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Sediment discharged from the Greenland Ice Sheet delivers nutrients to marine ecosystems around Greenland and shapes seafloor habitats. Current estimates of the total sediment flux are constrained by observations from land-terminating glaciers only. Addressing this gap, our study presents a budget derived from observations at 30 marine-margin locations. Analyzing sediment cores from nine glaciated fjords, we assess spatial deposition since 1950. A significant correlation is established between mass accumulation rates, normalized by surface runoff, and distance down-fjord. This enables calculating annual sediment flux at any fjord point based on nearby marine-terminating outlet glacier melt data. Findings reveal a total annual sediment flux of 1.324 + /- 0.79 Gt yr-1 over the period 2010-2020 from all marine-terminating glaciers to the fjords. These estimates are valuable for studies aiming to understand the basal ice sheet conditions and for studies predicting ecosystem changes in Greenland's fjords and offshore areas as the ice sheet melts and sediment discharge increase.

Sediment discharged from the Greenland Ice Sheet delivers nutrients to marine ecosystems around Greenland and shapes seafloor habitats. Current estimates of the total sediment flux are constrained by observations from land-terminating glaciers only. Addressing this gap, our study presents a budget derived from observations at 30 marine-margin locations. Analyzing sediment cores from nine glaciated fjords, we assess spatial deposition since 1950. A significant correlation is established between mass accumulation rates, normalized by surface runoff, and distance down-fjord. This enables calculating annual sediment flux at any fjord point based on nearby marine-terminating outlet glacier melt data. Findings reveal a total annual sediment flux of 1.324 + /− 0.79 Gt yr-1 over the period 2010-2020 from all marine-terminating glaciers to the fjords. These estimates are valuable for studies aiming to understand the basal ice sheet conditions and for studies predicting ecosystem changes in Greenland’s fjords and offshore areas as the ice sheet melts and sediment discharge increase.

Sediment discharged from the Greenland Ice Sheet delivers nutrients to marine ecosystems around Greenland and shapes seafloor habitats. Current estimates of the total sediment flux are constrained by observations from land-terminating glaciers only. Addressing this gap, our study presents a budget derived from observations at 30 marine-margin locations. Analyzing sediment cores from nine glaciated fjords, we assess spatial deposition since 1950. A significant correlation is established between mass accumulation rates, normalized by surface runoff, and distance down-fjord. This enables calculating annual sediment flux at any fjord point based on nearby marine-terminating outlet glacier melt data. Findings reveal a total annual sediment flux of 1.324 + /− 0.79 Gt yr-1 over the period 2010-2020 from all marine-terminating glaciers to the fjords. These estimates are valuable for studies aiming to understand the basal ice sheet conditions and for studies predicting ecosystem changes in Greenland’s fjords and offshore areas as the ice sheet melts and sediment discharge increase.

Environmental stresses can compromise the interactions of plants with beneficial microbes. In the present review, experimental results showing that stresses negatively affect the abundance and/or functionality of plant beneficial microbes are summarized. It is proposed that the environmental interference of these plant-microbe interactions is explained by the stress-mediated induction of plant signalling pathways associated with defence hormones and reactive oxygen species. These plant responses are recognized to regulate beneficial microbes within plants. The direct negative effect of stresses on microbes may also contribute to the environmental regulation of these plant mutualisms. It is also posited that, in stress situations, beneficial microbes harbour mechanisms that contribute to maintain the mutualistic associations. Beneficial microbes produce effector proteins and increase the antioxidant levels in plants that counteract the detrimental effects of plant stress responses on them. In addition, they deliver specific stress-protective mechanisms that assist to their plant hosts to mitigate the negative effects of stresses. Our study contributes to understanding how environmental stresses affect plant-microbe interactions and highlights why beneficial microbes can still deliver benefits to plants in stressful environments.

