C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response.
Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload-induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa α-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47(phox)), and collagen-I, the number of infiltrating Mac-2-positive macrophages, nuclear localization of phosphorylated NF-κB/p65 (p-p65) in cardiomyocytes, nuclear NF-κB-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, IL-6, GPx3, p47(phox), collagen-I, and transforming growth factor (TGF)-β1, the protein level of TGF-β1, and the numbers of Mac-2-positive macrophages and p-p65-positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload-induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress.


Age and binding within-dimension features in visual short-term memory.
Older adults have difficulties in binding information in long-term memory (e.g. objects with colours). The effect of age on visual short-term memory (VSTM) binding is less well understood. Recent evidence has suggested that older adults' VSTM for colours bound to shapes or for locations bound in configural representations may be preserved. In two experiments we investigated whether this lack of an age effect on VSTM for bound features can be reproduced when features are drawn from the same dimension (i.e. colour-colour binding) and when spatial clues are not available. Younger and older adults were presented with two sequential arrays of unicoloured or bicoloured objects and their accuracy in detecting changes between arrays was used as the measure of memory performance. Memory was assessed using a change detection paradigm for unicoloured objects and for bicoloured objects with changes in colour conjunctions (i.e. colours swapping between objects) or with changes in non-conjunctive colours (i.e. colours replacing colours in the study array). Both young and older adults were less accurate at remembering objects defined by colour conjunctions than unicoloured objects or objects composed of two non-conjunctive colours (Experiment 1). Increasing task demands in terms of memory and perceptual load had no greater effect on the older than the younger adults (Experiment 2). We suggest (1) that colours were not integrated into single units in VSTM; (2) that remembering the binding between colours has a cost; and (3) that neither of these effects are age-dependent.


Solution structure of the RBCC/TRIM B-box1 domain of human MID1: B-box with a RING.
B-box domains are a defining feature of the tripartite RBCC (RING, B-box, coiled-coil) or TRIM proteins, many of which are E3 ubiquitin ligases. However, little is known about the biological function of B-boxes. In some RBCC/TRIM proteins there is only a single B-box (type 2) domain, while others have both type 1 and type 2 B-box domains in tandem adjacent to their RING domain. These two types of B-boxes share little sequence similarity, except the presence of cysteine and histidine residues: eight in most B-box1 domains and seven in B-box2 domains. We report here the high-resolution solution structure of the first B-box1 domain (from the human RBCC protein, MID1) based on 670 nuclear Overhauser effect (NOE)-derived distance restraints, 12 hydrogen bonds, and 44 dihedral angles. The domain consists of a three-turn alpha-helix, two short beta-strands, and three beta-turns, encompassing Val117 to Pro164, which binds two zinc atoms. One zinc atom is coordinated by cysteine residues 119, 122, 142, 145, while cysteine 134, 137 and histidine 150, 159 coordinate the other. This topology is markedly different from the only other B-box structure reported; that of a type 2 B-box from Xenopus XNF7, which binds a single zinc atom. Of note, the B-box1 structure closely resembles the folds of the RING, ZZ and U-box domains of E3 and E4 ubiquitin enzymes, raising the possibility that the B-box1 domain either has E3 activity itself or enhances the activity of RING type E3 ligases (i.e. confers E4 enzyme activity). The structure of the MID1 B-box1 also reveals two potential protein interaction surfaces. One of these is likely to provide the binding interface for Alpha 4 that is required for the localized turnover of the catalytic subunit of PP2A, the major Ser/Thr phosphatase.


[A case of an end-of-life cancer patient in which lymphedema care improved the QOL enabling home hospice care].
Recently, the importance of prevention and care of lymphedema has been recognized. It appears that the complex physical therapy is relatively taboo for an end-of-life cancer patient with lymphedema. Therefore, an intervention of care is often difficult. In our case, the patient strongly desired a hospice care at home, so we introduced a home hospice care gradually taking a step by step approach with anticipated harmful symptoms. As a result, the home hospice care was doable with ADL and QOL improvements. For lymphedema care of an end-of-life cancer patient, a goal setting, sharing the patient's will based on anticipated symptoms, and an introduction of a gradual care were all important.


Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis.
Systemic bacterial infection induces a hematopoietic response program termed "emergency granulopoiesis" that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.


Controlled randomised trial of visual biofeedback versus muscle training without a visual display for intractable constipation.
Training to contract the abdominal muscles effectively and to relax the pelvic floor during defecation straining helps some patients with severe constipation. Hitherto all such training has used a visible or audible signal of sphincter muscle activity as a biofeedback method to assist in relaxation. A randomised controlled trial comparing the outcome of muscular training without any biofeedback device with the same training supplemented by an electromyographic (EMG) record visible to the patient is reported. Significant symptomatic improvement was noted and electromyographic measurements confirmed a decrease in pelvic floor muscle activity during defecation straining after treatment in both groups. The outcome was similar in the two treatment groups. Muscular coordination training using personal instruction and encouragement without a visual display is thus a potentially successful treatment suitable for outpatient use by paramedical personnel.


WITHDRAWN: Gluten- and casein-free diets for autistic spectrum disorder.
It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of people with autism. To determine the efficacy of gluten and/or casein free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism. The following electronic databases were searched: CENTRAL(The Cochrane Library Issue 2, 2007), MEDLINE (1966 to April 2007), PsycINFO (1971 to April 2007), EMBASE (1974 to April 2007), CINAHL (1982 to April 2007), ERIC (1965 to 2007), LILACS (1982 to April 2007), and the National Research register 2007 (Issue1). Review bibliographies were also examined to identify potential trials. All randomised controlled trials (RCT) involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with an autistic spectrum disorder. Abstracts of studies identified in searches of electronic databases were assessed to determine inclusion by two independent authors The included trials did not share common outcome measures and therefore no meta-analysis was possible. Data are presented in narrative form. Two small RCTs were identified (n = 35). No meta-analysis was possible. There were only three significant treatment effects in favour of the diet intervention: overall autistic traits, mean difference (MD) = -5.60 (95% CI -9.02 to -2.18), z = 3.21, p=0.001 (Knivsberg 2002) ; social isolation, MD = -3.20 (95% CI -5.20 to 1.20), z = 3.14, p = 0.002) and overall ability to communicate and interact, MD = 1.70 (95% CI 0.50 to 2.90), z = 2.77, p = 0.006) (Knivsberg 2003). In addition three outcomes showed no significant difference between the treatment and control group and we were unable to calculate mean differences for ten outcomes because the data were skewed. No outcomes were reported for disbenefits including harms. Research has shown of high rates of use of complementary and alternative therapies (CAM) for children with autism including gluten and/or casein exclusion diets. Current evidence for efficacy of these diets is poor. Large scale, good quality randomised controlled trials are needed.


Bacteriome and Mycobiome Interactions Underscore Microbial Dysbiosis in Familial Crohn's Disease.
Crohn's disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescens and Escherichia coli was elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicalis was significantly higher in CD than in NCDR (P = 0.003) samples and positively correlated with levels of anti-Saccharomyces cerevisiae antibodies (ASCA). The abundance of C. tropicalis was positively correlated with S. marcescens and E. coli, suggesting that these organisms interact in the gut. The mass and thickness of triple-species (C. tropicalis plus S. marcescens plus E. coli) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalis biofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescens used fimbriae to coaggregate or attach with C. tropicalis/E. coli, while E. coli was closely apposed with C. tropicalis Specific interkingdom microbial interactions may be key determinants in CD. Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal (Candida tropicalis) and bacterial (Serratia marcescens and Escherichia coli) species that are associated with CD dysbiosis. Additionally, we found that the level of anti-Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis We also identified positive interkingdom correlations between C. tropicalis, E. coli, and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.


Psychosocial variables, age, and angiographically-determined coronary artery disease in women.
The present study explored the relationship between psychosocial measures and the degree of coronary stenosis in a sample of 59 women between the ages of 39 and 84. Coronary occlusion was correlated with elevated cholesterol and marginally correlated with age and was inversely associated with years of education. Based on hierarchical multiple regression, an interview-based measure of hostility was associated with coronary stenosis after controlling for traditional risk factors, and age moderated the hostility-stenosis relationship. Further, a second regression model suggested that trait anxiety was inversely correlated with degree of occlusion, perhaps because low-anxious women are referred for catheterization later in the course of the disease. Contrary to hypotheses, there was no evidence that repression of interview-based hostility or anxiety predicted coronary occlusion. Given the small sample size, results should be considered preliminary. Future studies should explore the degree to which anxiety and hostility are associated with coronary heart disease (CHD) in larger samples of women and the degree to which age moderates the hostility-occlusion association.


