Probing the Type I Seesaw Mechanism with Displaced Vertices at the LHC

The observation of Higgs decays into heavy neutrinos would be strong evidence for new physics associated to neutrino masses. In this work we propose a search for such decays within the Type I seesaw model in the few-GeV mass range via displaced vertices. Using 300 fb−1 of integrated luminosity, at 13 TeV, we explore the region of parameter space where such decays are measurable. We show that, after imposing pseudorapidity cuts, there still exists a region where the number of events is larger than O(10). We also find that conventional triggers can greatly limit the sensitivity of our signal, so we display several relevant kinematical distributions which might aid in the optimization of a dedicated trigger selection

Origin of acidic surface waters and the evolution of atmospheric chemistry on early Mars

Observations from in situ experiments and planetary orbiters have shown that the sedimentary rocks found at Meridiani Planum, Mars were formed in the presence of acidic surface waters. The water was thought to be brought to the surface by groundwater upwelling, and may represent the last vestiges of the widespread occurrence of liquid water on Mars. However, it is unclear why the surface waters were acidic. Here we use geochemical calculations, constrained by chemical and mineralogical data from the Mars Exploration Rover Opportunity, to show that Fe oxidation and the precipitation of oxidized iron (Fe^(3+)) minerals generate excess acid with respect to the amount of base anions available in the rocks present in outcrop. We suggest that subsurface waters of near-neutral pH and rich in Fe^(2+) were rapidly acidified as iron was oxidized on exposure to O_2 or photo-oxidized by ultraviolet radiation at the martian surface. Temporal variation in surface acidity would have been controlled by the availability of liquid water, and as such, low-pH fluids could be a natural consequence of the aridification of the martian surface. Finally, because iron oxidation at Meridiani would have generated large amounts of gaseous H_2, ultimately derived from the reduction of H_2O, we conclude that surface geochemical processes would have affected the redox state of the early martian atmosphere

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Phase I trial of intravesical Suramin in recurrent superficial transitional cell bladder carcinoma

Suramin is an antitrypanosomal agent with antineoplastic activity, but with serious systemic side effects. We administered Suramin intravesically to determine a concentration with low toxicity but with evidence of a pharmacodynamic effect, to recommend a dose level for phase II trials. This was an open-labelled, nonrandomised dose-escalation phase I study. In all, 12 patients with a history of recurrent superficial bladder cancer were grouped into four dose levels (10–150 mg ml−1 in 60 ml saline). Six catheter instillations at weekly intervals were used. Cystoscopy and biopsy were performed before and 3 months after the start of treatment. Suramin was assayed using high-performance liquid chromatography, vascular endothelial growth factor (VEGF) using ELISA (enzyme-linked immunosorbent assay), and urinary protein profile using surface-enhanced laser desorption ionisation mass spectroscopy (SELDI). Minimal systemic absorption of Suramin was found at the highest dose of 150 mg ml−1. Urinary VEGF was affected by Suramin at doses above 50 mg ml−1, corresponding to the estimated threshold of saturation of Suramin binding to urine albumin. SELDI showed a specific disappearance of urinary protein peaks during treatment. Intravesical Suramin shows lack of toxicity and low systemic absorption. The results of this phase I trial support expanded clinical trials of efficacy at a dose of 100 mg ml−1 intravesically

A Common Ca2+-Driven Interdomain Module Governs Eukaryotic NCX Regulation

Na+/Ca2+ exchanger (NCX) proteins mediate Ca2+-fluxes across the cell membrane to maintain Ca2+ homeostasis in many cell types. Eukaryotic NCX contains Ca2+-binding regulatory domains, CBD1 and CBD2. Ca2+ binding to a primary sensor (Ca3-Ca4 sites) on CBD1 activates mammalian NCXs, whereas CALX, a Drosophila NCX ortholog, displays an inhibitory response to regulatory Ca2+. To further elucidate the underlying regulatory mechanisms, we determined the 2.7 Å crystal structure of mammalian CBD12-E454K, a two-domain construct that retains wild-type properties. In conjunction with stopped-flow kinetics and SAXS (small-angle X-ray scattering) analyses of CBD12 mutants, we show that Ca2+ binding to Ca3-Ca4 sites tethers the domains via a network of interdomain salt-bridges. This Ca2+-driven interdomain switch controls slow dissociation of “occluded” Ca2+ from the primary sensor and thus dictates Ca2+ sensing dynamics. In the Ca2+-bound conformation, the interdomain angle of CBD12 is very similar in NCX and CALX, meaning that the interdomain distances cannot account for regulatory diversity in NCX and CALX. Since the two-domain interface is nearly identical among eukaryotic NCXs, including CALX, we suggest that the Ca2+-driven interdomain switch described here represents a general mechanism for initial conduction of regulatory signals in NCX variants

An Imperfect Dopaminergic Error Signal Can Drive Temporal-Difference Learning

An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards

Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the ESICM Working Group on Abdominal Problems

Acute gastrointestinal (GI) dysfunction and failure have been increasingly recognized in critically ill patients. The variety of definitions proposed in the past has led to confusion and difficulty in comparing one study to another. An international working group convened to standardize the definitions for acute GI failure and GI symptoms and to review the therapeutic options

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics