Three-Dimensional Convolutional Neural Networks and a Cross-Docked Data Set for Structure-Based Drug Design.
One of the main challenges in drug discovery is predicting protein-ligand binding affinity. Recently, machine learning approaches have made substantial progress on this task. However, current methods of model evaluation are overly optimistic in measuring generalization to new targets, and there does not exist a standard data set of sufficient size to compare performance between models. We present a new data set for structure-based machine learning, the CrossDocked2020 set, with 22.5 million poses of ligands docked into multiple similar binding pockets across the Protein Data Bank, and perform a comprehensive evaluation of grid-based convolutional neural network (CNN) models on this data set. We also demonstrate how the partitioning of the training data and test data can impact the results of models trained with the PDBbind data set, how performance improves by adding more lower-quality training data, and how training with docked poses imparts pose sensitivity to the predicted affinity of a complex. Our best performing model, an ensemble of five densely connected CNNs, achieves a root mean squared error of 1.42 and Pearson R of 0.612 on the affinity prediction task, an AUC of 0.956 at binding pose classification, and a 68.4% accuracy at pose selection on the CrossDocked2020 set. By providing data splits for clustered cross-validation and the raw data for the CrossDocked2020 set, we establish the first standardized data set for training machine learning models to recognize ligands in noncognate target structures while also greatly expanding the number of poses available for training. In order to facilitate community adoption of this data set for benchmarking protein-ligand binding affinity prediction, we provide our models, weights, and the CrossDocked2020 set at https://github.com/gnina/models.


Development of an ice crystal scattering database for the global change observation mission/second generation global imager satellite mission: investigating the refractive index grid system and potential retrieval error.
Computing time and retrieval error of the effective particle radius are important considerations when developing an ice crystal scattering database to be used in radiative transfer simulation and satellite remote sensing retrieval. Therefore, the light scattering database should be optimized based on the specifications of the satellite sensor. In this study, the grid system of the complex refractive index in the 1.6 μm (SW3) channel of the Global Change Observation Mission/Second Generation Global Imager satellite sensor is investigated for optimizing the ice crystal scattering database. This grid system is separated into twelve patterns according to the step size of the real and imaginary parts of the refractive index. Specifically, the LIght Scattering solver Applicable to particles of arbitrary Shape/Geometrical-Optics Approximation technique is used to simulate the scattering of light by randomly oriented large hexagonal ice crystals. The difference of radiance with different step size of the refractive index is calculated from the developed light scattering database using the radiative transfer (R-STAR) solver. The results indicated that the step size of the real part is a significant factor in difference of radiance.


Frontal brain asymmetry in restrained eaters.
It is well known that the eating patterns that restrain chronic dieters (restrained eaters) can be disinhibited by anxiety, which in turn has been associated with relative right frontal brain activity in independent electroencephalographic (EEG) studies. Combining these two lines of evidence, the authors tested the hypothesis that chronic restrained eating is associated with relative right frontal asymmetry. Resting anterior brain asymmetry and self-reported measures of anxiety and depression were collected in 23 restrained and 32 unrestrained eaters. As hypothesized, groups differed in tonic frontal activity, with restrained eaters showing more relative right frontal activity. Furthermore, relative right frontal activity was associated with greater self-reported restraint. Right-sided prefrontal asymmetry may thus represent a diathesis associated with increased vulnerability toward restrained eating.


TGF-β signaling pathway and breast cancer susceptibility.
TGF-β acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-β ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)]. Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta-analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC). Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR(-)) tumors [1.18 (95% CI: 1.09-1.28), 4.1 × 10(-5) (P value for heterogeneity of ORs by PR status = 2.3 × 10(-4))]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis. Common variation in the TGF-β ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes. The subtype specific associations require very large studies to be confirmed.


Biomimetic heterogenous elastic tissue development.
There is an unmet need for artificial tissue to address current limitations with donor organs and problems with donor site morbidity. Despite the success with sophisticated tissue engineering endeavours, which employ cells as building blocks, they are limited to dedicated labs suitable for cell culture, with associated high costs and long tissue maturation times before available for clinical use. Direct 3D printing presents rapid, bespoke, acellular solutions for skull and bone repair or replacement, and can potentially address the need for elastic tissue, which is a major constituent of smooth muscle, cartilage, ligaments and connective tissue that support organs. Thermoplastic polyurethanes are one of the most versatile elastomeric polymers. Their segmented block copolymeric nature, comprising of hard and soft segments allows for an almost limitless potential to control physical properties and mechanical behaviour. Here we show direct 3D printing of biocompatible thermoplastic polyurethanes with Fused Deposition Modelling, with a view to presenting cell independent in-situ tissue substitutes. This method can expeditiously and economically produce heterogenous, biomimetic elastic tissue substitutes with controlled porosity to potentially facilitate vascularisation. The flexibility of this application is shown here with tubular constructs as exemplars. We demonstrate how these 3D printed constructs can be post-processed to incorporate bioactive molecules. This efficacious strategy, when combined with the privileges of digital healthcare, can be used to produce bespoke elastic tissue substitutes in-situ, independent of extensive cell culture and may be developed as a point-of-care therapy approach.


The small heat shock proteins αB-crystallin (HSPB5) and Hsp27 (HSPB1) inhibit the intracellular aggregation of α-synuclein.
Protein homeostasis, or proteostasis, is the process of maintaining the conformational and functional integrity of the proteome. Proteostasis is preserved in the face of stress by a complex network of cellular machinery, including the small heat shock molecular chaperone proteins (sHsps), which act to inhibit the aggregation and deposition of misfolded protein intermediates. Despite this, the pathogenesis of several neurodegenerative diseases has been inextricably linked with the amyloid fibrillar aggregation and deposition of α-synuclein (α-syn). The sHsps are potent inhibitors of α-syn aggregation in vitro. However, the limited availability of a robust, cell-based model of α-syn aggregation has, thus far, restricted evaluation of sHsp efficacy in the cellular context. As such, this work sought to establish a robust model of intracellular α-syn aggregation using Neuro-2a cells. Aggregation of α-syn was found to be sensitive to inhibition of autophagy and the proteasome, resulting in a significant increase in the proportion of cells containing α-syn inclusions. This model was then used to evaluate the capacity of the sHsps, αB-c and Hsp27, to prevent α-syn aggregation in cells. To do so, we used bicistronic expression plasmids to express the sHsps. Unlike traditional fluorescent fusion constructs, these bicistronic expression plasmids enable only individual transfected cells expressing the sHsps (via expression of the fluorescent reporter) to be analysed, but without the need to tag the sHsp, which can affect its oligomeric structure and chaperone activity. Overexpression of both αB-c and Hsp27 significantly reduced the intracellular aggregation of α-syn. Thus, these findings suggest that overexpressing or boosting the activity of sHsps may be a way of preventing amyloid fibrillar aggregation of α-syn in the context of neurodegenerative disease.


Effects of subanaesthetic sevoflurane on ventilation. 2: Response to acute and sustained hypoxia in humans.
We have determined the influence of 0.1 minimum alveolar concentration (MAC) of sevoflurane on the acute ventilatory response to hypoxia (AHVR), hypoxic ventilatory decline (HVD) and the magnitude of the rapid decline in ventilation on relief of sustained hypoxia (the off-response) in eight healthy adult volunteers. The following design was used with and without 0.1 MAC of sevoflurane: end-tidal PO2 was maintained at 13.3 kPa for 5 min, at 7.9 kPa for 20 min and at 13.3 kPa for 5 min. End-tidal PCO2 was held constant throughout at 1.3 kPa above the subject's normal value. A dynamic end-tidal forcing system was used to generate these gas changes. Sevoflurane reduced AHVR from 14.5 (SEM 1.2) to 11.6 (1.6) litre min-1, and the off-response at cessation of hypoxia from 7.1 (1.1) to 6.3 (1.4) litre min-1. The magnitude of HVD was slightly increased by sevoflurane from 8.2 (1.1) to 10.6 (2.8) litre min-1. None of these changes was significant (ANOVA). These results suggest that 0.1 MAC of sevoflurane had very little effect on the AHVR, and that it did not markedly alter the processes underlying HVD during sustained hypoxia.


Fast serotonin voltammetry as a versatile tool for mapping dynamic tissue architecture: I. Responses at carbon fibers describe local tissue physiology.
It is important to monitor serotonin neurochemistry in the context of brain disorders. Specifically, a better understanding of biophysical alterations and associated biochemical functionality within subregions of the brain will enable better of understanding of diseases such as depression. Fast voltammetric tools at carbon fiber microelectrodes provide an opportunity to make direct evoked and ambient serotonin measurements in vivo in mice. In this study, we characterize novel stimulation and measurement circuitries for serotonin analyses in brain regions relevant to psychiatric disease. Evoked and ambient serotonin in these brain areas, the CA2 region of the hippocampus and the medial prefrontal cortex, are compared to ambient and evoked serotonin in the substantia nigra pars reticulata, an area well established previously for serotonin measurements with fast voltammetry. Stimulation of a common axonal location evoked serotonin in all three brain regions. Differences are observed in the serotonin release and reuptake profiles between these three brain areas which we hypothesize to arise from tissue physiology heterogeneity around the carbon fiber microelectrodes. We validate this hypothesis mathematically and via confocal imaging. We thereby show that fast voltammetric methods can provide accurate information about local physiology and highlight implications for chemical mapping. Cover Image for this issue: doi: 10.1111/jnc.14739.


Quantitative mapping and minimization of super-resolution optical imaging artifacts.
Super-resolution microscopy depends on steps that can contribute to the formation of image artifacts, leading to misinterpretation of biological information. We present NanoJ-SQUIRREL, an ImageJ-based analytical approach that provides quantitative assessment of super-resolution image quality. By comparing diffraction-limited images and super-resolution equivalents of the same acquisition volume, this approach generates a quantitative map of super-resolution defects and can guide researchers in optimizing imaging parameters.