Lifestyle advice for hypertension or diabetes: trend analysis from 2002 to 2017 in England.
Guidelines recommend that GPs give patients lifestyle advice to manage hypertension and diabetes. Increasing evidence shows that this is an effective and practical treatment for these conditions, but it is unclear whether GPs offer this support. To investigate trends in the percentage of patients with hypertension/diabetes receiving lifestyle advice versus medication. This was a trend analysis of self-reported data from the annual Health Survey for England (HSE) (2003-2017) and GP-recorded data from the QResearch database (2002-2016). The percentage of patients with hypertension or diabetes who received lifestyle advice or medication was calculated in each year. Associations between likelihood of receiving lifestyle advice and characteristics were assessed using multivariable logistic regression. The percentage of patients receiving lifestyle advice was consistently lower than those receiving medication in both self-reported and medical records. There was consistent evidence of increasing trends in the percentage of patients with hypertension receiving lifestyle advice (HSE 13.8% to 20.1%; Ptrend <0.001; QResearch 11.0% to 22.7%; Ptrend <0.001). For diabetes, there was a non-significant decline in self-reported receipt of lifestyle advice (45.0% to 27.9%; Ptrend = 0.111) and a significant increase in medically recorded delivery of this advice (20.7% to 40.5%; Ptrend <0.001). Patients with hypertension who were overweight or obese were more likely to receive lifestyle advice than those of a healthy weight, whereas the opposite was true for diabetes. Only a minority of patients with diabetes or hypertension report receiving lifestyle advice or have this recorded in their medical records. Interventions beyond guidelines are needed to increase the delivery of behavioural interventions to treat these conditions.


Experiencing Seclusion in a Forensic Psychiatric Setting: A Phenomenological Study.
In hospital settings, and especially in forensic psychiatric ones, restlessness, aggression, and even violence are familiar issues to healthcare workers. Under these circumstances, the need for restrictive measures (seclusion, mechanical/chemical restraints) is sometimes needed. Although such measures should be considered as exceptional interventions, they continue to be widespread in general, psychiatric, and forensic psychiatric settings. Although there is a great deal of literature on a myriad of issues associated with the use of seclusion, very little research has focused on the lived experience of the seclusion room in forensic psychiatric settings, whether from the patient's perspective or from the perspective of nursing staff responsible for these patients. Such an examination could help ameliorate the experience of secluded forensic psychiatric patients while informing nursing staff about the impacts of seclusion. This article reports the results of a federally funded qualitative, phenomenological research study conducted in a Canadian forensic psychiatric environment. Our results show that the "structure of place" matters for both patients who experience seclusion and nursing staff who work therapeutically in these settings. "Place" is irreducible to the physical "space" in which bodies find themselves; this study of place took into consideration the ways the lived body experiences seclusion and interrelates with others. Although there can be no doubt that many patients who experience seclusion are oftentimes objectively at risk, with a heightened potential to self-harm and to harm other inpatients and nursing staff as well, as our study participants attested, the bodies secluded in this space are not "objects."


Deep Convolutional Neural Networks Outperform Feature-Based But Not Categorical Models in Explaining Object Similarity Judgments.
Recent advances in Deep convolutional Neural Networks (DNNs) have enabled unprecedentedly accurate computational models of brain representations, and present an exciting opportunity to model diverse cognitive functions. State-of-the-art DNNs achieve human-level performance on object categorisation, but it is unclear how well they capture human behavior on complex cognitive tasks. Recent reports suggest that DNNs can explain significant variance in one such task, judging object similarity. Here, we extend these findings by replicating them for a rich set of object images, comparing performance across layers within two DNNs of different depths, and examining how the DNNs' performance compares to that of non-computational "conceptual" models. Human observers performed similarity judgments for a set of 92 images of real-world objects. Representations of the same images were obtained in each of the layers of two DNNs of different depths (8-layer AlexNet and 16-layer VGG-16). To create conceptual models, other human observers generated visual-feature labels (e.g., "eye") and category labels (e.g., "animal") for the same image set. Feature labels were divided into parts, colors, textures and contours, while category labels were divided into subordinate, basic, and superordinate categories. We fitted models derived from the features, categories, and from each layer of each DNN to the similarity judgments, using representational similarity analysis to evaluate model performance. In both DNNs, similarity within the last layer explains most of the explainable variance in human similarity judgments. The last layer outperforms almost all feature-based models. Late and mid-level layers outperform some but not all feature-based models. Importantly, categorical models predict similarity judgments significantly better than any DNN layer. Our results provide further evidence for commonalities between DNNs and brain representations. Models derived from visual features other than object parts perform relatively poorly, perhaps because DNNs more comprehensively capture the colors, textures and contours which matter to human object perception. However, categorical models outperform DNNs, suggesting that further work may be needed to bring high-level semantic representations in DNNs closer to those extracted by humans. Modern DNNs explain similarity judgments remarkably well considering they were not trained on this task, and are promising models for many aspects of human cognition.


Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.
Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo. In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay. Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway. These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.


Genetic identification of residues involved in association of alpha and beta G-protein subunits.
The GPA1, STE4, and STE18 genes of Saccharomyces cerevisiae encode the alpha, beta, and gamma subunits, respectively, of a G protein involved in the mating response pathway. We have found that mutations G124D, W136G, W136R, and delta L138 and double mutations W136R L138F and W136G S151C of the Ste4 protein cause constitutive activation of the signaling pathway. The W136R L138F and W136G S151C mutant Ste4 proteins were tested in the two-hybrid protein association assay and found to be defective in association with the Gpa1 protein. A mutation at position E307 of the Gpa1 protein both suppresses the constitutive signaling phenotype of some mutant Ste4 proteins and allows the mutant alpha subunit to physically associate with a specific mutant G beta subunit. The mutation in the Gpa1 protein is adjacent to the hinge, or switch, region that is required for the conformational change which triggers subunit dissociation, but the mutation does not affect the interaction of the alpha subunit with the wild-type beta subunit. Yeast cells constructed to contain only the mutant alpha and beta subunits mate and respond to pheromones, although they exhibit partial induction of the pheromone response pathway. Because the ability of the modified G alpha subunit to suppress the Ste4 mutations is allele specific, it is likely that the residues defined by this analysis play a direct role in G-protein subunit association.


A Coarse-Grained Model of Stratum Corneum Lipids: Free Fatty Acids and Ceramide NS.
Ceramide (CER)-based biological membranes are used both experimentally and in simulations as simplified model systems of the skin barrier. Molecular dynamics studies have generally focused on simulating preassembled structures using atomistically detailed models of CERs, which limit the system sizes and time scales that can practically be probed, rendering them ineffective for studying particular phenomena, including self-assembly into bilayer and lamellar superstructures. Here, we report on the development of a coarse-grained (CG) model for CER NS, the most abundant CER in human stratum corneum. Multistate iterative Boltzmann inversion is used to derive the intermolecular pair potentials, resulting in a force field that is applicable over a range of state points and suitable for studying ceramide self-assembly. The chosen CG mapping, which includes explicit interaction sites for hydroxyl groups, captures the directional nature of hydrogen bonding and allows for accurate predictions of several key structural properties of CER NS bilayers. Simulated wetting experiments allow the hydrophobicity of CG beads to be accurately tuned to match atomistic wetting behavior, which affects the whole system, since inaccurate hydrophobic character is found to unphysically alter the lipid packing in hydrated lamellar states. We find that CER NS can self-assemble into multilamellar structures, enabling the study of lipid systems more representative of the multilamellar lipid structures present in the skin barrier. The coarse-grained force field derived herein represents an important step in using molecular dynamics to study the human skin barrier, which gives a resolution not available through experiment alone.


Range-wide population genetic structure of the Caribbean marine angiosperm Thalassia testudinum.
Many marine species have widespread geographic ranges derived from their evolutionary and ecological history particularly their modes of dispersal. Seagrass (marine angiosperm) species have ranges that are unusually widespread, which is not unexpected following recent reviews of reproductive strategies demonstrating the potential for long-distance dispersal combined with longevity through clonality. An exemplar of these dual biological features is turtle grass (Thalassia testudinum) which is an ecologically important species throughout the tropical Atlantic region. Turtle grass has been documented to have long-distance dispersal via floating fruits and also extreme clonality and longevity. We hypothesize that across its range, Thalassia testudinum will have very limited regional population structure due to these characteristics and under typical models of population structure would expect to detect high levels of genetic connectivity. There are very few studies of range-wide genetic connectivity documented for seagrasses or other sessile marine species. This study presents a population genetic dataset that represents a geographic area exceeding 14,000 km2. Population genetic diversity was evaluated from 32 Thalassia testudinum populations sampled across the Caribbean and Gulf of Mexico. Genotypes were based on nine microsatellites, and haplotypes were based on chloroplast DNA sequences. Very limited phylogeographic signal from cpDNA reduced the potential comparative analyses possible. Multiple analytical clustering approaches on population genetic data revealed two significant genetic partitions: (a) the Caribbean and (b) the Gulf of Mexico. Genetic diversity was high (H E = 0.641), and isolation by distance was significant; gene flow and migration estimates across the entire range were however modest, we suggest that the frequency of successful recruitment across the range is uncommon. Thalassia testudinum maintains genetic diversity across its entire distribution range. The genetic split may be explained by genetic drift during recolonization from refugia following relatively recent reduction in available habitat such as the last glacial maxima.


