Prognostic importance of quantitative analysis of coronary cineangiograms

Many studies have shown the prognostic value of angiographic data, but few have examined quantitative parameters of wall motion and shape or coronary stenosis severity. To determine whether these parameters have prognostic importance, baseline angiograms of 283 patients with up to 11.2 years (mean 8.3) of follow-up were quantitated. Event-free survival curves were constructed using log-rank testing. These indexes were also considered in 2 predictive models (Cox regression models): 1 with ("clinical") and 1 without ("quantitative") subjective angiographic analysis and clinical information. Regional shape (anterior and inferior walls) and motion (anterior wall only) indexes were predictive of event-free survival when considered singly. But these parameters were not of independent prognostic importance in the regression models. The most important independent parameters in the quantitative model for predicting overall cardiac mortality or an initial lethal cardiac event were the ejection fraction and the percent diameter narrowing of each major coronary artery. Myocardial infarction was predicted by the percent diameter stenosis of the left main and left anterior descending arteries but not the ejection fraction. In the clinical model, the factors of overriding prognostic importance were the ejection fraction and the subjective determination of the number of vessels involved with "significant" stenoses. Quantitative coronary arteriography still contributed independent prognostic value. Thus, quantification of the ejection fraction and severity of coronary lesions were of independent, prognostic importance, whereas indexes of regional function and shape were not.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30104/1/0000476.pd

Towards Logical Specification of Statistical Machine Learning

We introduce a logical approach to formalizing statistical properties of machine learning. Specifically, we propose a formal model for statistical classification based on a Kripke model, and formalize various notions of classification performance, robustness, and fairness of classifiers by using epistemic logic. Then we show some relationships among properties of classifiers and those between classification performance and robustness, which suggests robustness-related properties that have not been formalized in the literature as far as we know. To formalize fairness properties, we define a notion of counterfactual knowledge and show techniques to formalize conditional indistinguishability by using counterfactual epistemic operators. As far as we know, this is the first work that uses logical formulas to express statistical properties of machine learning, and that provides epistemic (resp. counterfactually epistemic) views on robustness (resp. fairness) of classifiers.Comment: SEFM'19 conference paper (full version with errors corrected

Cost-effectiveness of financial incentives to promote adherence to depot antipsychotic medication: economic evaluation of a cluster-randomised controlled trial

Background: Offering a modest financial incentive to people with psychosis can promote adherence to depot antipsychotic medication, but the cost-effectiveness of this approach has not been examined. Methods: Economic evaluation within a pragmatic cluster-randomised controlled trial. 141 patients under the care of 73 teams (clusters) were randomised to intervention or control; 138 patients with diagnoses of schizophrenia, schizo-affective disorder or bipolar disorder participated. Intervention participants received £15 per depot injection over 12 months, additional to usual acute, mental and community primary health services. The control group received usual health services. Main outcome measures: incremental cost per 20% increase in adherence to depot antipsychotic medication; incremental cost of ‘good’ adherence (defined as taking at least 95% of the prescribed number of depot medications over the intervention period). Findings: Economic and outcome data for baseline and 12-month follow-up were available for 117 participants. The adjusted difference in adherence between groups was 12.2% (73.4% control vs. 85.6% intervention); the adjusted costs difference was £598 (95% CI -£4 533, £5 730). The extra cost per patient to increase adherence to depot medications by 20% was £982 (95% CI -£8 020, £14 000). The extra cost per patient of achieving 'good' adherence was £2 950 (CI -£19 400, £27 800). Probability of cost-effectiveness exceeded 97.5%at willingness-to-pay values of £14 000 for a 20% increase in adherence and £27 800 for good adherence. Interpretation: Offering a modest financial incentive to people with psychosis is cost-effective in promoting adherence to depot antipsychotic medication. Direct healthcare costs (including costs of the financial incentive) are unlikely to be increased by this intervention. Trial Registration: ISRCTN.com 7776928

The FGLamide-Allatostatins Influence Foraging Behavior in Drosophila melanogaster

