A Locus for Hereditary Sensory Neuropathy with Cough and Gastroesophageal Reflux on Chromosome 3p22-p24

Hereditary sensory neuropathy type I (HSN I) is a group of dominantly inherited degenerative disorders of peripheral nerve in which sensory features are more prominent than motor involvement. We have described a new form of HSN I that is associated with cough and gastroesophageal reflux. To map the chromosomal location of the gene causing the disorder, a 10-cM genome screen was undertaken in a large Australian family. Two-point analysis showed linkage to chromosome 3p22-p24 (Zmax=3.51 at recombination fraction (θ) 0.0 for marker D3S2338). A second family with a similar phenotype shares a different disease haplotype but segregates at the same locus. Extended haplotype analysis has refined the region to a 3.42-cM interval, flanked by markers D3S2336 and D3S1266

Uncertainties in the modelled CO2 threshold for Antarctic glaciation

A frequently cited atmospheric CO2 threshold for the onset of Antarctic glaciation of ∼780 ppmv is based on the study of DeConto and Pollard (2003) using an ice sheet model and the GENESIS climate model. Proxy records suggest that atmospheric CO2 concentrations passed through this threshold across the Eocene-Oligocene transition ∼34 Ma. However, atmospheric CO2 concentrations may have been close to this threshold earlier than this transition, which is used by some to suggest the possibility of Antarctic ice sheets during the Eocene. Here we investigate the climate model dependency of the threshold for Antarctic glaciation by performing offline ice sheet model simulations using the climate from 7 different climate models with Eocene boundary conditions (HadCM3L, CCSM3, CESM1.0, GENESIS, FAMOUS, ECHAM5 and GISS-ER). These climate simulations are sourced from a number of independent studies, and as such the boundary conditions, which are poorly constrained during the Eocene, are not identical between simulations. The results of this study suggest that the atmospheric CO2 threshold for Antarctic glaciation is highly dependent on the climate model used and the climate model configuration. A large discrepancy between the climate model and ice sheet model grids for some simulations leads to a strong sensitivity to the lapse rate parameter

Impact of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

Background: Meningococcal conjugate vaccines protect individuals directly, but also confer herd protection by interrupting carriage transmission. This Phase III observer-blind, randomised, controlled study evaluated the effects of meningococcal quadrivalent (ACWY) glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in young adults. Methods: University students (aged 18–24 years) from ten sites in England were randomised to receive two vaccinations one month apart: two doses of Japanese Encephalitis vaccine (controls), two doses of 4CMenB (4CMenB), or one dose of MenACWY-CRM then placebo (MenACWY-CRM). Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over one year. Primary analysis was cross-sectional carriage one month after the vaccine course; secondary analyses included comparison of carriage at any time point after primary analysis until study termination. Findings: 2954 subjects were randomised (control, n=987; 4CMenB, n=988; MenACWY-CRM, n=979); approximately one-third of each group was positive for meningococcal carriage at study entry. By one month, there was no significant difference in carriage between controls and 4CMenB (Odds Ratios (OR) [95% CI]; 1·2 [0·8−1·7]) or MenACWY-CRM (OR [95% CI], 0·9 [0·6–1·3]) groups. From three months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (calculated efficacy 18·2% [95% CI: 3·4–30·8]) and capsular groups BCWY (calculated efficacy 26·6% [95% CI: 10·5–39·9]) compared to control vaccination. Significantly lower carriage rates were also observed in the MenACWY-CRM group compared with controls: calculated efficacies 39·0% [95%CI: 17·3-55·0] and 36.2% [95%CI: 15·6-51·7] for serogroups Y and CWY, respectively. Interpretation: MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates over 12 months post-vaccination and, therefore, may affect transmission where widely implemented

Development of Low-Cost Austenitic Stainless Gas-Turbine and Diesel Engine Components with Enhanced High-Temperature Reliability