Local critical stress correlates better than global maximum stress with plaque morphological features linked to atherosclerotic plaque vulnerability: an in vivo multi-patient study.
It is believed that mechanical stresses play an important role in atherosclerotic plaque rupture process and may be used for better plaque vulnerability assessment and rupture risk predictions. Image-based plaque models have been introduced in recent years to perform mechanical stress analysis and identify critical stress indicators which may be linked to rupture risk. However, large-scale studies based on in vivo patient data combining mechanical stress analysis, plaque morphology and composition for carotid plaque vulnerability assessment are lacking in the current literature. 206 slices of in vivo magnetic resonance image (MRI) of carotid atherosclerotic plaques from 20 patients (age: 49-71, mean: 67.4; all male) were acquired for model construction. Modified Mooney-Rivlin models were used for vessel wall and all plaque components with parameter values chosen to match available data. A morphological plaque severity index (MPSI) was introduced based on in vivo plaque morphological characteristics known to correlate with plaque vulnerability. Critical stress, defined as the maximum of maximum- principal-stress (Stress-P1) values from all possible vulnerable sites, was determined for each slice for analysis. A computational plaque stress index (CPSI, with 5 grades 0-4, 4 being most vulnerable) was defined for each slice using its critical stress value and stress interval for each CPSI grade was optimized to reach best agreement with MPSI. Correlations between CPSI and MPSI, plaque cap thickness, and lipid core size were analyzed. Critical stress values correlated positively with lipid core size (r = 0.3879) and negatively with cap thickness (r = -0.3953). CPSI classifications had 71.4% agreement with MPSI classifications. The Pearson correlation coefficient between CPSI and MPSI was 0.849 (p < 0.0001). Using global maximum Stress-P1 value for each slice to define a global maximum stress-based CPSI (G-CPSI), the agreement rate with MPSI was only 34.0%. The Pearson correlation coefficient between G-CPSI and MPSI was 0.209. Results from this in vivo study demonstrated that localized critical stress values had much better correlation with plaque morphological features known to be linked to plaque rupture risk, compared to global maximum stress conditions. Critical stress indicators have the potential to improve image-based screening and plaque vulnerability assessment schemes.


Measuring Responsible Gambling amongst Players: Development of the Positive Play Scale.
The modern gambling industry has, by-in-large, assumed a duty of care to minimize the risks associated with gambling, which has manifested in responsible gambling (RG) programming (e.g., educating players about the odds of success). The current study fills a void in gambling operators, regulators, and researchers ability to measure RG beliefs and behavior in their player-base, with the development and validation of the Positive Play Scale (PPS). In Study 1, we reviewed the literature and consulted 30 players as well as 10 RG experts to help generate a definition of RG beliefs and behavior that helped guide item generation. In Study 2, regular players (N = 1,551) of a Canadian provincial gambling operator completed a positive play survey. Four components from a principal components analysis (PCA) were extracted: Honesty and Control, Pre-commitment, Personal Responsibility, and Gambling Literacy. The PPS subscales were either not associated with gambling frequency or had small-to-moderate negative relationships with frequency of play for games most often associated with disordered gambling (e.g., electronic games). In Study 3 (N = 413), the factor structure of the PPS was confirmed and refined in a new sample of players. Moreover, a 1-month follow-up session demonstrated that the PPS has high test-retest reliability. The PPS is the first validated scale that reliably assesses the extent to which a consumer base has positive beliefs about gambling and gambles in a positive manner. The PPS can be used by the gambling industry to objectively assess the efficacy of their RG strategy, pinpoint specific areas for future focus, as well as examine the utility of new RG initiatives that aim to promote healthy patterns of gambling consumption. Furthermore, by examining the PPS scores for different player segments (e.g., sex, age, games played) it becomes possible to tailor RG strategy to the needs of specific players. In this way, RG strategy can be optimized by focusing resources where they will be most effective.


Homeopathic prescribing for chronic conditions in feline and canine veterinary practice.
The peer-review literature contains no controlled clinical research of homeopathy in cats and very little in dogs. To collect clinical outcomes data systematically from individualised homeopathic treatment of cats and dogs that would help to inform controlled research in feline and canine homeopathy. Twenty-one homeopathic veterinary surgeons recorded data systematically from consecutive feline and canine patients over a 12-month period. Records included: date; patient and owner identity (anonymised); medical problem treated; whether new or follow-up (FU) appointment; chronic or acute condition; owner-assessed clinical outcome (7-point scale, range -3 to +3) compared with first appointment. Data from 400 cats comprised a total of 372 individual chronic problems, of which 270 had FU assessment. Data from 1504 dogs comprised a total of 1408 individual chronic problems, of which 1070 had FU assessment. In both species, 22% of FUs in chronic cases received conventional medicines concurrently. In cats, 117 different chronic medical conditions in total were treated with homeopathy. Five of those conditions included ≥20 cases, in which owner-reported outcomes (in decreasing rank order of frequency) were: dermatitis (69.6% patients with +2 or +3 outcome, 0% patients with -2 or -3 outcome); renal failure (57.1%, 14.3%); overgrooming (57.1%, 7.2%); arthritis (80.0%, 0%); hyperthyroidism (66.7%, 0%). In dogs, of 301 different chronic medical conditions treated in total, those most commonly recorded (≥20 cases) were: dermatitis (66.2% with +2 or +3 outcome, 5.4% with -2 or -3 outcome); arthritis (80.2%, 0.8%); pyoderma (75.8%, 0%); colitis (85.2%, 0%); fear (31.6%, 0%); epilepsy (63.6%, 4.5%); otitis externa (72.7%, 0%); diarrhoea (68.2%, 0%); urinary incontinence (73.7%, 0%); aggression (57.1%, 0%); spondylosis (81.0%, 0%); lymphoma (40.0%, 6.7%). A programme of controlled research in veterinary homeopathy for these feline and canine conditions is clearly indicated.


Knowing nursing - The challenge of articulating knowing in practice.
Learning and teaching in the clinical environment is complex and challenging. Development of the ability to articulate knowing in practice is essential to allow exploration of the richness and complexity of this type of nursing knowledge. This paper describes an innovative approach developed in collaboration with practitioners to assist in revealing hitherto hidden aspects of knowing nursing. The interpretive paradigm provides one means of voicing nursing knowledge, specifically by accessing the lived-experience of nursing. The approach is qualitatively different to reflection and critical incident as it focuses on the taken-for-granted rather than being problem based or problem solving. Hermeneutic phenomenology and constructivism are combined in an innovative model that allows experience to be captured and meaning to be explored, thereby providing a means to articulate knowing in practice. Practitioners involved in operationalising this model considered that it allowed them to articulate a level of practice knowledge which they had previously experienced difficulty in accessing. This approach to knowledge articulation may therefore be useful in assisting to widen the horizon of nursing knowledge.


The role of the thrombospondins in healing myocardial infarcts.
The five current members of the thrombospondin (TSP) family can be divided in two subgroups according to their molecular architecture. TSP-1 and -2 (subgroup A) are trimeric matricellular proteins that do not contribute directly to tissue integrity, but influence cell function by modulating cell-matrix interactions, whereas TSP-3, -4 and -5 (subgroup B) are pentameric proteins. TSP-1 and TSP-2 are markedly induced in healing wounds and may regulate cellular responses important for tissue repair. TSP-1 is a crucial activator of TGF-beta, whereas both TSP-1 and TSP-2 inhibit angiogenesis. This manuscript reviews our current knowledge on the expression and role of the TSPs in healing myocardial infarcts. In both canine and murine infarcts, TSP-1 shows a strikingly selective localization in the infarct border zone. In the absence of injury, TSP-1 -/- mice exhibit normal cardiac morphology and show no evidence of myocardial inflammation. Infarcted TSP-1 -/- mice have an enhanced and protracted inflammatory response with subsequent expansion of granulation tissue in the non-infarcted area, resulting in myofibroblast infiltration into the viable myocardium neighboring the infarct. Infarcted TSP-1 -/- animals have enhanced left ventricular remodeling compared with their wildtype littermates. We suggest that TSP-1 is a critical component of the protective mechanisms induced in the infarct border zone in order to limit expansion of fibrosis into the non-infarcted myocardium. Localized TSP-1 expression may suppress expansion of the inflammatory process by activating TGF-beta or by inhibiting local angiogenesis. In addition, TSP-1-mediated inhibition of MMP activity may decrease adverse remodeling. TSP-2, on the other hand, appears to be a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading. The expression and potential role of the pentameric TSPs in the infarcted heart remain unknown. Understanding the specific mechanisms responsible for the protective effects of TSP-1 and TSP-2 in healing infarcts may lead to novel therapeutic interventions aiming at attenuating adverse left ventricular remodeling.


Effects of anoxia, aglycemia, and acidosis on cytosolic Mg2+, ATP, and pH in rat sensory neurons.
Sensory neurons can detect ischemia and transmit pain from various organs. Whereas the primary stimulus in ischemia is assumed to be acidosis, little is known about how the inevitable metabolic challenge influences neuron function. In this study we have investigated the effects of anoxia, aglycemia, and acidosis upon intracellular Mg(2+) concentration [Mg(2+)](i) and intracellular pH (pH(i)) in isolated sensory neurons. Anoxia, anoxic aglycemia, and acidosis all caused a rise in [Mg(2+)](i) and a fall in pH(i). The rise in [Mg(2+)](i) in response to acidosis appears to be due to H(+) competing for intracellular Mg(2+) binding sites. The effects of anoxia and aglycemia were mimicked by metabolic inhibition and, in a dorsal root ganglia (DRG)-derived cell line, the rise in [Mg(2+)](i) during metabolic blockade was closely correlated with fall in intracellular ATP concentration ([ATP](i)). Increase in [Mg(2+)](i) during anoxia and aglycemia were therefore assumed to be due to MgATP hydrolysis. Even brief periods of anoxia (<3 min) resulted in rapid internal acidosis and a rise in [Mg(2+)](i) equivalent to a decline in MgATP levels of 15-20%. With more prolonged anoxia (20 min) MgATP depletion is estimated to be around 40%. With anoxic aglycemia, the [Mg(2+)](i) rise occurs in two phases: the first beginning almost immediately and the second after an 8- to 10-min delay. Within 20 min of anoxic aglycemia [Mg(2+)](i) was comparable to that observed following complete metabolic inhibition (dinitrophenol + 2-deoxyglucose, DNP + 2-DOG) indicating a near total loss of MgATP. The consequences of these events therefore need to be considered in the context of sensory neuron function in ischemia.


