Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an 'Immune Cold' Phenotype Associated with Poor Survival.

New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an 'immune cold' tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC

Structured feedback on students’ concept maps: the proverbial path to learning?

Good conceptual knowledge is an essential requirement for health professions students, in that they are required to apply concepts learned in the classroom to a variety of different contexts. However, the use of traditional methods of assessment limits the educator’s ability to correct students’ conceptual knowledge prior to altering the educational context. Concept mapping (CM) is an educational tool for evaluating conceptual knowledge, but little is known about its use in facilitating the development of richer knowledge frameworks. In addition, structured feedback has the potential to develop good conceptual knowledge. The purpose of this study was to use Kinchin’s criteria to assess the impact of structured feedback on the graphical complexity of CM’s by observing the development of richer knowledge frameworks. Fifty-eight physiotherapy students created CM’s targeting the integration of two knowledge domains within a case-based teaching paradigm. Each student received one round of structured feedback that addressed correction, reinforcement, forensic diagnosis, benchmarking, and longitudinal development on their CM’s prior to the final submission. The concept maps were categorized according to Kinchin’s criteria as either Spoke, Chain or Net representations, and then evaluated against defined traits of meaningful learning. The inter-rater reliability of categorizing CM’s was good. Pre-feedback CM’s were predominantly Chain structures (57%), with Net structures appearing least often. There was a significant reduction of the basic Spoke- structured CMs (P = 0.002) and a significant increase of Net-structured maps (P < 0.001) at the final evaluation (post-feedback). Changes in structural complexity of CMs appeared to be indicative of broader knowledge frameworks as assessed against the meaningful learning traits. Feedback on CM’s seemed to have contributed towards improving conceptual knowledge and correcting naive conceptions of related knowledge. Educators in medical education could therefore consider using CM’s to target individual student development

Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery

Testing the cognitive-behavioural maintenance models across DSM-5 bulimic-type eating disorder diagnostic groups: A multi-centre study

The original cognitive-behavioural (CB) model of bulimia nervosa, which provided the basis for the widely used CB therapy, proposed that specific dysfunctional cognitions and behaviours maintain the disorder. However, amongst treatment completers, only 40–50 % have a full and lasting response. The enhanced CB model (CB-E), upon which the enhanced version of the CB treatment was based, extended the original approach by including four additional maintenance factors. This study evaluated and compared both CB models in a large clinical treatment seeking sample (N = 679), applying both DSM-IV and DSM-5 criteria for bulimic-type eating disorders. Application of the DSM-5 criteria reduced the number of cases of DSM-IV bulimic-type eating disorders not otherwise specified to 29.6 %. Structural equation modelling analysis indicated that (a) although both models provided a good fit to the data, the CB-E model accounted for a greater proportion of variance in eating-disordered behaviours than the original one, (b) interpersonal problems, clinical perfectionism and low self-esteem were indirectly associated with dietary restraint through over-evaluation of shape and weight, (c) interpersonal problems and mood intolerance were directly linked to binge eating, whereas restraint only indirectly affected binge eating through mood intolerance, suggesting that factors other than restraint may play a more critical role in the maintenance of binge eating. In terms of strength of the associations, differences across DSM-5 bulimic-type eating disorder diagnostic groups were not observed. The results are discussed with reference to theory and research, including neurobiological findings and recent hypotheses

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Molecular signature for receptor engagement in the metabolic peptide hormone amylin

The pancreatic peptide hormone, amylin, plays a critical role in the control of appetite, and synergizes with other key metabolic hormones such as glucagon-like peptide 1 (GLP-1). There is opportunity to develop potent and long-acting analogs of amylin or hybrids between these and GLP-1 mimetics for treating obesity. To achieve this, interrogation of how the 37 amino acid amylin peptide engages with its complex receptor system is required. We synthesized an extensive library of peptides to profile the human amylin sequence, determining the role of its disulfide loop, amidated C-terminus and receptor “capture” and “activation” regions in receptor signaling. We profiled four signaling pathways with different ligands at multiple receptor subtypes, in addition to exploring selectivity determinants between related receptors. Distinct roles for peptide sub-regions in receptor binding and activation were identified, resulting in peptides with greater activity than the native sequence. Enhanced peptide activity was preserved in the brainstem, the major biological target for amylin. Interpretation of our data using full-length active receptor models supported by molecular dynamics, metadynamics and supervised molecular dynamics simulations guided the synthesis of a potent dual agonist of GLP-1 and amylin receptors. The data offer new insights into the function of peptide amidation, how allostery drives peptide-receptor interactions, and provide a valuable resource for the development of novel amylin agonists for treating diabetes and obesity

