intercourse (UAI) either directly or indirectly in a manner largely consistent with Díaz's (1997, 1998) model of the effects of social oppression. Racism, homophobia, and socioeconomic distress were each associated with specific psychological vulnerabilities, which were in turn associated with participation in difficult sexual situations (e.g., in a public setting), and then UAI. The effects of racism were largely mediated by depressive symptoms and participation in difficult sexual situations. Homophobia was mediated by depressive symptoms, social support, and internalized homophobia. The effects of socioeconomic distress were partially mediated by decreased social support and greater participation in difficult sexual situations. Socioeconomic distress also had a significant direct effect on UAI not explained by the proposed mediators. Social oppression contributes to YBMSM's psychological vulnerabilities, participation in difficult sexual situations, and their UAI. Interventions to reduce sexual risk in YBMSM should address socioeconomic disadvantage, homophobia, and racism, as well as the psychological challenges that social oppression creates for them.


Intramolecular distances and dynamics from the combined photon statistics of single-molecule FRET and photoinduced electron transfer.
Single-molecule Förster resonance energy transfer (FRET) and photoinduced electron transfer (PET) have developed into versatile and complementary methods for probing distances and dynamics in biomolecules. Here we show that the two methods can be combined in one molecule to obtain both accurate distance information and the kinetics of intramolecular contact formation. In a first step, we show that the fluorescent dyes Alexa 488 and Alexa 594, which are frequently used as a donor and acceptor for single-molecule FRET, are also suitable as PET probes with tryptophan as a fluorescence quencher. We then performed combined FRET/PET experiments with FRET donor- and acceptor-labeled polyproline peptides. The placement of a tryptophan residue into the polyglycylserine tail incorporated in the peptides allowed us to measure both FRET efficiencies and the nanosecond dynamics of contact formation between one of the fluorescent dyes and the quencher. Variation of the linker length between the polyproline and the Alexa dyes and in the position of the tryptophan residue demonstrates the sensitivity of this approach. Modeling of the combined photon statistics underlying the combined FRET and PET process enables the accurate analysis of both the resulting transfer efficiency histograms and the nanosecond fluorescence correlation functions. This approach opens up new possibilities for investigating single biomolecules with high spatial and temporal resolution.


Dihydroergotamine nasal spray for the acute treatment of migraine.
We conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of dihydroergotamine (DHE) nasal spray and placebo over 4 hours in the treatment of migraine. Of the 112 patients enrolled, 100 were included in the "intent-to-treat" efficacy analysis. The patients self-administered either 2.0 mg DHE (0.5 mg per nostril, repeated after 15 minutes) or placebo at the onset of two separate headaches and rated hourly the drugs' effects on pain severity, pain relief, nausea, and vomiting. The physicians assessed the overall effectiveness of the drugs in relieving headache pain, nausea, and vomiting. Both the patients' and physicians' ratings indicated that DHE was significantly superior to placebo in improving headache and nausea; according to the patients' ratings, these between-group differences were already significant at the first (hour 1) evaluation. There were no significant differential treatment effects with respect to relief of vomiting. Most adverse events were mild or moderate, confined to the nasopharyngeal area, and probably related to the route of administration. We conclude that DHE nasal spray is a safe and effective treatment for the pain and nausea of migraine attacks.


Nurse practitioner and physician collaboration in long-term care homes: survey results.
This survey assessed the extent of and satisfaction with collaboration between physicians and nurse practitioners (NPs) working in Ontario long-term care homes. Questionnaires, which included the Measure of Current Collaboration and Provider Satisfaction with Current Collaboration instruments, were mailed to NPs and physicians with whom the NP most frequently worked. The 14 matched-pairs of NPs and physicians reported similar levels of collaboration; however, physicians were significantly more satisfied with collaboration than were NPs (z = -2.67, p = 0.008). The majority of physicians (85%) and NPs (86%) indicated that collaboration was occurring, and 96 per cent of physicians and 79 per cent of NPs were satisfied with their collaboration. About one third of physicians reported that the NP had a negative effect on their income, but their satisfaction with collaboration did not differ from those who reported a positive effect. Overall, these physicians and NPs collaborate in delivering care and are satisfied with their collaboration.


