Are we repeating mistakes of the past? A review of the evidence for esketamine – CORRIGENDUM

It should be emphasised that Table 1 in the Analysis1 combines data from Phase 2 trials (including open-label and placebo-controlled trial periods) and Phase 3 trials (placebo-controlled efficacy studies, a maintenance of effect study and a long-term open label safety study) submitted by Janssen to the FDA (as indicated by superscript 'b' in the Table), therefore the data does not represent a randomised comparison, and definitive causal inferences cannot be drawn. As indicated by the denominators for each entry there were more patients exposed to esketamine than placebo (and for longer periods) which may be one reason for the higher numbers of suicides in the esketamine group. However, it is worth noting other data that suggest that increased suicidality may be a feature of esketamine treatment. In the long-term safety study 14.5% of patients on esketamine (in a population selected for their lack of active suicidality) reported 'treatment-emergent' suicidal ideation (114/784), 6 patients attempted suicide in addition to the one completed suicide.2 Furthermore, a recent analysis of post-marketing surveillance data reported to the FDA for the 12 months since esketamine was licensed in the US there have already been 64 reports of suicidal ideation, 11 completed suicides, and 6 attempted suicides attributed to esketamine.3 This represents a 24-fold increased risk of report for suicidal ideation for esketamine compared with other drugs, and a 6-fold increased risk for completed suicide.3 The authors of this paper concluded that the safety of esketamine required "urgent clarification."3 It should also be clarified that although ketamine is not used routinely as an anaesthetic agent in high-income countries, like the UK, because of its unfavourable balance of risks and harms, it is used more frequently in low-income countries

Quantifying methane and nitrous oxide emissions from the UK and Ireland using a national-scale monitoring network

The UK is one of several countries around the world that has enacted legislation to reduce its greenhouse gas emissions. In this study, we present top-down emissions of methane (CH4) and nitrous oxide (N2O) for the UK and Ireland over the period August 2012 to August 2014. These emissions were inferred using measurements from a network of four sites around the two countries. We used a hierarchical Bayesian inverse framework to infer fluxes as well as a set of covariance parameters that describe uncertainties in the system. We inferred average UK total emissions of 2.09 (1.65–2.67) Tg yr−1 CH4 and 0.101 (0.068–0.150) Tg yr−1 N2O and found our derived UK estimates to be generally lower than the a priori emissions, which consisted primarily of anthropogenic sources and with a smaller contribution from natural sources. We used sectoral distributions from the UK National Atmospheric Emissions Inventory (NAEI) to determine whether these discrepancies can be attributed to specific source sectors. Because of the distinct distributions of the two dominant CH4 emissions sectors in the UK, agriculture and waste, we found that the inventory may be overestimated in agricultural CH4 emissions. We found that annual mean N2O emissions were consistent with both the prior and the anthropogenic inventory but we derived a significant seasonal cycle in emissions. This seasonality is likely due to seasonality in fertilizer application and in environmental drivers such as temperature and rainfall, which are not reflected in the annual resolution inventory. Through the hierarchical Bayesian inverse framework, we quantified uncertainty covariance parameters and emphasized their importance for high-resolution emissions estimation. We inferred average model errors of approximately 20 and 0.4 ppb and correlation timescales of 1.0 (0.72–1.43) and 2.6 (1.9–20 3.9) days for CH4 and N2O, respectively. These errors are a combination of transport model errors as well as errors due to unresolved emissions processes in the inventory. We found the largest CH4 errors at the Tacolneston station in eastern England, which may be due to sporadic emissions from landfills and offshore gas in the North Sea

Creation of 3D models from large unstructured image and video datasets

Exploration of various places using low-cost camera solutions over decades without having a photogrammetric application in mind has resulted in large collections of images and videos that may have significant cultural value. The purpose of collecting this data is often to provide a log of events and therefore the data is often unstructured and of varying quality. Depending on the equipment used there may be approximate location data available for the images but the accuracy of this data may also be of varying quality. In this paper we present an approach that can deal with these conditions and process datasets of this type to produce 3D models. Results from processing the dataset collected during the discovery and subsequent exploration of the HMAS Sydney and HSK Kormoran wreck sites shows the potential of our approach. The results are promising and show that there is potential to retrieve significantly more information from many of these datasets than previously thought possible

Production costs in the apple industry : comments on a survey

IN 1964 and 1965, light and heavy bearing years respectively, apples cost $2.40 per bushel to produce in Western Australia. This figure, to be considered with many other factors, was reached in a cost-of-production survey of 45 selected growers. Packing and labour costs, in that order, were the two biggest cost-of-production items

