The ShcA protein is a molecular chaperone that assists in the secretion of the HopPsyA effector from the type III (Hrp) protein secretion system of Pseudomonas syringae.
Pseudomonas syringae uses a type III protein secretion system encoded by the Hrp pathogenicity island (Pai) to translocate effector proteins into plant cells. One of these effector proteins is HopPsyA. A small open reading frame (ORF), named shcA, precedes the hopPsyA gene in the Hrp Pai of P. s. syringae 61. The predicted amino acid sequence of shcA shares general characteristics with chaperones used in type III protein secretion systems of animal pathogens. A functionally non-polar deletion of shcA in P. s. syringae 61 resulted in the loss of detectable HopPsyA in supernatant fractions, consistent with ShcA acting as a chaperone for HopPsyA. Cosmid pHIR11 carries a functional set of type III genes from P. s. syringae 61 and confers upon saprophytes the ability to secrete HopPsyA in culture and to elicit a HopPsyA-dependent hypersensitive response (HR) on tobacco. P. fluorescens carrying a pHIR11 derivative lacking shcA failed to secrete HopPsyA in culture, but maintained the ability to secrete another type III-secreted protein, HrpZ. This pHIR11 derivative was also greatly reduced in its ability to elicit an HR, indicating that the ability to translocate HopPsyA into plant cells was compromised. Using affinity chromatography, we showed that ShcA binds directly to HopPsyA and that the ShcA binding site must reside within the first 166 amino acids of HopPsyA. Thus, ShcA represents the first demonstrated chaperone used in a type III secretion system of a bacterial plant pathogen. We searched known P. syringae type III-related genes for neighbouring ORFs that shared the general characteristics of type III chaperones and identified five additional candidate type III chaperones. Therefore, it is likely that chaperones are as prevalent in bacterial plant pathogen type III systems as they are in their animal pathogenic counterparts.


Release of unassembled rat cardiac myosin light chain 1 following the calcium paradox.
To determine the intracellular source and release kinetics of myosin light chain 1 immediately following irreversible myocytic injury, we perfused rat hearts in a Langendorff apparatus under control conditions (20 minutes), or during global cellular injury produced by oxygenated, calcium-free perfusion (5 minutes), followed by reperfusion with buffer containing 2.5 mM calcium (15 minutes). Light chain 1 concentration (double antibody radioimmunoassay) and creatine kinase activity were measured in both the coronary effluent and the 140,000 g supernatant extract of perfused ventricular tissue (after homogenization and ultracentrifugation). Calcium reperfusion caused the rapid release of both light chain 1 and creatine kinase activity (peak light chain 1 = 1.09 +/- 0.19 micrograms/g; peak creatine kinase = 74.9 +/- 10.7 IU/ g at 1 minute, mean +/- SD, n = 3); 28.5 +/- 13.5% of total light chain 1 and 86.5 +/- 0.6% of total creatine kinase activity were depleted from the tissue extract during the 15-minute reperfusion. No light chain 1 or creatine kinase was detected in the effluents of control-perfused hearts. Dodecyl sulfate polyacrylamide gel electrophoresis and immunodetection with specific antibody to myosin heavy chain and light chain 1 showed that the effluent light chain 1 was of similar molecular weight (mol wt = 27,000) to the subunit bound to myofibrils. In addition, light chain 1 was released in the absence of myosin heavy chain. Thus, a small soluble pool of unassembled myosin light chain 1 subunits exists in the cytoplasm of cardiac myocytes that is released from irreversibly injured cells. This pool demonstrates initial washout kinetics similar to creatine kinase.


Simultaneous determination of 17 ginsenosides in rat urine by ultra performance liquid chromatography-mass spectrometry with solid-phase extraction.
A rapid analytical method for quantifying 17 ginsenosides in rat urine by ultra performance liquid chromatography (UPLC) coupled to electrospray ionization mass spectrometry (ESI-MS) is described. All analytes were extracted by solid-phase extraction optimized to obtain good recovery and quantified using digoxin as an internal standard. ESI-MS was optimized for different cone voltages at positive ionization mode to allow simultaneous analysis of all analytes in a relatively short time. Qualitative methodological considerations, including the linear range, precision, limit of quantification, limit of detection, recovery and sensitivity are also provided.


Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation.
Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media.


Framework for cyber risk loss distribution of hospital infrastructure: Bond percolation on mixed random graphs approach.
Networks like those of healthcare infrastructure have been a primary target of cyberattacks for over a decade. From just a single cyberattack, a healthcare facility would expect to see millions of dollars in losses from legal fines, business interruption, and loss of revenue. As more medical devices become interconnected, more cyber vulnerabilities emerge, resulting in more potential exploitation that may disrupt patient care and give rise to catastrophic financial losses. In this paper, we propose a structural model of an aggregate loss distribution across multiple cyberattacks on a prototypical hospital network. Modeled as a mixed random graph, the hospital network consists of various patient-monitoring devices and medical imaging equipment as random nodes to account for the variable occupancy of patient rooms and availability of imaging equipment that are connected by bidirectional edges to fixed hospital and radiological information systems. Our framework accounts for the documented cyber vulnerabilities of a hospital's trusted internal network of its major medical assets. To our knowledge, there exist no other models of an aggregate loss distribution for cyber risk in this setting. We contextualize the problem in the probabilistic graph-theoretical framework using a percolation model and combinatorial techniques to compute the mean and variance of the loss distribution for a mixed random network with associated random costs that can be useful for healthcare administrators and cybersecurity professionals to improve cybersecurity management strategies. By characterizing this distribution, we allow for the further utility of pricing cyber risk.


Mediterranean-style diet in pregnant women with metabolic risk factors (ESTEEM): A pragmatic multicentre randomised trial.
Pregnant women with metabolic risk factors are at high risk of complications. We aimed to assess whether a Mediterranean-style diet reduces adverse pregnancy outcomes in high-risk women. We conducted a multicentre randomised trial in 5 maternity units (4 in London and 1 in Birmingham) between 12 September 2014 and 29 February 2016. We randomised inner-city pregnant women with metabolic risk factors (obesity, chronic hypertension, or hypertriglyceridaemia) to a Mediterranean-style diet with high intake of nuts, extra virgin olive oil, fruits, vegetables, nonrefined grains, and legumes; moderate to high consumption of fish; low to moderate intake of poultry and dairy products; low intake of red and processed meat; and avoidance of sugary drinks, fast food, and food rich in animal fat versus usual care. Participants received individualised dietary advice at 18, 20, and 28 weeks' gestation. The primary endpoints were composite maternal (gestational diabetes or preeclampsia) and composite offspring (stillbirth, small for gestational age, or admission to neonatal care unit) outcomes prioritised by a Delphi survey. We used an intention-to-treat (ITT) analysis with multivariable models and identified the stratification variables and prognostic factors a priori. We screened 7,950 and randomised 1,252 women. Baseline data were available for 593 women in the intervention (93.3% follow-up, 553/593) and 612 in the control (95.6% follow-up, 585/612) groups. Over a quarter of randomised women were primigravida (330/1,205; 27%), 60% (729/1,205) were of Black or Asian ethnicity, and 69% (836/1,205) were obese. Women in the intervention arm consumed more nuts (70.1% versus 22.9%; adjusted odds ratio [aOR] 6.8, 95% confidence interval [CI] 4.3-10.6, p ≤ 0.001) and extra virgin olive oil (93.2% versus 49.0%; aOR 32.2, 95% CI 16.0-64.6, p ≤ 0.001) than controls; increased their intake of fish (p < 0.001), white meat (p < 0.001), and pulses (p = 0.05); and reduced their intake of red meat (p < 0.001), butter, margarine, and cream (p < 0.001). There was no significant reduction in the composite maternal (22.8% versus 28.6%; aOR 0.76, 95% CI 0.56-1.03, p = 0.08) or composite offspring (17.3% versus 20.9%; aOR 0.79, 95% CI 0.58-1.08, p = 0.14) outcomes. There was an apparent reduction in the odds of gestational diabetes by 35% (aOR 0.65, 95% CI 0.47-0.91, p = 0.01) but not in other individual components of the composite outcomes. Mothers gained less gestational weight (mean 6.8 versus 8.3 kg; adjusted difference -1.2 Kg, 95% CI -2.2 to -0.2, p = 0.03) with intervention versus control. There was no difference in any of the other maternal and offspring complications between both groups. When we pooled findings from the Effect of Simple, Targeted Diet in Pregnant Women With Metabolic Risk Factors on Pregnancy Outcomes (ESTEEM) trial with similar trials using random effects meta-analysis, we observed a significant reduction in gestational diabetes (odds ratio [OR] 0.67, 95% CI 0.53-0.84, I2 = 0%), with no heterogeneity (2 trials, 2,397 women). The study's limitations include the use of participant reported tools for adherence to the intervention instead of objective biomarkers. A simple, individualised, Mediterranean-style diet in pregnancy did not reduce the overall risk of adverse maternal and offspring complications but has the potential to reduce gestational weight gain and the risk of gestational diabetes. ClinicalTrials.gov NCT02218931.