Glomerular responses to platelet-activating factor in the rat: role of thromboxane A2.
In view of its role as a pro-inflammatory mediator in glomerular injury, we investigated the renal cortical microcirculatory responses to the intrarenal arterial administration of platelet-activating factor (PAF) in the anesthetized euvolemic Munich-Wistar rat. Close arterial administration of PAF led to dose-dependent reductions in renal plasma flow rate (RPF), glomerular filtration rate (GFR), and filtration fraction (FF), in the absence of hypotension or hemoconcentration. Single-nephron (SN) plasma flow rate (QA), SNGFR and SNFF also fell [126 +/- 7 to 101 +/- 6 nl/min (P less than 0.005), 40.6 +/- 2.1 to 21.5 +/- 2.5 nl/min (P less than 0.005), and 0.33 +/- 0.03 to 0.21 +/- 0.03 (P less than 0.025)]. PAF increased pre- and postglomerular arteriolar resistances [2.32 +/- 0.14 to 2.73 +/- 0.19 (P less than 0.005) and 1.32 +/- 0.13 to 1.45 +/- 0.10(10)dyn.s.cm-5 (P less than 0.05)]. PAF infusion also led to a dramatic reduction in the mean value for the glomerular capillary ultrafiltration coefficient, Kf [0.058 +/- 0.012 to 0.020 +/- 0.003 nl.s-1.mmHg (P less than 0.025)]. PAF-induced changes in renal hemodynamics were abolished in the presence of the cyclooxygenase inhibitors, indomethacin and ibuprofen. When administered concomitantly with a thromboxane A2 (TxA2) receptor antagonist, PAF led to significant increases in RPF and GFR. In isolated glomeruli, PAF stimulated the biosynthesis of TxB2 in a dose-dependent manner. Thus PAF depresses rat glomerular function by inducing contraction of arteriolar and mesangial smooth muscle. These effects are likely mediated via the secondary release of TxA2.


How myosin organization of the actin cytoskeleton contributes to the cancer phenotype.
The human genome contains 39 genes that encode myosin heavy chains, classified on the basis of their sequence similarity into 12 classes. Most cells express at least 12 different genes, from at least 8 different classes, which are typically composed of several class 1 genes, at least one class 2 gene and classes 5, 6, 9, 10, 18 and 19. Although the different myosin isoforms all have specific and non-overlapping roles in the cell, in combination they all contribute to the organization of the actin cytoskeleton, and the shape and phenotype of the cell. Over (or under) expression of these different myosin isoforms can have strong effects on actin organization, cell shape and contribute to the cancer phenotype as discussed in this review.


Suspended in time: Molecular responses to hibernation also promote longevity.
Aging in most animals is an inevitable process that causes or is a result of physiological, biochemical, and molecular changes in the body, and has a strong influence on an organism's lifespan. Although advancement in medicine has allowed humans to live longer, the prevalence of age-associated medical complications is continuously burdening older adults worldwide. Current animal models used in research to study aging have provided novel information that has helped investigators understand the aging process; however, these models are limiting. Aging is a complex process that is regulated at multiple biological levels, and while a single manipulation in these models can provide information on a process, it is not enough to understand the global regulation of aging. Some mammalian hibernators live up to 9.8-times higher than their expected average lifespan, and new research attributes this increase to their ability to hibernate. A common theme amongst these mammalian hibernators is their ability to greatly reduce their metabolic rate to a fraction of their normal rate and initiate cytoprotective responses that enable their survival. Metabolic rate depression is strictly regulated at different biological levels in order to enable the animal to not only survive, but to also do so by relying mainly on their limited internal fuels. As such, understanding both the global and specific regulatory mechanisms used to promote survival during hibernation could, in theory, allow investigators to have a better understanding of the aging process. This can also allow pharmaceutical industries to find therapeutics that could delay or reverse age-associated medical complications and promote healthy aging and longevity in humans.


In-air and underwater performance and finite element analysis of a flextensional device having electrostrictive poly(vinylidene fluoride-trifluoroethylene) polymers as the active driving element.
A flextensional transducer, in which the electrostrictive poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] copolymer was used as the active driving element, was fabricated and characterized. The results show that transducers of several millimeters thick can produce an axial displacement of more than 1 mm in air along the thickness direction, and a transmitting voltage response of 123 dB re 1 microPa/V at 1 m in water at frequencies of several kilohertz. A finite element code (ANSYS, Inc., Canonsburg, PA) was used to model the in-air and underwater responses of the flextensional transducer over a broad frequency range. The calculated resonance frequencies and transmitting voltage response spectra show good agreement with the experimental data. In addition, the performance of both the in-air actuator and underwater transducer was analyzed for different design parameters of the flextensional structure. These results show that the performance of the flextensional transducer could be tailored readily by adjusting the parameters of the flextensional metal shell.


Gastrostomy insertion in head and neck cancer patients: a 3 year review of insertion method and complication rates.
Patients with head and neck cancer who have resection, radiotherapy, chemoradiotherapy, or a combination of these require nutritional support to be implemented before treatment, and this may involve insertion of a prophylactic gastrostomy feeding tube. The aim of this study was to compare the use and complication rates of percutaneous endoscopic gastrostomy (PEG) and radiologically inserted gastrostomy (RIG) in these patients at a tertiary referral centre. We retrospectively reviewed gastrostomy data forms completed by nutritional support nursing staff over a recent 34-month period, which included information on method of insertion, 30-day postoperative serious and minor complications, and mortality. A total of 110 patients had prophylactic insertion of a gastrostomy (21 PEG, 89 RIG) over the study period. In the first 12 months 13 (31%) PEG feeding tubes were placed but in the last 12 months none were inserted using an endoscopic approach. Serious complications occurred with 2 (10%) PEG and 12 (13%) RIG; the most common cause was accidental removal of the tube (n=13, 12%). Minor complications of peristomal infection, leakage, or blockage of the tube occurred in 6 (5%) gastrostomies. No patients died during the study period. In recent years, and in the absence of recommended guidelines, there has been an increase in the elective insertion of RIG in patients with head and neck cancer. Serious complications for both methods of insertion in this study are comparable with similar reports. However, with RIG there is a high rate of tubes becoming dislodged with the potential for serious consequences. The most appropriate method to insert a gastrostomy tube in patients with head and neck cancer remains unclear.


Selected stormwater priority pollutants: a European perspective.
The chemical characteristics of stormwater are dependent on the nature of surfaces (roads, roofs etc.) with which it comes into contact during the runoff process as well as natural processes and anthropogenic activities in the catchments. The different types of pollutants may cause problems during utilisation, detention or discharge of stormwater to the environment and may pose specific demands to decentralised treatment. This paper proposes a scientifically justifiable list of selected stormwater priority pollutants (SSPP) to be used, e.g., for evaluation of the chemical risks occurring in different handling strategies. The SSPP-list consists of 25 pollutant parameters including eight of the priority pollutants currently identified in the European Water Framework Directive. It contains general water quality parameters (organic and suspended matter, nutrients and pH); metals (Cd, Cr, Cu, Ni, Pb, Pt and Zn); PAH (naphthalene, pyrene and benzo[a]pyrene); herbicides (pendimethalin, phenmedipham, glyphosate and terbutylazine); and other representative industrially derived compounds (nonylphenol ethoxylates, pentachlorophenol, di(2-ethylhexyl)phthalate, PCB-28 and methyl tert-butyl ether). Tools for flux modelling, enabling calculation of predicted environmental concentrations (PECs), and for ranking the susceptibility of a pollutant to removal within a range of structural stormwater treatment systems or best management practices (BMPs) have been developed, but further work is required to allow all SSPPs to be addressed in the development of future stormwater pollution control measures. In addition, the identified SSPPs should be considered for inclusion in stormwater related monitoring campaigns.


Arithmetic difficulties in females with the fragile X premutation.
Females with the fragile X full mutation have been reported to have difficulty learning mathematics. Women with the fragile X premutation often give a history of mathematics difficulties in themselves especially with higher level math. In order to evaluate whether women with the premutation have difficulty with math, we asked women with both the fragile X premutation and full mutation to complete the Wide Range Achievement Test-3. For the group of 39 women with the fragile X premutation, the median standard score on the Arithmetic portion was 93, which was significantly lower (P = 0.001) than the median of the standardized norm of 100. Only nine of the women had Arithmetic scores at or above the 50th centile, while over half of the women had standard scores at or above the 50th centile in Reading and Spelling. The eight women with the full mutation also had lower Arithmetic scores than Reading and Spelling scores. These data suggest that mathematics may be an area of relative weakness for the women with the premutation as well as the full mutation. This possibility should be evaluated further by using other measures. This information is important both for counseling purposes and to understand whether a mathematics deficit is evidence of low expression of the FMR1 gene in the premutation state.


