1945-12-12, James to William

https://digitalcommons.chapman.edu/wvasos_collection/1057/thumbnail.jp

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

An Analysis of the Cost of the Abatement of Ammonia Emissions in Irish Agriculture to 2030

peer-reviewedThis analysis quantifies the potential to abate national ammonia (NH3) emissions up to 2030. This report is an updated marginal abatement cost curve (MACC) analysis where Teagasc has quantified the abatement potential of a range of ammonia mitigation measures, as well as their associated costs/benefits (see Lanigan et al. 2015 for previous analysis). The objective of this analysis is to quantify the extent and costs associated with meeting future ammonia emission targets that were negotiated as part of the amended Clean Air Policy Package. The requirement to reduce ammonia emissions is urgent, both in terms of compliance with the National Emissions Ceilings Directive (NECD), and as a principal loss pathway for agricultural nitrogen (N). Improvement of N efficiency is a key focus for improving farm efficiency and sustainability as well as reducing the ammonia, nitrate and greenhouse gas (GHG) footprint of agriculture. This is particularly relevant in the context of the national strategies on the development of the agri-food sector: Food Wise 2025, Ag-food strategy 2030 and Ag-Climatise (currently under development) and the newly unveiled EU Farm to Fork Strategy, which is a part of the European Green Deal. Under the baseline scenario (S1), agricultural ammonia emissions are projected to increase by 9% (without any mitigation) by 2030 relative to 2005 levels. While these increases are small in comparison to the targeted increase in agricultural output, they will provide a major challenge to meeting emissions targets, particularly as agriculture comprises over 99% of national emissions. The analysis presented in this report seeks to quantify the ammonia mitigation potential under likely uptake pathways. This is not an exhaustive analysis of all mitigation measures, but represents an assessment of best available techniques, based on scientific, peer-reviewed research carried out by Teagasc and associated national and international research partners. Indeed, any future changes in the sector or in the national emission inventory calculations will require further analysis of the applicability of ammonia mitigation techniques, particularly in terms of housing and storage but also in the context of other reactive N1 emissions. It should also be noted that some mitigation measures, particularly those related to nitrogen application to soils, could result in either higher greenhouse gas emissions or higher nitrate leaching. Compared to a future where no mitigation measures are deployed to address emissions, by 2030 the average technical abatement2 potential was estimated to be approximately 15.26 kt NH3 at a net cost of €10.86 million per annum. However, it should be noted that the net cost (€10.86 million) is comprised of 6 measures that are cost negative (-€22.21 million) and 7 measures that are cost positive (€33.07) and that some of the cost negative measures are predicated on efficiency gains driven by best management practice adoption (e.g. liming and clover measures with associate chemical N reductions). Amongst the thirteen mitigation measures selected for this analysis, 80% of the mitigation potential can be achieved by the full implementation of the mitigation pathways for protected urea and low emission slurry spreading (LESS) techniques for bovines. It should be stressed that this is an assessment of the maximum abatement potential and realising this level of abatement in practice will be extremely challenging. Any increase in agricultural activity beyond the baseline scenario will increase absolute emissions. The level of mitigation achievable is based on the draft AgClimatise measures any delay or reduction in the uptake of these measures will reduce the mitigation achieved. It must also be ensured that all mitigation measures should, where possible, be synergistic with reductions in greenhouse gas emissions and N loss to water

Letter from Forrestal to McCloy with attachments

Letter from Undersecretary of the Navy James Forrestal to Assistant Secretary of War John J. McCloy regarding Navy Commander Melvin McCoy, who was quoted by the United Press as having made disparaging remarks about Japanese American soldiers, such as that they excel at killing Germans because they like killing white men. Forrestal indicates that McCoy has been unofficially reprimanded for his words

Letter to the Secretary of War from the Secretary of the Navy dated August 25, 1944

Letter to Henry L. Stimson regarding a plan to rescind the mass exclusion of citizens of Japanese ancestry from the West Coast and designating two officers for further discussion of the plan