Evidence for cognitive-behavioral strategies improving dyspnea and related distress in COPD.
Dyspnea is a complex, prevalent, and distressing symptom of chronic obstructive pulmonary disease (COPD) associated with decreased quality of life, significant disability, and increased mortality. It is a major reason for referral to pulmonary rehabilitation. We reviewed 23 COPD studies to examine the evidence for the effectiveness of cognitive-behavioral strategies for relieving dyspnea in COPD. Preliminary evidence from randomized controlled trials exists to support cognitive- behavioral strategies, used with or without exercise, for relieving sensory and affective components of dyspnea in COPD. Small to moderate treatment effects for relieving dyspnea were noted for psychotherapy (effect size [ES] = 0.08-0.25 for intensity; 0.26-0.65 for mastery) and distractive auditory stimuli (ES = 0.08-0.33 for intensity; 0.09 to -0.61 for functional burden). Small to large dyspnea improvements resulted from yoga (ES = 0.2-1.21 for intensity; 0.67 for distress; 0.07 for mastery; and -8.37 for functional burden); dyspnea self-management education with exercise (ES = -0.14 to -1.15 for intensity; -0.62 to -0.69 for distress; 1.04 for mastery; 0.14-0.35 for self-efficacy); and slow-breathing exercises (ES = -0.34 to -0.83 for intensity; -0.61 to -0.80 for distress; and 0.62 for self-efficacy). Cognitive-behavioral interventions may relieve dyspnea in COPD by (1) decreasing sympathetic nerve activity, dynamic hyperinflation, and comorbid anxiety, and (2) promoting arterial oxygen saturation, myelinated vagus nerve activity, a greater exercise training effect, and neuroplasticity. While evidence is increasing, additional randomized controlled trials are needed to evaluate the effectiveness of psychosocial and self-management interventions in relieving dyspnea, in order to make them more available to patients and to endorse them in official COPD, dyspnea, and pulmonary rehabilitation practice guidelines. By relieving dyspnea and related anxiety, such interventions may promote adherence to exercise programs and adaptive lifestyle change.


It's Game Time: Drinking Intentions, Alcohol Consumption, and Consequences at College Tailgates.
Alcohol consumption and related consequences is a problem on many college campuses. Tailgating parties before college sporting events may be contributing, however, little recent research has investigated alcohol consumption at these events. The purpose of this study is to evaluate the drinking behaviors of college game day tailgate attendees and subsequent alcohol-related consequences. Participants (N = 89; 44.9% female) were recruited from tailgates at a university in the Midwest United States on college football game days during fall 2014. Participants provided a breath sample, completed a questionnaire, and were given the opportunity to participate in a follow-up survey (n = 62) to assess resulting alcohol-related consequences. Over half of participants had BrACs greater than 0.000. However, one in three participants reported intentions to abstain from alcohol or to drink but not enough to get buzzed. Intoxication intentions were a significant and unique predictor of alcohol consumption and experience with alcohol-related consequences at follow-up. Conclusions/Importance: This study updates and extends the literature on alcohol-related consequences in the context of college football tailgates. The results suggest that consequences may be prevented through changes in intentions to become intoxicated.


Predictive factors for metastatic infection in patients with bacteremia caused by methicillin-sensitive Staphylococcus aureus.
Metastatic infections such as infective endocarditis and psoas abscess are serious complications of Staphylococcus aureus bacteremia because failure to identify these infections may result in bacteremia relapse or poor prognosis. In the present study, we determined the predictive factors for metastatic infection due to methicillin-sensitive S. aureus bacteremia. A retrospective cohort study was conducted among patients with methicillin-sensitive S. aureus bacteremia at the Jikei University Hospital between January 2008 and December 2012. Factors analyzed included the underlying disease, initial antimicrobial treatment and primary site of infection. During the 5-year study period, 73 patients met the inclusion criteria and were assessed. The most common primary site of bacteremia was catheter-related bloodstream infection (25/73 [34.2%]). Metastatic infection occurred in 14 of 73 patients (19.2%) (infective endocarditis [3], septic pulmonary abscess [3], spondylitis [4], psoas abscess [4], epidural abscess [3] and septic arthritis [1]). Six patients had multiple metastatic infections. Multivariate analysis revealed that the predictive factors associated with the development of metastatic infection were a delay in appropriate antimicrobial treatment of >48 hours, persistent fever for >72 hours after starting antibiotic treatment and lowest C-reactive protein levels of >3 mg/dL during 2 weeks after the onset of bacteremia. This study demonstrated that additional diagnostic tests should be conducted to identify metastatic infection, particularly in patients with delayed antimicrobial treatment, persistent fever and persistently high C-reactive protein levels.


Numerical analyses of intestinal microbiota by data mining.
The human intestinal microbiota has a close relationship with health control and causes of diseases, and a vast number of scientific papers on this topic have been published recently. Some progress has been made in identifying the causes or species of related microbiota, and successful results of data mining are reviewed here. Humans who are targets of a disease have their own individual characteristics, including various types of noise because of their individual life style and history. The quantitatively dominant bacterial species are not always deeply connected with a target disease. Instead of conventional simple comparisons of the statistical record, here the Gini-coefficient (i.e., evaluation of the uniformity of a group) was applied to minimize the effects of various types of noise in the data. A series of results were reviewed comparatively for normal daily life, disease and technical aspects of data mining. Some representative cases (i.e., heavy smokers, Crohn's disease, coronary artery disease and prediction accuracy of diagnosis) are discussed in detail. In conclusion, data mining is useful for general diagnostic applications with reasonable cost and reproducibility.


The dietary flavonol fisetin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is an endogenous agent that induces apoptosis selectively in cancer cells. Soluble or expressed in immune cells, TRAIL plays an important role in the defense against tumour cells. The resistance of cancer cells to TRAIL immune surveillance is implicated in tumour development. Naturally occurring flavonoids can sensitize TRAIL-resistant cancer cells and augment their apoptotic activity. Fisetin, a dietary flavonol has cancer preventive properties. This study was designed to investigate the effect of fisetin on the TRAIL-induced apoptosis potential in prostate cancer cells. Prostate cancer cell lines represent an ideal model for research in chemoprevention. Cytotoxicity was measured by MTT and LDH assays. Apoptosis was detected using Αnnexin V-FITC by flow cytometry and fluorescence microscopy. Mito-chondrial membrane potential (ΔΨm) was evaluated using DePsipher staining by fluorescence microscopy. Death receptor (TRAIL-R1 and TRAIL-R2) expression was analysed by flow cytometry. Inhibition of NF-κB (p65) activation was confirmed with an ELISA-based TransAM NF-κB kit. Caspase-8 and caspase-3 activities were determined by colorimetric protease assays. Our study demonstrates that fisetin sensitizes the TRAIL-resistant androgen-dependent LNCaP and the androgen-independent DU145 and PC3 prostate cancer cells to TRAIL-induced death. Fisetin augmented TRAIL-mediated cytotoxicity and apoptosis in prostate cancer LNCaP cells by engaging the extrinsic (receptor-mediated) and intrinsic (mitochondrial) apoptotic pathways. Fisetin increased the expression of TRAIL-R1 and decreased the activity of NF-κB. Co-treatment of cancer cells with TRAIL and fisetin caused significant activation of caspase-8 and caspase-3 and disruption of ΔΨm. Our data indicate the usefulness of fisetin in prostate cancer chemoprevention through enhancement of TRAIL-mediated apoptosis.


A cluster-randomised controlled trial to assess the effectiveness and cost-effectiveness of a childhood obesity prevention programme delivered through schools, targeting 6-7 year old children: the WAVES study protocol.
There is some evidence that school-based interventions are effective in preventing childhood obesity. However, longer term outcomes, equity of effects and cost-effectiveness of interventions have not been assessed. The aim of this trial is to assess the clinical and cost-effectiveness of a multi-component intervention programme targeting the school and family environment through primary schools, in preventing obesity in 6-7 year old children, compared to usual practice. This cluster randomised controlled trial is set in 54 primary schools within the West Midlands, UK, including a multi-ethnic, socioeconomically diverse population of children aged 6-7 years. The 12-month intervention consists of healthy diet and physical activity promotion. These include: activities to increase time spent doing physical activity within the school day, participation in the 'Villa Vitality' programme (a programme that is delivered by an iconic sporting institution (Aston Villa Football Club), which provides interactive learning opportunities for physical activity and healthy eating), healthy cooking skills workshops in school time for parents and children, and provision of information to families signposting local leisure opportunities. The primary (clinical) outcome is the difference in body mass index (BMI) z-scores between arms at 3 and 18 months post-intervention completion. Cost per Quality Adjusted Life Year (QALY) will also be assessed. The sample size estimate (1000 children split across 50 schools at follow-up) is based on 90% power to detect differences in BMI z-score of 0.25 (estimated ICC ≤ 0.04), assuming a correlation between baseline and follow-up BMI z-score of 0.9. Treatment effects will be examined using mixed model ANCOVA. Primary analysis will adjust for baseline BMI z-score, and secondary analysis will adjust for pre-specified baseline school and child level covariates. The West Midlands ActiVe lifestyle and healthy Eating in School children (WAVES) study is the first trial that will examine the cost-effectiveness and long term outcomes of a childhood obesity prevention programme in a multi-ethnic population, with a sufficient sample size to detect clinically important differences in adiposity. The intervention was developed using the Medical Research Council framework for complex interventions, and outcomes are measured objectively, together with a comprehensive process evaluation. Current Controlled Trials ISRCTN97000586 (registered May 2010).