[Curcumin attenuates left ventricular dysfunction and remodeling in rabbits with chronic heart failure.].
To investigate the effects of Curcumin on rabbits with chronic heart failure. Heart failure was induced by combined aortic regurgitation and aortic stenosis in 20 New Zealand rabbits and treated with placebo (HF, n = 10) and Curcumin (Cur, 100 mgxkg(-1)xd(-1), n = 10) for 8 weeks, 10 sham operated rabbits served as controls (Con). Echocardiography was performed in all rabbits at baseline and 8 weeks later. Aortic diameter (AO), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-systolic dimension (LVDs), left ventricular end-diastolic dimension (LVDd), left ventricular posterior wall thickness (LVPW) and interventricular septum thickness (IVS) were measured. Myocardial matrix metalloproteinase (MMP)-2 and MMP-9 expressions and fibrosis were determined by immunohistochemistry and Masson staining respectively. Compared to baseline, LVEF and LVFS were significantly decreased, AO, LVDs, LVDd, LVPW, and IVS significantly increased at 8 weeks after operation in HF group while these changes could be significantly attenuated in Curcumin treated rabbits. The protein expressions of MMP-2 and MMP-9 were significantly down-regulated in HF group and could be significantly up-regulated by Curcumin treatment. The increased collagen deposition in HF group was also significantly reduced by Curcumin treatment. Curcumin attenuated left ventricular dysfunction and remodeling by up-regulating MMPs expressions and reducing myocardial fibrosis.


Dominant transplantation tolerance. Opinion.
Long-term allograft survival in the absence of continuous immunosuppression can be induced following a short treatment of nondepleting antibodies, such as those that target CD4 or CD154 (CD40 ligand). It is now established that this may involve dominant tolerance mechanisms that are maintained by CD4+ regulatory T cells present within the lymphoid tissue and the tolerated graft. The phenotype of these cells, their relationship to CD4+CD25+ T cells, and the mechanism of action are still controversial.


Persistence of Low Pathogenic Influenza A Virus in Water: A Systematic Review and Quantitative Meta-Analysis.
Avian influenza viruses are able to persist in the environment, in-between the transmission of the virus among its natural hosts. Quantifying the environmental factors that affect the persistence of avian influenza virus is important for influencing our ability to predict future outbreaks and target surveillance and control methods. We conducted a systematic review and quantitative meta-analysis of the environmental factors that affect the decay of low pathogenic avian influenza virus (LPAIV) in water. Abiotic factors affecting the persistence of LPAIV have been investigated for nearly 40 years, yet published data was produced by only 26 quantitative studies. These studies have been conducted by a small number of principal authors (n = 17) and have investigated a narrow range of environmental conditions, all of which were based in laboratories with limited reflection of natural conditions. The use of quantitative meta-analytic techniques provided the opportunity to assess persistence across a greater range of conditions than each individual study can achieve, through the estimation of mean effect-sizes and relationships among multiple variables. Temperature was the most influential variable, for both the strength and magnitude of the effect-size. Moderator variables explained a large proportion of the heterogeneity among effect-sizes. Salinity and pH were important factors, although future work is required to broaden the range of abiotic factors examined, as well as including further diurnal variation and greater environmental realism generally. We were unable to extract a quantitative effect-size estimate for approximately half (50.4%) of the reported experimental outcomes and we strongly recommend a minimum set of quantitative reporting to be included in all studies, which will allow robust assimilation and analysis of future findings. In addition we suggest possible means of increasing the applicability of future studies to the natural environment, and evaluating the biological content of natural waterbodies.


The impact of dyskeratosis congenita mutations on the structure and dynamics of the human telomerase RNA pseudoknot domain.
The pseudoknot domain is a functionally crucial part of telomerase RNA and influences the activity and stability of the ribonucleoprotein complex. Autosomal dominant dyskeratosis congenita (DKC) is an inherited disease that is linked to mutations in telomerase RNA and impairs telomerase function. In this paper, we present a computational prediction of the influence of two base DKC mutations on the structure, dynamics, and stability of the pseudoknot domain. We use molecular dynamics simulations, MM-GBSA free energy calculations, static analysis, and melting simulations analysis. Our results show that the DKC mutations stabilize the hairpin form and destabilize the pseudoknot form of telomerase RNA. Moreover, the P3 region of the predicted DKC-mutated pseudoknot structure is unstable and fails to form as a defined helical stem. We directly compare our predictions with experimental observations by calculating the enthalpy of folding and melting profiles for each structure. The enthalpy values are in very good agreement with values determined by thermal denaturation experiments. The melting simulations and simulations at elevated temperatures show the existence of an intermediate structure, which involves the formation of two UU base pairs observed in the hairpin form of the pseudoknot domain.