In July of 1999, a Cooperative Research and Development Agreement (CRADA) was undertaken between Oak Ridge National Laboratory (ORNL) and Solar Turbines, Inc. and Caterpillar, Inc. (Caterpillar Technical Center) to evaluate commercial cast stainless steels for gas turbine engine and diesel engine exhaust component applications relative to the materials currently being used. If appropriate, the goal was to develop cast stainless steels with improved performance and reliability rather than switch to more costly cast Ni-based superalloys for upgraded performance. The gas-turbine components considered for the Mercury-50 engine were the combustor housing and end-cover, and the center-frame hot-plate, both made from commercial CF8C cast austenitic stainless steel (Fe-l9Cr-12Ni-Nb,C), which is generally limited to use at below 650 C. The advanced diesel engine components considered for truck applications (C10, C12, 3300 and 3400) were the exhaust manifold and turbocharger housing made from commercial high SiMo ductile cast iron with uses limited to 700-750 C or below. Shortly after the start of the CRADA, the turbine materials emphasis changed to wrought 347H stainless steel (hot-plate) and after some initial baseline tensile and creep testing, it was confirmed that this material was typical of those comprising the abundant database; and by 2000, the emphasis of the CRADA was primarily on diesel engine materials. For the diesel applications, commercial SiMo cast iron and standard cast CN12 austenitic stainless steel (Fe-25Cr-13Ni-Nb,C,N,S) baseline materials were obtained commercially. Tensile and creep testing from room temperature to 900 C showed the CN12 austenitic stainless steel to have far superior strength compared to SiMo cast iron above 550 C, together with outstanding oxidation resistance. However, aging at 850 C reduced room-temperature ductility of the standard CN12, and creep-rupture resistance at 850 C was less than expected, which triggered a focused laboratory-scale alloy development effort on modified cast austenitic stainless steels at ORNL. Isothermal fatigue testing at 700 C also showed that standard CN12 was far superior to SiMo cast iron, but somewhat less than the desired behavior. During the first year, 3 new modified CF8C heats and 8 new modified CN12 heats were made, based on compositional changes specifically designed to change the nature, dispersion and stability of the as-cast and high-temperature aging-induced microstructures that consisted of carbides and other precipitate phases. Screening of the alloys at room-temperature and at 850 C (tensile and creep-rupture) showed -a ten-fold increase in rupture life of the best modified CN12 relative to the baseline material, better room-temperature ductility after aging, caused by less precipitation in the as-cast material and much less aging-induced precipitation. The best new modified CF8C steel showed strength at tensile and creep-rupture strength comparable to standard CN12 steel at 850 C, due to a unique and very stable microstructure. The CRADA was scheduled to end in July 2001, but was extended twice until July 2002. Based on the very positive results on the newly developed modified CF8C and CN12 cast austenitic stainless steels, a new CRADA with Caterpillar has been set up to commercially scale-up, test and evaluate, and make trial components from the new steels

Semiparametric theory and empirical processes in causal inference

In this paper we review important aspects of semiparametric theory and empirical processes that arise in causal inference problems. We begin with a brief introduction to the general problem of causal inference, and go on to discuss estimation and inference for causal effects under semiparametric models, which allow parts of the data-generating process to be unrestricted if they are not of particular interest (i.e., nuisance functions). These models are very useful in causal problems because the outcome process is often complex and difficult to model, and there may only be information available about the treatment process (at best). Semiparametric theory gives a framework for benchmarking efficiency and constructing estimators in such settings. In the second part of the paper we discuss empirical process theory, which provides powerful tools for understanding the asymptotic behavior of semiparametric estimators that depend on flexible nonparametric estimators of nuisance functions. These tools are crucial for incorporating machine learning and other modern methods into causal inference analyses. We conclude by examining related extensions and future directions for work in semiparametric causal inference

Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease.

A new human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently developed. In this model, ingestion of 104 CFU of Salmonella resulted in 65% of subjects developing typhoid fever (referred here as typhoid diagnosis -TD-) 5-10 days post-challenge. TD criteria included meeting clinical (oral temperature ≥38°C for ≥12 h) and/or microbiological (S. Typhi bacteremia) endpoints. One of the first lines of defense against pathogens are the cells of the innate immune system (e.g., monocytes, dendritic cells -DCs-). Various changes in circulating monocytes and DCs have been described in the murine S. Typhimurium model; however, whether similar changes are present in humans remains to be explored. To address these questions, a subset of volunteers (5 TD and 3 who did not develop typhoid despite oral challenge -NoTD-) were evaluated for changes in circulating monocytes and DCs. Expression of CD38 and CD40 were upregulated in monocytes and DCs in TD volunteers during the disease days (TD-0h to TD-96h). Moreover, integrin α4β7, a gut homing molecule, was upregulated on monocytes but not DCs. CD21 upregulation was only identified in DCs. These changes were not observed among NoTD volunteers despite the same oral challenge. Moreover, monocytes and DCs from NoTD volunteers showed increased binding to S. Typhi one day after challenge. These monocytes showed phosphorylation of p38MAPK, NFkB and Erk1/2 upon stimulation with S. Typhi-LPS-QDot micelles. In contrast, monocytes from TD volunteers showed only a moderate increase in S. Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation. This is the first study to describe different activation and migration profiles, as well as differential signaling patterns, in monocytes and DCs which relate directly to the clinical outcome following oral challenge with wild type S. Typhi