Identification and characterization of a high-affinity interaction between v-Crk and tyrosine-phosphorylated paxillin in CT10-transformed fibroblasts.
The genome of avian sarcoma virus CT10 encodes a fusion protein in which viral Gag sequences are fused to cellular Crk sequences containing primarily Src homology 2 (SH2) and Src homology 3 (SH3) domains. Transformation of chicken embryo fibroblasts (CEF) with the Gag-Crk fusion protein results in the elevation of tyrosine phosphorylation on specific cellular proteins with molecular weights of 130,000, 110,000, and 70,000 (p130, p110, and p70, respectively), an event which has been correlated with cell transformation. In this study, we have identified the 70-kDa tyrosine-phosphorylated protein in CT10-transformed CEF (CT10-CEF) as paxillin, a cytoskeletal protein suggested to be important for organizing the focal adhesion. Tyrosine-phosphorylated paxillin was found to be complexed with v-Crk in vivo as evident from coimmunoprecipitation studies. Moreover, a bacterially expressed recombinant glutathione S-transferase (GST)-CrkSH2 fragment bound paxillin in vitro with a subnanomolar affinity, suggesting that the SH2 domain of v-Crk is sufficient for binding. Mapping of the sequence specificity of a GST-CrkSH2 fusion protein with a partially degenerate phosphopeptide library determined a motif consisting of pYDXP, and in competitive coprecipitation studies, an acetylated A(p)YDAPA hexapeptide was able to quantitatively inhibit the binding of GST-CrkSH2 to paxillin and p130, suggesting that it meets the minimal structural requirements necessary for the interaction of CrkSH2 with physiological targets. To investigate the mechanism by which v-Crk elevates the tyrosine phosphorylation of paxillin in vivo, we have treated normal CEF and CT10-CEF with sodium vanadate to inhibit protein tyrosine phosphatase activity. These data suggest that paxillin is involved in a highly dynamic kinase-phosphatase interplay in normal CEF and that v-Crk binding may interrupt this balance to increase the steady-state level of tyrosine phosphorylation. By contrast, the 130-kDa protein was not tyrosine phosphorylated upon vanadate treatment of normal CEF and only weakly affected in the CT10-CEF, suggesting that a different mechanism may be involved in its phosphorylation.


Interaction of fish aryl hydrocarbon receptor paralogs (AHR1 and AHR2) with the retinoblastoma protein.
The aryl hydrocarbon receptor (AHR) mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. In some mammalian cell lines, TCDD induces G1 cell cycle arrest, which depends on an interaction between the AHR and the retinoblastoma tumor suppressor (RB). Mammals possess one AHR, whereas fishes possess two or more AHR paralogs that differ in the domains important for AHR-RB interactions in mammals. To test the hypothesis that fish AHR paralogs differ in their ability to interact with RB, we cloned RB cDNA from Atlantic killifish, Fundulus heteroclitus, and studied the interactions of killifish RB protein with killifish AHR1 and AHR2. In coimmunoprecipitation experiments, in vitro-expressed killifish RB coprecipitated with both AHR1 and AHR2. Consistent with these results, both killifish AHR1 and AHR2 interacted with RB in mammalian two-hybrid assays. These results suggest that both fish AHR1 and AHR2 paralogs may have the potential to influence cell proliferation through interactions with RB.


Structures of protein-protein complexes involved in electron transfer.
Electron transfer reactions are essential for life because they underpin oxidative phosphorylation and photosynthesis, processes leading to the generation of ATP, and are involved in many reactions of intermediary metabolism. Key to these roles is the formation of transient inter-protein electron transfer complexes. The structural basis for the control of specificity between partner proteins is lacking because these weak transient complexes have remained largely intractable for crystallographic studies. Inter-protein electron transfer processes are central to all of the key steps of denitrification, an alternative form of respiration in which bacteria reduce nitrate or nitrite to N2 through the gaseous intermediates nitric oxide (NO) and nitrous oxide (N2O) when oxygen concentrations are limiting. The one-electron reduction of nitrite to NO, a precursor to N2O, is performed by either a haem- or copper-containing nitrite reductase (CuNiR) where they receive an electron from redox partner proteins a cupredoxin or a c-type cytochrome. Here we report the structures of the newly characterized three-domain haem-c-Cu nitrite reductase from Ralstonia pickettii (RpNiR) at 1.01 Å resolution and its M92A and P93A mutants. Very high resolution provides the first view of the atomic detail of the interface between the core trimeric cupredoxin structure of CuNiR and the tethered cytochrome c domain that allows the enzyme to function as an effective self-electron transfer system where the donor and acceptor proteins are fused together by genomic acquisition for functional advantage. Comparison of RpNiR with the binary complex of a CuNiR with a donor protein, AxNiR-cytc551 (ref. 6), and mutagenesis studies provide direct evidence for the importance of a hydrogen-bonded water at the interface in electron transfer. The structure also provides an explanation for the preferential binding of nitrite to the reduced copper ion at the active site in RpNiR, in contrast to other CuNiRs where reductive inactivation occurs, preventing substrate binding.


Developing classification criteria for skin-predominant dermatomyositis: the Delphi process.
The European League Against Rheumatism/American College of Rheumatology classification criteria for inflammatory myopathies are able to classify patients with skin-predominant dermatomyositis (DM). However, approximately 25% of patients with skin-predominant DM do not meet two of the three hallmark skin signs and fail to meet the criteria. To develop a set of skin-focused classification criteria that will distinguish cutaneous DM from mimickers and allow a more inclusive definition of skin-predominant disease. An extensive literature review was done to generate items for the Delphi process. Items were grouped into categories of distribution, morphology, symptoms, antibodies, histology and contextual factors. Using REDCap™, participants rated these items in terms of appropriateness and distinguishing ability from mimickers. The relevance score ranged from 1 to 100, and the median score determined a rank-ordered list. A prespecified median score cut-off was decided by the steering committee and the participants. There was a pre-Delphi and two rounds of actual Delphi. There were 50 participating dermatologists and rheumatologists from North America, South America, Europe and Asia. After a cut-off score of 70 during the first round, 37 of the initial 54 items were retained and carried over to the next round. The cut-off was raised to 80 during round two and a list of 25 items was generated. This project is a key step in the development of prospectively validated classification criteria that will create a more inclusive population of patients with DM for clinical research. What's already known about this topic? Proper classification of patients with skin-predominant dermatomyositis (DM) is indispensable in the appropriate conduct of clinical/translational research in the field. The only validated European League Against Rheumatism/American College of Rheumatology criteria for idiopathic inflammatory myopathies are able to classify skin-predominant DM. However, a quarter of amyopathic patients still fail the criteria and does not meet the disease classification. What does this study add? A list of 25 potential criteria divided into categories of distribution, morphology, symptomatology, pathology and contextual factors has been generated after several rounds of consensus exercise among experts in the field of DM. This Delphi project is a prerequisite to the development of a validated classification criteria set for skin-predominant DM.


Association between C reactive protein level and depressive symptoms in an elderly Korean population: Korean Social Life, Health and Aging Project.
The relationship between inflammatory markers and depressive symptoms has been reported inconsistently. Moreover, there were only a few studies conducted in an Asian population. The purpose of this study was to examine the association between C reactive protein (CRP) and depressive symptoms in an elderly Korean population. This study used data from the Korean Social Life, Health and Aging Project Health Examination Cohort, which started in 2011. Among participants aged 60 or over recruited from a rural community, 569 (224 men and 345 women) without a history of stroke, angina pectoris, myocardial infarction or CRP≥20 mg/L were employed for cross-sectional analyses. As a marker of systemic inflammation, CRP was measured. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression (CES-D) scale. Multiple linear regression analysis was used to investigate the relationship between CRP and depressive symptoms. In men, CRP levels had significant associations with depressive symptoms before (β=0.420, p=0.010) and after (β=0.336, p=0.025) adjusting for age, body mass index, systolic blood pressure, number of comorbidities, smoking status, alcohol intake, marital status, education and sleep duration. However, in women, the association between CRP and depressive symptoms was not significant before (p=0.250) and after (p=0.256) adjustment. Our findings suggest that elevated CRP levels are independently associated with the presence of depressive symptoms in elderly Korean men.


