Resuscitation Outcomes Consortium-Amiodarone, Lidocaine or Placebo Study (ROC-ALPS): Rationale and methodology behind an out-of-hospital cardiac arrest antiarrhythmic drug trial.
Despite their wide use, whether antiarrhythmic drugs improve survival after out-of-hospital cardiac arrest (OHCA) is not known. The ROC-ALPS is evaluating the effectiveness of these drugs for OHCA due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia (VF/VT). ALPS will randomize 3,000 adults across North America with nontraumatic OHCA, persistent or recurring VF/VT after ≥1 shock, and established vascular access to receive up to 450 mg amiodarone, 180 mg lidocaine, or placebo in the field using a double-blind protocol, along with standard resuscitation measures. The designated target population is all eligible randomized recipients of any dose of ALPS drug whose initial OHCA rhythm was VF/VT. A safety analysis includes all randomized patients regardless of their eligibility, initial arrhythmia, or actual receipt of ALPS drug. The primary outcome of ALPS is survival to hospital discharge; a secondary outcome is functional survival at discharge assessed as a modified Rankin Scale score ≤3. The principal aim of ALPS is to determine if survival is improved by amiodarone compared with placebo; secondary aim is to determine if survival is improved by lidocaine vs placebo and/or by amiodarone vs lidocaine. Prioritizing comparisons in this manner acknowledges where differences in outcome are most expected based on existing knowledge. Each aim also represents a clinically relevant comparison between treatments that is worth investigating. Results from ALPS will provide important information about the choice and value of antiarrhythmic therapies for VF/VT arrest with direct implications for resuscitation guidelines and clinical practice.


Better Movers and Thinkers (BMT): An Exploratory Study of an Innovative Approach to Physical Education.
Recent research has confirmed a positive relationship between levels of physical activity and academic achievement. Some of these studies have been informed by neurological models of Executive Functioning (EF). There is a general consensus within the literature that the three core EF skills are; working memory, inhibitory control and cognitive flexibility. The development of these core EF skills has been linked with learning and academic achievement and is an essential component in the delivery of PE using a new and innovative approach called 'Better Movers and Thinkers (BMT).' A mixed methods design was used to investigate the effectiveness and feasibility of a 16-week intervention programme using BMT where 46 children were tested on two separate occasions for coordination and balance control, academic skills, working memory and non-verbal reasoning skills. One school acted as the control condition (21 students, aged 9 - 10 years) and another school acted as the intervention condition (25 students, aged 9 - 10 years). Quantitative data revealed an effect between pre and post-test conditions in the areas of phonological skills (p = .042), segmentation skills (p = .014) and working memory (p = .040) in favour of the intervention condition. Further analysis identified a gender-interaction with male students in the intervention condition making significant gains in phonological skills (p = .005) segmentation skills (p = .014) and spelling (p = .007) compared to boys in the control condition. Analysis of qualitative data from a sample of students from the intervention condition and their class teacher indicated good acceptability of BMT as an alternative approach to PE.


The Positive Impact and Associated Mechanisms of Physical Activity on Mental Health in Underprivileged Children and Adolescents: An Integrative Review.
(1) Background: Review-based studies are required to consider the different designs and data that describe the association between physical activity and mental health for underprivileged children and adolescents. There is a particular need to identify mechanisms which could explain the association, and factors which influence the association in this population group. (2) Methods: An integrative review with a systematic search was conducted in three stages: (i) a systematic literature search on four databases from inception until May 2020. Studies were eligible if they examined underprivileged children, involved moderate to vigorous physical activity (MVPA) and had a focus on at least one outcome measure related to mental health. (ii) Two critical appraisal tools were used to assess quality across different study designs. (iii) Synthesis was undertaken in four stages, examining social, internal and physical outcomes and mechanisms. (3) Results: A total of 16 studies were included (2 qualitative; 12 quantitative and 2 mixed methods). Fifteen (15/16; 93.8%) showed an association between MVPA and a significant improvement in at least one mental health outcome. The most studied outcomes included: internal aspects (n = 14), significant effects were identified in 12/14 studies; social aspects (n = 6), significant effects were identified across all studies and finally physical aspects (n = 5), significant effects were found in 3/5 studies. Autonomy support was identified as a mechanism to explain the change, whilst age and gender influenced the strength of the association. (4) Conclusions: The findings provide confirmation of the link between MVPA and the improved mental health and wellbeing of disadvantaged children and adolescents. Future research must consider the long-term effect through longitudinal studies, along with determining whether any specific types of PA are more impactful than others.


Early Childhood Outcomes After Neonatal Encephalopathy in Uganda: A Cohort Study.
Neonatal encephalopathy (NE) is a leading cause of global child mortality. Survivor outcomes in low-resource settings are poorly described. We present early childhood outcomes after NE in Uganda. We conducted a prospective cohort study of term-born infants with NE (n = 210) and a comparison group of term non-encephalopathic (non-NE) infants (n = 409), assessing neurodevelopmental impairment (NDI) and growth at 27-30 months. Relationships between early clinical parameters and later outcomes were summarised using risk ratios (RR). Mortality by 27-30 months was 40·3% after NE and 3·8% in non-NE infants. Impairment-free survival occurred in 41·6% after NE and 98·7% of non-NE infants. Amongst NE survivors, 29·3% had NDI including 19·0% with cerebral palsy (CP), commonly bilateral spastic CP (64%); 10·3% had global developmental delay (GDD) without CP. CP was frequently associated with childhood seizures, vision and hearing loss and mortality. NDI was commonly associated with undernutrition (44·1% Z-score < - 2) and microcephaly (32·4% Z-score < - 2). Motor function scores were reduced in NE survivors without CP/GDD compared to non-NE infants (median difference - 8·2 (95% confidence interval; - 13·0, - 3·7)). Neonatal clinical seizures (RR 4.1(2.0-8.7)), abnormalities on cranial ultrasound, (RR 7.0(3.8-16.3), nasogastric feeding at discharge (RR 3·6(2·1-6·1)), and small head circumference at one year (Z-score < - 2, RR 4·9(2·9-5·6)) increased the risk of NDI. In this sub-Saharan African population, death and neurodevelopmental disability after NE were common. CP was associated with sensorineural impairment, malnutrition, seizures and high mortality by 2 years. Early clinical parameters predicted impairment outcomes.


Learning physical properties of liquid crystals with deep convolutional neural networks.
Machine learning algorithms have been available since the 1990s, but it is much more recently that they have come into use also in the physical sciences. While these algorithms have already proven to be useful in uncovering new properties of materials and in simplifying experimental protocols, their usage in liquid crystals research is still limited. This is surprising because optical imaging techniques are often applied in this line of research, and it is precisely with images that machine learning algorithms have achieved major breakthroughs in recent years. Here we use convolutional neural networks to probe several properties of liquid crystals directly from their optical images and without using manual feature engineering. By optimizing simple architectures, we find that convolutional neural networks can predict physical properties of liquid crystals with exceptional accuracy. We show that these deep neural networks identify liquid crystal phases and predict the order parameter of simulated nematic liquid crystals almost perfectly. We also show that convolutional neural networks identify the pitch length of simulated samples of cholesteric liquid crystals and the sample temperature of an experimental liquid crystal with very high precision.


Toxicogenomic analysis provides new insights into molecular mechanisms of the sublethal toxicity of 2,4,6-trinitrotoluene in Eisenia fetida.
Xenobiotics such as explosives and pesticides released into the environment can have lethal and sublethal impacts on soil organisms such as earthworms with potential subsequent impacts at highertrophic levels. To better understand the molecular toxicological mechanisms of 2,4,6-trinitrotoluene (TNT), a commonly used explosive, in Eisenia fetida, earthworms were exposed to a gradient of TNT-spiked soils for 28 days and impacts on gene expression were examined using a 4032 cDNA microarray. Reproduction was increased at low doses of TNT, whereas high doses of TNT reduced juvenile production. On the basis of reproduction responses to TNT, four treatments, that is, control, 2, 10.6, and 38.7 mg/kg, were selected for gene expression studies in a balanced interwoven loop design microarray experiment in which the expression of 311 transcripts was significantly affected. Reverse-transcription quantitative polymerase chain reaction (RT-QPCR) data on 68 selected differentially and nondifferentially expressed transcripts showed a significant correlation with microarray results. The expression of genes involved in multiple biological processes was altered, including muscle contraction, neuronal signaling and growth, ubiquitinylation, fibrinolysis and coagulation, iron and calcium homeostasis, oxygen transport, and immunity. Chitinase activity assays confirmed down-regulation of chitinase genes as indicated by array and RT-QPCR data. An acute toxicity test provided evidence that dermal contact with TNT can cause bleeding, inflammation, and constriction, which may be explained by gene expression results. Sublethal doses of TNT affected the nervous system, caused blood disorders similar to methemoglobinemia, and weakened immunity in E. fetida.


An approach to addressing governance from a health system framework perspective.
As countries strive to strengthen their health systems in resource constrained contexts, policy makers need to know how best to improve the performance of their health systems. To aid these decisions, health system stewards should have a good understanding of how health systems operate in order to govern them appropriately. While a number of frameworks for assessing governance in the health sector have been proposed, their application is often hindered by unrealistic indicators or they are overly complex resulting in limited empirical work on governance in health systems. This paper reviews contemporary health sector frameworks which have focused on defining and developing indicators to assess governance in the health sector. Based on these, we propose a simplified approach to look at governance within a common health system framework which encourages stewards to take a systematic perspective when assessing governance. Although systems thinking is not unique to health, examples of its application within health systems has been limited. We also provide an example of how this approach could be applied to illuminate areas of governance weaknesses which are potentially addressable by targeted interventions and policies. This approach is built largely on prior literature, but is original in that it is problem-driven and promotes an outward application taking into consideration the major health system building blocks at various levels in order to ensure a more complete assessment of a governance issue rather than a simple input-output approach. Based on an assessment of contemporary literature we propose a practical approach which we believe will facilitate a more comprehensive assessment of governance in health systems leading to the development of governance interventions to strengthen system performance and improve health as a basic human right.


