The “pain matrix” in pain-free individuals

Human functional imaging provides a correlative picture of brain activity during pain. A particular set of central nervous system structures (eg, the anterior cingulate cortex, thalamus, and insula) consistently respond to transient nociceptive stimuli causing pain. Activation of this so-called pain matrix or pain signature has been related to perceived pain intensity, both within and between individuals,1,2 and is now considered a candidate biomarker for pain in medicolegal settings and a tool for drug discovery. The pain-specific interpretation of such functional magnetic resonance imaging (fMRI) responses, although logically flawed,3,4 remains pervasive. For example, a 2015 review states that “the most likely interpretation of activity in the pain matrix seems to be pain.”4 Demonstrating the nonspecificity of the pain matrix requires ruling out the presence of pain when highly salient sensory stimuli are presented. In this study, we administered noxious mechanical stimuli to individuals with congenital insensitivity to pain and sampled their brain activity with fMRI. Loss-of-function SCN9A mutations in these individuals abolishes sensory neuron sodium channel Nav1.7 activity, resulting in pain insensitivity through an impaired peripheral drive that leaves tactile percepts fully intact.5 This allows complete experimental disambiguation of sensory responses and painful sensation

Introducción. El Placer en la Edad Media: artículos presentados en el 2013 International Medieval Congress, Leeds.

No disponible en català. Vegeu resum en anglèsThe papers in this edition of Mirabilia are derived from presentations at the 2013 Leeds International Medieval Congress (IMC). As a large gathering of scholars, the largest of its kind in Europe, with numerous sessions for short presentations, the IMC has proved an ideal forum for early career scholars. Many a young scholar, from both hemispheres and from every continent, has presented her or his first international paper at Leeds. But it is not only a forum for young scholars. Established academics come every year, presenting new ideas alongside their peers: as can be seen in the following collection

New Zealand Guideline for the Connection of PV Solar Power and Determining Hosting Capacity for PV Solar Power

Small-scale distributed generation (DG) in New Zealand, particularly photovoltaic (PV) generation, has been growing steadily over the past few years. In the last year alone to 31 March 2016, installed PV generation of all capacities has grown by a factor of about 1.6 to reach 37 MW. Approximately 90% (33 MW) of this installed PV capacity is made up of small-scale, single phase residential grid-tied systems with ratings below 10 kW. This corresponds, on average, to approximately 300-400 new PV systems being installed each month within low voltage (LV) distribution networks. Traditionally, the flow of power in electricity distribution networks has been largely unidirectional. However, distributed generation introduces reverse power flows into the LV network when the power produced by DG systems is greater than what can be consumed locally. This introduction of reverse power flows and the dynamic behavior of DG system inverters can negatively impact the electricity network, causing issues such as over-voltage, phase imbalance, overloading of conductors and transformers, and create unique safety challenges. As such, each DG connection application received by electricity distribution businesses (EDBs) presently needs to be carefully considered for its impact on the electricity network. The resourcing demand imposed by larger numbers of connection applications, and the difficulty of technical assessment including congestion evaluation, are likely to increase substantially as DG uptake intensifies. This has prompted the Electric Power Engineering Centre (EPECentre) via its GREEN Grid programme, with the assistance of the electricity industry based Network Analysis Group (NAG), to develop a small-scale inverter based DG connection guideline for New Zealand EDBs. This has been developed on behalf of the Electricity Engineers’ Association (EEA) specifically for the connection of inverter energy systems (IES) of 10 kW or less. This paper summarizes key aspects of this guideline. This includes a streamlined connection application evaluation process that enables EDBs to efficiently categorize DG applications into three groups. These groups vary from those with minimal or moderate network impact that can be autoassessed, to those most likely to cause network congestion that require manual assessment. These categories are determined by looking at the DG hosting capacity specific to the LV network that the DG is connecting to. For two of these categories, mitigation measures for connection, are prescribed. It is also shown how DG hosting capacity can be used to simply evaluate LV network congestion in order to satisfy Electricity Industry Participation Code (EIPC) Part 6 requirements. Key technical requirements for all IES, appropriate for New Zealand conditions, are also summarized

Bayesian fitting of Taurus brown dwarf spectral energy distributions

We present derived stellar and disc parameters for a sample of Taurus brown dwarfs both with and without evidence of an associated disc. These parameters have been derived using an online fitting tool (http://bd-server.astro.ex.ac.uk/), which includes a statistically robust derivation of uncertainties, an indication of pa- rameter degeneracies, and a complete treatment of the input photometric and spectroscopic observations. The observations of the Taurus members with indications of disc presence have been fitted using a grid of theoretical models including detailed treatments of physical processes accepted for higher mass stars, such as dust sublimation, and a simple treatment of the accretion flux. This grid of models has been designed to test the validity of the adopted physical mechanisms, but we have also constructed models using parameterisation, for example semi-empirical dust sublimation radii, for users solely interested in parameter derivation and the quality of the fit. The parameters derived for the naked and disc brown dwarf systems are largely consistent with literature observations. However, our inner disc edge locations are consistently closer to the star than previous results and we also derive elevated accretion rates over non-SED based accretion rate derivations. For inner edge locations we attribute these differences to the detailed modelling we have performed of the disc structure, particularly at the crucial inner edge where departures in geometry from the often adopted vertical wall due to dust sublimation (and therefore accretion flux) can compensate for temperature (and therefore distance) changes to the inner edge of the dust disc. In the case of the elevated derived accretion rates, in some cases, this may be caused by the intrinsic stellar luminosities of the targets exceeding that predicted by the isochrones we have adopted.Comment: The paper contains 35 pages with 15 figures and 17 tables. Accepted for publication in MNRA