Understanding Business Travel Time and Its Place in the Working Day

This article argues that there is a need to understand business travel time in the context of the wider organization of work time. It considers why travel time use is potentially changing with the use of mobile technologies by the increasing number of individuals engaged in ‘knowledge work’, and examines existing evidence that indicates that travel time use is part of a wider work-related ‘taskscape’. However, it not only considers material productive output, but suggests that travel time as ‘time out’ from work-related activities also plays a vital role for employees. It also suggests that business travel time use that is not of benefit to the employer may not be at the employer's expense. This is contrasted with the assumptions used in UK transport appraisal. Data gathered from the autumn 2004 wave of the National Rail Passenger Survey (GB) is used to illustrate some key issues concerning productivity and ‘anti-activity’. A case study of an individual business traveller then points towards the need for a new approach to exploring the role played by travel time in the organization of work practices to be considered. © 2008, Sage Publications. All rights reserved

Computer modeling of diabetes and Its transparency: a report on the Eighth Mount Hood Challenge

Objectives The Eighth Mount Hood Challenge (held in St. Gallen, Switzerland, in September 2016) evaluated the transparency of model input documentation from two published health economics studies and developed guidelines for improving transparency in the reporting of input data underlying model-based economic analyses in diabetes. Methods Participating modeling groups were asked to reproduce the results of two published studies using the input data described in those articles. Gaps in input data were filled with assumptions reported by the modeling groups. Goodness of fit between the results reported in the target studies and the groups’ replicated outputs was evaluated using the slope of linear regression line and the coefficient of determination (R2). After a general discussion of the results, a diabetes-specific checklist for the transparency of model input was developed. Results Seven groups participated in the transparency challenge. The reporting of key model input parameters in the two studies, including the baseline characteristics of simulated patients, treatment effect and treatment intensification threshold assumptions, treatment effect evolution, prediction of complications and costs data, was inadequately transparent (and often missing altogether). Not surprisingly, goodness of fit was better for the study that reported its input data with more transparency. To improve the transparency in diabetes modeling, the Diabetes Modeling Input Checklist listing the minimal input data required for reproducibility in most diabetes modeling applications was developed. Conclusions Transparency of diabetes model inputs is important to the reproducibility and credibility of simulation results. In the Eighth Mount Hood Challenge, the Diabetes Modeling Input Checklist was developed with the goal of improving the transparency of input data reporting and reproducibility of diabetes simulation model results

Use of dispersion modelling for Environmental Impact Assessment of biological air pollution from composting: Progress, problems and prospects

© 2017 The Authors With the increase in composting as a sustainable waste management option, biological air pollution (bioaerosols) from composting facilities have become a cause of increasing concern due to their potential health impacts. Estimating community exposure to bioaerosols is problematic due to limitations in current monitoring methods. Atmospheric dispersion modelling can be used to estimate exposure concentrations, however several issues arise from the lack of appropriate bioaerosol data to use as inputs into models, and the complexity of the emission sources at composting facilities. This paper analyses current progress in using dispersion models for bioaerosols, examines the remaining problems and provides recommendations for future prospects in this area. A key finding is the urgent need for guidance for model users to ensure consistent bioaerosol modelling practices

Le magmatisme de la région de Kwyjibo, Province\ud du Grenville (Canada) : intérêt pour les\ud minéralisations de type fer-oxydes associées

The granitic plutons located north of the Kwyjibo property in Quebec’s Grenville Province are of\ud Mesoproterozoic age and belong to the granitic Canatiche Complex . The rocks in these plutons are calc-alkalic, K-rich,\ud and meta- to peraluminous. They belong to the magnetite series and their trace element characteristics link them to\ud intraplate granites. They were emplaced in an anorogenic, subvolcanic environment, but they subsequently underwent\ud significant ductile deformation. The magnetite, copper, and fluorite showings on the Kwyjibo property are polyphased\ud and premetamorphic; their formation began with the emplacement of hydraulic, magnetite-bearing breccias, followed by\ud impregnations and veins of chalcopyrite, pyrite, and fluorite, and ended with a late phase of mineralization, during\ud which uraninite, rare earths, and hematite were emplaced along brittle structures. The plutons belong to two families:\ud biotite-amphibole granites and leucogranites. The biotite-amphibole granites are rich in iron and represent a potential\ud heat and metal source for the first, iron oxide phase of mineralization. The leucogranites show a primary enrichment in\ud REE (rare-earth elements), F, and U, carried mainly in Y-, U-, and REE-bearing niobotitanates. They are metamict and\ud underwent a postmagmatic alteration that remobilized the uranium and the rare earths. The leucogranites could also be\ud a source of rare earths and uranium for the latest mineralizing events