Dynamic privacy in public surveillance

In implementing privacy protection in surveillance systems, designers must maximize privacy while retaining the system?s purpose. One way to achieve this is to combine data-hiding techniques with context-aware policies governing access to securely collected and stored data

"Being Bipolar": A Qualitative Analysis of the Experience of Bipolar Disorder as Described in Internet Blogs

In the light of debates about the nature of bipolar disorder (BD), the current article presents a thematic analysis of Internet “blogs” by self-identified bipolar sufferers. Extreme and frequent fluctuation of mood was considered the principal feature of BD, along with a broad range of other problems. BD was often invoked as an explanation for life difficulties or lack of achievement, and was mostly regarded as a brain disease. Most bloggers emphasized the importance of drug treatment, along with the self-management techniques. The blogs present a “bipolar identity,” which is much broader than traditional definitions, are based on a medicalized model of the disorder, and are connected to the moral function of enabling people to externalize unwanted aspects of the self

Atmospheric transport and chemistry of trace gases in LMDz5B: evaluation and implications for inverse modelling

Representation of atmospheric transport is a major source of error in the estimation of greenhouse gas sources and sinks by inverse modelling. Here we assess the impact on trace gas mole fractions of the new physical parameterizations recently implemented in the atmospheric global climate model LMDz to improve vertical diffusion, mesoscale mixing by thermal plumes in the planetary boundary layer (PBL), and deep convection in the troposphere. At the same time, the horizontal and vertical resolution of the model used in the inverse system has been increased. The aim of this paper is to evaluate the impact of these developments on the representation of trace gas transport and chemistry, and to anticipate the implications for inversions of greenhouse gas emissions using such an updated model. Comparison of a one-dimensional version of LMDz with large eddy simulations shows that the thermal scheme simulates shallow convective tracer transport in the PBL over land very efficiently, and much better than previous versions of the model. This result is confirmed in three-dimensional simulations, by a much improved reproduction of the radon-222 diurnal cycle. However, the enhanced dynamics of tracer concentrations induces a stronger sensitivity of the new LMDz configuration to external meteorological forcings. At larger scales, the inter-hemispheric exchange is slightly slower when using the new version of the model, bringing them closer to observations. The increase in the vertical resolution (from 19 to 39 layers) significantly improves the representation of stratosphere/troposphere exchange. Furthermore, changes in atmospheric thermodynamic variables, such as temperature, due to changes in the PBL mixing modify chemical reaction rates, which perturb chemical equilibriums of reactive trace gases. One implication of LMDz model developments for future inversions of greenhouse gas emissions is the ability of the updated system to assimilate a larger amount of high-frequency data sampled at high-variability stations. Others implications are discussed at the end of the paper

The Neutrophil-Lymphocyte Ratio and Locoregional Melanoma: A Multicentre Cohort Study

Objectives The neutrophil–lymphocyte ratio (NLR) is an inflammatory biomarker which is useful in cancer prognostication. We aimed to investigate the differences in baseline NLR between patients with localised and metastatic cutaneous melanoma and how this biomarker changed over time with the recurrence of disease. Methods This multicentre cohort study describes patients treated for Stage I–III cutaneous melanoma over 10 years. The baseline NLR was measured immediately prior to surgery and again at the time of discharge or disease recurrence. The odds ratios (OR) for sentinel node involvement are estimated using mixed-effects logistic regression. The risk of recurrence is estimated using multivariable Cox regression. Results Overall 1489 individuals were included. The mean baseline NLR was higher in patients with palpable nodal disease compared to those with microscopic nodal or localised disease (2.8 versus 2.4 and 2.3, respectively; p < 0.001). A baseline NLR ≥ 2.3 was associated with 30% higher odds of microscopic metastatic melanoma in the sentinel lymph node [adjusted OR 1.3 (95% CI 1.3, 1.3)]. Following surgery, 253 patients (18.7%) developed recurrent melanoma during surveillance although there was no statistically significant association between the baseline NLR and the risk of recurrence [adjusted HR 0.9 (0.7, 1.1)]. Conclusion The NLR is associated with the volume of melanoma at presentation and may predict occult sentinel lymph metastases. Further prospective work is required to investigate how NLR may be modelled against other clinicopathological variables to predict outcomes and to understand the temporal changes in NLR following surgery for melanoma