Multi-subject analyses with dynamic causal modeling.
Currently, most studies that employ dynamic causal modeling (DCM) use random-effects (RFX) analysis to make group inferences, applying a second-level frequentist test to subjects' parameter estimates. In some instances, however, fixed-effects (FFX) analysis can be more appropriate. Such analyses can be implemented by combining the subjects' posterior densities according to Bayes' theorem either on a multivariate (Bayesian parameter averaging or BPA) or univariate basis (posterior variance weighted averaging or PVWA), or by applying DCM to time-series averaged across subjects beforehand (temporal averaging or TA). While all these FFX approaches have the advantage of allowing for Bayesian inferences on parameters a systematic comparison of their statistical properties has been lacking so far. Based on simulated data generated from a two-region network we examined the effects of signal-to-noise ratio (SNR) and population heterogeneity on group-level parameter estimates. Data sets were simulated assuming either a homogeneous large population (N=60) with constant connectivities across subjects or a heterogeneous population with varying parameters. TA showed advantages at lower SNR but is limited in its applicability. Because BPA and PVWA take into account posterior (co)variance structure, they can yield non-intuitive results when only considering posterior means. This problem is relevant for high SNR data, pronounced parameter interdependencies and when FFX assumptions are violated (i.e. inhomogeneous groups). It diminishes with decreasing SNR and is absent for models with independent parameters or when FFX assumptions are appropriate. Group results obtained with these FFX approaches should therefore be interpreted carefully by considering estimates of dependencies among model parameters.


Resolution enhancement in confocal microscopy using Bessel-Gauss beams.
Laser scanning microscopy is limited in lateral resolution by the diffraction of light. We show that we can obtain twenty percent improvement in the resolution of confocal microscopy using Bessel-Gauss beams with the right pinhole size compared to conventional Gaussian beam based confocal microscopy. Advantages of this strategy include simplicity of installation and use, linear polarization compatibility, possibility to combine it with other resolution enhancement and superresolution strategies. We demonstrate the resolution enhancement capabilities of Bessel-Gauss beams both theoretically and experimentally on nano-spheres and biological tissue samples without any residual artifacts coming from the Bessel-Gauss beam side lobes with a resolution of 0.39λ. We also show that the resolution enhancement of Bessel-Gauss beams yields a better statistical colocalization analysis with fewer false positive results than when using Gaussian beams. We have also used Bessel-Gauss beams of different orders to further improve the resolution by combining them in SLAM microscopy (Switching LAser Modes : Dehez, Optics Express, 2013) achieving a resolution of 0.2λ.


Rapid adaptive optical recovery of optimal resolution over large volumes.
Using a descanned, laser-induced guide star and direct wavefront sensing, we demonstrate adaptive correction of complex optical aberrations at high numerical aperture (NA) and a 14-ms update rate. This correction permits us to compensate for the rapid spatial variation in aberration often encountered in biological specimens and to recover diffraction-limited imaging over large volumes (>240 mm per side). We applied this to image fine neuronal processes and subcellular dynamics within the zebrafish brain.


Cognitive function in children with type 1 diabetes: a meta-analysis.
To quantify the magnitude and pattern of cognitive difficulties in pediatric type 1 diabetes as well as the effects associated with earlier disease onset and severe hypoglycemia. Pediatric studies of cognitive function since 1985 were identified for study inclusion using MEDLINE and PsycInfo. Effect size (ES, Cohen's d) between the diabetic and control groups, expressed in SD units, were calculated within cognitive domains to standardize meta-analysis test performance. The meta-analysis sample of 2,144 children consisted of 1,393 study subjects with type 1 diabetes and 751 control subjects from 19 studies. Overall, type 1 diabetes was associated with slightly lower overall cognition (ES -0.13), with small differences compared with control subjects across a broad range of domains, excluding learning and memory, which were similar for both groups. Learning and memory skills, both verbal and visual (-0.28 and -0.25), were more affected for children with early-onset diabetes (EOD) than late-onset diabetes (LOD), along with attention/executive function skills (-0.27). Compared with nondiabetic control subjects, EOD effects were larger, up to one-half SD lower, particularly for learning and memory (-0.49). Generally, seizures were associated with a negligible overall cognition ES of -0.06, with slight and inconsistent cognitive effects found on some measures, possibly reflecting the opposing effects of poorer versus better metabolic control. Pediatric diabetes generally relates to mildly lower cognitive scores across most cognitive domains. Cognitive effects are most pronounced and pervasive for EOD, with moderately lower performance compared with control subjects. Seizures are generally related to nominal, inconsistent performance differences.


Interindividual differences in circadian rhythmicity and sleep homeostasis in older people: effect of a PER3 polymorphism.
Aging is associated with marked changes in the timing, consolidation and structure of sleep. Older people wake up frequently, get up earlier and have less slow wave sleep than young people, although the extent of these age-related changes differs considerably between individuals. Interindividual differences in homeostatic sleep regulation in young volunteers are associated with the variable-number, tandem-repeat (VNTR) polymorphism (rs57875989) in the coding region of the circadian clock gene PERIOD3 (PER3). However, predictors of these interindividual differences have yet to be identified in older people. Sleep electroencephalographic (EEG) characteristics and circadian rhythms were assessed in 26 healthy older volunteers (55-75 years) selected on the basis of homozygosity for either the long or short allele of the PER3 polymorphism. Homozygosity for the longer allele (PER3(5/5)) associated with a phase-advance in the circadian melatonin profile and an earlier occurrence of the melatonin peak within the sleep episode. Furthermore, older PER3(5/5) participants accumulated more nocturnal wakefulness, had increased EEG frontal delta activity (0.75-1.50 Hz), and decreased EEG frontal sigma activity (11-13 Hz) during non-rapid eye movement (REM) sleep compared with PER3(4/4) participants. Our results indicate that the polymorphism in the clock gene PER3 may contribute to interindividual differences in sleep and circadian physiology in older people.


What #theDress reveals about the role of illumination priors in color perception and color constancy.
The disagreement between people who named #theDress (the Internet phenomenon of 2015) "blue and black" versus "white and gold" is thought to be caused by individual differences in color constancy. It is hypothesized that observers infer different incident illuminations, relying on illumination "priors" to overcome the ambiguity of the image. Different experiences may drive the formation of different illumination priors, and these may be indicated by differences in chronotype. We assess this hypothesis, asking whether matches to perceived illumination in the image and/or perceived dress colors relate to scores on the morningness-eveningness questionnaire (a measure of chronotype). We find moderate correlations between chronotype and illumination matches (morning types giving bluer illumination matches than evening types) and chronotype and dress body matches, but these are significant only at the 10% level. Further, although inferred illumination chromaticity in the image explains variation in the color matches to the dress (confirming the color constancy hypothesis), color constancy thresholds obtained using an established illumination discrimination task are not related to dress color perception. We also find achromatic settings depend on luminance, suggesting that subjective white point differences may explain the variation in dress color perception only if settings are made at individually tailored luminance levels. The results of such achromatic settings are inconsistent with their assumed correspondence to perceived illumination. Finally, our results suggest that perception and naming are disconnected, with observers reporting different color names for the dress photograph and their isolated color matches, the latter best capturing the variation in the matches.


The oestrogen receptor in the rat uterus in relation to intra-uterine devices and the oestrous cycle.
We investigated the binding characteristics, content and intracellular distribution of nuclear and cytosolic oestrogen receptors in the uteri of rats bearing a unilateral intrauterine device, fitted 14--18 days earlier, at four phases of a 5-day oestrous cycle. The patterns of changes in wet weight and content of cytosolic and nuclear receptor that normally occur during the oestrous cycle were not altered by the presence of the device. At all stages of the cycle the intra-uterine-device-containing horn had a greater wet weight and a correspondingly higher content of cytosolic receptor than its contralateral control horn, the cellular concentration of cytosolic receptor being apparently maintained. However, the intra-uterine-device-containing horn had significantly lower cellular concentrations (i.e. per mg of DNA) of nuclear receptor, particularly at late dioestrus and pro-oestrus. Thus the treated horn showed a decreased translocation of receptor in response to increases in circulating oestrogens. Both horns contained equivalent amounts of an activating factor implicated in translocation and measured in vitro by binding of cytosol receptor to oligo(dT)-cellulose. The presence of an intra-uterine device neither altered the dissociation constants (Kd) of the nuclear and cytosolic oestrogen-receptor complexes nor the stability of the nuclear receptor complex in vitro. The decreased translocation cannot thus be directly attributed to changes in the physical properties of the receptor. This decrease may be responsible for the anti-fertility effect of the intra-uterine device (which affects only the treated horn of the bicornuate rat uterus), since implantation of the blastocyst requires correct concentrations of nuclear oestrogen receptor.


Echocardiographic reference ranges for normal cardiac Doppler data: results from the NORRE Study.
Reference values for Doppler parameters according to age and gender are recommended for the assessment of heart physiology, specifically for left ventricular (LV) diastolic function. In this study, we report normal reference ranges for Doppler parameters obtained in a large group of healthy volunteers. Echocardiographic data were acquired using state-of-the-art cardiac ultrasound equipment following Doppler acquisition and measurement protocols approved by the European Association of Cardiovascular Imaging. A total of 449 (mean age: 45.8 ± 13.7 years) healthy volunteers (198 men and 251 women) were enrolled at the collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. A comprehensive echocardiographic examination was obtained from all subjects following predefined protocols. The majority of the Doppler diastolic parameters (e', E/e') as well as right ventricle systolic s' wave velocity were similar in men and women. Left ventricle s' wave velocity was higher in men than in women. E wave and e' were higher in younger subjects and decreased progressively in the older ones. E/e' ratio increased with ageing. Septal e' <8 cm/s was present in 19.7% of the subjects in the 40-60 year group and in 55% of those in the ≥60 year group. However, the cut-off value of average E/e' or lateral E/e' remained <15 or 13, respectively, in the majority of patients. The NORRE study provides the reference values for the most useful Doppler parameters in the evaluation of heart physiology. These data highlight the need of using age-specific reference values especially for the diagnosis of LV systolic and diastolic dysfunction and for the estimation of LV filling pressures.