Surface ultrastructure of juvenile and adult Acanthoparyphium tyosenense (Digenea: Echinostomatidae).
The tegumental ultrastructure of juvenile and adult Acanthoparyphium tyosenense (Digenea: Echinostomatidae) was observed by scanning electron microscopy. One- to 3-day-old juveniles and 10-day-old adults were harvested from chicks experimentally fed metacercariae from a bivalve, Mactra veneriformis. The juvenile worms were minute, curved ventrally, and had 23 collar spines characteristically arranged in a single row. The lips of the oral sucker had 7 single aciliated sensory papillae and 4 grouped uniciliated sensory papillae. The ventral sucker had 25 aciliated round swellings on its lip. The anterolateral surface between the 2 suckers was densely packed with tongue-shaped tegumental spines, and the ventral surface just posterior to the ventral sucker was covered with peg-like spines. Retractile, peg-like spines were seen on the anterolateral surface, whereas scale-like spines with round tips and broad bases were sparsely distributed posterior to the ventral sucker. The cirrus was characteristically protruding and armed with minute spines. The surface ultrastructure of A. tyosenense was unique, especially in the number and arrangement of collar spines, shape, and distribution of tegumental spines and in distribution of sensory papillae.


Management of resistant cardiac depression after hepatic trauma controlled with a packing procedure.
In addition to hemorrhage, which is one of the most well-known factors, there are many other causative factors for serious hypotension after hepatic trauma. In this report, we present patients with persistent cardiac depression after perihepatic packing due to high grade liver injury and report on treatment modalities, including the early second-look procedure. Three patients with isolated hepatic trauma were included. Two of the patients who underwent perihepatic packing were transferred from outside hospitals, and one patient required repacking due to severe hemorrhage. All patients had grade IV injuries due to blunt (n=2) or penetrating injury (n=1). In the intensive care unit, central venous pressure (8, 12, 13 mmHg) and hematocrit (26, 27, 29%) were in the normal range, but blood pressure (40/60, 50/70, 45/75mmHg) was abnormal despite the use of inotropic support. The three patients underwent an unpacking procedure 8, 10, and 14 hours later, respectively. Inotropic support was not required after postoperative hours 3, 5, and 6, respectively. The management of post reperfusion syndrome due to hepatic trauma can be achieved, but close collaboration between the surgeon and anesthesiologist is absolutely necessary. In the case of resistance cardiac depression in patients with packing, second-look procedures should be performed as early as possible.


Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary.
Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer. Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients. Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer. Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.


Statistical upscaling of ecosystem CO2 fluxes across the terrestrial tundra and boreal domain: Regional patterns and uncertainties.
The regional variability in tundra and boreal carbon dioxide (CO2 ) fluxes can be high, complicating efforts to quantify sink-source patterns across the entire region. Statistical models are increasingly used to predict (i.e., upscale) CO2 fluxes across large spatial domains, but the reliability of different modeling techniques, each with different specifications and assumptions, has not been assessed in detail. Here, we compile eddy covariance and chamber measurements of annual and growing season CO2 fluxes of gross primary productivity (GPP), ecosystem respiration (ER), and net ecosystem exchange (NEE) during 1990-2015 from 148 terrestrial high-latitude (i.e., tundra and boreal) sites to analyze the spatial patterns and drivers of CO2 fluxes and test the accuracy and uncertainty of different statistical models. CO2 fluxes were upscaled at relatively high spatial resolution (1 km2 ) across the high-latitude region using five commonly used statistical models and their ensemble, that is, the median of all five models, using climatic, vegetation, and soil predictors. We found the performance of machine learning and ensemble predictions to outperform traditional regression methods. We also found the predictive performance of NEE-focused models to be low, relative to models predicting GPP and ER. Our data compilation and ensemble predictions showed that CO2 sink strength was larger in the boreal biome (observed and predicted average annual NEE -46 and -29 g C m-2 yr-1 , respectively) compared to tundra (average annual NEE +10 and -2 g C m-2 yr-1 ). This pattern was associated with large spatial variability, reflecting local heterogeneity in soil organic carbon stocks, climate, and vegetation productivity. The terrestrial ecosystem CO2 budget, estimated using the annual NEE ensemble prediction, suggests the high-latitude region was on average an annual CO2 sink during 1990-2015, although uncertainty remains high.


Webril-only Soft Spica Cast for Pediatric Femoral Fractures: A Preliminary Study.
We report using a spica cast created with cotton padding and Ace wrap without a rigid component for femur fracture in infants. Outcomes and complications of this soft spica cast were retrospectively compared with other treatments. There were 43 children younger than 6 months (43 diaphyseal fractures) included in the study. Treatment was a Pavlik harness (26 patients), a hard spica cast (8), or a soft spica cast (9) for an average of 3 weeks. All fractures demonstrated healing with similar final angulation and shortening. Hard spica casts caused the most complications. As for material costs, the soft spica is the least costly method ($2 per cast versus $87-$107 for Pavlik harness and $150 for hard spica). In conclusion, soft spica casts are as effective as other treatment options for femoral shaft fractures in young children. These casts are advantageous since they are easier to apply, easier to manage, and have a lower cost. (Journal of Surgical Orthopaedic Advances 30(1):040-043, 2021).


Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells.
The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.


Youth on the virtual edge: researching marginalized sexualities and genders online.
Research shows clear links between lesbian, gay, bisexual, and transgender (LGBT) youth and deliberate self-harm (DSH), but there is a lack of research investigating the social context of young LGBT people's lives and helping to explain the higher DSH risk. In this article, we report on a small-scale methodological study intended to test the feasibility of online qualitative interviews for investigating young people, sexual and gender identity, and emotional distress. There are many methodological dilemmas arising from researching such sensitive issues with marginalized groups. The study reported here was designed to examine (a) sampling diversity in terms of sexuality, gender identities, and class; and (b) the type of data produced. We found that a virtual methodology was effective in recruiting young LGBT participants who might otherwise not take part in research. Online interviewing successfully produced in-depth, "immediate" data that potentially gave access to insights that might not emerge through face-to face interviews.


Merging ultrasound in the intensive care routine.
Goal-oriented ultrasound examination is gaining a place in the intensive care unit. Some protocols have been proposed but the applicability of ultrasound as part of a routine has not been studied. To assess the influence of ultrasound performed by intensive care physicians. This retrospective descriptive clinical study was performed in a medical-surgical intensive care unit of a university-affiliated general hospital. Data were collected from patients undergoing ultrasound examinations performed by a critical care physician during the period 2010 to June 2011. A total of 299 ultrasound exams were performed in 113 mechanically ventilated patients (70 males, mean age 65 years). Exams included trans-cranial Doppler (n = 24), neck evaluation before tracheostomy (n = 15), chest exam (n = 83), focuse cardiac echocardiography (n = 60), abdominal exam (n = 41), and comprehensive screening at patient admission (n = 30). Ultrasound was used to guide invasive procedures for vascular catheter insertion (n = 42), pleural fluid drainage (n = 24), and peritoneal fluid drainage (n = 7). One pneumothorax was seen during central venous line insertion but no complications were observed after pleural or abdominal drainage. The ultrasound study provided good quality visualization in 86% (258 of 299 exams) and was a diagnostic tool that induced a change in treatment in 58% (132 of 226 exams). Bedside ultrasound examinations performed by critical care physicians provide an important adjunct to diagnostic and therapeutic performance, improving quality of care and patient safety.


Diurnal variation of retina thickness measured with time domain and spectral domain optical coherence tomography in healthy subjects.
PURPOSE. To investigate diurnal variations in macular thickness and total macular volume using time domain optical coherence tomography (TD-OCT) and spectral domain OCT (SD-OCT) in healthy subjects. METHODS. Data were derived from 52 eyes of 52 healthy subjects. Macular thickness, macular volume was measured by using TD-OCT and SD-OCT at 8 AM and 6 PM. RESULTS. Comparing TD-OCT measurements, retinal thickness was significantly greater in the afternoon than in the morning in 3 of 9 grid subfields: central macular thickness (CMT) (194 vs. 190 μm; P = 0.006), superior inner area (276 vs. 273 μm; P = 0.010), and temporal inner area (261 vs. 258 μm; P = 0.006). In SD-OCT measurements, CMT, pericentral macular thickness, and macular volume did not differ significantly between the morning and the afternoon. Comparing the absolute variation in the parameters measured by the two devices, central macular thickness and temporal inner area thickness differed significantly (P = 0.015, P = 0.029), whereas other area thicknesses and macular volumes did not. Comparing the relative variation of the two devices, CMT and temporal inner area thickness differed significantly (P = 0.014, P = 0.027), whereas other area thicknesses and macular volume showed no significant difference. The moduli of variations for CMT, macular volume, and pericentral macular thickness were significantly lower using SD-OCT than using TD-OCT. CONCLUSIONS. The diurnal variation of the TD-OCT measurements was likely due to the limited repeatability of the device rather than to tissue variation. Diurnal variation was not found using SD-OCT, which has better repeatability.


Tracking antigen-specific T-cells during clinical tolerance induction in humans.
Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3-5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.