Characterization of a receptor for interleukin-5 on human eosinophils and the myeloid leukemia line HL-60.
Interleukin-5 (IL-5) promotes the growth and differentiation of human eosinophils and may regulate the selective eosinophilia and eosinophil activation seen in certain diseases. Radiolabeled recombinant human IL-5 (hIL-5) was used to characterize the IL-5 receptor present on normal human eosinophils and on the myeloid leukemia line HL-60, which can be induced to differentiate into eosinophilic cells. Binding studies with eosinophils and HL-60 cells grown under alkaline conditions demonstrated similar high-affinity binding sites for hIL-5 on both cell types with kd values of approximately 400 pmol/L. The binding observed was specific in that it was not inhibited by hIL-3, human granulocyte-macrophage colony-stimulating factor, or hIL-2. Binding studies with a number of other human cell lines, including a B-lymphoma line, and with lymphocyte and neutrophil preparations were also performed, but IL-5 receptors were not detectable on these cells. The number of hIL-5 receptors on HL-60 cells could be correlated with its propensity to differentiate towards an eosinophilic cell type. Expression of hIL-5 receptors on HL-60 cells was upregulated by butyric acid under alkaline conditions, downregulated by hIL-3, virtually eliminated by dimethyl sulfoxide and hIL-5, while hIL-2 had no detectable effect. One major 125I-hIL-5-crosslinked complex of 75 to 85 Kd in Mr was detected on HL-60 cells using crosslinking agents giving a molecular mass of 55 to 60 Kd for the hIL-5 receptor itself. Studies using cellular autoradiography showed that IL-5 receptors were evenly distributed on eosinophils but that receptor distribution on HL-60 cells was noticeably heterogeneous. Eosinophils were the only cells in slides prepared from peripheral blood that had detectable levels of IL-5 receptors in agreement with the specific action of IL-5 on the human eosinophil lineage.


Optimal antihypertensive level for improvement of coronary microvascular dysfunction: the lower, the better?
Recently, coronary microvascular function was documented to be impaired even in patients with prehypertension. However, the impact of antihypertensive level on improvement of coronary microvascular dysfunction in hypertensive patients remains to be established. We investigated the optimal blood pressure achieved with treatment of antihypertensive agents for improvement of coronary microvascular dysfunction in hypertensive patients. We prospectively studied 108 untreated hypertensive patients. All patients were treated with antihypertensive agents for approximately 12 months. Coronary flow reserve (CFR) was measured before and after treatment. The patients were divided into hypertensive, prehypertensive, and normal groups based on their average blood pressure during the treatment period. Pretreatment CFR was similar among all groups. CFR increased significantly in the normal group during the treatment period, but decreased significantly in the prehypertensive and hypertensive groups. This decrease was significantly greater in the hypertensive group than in the prehypertensive group. Multivariate analysis showed lowering blood pressure to normal level to be an independent determinant of improvement in CFR. The normal group was divided into normal-higher and normal-lower subgroups based on their average diastolic blood pressure during the treatment period. Increase in CFR was significantly greater in the normal-higher group than in the normal-lower group. These findings indicate that lowering blood pressure to a normal level is necessary to improve coronary microvascular dysfunction in hypertensive patients. Furthermore, raising diastolic blood pressure to a higher level within normal range has the most beneficial effect. However, as this study is based on observational design, it may have several limitations.


Genito-urinary tuberculosis: a review of 83 cases.
We evaluated 83 cases of genito-urinary tuberculosis retrospectively. Flank pain and non-specific urinary complaints were the major symptoms. Although some authors prefer short-term medical therapy, the relapse rate in our series with six-month therapy was 22%, and we therefore suggest a therapy period of at least 12 months is necessary. The poor nutritional status and social conditions characteristic of subjects from our region may, however, be a factor in this high relapse rate.


Strategic priorities for hematopoietic stem cell transplantation in the EMRO region.
The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.


A New Wilt of Cyclamen Caused by Phytophthora tropicalis in Germany and the Netherlands.
Unusual symptoms were observed on cyclamen (Cyclamen persicum Mill.) in Germany and the Netherlands in 1997. Symptoms began with a change of leaf color from dark green to olive green and an unspecified flagging of leaves, followed by a yellowing of the margins of older leaves and then yellowing of entire leaves. Corms, sectioned lengthwise, were firm, cream colored, without discoloration of vascular bundles, but with some browning at the base and dark brown discolored roots. Eventually, the plants died. Five isolates (one from Netherlands, two from Northern Germany, and two from Southern Germany) of a Phytophthora species recovered from diseased corms of cyclamen were heterothallic, all A1 mating type, and occasionally formed a few chlamydospores in culture. Sporangia were commonly produced in umbellate clusters. Sporangial shape was naviculate to limoniform with a tapered base. They were papillate, occasionally bipapillate, caducous, with a pedicel of about 1.5 times of the sporangial length. Sporangial dimensions were 52 × 26 μm, with a length to width ratio of 2:1. Cardinal temperatures were 10 and 35°C; optimum growth occurred at 30°C. The pathogen was originally described as a taxonomically nonclassified species closely related to the Phytophthora palmivora complex (2). Based on isolate ATCC No. 76656, received from Uchida (1), we recognized that the above-mentioned cyclamen pathogen exhibits morphological characteristics typical of Phytophthora tropicalis. This taxon has been proposed by Aragaki and Uchida (1) for a number of Phytophthora capsici-like isolates (3) which differ from the type isolate of Phytophthora capsici Leonian. Pathogen identity was further confirmed by cloning subgenomic DNA fragments. Oligonucleotide primers and polymerase chain reaction were employed to amplify the internal transcribed spacer regions ITS1/ITS2 including the 5.8S subunit of the rRNA gene repeat. Both 809-bp products obtained from the American and the European P. tropicalis isolates H 778-1 (Isle of Oahu, Hawaii; host: Dianthus caryophyllus L.) and 066 (Bavaria; host: Cyclamen persicum) respectively, reveal identical nucleotide sequences with the exception of two single bp changes (EMBL accession numbers AJ299734 and AJ299733). In public electronic databases, there were no similar sequences with other Phytophthora spp. Using a sand-corn meal mixture added as inoculum to the planting substrate, pathogenicity of the European P. tropicalis-isolates was shown on Cyclamen persicum, Epipremnum aureum (Linden et André) Bunting, Dianthus caryophyllus, partially on Diascia vigilis Hilliard et B. C. Burtt and Hedera helix L. No pathogenicity was observed on Lycopersicon esculentum Mill., Capsicum annuum L., Cucurbita pepo L., and Cucumis sativus L., representing important hosts of P. capsici, and not on Carica papaya L., a typical host for P. palmivora (Butler) Butler. All data described here confirm the identity of the new cyclamen pathogen as P. tropicalis. The uniformity of the mating type, A1, suggests that the pathogen was inadvertently introduced at one point into Europe and possibly was distributed on seedling plants of cyclamen, since apparently no other host of this pathogen has been observed so far in Europe. References: (1) M. Aragaki and J. Y. Uchida. Phytopathology 82:1164, 1992. (2) E. Idczak et al. Nachrichtenbl. Deut. Pflanzenschutzd. 50:1, 1998. (3) G. R. A. Mchau and M. D. Coffey. Mycol. Res. 99:89, 1995.


Endorectal digital prostate tomosynthesis (endoDPT): a proof-of-concept study.
In this study we present endorectal digital prostate tomosynthesis (endoDPT), a proposed method of high resolution prostate imaging using an endorectal x-ray sensor and an external x-ray source. endoDPT may be useful for visualizing the fine detail of small structures such as low dose rate brachytherapy (LDRBT) seeds that are difficult to visualize with current methods. The resolution of endoDPT was characterized through measurement of the modulation transfer function (MTF) and artifact spread function (ASF) in computational and physical phantoms. The qualitative resolution of endoDPT was assessed relative to computed tomography (CT) through imaging of LDRBT seeds implanted inex vivocanine prostates. The x-ray sensor MTF reached 10% at 11.50 mm-1, the reconstruction algorithm MTF reached a maximum at 7.08 mm-1, and the ASF was 2.5 mm (full-width at half-maximum). Fine structures in LDRBT seeds like the 0.05 mm thick shell were visible with endoDPT but not CT. All endoDPT images exhibited an overshoot artifact. The measured MTFs were consistent with other studies using similar x-ray sensors and demonstrated improved resolution compared to digital breast tomosynthesis; this result was due to the smaller endoDPT x-ray sensor detection element size and quantitatively demonstrates the high resolution of endoDPT. The ASF demonstrated worse depth resolution compared to in-plane resolution, due to partial angular sampling; partial angular sampling also caused the observed overshoot artifact in the endoDPT images. However, endoDPT still was able to visualize fine structures such as the LDRBT seed shell to a much higher degree than CT. This high-resolution visualization may be useful for improvements in patient specific LDRBT dosimetry. Overall, these results indicate endoDPT is capable of high in-plane spatial resolution and is thus well poised for optimization and studies assessing clinical utility.