Effect of oocyte vitrification on glucose transport in mouse metaphase II oocytes.
Oocyte vitrification has significantly improved the survival rate and become the mainstream method for cryopreserving oocytes. Previous studies have demonstrated that the ultrastructure, mitochondrial function, DNA methylation, and histone modification exhibit an irreversible effect after oocyte vitrification. However, little is known about the effects of oocyte vitrification on glucose transport and metabolism. This study aims to determine whether mouse oocyte vitrification causes abnormal glucose metabolism and identify a strategy to correct abnormal glucose metabolism. Furthermore, this study further investigates the effects of oocyte vitrification on glucose uptake, and glucose metabolism, and energy levels. The results indicated that vitrification significantly reduced the glucose transport activity, NADPH, glutathione, and ATP levels, and increased reactive oxygen species levels in oocytes (P < 0.01). Vitrification also reduced the expression of glucose transporter isoform 1 (GLUT1) (P < 0.01). Adding a GLUT1 inhibitor reduced the glucose uptake capacity of oocytes. Furthermore, the inclusion of vitamin C into thawing and culture solutions restored abnormal glucose transportation and metabolism and improved the survival, two-cell embryo, and blastocyst rates of the vitrified groups via parthenogenesis (P < 0.05). Overall, this method may improve the quality and efficiency of oocyte vitrification.


Identifying injection drug use and estimating population size of people who inject drugs using healthcare administrative datasets.
Large linked healthcare administrative datasets could be used to monitor programs providing prevention and treatment services to people who inject drugs (PWID). However, diagnostic codes in administrative datasets do not differentiate non-injection from injection drug use (IDU). We validated algorithms based on diagnostic codes and prescription records representing IDU in administrative datasets against interview-based IDU data. The British Columbia Hepatitis Testers Cohort (BC-HTC) includes ∼1.7 million individuals tested for HCV/HIV or reported HBV/HCV/HIV/tuberculosis cases in BC from 1990 to 2015, linked to administrative datasets including physician visit, hospitalization and prescription drug records. IDU, assessed through interviews as part of enhanced surveillance at the time of HIV or HCV/HBV diagnosis from a subset of cases included in the BC-HTC (n = 6559), was used as the gold standard. ICD-9/ICD-10 codes for IDU and injecting-related infections (IRI) were grouped with records of opioid substitution therapy (OST) into multiple IDU algorithms in administrative datasets. We assessed the performance of IDU algorithms through calculation of sensitivity, specificity, positive predictive, and negative predictive values. Sensitivity was highest (90-94%), and specificity was lowest (42-73%) for algorithms based either on IDU or IRI and drug misuse codes. Algorithms requiring both drug misuse and IRI had lower sensitivity (57-60%) and higher specificity (90-92%). An optimal sensitivity and specificity combination was found with two medical visits or a single hospitalization for injectable drugs with (83%/82%) and without OST (78%/83%), respectively. Based on algorithms that included two medical visits, a single hospitalization or OST records, there were 41,358 (1.2% of 11-65 years individuals in BC) recent PWID in BC based on health encounters during 3- year period (2013-2015). Algorithms for identifying PWID using diagnostic codes in linked administrative data could be used for tracking the progress of programing aimed at PWID. With population-based datasets, this tool can be used to inform much needed estimates of PWID population size.


Bacterial biosorbent for removing and recovering copper from electroplating effluents.
Investigations were carried out to study the removal and recovery of Cu(II) ions from wastewater by Micrococcus sp. The Langmuir isotherm model described very well the equilibrium behavior of copper biosorption, with maximum biosorption capacity (q(max)) reaching 52.1 mg Cu2+/g dry cell at pH 6. Biomass prewashed with sulfuric acid (0.05 mol 1(-1)) and sodium sulfate (1 mol l(-1)) solutions were shown to increase the copper removal capabilities up to 27% and 16%, respectively. Copper uptake by cells was negligible at pH 2.0 and then increased quickly with increasing pH until 6.0. Cells of Micrococcus sp. were immobilized in 2% calcium alginate and 10% polyacrylamide gel beads. A counter-current process comprising a series of immobilized cell reactors was developed for removing and recovering copper from electroplating effluents. This process was capable of producing an effluent at low copper concentration, with only a minimum amount of desorbing agent used. The technique of scanning electron microscopy coupled with X-ray dispersion analysis shows that Cu2+ exchanged with K+ and Ca2+ on the cell wall of Micrococcus sp., thereby suggesting ion exchange as one of the dominant mechanisms of metal biosorption for this bacterial strain.


Time-domain optical data storage by use of Raman coherent population trapping.
We experimentally demonstrate time-domain storage and retrieval of amplitude- and phase-encoded optical data, using Raman coherent population trapping, despite the loss of information about absolute optical phases that occurs as a result of the dissipative nature of the process. In this Raman optical storage process homogeneous decay of the optical coherence does not prevent interference between time-separated fields, thus relaxing the requirement for long-lived optical coherences.


Bronchiolitis in US emergency departments 1992 to 2000: epidemiology and practice variation.
To describe the epidemiology of US emergency department (ED) visits for bronchiolitis, including the characteristics of children presenting to the ED and the variability in bronchiolitis care in the ED. Data were obtained from the 1992 to 2000 National Hospital Ambulatory Medical Care Survey. Cases had International Classification of Diseases, Ninth Revision, Clinical Modification code 466 and were younger than 2 years. National estimates were obtained using assigned patient visit weights; 95% confidence intervals were calculated using the relative standard error of the estimate; analysis used chi2 and logistic regression. From 1992 to 2000, bronchiolitis accounted for approximately 1,868,000 ED visits for children younger than 2 years. Among this same age group, the overall rate was 26 (95% confidence interval 22-31) per 1000 US population and 31 (95% confidence interval 26-36) per 1000 ED visits. These rates were stable over the 9-year period. Comparing children with bronchiolitis to those presenting with other problems, children with bronchiolitis were more likely boys (61% vs. 53%; P = 0.01) and Hispanic (27% vs. 20%; P = 0.008). Therapeutic interventions varied and 19% were admitted to the hospital. The multivariate predictor for receiving systemic steroids was urgent/emergent status at triage (odds ratio 4.0, 1.9-8.4). Multivariate predictors for admission were Hispanic ethnicity (odds ratio 2.3, 1.1-5.0) and urgent/emergent status at triage (odds ratio 3.7, 2.0-6.9). ED visit rates for bronchiolitis among children younger than 2 years were stable between 1992 and 2000. The observed ED practice variation demonstrates that children are receiving medications for which there is little supporting evidence. Boys and Hispanics are at-risk groups for presentation to the ED, and Hispanics are more likely to be hospitalized.


[Hyperbaric treatment in the post-bronchitic emphysema].
Following some introductory mention of the physiology of hyperbaric oxygen therapy and some notes on the physiology of postbronchitic emphysema and its cardiac, hepatic, renal and neurological sequelae, a personal method of hyperbaric treatment is described. The results in the first 50 emphysematous patients submitted to this therapy are reported along with those of the examinations carried out to evaluate respiratory function, and changes in haematosis, and cardiac, hepatic, neurological and renal function. It is concluded that hyperbaric treatment of postbronchitic emphysema should be considered of choice for quick, effective resolution of alterations in haematosis and the organic sequelae deriving from respiratory insufficiency. In association with other therapy (antibiotics, anti-inflammatory and balsamic drugs) it is also capable of stopping or usefully delaying the disease's development.


Qualitative assessment of telemedicine network and computer-based telecolposcopy.
To qualitatively assess telemedicine network and computer-based telecolposcopy. A site expert and local colposcopist examined women presenting consecutively for colposcopic examination at 1 of 2 rural clinics. Images from the exam were transmitted to distant experts at a telemedicine center by an existing telemedicine network and computer-based telecolposcopy system. Colposcopists rated both systems with respect to complications, ease and confidence of procedure, and system resolution and visualization. Rates of technically defective examinations were similar for network (25.1%) and computer-based (22.5%) telecolposcopy (p =.46). The ease of telecolposcopic examinations and colposcopists' confidence in and comfort with telecolposcopy were practically equal for both systems. Mean perceived quality of care was greater for network (3.92) compared with computer-based (3.82) telecolposcopy (Wilcoxon signed rank test, p =.03; Likert scale, 1 = minimal, 5 = maximum). Image resolution was rated better for computer-based (3.36) compared with network (3.07, p <.0001) telecolposcopy. However, visualization was better for the latter system in comparison (3.43 vs 3.07, p <.0001). The quality of telecolposcopy was considered above average based on all parameters evaluated for each type of telecolposcopy. Although a few significant differences were detected, colposcopists perceived network and computer-based telecolposcopy to be very similar by subjective assessment.


Polyclonal bovine sera but not virus-neutralizing monoclonal antibodies block bovine leukemia virus (BLV) gp51 binding to recombinant BLV receptor BLVRcp1.
Bovine leukemia virus (BLV), a transactivating lymphotropic retrovirus, is the etiologic agent of enzootic lymphosarcoma or leukemia in cattle. Sera from BLV-infected animals possess high BLV-neutralizing antibody titres. The availability of the recombinant BLV receptor candidate, BLVRcp1, allowed us to determine a mechanism of virus neutralization by polyclonal sera and monoclonal antibodies (MAbs). Bovine sera from animals naturally infected with BLV blocked gp51 binding to recombinant BLVRcp1. In contrast, virus-neutralizing MAbs specific for gp51 F, G, and H epitopes did not prevent gp51-receptor attachment. Furthermore, gp51 neutralization epitopes F, G, and H were accessible to antibodies following gp51 attachment to BLVRcp1. This finding implies that virus neutralization by MAbs to defined BLV gp51 epitopes can occur subsequent to virus engagement of the receptor while polyclonal sera can specifically block virus attachment to the receptor. In conclusion, these data suggest that cell infection by BLV is a multistep process requiring receptor binding (inhibited by polyclonal sera) followed by a second, postbinding event(s) at the cell membrane (inhibited by anti-gp51 MAbs).