The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders.
Metoclopramide hydrochloride, a neuroleptic dopamine receptor antagonist used to treat gastric ailments, is reported to cause extrapyramidal movement disorders. The goals of this study were (1) to determine the prevalence and severity of tardive dyskinesia and acute extrapyramidal movement syndromes including akathisia, acute dystonia, and drug-induced parkinsonism in metoclopramide-treated patients and (2) to compare the prevalence and severity of tardive dyskinesia in metoclopramide-treated diabetics and nondiabetics. From a list of metoclopramide-treated patients received from the Portland (Ore) Veterans Affairs Medical Center pharmacy, 53 patients met inclusion criteria and 51 (96%) agreed to participate. Controls consisted of a convenience sample drawn from the Portland Veterans Affairs Medical Center Outpatient Clinic who were matched to subjects on age (+/- 10 years), gender, and presence or absence of diabetes. Of 61 potential controls contacted, 51 (84%) agreed to participate. Metoclopramide-treated subjects and controls were seen by a rater who was "blind" to all diagnoses and treatments. The rater performed a standardized examination used to elicit signs and symptoms of tardive dyskinesia and acute extrapyramidal movement syndromes. The relative risk for tardive dyskinesia was 1.67 (95% confidence interval, 0.93 to 2.97), and the relative risk for drug-induced parkinsonism was 4.0 (95% confidence interval, 1.5 to 10.5). Metoclopramide-treated patients had significantly greater severity of tardive dyskinesia, drug-induced parkinsonism, and subjective akathisia than controls. Use of metoclopramide was associated with impairment in ambulation and increased use of benzodiazepines. Metoclopramide-treated diabetics had significantly greater severity of tardive dyskinesia than metoclopramide-treated nondiabetics. Metoclopramide use is associated with a significantly increased prevalence and severity of several extrapyramidal movement disorders.


Nationwide distribution of varicella-zoster virus clades in China.
In 2010, a universal nomenclature for varicella-zoster virus (VZV) clades was established, which is very useful in the monitoring of viral evolution, recombination, spread and genetic diversity. Currently, information about VZV clades has been disclosed worldwide, however, there are limited data regarding the characterization of circulating VZV clades in China, even where varicella remains widely epidemic. From 2008 to 2012, clinical samples with varicella or zoster were collected in General Hospital in eight provinces and analyzed by PCR, restriction endonuclease digestion and sequencing. The viral clades were determined by analysis of five single nucleotide polymorphisms (SNPs) within the 447-bp fragment of open reading frame (ORF) 22, and the restriction fragment length polymorphisms (RFLPs) of ORF 38 (PstI), ORF 54 (BglI) and ORF 62 (SmaI) were evaluated to understand genetic diversity of VZV and determinate varicella vaccine adverse event (VVAE). Seventy-seven varicella and 11 zoster samples were identified as being positive for VZV. The five SNPs profile showed that the majority of VZV strains belonged to clade 2, but clade 5 and clade 4 strains were also found in Guangdong. The RFLPs analysis of the DNA fragments of ORF 38, 54 and 62 showed that 85 of these samples were characterized as PstI + BglI + SamI-, and the remaining three VZV strains from varicella patients were characterized as PstI-BglI + SamI+ which is the genetic profile of VVAEs. The study suggested that the predominant clade 2 VZVs had been continually circulating since at least the 1950s in China. Nearly all VZV strains except VVAEs possessed the genetic profile of PstI + BglI + Sam-. However, the other clades were also found to be co-circulating with clade 2, especially in the border regions. These results highlighted the need for the constant and broad use of virologic surveillance to provide an important genetic baseline for varicella control and vaccination programs in China.


Venous Thromboembolism Prophylaxis: A Narrative Review With a Focus on the High-Risk Critically Ill Patient.
Venous thromboembolism (VTE) is a major health concern associated with significant morbidity and mortality. Critically ill patients are at an increased risk of VTE compared to general medical patients due to unique risk factors: prolonged immobilization, invasive lines and devices, certain medications, and acquired thrombophilia. Furthermore, VTE in the critically ill is associated with increased duration of mechanical ventilation, increased length of intensive care unit and hospital stay, and a trend toward increased mortality. Clinical practice guidelines therefore recommend VTE prophylaxis with either subcutaneous heparin or low-molecular-weight heparin for all critically ill patients without contraindication. Yet, many patients will develop VTE despite appropriate pharmacologic prophylaxis, which has led to interest in risk-stratifying critically ill patients for more aggressive prophylaxis strategies. Recent research identified patients at highest risk of failure of thromboprophylaxis and provided insight into the pathophysiologic mechanisms. Obesity and the receipt of vasopressors are 2 risk factors consistently identified in observational studies; further clinical data support decreased absorption of anticoagulant administered via the subcutaneous route as the likely mechanism behind thromboprophylaxis failure in these patient populations. Several studies have investigated novel thromboprophylaxis strategies to circumvent pharmacokinetic limitations in patients who are obese or on vasopressors: increased fixed-dose, weight-based subcutaneous, or continuous intravenous infusion of a prophylactic dose of anticoagulant has shown promise in limited studies; however, the results have yet to demonstrate superiority compared to current standard-of-care. This review discusses observational studies identifying patients at risk of thromboprophylaxis failure and critiques clinical studies evaluating novel thromboprophylaxis strategies in high-risk, critically ill patients with a focus on their limitations. Future studies are currently being conducted that will provide further guidance into the appropriate use of individualized thromboprophylaxis.


Nucleation of NaCl from Aqueous Solution: Critical Sizes, Ion-Attachment Kinetics, and Rates.
Nucleation and crystal growth are important in material synthesis, climate modeling, biomineralization, and pharmaceutical formulation. Despite tremendous efforts, the mechanisms and kinetics of nucleation remain elusive to both theory and experiment. Here we investigate sodium chloride (NaCl) nucleation from supersaturated brines using seeded atomistic simulations, polymorph-specific order parameters, and elements of classical nucleation theory. We find that NaCl nucleates via the common rock salt structure. Ion desolvation-not diffusion-is identified as the limiting resistance to attachment. Two different analyses give approximately consistent attachment kinetics: diffusion along the nucleus size coordinate and reaction-diffusion analysis of approach-to-coexistence simulation data from Aragones et al. ( J. Chem. Phys. 2012, 136, 244508 ). Our simulations were performed at realistic supersaturations to enable the first direct comparison to experimental nucleation rates for this system. The computed and measured rates converge to a common upper limit at extremely high supersaturation. However, our rate predictions are between 15 and 30 orders of magnitude too fast. We comment on possible origins of the large discrepancy.


Visualizing a Thinker's Life.
This paper presents a visualization framework that aids readers in understanding and analyzing the contents of medium-sized text collections that are typical for the opus of a single or few authors. We contribute several document-based visualization techniques to facilitate the exploration of the work of the German author Bazon Brock by depicting various aspects of its texts, such as the TextGenetics that shows the structure of the collection along with its chronology. The ConceptCircuit augments the TextGenetics with entities - persons and locations that were crucial to his work. All visualizations are sensitive to a wildcard-based phrase search that allows complex requests towards the author's work. Further development, as well as expert reviews and discussions with the author Bazon Brock, focused on the assessment and comparison of visualizations based on automatic topic extraction against ones that are based on expert knowledge.


Serum and peritoneal dialysate thyroid hormone levels in patients on continuous ambulatory peritoneal dialysis.
Thyroid function tests were performed on 16 clinically euthyroid patients with end-stage renal failure undergoing regular haemodialysis or continuous ambulatory peritoneal dialysis and compared with 8 healthy subjects. The patient groups were carefully matched, especially regarding relative duration of dialysis (mean of 24 months). Total serum thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine and reverse triiodothyronine were significantly lower in both patient groups than control. The thyrothrophin response to the standard thyrotrophin-releasing hormone test was delayed and blunted. Using a novel concentration technique we measured loss of T4 in peritoneal dialysate effluent and found it to be approximately 10% of daily thyroidal T4 release.


Longer term clinical and virological outcome of sub-Saharan African participants on antiretroviral treatment in the Swiss HIV Cohort Study.
Persons from sub-Saharan Africa (SSA) are increasingly enrolled in the Swiss HIV Cohort Study (SHCS). Cohorts from other European countries showed higher rates of viral failure among their SSA participants. We analyzed long-term outcomes of SSA versus North Western European participants. We analyzed data of the SHCS, a nation-wide prospective cohort study of HIV-infected adults at 7 sites in Switzerland. SSA and North Western European participants were included if their first treatment combination consisted of at least 3 antiretroviral drugs (cART), if they had at least 1 follow-up visit, did not report active injecting drug use, and did not start cART with CD4 counts >200 cells per microliter during pregnancy. Early viral response, CD4 cell recovery, viral failure, adherence, discontinuation from SHCS, new AIDS-defining events, and survival were analyzed using linear regression and Cox proportional hazard models. The proportion of participants from SSA within the SHCS increased from 2.6% (<1995) to 20.8% (2005-2009). Of 4656 included participants, 808 (17.4%) were from SSA. Early viral response (6 months) and rate of viral failure in an intent-to-stay-on-cART approach were similar. However, SSA participants had a higher risk of viral failure on cART (adjusted hazard ratio: 2.03, 95% confidence interval: 1.50 to 2.75). Self-reported adherence was inferior for SSA. There was no increase of AIDS-defining events or mortality in SSA participants. Increased attention must be given to factors negatively influencing adherence to cART in participants from SSA to guarantee equal longer-term results on cART.