Modulation of Host Innate Immune Response in the Bladder by Uropathogenic Escherichia coli▿

Uropathogenic Escherichia coli (UPEC), the most frequent cause of urinary tract infection (UTI), is associated with an inflammatory response which includes the induction of cytokine/chemokine secretion by urothelial cells and neutrophil recruitment to the bladder. Recent studies indicate, however, that UPEC can evade the early activation of urothelial innate immune response in vitro. In this study, we report that infection with the prototypic UPEC strain NU14 suppresses tumor necrosis factor alpha (TNF-α)-mediated interleukin-8 (CXCL-8) and interleukin-6 (CXCL-6) secretion from urothelial cell cultures compared to infection with a type 1 piliated E. coli K-12 strain. Furthermore, examination of a panel of clinical E. coli isolates revealed that 15 of 17 strains also possessed the ability to suppress cytokine secretion. In a murine model of UTI, NU14 infection resulted in diminished levels of mRNAs encoding keratinocyte-derived chemokine, macrophage inflammatory peptide 2, and CXCL-6 in the bladder relative to infection with an E. coli K-12 strain. Furthermore, reduced stimulation of inflammatory chemokine production during NU14 infection correlated with decreased levels of bladder and urine myeloperoxidase and increased bacterial colonization. These data indicate that a broad phylogenetic range of clinical E. coli isolates, including UPEC, may evade the activation of innate immune response in the urinary tract, thereby providing a pathogenic advantage

Evaluation of the impacts of different treatments of spatio-temporal variation in catch-per-unit-effort standardization models

•We evaluated nine catch-per-unit-effort (CPUE) standardization methods.•Our study population was Atlantic blue marlin.•We relied on simulations mimicking data collected by observers on longline fisheries.•The spatio-temporal method VAST was found to perform the best.•We also applied the CPUE standardization methods to real data collected by observers. Many stock assessments heavily rely on indices of relative abundance derived from fisheries-dependent catch-per-unit-effort (CPUE) data. Therefore, it is critical to evaluate different CPUE standardization methods under varying scenarios of data generating processes. Here, we evaluated nine CPUE standardization methods offering contrasting treatments of spatio-temporal variation, ranging from the basic generalized linear model (GLM) method not integrating a year-area interaction term to a sophisticated method using the spatio-temporal modeling platform VAST. We compared the performance of these methods against simulated data constructed to mimic the processes generating fisheries-dependent information for Atlantic blue marlin (Makaira nigricans), a common bycatch population in pelagic longline fisheries. Data were generated using a longline data simulator for different population trajectories (increasing, decreasing, and static). These data were further subsampled to mimic an observer program where trips rather than sets form the sampling frame, with or without a bias towards trips with low catch rates, which might occur if the presence of an observer alters fishing behavior to avoid bycatch. The spatio-temporal modeling platform VAST achieved the best performance in simulation, namely generally had one of the lowest biases, one of the lowest mean absolute errors (MAEs), and 50% confidence interval coverage closest to 50%. Generalized additive models accounting for spatial autocorrelation at a broad spatial scale (one of the lowest MAEs and one of the lowest biases) and, to a lesser extent, non-spatial delta-lognormal GLMs including a year-area interaction as a random effect (one of the lowest MAEs and one of the best confidence interval coverages) also performed adequately. The VAST method provided the most comprehensive and consistent treatment of spatio-temporal variation, in contrast with methods that simply weight predictions by large spatial areas, where it is critical, but difficult, to get the a priori spatial stratification correct before weighting. Next, we applied the CPUE standardization methods to real data collected by the National Marine Fisheries Service Pelagic Observer Program. The indices of relative abundance predicted from real observer data were relatively similar across CPUE standardization methods for the period 1998–2017 and suggested that the blue marlin population of the Atlantic declined over the period 1998–2004 and was relatively stable afterwards. As spatio-temporal variation related to environmental changes or depletion becomes increasingly necessary to consider, greater use of spatio-temporal models for standardizing fisheries-dependent CPUE data will likely be warranted