Exploring the impact of hippocampal sclerosis on white matter tracts and memory in individuals with mesial temporal lobe epilepsy.
To investigate how the presence/side of hippocampal sclerosis (HS) are related to the white matter structure of cingulum bundle (CB), arcuate fasciculus (AF), and inferior longitudinal fasciculus (ILF) in mesial temporal lobe epilepsy (MTLE). We acquired diffusion-weighted magnetic resonance imaging (MRI) from 86 healthy and 71 individuals with MTLE (22 righ-HS; right-HS, 34 left-HS; left-HS, and 15 nonlesional MTLE). We utilized two-tensor tractography and fiber clustering to compare fractional anisotropy (FA) of each side/tract between groups. Additionally, we examined the association between FA and nonverbal (WMS-R) and verbal (WMS-R, RAVLT codification) memory performance for MTLE individuals. White matter abnormalities depended on the side and presence of HS. The left-HS demonstrated widespread abnormalities for all tracts, the right-HS showed lower FA for ipsilateral tracts and the nonlesional MTLE group did not differ from healthy individuals. Results indicate no differences in verbal/nonverbal memory performance between the groups, but trend-level associations between higher FA of visual memory and the left CB (r = 0.286, P = 0.018), verbal memory (RAVLT) and -left CB (r = 0.335, P = 0.005), -right CB (r = 0.286, P = 0.016), and -left AF (r = 0.287, P = 0.017). Our results highlight that the presence and side of HS are crucial to understand the pathophysiology of MTLE. Specifically, left-sided HS seems to be related to widespread bilateral white matter abnormalities. Future longitudinal studies should focus on developing diagnostic and treatment strategies dependent on HS's presence/side.


Toward In Vitro Epigenetic Drug Design for Thyroid Cancer: The Promise of PF-03814735, an Aurora Kinase Inhibitor.
Thyroid cancer (TC) is a very common malignancy worldwide. Chief among the innovative molecular drug targets for TC are epigenetic modifications. Increased telomerase activity in cancer cells makes telomerase a novel target for epigenetic anticancer drug innovation. Recently, telomerase reverse transcriptase (TERT) gene promoter (TERTp) mutations (C228T and C250T) were reported at high frequency in TC cell lines and tumor biopsies. In this study, three representative TC cell lines, mutant TERTp (TPC1), mutant BRAF/TERTp (KTC2), and wild-type TERTp (WRO), were screened with a drug library composed of 51 epigenetic drugs: 14 Aurora kinase inhibitors; 23 histone deacetylase inhibitors; 5 sirtuin modifiers; 3 hypoxia-inducible factor inhibitors; 2 DNA methyltransferase inhibitors; 2 histone methyltransferase inhibitors, a histone demethylase inhibitor, and a bromodomain inhibitor. Effects of the drugs on cell growth at 48 and 72 h were compared. PF-03814735, a small-molecule inhibitor of Aurora kinase A (IC50 = 0.8 nM) and B (IC50 = 5 nM), was the most potent on KTC2 cells, whereas CUDC-101, a multitarget inhibitor, was effective on both WRO and KTC2 cells. Notably, PF-03814735 was found to be the most effective epigenetic drug on cell lines harboring the C228T mutation. In conclusion, these new findings offer specific guidance on dose and time course selection to design novel therapeutic interventions against TC using PF-03814735, and specifically target cells carrying the TERTpC228T mutation. In a larger context of drug discovery science, these findings inform new strategies to forecast optimal treatment regimens for TC, particularly with Aurora kinase inhibitors and in ways guided by epigenetic drug design.


A self-renewal program controls the expansion of genetically unstable cancer stem cells in pluripotent stem cell-derived tumors.
Human germ cell tumors are often metastatic, presumably due to distal site tumor growth by cancer stem cells. To determine whether cancer stem cells can be identified in a transplantation model of testicular germ cell tumor, we transplanted murine embryonic germ cells (EGCs) into the testis of adult severe combined immunodeficient mice. Transplantation resulted in a locally invasive solid tumor, with a cellular component that generated secondary tumors upon serial transplantation. The secondary tumors were invariably metastatic, a feature not observed in the primary tumors derived from EGCs. To characterize the differences between EGCs and the tumor-derived stem cells, we performed karyotype and microarray analysis. Our results show that generation of cancer stem cells is associated with the acquisition of nonclonal genomic rearrangements not found in the originating population. Furthermore, pretreatment of EGCs with a potent inhibitor of self-renewal, retinoic acid, prevented tumor formation and the emergence of these genetically unstable cancer stem cells. Microarray analysis revealed that EGCs and first- and second-generation cancer stem cells were highly similar; however, approximately 1,000 differentially expressed transcripts could be identified corresponding to alterations in oncogenes and genes associated with motility and development. Combined, the data suggest that the activation of oncogenic pathways in a cellular background of genetic instability, coupled with an inherent ability to self-renew, is involved in the acquisition of metastatic behavior in the cancer stem cell population of tumors derived from pluripotent cells.