Spatial analysis and risk mapping of soil-transmitted helminth infections in Brazil, using Bayesian geostatistical models.
Soil-transmitted helminths (Ascaris lumbricoides, Trichuris trichiura and hookworm) negatively impact the health and wellbeing of hundreds of millions of people, particularly in tropical and subtropical countries, including Brazil. Reliable maps of the spatial distribution and estimates of the number of infected people are required for the control and eventual elimination of soil-transmitted helminthiasis. We used advanced Bayesian geostatistical modelling, coupled with geographical information systems and remote sensing to visualize the distribution of the three soil-transmitted helminth species in Brazil. Remotely sensed climatic and environmental data, along with socioeconomic variables from readily available databases were employed as predictors. Our models provided mean prevalence estimates for A. lumbricoides, T. trichiura and hookworm of 15.6%, 10.1% and 2.5%, respectively. By considering infection risk and population numbers at the unit of the municipality, we estimate that 29.7 million Brazilians are infected with A. lumbricoides, 19.2 million with T. trichiura and 4.7 million with hookworm. Our model-based maps identified important risk factors related to the transmission of soiltransmitted helminths and confirm that environmental variables are closely associated with indices of poverty. Our smoothed risk maps, including uncertainty, highlight areas where soil-transmitted helminthiasis control interventions are most urgently required, namely in the North and along most of the coastal areas of Brazil. We believe that our predictive risk maps are useful for disease control managers for prioritising control interventions and for providing a tool for more efficient surveillance-response mechanisms.


Abnormal face identity coding in the middle fusiform gyrus of two brain-damaged prosopagnosic patients.
We report a functional magnetic resonance imaging (fMRI) adaptation study of two well-described patients, DF and PS, who present face identity recognition impairments (prosopagnosia) following brain-damage. Comparing faces to non-face objects elicited activation in all visual areas of the cortical face processing network that were spared subsequent to brain damage. The common brain lesion in the two patients was in the right inferior occipital cortex, in the territory of the right "occipital face area" ('OFA'), which strengthens the critical role of this region in processing faces. Despite the lesion to the right 'OFA', there was normal range of sensitivity to faces in the right "fusiform face area" ('FFA') in both patients, supporting a non-hierarchical model of face processing at the cortical level. At the same time, however, sensitivity to individual face representations, as indicated by release from adaptation to identity, was abnormal in the right 'FFA' of both patients. This suggests that the right 'OFA' is necessary to individualize faces, perhaps through reentrant interactions with other cortical face sensitive areas. The lateral occipital area (LO) is damaged bilaterally in patient DF, who also shows visual object agnosia. However, in patient PS, in whom LO was spared, sensitivity to individual representations of non-face objects was still found in this region, as in the normal brain, consistent with her preserved object recognition abilities. Taken together, these observations, which fruitfully combine functional imaging and neuropsychology, place strong constraints on the possible functional organization of the cortical areas mediating face processing in the human brain.


Effectiveness of topical skin products in the treatment and prevention of incontinence-associated dermatitis: a systematic review.
Incontinence-associated dermatitis (IAD) is inflammation of the skin resulting from repeated contact with urine and/or feces. It causes pain, redness, swelling and excoriation, and may lead to complications such as fungal skin infections and pressure injuries. It is important to prevent and treat IAD to avoid complications and improve patient outcomes. A number of products are available for protecting skin, but evidence on their effectiveness is limited. The current review aimed to establish the effectiveness of topical skin products in reducing the occurrence and/or severity of IAD. Adult patients over the age of 18 years with incontinence and/or diarrhea. Topical skin products as individual interventions or part of a skin care regimen. Both published and unpublished study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after, prospective and retrospective cohort, case-control, analytical cross-sectional, descriptive study designs including case series, individual case reports and descriptive cross-sectional studies across all care settings for inclusion. The primary outcome of interest was the absence or non-development, reduction or resolution, new development or increase in the occurrence of IAD or the increase in severity of IAD. The secondary outcome was any adverse effect caused by the skin care products used. A three-step search strategy to find both published and unpublished papers was utilized in this review. Studies were limited to those published in English from 1980 to 2016. Papers selected were assessed by two independent reviewers using the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). Data were extracted using the standardized data extraction tool in JBI-MAStARI. The data extracted included specific details about the interventions, populations, study methods and outcomes. Studies were assessed for methodological quality and statistical significance to determine validity and generalizability of study results. It was not possible to pool studies to conduct meta-analysis or test for heterogeneity. There were a limited number of clinical trials that compared products for efficacy in preventing and treating IAD. Assessment tools and severity scores used to measure skin damage outcomes were dissimilar and prone to subjectivity. It was difficult to ascertain superiority of any individual product. Information on barrier protective efficacy, side effects and cost can be valuable to both clinicians and care providers. More randomized controlled trials on product effectiveness for prevention and treatment of IAD are highly recommended.


The role of glucocorticoid and mineralocorticoid receptor DNA methylation in antenatal depression and infant stress regulation.
Understanding fetal programming pathways that underpin the relationship between maternal and offspring mental health necessitates an exploration of potential role of epigenetic variation in early development. Two genes involved in stress response regulation, the glucocorticoid and mineralocorticoid receptors (NR3C1 and NR3C2) have been a focus in understanding stressful exposures and mental health outcomes. Data were obtained from 236 pregnant women from the Mercy Pregnancy Emotional Wellbeing Study (MPEWS), a selected pregnancy cohort, recruited in early pregnancy. Depression was measured using the Structured Clinical Interview for DSM-IV (SCID-IV) and repeated measures of the Edinburgh Postnatal Depression Scale (EPDS). Antidepressant use, stressful events and anxiety symptoms were measured. NR3C1 and NR3C2 DNA methylation was measured in placental and infant buccal samples. Infant cortisol was measured in repeat saliva samples across a task. This study found maternal early pregnancy depressive disorder and symptoms were associated with lower DNA methylation at NR3C2 CpG_24 in placental tissue. There were no significant differences for depression or antidepressant use for DNA methylation of NR3C1. Antenatal depression was associated with lower infant cortisol reactivity at 12 months. DNA methylation in CpG_24 site in NR3C2 in placental samples suppressed the relationship between early maternal depressive symptoms and infant cortisol reactivity. These findings show a relationship between antenatal depression, NR3C2 DNA methylation and infant cortisol response providing support for a specific fetal programming pathway. Further research is required to examine the stability of this epigenetic mark across childhood and long-term mental health outcomes.


Population pharmacokinetics of mycophenolic acid in renal transplant recipients.
Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal, heart, lung and liver transplantation. Although MPA plasma concentrations have been shown to correlate with clinical outcome, there is considerable inter- and intrapatient pharmacokinetic variability. Consequently, it is important to study demographic and pathophysiological factors that may explain this variability in pharmacokinetics. The aim of the study was to develop a population pharmacokinetic model for MPA following oral administration of mycophenolate mofetil, and evaluate relationships between patient factors and pharmacokinetic parameters. Pharmacokinetic data were obtained from a randomised concentration-controlled trial involving 140 renal transplant patients. Pharmacokinetic profiles were assessed on nine occasions during a 24-week period. Plasma samples for description of full 12-hour concentration-time profiles on the first three sampling days were taken predose and at 0.33, 0.66, 1.25, 2, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. For the remaining six occasions, serial plasma samples were taken according to a limited sampling strategy predose and at 0.33, 0.66, 1.25 and 2 hours after mycophenolate mofetil administration. The resulting 6523 plasma concentration-time data were analysed using nonlinear mixed-effects modelling. The pharmacokinetics of MPA were best described by a two-compartment model with time-lagged first-order absorption. The following population parameters were estimated: absorption rate constant (k(a)) 4.1h(-1), central volume of distribution (V1) 91 L, peripheral volume of distribution (V2) 237 L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21 h. The interpatient variability for k(a), V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for k(a), V1 and CL were 116%, 53% and 20%, respectively. For MPA clearance, statistically significant correlations were found with creatinine clearance, plasma albumin concentration, sex and ciclosporin daily dose (p < 0.001). For V1, significant correlations were identified with creatinine clearance and plasma albumin concentration (p < 0.001). The developed population pharmacokinetic model adequately describes the pharmacokinetics of MPA in renal transplant recipients. The identified correlations appear to explain part of the observed inter- and intrapatient pharmacokinetic variability. The clinical consequences of the observed correlations remain to be investigated.