Low affinity interaction of human or rat T cell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity.
The mechanism by which low affinity adhesion molecules function to produce stable cell-cell adhesion is unknown. In solution, the interaction of human CD2 with its ligand CD58 is of low affinity (500 mM-1) and the interaction of rat CD2 with its ligand CD48 is of still lower affinity (40 mM-1). At the molecular level, however, the two systems are likely to be topologically identical. Fluorescently labeled glycosylphosphatidylinositol-anchored CD48 and CD58 were prepared and incorporated into supported phospholipid bilayers, in which the ligands were capable of free lateral diffusion. Quantitative fluorescence imaging was used to study the binding of cell surface human and rat CD2 molecules to the fluorescent ligands in contact areas between Jurkat cells and the bilayers. These studies provide two major conclusions. First, CD2/ligand interactions cooperate to align membranes with nanometer precision leading to a physiologically effective two-dimensional affinity. This process does not require the intact cytoplasmic tail of CD2. Second, the degree of membrane alignment that can be achieved by topologically similar receptors deteriorates with decreasing affinity. This suggests an affinity limit for the ability of this mode of cooperativity to achieve stable cell-cell adhesion at approximately 10 mM-1.


Why Eberl is wrong. Reflections on the beginning of personhood.
In a paper published in Bioethics, Jason Eberl has argued that early embryos are not persons and should not be granted the status possessed by them. Eberl bases this position upon the following claims: (1) The early embryo has a passive potentiality for development into a person. (2) The early embryo has not established both 'unique genetic identity' and 'ongoing ontological identity', which are necessary conditions for ensoulment. (3) The early embryo has a low probability of developing into a more developed embryo. This paper examines these claims. I argue against (1) that a plausible view is that the early embryo has an active potentiality to grow into a more developed embryo. Against (2), I argue that neither 'unique genetic identity' nor 'ongoing ontological identity' are necessary conditions for ensoulment, and that 'ongoing ontological identity' is established between early embryos and more developed embryos. Against (3), I argue that the fact that the early embryo has a low probability of developing into a more developed embryo, if true, does not warrant the conclusion that the early embryo is not a person. If Eberl is right that the human soul is that which organises the activities of a human being and that ensouled humans are persons, embryos are persons from conception.


Treatment Patterns, Healthcare Resource Utilization, and Spending Among Medicaid-Enrolled Children with Chronic Idiopathic/Spontaneous Urticaria in the United States.
Few studies have described chronic idiopathic/spontaneous urticaria (CIU/CSU) healthcare burden in adults, while this information remains largely unknown in children. We aimed to describe treatment patterns, healthcare resource utilization (HRU), and costs in CIU/CSU pediatric patients, as well as to compare HRU and costs in CIU/CSU and CIU/CSU-free pediatric patients. Medicaid claims from four states (09/01/2013-03/31/2016) were used to identify patients less than 12 years old. The CIU/CSU cohort included patients with either at least two claims for idiopathic, other, or unspecified urticaria at least 6 weeks apart, or at least one claim for urticaria and at least one claim for angioedema at least 6 weeks apart (index date defined as the first claim). The control cohort included patients without urticaria/angioedema claims (index date randomly assigned). Patients without at least 6 months of continuous Medicaid eligibility pre- and post-index were excluded. HRU and costs were compared between propensity score-matched cohorts during the post-index follow-up. A total of 548 CIU/CSU patients (mean [SD] age 4.5 [3.3] years; 51.3% male) were matched 1:1 with controls. In the CIU/CSU cohort, 51.8% used non-sedating prescription H1-antihistamines, 24.3% used oral corticosteroids, and 23.5% used other prescription H1-antihistamines; 13.5% consulted allergist/immunologists and 2.4% consulted dermatologists in the first 6 months of follow-up. Compared to controls, CIU/CSU patients had significantly more per patient per year (PPPY) inpatient (incidence rate ratio [IRR] 2.05), outpatient (IRR 2.20), and emergency department (IRR 1.64) visits (all p values < 0.05). Moreover, CIU/CSU patients also had significantly higher PPPY healthcare costs (mean cost difference [MCD] $1853), driven by incremental outpatient (MCD $1286) costs (all p values < 0.01). CIU/CSU pediatric patients had low use of non-sedating H1-antihistamines and high use of oral corticosteroids. Compared to CIU/CSU-free controls in the same age group, CIU/CSU pediatric patients had higher HRU and healthcare costs. Novartis Pharmaceuticals Corporation.


Management strategies for pulmonary sarcoidosis.
SARCOIDOSIS IS A SYSTEMIC INFLAMMATORY CONDITION WITH AN UNEXPLAINED PREDILECTION FOR THE LUNG: over 90% of patients have radiographic or physiological abnormalities. Respiratory physicians therefore often manage patients, but any organ may be involved, with noncaseating granulomas the characteristic feature. Sarcoidosis is the commonest interstitial lung disease (ILD), differing from most other ILDs in that many patients remain asymptomatic or improve spontaneously. Careful baseline assessment of disease distribution and severity is thus central to initial management. Subsequently, the unpredictable clinical course necessitates regular monitoring. Sarcoidosis occurs worldwide, with a high prevalence in Afro-Caribbeans and those of Swedish or Danish origin. African Americans also tend to have severe disease. Oral corticosteroids have been used since the 1950s, with evidence of short to medium response; more recent studies have examined the role of inhaled steroids. Long-term benefits of steroids remain uncertain. International guidelines published in 1999 represent a consensus view endorsed by North American and European respiratory societies. Updated British guidelines on interstitial lung disease, including sarcoidosis, were published in 2008. This review describes current management strategies for pulmonary disease, including oral and inhaled steroids, commonly used alternative immunosuppressant agents, and lung transplantation. Tumor necrosis factor alpha inhibitors are briefly discussed.


Targeted quantitation of proteins by mass spectrometry.
Quantitative measurement of proteins is one of the most fundamental analytical tasks in a biochemistry laboratory, but widely used immunochemical methods often have limited specificity and high measurement variation. In this review, we discuss applications of multiple-reaction monitoring (MRM) mass spectrometry, which allows sensitive, precise quantitative analyses of peptides and the proteins from which they are derived. Systematic development of MRM assays is permitted by databases of peptide mass spectra and sequences, software tools for analysis design and data analysis, and rapid evolution of tandem mass spectrometer technology. Key advantages of MRM assays are the ability to target specific peptide sequences, including variants and modified forms, and the capacity for multiplexing that allows analysis of dozens to hundreds of peptides. Different quantitative standardization methods provide options that balance precision, sensitivity, and assay cost. Targeted protein quantitation by MRM and related mass spectrometry methods can advance biochemistry by transforming approaches to protein measurement.


Patient navigators for people with chronic disease: A systematic review.
People with chronic diseases experience barriers to managing their diseases and accessing available health services. Patient navigator programs are increasingly being used to help people with chronic diseases navigate and access health services. The objective of this review was to summarize the evidence for patient navigator programs in people with a broad range of chronic diseases, compared to usual care. We searched MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, and Social Work Abstracts from inception to August 23, 2017. We also searched the reference lists of included articles. We included original reports of randomized controlled trials of patient navigator programs compared to usual care for adult and pediatric patients with any one of a defined set of chronic diseases. From a total of 14,672 abstracts, 67 unique studies fit our inclusion criteria. Of these, 44 were in cancer, 8 in diabetes, 7 in HIV/AIDS, 4 in cardiovascular disease, 2 in chronic kidney disease, 1 in dementia and 1 in patients with more than one condition. Program characteristics varied considerably. Primary outcomes were most commonly process measures, and 45 of 67 studies reported a statistically significant improvement in the primary outcome. Our findings indicate that patient navigator programs improve processes of care, although few studies assessed patient experience, clinical outcomes or costs. The inability to definitively outline successful components remains a key uncertainty in the use of patient navigator programs across chronic diseases. Given the increasing popularity of patient navigators, future studies should use a consistent definition for patient navigation and determine which elements of this intervention are most likely to lead to improved outcomes. PROSPERO #CRD42013005857.


Marijuana use and increased risk of squamous cell carcinoma of the head and neck.
Marijuana is the most commonly used illegal drug in the United States. In some subcultures, it is widely perceived to be harmless. Although the carcinogenic properties of marijuana smoke are similar to those of tobacco, no epidemiological studies of the relationship between marijuana use and head and neck cancer have been published. The relationship between marijuana use and head and neck cancer was investigated by a case-control study of 173 previously untreated cases with pathologically confirmed diagnoses of squamous cell carcinoma of the head and neck and 176 cancer-free controls at Memorial Sloan-Kettering Cancer Center between 1992 and 1994. Epidemiological data were collected by using a structured questionnaire, which included history of tobacco smoking, alcohol use, and marijuana use. The associations between marijuana use and head and neck cancer were analyzed by Mantel-Haenszel methods and logistic regression models. Controlling for age, sex, race, education, alcohol consumption, pack-years of cigarette smoking, and passive smoking, the risk of squamous cell carcinoma of the head and neck was increased with marijuana use [odds ratio (OR) comparing ever with never users, 2.6; 95% confidence interval (CI), 1.1-6.6]. Dose-response relationships were observed for frequency of marijuana use/day (P for trend <0.05) and years of marijuana use (P for trend <0.05). These associations were stronger for subjects who were 55 years of age and younger (OR, 3.1; 95% CI, 1.0-9.7). Possible interaction effects of marijuana use were observed with cigarette smoking, mutagen sensitivity, and to a lesser extent, alcohol use. Our results suggest that marijuana use may increase the risk of head and neck cancer with a strong dose-response pattern. Our analysis indicated that marijuana use may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. The results need to be interpreted with some caution in drawing causal inferences because of certain methodological limitations, especially with regard to interactions.