Allatostatins (ASTs) are multifunctional neuropeptides that generally act in an inhibitory fashion. ASTs were identified as inhibitors of juvenile hormone biosynthesis. Juvenile hormone regulates insect metamorphosis, reproduction, food intake, growth, and development. Drosophila melanogaster RNAi lines of PheGlyLeu-amide-ASTs (FGLa/ASTs) and their cognate receptor, Dar-1, were used to characterize roles these neuropeptides and their respective receptor may play in behavior and physiology. Dar-1 and FGLa/AST RNAi lines showed a significant reduction in larval foraging in the presence of food. The larval foraging defect is not observed in the absence of food. These RNAi lines have decreased for transcript levels which encodes cGMP- dependent protein kinase. A reduction in the for transcript is known to be associated with a naturally occuring allelic variation that creates a sitter phenotype in contrast to the rover phenotype which is caused by a for allele associated with increased for activity. The sitting phenotype of FGLa/AST and Dar-1 RNAi lines is similar to the phenotype of a deletion mutant of an AST/galanin-like receptor (NPR-9) in Caenorhabditis elegans. Associated with the foraging defect in C. elegans npr-9 mutants is accumulation of intestinal lipid. Lipid accumulation was not a phenotype associated with the FGLa/AST and Dar-1 RNAi lines

Effects of in vitro potassium on ammoniagenesis in rat and canine kidney tissue

Effects of in vitro potassium on ammoniagenesis in rat and canine kidney tissue. Decreased ammonium (NH4+) excretion is associated with hyperkalemia. To determine if potassium could directly influence renal ammonia production, we investigated ammoniagenesis by rat and canine renal cortical tissues in vitro at different potassium concentrations. Renal tissue from normal and acidotic rats and normal dogs incubated in glutamine, lactate, and 7 to 10mEq/liters of potassium or 25mEq/liters of potassium produced significantly less ammonia than slices incubating in glutamine, lactate, and 4 to 5mEq of potassium. Glutamate accumulation, which follows glutamine deamidation, did not decrease and even increased at 25mEq/liters of potassium. With glutamine as the sole substrate, decreased ammoniagenesis was seen only at higher potassium concentrations (> 16mEq/liters) than when lactate was also present. The depression to glutamine ammoniagenesis by high concentrations of potassium was partially obliterated in an anaerobic environment. When glutamate replaced glutamine as the precursor, renal ammonia produced by slices in 7 and 25mEq/liters was again significantly lower than by slices incubating in 4mEq/liters. We blocked glutamine synthesis by rat kidney slices with dl-methionine dl-sulfoximine when glutamate was the renal ammonia precursor. This essentially allows glutamate deamination to produce ammonia. Potassium depressed glutamate deamination significantly at 7mEq/liters (↓ 13%) and at 25mEq/liters of potassium (↓ 35%) as compared to 4mEq/liters. The above findings are consistent with a major depressive effect of in vitro potassium on glutamate deamination in rat and canine kidneys. Other evidence, especially from rat tissue studies, suggests that potassium also may affect glutamine deamination directly. Rat kidney slices incubating in the high potassium medium of 7mEq/liter or greater also consumed less oxygen in the presence of glutamine (P < 0.01), oxidatively decarboxylated less glutamine (P < 0.02) and produced less glucose from glutamine (P < 0.01).Effet du potassium in vitro sur l'ammoniogenèse dans tissu rénal de rat et de chien. Une diminution de l'excrétion d'ammoniaque (NH4+) est associée à l'hyperkaliémie. Afin de déterminer si le potassium peut influencer directement la production rénale d'ammoniac, nous avons étudié l'ammoniogenèse dans le tissu rénal cortical de rat et de chien in vitro à différentes concentrations de potassium. Du tissu rénal provenant de rats normaux et en acidose et de chiens normaux incubés dans de la glutamine, du lactate, et 7 à 10mEq/litres de potassium ou 25mEq/litres de potassium produit significativement moins d'ammoniac que des tranches incubées dans de la glutamine, du lactate, et 4 à 5mEq/litres de potassium. L'accumulation de glutamate, consécutive à la deamination de la glutamine, n'a pas diminué et même a augmenté à 25mEq/litres de potassium. Avec la glutamine comme seul substrat, la diminution de l'ammoniogenèse n'a été observée qu'à des concentrations de potassium supérieures (> 16mEq/litres) à celle nécessaire quand le lactate est présent. La dépression de l'ammoniogenèse due à la glutamine au moyen de concentrations élevées de potassium est partiellement abolie par un environnement anaérobique. Quand la glutamine est remplacée par du glutamate, le rénale d'ammoniac produit par des tranches dans des milieux à 7mEq/litres et 25mEq/litres est là encore significativement inférieur à celui produit par des tranches incubées dans un milieu à 4mEq/litres. Nous avons bloqué la synthèse de glutamine dans les tranches de rein de rat au moyen de la dl-méthionine dl-sulfoximine quand le glutamate était le précurseur de rénale d'ammoniac. Ceci permet à la déamination du glutamate de produire de l'ammoniac. Potassium diminue significativement la déamination du glutamate à 7mEq/litres (diminution de 13%), et à 25mEq/litres (diminution de 35%) par comparaison avec les valeurs obtenues à 4mEq/litres. Ces constatations sont compatibles avec un effet dépresseur majeur du potassium in vitro sur la déamination du glutamate dans les reins de rat et de chien. D'autres arguments, tirés essentiellement des études sur le tissu de rat, suggèrent que le potassium peut aussi affecter la déamination du glutamate directement. Des tranches de rein de rat incubées dans un milieu riche en potassium (7mEq/litres ou plus) consomment moins d'oxygène en présence de glutamine (P < 0,01), décarboxylent moins de glutamine par oxydation (P < 0,02) et produisent moins de glucose à partir de la glutamine (P < 0,01)

Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in European populations.

Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3.99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases. We used country-specific Prentice-weighted Cox regression models and random-effects meta-analysis methods to estimate HRs. Among the flavanol subclass, we observed significant inverse trends between intakes of all individual flavan-3-ol monomers and risk of T2D in multivariable models (all P-trend < 0.05). We also observed significant trends for the intakes of proanthocyanidin dimers (HR for the highest vs. the lowest quintile: 0.81; 95% CI: 0.71, 0.92; P-trend = 0.003) and trimers (HR: 0.91; 95% CI: 0.80, 1.04; P-trend = 0.07) but not for proanthocyanidins with a greater polymerization degree. Among the flavonol subclass, myricetin (HR: 0.77; 95% CI: 0.64, 0.93; P-trend = 0.001) was associated with a lower incidence of T2D. This large and heterogeneous European study showed inverse associations between all individual flavan-3-ol monomers, proanthocyanidins with a low polymerization degree, and the flavonol myricetin and incident T2D. These results suggest that individual flavonoids have different roles in the etiology of T2D.The EPIC-InterAct Study was supported by the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). In addition, InterAct investigators acknowledge funding from the following agencies: R.Z.-R. was supported by a postdoctoral program Fondo de Investigación Sanitaria (FIS; no. CD09/00133) from the Spanish Ministry of Science; R.Z.-R. and C.A.G. were supported by the Health Research Fund (FIS) of the Spanish Ministry of Health (RTICC DR06/0020/0091); core support from the Medical Research Council (MRC) Epidemiology Unit is acknowledged for program MC_UU_12015/1 and MC_UU_12015/5; Y.T.v.d.S. was supported by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht (Netherlands); A.M.W.S. and D.L.v.d.A. were supported by the Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON, World Cancer Research Fund, and Statistics Netherlands; T.J.K. and K.-T.K. were supported by Cancer Research UK; G.F., M.T., and F.P. were supported by Ligue contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, INSERM; G.M. was supported by Ministero della Salute Regione Toscana Progetto Integrato Oncologia–PIO; P.W.F. was supported by the Swedish Research Council, Novo Nordisk, the Swedish Heart Lung Foundation, and the Swedish Diabetes Association; L.B., K.O., N.R., and A.T. were supported by the Danish Cancer Society; V.K. and T.K. were supported by Deutsche Krebshilfe; A.M. was supported by Associazione Italiana per la Ricerca sul Cancro; M.L.R. was supported by the Asturias Regional Government; M.G., P.A., E.M.-M., and M.J.T. were supported by the Health Research Fund of the Spanish Ministry of Health, CIBER Epidemiology and Public Health (Spain); M.J.T. was supported by the Murcia Regional Government; and R.T. was supported by AIRE-ONLUS Ragusa, AVIS-Ragusa, the Sicilian Regional Government.This is the final published version distributed under a Creative Commons Attribution Licence, which can also be found on the publisher's website at: http://jn.nutrition.org/content/144/3/335.ful