Negative feedbacks on bark beetle outbreaks: widespread and severe spruce beetle infestation restricts subsequent infestation.
Understanding disturbance interactions and their ecological consequences remains a major challenge for research on the response of forests to a changing climate. When, where, and how one disturbance may alter the severity, extent, or occurrence probability of a subsequent disturbance is encapsulated by the concept of linked disturbances. Here, we evaluated 1) how climate and forest habitat variables, including disturbance history, interact to drive 2000s spruce beetle (Dendroctonus rufipennis) infestation of Engelmann spruce (Picea engelmannii) across the Southern Rocky Mountains; and 2) how previous spruce beetle infestation affects subsequent infestation across the Flat Tops Wilderness in northwestern Colorado, which experienced a severe landscape-scale spruce beetle infestation in the 1940s. We hypothesized that drought and warm temperatures would promote infestation, whereas small diameter and non-host trees, which may reflect past disturbance by spruce beetles, would inhibit infestation. Across the Southern Rocky Mountains, we found that climate and forest structure interacted to drive the 2000s infestation. Within the Flat Tops study area we found that stands infested in the 1940s were composed of higher proportions of small diameter and non-host trees ca. 60 years later. In this area, the 2000s infestation was constrained by a paucity of large diameter host trees (> 23 cm at diameter breast height), not climate. This suggests that there has not been sufficient time for trees to grow large enough to become susceptible to infestation. Concordantly, we found no overlap between areas affected by the 1940s infestation and the current infestation. These results show a severe spruce beetle infestation, which results in the depletion of susceptible hosts, can create a landscape template reducing the potential for future infestations.


Thermal force approach to molecular evolution.
Recent experiments are discussed where temperature gradients across mesoscopic pores are shown to provide essential mechanisms for autonomous molecular evolution. On the one hand, laminar thermal convection can drive DNA replication as the molecules are continuously cycled between hot and cold regions of a chamber. On the other hand, thermophoresis can accumulate charged biopolymers in similar convection settings. The experiments show that temperature differences analogous to those across porous rocks present a robust nonequilibrium boundary condition to feed the replication and accumulation of evolving molecules. It is speculated that similar nonequilibrium conditions near porous submarine hydrothermal mounds could have triggered the origin of life. In such a scenario, the encapsulation of cells with membranes would be a later development. It is expected that detailed studies of mesoscopic boundary conditions under nonequilibrium conditions will reveal new connecting pieces in the fascinating puzzle of the origins of life.


Changes in ovarian luteinizing hormone and follicle-stimulating hormone receptor content and in gonadotropin-induced ornithine decarboxylase activity during prepubertal and pubertal development of the female rat.
Ovarian hCG and FSH receptor content was measured at different postnatal ages (days 4-32), at 4-day intervals, and expressed as counts per min 125I-labeled hormone bound/micrograms DNA. Specific FSH binding was minimal at day 4 and increased to a maximum at day 28, with the greatest rate of increase between day 4 and 16. hCG receptor content increased 6-fold between day 4 and 32, but contrasting with FSH, its greatest rate of increase occurred between day 16 and 28. The effectiveness of in vivo treatment with LH in inducing ovarian ornithine decarboxylase (ODC) activity, measured in 20,000 X g supernatants by the in vitro formation of 14CO2 from labeled ornithine, increased significantly during prepubertal development (days 21-33), paralleling the changes in hCG receptors. Ovarian hCG and FSH receptor content was also measured during the time of puberty. Specific hCG binding increased from anestrus (juvenile 32-day-old animals) to 1300 h of the first proestrus. The levels declined significantly by 1600 h of first proestrus and reached minimal values by the morning of estrus. Specific FSH binding also increased from anestrus to first proestrus, but to a much lesser degree, the levels showing only minor fluctuations during the rest of the cycle. hCG receptors measured in granulosa cells during puberty increased to an even greater extent than in the whole ovary; binding exhibited an 8-fold increase from anestrus to 1300 h of first proestrus and then declined to much lower values on estrus and the first diestrus. The capacity of LH to induce ovarian ODC activity increased markedly between anestrus and first proestrus, declining thereafter, and again paralleled the changes in LH receptor content. Evaluation of the kinetics of binding of hCG and FSH with their respective receptors in ovaries of 28-day-old rats revealed that the binding of hCG reached equilibrium within 4-8 h, whereas the binding of FSH attained equilibrium between 12-24 h. In both cases, however, the labeled hormones were clearly dissociable from their respective receptors by addition of an excess of unlabeled hormone. Moreover, although the ovarian receptor content of both hCG and FSH increased during prepubertal development, the equilibrium association constant of either hormone with its receptor remained unchanged. The results suggest that the infantile increase in FSH receptors may be induced by the high serum FSH levels present at that age and that, as shown by others in hypophysectomized rats, the subsequent increase in hCG receptors is, at least in part, an FSH-dependent phenomenon. The parallel changes in hCG receptors and LH-induced ODC activity during pre- and peripubertal development strongly suggest that an increase in LH binding capacity plays a fundamental role in the process of ovarian growth. It is also suggested that the changes in the steroidogenic ovarian response to hCG previously observed in peripubertal rats are, at least in part, determined by changes in ovarian LH receptor content.


Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.
During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV.


Colorizing pure copper surface by ultrafast laser-induced near-subwavelength ripples.
We demonstrate that the colorizing effect of angle dependence can be efficiently and conveniently achieved on the rippled surface of pure copper processed by the femtosecond laser with an out-of-focus method, which greatly improves the machining speed. Such a laser-induced colorization can occur in a wide range of laser fluence, which determines the coverage and morphological characteristics of laser-induced ripples and thus can finely tune the colorizing effect. By inspecting the colors and corresponding spectra of treated areas at different angles, the relationship between the diffracted light central wavelength and the laser-induced near-subwavelength grating is analyzed quantitatively based on the fundamental grating equation with the experimental grating parameters. The spectrum analysis indicates that for the laser fluence increasing in a suitable range, the more clarity and regularity of formed ripples should bring out a more prominent grating effect, which becomes further matching of the grating equation in a larger inspecting angle for the elimination of the influence of the diffused reflection light. In short, the study confirms that the colorizing phenomenon mainly ascribes to the grating diffraction effect of the laser-induced periodic surface ripples, which would help to enable the flexible control of the colorizing effect induced by laser processing on pure copper.


Interferometric supermultispectral imaging.
Multispectral images that have spectral resolution as high as their spatial resolution may be called supermultispectral images or simply spectral images. The principle of an interferometric method of supermultispectral imaging has been developed by unifying the principles of incoherent holography and Fourier spectroscopy. The method is expected to inherit the multiplex and throughput advantages from Fourier spectroscopy. We present our first experimental results of the method applied to diffusely illuminated objects and self-radiating thermal objects along with a simplified theory and brief discussion on the signal-to-noise ratios.


Mortality deceleration and mortality selection: three unexpected implications of a simple model.
Unobserved heterogeneity in mortality risk is pervasive and consequential. Mortality deceleration-the slowing of mortality's rise with age-has been considered an important window into heterogeneity that otherwise might be impossible to explore. In this article, I argue that deceleration patterns may reveal surprisingly little about the heterogeneity that putatively produces them. I show that even in a very simple model-one that is composed of just two subpopulations with Gompertz mortality-(1) aggregate mortality can decelerate even while a majority of the cohort is frail; (2) multiple decelerations are possible; and (3) mortality selection can produce acceleration as well as deceleration. Simulations show that these patterns are plausible in model cohorts that in the aggregate resemble cohorts in the Human Mortality Database. I argue that these results challenge some conventional heuristics for understanding the relationship between selection and deceleration; undermine certain inferences from deceleration timing to patterns of social inequality; and imply that standard parametric models, assumed to plateau at most once, may sometimes badly misestimate deceleration timing-even by decades.


Country specific predictions of the cost-effectiveness of malaria vaccine RTS,S/AS01 in endemic Africa.
RTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions. The impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9months, and fourth dose at 27months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted. If implemented in all 43 countries the vaccine has the potential to avert 123 (117;129) million malaria episodes over the first 10years. Burden averted averages 18,413 (range of country median estimates 156-40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average $39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range $78-$22,448) per DALY averted; the ratio is lower by one third - $136 (range $116-$220) - in settings where parasite prevalence in children aged 2-10years is at or above 10%. RTS,S/AS01has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule.


Trade policy, health, and corporate influence: British American tobacco and China's accession to the World Trade Organization.
Tobacco market liberalization can have a profound impact on health. This article analyzes internal documents of British American Tobacco (BAT), released as a result of litigation in the United States, in order to examine the company's attempts to influence negotiations over China's accession to the World Trade Organization. The documents demonstrate that BAT attempted to influence these negotiations through a range of mechanisms, including personal access of BAT employees and lobbyists to policymakers; employment of former civil servants from key U.K. government departments; use of organized business groups such as the Multinational Chairmen's Group and the European Round Table; and participation and leadership in forums organized by Chatham House. These processes contributed to significant concessions on the liberalization of the tobacco market in China, although the failure to break the Chinese state monopoly over the manufacture and distribution of cigarettes has ensured that foreign tobacco companies' share of the Chinese market has remained small. World Trade Organization accession has nevertheless led to a profound restructuring of the Chinese tobacco industry in anticipation of foreign competition, which may result in more market-based and internationally oriented Chinese tobacco firms.