Comparison of breast cancer patient satisfaction with follow-up in primary care versus specialist care: results from a randomized controlled trial.
Routine follow-up of breast cancer patients in specialist clinics is standard practice in most countries. Follow-up involves regularly scheduled breast cancer check-ups during the disease-free period. The aims of follow-up are to detect breast cancer recurrence and to provide psychosocial support to the patient; however, little is known about patients' views on breast cancer follow-up. To assess the effect on patient satisfaction of transferring primary responsibility for follow-up of women with breast cancer in remission from hospital outpatient clinics to general practice. Randomized controlled trial with 18 months' follow-up in which women received routine follow-up either in hospital outpatient clinics or from their own general practitioner. Two hundred and ninety-six women with breast cancer in remission receiving regular follow-up care at two district general hospitals in England were included in the study. Patient satisfaction was measured by means of a self-administered questionnaire supplied three times during the 18-month study period. The general practice group selected responses indicating greater satisfaction than did the hospital group on virtually every question. Furthermore, in the general practice group there was a significant increase in satisfaction over baseline; a similar significant increase in satisfaction over baseline was not found in the hospital group. Patients with breast cancer were more satisfied with follow-up in general practice than in hospital outpatient departments. When discussing follow-up with breast cancer patients, they should be provided with complete and accurate information about the goals, expectations, and limitations of the follow-up programme so that they can make an informed choice.


A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole.
The Vps15 protein kinase and the Vps34 phosphatidylinositol 3-kinase (PI 3-kinase) are required for the sorting of soluble hydrolases to the yeast vacuole. Over-production of Vps34p suppresses the growth and vacuolar protein sorting defects associated with vps15 kinase domain mutants, suggesting that Vps15p and Vps34p functionally interact. Subcellular fractionation and sucrose density gradients indicate that Vps15p is responsible for the association of Vps34p with an intracellular membrane fraction. Chemical cross-linking and native immunoprecipitation experiments demonstrate that Vps15p and Vps34p interact as components of a hetero-oligomeric protein complex. In addition, we show that an intact Vps15 protein kinase domain is required for activation of the Vps34 PI 3-kinase, suggesting that the Vps34 lipid kinase is regulated by a Vps15p-mediated protein phosphorylation event. We propose that Vps15p and Vps34p function together as components of a membrane-associated signal transduction complex that regulates intracellular protein trafficking decisions through protein and lipid phosphorylation events.


Corneal endothelial degeneration in dentatorubral-pallidoluysian atrophy.
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar degeneration that exhibits a variety of neurologic manifestations. However, only a few reports have studied disturbances outside the central nervous system. We described 2 unrelated patients with DRPLA accompanied by corneal endothelial degeneration. A 52-year-old man presented with cerebellar ataxia and dementia. Magnetic resonance imaging of the brain showed cerebellar atrophy. Dentatorubral-pallidoluysian atrophy was diagnosed because of the detection of expansion of CAG repeats at the DRPLA locus. On admission, his visual acuity was severely impaired. Specular microscopy showed decreased endothelial cell density (500 cells/mm(2)) compared with that of healthy subjects. The second patient was a 69-year-old man with cerebellar ataxia. Magnetic resonance imaging of the brain showed cerebellar and brainstem atrophy. The diagnosis of DRPLA was based on expanded CAG repeats of the DRPLA gene. Specular microscopy showed significant decrease of endothelial cell density (1506 cells/mm(2)). Reverse transcriptase-polymerase chain reaction analysis showed DRPLA gene expression in corneal endothelial cells. Mutant DRPLA protein may be directly associated with corneal endothelial degeneration. Corneal endothelial cell loss is an important sign of DRPLA, and the corneas of patients with DRPLA should be examined.


Immunogenicity and Safety of a 9-Valent HPV Vaccine.
Prophylactic vaccination of youngwomen aged 16 to 26 years with the 9-valent (6/11/16/18/31/33/45/52/58) human papillomavirus (HPV) virus-like particle (9vHPV) vaccine prevents infection and disease. We conducted a noninferiority immunogenicity study to bridge the findings in young women to girls and boys aged 9 to 15 years. Subjects (N = 3066) received a 3-dose regimen of 9vHPV vaccine administered at day 1, month 2, and month 6. Anti-HPV serologic assays were performed at day 1 and month 7. Noninferiority required that the lower bound of 2-sided 95% confidence intervals of geometric mean titer ratios (boys:young women or girls:young women) be >0.67 for each HPV type. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored. At 4 weeks after dose 3, >99% of girls, boys, and young women seroconverted for each vaccine HPV type. Increases in geometric mean titers to HPV types 6/11/16/18/31/33/45/52/58 were elicited in all vaccine groups. Responses in girls and boys were noninferior to those of young women. Persistence of anti-HPV responses was demonstrated through 2.5 years after dose 3. Administration of the 9vHPV vaccine was generally well tolerated. A lower proportion of girls (81.9%) and boys (72.8%) than young women (85.4%) reported injection-site AEs, most of which were mild to moderate in intensity. These data support bridging the efficacy findings with 9vHPV vaccine in young women 16 to 26 years of age to girls and boys 9 to 15 years of age and implementing gender-neutral HPV vaccination programs in preadolescents and adolescents.


Further analysis of the human spontaneous eye blink rate by a cluster analysis-based approach to categorize individuals with 'normal' versus 'frequent' eye blink activity.
To further analyze the possible causes of variability in spontaneous eye blink activity in apparently healthy humans. One hundred men, aged between 23 and 57 years and with no significant eye disease, were questioned on the number of ocular symptoms they experienced (one, two, three, and so forth). Five-minute video recordings were made of the eyes in primary gaze and in silence between 11:00 and 17:00 hours. The spontaneous eye blink rate (SEBR) and palpebral aperture features were assessed from the video recordings. The central corneal threshold touch sensitivity was then assessed with a Cochet-Bonnet aesthesiometer. The average SEBR was 13.8 +/- 9.7 blinks per minute (range, 2.8-48 blinks per minute), but the distribution was heterogeneous and skewed to higher values. The SEBR was not obviously dependent on the time of day that the recordings were made, on the number of mild symptoms that the subjects reported, or on the central corneal sensitivity (P> or =0.6). Analysis of SEBR in relation to age showed a possible weak association (P=0.082, r = 0.175), but SEBR showed absolutely no correlation with palpebral aperture height (P=0.546). A hierarchic cluster analysis clearly resolved the distribution of SEBR values into two distinct groups (P<0.001, F ratio = 222). Spontaneous eye blink activity can be rather different between healthy individuals, even under a single experimental condition. These differences do not appear to be caused by the time of day, mild symptoms, corneal sensitivity, age, or palpebral aperture features. In line with previous metaanalyses, it is therefore proposed that individuals could be grouped as to whether they have "normal" eye blink activity or be classified as having "frequent" eye blink activity. The latter group would include those who had an SEBR greater than 20 blinks per minute when assessed in primary eye gaze and in silence.


Adolescent social networks matter for suicidal trajectories: disparities across race/ethnicity, sex, sexual identity, and socioeconomic status.
Examining social networks, characterized by interpersonal interactions across family, peer, school, and neighborhoods, offer alternative explanations to suicidal behaviors and shape effective suicide prevention. This study examines adolescent social networks predicting suicide ideation and attempt trajectories transitioning to adulthood, while revealing differences across racial/ethnic, sex, sexual identity, and socioeconomic status. Participants included 9421 high school students (Mage = 15.30 years; 54.58% females, baseline) from Waves I-IV of the National Longitudinal Study of Adolescent to Adult Health, 1994-2008. Latent class growth analyses were conducted to identify suicide ideation and attempt trajectories. Multivariate multinomial logistic regressions examined the relationships between social network characteristics during adolescence and suicidal trajectories. Interaction terms between social networks and sociodemographic characteristics were included to test moderation effects. Three suicidal ideation trajectories (low-stable, high-decreasing, moderate-decreasing-increasing) and two suicide attempt trajectories (low-stable, moderate-decreasing) were identified. Greater family cohesion significantly reduced the probability of belonging to high-decreasing (Trajectory 2) and moderate-decreasing-increasing (Trajectory 3) suicidal ideation trajectories, and moderate-decreasing (Trajectory 2) suicide attempt trajectory. Race/ethnicity, sex, and sexual identity significantly moderated the associations between social networks (household size, peer network density, family cohesion, peer support, neighborhood support) and suicidal trajectories. Social networks during adolescence influenced the odds of belonging to distinct suicidal trajectories. Family cohesion protected youth from being in high-risk developmental courses of suicidal behaviors. Social networks, especially quality of interactions, may improve detecting adolescents and young adults at-risk for suicide behaviors. Network-based interventions are key to prevent suicidal behaviors over time and suicide intervention programming.


Supplemental protein from dairy products increases body weight and vitamin D improves physical performance in older adults: a systematic review and meta-analysis.
The purpose of these systematic review and meta-analysis was to assess the effectiveness of dairy components on nutritional status and physical fitness in older adults, as evidence for efficacy of the supplementation of these components is inconclusive. Scopus and MEDLINE were searched. Main inclusion criteria for articles were as follows: double-blind, randomized, placebo-controlled trials including participants aged ≥55 years who received dairy components or a placebo. Outcome measures were nutrient status (body weight and body mass index) and physical fitness (body composition, muscle strength, and physical performance). Thirty-six trials with 4947participants were included. Most trials investigated protein and vitamin D supplementation and showed no effect on the outcomes. Meta-analysis on the effect of protein on body weight showed a significant increase in mean difference of 1.13 kg (95% confidence interval, 0.59-1.67). This effect increased by selecting trials with study a duration of 6 months in which less nourished and physically fit participants were included. Trials where the participants were (pre-)frail, inactive older adults or when supplementing ≥20 g of protein per day tended to increase lean body mass. Only small significant effects of vitamin D supplementation on Timed Up and Go (mean difference -0.75 seconds; 95% confidence interval -1.44 to -0.07) were determined. This effect increased when vitamin D doses ranged between 400 and 1000 IU. Additional large randomized controlled trials of ≥6 months are needed regarding the effect of dairy components containing an adequate amount of vitamin D (400-1000 IU) and/or protein (≥20 g) on nutritional status and physical fitness in malnourished or frail older adults.


Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer.
X chromosome inactivation (XCI) is a key epigenetic gene expression regulatory process, which may play a role in women's cancer. In particular tissues, some genes are known to escape XCI, yet patterns of XCI in ovarian cancer (OC) and their clinical associations are largely unknown. To examine XCI in OC, we integrated germline genotype with tumor copy number, gene expression and DNA methylation information from 99 OC patients. Approximately 10% of genes showed different XCI status (either escaping or being subject to XCI) compared with the studies of other tissues. Many of these genes are known oncogenes or tumor suppressors (e.g. DDX3X, TRAPPC2 and TCEANC). We also observed strong association between cis promoter DNA methylation and allele-specific expression imbalance (P = 2.0 × 10-10). Cluster analyses of the integrated data identified two molecular subgroups of OC patients representing those with regulated (N = 47) and dysregulated (N = 52) XCI. This XCI cluster membership was associated with expression of X inactive specific transcript (P = 0.002), a known driver of XCI, as well as age, grade, stage, tumor histology and extent of residual disease following surgical debulking. Patients with dysregulated XCI (N = 52) had shorter time to recurrence (HR = 2.34, P = 0.001) and overall survival time (HR = 1.87, P = 0.02) than those with regulated XCI, although results were attenuated after covariate adjustment. Similar findings were observed when restricted to high-grade serous tumors. We found evidence of a unique OC XCI profile, suggesting that XCI may play an important role in OC biology. Additional studies to examine somatic changes with paired tumor-normal tissue are needed.


Natural environmental water sources in endemic regions of northeastern Brazil are potential reservoirs of viable Mycobacterium leprae.
The detection of live Mycobacterium leprae in soil and animals other than humans suggests that the environment plays a role in the transmission of leprosy. The objective of this study was to investigate the presence of viable M. leprae in natural water sources used by the local population in five municipalities in the state of Ceará, northeastern Brazil. Samples were collected from 30 different sources. Viable bacilli were identified by reverse transcriptase polymerase chain reaction (PCR) of the M. leprae gyrA gene and sequencing of the PCR products. Physicochemical properties of each water source were also assessed. M. leprae gyrA mRNA was found in 23 (76.7%) of the water sources. No association was found between depth of the water and sample positivity, nor was there any association between the type of water used by the population and sample positivity. An association between viable M. leprae and temperature and pH was found. Georeferencing showed a relation between the residences of leprosy cases and water source containing the bacterium. The finding of viable M. leprae in natural water sources associated with human contact suggests that the environment plays an important role in maintaining endemic leprosy in the study region.


Bridging care transitions: findings from a resident-staffed early postdischarge program.
Academic medical centers face unique challenges to ensuring patient safety after a hospital discharge, including those related to providing patient follow-up care in practices staffed by residents who are not comfortable managing care transitions. In 2011, the authors designed a quality improvement program for early postdischarge follow-up (bridge visits) at a resident primary care outpatient practice, using existing resources. The authors added a unique appointment template to the outpatient electronic health record to guide residents during the visit. Residents completed both postvisit and postprogram surveys regarding their experience with the program, and patients completed postvisit phone surveys regarding their satisfaction with the program. Fifty-eight residents completed postvisit surveys, of which 31.0% (18/58) reported problems with medication reconciliation and 25.9% (15/58) with adherence to discharge medications. Of those residents who completed postprogram surveys, almost half (18/38; 47.4%) agreed that their experience changed the way they discharge patients. Nearly all patients who responded to the postvisit phone surveys reported that the program reinforced their discharge and medication instructions (44/46; 95.7%); 81.8% (18/22) of patients with established providers did not mind seeing an interim physician for expedited postdischarge care. An early postdischarge program at a resident outpatient primary care practice is valuable both in ensuring patient safety and as a model to promote experiential learning in medical education. Findings from this study will be used to develop a formal curriculum in care transitions for all residents.


Factors influencing the access of severely injured children and elderly patients involved in motor vehicle collisions to trauma center care.
This study was undertaken to determine factors that influence the access to trauma center care of pediatric and geriatric patients injured in motor vehicle collisions (MVC). Hospital discharge records for 1997 were obtained from the Pennsylvania Health Care Cost Containment Council and were analyzed. Of cases with an Injury Severity Score of > 15, 52.6% of elderly cases and 48.6% of pediatric cases were transported to and received their care in non-trauma center hospitals. These very high "mis-triage" rates could not be explained by differences in injury severity, body region or population density. In order to assess potential out-of-hospital factors, a file containing matched records from Emergency Medical Services (EMS) calls and hospital discharges from MVC cases across Pennsylvania for the year 1996 was constructed and analyzed. There were no significant vital signs differences between trauma center and non-trauma center cases, with the single exception of the Glasgow Coma Scale score, for both the pediatric and geriatric age groups. A reevaluation of out-of-hospital trauma triage is needed.


Characterization of low-pathogenicity H5N1 avian influenza viruses from North America.
Wild-bird surveillance in North America for avian influenza (AI) viruses with a goal of early identification of the Asian H5N1 highly pathogenic AI virus has identified at least six low-pathogenicity H5N1 AI viruses between 2004 and 2006. The hemagglutinin (HA) and neuraminidase (NA) genes from all 6 H5N1 viruses and an additional 38 North American wild-bird-origin H5 subtype and 28 N1 subtype viruses were sequenced and compared with sequences available in GenBank by phylogenetic analysis. Both HA and NA were phylogenetically distinct from those for viruses from outside of North America and from those for viruses recovered from mammals. Four of the H5N1 AI viruses were characterized as low pathogenicity by standard in vivo pathotyping tests. One of the H5N1 viruses, A/MuteSwan/MI/451072-2/06, was shown to replicate to low titers in chickens, turkeys, and ducks. However, transmission of A/MuteSwan/MI/451072-2/06 was more efficient among ducks than among chickens or turkeys based on virus shed. The 50% chicken infectious dose for A/MuteSwan/MI/451072-2/06 and three other wild-waterfowl-origin H5 viruses were also determined and were between 10(5.3) and 10(7.5) 50% egg infective doses. Finally, seven H5 viruses representing different phylogenetic clades were evaluated for their antigenic relatedness by hemagglutination inhibition assay, showing that the antigenic relatedness was largely associated with geographic origin. Overall, the data support the conclusion that North American H5 wild-bird-origin AI viruses are low-pathogenicity wild-bird-adapted viruses and are antigenically and genetically distinct from the highly pathogenic Asian H5N1 virus lineage.


The physiologic basis for goal-directed hemodynamic and fluid therapy: the pivotal role of the venous circulation.
Understanding cardiovascular physiology should help clinicians to understand the purpose of fluid and drug management during the perioperative period. The purpose of this narrative review is to describe the pivotal role of the venous circulation in goal-directed hemodynamic and fluid therapy. We selected relevant literature that examines the appropriateness of fluid therapy and pharmacologic interventions during the perioperative period. The interaction between the stressed and unstressed intravascular volume (Vs and Vu, respectively) regulates the venous return, which is the main determinant of cardiac output. The lack of hemodynamic response to an intravascular fluid challenge likely results from an unpredictable distribution of infused fluid between the Vs and Vu. Other factors affecting hemodynamic responses include the pharmacodynamics of common vasoactive drugs, which further highlight the complexity of the regulation of venous return during infusion of exogenous catecholamines. The response to even a highly selective agent can result in different hemodynamic effects. Low doses of α-adrenergic agonists constrict veins and may often shift blood from the Vu to the Vs, subsequently increasing the venous return and cardiac output, whereas higher drug doses constrict arteries and usually decrease cardiac output. The physiologic basis of goal-directed hemodynamic therapy is complex and not necessarily reflected in the information received from hemodynamic monitors. Understanding the physiologic basis of such therapy is a logical step towards its optimal use.


Modelling multiple hospital outcomes: the impact of small area and primary care practice variation.
Appropriate management of care--for example, avoiding unnecessary attendances at, or admissions to, hospital emergency units when they could be handled in primary care--is an important part of health strategy. However, some variations in these outcomes could be due to genuine variations in health need. This paper proposes a new method of explaining variations in hospital utilisation across small areas and the general practices (GPs) responsible for patient primary care. By controlling for the influence of true need on such variations, one may identify remaining sources of excess emergency attendances and admissions, both at area and practice level, that may be related to the quality, resourcing or organisation of care. The present paper accordingly develops a methodology that recognises the interplay between population mix factors (health need) and primary care factors (e.g. referral thresholds), that allows for unobserved influences on hospitalisation usage, and that also reflects interdependence between hospital outcomes. A case study considers relativities in attendance and admission rates at a North London hospital involving 149 small areas and 53 GP practices. A fixed effects model shows variations in attendances and admissions are significantly related (positively) to area and practice need, and nursing home patients, and related (negatively) to primary care access and distance of patient homes from the hospital. Modelling the impact of known factors alone is not sufficient to produce a satisfactory fit to the observations, and random effects at area and practice level are needed to improve fit and account for overdispersion. The case study finds variation in attendance and admission rates across areas and practices after controlling for need, and remaining differences between practices may be attributable to referral behaviour unrelated to need, or to staffing, resourcing, and access issues. In managerial terms, the analysis points to the utility of formal statistical analysis of hospitalisation rates as a prelude to non-statistical investigation of primary care resourcing and organisation. For example, there may be implications for the location of staff involved in community management of chronic conditions; health managers may also investigate whether some practices have unusual populations (homeless, asylum seekers, students) that explain different hospital use patterns.