Priming prepositional-phrase attachment during comprehension.
Strong evidence suggests that prior syntactic context affects language production (e.g., J. K. Bock, 1986). The authors report 4 experiments that used an expression-picture matching task to investigate whether it also affects ambiguity resolution in comprehension. All experiments examined the interpretation of prepositional phrases that were ambiguous between high and low attachment. After reading a prime expression with a high-attached interpretation, participants tended to interpret an ambiguous prepositional phrase in a target expression as highly attached if it contained the same verb as the prime (Experiment 1), but not if it contained a different verb (Experiment 2). They also tended to adopt the high-attached interpretation after producing a prime with the high-attached interpretation that included the same verb (Experiment 3). Finally, they were faster to adopt a high-attached interpretation after reading an expression containing the same verb that was disambiguated to the high-attached versus the low-attached interpretation (Experiment 4).


Plasmonic ruler on field-effect devices for kinase drug discovery applications.
Protein kinases are cellular switches that mediate phosphorylation of proteins. Abnormal phosphorylation of proteins is associated with lethal diseases such as cancer. In the pharmaceutical industry, protein kinases have become an important class of drug targets. This study reports a versatile approach for the detection of protein phosphorylation. The change in charge of the myelin basic protein upon phosphorylation by the protein kinase C-alpha (PKC-α) in the presence of adenosine 5'-[γ-thio] triphosphate (ATP-S) was detected on gold metal-insulator-semiconductor (Au-MIS) capacitor structures. Gold nanoparticles (AuNPs) can then be attached to the thio-phosphorylated proteins, forming a Au-film/AuNP plasmonic couple. This was detected by a localized surface plasmon resonance (LSPR) technique alongside MIS capacitance. All reactions were validated using surface plasmon resonance technique and the interaction of AuNPs with the thio-phosphorylated proteins quantified by quartz crystal microbalance. The plasmonic coupling was also visualized by simulations using finite element analysis. The use of this approach in drug discovery applications was demonstrated by evaluating the response in the presence of a known inhibitor of PKC-α kinase. LSPR and MIS on a single platform act as a cross check mechanism for validating kinase activity and make the system robust to test novel inhibitors.


The impact of body fat on three dimensional motion of the paediatric foot during walking.
Childhood obesity is commonly associated with a pes planus foot type and altered lower limb joint function during walking. However, limited information has been reported on dynamic intersegment foot motion with the level of obesity in children. The aim of this study was to explore the relationships between intersegment foot motion during gait and body fat in boys age 7-11 years. Fat mass was measured in fifty-five boys using air displacement plethysmography. Three-dimensional gait analysis was conducted on the right foot of each participant using the 3DFoot model to capture angular motion of the shank, calcaneus, midfoot and metatarsals. Two multivariate statistical techniques were employed; principle component analysis reduced the multidimensional nature of gait analysis, and multiple linear regression analysis accounted for potential confounding factors. Higher fat mass predicted greater plantarflexion of the calcaneus during the first half and end of stance phase and at the end of swing phase. Greater abduction of the calcaneus throughout stance and swing was predicted by greater fat mass. At the midfoot, higher fat mass predicted greater dorsiflexion and eversion throughout the gait cycle. The findings present novel information on the relationships between intersegment angular motion of the foot and body fat in young boys. The data indicates a more pronated foot type in boys with greater body fat. These findings have clinical implications for pes planus and a predisposition for pain and discomfort during weight bearing activities potentially reducing motivation in obese children to be physically active.


Three-dimensional structure of the flavoenzyme acyl-CoA oxidase-II from rat liver, the peroxisomal counterpart of mitochondrial acyl-CoA dehydrogenase.
Acyl-CoA oxidase (ACO) catalyzes the first and rate-determining step of the peroxisomal beta-oxidation of fatty acids. The crystal structure of ACO-II, which is one of two forms of rat liver ACO (ACO-I and ACO-II), has been solved and refined to an R-factor of 20.6% at 2.2-A resolution. The enzyme is a homodimer, and the polypeptide chain of the subunit is folded into the N-terminal alpha-domain, beta-domain, and C-terminal alpha-domain. The X-ray analysis showed that the overall folding of ACO-II less C-terminal 221 residues is similar to that of medium-chain acyl-CoA dehydrogenase (MCAD). However, the N-terminal alpha- and beta-domains rotate by 13 with respect to the C-terminal alpha-domain compared with those in MCAD to give a long and large crevice that accommodates the cofactor FAD and the substrate acyl-CoA. FAD is bound to the crevice between the beta- and C-terminal domains with its adenosine diphosphate portion interacting extensively with the other subunit of the molecule. The flavin ring of FAD resides at the active site with its si-face attached to the beta-domain, and is surrounded by active-site residues in a mode similar to that found in MCAD. However, the residues have weak interactions with the flavin ring due to the loss of some of the important hydrogen bonds with the flavin ring found in MCAD. The catalytic residue Glu421 in the C-terminal alpha-domain seems to be too far away from the flavin ring to abstract the alpha-proton of the substrate acyl-CoA, suggesting that the C-terminal domain moves to close the active site upon substrate binding. The pyrimidine moiety of flavin is exposed to the solvent and can readily be attacked by molecular oxygen, while that in MCAD is protected from the solvent. The crevice for binding the fatty acyl chain is 28 A long and 6 A wide, large enough to accommodate the C23 acyl chain.


Clinic variation in the cost-effectiveness of contingency management.
This study determined whether, and by how much, the cost-effectiveness of contingency management (CM) varied across the eight clinics in the National Institute on Drug Abuse Clinical Trials Network MIEDAR trial. Incremental costs, incremental outcomes, and incremental cost-effectiveness ratios (ICERs) of CM compared to usual care were calculated, compared and contrasted for each of the clinics. Results showed that the incremental cost of using CM compared to usual care varied by a factor of 1.9 across the clinics, ranging from an additional $306 to an additional $582 per patient. The effect of CM on the longest duration of continuous stimulant abstinence (LDA) varied by a factor of 8.0 across the clinics, ranging from an additional 0.5 to an additional 4.0 weeks. The ICERs for the LDA varied by a factor of 4.6 across the clinics, ranging from $145 to $666. These results show that the cost-effectiveness of CM varied widely among the clinics in the MIEDAR trial. Future research should focus on identifying the sources of this variation, perhaps by identifying clinic-level best practices and/or identifying those subgroups of patients that respond the most cost-effectively, with the ultimate goal of improving the cost-effectiveness of CM overall.


Bio-physically plausible visualization of highly scattering fluorescent neocortical models for in silico experimentation.
We present a visualization pipeline capable of accurate rendering of highly scattering fluorescent neocortical neuronal models. The pipeline is mainly developed to serve the computational neurobiology community. It allows the scientists to visualize the results of their virtual experiments that are performed in computer simulations, or in silico. The impact of the presented pipeline opens novel avenues for assisting the neuroscientists to build biologically accurate models of the brain. These models result from computer simulations of physical experiments that use fluorescence imaging to understand the structural and functional aspects of the brain. Due to the limited capabilities of the current visualization workflows to handle fluorescent volumetric datasets, we propose a physically-based optical model that can accurately simulate light interaction with fluorescent-tagged scattering media based on the basic principles of geometric optics and Monte Carlo path tracing. We also develop an automated and efficient framework for generating dense fluorescent tissue blocks from a neocortical column model that is composed of approximately 31000 neurons. Our pipeline is used to visualize a virtual fluorescent tissue block of 50 μm3 that is reconstructed from the somatosensory cortex of juvenile rat. The fluorescence optical model is qualitatively analyzed and validated against experimental emission spectra of different fluorescent dyes from the Alexa Fluor family. We discussed a scientific visualization pipeline for creating images of synthetic neocortical neuronal models that are tagged virtually with fluorescent labels on a physically-plausible basis. The pipeline is applied to analyze and validate simulation data generated from neuroscientific in silico experiments.


Preparation of nucleosomes containing a specific H2A-H2A cross-link forming a DNA-constraining loop structure.
ATP-dependent chromatin-remodeling complexes use the energy of ATP hydrolysis to alter nucleosome structure, increase the accessibility of trans-acting factors, and induce nucleosome movement on the nucleosomal DNA. Recent studies suggest that bulge propagation is a major component of the mechanism for SWI/SNF remodeling. We describe in detail a method to prepare a mononucleosomal substrate in which the two H2A N-terminal tails are cross-linked in an intranucleosomal fashion, forming a closed loop around the two superhelical winds of DNA. This substrate is useful for researchers who wish to test processes in which the DNA is transiently or permanently lifted off the histone surface, such as in the bulge propagation model. Our method allows assessment of the extent of cross-linking within the population of nucleosomes used in small-scale experiments, such as assays to test SWI/SNF-remodeling activities.