Excision of Sleeping Beauty transposons: parameters and applications to gene therapy.
A major problem in gene therapy is the determination of the rates at which gene transfer has occurred. Our work has focused on applications of the Sleeping Beauty (SB) transposon system as a non-viral vector for gene therapy. Excision of a transposon from a donor molecule and its integration into a cellular chromosome are catalyzed by SB transposase. In this study, we used a plasmid-based excision assay to study the excision step of transposition. We used the excision assay to evaluate the importance of various sequences that border the sites of excision inside and outside the transposon in order to determine the most active sequences for transposition from a donor plasmid. These findings together with our previous results in transposase binding to the terminal repeats suggest that the sequences in the transposon-junction of SB are involved in steps subsequent to DNA binding but before excision, and that they may have a role in transposase-transposon interaction. We found that SB transposons leave characteristically different footprints at excision sites in different cell types, suggesting that alternative repair machineries operate in concert with transposition. Most importantly, we found that the rates of excision correlate with the rates of transposition. We used this finding to assess transposition in livers of mice that were injected with the SB transposon and transposase. The excision assay appears to be a relatively quick and easy method to optimize protocols for delivery of genes in SB transposons to mammalian chromosomes in living animals.


MicroRNA-regulated non-viral vectors with improved tumor specificity in an orthotopic rat model of hepatocellular carcinoma.
In hepatocellular carcinoma (HCC), tumor specificity of gene therapy is of utmost importance to preserve liver function. MicroRNAs (miRNAs) are powerful negative regulators of gene expression and many are downregulated in human HCC. We identified seven miRNAs that are also downregulated in tumors in a rat hepatoma model (P<0.05) and attempted to improve tumor specificity by constructing a panel of luciferase-expressing vectors containing binding sites for these miRNAs. Attenuation of luciferase expression by the corresponding miRNAs was confirmed across various cell lines and in mouse liver. We then tested our vectors in tumor-bearing rats and identified two miRNAs, miR-26a and miR-122, that significantly decreased expression in liver compared with the control vector (6.40 and 0.26%, respectively; P<0.05). In tumor, miR-122 had a nonsignificant trend towards decreased (∼50%) expression, whereas miR-26 had no significant effect on tumor expression. To our knowledge, this is the first work using differentially expressed miRNAs to de-target transgene expression in an orthotopic hepatoma model and to identify miR-26a, in addition to miR-122, for de-targeting liver. Considering the heterogeneity of miRNA expression in human HCC, this information will be important in guiding development of more personalized vectors for the treatment of this devastating disease.


Development and Validation of a Photonumeric Scale for Evaluation of Infraorbital Hollows.
A validated scale is needed for objective and reproducible comparisons of infraorbital hollows (i.e., tear troughs) before and after treatment in practice and clinical studies. To describe the development and validation of the 5-point photonumeric Allergan Infraorbital Hollows Scale. The scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each grade. The clinical significance of a 1-point score difference was evaluated in a review of image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject validation study (N = 297) completed during 2 sessions occurring 3 weeks apart. A score difference of ≥1 point was shown to reflect a clinically significant difference (mean [95% confidence interval] absolute score difference, 0.90 [0.79-1.02] for clinically different image pairs and 0.33 [0.19-0.46] for not clinically different pairs). Intrarater agreement between the 2 validation sessions was substantial (mean weighted kappa = 0.79). Interrater agreement was substantial during the second rating session (0.70, primary end point). The Allergan Infraorbital Hollows Scale is a validated and reliable scale for physician rating severity of hollowing in the infraorbital area.


Laser scribing of high-performance and flexible graphene-based electrochemical capacitors.
Although electrochemical capacitors (ECs), also known as supercapacitors or ultracapacitors, charge and discharge faster than batteries, they are still limited by low energy densities and slow rate capabilities. We used a standard LightScribe DVD optical drive to do the direct laser reduction of graphite oxide films to graphene. The produced films are mechanically robust, show high electrical conductivity (1738 siemens per meter) and specific surface area (1520 square meters per gram), and can thus be used directly as EC electrodes without the need for binders or current collectors, as is the case for conventional ECs. Devices made with these electrodes exhibit ultrahigh energy density values in different electrolytes while maintaining the high power density and excellent cycle stability of ECs. Moreover, these ECs maintain excellent electrochemical attributes under high mechanical stress and thus hold promise for high-power, flexible electronics.


Video Gaming and Children's Psychosocial Wellbeing: A Longitudinal Study.
The effects of video games on children's psychosocial development remain the focus of debate. At two timepoints, 1 year apart, 194 children (7.27-11.43 years old; male = 98) reported their gaming frequency, and their tendencies to play violent video games, and to game (a) cooperatively and (b) competitively; likewise, parents reported their children's psychosocial health. Gaming at time one was associated with increases in emotion problems. Violent gaming was not associated with psychosocial changes. Cooperative gaming was not associated with changes in prosocial behavior. Finally, competitive gaming was associated with decreases in prosocial behavior, but only among children who played video games with high frequency. Thus, gaming frequency was related to increases in internalizing but not externalizing, attention, or peer problems, violent gaming was not associated with increases in externalizing problems, and for children playing approximately 8 h or more per week, frequent competitive gaming may be a risk factor for decreasing prosocial behavior. We argue that replication is needed and that future research should better distinguish between different forms of gaming for more nuanced and generalizable insight.


Long-term intake of nuts in relation to cognitive function in older women.
Nuts contain nutrients that may benefit brain health; thus, we examined long-term intake of nuts in relation to cognition in older women. Population-based prospective cohort study. Academic research using data from the Nurses' Health Study. Nut intake was assessed in a food-frequency questionnaire beginning in1980, and approximately every four years thereafter. Between 1995-2001, 16,010 women age 70 or older (mean age = 74 years) without a history of stroke were administered 4 repeated telephone-based cognitive interviews over 6 years. Our final sample included 15,467 women who completed an initial cognitive interview and had complete information on nut intake. The Telephone Interview for Cognitive Status (TICS), a global score averaging the results of all tests (TICS, immediate and delayed verbal recall, category fluency, and attention), and a verbal memory score averaging the results of tests of verbal recall. In multivariable-adjusted linear regression models, higher long-term total nut intake was associated with better average cognitive status for all cognitive outcomes. For the global composite score combining all tests, women consuming at least 5 servings of nuts/week had higher scores than non-consumers (mean difference=0.08 standard units, 95% confidence interval 0.00-0.15; p-trend=0.003). This mean difference of 0.08 is equivalent to the mean difference we find between women 2 years apart in age. Long-term intake of nuts was not associated with rates of cognitive decline. Higher nut intake may be related to better overall cognition at older ages, and could be an easily-modifiable public health intervention.


Molecular analysis of clinical Burkholderia pseudomallei isolates from southwestern coastal region of India, using multi-locus sequence typing.
The Gram-negative soil dwelling bacterium Burkholderia pseudomallei is the etiological agent of melioidosis. The disease is endemic in most parts of Southeast Asia and northern Australia. Over last few years, there has been an increase in number of melioidosis cases from India; however the disease epidemiology is less clearly understood. Multi-locus sequence typing (MLST) is a powerful genotypic method used to characterize the genetic diversity of B. Pseudomallei both within and across the geographic regions. In this study, MLST analysis was performed on 64 B. pseudomallei clinical isolates. These isolates were obtained between 2008-2014 from southwestern coastal region of India. Broad population patterns of Indian B. pseudomallei isolates in context with isolates of Southeast Asia or global collection was determined using in silico phylogenetic tools. A total of 32 Sequence types (STs) were reported among these isolates of which 17 STs (53%) were found to be novel. ST1368 was found as group founder and the most predominant genotype (n = 11, 17%). Most of the B. pseudomallei isolates reported in this study (or other Indian isolates available in MLST database) clustered in one major group suggesting clonality in Indian isolates; however, there were a few outliers. When analyzed by measure of genetic differentiation (FST) and other phylogenetic tools (e.g. PHYLOViZ), Indian STs were found closer to Southeast Asian isolates than Australian isolates. The phylogenetic analysis further revealed that within Asian clade, Indian isolates grouped more closely with isolates from Sri Lanka, Vietnam, Bangladesh and Thailand. Overall, the results of this study suggest that the Indian B. pseudomallei isolates are closely related with lesser heterogeneity among them and cluster in one major group suggesting clonality of the isolates. However, it appears that there are a few outliers which are distantly related to the majority of Indian STs. Phylogenetic analysis suggest that Indian isolates are closely related to isolates from Southeast Asia, particularly from South Asia.


Genetic variation in human drug-related genes.
Variability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classic pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied. Based on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional variants in 806 drug-related genes, including 628 known drug targets. We further computed the likelihood of 1236 FDA-approved drugs to be affected by functional variants in their targets in the whole ExAC population as well as different geographic sub-populations. We find that most genetic variants in drug-related genes are very rare (f < 0.1%) and thus will likely not be observed in clinical trials. Furthermore, we show that patient risk varies for many drugs and with respect to geographic ancestry. A focused analysis of oncological drug targets indicates that the probability of a patient carrying germline variants in oncological drug targets is, at 44%, high enough to suggest that not only somatic alterations but also germline variants carried over into the tumor genome could affect the response to antineoplastic agents. This study indicates that even though many variants are very rare and thus likely not observed in clinical trials, four in five patients are likely to carry a variant with possibly functional effects in a target for commonly prescribed drugs. Such variants could potentially alter drug efficacy.