Anterior cingulate cortex γ-aminobutyric acid deficits in youth with depression.
Abnormally low γ-aminobutyric acid (GABA) levels have been consistently reported in adults with major depressive disorder (MDD). Our group extended this finding to adolescents, and documented that GABA deficits were associated with anhedonia. Here we aimed to confirm our prior finding of decreased brain GABA in youth with depression and explore its associations with clinical variables. Forty-four psychotropic medication-free youth with MDD and 36 healthy control (HC) participants (12-21 years) were studied. Participants represent a combined sample of 39 newly recruited youth (MDD=24) and 41 youth from our previously reported study (MDD=20). GABA levels and the combined resonances of glutamate and glutamine (Glx) were measured in vivo in the anterior cingulate cortex using proton magnetic resonance spectroscopy. Youth with depression exhibited significantly lower GABA levels than HC in both the newly reported (P=0.003) and the combined (P=0.003) samples. When depressed participants were classified based on the presence of anhedonia, only the anhedonic MDD subgroup showed reduced GABA levels compared to HC (P=0.002). While there were no associations between any clinical measures and GABA or Glx levels in the new sample, GABA was negatively correlated with only anhedonia severity in the combined MDD group. Furthermore, in the combined sample, hierarchical regression models showed that anhedonia, but not depression severity, anxiety or suicidality, contributed significant variance in GABA levels. This report solidifies the evidence for a GABA deficit early in the course of MDD, which correlates specifically with anhedonia in the disorder.


Search and foraging behaviors from movement data: A comparison of methods.
Search behavior is often used as a proxy for foraging effort within studies of animal movement, despite it being only one part of the foraging process, which also includes prey capture. While methods for validating prey capture exist, many studies rely solely on behavioral annotation of animal movement data to identify search and infer prey capture attempts. However, the degree to which search correlates with prey capture is largely untested. This study applied seven behavioral annotation methods to identify search behavior from GPS tracks of northern gannets (Morus bassanus), and compared outputs to the occurrence of dives recorded by simultaneously deployed time-depth recorders. We tested how behavioral annotation methods vary in their ability to identify search behavior leading to dive events. There was considerable variation in the number of dives occurring within search areas across methods. Hidden Markov models proved to be the most successful, with 81% of all dives occurring within areas identified as search. k-Means clustering and first passage time had the highest rates of dives occurring outside identified search behavior. First passage time and hidden Markov models had the lowest rates of false positives, identifying fewer search areas with no dives. All behavioral annotation methods had advantages and drawbacks in terms of the complexity of analysis and ability to reflect prey capture events while minimizing the number of false positives and false negatives. We used these results, with consideration of analytical difficulty, to provide advice on the most appropriate methods for use where prey capture behavior is not available. This study highlights a need to critically assess and carefully choose a behavioral annotation method suitable for the research question being addressed, or resulting species management frameworks established.


Effect of lifetime lactation on breast cancer risk: a Korean women's cohort study.
The objective of our study was to examine the effect of lifetime lactation on breast cancer risk among premenopausal women. The data were from a prospective cohort study with a follow-up period of 6 years in Korea (1995-2000). The cohort was composed of 110,604 premenopausal parous Korean women, aged 20 years and older, who received health insurance from the Korea Medical Insurance Corporation and who had medical evaluations in 1992 and 1994. Multivariate Cox proportional hazard models were tested, controlling for age, age at menarche, number of children, age at first pregnancy, oral contraceptive use, smoking, exercise and obesity. At baseline, 57,440 (51.9%) reported breastfeeding and 4,584 (4.1%) reported breastfeeding more than 24 months. From 1995-2000, 360 incident cases of breast cancer (61.8/100,000 person-years) occurred. Compared to parous women who had no history of lactation, a period of lactation of 13-24 months decreased the risk of breast cancer (RR, 0.7; 95% CI, 0.5-1.1), and this risk was decreased even further for those who breastfed for more than 24 months (RR, 0.6; 95% CI, 0.3-1.0). There was a clear trend of decreasing breast cancer risk with the duration of lactation (p for trend <0.001). In conclusion, our study of a large Korean cohort provides additional empirical evidence to current theoretical conjecture that lactation decreases the risk of breast cancer among premenopausal women.


Collision-induced dissociative chemical cross-linking reagents and methodology: Applications to protein structural characterization using tandem mass spectrometry analysis.
Chemical cross-linking combined with mass spectrometry is a viable approach to study the low-resolution structure of protein and protein complexes. However, unambiguous identification of the residues involved in a cross-link remains analytically challenging. To enable a more effective analysis across various MS platforms, we have developed a novel set of collision-induced dissociative cross-linking reagents and methodology for chemical cross-linking experiments using tandem mass spectrometry (CID-CXL-MS/MS). These reagents incorporate a single gas-phase cleavable bond within their linker region that can be selectively fragmented within the in-source region of the mass spectrometer, enabling independent MS/MS analysis for each peptide. Initial design concepts were characterized using a synthesized cross-linked peptide complex. Following verification and subsequent optimization of cross-linked peptide complex dissociation, our reagents were applied to homodimeric glutathione S-transferase and monomeric bovine serum albumin. Cross-linked residues identified by our CID-CXL-MS/MS method were in agreement with published crystal structures and previous cross-linking studies using conventional approaches. Common LC/MS/MS acquisition approaches such as data-dependent acquisition experiments using ion trap mass spectrometers and product ion spectral analysis using SEQUEST were shown to be compatible with our CID-CXL-MS/MS reagents, obviating the requirement for high resolution and high mass accuracy measurements to identify both intra- and interpeptide cross-links.


The cold face test (diving reflex) in clinical autonomic assessment: methodological considerations and repeatability of responses.
1. Cold stimulus applied to the face causes bradycardia and peripheral vasoconstriction (i.e. the diving reflex), and has been suggested as a test of the autonomic pathways involved. The purpose of this study was to define standard procedures for conducting the test and analysing the responses to the cold face test, to evaluate variability in responses between subjects and within subjects when the same test is repeated, and to examine its usefulness in clinical autonomic assessment. 2. Sixteen (nine female, seven male) healthy adult (21-35 years old) subjects were used. Cold stimulus was applied with gel-filled compresses. Forehead temperature under the compress as an indication of stimulus magnitude, heart rate, blood flow in the finger, toe and calf by venous occlusion plethysmography, and systolic and diastolic blood pressure were monitored. Three protocols were carried out in which the temperature (0, 5, 10, 15 degrees C), placement (whole face, unilateral, forehead) and duration (20, 40, 60, 120 s) of the cold compress application were varied. 3. The data indicate that 0 degrees C compresses applied bilaterally for 40 s produced the maximum bradycardia and peripheral vasoconstriction. No subject found this test to be obnoxious, but a 120 s application was objectionable to some subjects. This cold face test resulted in 22%, 72%, 59% and 44% reductions in heart rate and blood flow to the finger, toe and calf, respectively. There was significant between-subject variability, but good consistency in responses to tests repeated in the same subject on different days, at different times of day and in different seasons.(ABSTRACT TRUNCATED AT 250 WORDS)


Electrocatalytic hydrogenation of 5-hydroxymethylfurfural in the absence and presence of glucose.
Electrocatalytic hydrogenation of 5-hydroxymethylfurfural (HMF) to 2,5-dihydroxymethylfuran (DHMF) or other species, such as 2,5-dimethylfuran, on solid metal electrodes in neutral media is addressed, both in the absence and in the presence of glucose. The reaction is studied by combining voltammetry with on-line product analysis by using HPLC, which provides both qualitative and quantitative information about the reaction products as a function of electrode potential. Three groups of catalysts show different selectivity towards: (1) DHMF (Fe, Ni, Ag, Zn, Cd, and In), (2) DHMF and other products (Pd, Al, Bi, and Pb), depending on the applied potential, and (3) other products (Co, Au, Cu, Sn, and Sb) through HMF hydrogenolysis. The rate of electrocatalytic HMF hydrogenation is not strongly catalyst-dependent because all catalysts show similar onset potentials (-0.5 ± 0.2 V) in the presence of HMF. However, the intrinsic properties of the catalysts determine the reaction pathway towards DHMF or other products. Ag showed the highest activity towards DHMF formation (up to 13.1 mM cm(-2) with high selectivity> 85%). HMF hydrogenation is faster than glucose hydrogenation on all metals. For transition metals, the presence of glucose enhances the formation of DHMF and suppresses the hydrogenolysis of HMF. On poor metals such as Zn, Cd, and In, glucose enhances DHMF formation; however, its contribution in the presence of Bi, Pb, Sn, and Sb is limited. Remarkably, in the presence of HMF, glucose hydrogenation itself is largely suppressed or even absent. The first electron-transfer step during HMF reduction is not metal-dependent, suggesting a non-catalytic reaction with proton transfer directly from water in the electrolyte.


Mass movements and conservation management in Malta.
Mass movements at an environmentally sensitive but very popular leisure site in Malta were investigated in order to establish whether they were naturally occurring or whether they might in some way have resulted from the chronic long-term degradation of the site. Field surveys of the slopes were undertaken and physical and geotechnical properties of the Maltese Blue Clay Formation, which forms the slopes, were determined from laboratory analysis of samples. Slope stability was analysed using the infinite slope model; analysis of two 1996 mudflows indicates that these mass movements are natural processes. A landslide hazard analysis based on this finding suggested that whilst future mudflows constitute a small hazard, the risk of harm arising from them is even smaller. The implications of this for conservation management of the site are important, given the objective of restoring and then maintaining a natural ecological environment at the site. The mudflows are integral components of this natural environment, shaping the landscape and the ecological communities. The provision of information to visitors constitutes a valuable education and management tool that should further reduce the risk of harm and promote responsible recreational use of the site. However, it is essential that managers understand the nature of all relevant components of an environmentally sensitive site, in order that appropriate management strategies are devised. In the case discussed, these might include avoiding unnecessary future intervention on the clay slopes.


The role of endocrine disrupters in water recycling: risk or mania?
The widespread occurrence of endocrine disrupting chemicals (EDCs), such as steroid hormones, in secondary wastewater effluents has become a major concern in the water recycling practice. This paper investigates the risk of steroid hormone breakthrough during nanofiltration membrane filtration in water recycling applications. The results indicate a dynamic equilibrium between adsorption and desorption of steroid hormone with regard to the membrane. This equilibrium can be pH dependent and there is a possibility for release of steroid hormones at high pH during membrane cleaning procedures or erratic pH variations. Increase in water recovery can severely increase the hormone breakthrough concentration. The results also indicate a possibility of accumulation of steroid hormones in the NF membrane, followed by subsequent release.


Gene transcription profiling in wild and laboratory-exposed eels: Effect of captivity and in situ chronic exposure to pollution.
Aquatic ecosystems are subjected to a variety of man-induced stressors but also vary spatially and temporally due to variation in natural factors. In such complex environments, it remains difficult to detect, dissociate and evaluate the effects of contaminants in wild organisms. In this context, the aim of this study was to test whether the hepatic transcriptome profile of fish may be used to detect in situ exposure to a particular contaminant. Transcriptomic profiles from laboratory-exposed and wild eels sampled along a contamination gradient were compared. During laboratory experiments, fish were exposed during 45days to different pollutants (Hg, PCBs, OCPs or Cd) or natural factors (temperature, salinity or low food supply) at levels close to those found in the sampling sites. A strong difference was observed between the transcriptomic profiles obtained from wild and laboratory-exposed animals (whatever the sites or experimental conditions), suggesting a general stress induced by captivity in the laboratory. Among the biological functions that were up-regulated in laboratory eels in comparison to wild eels, histone modification was the most represented. This finding suggests that laboratory conditions could affect the epigenome of fish and thus modulate the transcriptional responses developed by fish in response to pollutant exposure. Among experimental conditions, only the transcription profiles of laboratory animals exposed to cold temperature were correlated with those obtained from wild fish, and more significantly with fish from contaminated sites. Common regulated genes were mainly involved in cell differentiation and liver development, suggesting that stem/progenitor liver cells could be involved in the adaptive response developed by fish chronically exposed to pollutant mixtures.


Using Mobile Health and the Impact on Health-Related Quality of Life: Perceptions of Older Adults with Cognitive Impairment.
Digital health technologies such as mobile health (mHealth) are considered to have the potential to support the needs of older adults with cognitive impairment. However, the evidence for improving health with the use of mHealth applications is of limited quality. Few studies have reported on the consequences of technology use concerning the older adults' quality of life. The purpose of this study was to describe perceptions of mHealth and its impact on health-related quality of life (HRQoL) among older adults with cognitive impairment. The study was conducted using a qualitative design with a phenomenographic approach. A total of 18 older participants with cognitive impairment were interviewed. The interviews were analyzed in order to apply phenomenography in a home-care context. The results showed variations in the older adults' perceptions that were comprised within three categories of description; Require technology literacy, Maintain social interaction, and Facilitate independent living. In conclusion, the development and design of mHealth technologies need to be tailored based on older adults´ needs in order to be understood and perceived as useful in a home-care context. For mHealth to support HRQoL, healthcare should be provided in a way that encourages various forms of communication and interaction.


A shared Y-chromosomal heritage between Muslims and Hindus in India.
Arab forces conquered the Indus Delta region in 711 AD: and, although a Muslim state was established there, their influence was barely felt in the rest of South Asia at that time. By the end of the tenth century, Central Asian Muslims moved into India from the northwest and expanded throughout the subcontinent. Muslim communities are now the largest minority religion in India, comprising more than 138 million people in a predominantly Hindu population of over one billion. It is unclear whether the Muslim expansion in India was a purely cultural phenomenon or had a genetic impact on the local population. To address this question from a male perspective, we typed eight microsatellite loci and 16 binary markers from the Y chromosome in 246 Muslims from Andhra Pradesh, and compared them to published data on 4,204 males from East Asia, Central Asia, other parts of India, Sri Lanka, Pakistan, Iran, the Middle East, Turkey, Egypt and Morocco. We find that the Muslim populations in general are genetically closer to their non-Muslim geographical neighbors than to other Muslims in India, and that there is a highly significant correlation between genetics and geography (but not religion). Our findings indicate that, despite the documented practice of marriage between Muslim men and Hindu women, Islamization in India did not involve large-scale replacement of Hindu Y chromosomes. The Muslim expansion in India was predominantly a cultural change and was not accompanied by significant gene flow, as seen in other places, such as China and Central Asia.


Can Consideration of the Microbiome Improve Antimicrobial Utilization and Treatment Outcomes in the Oncology Patient?
The need to provide effective and timely antimicrobial treatment to cancer patients with infections is well recognized but tempered by preliminary, but accumulating, evidence that antibiotic-induced microbiome dysbiosis affects cancer therapy response, noninfectious toxicities, and infectious complications. Given only a minority of empirically treated cancer patients are proven to have a true bacterial infection, it is important to consider the potential negative consequences of extensive broad-spectrum antimicrobial use on the commensal microbiota. Herein, we review the literature substantiating the dilemma oncologists face when treating suspected or documented infections with respect to the interaction between the host microbiome, antibiotics, and cancer-related clinical outcomes. We propose microbiome-based explorations that could assist oncologists in optimizing treatment strategies for cancer-related infections as well as the cancer itself. In addition, we discuss knowledge gaps and challenges in this nascent field that must be addressed to deliver medically relevant, translational applications. We anticipate that the emerging knowledge regarding the role of the microbiota in the health of cancer patients may cause a reappraisal of the manner in which antibiotics are used in the oncologic setting and how microorganisms are viewed by oncologists. Clin Cancer Res; 23(13); 3263-8. ©2017 AACRSee related commentary by Fessler and Gajewski, p. 3229.


Systematic review with meta-analysis: breastfeeding and the risk of Crohn's disease and ulcerative colitis.
Breastfeeding is a modifiable factor that may influence development of inflammatory bowel diseases. However, literature on this has been inconsistent and not accounted for heterogeneity in populations and exposure. To conduct a meta-analysis to examine the association between breastfeeding in infancy and risk of Crohn's disease (CD) and ulcerative colitis (UC). A systematic search of Medline/PubMed and Embase was performed for full text, English-language literature through November 2016. Studies were included if they described breastfeeding in infancy in patients with CD or UC, and healthy controls. Data were pooled using a random effects model for analysis. A total of 35 studies were included in the final analysis, comprising 7536 individuals with CD, 7353 with UC and 330 222 controls. Ever being breastfed was associated with a lower risk of CD (OR 0.71, 95% CI 0.59-0.85) and UC (OR 0.78, 95% CI 0.67-0.91). While this inverse association was observed in all ethnicity groups, the magnitude of protection was significantly greater among Asians (OR 0.31, 95% CI 0.20-0.48) compared to Caucasians (OR 0.78, 95% CI 0.66-0.93; P = .0001) in CD. Breastfeeding duration showed a dose-dependent association, with strongest decrease in risk when breastfed for at least 12 months for CD (OR 0.20, 95% CI 0.08-0.50) and UC (OR 0.21, 95% CI 0.10-0.43) as compared to 3 or 6 months. Breastfeeding in infancy protects against the development of CD and ulcerative colitis.


Dendritic cell function can be modulated through cooperative actions of TLR ligands and invariant NKT cells.
The quality of signals received by dendritic cells (DC) in response to pathogens influences the nature of the adaptive response. We show that pathogen-derived signals to DC mediated via TLRs can be modulated by activated invariant NKT (iNKT) cells. DC maturation induced in vivo with any one of a variety of TLR ligands was greatly improved through simultaneous administration of the iNKT cell ligand alpha-galactosylceramide. DC isolated from animals treated simultaneously with TLR and iNKT cell ligands were potent stimulators of naive T cells in vitro compared with DC from animals treated with the ligands individually. Injection of protein Ags with both stimuli resulted in significantly improved T cell and Ab responses to coadministered protein Ags over TLR stimulation alone. Ag-specific CD8(+) T cell responses induced in the presence of the TLR4 ligand monophosphoryl lipid A and alpha-galactosylceramide showed faster proliferation kinetics, and increased effector function, than those induced with either ligand alone. Human DC exposed to TLR ligands and activated iNKT cells in vitro had enhanced expression of maturation markers, suggesting that a cooperative action of TLR ligands and iNKT cells on DC function is a generalizable phenomenon across species. These studies highlight the potential for manipulating the interactions between TLR ligands and iNKT cell activation in the design of effective vaccine adjuvants.


Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial.
Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m(2), l-folinic acid 175 mg, fluorouracil 400 mg/m(2) bolus, then 2400 mg/m(2) by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3-4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate. Cancer Research UK.


Begomoviral βC1 orchestrates organellar genomic instability to augment viral infection.
Chloroplast is the site for transforming light energy to chemical energy. It also acts as a production unit for a variety of defense-related molecules. These defense moieties are necessary to mount a successful counter defense against pathogens, including viruses. Previous studies indicated disruption of chloroplast homeostasis as a basic strategy of Begomovirus for its successful infection leading to the production of vein-clearing, mosaic, and chlorotic symptoms in infected plants. Although begomoviral pathogenicity determinant protein Beta C1 (βC1) was implicated for pathogenicity, the underlying mechanism was unclear. Here we show that, begomoviral βC1 directly interferes with the host plastid homeostasis. βC1 induced DPD1, an organelle-specific nuclease, implicated in nutrient salvage and senescence, as well as modulated the function of a major plastid genome maintainer protein RecA1, to subvert plastid genome. We show that βC1 was able to physically interact with bacterial RecA and its plant homolog RecA1, resulting in its altered activity. We observed that knocking-down DPD1 during virus infection significantly reduced virus-induced necrosis. These results indicate the presence of a strategy in which a viral protein alters host defense by targeting modulators of chloroplast DNA. We predict that the mechanism identified here might have similarities in other plant-pathogen interactions.


Glycosides of hydroxyproline: some recent, unusual discoveries.
Glycosides of hydroxyproline (Hyp) in the plant cell wall matrix were discovered by Lamport and co-workers in the 1960s. Since then, much has been learned about these Hyp-rich glycoproteins. The intent of this review was to compare and contrast some less common structural motifs, in nontraditional roles, to uncover themes. Arabinosylation of short-peptide plant hormones is essential for growth, cell differentiation and defense. In a very recent development, prolyl hydroxylase and arabinosyltransferase activity has been shown to have a direct impact on the growth of root hairs in Arabidopsis thaliana. Pollen allergens of mugwort and ragweed contain proline-rich domains that are hydroxylated and glycosylated and play a structural role. In the case of mugwort, this domain also presents a significant immunogenic epitope. Major crops, including tobacco and maize, have been used to express and produce recombinant proteins of mammalian origin. The risks of plant-imposed glycosylation are discussed. In unicellular eukaryotes, Skp1 (a subunit of the E3(SCF) ubiquitin ligase complex) harbors a key Hyp residue that is modified by a linear pentasaccharide. These modifications may be involved in sensing oxygen levels. A few studies have probed the impact of glycosylation on the structure of Hyp-containing peptides. These have necessarily looked at small, synthetic molecules, since natural peptides and proteins are often isolable in only minuscule amounts and/or are heterogeneous in nature. The characterization of native structural motifs, together with the determination of glycopeptide conformation and properties, holds the key to rationalizing nature's architectural design.


Alzheimer's disease-do tauists and baptists finally shake hands?
The amyloid cascade hypothesis has been the predominant model of molecular pathogenesis in Alzheimer's disease. The finding of tau mutations in other dementias has added weight to the hypothesis as it suggests that tau-pathology is a downstream but essential part of the dementing process. However, some observations remain difficult to reconcile with the hypothesis. In transgenic mice, for example, amyloid generation does not induce the predicted cascade and in man, plaques and tangles are separated temporally and spatially. One alternative possibility is that some common factor, loss of wnt signalling for example, might induce both plaques and tangles.


Transmembrane signalling by a hybrid protein: communication from the domain of chemoreceptor Trg that recognizes sugar-binding proteins to the kinase/phosphatase domain of osmosensor EnvZ.
Chemoreceptor Trg and osmosensor EnvZ of Escherichia coli share a common transmembrane organization but have essentially unrelated primary structures. We created a hybrid gene coding for a protein in which Trg contributed its periplasmic and transmembrane domains as well as a short cytoplasmic segment and EnvZ contributed its cytoplasmic kinase/phosphatase domain. Trz1 transduced recognition of sugar-occupied, ribose-binding protein by its periplasmic domain into activation of its cytoplasmic kinase/phosphatase domain as assessed in vivo by using an ompC-lacZ fusion gene. Functional coupling of sugar-binding protein recognition to kinase/phosphatase activity indicates shared features of intramolecular signalling in the two parent proteins. In combination with previous documentation of transduction of aspartate recognition by an analogous fusion protein created from chemoreceptor Tar and EnvZ, the data indicate a common mechanism of transmembrane signal transduction by chemoreceptors and EnvZ. Signalling through the fusion proteins implies functional interaction between heterologous domains, but the minimal sequence identity among relevant segments of EnvZ, Tar, and Trg indicates that the link does not require extensive, specific interactions among side chains. The few positions of identity in those three sequences cluster in transmembrane segment 1 and the short chemoreceptor sequence in the cytoplasmic part of the hybrid proteins. These regions may be particularly important in physical and functional coupling. The specific cellular conditions necessary to observe ligand-dependent activation of Trz1 can be understood in the context of the importance of phosphatase control in EnvZ signalling and limitations on maximal receptor occupancy in binding protein-mediated recognition.


Group size, vocal grooming and the origins of language.
I argue that speech and language evolved through a series of stages individually designed to break through successive glass ceilings on group size. Language was simply the last of these (and hence evolved late in hominin evolution), but its precursors (laughter and singing) each played a crucial role in preparing the way for speech production.


Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic?
Botulinum neurotoxins (BoNTs) are the most lethal toxins among all bacterial, animal, plant and chemical poisonous compounds. Although a great effort has been made to understand their mode of action, some questions are still open. Why, and for what benefit, have environmental bacteria that accidentally interact with their host engineered so diverse and so specific toxins targeting one of the most specialized physiological processes, the neuroexocytosis of higher organisms? The extreme potency of BoNT does not result from only one hyperactive step, but in contrast to other potent lethal toxins, from multi-step activity. The cumulative effects of the different steps, each having a limited effect, make BoNTs the most potent lethal toxins. This is a unique mode of evolution of a toxic compound, the high potency of which results from multiple steps driven by unknown selection pressure, targeting one of the most critical physiological process of higher organisms.


Burnout and medical errors among American surgeons.
To evaluate the relationship between burnout and perceived major medical errors among American surgeons. Despite efforts to improve patient safety, medical errors by physicians remain a common cause of morbidity and mortality. Members of the American College of Surgeons were sent an anonymous, cross-sectional survey in June 2008. The survey included self-assessment of major medical errors, a validated depression screening tool, and standardized assessments of burnout and quality of life (QOL). Of 7905 participating surgeons, 700 (8.9%) reported concern they had made a major medical error in the last 3 months. Over 70% of surgeons attributed the error to individual rather than system level factors. Reporting an error during the last 3 months had a large, statistically significant adverse relationship with mental QOL, all 3 domains of burnout (emotional exhaustion, depersonalization, and personal accomplishment) and symptoms of depression. Each one point increase in depersonalization (scale range, 0-33) was associated with an 11% increase in the likelihood of reporting an error while each one point increase in emotional exhaustion (scale range, 0-54) was associated with a 5% increase. Burnout and depression remained independent predictors of reporting a recent major medical error on multivariate analysis that controlled for other personal and professional factors. The frequency of overnight call, practice setting, method of compensation, and number of hours worked were not associated with errors on multivariate analysis. Major medical errors reported by surgeons are strongly related to a surgeon's degree of burnout and their mental QOL. Studies are needed to determine how to reduce surgeon distress and how to support surgeons when medical errors occur.


Antibodies from the Lyb-5- B cell subset predominate in the secondary IgG response to phosphocholine.
The X-linked CBA/N immune defect was used to investigate the role of the Lyb-5- B cell subset in phosphocholine- (PC) specific memory responses. Immune-defective mice, which express only the Lyb-5- B cell subset, are unable to mount a primary or secondary T15+, IgM response to PC but can produce a substantial secondary IgG response. The majority of these IgG anti-PC antibodies are T15- and can be inhibited by phenylphosphocholine, but not PC. Normal mice, which possess Lyb-5+ and Lyb-5- B cells, produce both IgM and IgG anti-PC antibodies; however, there is a striking difference in the idiotype and fine specificity of antibodies expressed by these two classes. The IgM anti-PC antibodies are T15+ and PC-inhibitable, whereas the IgG antibodies are identical to those observed in the immune-defective mice, i.e., T15- and PC-noninhibitable. This unexpected difference in both idiotype and fine specificity between IgM and IgG anti-PC antibodies results from activation of different B cell subsets. Lyb-5+ B cells produce T15+, PC-inhibitable IgM antibodies, whereas T15-, PC-noninhibitable IgG antibodies are produced by Lyb-5- B cells. These data indicate that a majority of the thymus-dependent, anti-PC IgG memory responses arises from Lyb-5- B cells.


Iron storage disease in captive Egyptian fruit bats (Rousettus aegyptiacus): relationship of blood iron parameters to hepatic iron concentrations and hepatic histopathology.
This study evaluated the relationship between blood iron parameters and hepatic iron concentrations, and correlation of histologic findings with hepatic iron concentrations in a captive population of Egyptian fruit bats (Rousettus aegyptiacus) and island flying foxes (Pteropus hypomelanus). Blood samples were collected for complete blood counts, plasma biochemical profiles, serum iron concentrations, total iron-binding capacity, whole-blood lead concentrations, and plasma ferritin assays. Liver samples obtained by laparotomy were divided, with one half processed for histologic examination and the other half frozen and submitted for tissue mineral analysis. The histologic sections were scored by two blinded observers for iron deposition, necrosis, and fibrosis. The Egyptian fruit bats had significantly higher liver iron (mean = 3,669 +/- 1,823 ppm) and lead (mean = 8.9 +/- 5.8 ppm) concentrations than the island flying foxes (mean [Fe] = 174 +/- 173 ppm, mean [Pb] = 1.9 +/- 0.5 ppm). Hepatic iron concentrations significantly correlated with tissue lead concentrations, histologic grading for iron and necrosis, serum iron, transferrin saturation, and plasma ferritin (P < 0.001). Blood lead concentrations negatively correlated with tissue lead concentrations (P < 0.001). When the product of transferrin saturation and serum iron was greater than 51, an individual animal had a high probability of having iron overload. When the product of these two variables was greater than 90, there was a high probability that the animal had hemochromatosis. On the basis of this study, it appears that evaluation of serum iron, transferrin saturation, and plasma ferritin are useful and noninvasive methods for diagnosis of hemochromatosis in Egyptian fruit bats.


