Counting and enumerating aggregate classifiers

peer reviewedaudience: researcherWe propose a generic model for the "weighted voting" aggregation step performed by several methods in supervised classification. Further, we construct an algorithm to count the number of distinct aggregate classifiers that arise in this model. When there are only two classes in the classification problem, we show that a class of functions that arises from aggregate classifiers coincides with the class of self-dual positive threshold Boolean functions

Effects of Non‐Surface‐Disturbing Treatments for Native Grass Revegetation on Cheatgrass (\u3ci\u3eBromus tectorum\u3c/i\u3e L.) Metrics and Soil Ion Availabilities

Several restoration methods intended to increase the success of aerially‐seeded perennial grasses were assessed to determine their effects on cheatgrass metrics and soil nutrient bioavailabilities. These methods were: 1) imazapic herbicide application (140 g ai ∙ ha‐1, 210 g ai ∙ ha‐1, and no application [control]), 2) vegetation manipulation treatments (50% sagebrush overstory thinning, 100% sagebrush overstory thinning, sagebrush overstory and/or vegetative thatch burning, and no manipulation [control]), and 3) alternative seeding treatments (aerial seeding with raking, aerial seeding with activated carbon [AC] addition, aerial seeding with sucrose addition, and regular aerial seeding [control]). Treatments were arranged in 3‐way factorial designs, which allowed main effects and interactions between treatments to be assessed. Responses were followed for two growing seasons following treatment. Main effects of treatments and their interactions on cheatgrass metrics are described in Chapter 2. Herbicide reduced cheatgrass weights and tiller and spikelet numbers in 2009, but these variables were greater than in no‐herbicide plots in 2010. Burning decreased cheatgrass densities but increased weights and tiller and spikelet numbers in both years. One hundred percent sagebrush thinning resulted in greater cheatgrass weights and tiller and spikelet numbers in both years and greater densities in 2010. Sucrose addition decreased cheatgrass weights and tiller and spikelet numbers in 2009, but increased these variables in 2010. An interaction between AC and herbicide treatment was observed, with AC potentially sequestering and lessening the negative effect of herbicide on cheatgrass. Aerial seeding with raking and 50% sagebrush thinning treatments were not found to significantly affect cheatgrass either year. The effects of treatments (herbicide, 50% sagebrush thinning, aerial seeding on snow, and aerial seeding with raking treatments omitted) on soil nutrient availabilities are described in Chapter 3. We used ion exchange resin (IER) membrane probes to measure extractable quantities of 15 ions over three time periods following treatment applications. Burning resulted in short‐term increases in many soil nutrient availabilities, including nitrate (NO3 ‐), phosphate (H2PO4 ‐), and sulfate (SO4 2‐). Sucrose addition reduced availabilities of NO3 ‐ and H2PO4 ‐ during the first winter and growing season. No changes were detected with AC addition or 100% sagebrush thinning during any sampling time

MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation

Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors

Estimating the sustainability of towed fishing-gear impacts on seabed habitats: a simple quantitative risk assessment method applicable to data-limited fisheries

1. Impacts of bottom fishing, particularly trawling and dredging, on seabed (benthic) habitats are commonly perceived to pose serious environmental risks. Quantitative ecological risk assessment can be used to evaluate actual risks and to help guide the choice of management measures needed to meet sustainability objectives. 2. We develop and apply a quantitative method for assessing the risks to benthic habitats by towed bottom-fishing gears. The method is based on a simple equation for relative benthic status (RBS), derived by solving the logistic population growth equation for the equilibrium state. Estimating RBS requires only maps of fishing intensity and habitat type — and parameters for impact and recovery rates, which may be taken from meta-analyses of multiple experimental studies of towed-gear impacts. The aggregate status of habitats in an assessed region is indicated by the distribution of RBS values for the region. The application of RBS is illustrated for a tropical shrimp-trawl fishery. 3. The status of trawled habitats and their RBS value depend on impact rate (depletion per trawl), recovery rate and exposure to trawling. In the shrimp-trawl fishery region, gravel habitat was most sensitive, and though less exposed than sand or muddy-sand, was most affected overall (regional RBS=91% relative to un-trawled RBS=100%). Muddy-sand was less sensitive, and though relatively most exposed, was less affected overall (RBS=95%). Sand was most heavily trawled but least sensitive and least affected overall (RBS=98%). Region-wide, >94% of habitat area had >80% RBS because most trawling and impacts were confined to small areas. RBS was also applied to the region's benthic invertebrate communities with similar results. 4. Conclusions. Unlike qualitative or categorical trait-based risk assessments, the RBS method provides a quantitative estimate of status relative to an unimpacted baseline, with minimal requirements for input data. It could be applied to bottom-contact fisheries worldwide, including situations where detailed data on characteristics of seabed habitats, or the abundance of seabed fauna are not available. The approach supports assessment against sustainability criteria and evaluation of alternative management strategies (e.g. closed areas, effort management, gear modifications)

ICON 2019: International Scientific Tendinopathy Symposium Consensus: Clinical Terminology

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.Background Persistent tendon pain that impairs function has inconsistent medical terms that can influence choice of treatment.1 When a person is told they have tendinopathy by clinician A or tendinitis by clinician B, they might feel confused or be alarmed at receiving what they might perceive as two different diagnoses. This may lead to loss of confidence in their health professional and likely adds to uncertainty if they were to search for information about their condition. Clear and uniform terminology also assists inter-professional communication. Inconsistency in terminology for painful tendon disorders is a problem at numerous anatomical sites. Historically, the term ‘tendinitis’ was first used to describe tendon pain, thickening and impaired function (online supplementary figure S1). The term ‘tendinosis’ has also been used in a small number of publications, some of which were very influential.2 3 Subsequently, ‘tendinopathy’ emerged as the most common term for persistent tendon pain.4 5 To our knowledge, experts (clinicians and researchers) or patients have never engaged in a formal process to discuss the terminology we use. We believe that health professionals have not yet agreed on the appropriate terminology for painful tendon conditions.Peer reviewedFinal Accepted Versio

The role of renin-angiotensin-aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM

Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNAdamaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging

Reliability of quantitative sensory testing in the assessment of somatosensory function after high-frequency stimulation-induced sensitisation of central nociceptive pathways

The high frequency stimulation (HFS) model can be used alongside quantitative sensory testing (QST) to assess the sensitisation of central nociceptive pathways. However, the validity and between-session reliability of using QST z -score profiles to measure changes in mechanical and thermal afferent pathways in the HFS model are poorly understood. In this study, 32 healthy participants underwent QST before and after HFS (5× 100 Hz trains; 10× electrical detection threshold) in the same heterotopic skin area across 2 repeated sessions. The only mechanical QST z -score profiles that demonstrated a consistent gain of function across repeated test sessions were mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS), which were associated with moderate and good reliability, respectively. There was no relationship between HFS intensity and MPT and MPS z -score profiles. There was no change in low intensity, but a consistent facilitation of high-intensity pin prick stimuli in the mechanical stimulus response function across repeated test sessions. There was no change in cold pain threshold (CPT) and heat pain threshold (HPT) z -score profiles across session 1 and 2, which were associated with moderate and good reliability, respectively. There were inconsistent changes in the sensitivity to innocuous thermal QST parameters, with cool detection threshold (CDT), warm detection threshold (WDT), and thermal sensory limen (TSL) all producing poor reliability. These data suggest that HFS-induced changes in MPS z -score profiles is a reliable way to assess experimentally induced central sensitisation and associated secondary mechanical hyperalgesia in healthy participants.</p

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness