Measuring “waiting” impulsivity in substance addictions and binge eating disorder in a novel analogue of rodent serial reaction time task

Background Premature responding is a form of motor impulsivity that preclinical evidence has shown to predict compulsive drug seeking but has not yet been studied in humans. We developed a novel translation of the task, based on the rodent 5-choice serial reaction time task, testing premature responding in disorders of drug and natural food rewards. Methods Abstinent alcohol- (n = 30) and methamphetamine-dependent (n = 23) subjects, recreational cannabis users (n = 30), and obese subjects with (n = 30) and without (n = 30) binge eating disorder (BED) were compared with matched healthy volunteers and tested on the premature responding task. Results Compared with healthy volunteers, alcohol- and methamphetamine-dependent subjects and cannabis users showed greater premature responding with no differences observed in obese subjects with or without BED. Current smokers exhibited greater premature responding versus ex-smokers and nonsmokers. Alcohol-dependent subjects also had lower motivation for explicit monetary incentives. A Motivation Index correlated negatively with alcohol use and binge eating severity. Conclusions Premature responding on a novel translation of a serial reaction time task was more evident in substance use disorders but not in obese subjects with or without BED. Lower motivation for monetary incentives linked alcohol use and binge eating severity. Our findings add to understanding the relationship between drug and natural food rewards

Risk-taking in disorders of natural and drug rewards: neural correlates and effects of probability, valence, and magnitude.

Pathological behaviors toward drugs and food rewards have underlying commonalities. Risk-taking has a fourfold pattern varying as a function of probability and valence leading to the nonlinearity of probability weighting with overweighting of small probabilities and underweighting of large probabilities. Here we assess these influences on risk-taking in patients with pathological behaviors toward drug and food rewards and examine structural neural correlates of nonlinearity of probability weighting in healthy volunteers. In the anticipation of rewards, subjects with binge eating disorder show greater risk-taking, similar to substance-use disorders. Methamphetamine-dependent subjects had greater nonlinearity of probability weighting along with impaired subjective discrimination of probability and reward magnitude. Ex-smokers also had lower risk-taking to rewards compared with non-smokers. In the anticipation of losses, obesity without binge eating had a similar pattern to other substance-use disorders. Obese subjects with binge eating also have impaired discrimination of subjective value similar to that of the methamphetamine-dependent subjects. Nonlinearity of probability weighting was associated with lower gray matter volume in dorsolateral and ventromedial prefrontal cortex and orbitofrontal cortex in healthy volunteers. Our findings support a distinct subtype of binge eating disorder in obesity with similarities in risk-taking in the reward domain to substance use disorders. The results dovetail with the current approach of defining mechanistically based dimensional approaches rather than categorical approaches to psychiatric disorders. The relationship to risk probability and valence may underlie the propensity toward pathological behaviors toward different types of rewards.This is the final version. It was first published by NPG at http://www.nature.com/npp/journal/v40/n4/full/npp2014242a.htm

Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Origine et remise en cause de la théorie des glaciations pléistocènes de la Chine du Sud-Est : le cas des massifs de Lushan et Huangshan

Both the Lushan and the Huangshan have been regarded as sites of Pleistocene glaciation since the pioneer research of Li Szeguang (J.S. Lee) in the 1930s. He adduced a glacial stratigraphy for the Lushan based on the interpretation of valley morphology and the abundant piedmont diamictons as glacial. Li's framework became the dominant hypothesis in Chinese glacial stratigraphy for over 50 years. The status of glacial hypothesis for these small mountain massifs of south-east China (c. 30°N) is crucial for soundly-based palaeoclimatic modelling of the Pleistocene. This paper offers new interpretations based on recent field and laboratory analysis. Both massifs are shown to have an erosional geomorphology produced by structurally-controlled fluvial dissection and the widespread diamictons are shown to be deeply-weathered piedmont fans of alluvial and debrisflow origin. There is no incontrovertible evidence of glaciation in either the Lushan or the Huangshan.L'existence de glaciations pléistocènes a été admise dans les massifs de Lushan et Huangshan, depuis le travail pionnier de Li Szeguang dans la décennie 1930. D'après la morphologie des vallées et la présence d'abondants diamictons de piedmont, Li a élaboré dans le Lushan une stratigraphie qui, en dépit de contestations ultérieures, s'est imposée en Chine pendant plus de cinquante années. Dans la perspective d'une modélisation des changements paléoclimatiques du Pléistocène, il est devenu crucial de vérifier la réalité de l'englacement de ces petits massifs montagneux de la Chine du Sud-Est situés à une latitude d'environ 30°N. Sur la base d'une étude morphologique et sédimentologique et d'une revue de la littérature, le présent article réfute l'interprétation de Li. Les vastes diamictons de piedmont s'avèrent correspondre à des cônes d'alluvions et de coulées de débris profondément altérées. Aucune preuve d'englacement n'est apportée par les deux massifs que caractérise une morphologie de dissection fluviatile commandée par la structure et affectant des volumes rocheux fortement météorisés.Derbyshire Edward. Origine et remise en cause de la théorie des glaciations pléistocènes de la Chine du Sud-Est : le cas des massifs de Lushan et Huangshan . In: Annales de Géographie, t. 101, n°566, 1992. pp. 472-490

Fluvioglacial erosion in central Quebec-Labrador.

Note: a corner of paper is cut p. 176.Scientifically, the peninsula of Quebec-Labrador is a new land. The establishment of the mining town at Knob Lake has served to open up to scientific exploration a piece of country of great interest to all field scientists, but especially to the glacial geomorphologists. Since the early days of the acceptance of the Glacial Theory, Labrador has been considered to have been a region of prime importance in the development of the North American ice-sheet. It has also been implied that the final remnants of the ice-sheet wasted away in the Labrador peninsula. [...]The morphological effects produced by waning ice-sheets can be interpreted to indicate the precise course of events at the time of the deglaciation. The morphological evidence is both widespread and well preserved in the central portion of Quebec-Labrador and the first results of a study of it are presented in this thesis. Fluvioglacial erosion, or erosion effected by waters issuing from and flowing marginally and beneath a mass of glacial ice, results in the cutting of valleys which today are mainly unoccupied by streams and which constitute a relatively precise means by which the behaviour and condition of past ice-sheets and glaciers can be assessed. Glacial drainage channels, the significance of which was first fully appreciated by Kendall at the turn of the century, are sensitive indicators of the position and condition of formerly ice-covered terrain