Modeling Left Ventricular Blood Flow Using Smoothed Particle Hydrodynamics.
This study aims to investigate the capability of smoothed particle hydrodynamics (SPH), a fully Lagrangian mesh-free method, to simulate the bulk blood flow dynamics in two realistic left ventricular (LV) models. Three dimensional geometries and motion of the LV, proximal left atrium and aortic root are extracted from cardiac magnetic resonance imaging and multi-slice computed tomography imaging data. SPH simulation results are analyzed and compared with those obtained using a traditional finite volume-based numerical method, and to in vivo phase contrast magnetic resonance imaging and echocardiography data, in terms of the large-scale blood flow phenomena usually clinically measured. A quantitative comparison of the velocity fields and global flow parameters between the in silico models and the in vivo data shows a reasonable agreement, given the inherent uncertainties and limitations in the modeling and imaging techniques. The results indicate the capability of SPH as a promising tool for predicting clinically relevant large-scale LV flow information.


The Yucatan Minipig Temporomandibular Joint Disc Structure-Function Relationships Support Its Suitability for Human Comparative Studies.
Frequent involvement of the disc in temporomandibular joint (TMJ) disorders warrants attempts to tissue engineer TMJ disc replacements. Physiologically, a great degree of similarity is seen between humans and farm pigs (FPs), but the pig's rapid growth confers a significant challenge for in vivo experiments. Minipigs have a slower growth rate and are smaller than FPs, but minipig TMJ discs have yet to be fully characterized. The objective of this study was to determine the suitability of the minipig for TMJ studies by extensive structural and functional characterization. The properties of minipig TMJ discs closely reproduced previously reported morphological, biochemical, and biomechanical values of human and FP discs. The width/length dimension ratio of the minipig TMJ disc was 1.95 (1.69 for human and 1.94 for FP). The biochemical evaluation revealed, on average per wet weight, 24.3% collagen (22.8% for human and 24.9% for FP); 0.8% glycosaminoglycan (GAG; 0.5% for human and 0.4% for FP); and 0.03% DNA (0.008% for human and 0.02% for FP). Biomechanical testing revealed, on average, compressive relaxation modulus of 50 kPa (37 kPa for human and 32 kPa for FP), compressive instantaneous modulus of 1121 kPa (1315 kPa for human and 1134 kPa for FP), and coefficient of viscosity of 13 MPa·s (9 MPa·s for human and 3 MPa·s for FP) at 20% strain. These properties also varied topographically in accordance to those of human and FP TMJ discs. Anisotropy, quantified by bidirectional tensile testing and histology, again was analogous among minipig, human, and FP TMJ discs. The minipig TMJ's ginglymoarthrodial nature was verified through cone beam computer tomography. Collectively, the similarities between minipig and human TMJ discs support the use of minipig as a relevant model for TMJ research; considering the practical advantages conferred by its growth rate and size, the minipig may be a preferred model over FP.


Interaction of endothelin and Ca++ entry blockers on renal circulation in anesthetized rabbits.
We examined an interaction of endothelium-derived vasoconstrictor endothelin and Ca++ entry blockers on renal blood flow in anesthetized rabbits. A bolus intrarenal arterial injection of endothelin at doses of 10, 25 and 50 ng produced a decrease in renal blood flow with a dose-dependent fashion, while there was no change in systemic arterial pressure. A similar extent of the decrease in renal blood flow was produced at doses of endothelin 50 ng(2.0 x 10(-11)M), angiotensin II 10 ng (9.7 x 10(-12)M) and norepinephrine 250 ng (1.5 x 10(-9)M), although the decrease in renal blood flow by endothelin was sustained in contrast to angiotensin II or norepinephrine. Pretreatment with Ca++ entry blocker nifedipine (1.0 microgram/kg/min) or diltiazem (20 micrograms/kg/min) attenuated the decrease in renal blood flow and reduced the duration time. These results suggest that exogenous endothelin produces a renal vasoconstriction in vivo. However, it seems that endothelin is less potent than angiotensin II in renal circulation in anesthetized rabbits. It is also indicated that the decrease in renal blood flow by endothelin could be mediated through a common Ca++ channel pathway in renal vasculatures.


Growth hormone and pulmonary disease. Metabolic effects in patients receiving parenteral nutrition.
Six severely malnourished patients with chronic obstructive pulmonary disease were maintained for 3 days with infusions of 5% dextrose in water followed by 12 days of eucaloric total parenteral nutrition. On days 8 through 11, they received 30 micrograms/d of growth hormone and twice this amount on days 11 through 15. Growth hormone had no significant effects on the plasma concentration of glucose, cortisol, or glucagon but caused a 50% increase in insulin and a 250% increase in somatomedin C concentrations. A positive nitrogen balance of 2 g/d due to growth hormone was probably mediated by insulin. Growth hormone-induced increases in energy expenditure and fat oxidation and decrease in glucose oxidation cannot be accounted for by insulin. The ability of growth hormone to improve nitrogen balance may be particularly important for malnourished patients with chronic obstructive pulmonary disease who, because of their pulmonary insufficiency, are intolerant of excess nutrients.


5 competencies needed by new baccalaureate graduates.
As nurse educators prepare new graduates for practice, part of the challenge is to ensure that these nurses are capable of functioning in a broad continuum of care with increased responsibilities. To identify competencies needed by new baccalaureate graduates in today's health care environment and determine whether these competencies fall into particular dimensions, a cross-sectional survey design was used to query 363 nurse administrators from three health care settings. Nurse administrators rated the importance of 45 nursing competencies. Factor analysis was conducted on the competency items, and factor scores were calculated to determine the importance ratings by work setting groups. Findings revealed a simple six-factor competency structure (Health Promotion Competency, Supervision Competency, Interpersonal Communication Competency, Direct Care Competency, Computer Competency, and Caseload Management Competency). MANOVA indicated significant differences in the importance of these competence factors by work setting. The findings are an important beginning for evidence-based decision-making about nursing curriculum reform, both in the classroom and clinical practice areas. The study also provides a foundation for further measurement of nursing competencies.


Self-reported incidence and age of onset of chronic comorbid medical conditions in adults aging with long-term physical disability.
Adults with long-term disability are living longer and may experience accelerated aging. More information is needed to understand the incidence of chronic comorbid medical conditions in this population. To examine the incidence, prevalence, age of onset and predictors of five chronic conditions in a sample of adults with long-term physical disability. Longitudinal self-report surveys were mailed to 1594 adults with multiple sclerosis, muscular dystrophy, post-polio syndrome or spinal cord injury twice, 3.5 years apart. Survey questions assessed demographics (date of birth, sex, income, disability type, height/weight), self-reported diagnosis of coronary heart disease, hypertension, arthritis, diabetes and cancer, and health behaviors (alcohol use, smoking, physical activity). Over the course of the study, the most commonly reported new onset chronic comorbid medical condition was arthritis (percent incidence = 14%), followed by hypertension (9%) and cancer (7%). Report of a new condition was greatest in adults aged between 56 and 65 years, and risk factors included greater BMI, waist circumference, and the presence of another chronic comorbid medical condition at baseline. Chronic comorbid medical conditions are prevalent in persons with long-term physical disability. Midlife appears to be the period of greatest risk for onset of a new condition, and risk for incidence increases in the presence of other chronic comorbid medical conditions. Modifiable risk factors include BMI and waist circumference. Future research should explore whether changes in modifiable factors at midlife or earlier (e.g., diet, exercise) would help prevent or delay onset of comorbid conditions in this population.


Increased GnRH mRNA in the GnRH neurons expressing cFos during the proestrous LH surge.
GnRH neuronal activity is increased during the proestrous LH surge as assessed by the expression of cFos. Whether there is an increase in GnRH mRNA concomitant with GnRH neuronal activation is still controversial. In the present study we have compared GnRH mRNA levels in GnRH neurons expressing cFos (activated) with those not expressing cFos during the proestrous LH surge. Brain tissue was obtained from adult female rats perfused on proestrus before (1100-1300 hr) or during (1500-1900 hr) the LH surge. Twenty-five microns free-floating brain sections were subjected to double labeling of cFos by immunocytochemistry and of GnRH mRNA by in situ hybridization using an 35S-labeled cRNA probe. Another series of sections were stained by double-label immunocytochemistry for cFos and GnRH. Serum LH concentrations and cFos expression in GnRH neurons indicated that rats sacrificed at or before 1300 hr had basal levels of LH secretion, and no cFos activity was detected in GnRH neurons. In animals sacrificed between 1500 and 1900 hr, LH concentrations were at levels indicative of the ascending phase of the LH surge. A significant positive correlation between plasma LH values and the proportion of GnRH mRNA-containing neurons expressing cFos was observed. The average cellular GnRH mRNA content (silver grain numbers per cell) during the LH surge was not different from that before the surge. However, if GnRH neurons during the surge were further divided into cFos-positive and cFos-negative neurons, GnRH mRNA levels in the cFos-positive GnRH neurons were significantly increased by 28% when compared with GnRH neurons without cFos expression. These data suggest that cFos expression in GnRH neurons during the proestrous LH surge identifies transcriptionally more active GnRH neurons.


Knowledge, attitudes and practice among nursing staff concerning pressure ulcer prevention and treatment--a survey in a Swedish healthcare setting.
The aim of this study was to investigate (i) attitudes among Registered Nurses (RNs) and Nursing Assistants (NAs) regarding pressure ulcer prevention, (ii) knowledge among RNs and NAs of pressure ulcer prevention and treatment, (iii) practice of risk assessment and documentation regarding pressure ulcers among RNs and NAs and (iv) to identify perceived possibilities and barriers in pressure ulcer prevention and treatment. In this cross-sectional study, a total of 230 questionnaires were distributed to an equal number of RNs and NAs in both municipality as well as hospital care settings. The response rate was 67% (n = 154). In general, all respondents displayed good knowledge on prevention and treatment of pressure ulcers and demonstrated a positive attitude towards this area of care. However, answers provided to some questions indicate that recent research findings and guidelines have not succeeded in reaching out to these occupational groups. Furthermore, only 37% (n = 55) of the participants said that they have an agreed strategy for the prevention of pressure ulcers in their unit. These shortcomings may affect the quality of care provided to the patient and lead to pressure ulcers developing as a consequence. Today, evidence-based methods for risk assessment are available but are not adopted and used in practice. The study highlights the need to further reduce the gap between research and practice.