A new autosomal-dominant locus (DFNA12) is responsible for a nonsyndromic, midfrequency, prelingual and nonprogressive sensorineural hearing loss.
This study aimed to report on the audiologic findings of a nonsyndromic autosomal-dominant hearing loss of which the gene (DFNA 12) recently was found to map to chromosome 11q22-24. The study also aimed to propose and evaluate an algorithm based on the audiometric findings to discriminate between affected and unaffected family members before genetic linkage analysis. The study design was a retrospective analysis of the audiometric data of genetically affected and unaffected patients. The study was conducted at a tertiary referral center. A total of 17 genetically affected and 54 unaffected family members were studied. Pure-tone audiometry with air and bone conduction and construction and evaluation of an algorithm were performed. The type and degree of hearing loss as compared to age and gender-dependent values according to the International Organization for Standardization 7029 standard were measured. For this comparison, the variable "hearing standard deviations" (HSD) is introduced and is defined as the number of standard deviations that a hearing threshold is lying above the age and gender-related median at the given frequency. A description of the algorithm and an evaluation in terms of alpha- and beta-error also were measured. The hearing loss is nonsyndromic, sensorineural, moderate-to-moderately severe (pure-tone average, 51 dB at age 18 years), with an early onset (probably prelingual) and no progression. It affects all frequencies but mainly the midfrequencies (500, 1,000, and 2,000 Hz). The algorithm consists of an analysis of variance to determine the frequency that is most sensitive for the genetic trait under study and on the ranking of the family members according to their hearing loss (HSD) at this frequency. Individual persons are labeled as "affected" or "unaffected" according to this ranking.


MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.
In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism. Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Biochemical and cell biological analyses were carried out to elucidate the pathophysiological significance of the identified gene mutation. We identified a heterozygous missense mutation (c.173C>T; p.Thr58Met) in the MYCN gene, at the Thr58 phosphorylation site essential for ubiquitination and subsequent MYCN degradation. The mutant MYCN (MYCN-T58M) was non-phosphorylatable at Thr58 and subsequently accumulated in cells and appeared to induce CCND1 and CCND2 expression in neuronal progenitor and stem cells in vitro. Overexpression of Mycn mimicking the p.Thr58Met mutation also promoted neuronal cell proliferation, and affected neuronal cell migration during corticogenesis in mouse embryos. We identified a de novo c.173C>T mutation in MYCN which leads to stabilisation and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation in MYCN identified in a patient with a novel megalencephaly syndrome similar to, but distinct from, CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The data obtained here provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.


Glioblastoma patients in Slovenia from 1997 to 2008.
Glioblastoma is the most common primary brain tumour. It has a poor prognosis despite some advances in treatment that have been achieved over the last ten years. In Slovenia, 50 to 60 glioblastoma patients are diagnosed each year. In order to establish whether the current treatment options have any influence on the survival of the Slovenian glioblastoma patients, their data in the period from the beginning of the year 1997 to the end of the year 2008 have been analysed. All patients treated at the Institute of Oncology Ljubljana from 1997 to 2008 were included in the retrospective study. Demographics, treatment details, and survival time after the diagnosis were collected and statistically analysed for the group as a whole and for subgroups. From 1997 to 2008, 527 adult patients were diagnosed with glioblastoma and referred to the Institute of Oncology for further treatment. Their median age was 59 years (from 20 to 85) and all but one had the diagnosis confirmed by a pathologist. Gross total resection was reported by surgeons in 261 (49.5%) patients; good functional status (WHO 0 or 1) after surgery was observed in 336 (63.7%) patients, radiotherapy was performed in 422 (80.1%) patients, in 317 (75.1%) of them with radical intent, and 198 (62.5 %) of those received some form of systemic treatment (usually temozolomide). The median survival of all patients amounted to 9.7 months. There was no difference in median survival of all patients or of all treated patients before or after the chemo-radiotherapy era. However, the overall survival of patients treated with radical intent was significantly better (11.4 months; p < 0.05). A better survival was also noticed in radically treated patients who received additional temozolomide therapy (11.4 vs. 13.1 months; p = 0.014). The longer survival was associated with a younger age and a good performance status as well as with a more extensive tumour resection. In patients treated with radical intent, having a good performance status, and receiving radiotherapy and additional temozolomide therapy, the survival was significantly longer, based on multivariate analysis. We observed a gradual increase in the survival of glioblastoma patients who were treated with radical intent over the last ten years. Good functional surgery, advances in radiotherapy and addition of temozolomide all contributed to this increase. Though the increased survival seems to be more pronounced in certain subgroups, we have still not been able to exactly define them. Further research, especially in tumour biology and genetics is needed.


Coherent versus incoherent Raman scattering: molecular coherence excitation and measurement.
We present a comparative analysis of spontaneous and coherent Raman scattering on pyridine. The instantaneous excitation of the molecular coherence is done by a pair of ultrashort preparation pulses. Then, a long narrowband probe pulse is scattered off the molecular vibrations. The described hybrid technique allows for the single-shot acquisition of a background-free coherent Raman spectrum within the excitation band and its straightforward comparison with the spontaneous Raman measurements, performed in the same setup. We report a 10(5)-fold increase in the efficiency of the Raman scattering process due to the broadband pump-Stokes preparation. The coherence magnitude (approximately 0.5x10(-3)) is inferred experimentally, without a priori knowledge about the molecular structure.


Improvement of skeletal lesions in mice with mucopolysaccharidosis type VII by neonatal adenoviral gene transfer.
Neonatal gene transfer using adenovirus vectors expressing human beta-glucuronidase (AxCAhGUS) resulted in pathological improvement in multiple visceral organs of mice with mucopolysaccharidosis type VII (MPSVII). However, the therapeutic effect on skeletal deformities and growth retardation, the major clinical symptoms in MPSVII, was not fully investigated by biochemical and histopathological analyses. In this study, we injected AxCAhGUS into a murine model of MPSVII (B6/MPSVII) within 24 h of birth and evaluated the therapeutic effects on skeletal deformities and growth retardation. High levels of beta-glucuronidase (GUSB) activity (approximately threefold higher than normal GUSB activity) were observed in the articular cartilage of the mice 30 days after the treatment. Histopathological study in the knee joints showed elimination of vacuole cells in the articular cartilage and growth plate. Subchondral bone near the articular surface was almost normal in the treated MPSVII mice. Long-term observation (for 140 days after treatment) indicated that characteristic phenotypes such as flattened face, hunched stature, and shortening of bone length in the treated mice were almost normal. These results demonstrate that a single injection of adenovirus vector into neonatal MPSVII mice is sufficient for long-term normalization of skeletal deformities and effective in pathological correction of the articular cartilage and growth plate.


Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2.
Multisystem inflammatory syndrome in children (MIS-C) is associated with recent or current SARS-CoV-2 infection. Information on MIS-C incidence is limited. To estimate population-based MIS-C incidence per 1 000 000 person-months and to estimate MIS-C incidence per 1 000 000 SARS-CoV-2 infections in persons younger than 21 years. This cohort study used enhanced surveillance data to identify persons with MIS-C during April to June 2020, in 7 jurisdictions reporting to both the Centers for Disease Control and Prevention national surveillance and to Overcoming COVID-19, a multicenter MIS-C study. Denominators for population-based estimates were derived from census estimates; denominators for incidence per 1 000 000 SARS-CoV-2 infections were estimated by applying published age- and month-specific multipliers accounting for underdetection of reported COVID-19 case counts. Jurisdictions included Connecticut, Georgia, Massachusetts, Michigan, New Jersey, New York (excluding New York City), and Pennsylvania. Data analyses were conducted from August to December 2020. Race/ethnicity, sex, and age group (ie, ≤5, 6-10, 11-15, and 16-20 years). Overall and stratum-specific adjusted estimated MIS-C incidence per 1 000 000 person-months and per 1 000 000 SARS-CoV-2 infections. In the 7 jurisdictions examined, 248 persons with MIS-C were reported (median [interquartile range] age, 8 [4-13] years; 133 [53.6%] male; 96 persons [38.7%] were Hispanic or Latino; 75 persons [30.2%] were Black). The incidence of MIS-C per 1 000 000 person-months was 5.1 (95% CI, 4.5-5.8) persons. Compared with White persons, incidence per 1 000 000 person-months was higher among Black persons (adjusted incidence rate ratio [aIRR], 9.26 [95% CI, 6.15-13.93]), Hispanic or Latino persons (aIRR, 8.92 [95% CI, 6.00-13.26]), and Asian or Pacific Islander (aIRR, 2.94 [95% CI, 1.49-5.82]) persons. MIS-C incidence per 1 000 000 SARS-CoV-2 infections was 316 (95% CI, 278-357) persons and was higher among Black (aIRR, 5.62 [95% CI, 3.68-8.60]), Hispanic or Latino (aIRR, 4.26 [95% CI, 2.85-6.38]), and Asian or Pacific Islander persons (aIRR, 2.88 [95% CI, 1.42-5.83]) compared with White persons. For both analyses, incidence was highest among children aged 5 years or younger (4.9 [95% CI, 3.7-6.6] children per 1 000 000 person-months) and children aged 6 to 10 years (6.3 [95% CI, 4.8-8.3] children per 1 000 000 person-months). In this cohort study, MIS-C was a rare complication associated with SARS-CoV-2 infection. Estimates for population-based incidence and incidence among persons with infection were higher among Black, Hispanic or Latino, and Asian or Pacific Islander persons. Further study is needed to understand variability by race/ethnicity and age group.