Equilibrium and nonequilibrium features in the morphology and structure of physisorbed polyelectrolyte layers.
AFM is used to characterize sodium poly(styrene sulfonate) (PSS) layers physisorbed from NaCl solutions with an ionic strength ranging between 0 and 1 M NaCl. Colloidal probe tapping mode imaging shows that domains of PSS salted brushes coexist with flatly adsorbed PSS. The brush area fraction increases with rising degree of polymerization. The surface forces (as measured with colloidal probe technique) are a superposition of steric and electrostatic forces; their respective contribution is determined by the brush area fraction. Unexpectedly, the internal properties of the brush domains (brush thickness and average chain distance) are independent of the deposition salt concentration. Both properties increase with rising polymer length/degree of polymerization, whereas only the brush thickness can be controlled by the surrounding salt concentration (equilibrium feature). Furthermore, we show that the amount of brush-like physisorbed PSS chains leads to an increase in PSS surface coverage, which is also observed with other techniques after addition of salt to the deposition solution (as is extensively described in literature).


Significance of cardiac troponin I and creatine kinase release after coronary intervention.
Cardiac troponin I is a highly sensitive and specific marker for early detection of myocardial injury. Whether it can be used to monitor myocardial injury after coronary intervention is uncertain. This study was designed to measure the cardiac troponin I and creatine kinase (CK) after coronary intervention and investigate their clinical significance. We measured cardiac troponin I and CK levels before intervention and 4 hours, 8 hours, 12 hours and 24 hours after apparently successful coronary intervention in 106 eligible patients. Nine patients were excluded due to missing data. We also followed up the clinical outcome to record major cardiac events (MACE). The frequency of cardiac troponin I increase after coronary intervention was higher than that of CK increase (40.2% vs 8.2%). The frequency of cardiac troponin I increase in the stent group was significantly higher than that in the PTCA group (49.2% vs 21.9%, p < 0.001). The frequency of cardiac troponin I increase was also higher than that of CK increase in patients with in-hospital events (58.8% vs 14.7%). Cardiac troponin I is more sensitive than creatine kinase in detecting myocardial injury after coronary intervention. The incidence of cardiac troponin I increase is significantly higher in patients undergoing stenting than in patients treated with balloon angioplasty only. The cardiac troponin I increase is more highly correlated with in-hospital events than is creatine kinase.


Skimboard injuries.
Skimboarding is a recreational activity performed in shallow water in a beach setting. We reviewed patient records from our emergency department for a 52-month period and identified 79 patients with skimboard-related injuries. Mean age of patients was 15.2 years; 73.4% presented with a fracture. Lower-extremity fractures were found 63.8% of the time, and upper extremity were found 36.2%. Distal radius fractures were the most common (61.9%) upper-extremity fracture, and ankle fractures were the most common (83.8%) lower-extremity fracture. The prevalence of fractures sustained while skimboarding was compared with that of other published series of recreational activities, including trampoline injuries, and was found to be higher. Skimboarding is a sport in which injuries occur by the sudden deceleration of the board as it transitions from water to land or from falls into shallow water. The lower-extremity fracture prevalence is much higher than in similar sports such as skateboarding and surfing. The prevalence of fracture is also higher than that found in trampoline-related injury reports.


Diarrheal outbreak caused by atypical enteropathogenic Escherichia coli O157:H45 in South Korea.
Background: In May 2013, an outbreak of gastroenteritis occurred in a high school in Incheon, South Korea. We investigated the outbreak in order to identify the pathogen and mode of transmission. A case-control study was performed using standardized questionnaires with a case definition of illness with diarrhea. Stool samples, environmental samples, and samples from preserved food items were collected to test pathogens. Pulsed-field gel electrophoresis (PFGE) was performed on the outbreak-related Escherichia coli strains. Thirty-three people (attack rate: 2.5%) met the case definition, and the pattern of the epidemic curve suggested a point-source outbreak. The common symptoms of cases were diarrhea (100.0%), abdominal pain (75.8%), chills (45.5%), and nausea (39.4%). Cases were found to be 8.26 times more likely to have eaten spicy fish soup with cod (95% confidence interval: 1.05-65.01). Consumption of egg soup with spring onions or braised eggs with razor clam flesh was significantly associated with illness. Atypical enteropathogenic E. coli O157:H45 was isolated from samples of 9 cases (27.3%) and tuna bibimbap. PFGE patterns of all tested isolates of O157 serotype were indistinguishable. This outbreak was caused by atypical enteropathogenic E. coli O157:H45 and the food vehicle was suspected to be tuna bibimbap. The statistical analysis was not in concordance with the microbiologic tests, probably owing to low pathogenicity of atypical enteropathogenic E. coli O157. This is the first report of an outbreak caused by atypical enteropathogenic E. coli O157.