PLI-Based Connectivity in Resting-EEG is a Robust and Generalizable Feature for Detecting MCI and AD: A Validation on a Diverse Multisite Clinical Dataset.
The high prevalence rate of Alzheimer's disease (AD) and mild cognitive impairment (MCI) has been a serious public health threat to the modern society. Recently, many studies have demonstrated the potential of using non-invasive electroencephalography (EEG) and machine learning to assist the diagnosis of AD/MCI. However, the majority of these research recorded EEG signals from a single center, leading to significant concerns regarding the generalizability of the findings in clinical settings. The current study aims to reevaluate the effectiveness of EEG-based machine learning model for the detection of AD/MCI in the case of a relatively large and diverse data set. We collected resting-state EEG data from 150 participants across six hospitals and examined the classification performances of Linear Discriminative Analysis (LDA) classifiers on the phase lag index (PLI) feature. We also compared the performance of PLI over the other commonly-used EEG features and other classifiers. The model was first tested on a training set to select the feature subset and then further validated with an independent test set. The results demonstrate that PLI performs the best compared to other features. The LDA classifier trained with the optimal PLI features can provide 82.50% leave-one-participant-out cross-validation (LOPO-CV) accuracy on the training set and maintain a good enough performance with 75.00% accuracy on the test set. Our results suggest that PLI-based functional connectivity could be considered as a reliable bio-maker to detect AD/MCI in the real-world clinical settings.


Body image, body dissatisfaction and weight status in South Asian children: a cross-sectional study.
Childhood obesity is a continuing problem in the UK and South Asian children represent a group that are particularly vulnerable to its health consequences. The relationship between body dissatisfaction and obesity is well documented in older children and adults, but is less clear in young children, particularly South Asians. A better understanding of this relationship in young South Asian children will inform the design and delivery of obesity intervention programmes. The aim of this study is to describe body image size perception and dissatisfaction, and their relationship to weight status in primary school aged UK South Asian children. Objective measures of height and weight were undertaken on 574 predominantly South Asian children aged 5-7 (296 boys and 278 girls). BMI z-scores, and weight status (underweight, healthy weight, overweight or obese) were calculated based on the UK 1990 BMI reference charts. Figure rating scales were used to assess perceived body image size (asking children to identify their perceived body size) and dissatisfaction (difference between perceived current and ideal body size). The relationship between these and weight status were examined using multivariate analyses. Perceived body image size was positively associated with weight status (partial regression coefficient for overweight/obese vs. non-overweight/obese was 0.63 (95% CI 0.26-0.99) and for BMI z-score was 0.21 (95% CI 0.10-0.31), adjusted for sex, age and ethnicity). Body dissatisfaction was also associated with weight status, with overweight and obese children more likely to select thinner ideal body size than healthy weight children (adjusted partial regression coefficient for overweight/obese vs. non-overweight/obese was 1.47 (95% CI 0.99-1.96) and for BMI z-score was 0.54 (95% CI 0.40-0.67)). Awareness of body image size and increasing body dissatisfaction with higher weight status is established at a young age in this population. This needs to be considered when designing interventions to reduce obesity in young children, in terms of both benefits and harms.


Molecular allergology and its impact in specific allergy diagnosis and therapy.
Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component-resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decisions.


Lessons learnt: pilot of mid rotation feedback.
The Aga Khan University went through an external review of its undergraduate medical education in December 2006 based on the accreditation guidelines by the Liaison Committee for Medical Education (LCME). The external review panel comprised of international and local experts which developed a comprehensive report on its findings with regards to LCME standards of accreditation. In the final report of the external review one of the areas highlighted as not meeting the standards of LCME was documentation of formal mid-rotation feedback of the students by the faculty in AKU clerkships through years 3 to 5. A four hour faculty development workshop was organized by the Department of Medicine in collaboration with the Department for Educational Development to emphasize the role of feedback in improving student's performance, improve faculty's skill in giving effective feedback, and to come up with recommendations for documenting the formative feedback process. A mid-rotation feedback form was designed to facilitate the documentation process. Faculty members who participated in the workshop took a lead in piloting this form and reported the areas that could be further improved upon to facilitate the process of timely and effective feedback.


Study on COD removal mechanism and reaction kinetics of oilfield wastewater.
The chemical oxygen demand (COD) removal mechanism and reaction kinetics were mainly studied in the treatment of oilfield oily sewage containing polymer by three-dimensional electrode reactor. The results proved that the residual active oxides O3, H2O2, •OH and active chlorine in the system of electrochemical reaction could be effectively detected, and the COD removal mechanism was co-oxidation of active oxides; Under these experimental conditions: the electrolysis current of 6 A, surface/volume ratio of 6/25(cm2·L-1), the reaction time of 50 min, the CODcr of treated sewage was no more than 50 mg·L-1; the removal reaction of COD conformed to apparent second-order reaction kinetic model, the correlation coefficient R2 was 0.9728, and the apparent reaction rate constant was k = 3.58 × 10-4 (L·min-1·mg-1·m-2). To reach the goal, the CODcr was no more than 50 mg·L-1 in treated sewage, and the theory minimum processing time was 45.73 min. The verification of experimental results was consistent with kinetic equations.


Polarization sensing with visual detection.
We describe a new approach to fluorescence sensing which relies on visual determination the polarization. The sensing device consists of a fluorescent probe, which changes intensity in responses to the analyte, and an oriented fluorescent film, which is not affected by the analyte. An emission filter is selected to observe the emission from both the film and the sensing fluorophore. Changes in the probe intensity result in changes in the polarization of the combined emission from the sensor and reference. The degree of polarization can be detected visually using a dual polarizer with adjacent sections oriented orthogonally to each other. The emission passing through the dual polarizer is viewed with a second analyzing polarizer. This analyzer is rotated manually to yield equal intensities from both sides of the dual polarizer. This approach was used to measure the concentration of RhB in intralipid and to measure pH using 6-carboxyfluorescein. The analyzer angle is typically accurate to 1 degree, providing pH values accurate to +/- 0.1 pH unit at the midpoint of the titration curve. We also describe a method of visual polarization sensing that does not require an oriented film and that can use the same fluorophore for the sample and reference. These approaches to visual sensing are generic and can be applied to a wide variety of analytes for which fluorescent probes are available. Importantly, the devices are simple, with the only electronic component being the light source.


Inhibition of poliovirus RNA synthesis by brefeldin A.
Brefeldin A (BFA), a fungal metabolite that blocks transport of newly synthesized proteins from the endoplasmic reticulum, was found to inhibit poliovirus replication 10(5)- to 10(6)-fold. BFA does not inhibit entry of poliovirus into the cell or translation of viral RNA. Poliovirus RNA synthesis, however, is completely inhibited by BFA. A specific class of membranous vesicles, with which the poliovirus replication complex is physically associated, is known to proliferate in poliovirus-infected cells. BFA may inhibit poliovirus replication by preventing the formation of these vesicles.


Emerging issues on comprehensive hemophilia care: preventing, identifying, and monitoring age-related comorbidities.
Life expectancy for persons with hemophilia (PWH) has considerably increased in the last decades as a direct result of the availability of modern therapies to control the clotting defect. Because their life expectancy now matches that of the general population, PWH are experiencing age-related comorbidities, such as, cardiovascular diseases, metabolic syndrome, renal diseases, sexuality issues, malignancies, and neurologic problems, that until recently have been rarely seen in this group of patients. In this article, we present a summary of the current knowledge on the aging PWH along with the clinical approaches that may be integrated into the routine comprehensive care of these patients for preventing, diagnosing, and monitoring age-related comorbidities. In general, patients with and without hemophilia should receive similar care, with close collaboration between the physician treating PWH and the specialty expert treating the comorbid disease.


Predicting Intraserotypic Recombination in Enterovirus 71.
Enteroviruses are well known for their ability to cause neurological damage and paralysis. The model enterovirus is poliovirus (PV), the causative agent of poliomyelitis, a condition characterized by acute flaccid paralysis. A related virus, enterovirus 71 (EV-A71), causes similar clinical outcomes in recurrent outbreaks throughout Asia. Retrospective phylogenetic analysis has shown that recombination between circulating strains of EV-A71 produces the outbreak-associated strains which exhibit increased virulence and/or transmissibility. While studies on the mechanism(s) of recombination in PV are ongoing in several laboratories, little is known about factors that influence recombination in EV-A71. We have developed a cell-based assay to study recombination of EV-A71 based upon previously reported assays for poliovirus recombination. Our results show that (i) EV-A71 strain type and RNA sequence diversity impacts recombination frequency in a predictable manner that mimics the observations found in nature; (ii) recombination is primarily a replicative process mediated by the RNA-dependent RNA polymerase; (iii) a mutation shown to reduce recombination in PV (L420A) similarly reduces EV-A71 recombination, suggesting conservation in mechanism(s); and (iv) sequencing of intraserotypic recombinant genomes indicates that template switching occurs by a mechanism that may require some sequence homology at the recombination junction and that the triggers for template switching may be sequence independent. The development of this recombination assay will permit further investigation on the interplay between replication, recombination and disease.IMPORTANCE Recombination is a mechanism that contributes to genetic diversity. We describe the first assay to study EV-A71 recombination. Results from this assay mimic what is observed in nature and can be used by others to predict future recombination events within the enterovirus species A group. In addition, our results highlight the central role played by the viral RNA-dependent RNA polymerase (RdRp) in the recombination process. Further, our results show that changes to a conserved residue in the RdRp from different species groups have a similar impact on viable recombinant virus yields, which is indicative of conservation in mechanism.