Uniformly sized molecularly imprinted polymers for bisphenol A and beta-estradiol: retention and molecular recognition properties in hydro-organic mobile phases.
Uniformly sized molecularly imprinted polymers (MIPs) for bisphenol A (BPA) have been prepared using ethylene glycol dimethacrylate (EDMA) as a cross-linker and methacrylic acid, 2-diethylaminoethyl methacrylate or 4-vinylpyridine (4-VPY) as a functional monomer or without use of a functional monomer. The MIPs obtained for BPA were evaluated using a mixture of phosphate buffer (or water) and acetonitrile or only acetonitrile as the mobile phase. Among the MIPs prepared, that using 4-VPY showed the highest retentivity and selectivity for BPA. The highest selectivity factor, which is defined as the ratio of the retention factors (k) on the molecularly imprinted and non-imprinted polymers, k(imprinted)/k(non-imprinted), was 9.4 for BPA on the BPA-imprinted 4-VPY-co-EDMA polymers, while that for beta-estradiol on the beta-estradiol-imprinted 4-VPY-co-EDMA polymers was 2.4. The differences in the selectivity factors between BPA and beta-estradiol on the respective MIPs could be ascribable to differences in the number of interaction sites. It is plausible that the phenol groups of BPA could interact with two pyridyl groups of the MIP by hydrogen bonding interactions, while there is only one such site for beta-estradiol. Furthermore, the results suggest that hydrophobic and hydrogen bonding interactions can play an important role in the retention and recognition of BPA and beta-estradiol in the hydro-organic mobile phase, while hydrogen bonding interactions seem to be useful for the retention and recognition when acetonitrile is used as the mobile phase.


Treatment strategies for acute fractures and nonunions of the proximal fifth metatarsal.
There are at least three distinct fracture patterns that occur in the proximal fifth metatarsal: tuberosity avulsion fractures, acute Jones fractures, and diaphyseal stress fractures. Each of these fracture patterns has its own mechanism of injury, location, treatment options, and prognosis regarding delayed union and nonunion. Tuberosity avulsion fractures are the most common in this region of the foot. The majority heal with symptomatic care in a hard-soled shoe. The true Jones fracture is an acute injury involving the fourth-fifth intermetatarsal facet. These injuries are best treated with non-weight-bearing cast immobilization for 6 to 8 weeks. The rate of successful union with this treatment has been reported to be between 72% and 93%. For the high-performance athlete with an acute Jones fracture, early intramedullary-screw fixation is an accepted treatment option. Nonacute diaphyseal stress fractures of the proximal fifth metatarsal and Jones fractures that develop into delayed unions and nonunions can both be managed with operative fixation with either closed axial intramedullary-screw fixation or autogenous corticocancellous grafting. Early results with the use of electrical stimulation are promising; however, prospective studies are needed to better define the role of this modality in managing these injuries.


Improvement in irritable bowel syndrome following ano-rectal surgery.
To assess the effect on irritable bowel syndrome (IBS) of treating ano-rectal problems by applying multiple Barron's bands to prolapsing mucosa and excising haemorrhoids, with or without a low lateral sphincterotomy. 144 patients with IBS whose ano-rectal abnormalities were treated by a single consultant surgeon. A prospective "within person" study of consecutive patients referred with ano-rectal problems who also had IBS symptoms according to the Rome criteria. All patients completed structured questionnaires about anal and IBS symptoms before operation and 6-60 months later. The findings were compared with those from patients who had no abdominal pains. The principal IBS symptoms of abdominal pain, abdominal distension, and altered bowel habit all improved significantly after operation. Those with persistent anal problems had more problems with persistent IBS symptoms, but when the anal problems were corrected, the IBS tended to settle. Posterior anal tenderness is present in 80% of IBS patients and is a useful diagnostic sign. This work suggests that in many patients with IBS there is a physical ano-rectal disorder amenable to physical treatment. Patients with IBS should all be proctoscoped carefully, with and without the patient straining, looking for abnormalities. Correcting mucosal prolapse and other anal problems produced an improvement in IBS symptoms in 86% of patients. This suggests that ano-enteric reflexes are a significant factor in irritable bowel syndrome, if not the major cause.


p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses.
The mitogen-activated protein (MAP) kinase protein family has a critical role in cellular signaling events, with MAP kinase p38alpha acting in inflammatory processes and being an important drug discovery target. MAP kinase drug design efforts have focused on small-molecule inhibitors of the ATP catalytic site, which exhibit dose-limiting adverse effects. Therefore, characterizing other potential sites that bind substrates, inhibitors, or allosteric effectors is of great interest. Here, we present the crystal structure of human p38alpha MAP kinase, which has a lead compound bound both in the active site and in the lipid-binding site of the C-terminal cap. This C-terminal cap is formed from an extension to the kinase fold, unique to the MAP kinase and cyclin-dependent kinase families and glycogen synthase kinase 3. Binding of this lead, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine, to wild-type p38alpha induces movement of the C-terminal cap region, creating a hydrophobic pocket centered around residue Trp197. Computational analysis of this C-terminal domain pocket indicates notable flexibility for potentially binding different-shaped compounds, including lipids, oxidized arachidonic acid species such as leukotrienes, and small-molecule effectors. Furthermore, our structural results defining the open p38alpha C-lobe pocket provide a detailed framework for the design of novel small molecules with affinities comparable to active-site binders: to bind and potentially modulate the shape and activity of p38alpha in predetermined ways. Moreover, these results and analyses of p38alpha suggest strategies for designing specific binding compounds applicable to other MAP kinases, as well as the cyclin-dependent kinase family and glycogen synthase kinase 3beta that also utilize the C-terminal insert in their interactions.


Selective IgA deficiency and Crohn's disease: report of two cases.
Two patients are described with Crohn's disease and selective IgA deficiency. Serum IgA was undetectable in each case, and immunoperoxidase studies of the lamina propria showed a gross diminution of IgA-bearing plasma cells. Peripheral blood lymphocytes, however, showed normal numbers of IgA-bearing lymphocytes. The typical clinical course and histology in these two patients suggest that IgA-mediated responses in the mucosa are not involved in the pathogenesis of Crohn's disease.


A pilot study of faith healers' views on evil eye, jinn possession, and magic in the kingdom of saudi arabia.
Faith healers usually offer unorthodox therapies to their clients who present with an array of physical and psychological symptoms suggestive of the evil eye, jinn possession, and magic. This exploratory pilot study aims to analyse the pattern of narrated symptoms and treatments given by faith healers practising in the Al-Qassim region, Saudi Arabia. Forty five faith healers who consented to this study were given a predesigned, self-administered, semistructured questionnaire to collect the relevant data. Notably, most faith healers have a poor repertoire of psychiatric symptoms, which could not specifically differentiate the three spiritual disorders. They tend to recommend an array of therapies rooted in religious concepts for the treatment of their clients who, they claim, show substantial improvement in their mental suffering. The revealed symptomatology of each disorder alone may not be specific but it certainly helps them not only to identify these disorders but also to prescribe unconventional therapies. Future research should look systematically into the diagnostic and treatment methods for these disorders.


High-order spectral/hp element discretisation for reaction-diffusion problems on surfaces: Application to cardiac electrophysiology.
We present a numerical discretisation of an embedded two-dimensional manifold using high-order continuous Galerkin spectral/hp elements, which provide exponential convergence of the solution with increasing polynomial order, while retaining geometric flexibility in the representation of the domain. Our work is motivated by applications in cardiac electrophysiology where sharp gradients in the solution benefit from the high-order discretisation, while the computational cost of anatomically-realistic models can be significantly reduced through the surface representation and use of high-order methods. We describe and validate our discretisation and provide a demonstration of its application to modelling electrochemical propagation across a human left atrium.


Developing laboratory capacity for Good Laboratory Practice certification: lessons from a Tanzanian insecticide testing facility.
Background: With increasing insecticide resistance in malaria-endemic countries there is an urgent need for safe and effective novel vector control products. To improve the capacity of facilities that test insecticides in sub-Saharan Africa, a programme is supporting seven facilities towards Good Laboratory Practice (GLP) certification, the globally recognized standard for quality management system (QMS) for the conduct of non-clinical and environmental studies. The World Health Organization (WHO) GLP Handbook provides guidance on a stepwise approach to implement a GLP compliant QMS. This study assesses auditor GLP checklists and timings outlined in the WHO GLP Handbook in the real-life context of a Tanzanian insecticide-testing facility, evaluating their implementation in this context. Methods and Principle Findings: We conducted document review and semi-structured interviews with staff at all levels of the test facility to explore factors that influenced progress towards GLP certification. We found that while auditor GLP checklists underemphasised computer systems, they were otherwise broadly applicable. Factors that delayed time to completion of GLP certification included the need for extensive infrastructure improvements, the availability of regional expertise related to GLP, the capacity of national and regional external systems and services to meet GLP compliance requirements, and training development required for Standard Operating Procedure implementation. Conclusion: The standards required for full GLP compliance are rigorous, with an expected completion timeline to implementation of 24 months. This study shows that in low and middle-income countries this timeline may be unrealistic due to challenges related to infrastructure development and lack of regional capacity and expertise. We recommend a comprehensive gap analysis when starting a project, including these areas which are beyond those recommended by the WHO GLP Handbook. These challenges can be successfully overcome and the experience in Tanzania provides key lessons for other facilities seeking GLP certification or the development of similar QMS.