The cognitive underpinnings of emerging mathematical skills: executive functioning, patterns, numeracy, and arithmetic.
Exposure to mathematical pattern tasks is often deemed important for developing children's algebraic thinking skills. Yet, there is a dearth of evidence on the cognitive underpinnings of pattern tasks and how early competencies on these tasks are related to later development. We examined the domain-specific and domain-general determinants of performances on pattern tasks by using (a) a standardized test of numerical and arithmetic proficiency and (b) measures of executive functioning, respectively. Participants were 163 6-year-olds enrolled in primary schools that typically serve families from low to middle socioeconomic backgrounds. Children were administered a battery of executive functioning (inhibitory, switching, updating), numerical and arithmetic proficiency (the Numerical Operations task from the Wechsler Individual Achievement Test-II), and three types of pattern tasks. Contrary to findings from the adult literature, we found all the executive functioning measures coalesced into two factors: updating and an inhibition/switch factor. Only the updating factor predicted performances on the pattern tasks. Although performance on the pattern tasks were correlated with numerical and arithmetic proficiency, findings from structural equation modelling showed that there were no direct or independent relationships between them. The findings suggest that the bivariate relationships between pattern, numeracy, and arithmetic tasks are likely due to their shared demands on updating resources. Unlike older children, these findings suggest that for 6-year-olds, better numerical and arithmetic proficiency, without accompanying advantages in updating capacities, will no more likely lead to better performance on the pattern tasks.


Effect of Washing, Waxing and Low-Temperature Storage on the Postharvest Microbiome of Apple.
There is growing recognition of the role that the microbiome plays in the health and physiology of many plant species. However, considerably less research has been conducted on the postharvest microbiome of produce and the impact that postharvest processing may have on its composition. Here, amplicon sequencing was used to study the effect of washing, waxing, and low-temperature storage at 2 °C for six months on the bacterial and fungal communities of apple calyx-end, stem-end, and peel tissues. The results of the present work reveal that tissue-type is the main factor defining fungal and bacterial diversity and community composition on apple fruit. Both postharvest treatments and low temperature storage had a strong impact on the fungal and bacterial diversity and community composition of these tissue types. Distinct spatial and temporal changes in the composition and diversity of the microbiota were observed in response to various postharvest management practices. The greatest impact was attributed to sanitation practices with major differences among unwashed, washed and washed-waxed apples. The magnitude of the differences, however, was tissue-specific, with the greatest impact occurring on peel tissues. Temporally, the largest shift occurred during the first two months of low-temperature storage, although fungi were more affected by storage time than bacteria. In general, fungi and bacteria were impacted equally by sanitation practices, especially the epiphytic microflora of peel tissues. This research provides a foundation for understanding the impact of postharvest management practices on the microbiome of apple and its potential subsequent effects on postharvest disease management and food safety.


Modality-specific temporal constraints for state-dependent interval timing.
The ability to discriminate temporal intervals in the milliseconds-to-seconds range has been accounted for by proposing that duration is encoded in the dynamic change of a neuronal network state. A critical limitation of such networks is that their activity cannot immediately return to the initial state, a restriction that could hinder the processing of intervals presented in rapid succession. Empirical evidence in the literature consistently shows impaired duration discrimination performance for 100 ms intervals demarked by short auditory stimuli immediately preceded by a similar interval. Here we tested whether a similar interference is present with longer intervals (300 ms) demarked either by auditory or by visual stimuli. Our results show that while temporal estimates of auditory stimuli in this range are not affected by the interval between them, duration discrimination with this duration is significantly impaired with visual intervals presented in rapid succession. The difference in performance between modalities is overall consistent with state-dependent temporal computations, as it suggests that the limits due to slow neuronal dynamics greatly depends on the sensory modality with which the intervals are demarked, in line with the idea of intrinsic, modality-specific neural mechanisms for interval timing.