Widening the view on dispersant-pigment interactions in colloidal dispersions with saturation transfer difference NMR spectroscopy.
The application of Saturation Transfer Difference (STD) NMR spectroscopy for the characterization of dispersant particle interactions is introduced. STD NMR has hitherto been applied, with great success, to the characterization of ligand-protein interactions and is currently a standard tool in biomolecular NMR spectroscopy. Nevertheless, the STD NMR technique has so far not yet crossed the boundaries of the biomolecular field. Here, we demonstrate that in spite of clear differences between a protein binding site and the surface of a pigment nanoparticle, the latter can also be subjected to STD NMR analysis, allowing us to detect (screen for) binding ligands, discriminate ligand from nonligand, and obtain information on the binding epitope. The approach should be generally applicable as long as the nanoparticle is comprised of a dense network of hydrogens, implicating almost all organic molecular nanocrystals. Thus it provides a novel investigative tool for the study of dispersions that is highly complementary to existing ones.


Detailed features of hematological involvement and medication-induced cytopenia in systemic lupus erythematosus patients: single center results of 221 patients.
Systemic lupus erythematosus (SLE) may affect a number of systems, with the hematological system being one of the most common. Our aim is to determine the existence of cytopenia at diagnosis or during follow-up of our SLE patients as well as the associated factors. A cohort of SLE patients that had been followed-up in the Department of Rheumotology from 1998 to 2015 was retrospectively assessed. Clinical and laboratory findings about the patients were recorded. Out of 221 patients composing the cohort, cytopenia was already present in 83.3% (n=184) at the time of diagnosis. Anemia was detected in 56.1% (n=124), leukopenia in 28.9% (n=64), lymphopenia in 76% (n=168), neutropenia in 4.5% (n=10), and thrombocytopenia in 17.2% (n=38) of patients. The proportion of patients with cumulative cytopenia was 90% (n=199). Cumulative cytopenia was disease-related in 83.4% (n=166) and medication-related in 16.6% (n=33) of the patients. In cases of drug-induced cytopenia, azathioprine was the most frequently prescribed drug. In patients with cytopenia at the time of diagnosis, erythrocyte sedimentation rates (ESR) were higher, C3 and C4 hypocomplementemia was more prevalent, and they were positive for anti-ds-DNA at a greater proportion (p<0.001, p=0.015, p=0.028, and p=0.019, respectively). Moreover, photosensitivity, renal involvement, and antiphospholipid syndrome (APS) were detected more frequently in patients with cytopenia at the time of diagnosis. There was no difference between the two patient sets in terms of other organ involvement (p>0.05). The most common hematological disorders in SLE patients are lymphopenia and anemia, and patients must be further examined for APS and renal involvement if they suffer cytopenia.


The HVAD Left Ventricular Assist Device: Risk Factors for Neurological Events and Risk Mitigation Strategies.
The purpose of this study was to determine the risk factors for ischemic in hemorrhage cerebrovascular events in patients supported by the HeartWare ventricular assist device (HVAD). Patients supported with left ventricular assist devices are at risk for both ischemic and hemorrhagic cerebrovascular events. Patients undergoing implantation with a HVAD as part of the bridge-to-transplant trial and subsequent continued access protocol were included. Neurological events (ischemic cerebrovascular accidents [ICVAs] and hemorrhagic cerebrovascular accidents [HCVAs]) were assessed, and the risk factors for these events were evaluated in a multivariable model. A total of 382 patients were included: 140 bridge-to-transplant patients from the ADVANCE (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) clinical trial and 242 patients from the continued access protocol. Patients had a mean age of 53.2 years; 71.2% were male, and 68.1% were white. Thirty-eight percent had ischemic heart disease, and the mean duration of support was 422.7 days. The overall prevalence of ICVA was 6.8% (26 of 382); for HCVA, it was 8.4% (32 of 382). Pump design modifications and a protocol-driven change in the antiplatelet therapy reduced the prevalence of ICVA from 6.3% (17 of 272) to 2.7% (3 of 110; p = 0.21) but had a negligible effect on the prevalence of HVCA (8.8% [24 of 272] vs. 6.4% [7 of 110]; p = 0.69). Multivariable predictors of ICVA were aspirin ≤81 mg and atrial fibrillation; predictors of HCVA were mean arterial pressure >90 mm Hg, aspirin ≤81 mg, and an international normalized ratio >3.0. Eight of the 30 participating sites had established improved blood pressure management (IBPM) protocols. Although the prevalence of ICVA for those with and without IBPM protocols was similar (5.3% [6 of 114] vs. 5.2% [14 of 268]; p = 0.99), those with IBPM protocols had a significantly lower prevalence of HCVA (1.8% [2 of 114] vs. 10.8% [29 of 268]; p = 0.0078). Anticoagulation, antiplatelet therapy, and blood pressure management affected the prevalence of cerebrovascular events after implantation of the HVAD. Attention to these clinical parameters can have a substantial impact on the occurrence of serious neurological events. (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure [ADVANCE]; NCT00751972).


Chronic cerebral hypoperfusion and impaired neuronal function in rats.
Studies in acute cerebral ischemia have shown that reductions in cerebral blood flow of up to 50% do not lead to infarction or alterations in neuronal electric activity. Little is known about the effects of chronic reductions in cerebral blood flow. The purpose of this study was to evaluate neuronal electrophysiological function in brain that had been subjected to a chronic reduction of cerebral blood flow of less than 50%. Based on existing knowledge of thresholds of cerebral ischemia, neuronal electrophysiological function should be unaffected by hypoperfusion of this magnitude. An arteriovenous fistula model in the rat was used to induce chronic cerebral hypoperfusion with reductions of cerebral blood flow of 25% to 50% as measured previously by 14C-labeled autoradiography. Using in vitro electrophysiological brain slice techniques, long-term potentiation in hippocampal CA1 neurons was examined extracellularly after 6 months of chronic noninfarctional cerebral hypoperfusion. Brains were also examined histologically at this time for evidence of cerebral infarction. There was no evidence of cerebral infarction. Long-term potentiation was produced in 9 of 12 control animals and only 2 of 8 hypoperfused animals. This difference was significant (P < .05) and demonstrated that long-term potentiation was impaired in animals with chronic hypoperfusion. Noninfarctional reductions in cerebral blood flow of up to 50% do impair neuronal function in chronic cerebral ischemia, a result quite distinct from that seen in acute ischemia. The threshold for neuronal dysfunction in chronic cerebral hypoperfusion is lower than that found in acute cerebral ischemia, suggesting that duration as well as severity of ischemic insult determines cellular viability. Chronic hypoperfusion may lead to a noninfarctional state with impaired neuronal function, a category of chronic cerebral ischemia not previously identified.


Comparison of the Pharmacokinetics and Pharmacodynamics of Single-Dose Tenofovir Vaginal Film and Gel Formulation (FAME 05).
Although preexposure prophylaxis with oral tenofovir (TFV) disoproxil fumarate/emtricitabine reduces HIV acquisition rates, poor adherence to and acceptability of daily vaginal gels have led to development of vaginal film formulations to improve adherence and, potentially, to enable episodic use. In this 2-arm, cross-over study of a fast-dissolving tenofovir film (40 mg) compared with a previously studied semisolid tenofovir 1% gel (40 mg), 10 healthy women received a single vaginal dose of each study product. Clinical, pharmacokinetic, and antiviral assessments were performed over 1 week after dose. Nine of 10 participants experienced mild to moderate adverse effects, similar between products, with no severe adverse events or events attributed to study products. TFV concentrations after film dosing exceeded concentrations after gel dosing in plasma between 8 and 24 hours (P ≤ 0.02). TFV concentrations in cervicovaginal fluid and both TFV and TFV diphosphate concentrations in cervical tissue homogenates were higher after film dosing (all P values < 0.04). The differences ranged from median (interquartile range) 2.9-fold (1.1, 9.0; midvaginal cervicovaginal fluid) to 4.4-fold (2.9, 7.7; plasma). Neither film nor gel demonstrated reduced cervical tissue biopsy infectivity after ex vivo HIV challenge. Single-dose tenofovir film demonstrated consistently higher concentrations in plasma and cervicovaginal samples when compared with gel during the first day after dosing. Single-dose cervical tissue TFV-diphosphate concentrations at 5 hours exceeded steady-state concentrations previously reported with daily oral Truvada dosing. Tenofovir film may provide an alternative to tenofovir oral and gel formulations. Clinical efficacy remains to be tested.


Transcriptomic profiling of adaptive responses to ocean acidification.
Some populations of marine organisms appear to have inherent tolerance or the capacity for acclimation to stressful environmental conditions, including those associated with climate change. Sydney rock oysters from the B2 breeding line exhibit resilience to ocean acidification (OA) at the physiological level. To understand the molecular basis of this physiological resilience, we analysed the gill transcriptome of B2 oysters that had been exposed to near-future projected ocean pH over two consecutive generations. Our results suggest that the distinctive performance of B2 oysters in the face of OA is mediated by the selective expression of genes involved in multiple cellular processes. Subsequent high-throughput qPCR revealed that some of these transcriptional changes are exclusive to B2 oysters and so may be associated with their resilience to OA. The intracellular processes mediated by the differentially abundant genes primarily involve control of the cell cycle and maintenance of cellular homeostasis. These changes may enable B2 oysters to prevent apoptosis resulting from oxidative damage or to alleviate the effects of apoptosis through regulation of the cell cycle. Comparative analysis of the OA conditioning effects across sequential generations supported the contention that B2 and wild-type oysters have different trajectories of changing gene expression and responding to OA. Our findings reveal the broad set of molecular processes underlying transgenerational conditioning and potential resilience to OA in a marine calcifier. Identifying the mechanisms of stress resilience can uncover the intracellular basis for these organisms to survive and thrive in a rapidly changing ocean.


Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference.
Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self-administration and hyperlocomotion paradigms. In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence the induction, extinction or reinstatement of a conditioned cocaine response. We found that the Y5 antagonist L-152,804 causes faster extinction and reduced reinstatement of cocaine-induced CPP but did not reduce the ability of cocaine to induce CPP. Similarly, Y5-KO mice displayed faster extinction, and reinstatement of cocaine-induced CPP was absent. The development of CPP for cocaine was similar between Y5-KO and WT mice. Taken together, the present data show that Y5 antagonism attenuates relapse to cocaine addiction-related behavior. Prevention of relapse is considered to be of pivotal importance for the development of an effective treatment against cocaine addiction and therefore Y5 receptors could be a potential future therapeutic target in cocaine addiction.


Evidence for exocellular Arsenic in Fronds of Pteris vittata.
The arsenic (As) hyperaccumulating fern species Pteris vittata (PV) is capable of accumulating large quantities of As in its aboveground tissues. Transformation to AsIII and vacuolar sequestration is believed to be the As detoxification mechanism in PV. Here we present evidence for a preponderance of exocellular As in fronds of Pteris vittata despite numerous reports of a tolerance mechanism involving intracellular compartmentalization. Results of an extraction experiment show that 43-71% of the As extruded out of the fronds of PV grown in 0.67, 3.3 and 6.7 mM AsV. SEM-EDX analysis showed that As was localized largely on the lower pinna surface, with smaller amounts on the upper surface, as crystalline deposits. X-ray fluorescence imaging of pinna cross-sections revealed preferential localization of As on the pinna surface in the proximity of veins, with the majority localized near the midrib. Majority of the As in the pinnae is contained in the apoplast rather than vacuoles. Our results provide evidence that exocellular sequestration is potentially a mechanism of As detoxification in PV, particularly at higher As concentrations, raising concern about its use for phytoremediation.


Controlled excitation of scar modes in passive and active multimode chaotic fiber.
A multimode optical fiber with a D-shaped cross section is an experimental paradigm of a wave system with chaotic ray dynamics. We show that seldom but usable modes, called scar modes, localized along some particular direction of the geometric trajectories, can be selectively excited. We report numerical simulations that demonstrate the importance of the so-called self-focal point in the scar mode selection process. We use a localized illumination in a passive fiber, or a localized gain in a ytterbium-doped fiber, located in the vicinity of this special point to control scar mode selection.


Attenuated Psychophysiological Reactivity following Single-Session Group Imagery Rescripting versus Verbal Restructuring in Social Anxiety Disorder: Results from a Randomized Controlled Trial.
The effectiveness of psychotherapies for social anxiety disorder (SAD) is typically evaluated using self- and clinician-reported symptom change, while biomarkers of treatment response are rarely measured. The current study aimed to compare biomarkers of response following two brief group interventions for SAD. This randomized controlled trial evaluated the effectiveness of single-session group interventions for SAD (n = 58) - imagery rescripting (IR) and verbal restructuring (VR) versus waitlist control (WC). The IR intervention guided participants to rescript autobiographical memories through visualization whilst the VR intervention focused on thought challenging. Trial outcomes included change in psychophysiological reactivity (heart rate variability (HRV) and electrodermal responding) to social stress, and symptom-based measures (social interaction anxiety, negative self-portrayal, cognitive avoidance, repetitive negative thinking, memory modification, anxious behaviors). Psychophysiological reactivity was selectively attenuated following IR treatment, compared to VR and WC groups. The specific influence of the imagery-based intervention in modulating autonomic reactivity was evident across HRV parameters, including the standard deviation of intervals between heartbeats (IR vs. WC, d = 0.67, p = 0.021; IR vs. VR, d = 0.58, p = 0.041), and high frequency power - an indicator of parasympathetically mediated emotion regulation (IR vs. WC, d = 0.75, p = 0.034; IR vs. VR, d = 0.95, p = 0.006). Few group differences were observed across self-report measures. The current study highlights the specificity of brief imagery-based interventions in influencing psychophysiological reactivity in SAD and establishes the sensitivity of objective markers of treatment response in quantifying change over symptom-based measurements.


CRF1 receptor signaling regulates food and fluid intake in the drinking-in-the-dark model of binge alcohol consumption.
Several recent studies implementing the standard "drinking-in-the-dark" (DID) model of short-term binge-like ethanol (EtOH) intake in C57BL/6J mice highlighted a role for the stress-related neuropeptide corticotropin-releasing factor (CRF) and its primary binding partner, the CRF type-1 (CRF1) receptor. We evaluated the selectivity of CRF1 involvement in binge-like EtOH intake by interrupting CRF1 function via pharmacological and genetic methods in a slightly modified 2-bottle choice DID model that allowed calculation of an EtOH preference ratio. In addition to determining EtOH intake and preference, we also measured consumption of food and H2 O during the DID period, both in the presence and absence of EtOH and sweet tastant solutions. Treatment with either of the CRF1-selective antagonists CP-376,395 (CP; 10 to 20 mg/kg, i.p.) or NBI-27914 (10 to 30 mg/kg, i.p.) decreased intake of 15% EtOH in male C57BL/6J mice, but did so in the absence of a concomitant decrease in EtOH preference. These findings were replicated genetically in a CRF1 knockout (KO) mouse model (also on a C57BL/6J background). In contrast to effects on EtOH intake, pharmacological blockade of CRF1 with CP increased intake of 10% sucrose, consistent with previous findings in CRF1 KO mice. Finally, pharmacological and genetic disruption of CRF1 activity significantly reduced feeding and/or total caloric intake in all experiments, confirming the existence of nonspecific effects. Our findings indicate that blockade of CRF1 receptors does not exert specific effects on EtOH intake in the DID paradigm, and that slight modifications to this procedure, as well as additional consummatory control experiments, may be useful when evaluating the selectivity of pharmacological and genetic manipulations on binge-like EtOH intake.


Orbito-frontal cortex is necessary for temporal context memory.
Lesion and neuroimaging studies suggest that orbito-frontal cortex (OFC) supports temporal aspects of episodic memory. However, it is unclear whether OFC contributes to the encoding and/or retrieval of temporal context and whether it is selective for temporal relative to nontemporal (spatial) context memory. We addressed this issue with two complimentary studies: functional magnetic resonance imaging to measure OFC activity associated with successful temporal and spatial context memory during encoding and retrieval in healthy young participants, and a neuropsychological investigation to measure changes in spatial and temporal context memory in OFC lesion patients. Imaging results revealed that OFC contributed to encoding and retrieval of associations between objects and their temporal but not their spatial contexts. Consistent with this, OFC patients exhibited impairments in temporal but not spatial source memory accuracy. These results suggest that OFC plays a critical role in the formation and subsequent retrieval of temporal context.


A neural correlate of reward-based behavioral learning in caudate nucleus: a functional magnetic resonance imaging study of a stochastic decision task.
Humans can acquire appropriate behaviors that maximize rewards on a trial-and-error basis. Recent electrophysiological and imaging studies have demonstrated that neural activity in the midbrain and ventral striatum encodes the error of reward prediction. However, it is yet to be examined whether the striatum is the main locus of reward-based behavioral learning. To address this, we conducted functional magnetic resonance imaging (fMRI) of a stochastic decision task involving monetary rewards, in which subjects had to learn behaviors involving different task difficulties that were controlled by probability. We performed a correlation analysis of fMRI data by using the explanatory variables derived from subject behaviors. We found that activity in the caudate nucleus was correlated with short-term reward and, furthermore, paralleled the magnitude of a subject's behavioral change during learning. In addition, we confirmed that this parallelism between learning and activity in the caudate nucleus is robustly maintained even when we vary task difficulty by controlling the probability. These findings suggest that the caudate nucleus is one of the main loci for reward-based behavioral learning.


First shark from the Late Devonian (Frasnian) Gogo Formation, Western Australia sheds new light on the development of tessellated calcified cartilage.
Living gnathostomes (jawed vertebrates) comprise two divisions, Chondrichthyes (cartilaginous fishes, including euchondrichthyans with prismatic calcified cartilage, and extinct stem chondrichthyans) and Osteichthyes (bony fishes including tetrapods). Most of the early chondrichthyan ('shark') record is based upon isolated teeth, spines, and scales, with the oldest articulated sharks that exhibit major diagnostic characters of the group--prismatic calcified cartilage and pelvic claspers in males--being from the latest Devonian, c. 360 Mya. This paucity of information about early chondrichthyan anatomy is mainly due to their lack of endoskeletal bone and consequent low preservation potential. Here we present new data from the first well-preserved chondrichthyan fossil from the early Late Devonian (ca. 380-384 Mya) Gogo Formation Lägerstatte of Western Australia. The specimen is the first Devonian shark body fossil to be acid-prepared, revealing the endoskeletal elements as three-dimensional undistorted units: Meckel's cartilages, nasal, ceratohyal, basibranchial and possible epibranchial cartilages, plus left and right scapulocoracoids, as well as teeth and scales. This unique specimen is assigned to Gogoselachus lynnbeazleyae n. gen. n. sp. The Meckel's cartilages show a jaw articulation surface dominated by an expansive cotylus, and a small mandibular knob, an unusual condition for chondrichthyans. The scapulocoracoid of the new specimen shows evidence of two pectoral fin basal articulation facets, differing from the standard condition for early gnathostomes which have either one or three articulations. The tooth structure is intermediate between the 'primitive' ctenacanthiform and symmoriiform condition, and more derived forms with a euselachian-type base. Of special interest is the highly distinctive type of calcified cartilage forming the endoskeleton, comprising multiple layers of nonprismatic subpolygonal tesserae separated by a cellular matrix, interpreted as a transitional step toward the tessellated prismatic calcified cartilage that is recognized as the main diagnostic character of the chondrichthyans.