Reaction time as a measure of binocular interaction in human vision.
In a series of psychophysical experiments monocular and binocular reaction times (RTs) were measured in response to the presentation of sinusoidal grating patterns. Over a wide range of contrast values, binocular RT was consistently faster than monocular RT, even at high-contrast levels where RT had reached asymptotic levels. For observers with good stereopsis this binocular summation effect was greater than that expected on the basis of probability summation alone, whereas observers with deficient stereopsis performed at the level of probability summation. For normal observers broadband random noise presented to one eye produced an elevation in RT to gratings presented to the other eye; no such dichoptic masking effect was found in a stereoblind observer. These results validate the use of RT as an efficient, reliable measure of binocular interaction in human vision.


Changes in latent fingermark glyceride composition as a function of sample age using UPLC-IMS-QToF-MSE.
The composition of fingermark residue has been an important topic in forensic science, mainly in efforts to better understand and eventually improve the efficacy of latent fingermark detection methods. While the lipid fraction has been extensively studied, there is currently little information about how the glyceride fraction of latent fingermarks is chemically altered over time following deposition. A previously reported untargeted ultra performance liquid chromatography-ion mobility spectrometry-quadrupole time-of-flight mass spectrometry (UPLC-IMS-QToF-MSE) method was used to investigate changes over time in fingermark di- and triglycerides. Charged latent fingermark samples from 5 donors were analysed up to 28 days following deposition. Significant changes in glyceride composition occurred with increased sample age, attributed primarily to the oxidation of unsaturated triglycerides through ozonolysis. Considerably fewer unsaturated TGs were identified in samples 7 and 28 days following deposition, while mono- and diozonides of these lipids were identified as major components of aged samples. Additional compounds were identified as possible aldehyde and carboxylic acid derivatives resulting from the reaction of water with ozonolysis intermediates. While the onset of these processes occurred rapidly following deposition, continuing oxidation over time was seen via the progressive ozonolysis of diunsaturated triglycerides. These results represent a further step towards understanding the factors affecting fingermark composition, ageing and subsequent detection under operational conditions.


Influence of Therapeutic Play on the anxiety of hospitalized school-age children: Clinical trial.
To evaluate the effects of Dramatic Therapeutic Play (DTP) technique on the degree of anxiety in hospitalized school-age children. Randomized clinical trial performed in two hospitals ofSão Paulo, between May and October 2015. The intervention consisted of the application of DTP and the outcome was evaluated through the Child Drawing: Hospital (CD: H) instrument. The Wilcoxon-Mann Whitney, Corrected t, Fisher's exact and Chi-square tests were used in the analysis. Statistical significance was set at 5%. In all, 28 children participated in the study. The majority of children (75%) had a low anxiety score, with a mean CD: H score of 73.9 and 69.4 in the intervention and control groups respectively, and with no significant difference. Children submitted to DTP had the same degree of anxiety as those in the control group. However, it is suggested that new studies be performed with a larger number of children in different hospitalization scenarios.


Genome wide characterization of enterotoxigenic Escherichia coli serogroup O6 isolates from multiple outbreaks and sporadic infections from 1975-2016.
Enterotoxigenic Escherichia coli (ETEC) are an important cause of diarrhea globally, particularly among children under the age of five in developing countries. ETEC O6 is the most common ETEC serogroup, yet the genome wide population structure of isolates of this serogroup is yet to be determined. In this study, we have characterized 40 ETEC O6 isolates collected between 1975-2016 by whole genome sequencing (WGS) and by phenotypic antimicrobial susceptibility testing. To determine the relatedness of isolates, we evaluated two methods-whole genome high-quality single nucleotide polymorphism (whole genome-hqSNP) and core genome SNP analyses using Lyve-SET and Parsnp respectively. All isolates were tested for antimicrobial susceptibility using a panel of 14 antibiotics. ResFinder 2.1 and a custom quinolone resistance determinants workflow were used for resistance determinant detection. VirulenceFinder 1.5 was used for prediction of the virulence genes. Thirty-seven isolates clustered into three major clades (I, II, III) by whole genome-hqSNP and core genome SNP analyses, while three isolates included in the whole genome-hqSNP analysis only did not cluster with clades I-III by both analyses and formed a distantly related outgroup, designated clade IV. Median number of pairwise whole genome-hqSNPs in clonal ETEC O6 outbreaks ranged from 0 to 5. Of the 40 isolates tested for antimicrobial susceptibility, 18 isolates were pansusceptible. Twenty-two isolates were resistant to at least one antibiotic, nine of which were multidrug resistant. Phenotypic antimicrobial resistance (AR) correlated with AR determinants in 22 isolates. Thirty-two isolates harbored both enterotoxin virulence genes while the remaining 8 isolates had only one of the two virulence genes. In summary, whole genome-hqSNP and core genome SNP analyses from this study revealed similar evolutionary relationships and an overall diversity of ETEC O6 isolates independent of time of isolation. Less than 5 pairwise hqSNPs between ETEC O6 isolates is circumstantially indicative of an outbreak cluster. Findings from this study will be a basis for quicker outbreak detection and control by efficient subtyping by WGS.


ICD-11 (JLMMS) and SCT Inter-Operation.
The goal of this work is to contribute to a smooth and semantically sound inter-operability between the ICD-11 (International Classification of Diseases-11th revision Joint Linearization for Mortality, Morbidity and Statistics) and SNOMED CT (SCT). To guarantee such inter-operation between a classification, characterized by a single hierarchy of mutually exclusive and exhaustive classes, as is the JLMMS successor of ICD-10 on the one hand, and the multi-hierarchical, ontology-based clinical terminology SCT on the other hand, we use ontology axioms that logically express generalizable truths. This is expressed by the compositional grammar of SCT, together with queries on axiomsof SCT. We test the feasibility of the method on the circulatory chapter of ICD-11 JLMMS and present limitations and results.


Self-assembled SnO2 micro- and nanosphere-based gas sensor thick films from an alkoxide-derived high purity aqueous colloid precursor.
Tin oxide is considered to be one of the most promising semiconductor oxide materials for use as a gas sensor. However, a simple route for the controllable build-up of nanostructured, sufficiently pure and hierarchical SnO2 structures for gas sensor applications is still a challenge. In the current work, an aqueous SnO2 nanoparticulate precursor sol, which is free of organic contaminants and sorbed ions and is fully stable over time, was prepared in a highly reproducible manner from an alkoxide Sn(OR)4 just by mixing it with a large excess of pure neutral water. The precursor is formed as a separate liquid phase. The structure and purity of the precursor is revealed using XRD, SAXS, EXAFS, HRTEM imaging, FTIR, and XRF analysis. An unconventional approach for the estimation of the particle size based on the quantification of the Sn-Sn contacts in the structure was developed using EXAFS spectroscopy and verified using HRTEM. To construct sensors with a hierarchical 3D structure, we employed an unusual emulsification technique not involving any additives or surfactants, using simply the extraction of the liquid phase, water, with the help of dry butanol under ambient conditions. The originally generated crystalline but yet highly reactive nanoparticles form relatively uniform spheres through self-assembly and solidify instantly. The spheres floating in butanol were left to deposit on the surface of quartz plates bearing sputtered gold electrodes, producing ready-for-use gas sensors in the form of ca. 50 μm thick sphere-based-films. The films were dried for 24 h and calcined at 300 °C in air before use. The gas sensitivity of the structures was tested in the temperature range of 150-400 °C. The materials showed a very quickly emerging and reversible (20-30 times) increase in electrical conductivity as a response to exposure to air containing 100 ppm of H2 or CO and short (10 s) recovery times when the gas flow was stopped.


Gender-informed, psychoeducational programme for couples to prevent postnatal common mental disorders among primiparous women: cluster randomised controlled trial.
Interventions to prevent postpartum common mental disorders (PCMD) among unselected populations of women have had limited success. The aim was to determine whether What Were We Thinking (WWWT) a gender-informed, psychoeducational programme for couples and babies can prevent PCMD among primiparous women 6 months postpartum. Cluster-randomised controlled trial. 48 Maternal and Child Health Centres (MCHCs) from 6 Local Government Areas in Melbourne, Australia were allocated randomly to usual care (24) or usual care plus WWWT (24). English-speaking primiparous women receiving primary care at trial MCHCs were recruited to the intervention (204) and control (196) conditions. Of these, 187 (91.7%) and 177 (90.3%) provided complete data. WWWT is a manualised programme comprising primary care from a trained nurse, print materials and a face-to-face seminar. Data sources were standardised and study-specific measures collected in blinded computer-assisted telephone interviews at 6 and 26 weeks postpartum. The primary outcome was PCMD assessed by Composite International Diagnostic Interviews and Patient Health Questionnaire (PHQ) Depression and Generalised Anxiety Disorder modules. In intention-to-treat analyses the adjusted OR (AOR) of PCMD in the intervention compared to the usual care group was 0.78 (95% CI 0.38 to 1.63, ns), but mild to moderate anxiety symptoms (AOR 0.58, 95% CI 0.35 to 0.97) and poor self-rated health (AOR 0.46, 95% CI 0.22 to 0.97) were significantly lower. In a per protocol analysis, comparing the full (three component) intervention and usual care groups, the AOR of PCMD was 0.36, (95% CI 0.14 to 0.95). The WWWT seminar was appraised as salient, comprehensible and useful by >85% participants. No harms were detected. WWWT is readily integrated into primary care, enables inclusion of fathers and addresses modifiable risks for PCMD directly. The full intervention appears a promising programme for preventing PCMD, optimising family functioning, and as the first component of a stepped approach to mental healthcare. ACTRN12613000506796; Results.