Interventions to Influence Consulting and Antibiotic Use for Acute Respiratory Tract Infections in Children: A Systematic Review and Meta-Analysis

BACKGROUND: Respiratory tract infections (RTIs) are common in children and generally self-limiting, yet often result in consultations to primary care. Frequent consultations divert resources from care for potentially more serious conditions and increase the opportunity for antibiotic overuse. Overuse of antibiotics is associated with adverse effects and antimicrobial resistance, and has been shown to influence how patients seek care in ensuing illness episodes. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic review and meta-analysis to assess the effectiveness of interventions directed towards parents or caregivers which were designed to influence consulting and antibiotic use for respiratory tract infections (RTIs) in children in primary care. Main outcomes were parental consulting rate, parental knowledge, and proportion of children subsequently consuming antibiotics. Of 5,714 references, 23 studies (representing 20 interventions) met inclusion criteria. Materials designed to engage children in addition to parents were effective in modifying parental knowledge and behaviour, resulting in reductions in consulting rates ranging from 13 to 40%. Providing parents with delayed prescriptions significantly decreased reported antibiotic use (Risk Ratio (RR) 0.46 (0.40, 0.54); moreover, a delayed or no prescribing approach did not diminish parental satisfaction. CONCLUSIONS: IN ORDER TO BE MOST EFFECTIVE, INTERVENTIONS TO INFLUENCE PARENTAL CONSULTING AND ANTIBIOTIC USE SHOULD: engage children, occur prior to an illness episode, employ delayed prescribing, and provide guidance on specific symptoms. These results support the wider implementation of interventions to reduce inappropriate antibiotic use in children

The spatial and temporal patterns of falciparum and vivax malaria in Perú: 1994–2006

<p>Abstract</p> <p>Background</p> <p>Malaria is the direct cause of approximately one million deaths worldwide each year, though it is both preventable and curable. Increasing the understanding of the transmission dynamics of falciparum and vivax malaria and their relationship could suggest improvements for malaria control efforts. Here the weekly number of malaria cases due to <it>Plasmodium falciparum </it>(1994–2006) and <it>Plasmodium vivax </it>(1999–2006) in Perú at different spatial scales in conjunction with associated demographic, geographic and climatological data are analysed.</p> <p>Methods</p> <p>Malaria periodicity patterns were analysed through wavelet spectral analysis, studied patterns of persistence as a function of community size and assessed spatial heterogeneity via the Lorenz curve and the summary Gini index.</p> <p>Results</p> <p>Wavelet time series analyses identified annual cycles in the incidence of both malaria species as the dominant pattern. However, significant spatial heterogeneity was observed across jungle, mountain and coastal regions with slightly higher levels of spatial heterogeneity for <it>P. vivax </it>than <it>P. falciparum</it>. While the incidence of <it>P. falciparum </it>has been declining in recent years across geographic regions, <it>P. vivax </it>incidence has remained relatively steady in jungle and mountain regions with a slight decline in coastal regions. Factors that may be contributing to this decline are discussed. The time series of both malaria species were significantly synchronized in coastal (ρ = 0.9, P < 0.0001) and jungle regions (ρ = 0.76, P < 0.0001) but not in mountain regions. Community size was significantly associated with malaria persistence due to both species in jungle regions, but not in coastal and mountain regions.</p> <p>Conclusion</p> <p>Overall, findings highlight the importance of highly refined spatial and temporal data on malaria incidence together with demographic and geographic information in improving the understanding of malaria persistence patterns associated with multiple malaria species in human populations, impact of interventions, detection of heterogeneity and generation of hypotheses.</p