An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Towards a conceptual framework demonstrating the effectiveness of audiovisual patient descriptions (patient video cases): a review of the current literature

Background: Technological advances have enabled the widespread use of video cases via web-streaming and online download as an educational medium. The use of real subjects to demonstrate acute pathology should aid the education of health care professionals. However, the methodology by which this effect may be tested is not clear. Methods: We undertook a literature review of major databases, found relevant articles relevant to using patient video cases as educational interventions, extracted the methodologies used and assessed these methods for internal and construct validity. Results: A review of 2532 abstracts revealed 23 studies meeting the inclusion criteria and a final review of 18 of relevance. Medical students were the most commonly studied group (10 articles) with a spread of learner satisfaction, knowledge and behaviour tested. Only two of the studies fulfilled defined criteria on achieving internal and construct validity. The heterogeneity of articles meant it was not possible to perform any meta-analysis. Conclusions: Previous studies have not well classified which facet of training or educational outcome the study is aiming to explore and had poor internal and construct validity. Future research should aim to validate a particular outcome measure, preferably by reproducing previous work rather than adopting new methods. In particular cognitive processing enhancement, demonstrated in a number of the medical student studies, should be tested at a postgraduate level

Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation

notes: PMCID: PMC3655956This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ≤ MAF <5%) and rare variants (<1%)) can enhance previously identified associations and identify novel loci, we selected 93 quantitative circulating factors where data was available from the InCHIANTI population study. These phenotypes included cytokines, binding proteins, hormones, vitamins and ions. We selected these phenotypes because many have known strong genetic associations and are potentially important to help understand disease processes. We performed a genome-wide scan for these 93 phenotypes in InCHIANTI. We identified 21 signals and 33 signals that reached P<5×10(-8) based on HapMap and 1000 Genomes imputation, respectively, and 9 and 11 that reached a stricter, likely conservative, threshold of P<5×10(-11) respectively. Imputation of 1000 Genomes genotype data modestly improved the strength of known associations. Of 20 associations detected at P<5×10(-8) in both analyses (17 of which represent well replicated signals in the NHGRI catalogue), six were captured by the same index SNP, five were nominally more strongly associated in 1000 Genomes imputed data and one was nominally more strongly associated in HapMap imputed data. We also detected an association between a low frequency variant and phenotype that was previously missed by HapMap based imputation approaches. An association between rs112635299 and alpha-1 globulin near the SERPINA gene represented the known association between rs28929474 (MAF = 0.007) and alpha1-antitrypsin that predisposes to emphysema (P = 2.5×10(-12)). Our data provide important proof of principle that 1000 Genomes imputation will detect novel, low frequency-large effect associations

Systematic identification of signaling pathways with potential to confer anticancer drug resistance

Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)–mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF[superscript V600E] melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.National Institutes of Health (U.S.) (Grant CA103866)National Institutes of Health (U.S.) (Grant AI07389

Selective culture enrichment and sequencing of feces to enhance detection of antimicrobial resistance genes in third-generation cephalosporin resistant Enterobacteriaceae

Metagenomic sequencing of fecal DNA can usefully characterise an individual’s intestinal resistome but is limited by its inability to detect important pathogens that may be present at low abundance, such as carbapenemase or extended-spectrum beta-lactamase producing Enterobacteriaceae. Here we aimed to develop a hybrid protocol to improve detection of resistance genes in Enterobacteriaceae by using a short period of culture enrichment prior to sequencing of DNA extracted directly from the enriched sample. Volunteer feces were spiked with carbapenemase-producing Enterobacteriaceae and incubated in selective broth culture for 6 hours before sequencing. Different DNA extraction methods were compared, including a plasmid extraction protocol to increase the detection of plasmid-associated resistance genes. Although enrichment prior to sequencing increased the detection of carbapenemase genes, the differing growth characteristics of the spike organisms precluded accurate quantification of their concentration prior to culture. Plasmid extraction increased detection of resistance genes present on plasmids, but the effects were heterogeneous and dependent on plasmid size. Our results demonstrate methods of improving the limit of detection of selected resistance mechanisms in a fecal resistome assay, but they also highlight the difficulties in using these techniques for accurate quantification and should inform future efforts to achieve this goa