Drug release by pH-responsive molecular tweezers: atomistic details from molecular modeling.
pH-responsive molecular tweezers have been proposed as an approach for targeting drug-delivery to tumors, which tend to have a lower pH than normal cells. We performed a computational study of a pH-responsive molecular tweezer using ab initio quantum chemistry in the gas-phase and molecular dynamics (MD) simulations in solution. The binding free energy in solution was calculated using steered MD. We observe, in atomistic detail, the pH-induced conformational switch of the tweezer and the resulting release of the drug molecule. Even when the tweezer opens, the drug molecule remains near a hydrophobic arm of the molecular tweezer. Drug release cannot occur, it seems, unless the tweezer is in a hydrophobic environment with low pH.


Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson's disease.
Excessive synchronization of basal ganglia neural activity at low frequencies is considered a hallmark of Parkinson's disease (PD). However, few studies have unambiguously linked this activity to movement impairment through direct stimulation of basal ganglia targets at low frequency. Furthermore, these studies have varied in their methodology and findings, so it remains unclear whether stimulation at any or all frequencies < or = 20 Hz impairs movement and if so, whether effects are identical across this broad frequency band. To address these issues, 18 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both subthalamic nuclei were stimulated bilaterally at 5, 10 and 20 Hz after overnight withdrawal of their medication and the effects of the DBS on a finger tapping task were compared to performance without DBS (0 Hz). Tapping rate decreased at 5 and 20 Hz compared to 0 Hz (by 11.8+/-4.9%, p=0.022 and 7.4+/-2.6%, p=0.009, respectively) on those sides with relatively preserved baseline task performance. Moreover, the coefficient of variation of tap intervals increased at 5 and 10 Hz compared to 0 Hz (by 70.4+/-35.8%, p=0.038 and 81.5+/-48.2%, p=0.043, respectively). These data suggest that the susceptibility of basal ganglia networks to the effects of excessive synchronization may be elevated across a broad low-frequency band in parkinsonian patients, although the nature of the consequent motor impairment may depend on the precise frequencies at which synchronization occurs.


Having lived on a farm and protection against allergic diseases in Australia.
Farmers' children in northern Europe have a lower prevalence of atopy, hay fever and asthma than other children. Farms in Australia differ in scale and operation from those in Europe and the prevalence of allergic diseases in children is higher. To investigate whether having lived on a farm as a child in Australia is associated with a lower risk of allergic diseases. Cross-sectional study of children (n = 1500) aged 7-12 years from two rural towns: Wagga Wagga in a mixed farming region, and Moree in a crop farming region. Parents answered a questionnaire and children had a skin prick test for atopy. Twenty percent of children had lived on a farm for at least 1 year. The effect of having lived on a farm differed between the towns (P < 0.001). It was associated with a lower risk of atopy in Wagga (adjusted odds ratio (aOR) 0.47, 95% confidence interval (CI) 0.32-0.72) but not in Moree (aOR 0.97, 95% CI 0.62-1.53). Children from Wagga were more likely to have lived on a livestock farm than children from Moree (26.1% vs. 9.1%, 95% CI for the difference 8.9-25.4). Having lived on a farm in Australia can confer protection against atopy in children. Further studies are needed to identify possible protective mechanisms associated with farm animals or to establish whether the protective effect is explained by other related exposures.


Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in female prairie voles.
The present study examines the developmental consequences of neonatal exposure to oxytocin on adult social behaviors in female prairie voles (Microtus ochrogaster). Female neonates were injected within 24 h of birth with isotonic saline or one of four dosages of oxytocin (OT). As adults, females were tested in an elevated plus-maze paradigm (a measure of anxiety and exploratory behavior), and for alloparental behavior and partner preferences. At 2 mg/kg OT, females took longer to approach pups, but were the only group to form a statistically significant within-group partner preference. At 4 mg/kg OT, females retrieved pups significantly more frequently but no longer displayed a partner preference; while females treated developmentally with 8 mg/kg spent significantly more time in side-to-side contact with a male stranger than any other treatment group. OT may have broad developmental consequences, but these effects are not linear and may both increase and decrease the propensity to display behaviors such as pair-bonding.


Mechanisms of vortices termination in the cardiac muscle.
We propose a solution to a long-standing problem: how to terminate multiple vortices in the heart, when the locations of their cores and their critical time windows are unknown. We scan the phases of all pinned vortices in parallel with electric field pulses (E-pulses). We specify a condition on pacing parameters that guarantees termination of one vortex. For more than one vortex with significantly different frequencies, the success of scanning depends on chance, and all vortices are terminated with a success rate of less than one. We found that a similar mechanism terminates also a free (not pinned) vortex. A series of about 500 experiments with termination of ventricular fibrillation by E-pulses in pig isolated hearts is evidence that pinned vortices, hidden from direct observation, are significant in fibrillation. These results form a physical basis needed for the creation of new effective low energy defibrillation methods based on the termination of vortices underlying fibrillation.


Human xeno-autoantibodies against a non-human sialic acid serve as novel serum biomarkers and immunotherapeutics in cancer.
Human carcinomas can metabolically incorporate and present the dietary non-human sialic acid Neu5Gc, which differs from the human sialic acid N-acetylneuraminic acid (Neu5Ac) by 1 oxygen atom. Tumor-associated Neu5Gc can interact with low levels of circulating anti-Neu5Gc antibodies, thereby facilitating tumor progression via chronic inflammation in a human-like Neu5Gc-deficient mouse model. Here we show that human anti-Neu5Gc antibodies can be affinity-purified in substantial amounts from clinically approved intravenous IgG (IVIG) and used at higher concentrations to suppress growth of the same Neu5Gc-expressing tumors. Hypothesizing that this polyclonal spectrum of human anti-Neu5Gc antibodies also includes potential cancer biomarkers, we then characterize them in cancer and noncancer patients' sera, using a novel sialoglycan microarray presenting multiple Neu5Gc-glycans and control Neu5Ac-glycans. Antibodies against Neu5Gcα2-6GalNAcα1-O-Ser/Thr (GcSTn) were found to be more prominent in patients with carcinomas than with other diseases. This unusual epitope arises from dietary Neu5Gc incorporation into the carcinoma marker Sialyl-Tn, and is the first example of such a novel mechanism for biomarker generation. Finally, human serum or purified antibodies rich in anti-GcSTn-reactivity kill GcSTn-expressing human tumors via complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. Such xeno-autoantibodies and xeno-autoantigens have potential for novel diagnostics, prognostics, and therapeutics in human carcinomas.


A multi-institutional consensus on how to perform endoscopic ultrasound-guided peri-pancreatic fluid collection drainage and endoscopic necrosectomy.
There is a lack of consensus on how endoscopic ultrasound (EUS)-guided pseudocyst drainage and endoscopic necrosectomy should be performed. This survey was carried out amongst members of the EUS Journal Editorial Board to describe their practices in performing this procedure. This was a worldwide multi-institutional survey amongst members of the EUS Journal Editorial Board in May 2017. The responses to a 22-question survey with respect to the practice of EUS-guided pseudocyst drainage and endoscopic necrosectomy were obtained. Twenty-two endoscopists responded to the questionnaire as follows: 72.7% (16/22) were of the opinion that lumen-apposing metal stents (LAMS) should be the standard of care for the creation of an endoscopic cystenterostomy in patients with pancreatic walled-off necrosis (WON); 95.5% (21/22) recommended large diameter (d=15 mm) LAMS for drainage in patients with WON; 54.5% (12/22) would not dilate LAMS after placement into the WOPN; 86.4% (19/22) would not perform endoscopic necrosectomy during the same procedure as the creation of the cystenterostomy; 45.5% (10/22) recommend that agents, such as diluted hydrogen peroxide, should be used to lavage the peri-pancreatic fluid collection (PFC) cavity in patients with WON; and 45.5% (10/22) considered a naso-cystic or other tube to be necessary for lavage of WON after initial drainage. The mean optimal interval recommended for endoscopic necrosectomy procedures after EUS-guided drainage was 6.23 days. The mean optimal interval recommended for repeat imaging in patients undergoing endoscopic necrosectomy was 12.32 days. The mean time recommended for LAMS removal was 4.59 weeks. This is the first worldwide survey on the practice of EUS-guided pseudocyst drainage and endoscopic necrosectomy. There were wide variations in practice and randomized studies are urgently needed to establish the best approach for management of this condition. There is also a pressing need to establish a best practice consensus.


Discovery of Miller's Grizzled Langur (Presbytis hosei canicrus) in Wehea Forest confirms the continued existence and extends known geographical range of an endangered primate.
Miller's Grizzled Langur (Presbytis hosei canicrus) is one of the least known and rarest primates in Borneo. With a limited geographic range along the central coast of East Kalimantan and the highly degraded Kutai National Park, its former stronghold, this subspecies is now extremely rare and has been listed as one of the world's 25 most endangered primates. From June 6 to August 2, 2011, we carried out both direct observation and camera trap surveys at two mineral springs (sepans) in the Wehea Forest, East Kutai district, East Kalimantan. Presbytis hosei canicrus was observed at the large sepan on 3 of 6 observation days and at the small sepan on 2 of 3 observation days with up to 11 individuals observed in a single day at a single site. Camera traps recorded a per day capture rate of 0.72 at the small sepan and 0.25 at the large sepan and a per photo capture rate of 0.50 and 0.005, respectively. These data suggest relatively frequent occurrence of P. h. canicrus at the sepans, but the langurs are rarely encountered elsewhere in the Wehea Forest. The discovery of P. h. canicrus in the Wehea Forest confirms the continued existence of this endangered primate and is the first solid evidence demonstrating that its geographic range extends further inland than previously thought. It is not known whether the population of P. h. canicrus within Wehea Forest is large and stable enough to be considered viable, but it is likely part of a larger population that may possibly occur across surrounding protected forests and logging concessions. Surveying this potentially large population, and securing its protection, should be a priority measure for ensuring the continued existence of P. h. canicrus.