Pervasive Hitchhiking at Coding and Regulatory Sites in Humans

Much effort and interest have focused on assessing the importance of natural selection, particularly positive natural selection, in shaping the human genome. Although scans for positive selection have identified candidate loci that may be associated with positive selection in humans, such scans do not indicate whether adaptation is frequent in general in humans. Studies based on the reasoning of the MacDonald–Kreitman test, which, in principle, can be used to evaluate the extent of positive selection, suggested that adaptation is detectable in the human genome but that it is less common than in Drosophila or Escherichia coli. Both positive and purifying natural selection at functional sites should affect levels and patterns of polymorphism at linked nonfunctional sites. Here, we search for these effects by analyzing patterns of neutral polymorphism in humans in relation to the rates of recombination, functional density, and functional divergence with chimpanzees. We find that the levels of neutral polymorphism are lower in the regions of lower recombination and in the regions of higher functional density or divergence. These correlations persist after controlling for the variation in GC content, density of simple repeats, selective constraint, mutation rate, and depth of sequencing coverage. We argue that these results are most plausibly explained by the effects of natural selection at functional sites—either recurrent selective sweeps or background selection—on the levels of linked neutral polymorphism. Natural selection at both coding and regulatory sites appears to affect linked neutral polymorphism, reducing neutral polymorphism by 6% genome-wide and by 11% in the gene-rich half of the human genome. These findings suggest that the effects of natural selection at linked sites cannot be ignored in the study of neutral human polymorphism

Ecological impacts of non-native Pacific oysters (Crassostrea gigas) and management measures for protected areas in Europe

Pacific oysters are now one of the most ‘globalised’ marine invertebrates. They dominate bivalve aquaculture production in many regions and wild populations are increasingly becoming established, with potential to displace native species and modify habitats and ecosystems. While some fishing communities may benefit from wild populations, there is now a tension between the continued production of Pacific oysters and risk to biodiversity, which is of particular concern within protected sites. The issue of the Pacific oyster therefore locates at the intersection between two policy areas: one concerning the conservation of protected habitats, the other relating to livelihoods and the socio-economics of coastal aquaculture and fishing communities. To help provide an informed basis for management decisions, we first summarise evidence for ecological impacts of wild Pacific oysters in representative coastal habitats. At local scales, it is clear that establishment of Pacific oysters can significantly alter diversity, community structure and ecosystem processes, with effects varying among habitats and locations and with the density of oysters. Less evidence is available to evaluate regional-scale impacts. A range of management measures have been applied to mitigate negative impacts of wild Pacific oysters and we develop recommendations which are consistent with the scientific evidence and believe compatible with multiple interests. We conclude that all stakeholders must engage in regional decision making to help minimise negative environmental impacts, and promote sustainable industry development

Anxiety Levels in Children with Autism Spectrum Disorder:A Meta-Analysis

The aim of the current study was to meta-analytically examine whether anxiety levels in children with autism spectrum disorders (ASD) are elevated. A total of 83 articles were selected from a systematic literature search and were included in the meta-analyses. Results demonstrated that children with ASD had higher anxiety levels compared to typically developing children, and this difference increased with IQ. Youth with ASD also tended to have higher anxiety levels compared to clinically referred children, and this difference increased with age. Children with ASD had higher anxiety levels compared to youth with externalizing or developmental problems, but not when compared to youth with internalizing problems. The study findings highlight the importance of more research in order to fully understand the nature and development of anxiety in children with ASD. More specifically, the results suggest that especially high-functioning adolescents with ASD may be at risk for developing anxiety disorders. Therefore, it seems important to carefully follow and monitor children with ASD transcending to adolescenc