We assessed the efficacy of ozonation as an indoor remediation strategy by evaluating how a carpet serves as a sink and long-term source of thirdhand tobacco smoke (THS) while protecting contaminants absorbed in deep reservoirs by scavenging ozone. Specimens from unused carpet that was exposed to smoke in the lab ("fresh THS") and contaminated carpets retrieved from smokers' homes ("aged THS") were treated with 1000 ppb ozone in bench-scale tests. Nicotine was partially removed from fresh THS specimens by volatilization and oxidation, but it was not significantly eliminated from aged THS samples. By contrast, most of the 24 polycyclic aromatic hydrocarbons detected in both samples were partially removed by ozone. One of the home-aged carpets was installed in an 18 m3 room-sized chamber, where its nicotine emission rate was 950 ng day-1 m-2. In a typical home, such daily emissions could amount to a non-negligible fraction of the nicotine released by smoking one cigarette. The operation of a commercial ozone generator for a total duration of 156 min, reaching concentrations up to 10,000 ppb, did not significantly reduce the carpet nicotine loading (26-122 mg m-2). Ozone reacted primarily with carpet fibers, rather than with THS, leading to short-term emissions of aldehydes and aerosol particles. Hence, by being absorbed deeply into carpet fibers, THS constituents can be partially shielded from ozonation.

Starting in the 1970s, individuals, businesses and the public have increasingly benefited from policies prohibiting smoking indoors, saving thousands of lives and billions of dollars in healthcare expenditures. Smokefree policies to protect against secondhand smoke exposure, however, do not fully protect the public from the persistent and toxic chemical residues from tobacco smoke (also known as thirdhand smoke) that linger in indoor environments for years after smoking stops. Nor do these policies address the economic costs that individuals, businesses and the public bear in their attempts to remediate this toxic residue. We discuss policy-relevant differences between secondhand smoke and thirdhand smoke exposure: persistent pollutant reservoirs, pollutant transport, routes of exposure, the time gap between initial cause and effect, and remediation and disposal. We examine four policy considerations to better protect the public from involuntary exposure to tobacco smoke pollutants from all sources. We call for (a) redefining smokefree as free of tobacco smoke pollutants from secondhand and thirdhand smoke; (b) eliminating exemptions to comprehensive smoking bans; (c) identifying indoor environments with significant thirdhand smoke reservoirs; and (d) remediating thirdhand smoke. We use the case of California as an example of how secondhand smoke-protective laws may be strengthened to encompass thirdhand smoke protections. The health risks and economic costs of thirdhand smoke require that smokefree policies, environmental protections, real estate and rental disclosure policies, tenant protections, and consumer protection laws be strengthened to ensure that the public is fully protected from and informed about the risks of thirdhand smoke exposure.

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

Expansins are proteins involved in cell wall metabolism that play an important role in plant growth, development, fruit ripening and abiotic stress tolerance. In the present study, we analyzed putative expansins that respond to drought stress. Five expansin genes were identified in cDNA libraries isolated from Colobanthus quitensis gown either with or without endophytic fungi under hydric stress. A differential transcript abundance was observed by qPCR analysis upon drought stress. To compare these expansin genes, and to suggest a possible mechanism of action at the molecular level, the structural model of the deduced proteins was obtained by comparative modeling methodology. The structures showed two domains and an open groove on the surface of the proteins was observed in the five structural models. The proteins were evaluated in terms of their protein-ligand interactions using four different ligands. The results suggested differences in their mode of protein-ligand interaction, in particular concerning the residues involved in the protein-ligand interaction. The presented evidence supports the participation of some members of the expansin multiprotein family in the response to drought stress in C. quitensis and suggest that the response is modulated by endophytic fungi.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Im Rahmen der ISAR (“rISk strAtification in end stage Renal disease”) Studie wurde die Assoziation der EKG-LVH-Parameter Sokolow-Lyon, Cornell und Peguero-Lo Presti Index mit der kardiovaskulären Mortalität und Gesamtmortalität bei 308 Hämodialysepatienten untersucht. Sowohl der Cornell als auch der Peguero-Lo Presti Index, nicht aber der Sokolow-Lyon Index, waren auch nach Adjustierung auf verschiedene Risikomodelle signifikant mit der kardiovaskulären Mortalität assoziiert., As part of the ISAR (rISk strAtification in end stage Renal disease) study the association of the ECG-LVH criteria Sokolow-Lyon, Cornell and Peguero-Lo Presti Index with cardiovascular and all-cause mortality in 308 hemodialysis patients was investigated. Both the Cornell and Peguero-Lo Presti Index, but not the Sokolow-Lyon Index, were significantly associated with cardiovascular mortality even after adjustement for different risk models.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

ObjectiveA major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS).MethodsFrom a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion.ResultsPatients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively.InterpretationSilent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.

Tobacco-specific nitrosamines (TSNAs) are emitted during smoking and form indoors by nitrosation of nicotine. Two of them, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are human carcinogens with No Significant Risk Levels (NSRLs) of 500 and 14 ng day-1, respectively. Another TSNA, 4-(methylnitrosamino)-4-(3-pyridyl) butanal (NNA), shows genotoxic and mutagenic activity in vitro. Here, we present additional evidence of genotoxicity of NNA, an assessment of TSNA dermal uptake, and predicted exposure risks through different pathways. Dermal uptake was investigated by evaluating the penetration of NNK and nicotine through mice skin. Comparable mouse urine metabolite profiles suggested that both compounds were absorbed and metabolized via similar mechanisms. We then investigated the effects of skin constituents on the reaction of adsorbed nicotine with nitrous acid (epidermal chemistry). Higher TSNA concentrations were formed on cellulose and cotton substrates that were precoated with human skin oils and sweat compared to clean substrates. These results were combined with reported air, dust, and surface concentrations to assess NNK intake. Five different exposure pathways exceeded the NSRL under realistic scenarios, including inhalation, dust ingestion, direct dermal contact, gas-to-skin deposition, and epidermal nitrosation of nicotine. These results illustrate potential long-term health risks for nonsmokers in homes contaminated with thirdhand tobacco smoke.

Objectives: Cutaneous leishmaniasis (CL) in Asia, Northern, and Sub-Saharan Africa is mainly caused by Leishmania major and Leishmania tropica. We describe and evaluate the treatment outcome of CL among travelers and migrants in Europe.Methods: We conducted a retrospective study of parasitological confirmed CL cases caused by L. major and L. tropica during 2013-2019 in Europe. Data were collected from medical records and databases within the LeishMan network.Results: Of 206 included cases of CL, 75 were identified as L. major and 131 as L. tropica. Of patients with L. tropica infection, 80% were migrants, whereas 53% of patients with L. major infection had been visiting friends and relatives. Among patients with L. tropica, 48% were younger than 15 years. Pentavalent antimony cured 73% ( L. major ) and 78% ( L. tropica) of patients. The cure rate for intralesional administration was 86% and 67% for systemic, on L. tropica. Liposomal amphotericin B had a cure rate of 44-63%. Conclusion: L. major infections were mostly found in individuals visiting friends and relatives, whereas L. tropica were mainly identified in migrants. No patients with L. major relapsed. Pentavalent antimony, liposomal amphotericin B, and cryotherapy had cure rates in accordance with previous studies.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Background Invasive plants may displace native species. This is the case of Poa annua, the only non-native plant species successfully established in Maritime Antarctica. Nonetheless, it is uncertain which factors drive the competitive success of P. annua in the harsh environmental conditions of the region. The ability of this plant species to establish novel mutualistic interactions with resident soil fungi may be crucial for its invasiveness. Such ability may be linked to the vertical transmission of the fungal endophytes via seeds. Aims We undertook a study to assess the role of seed fungal endophytes as promoters of the establishment and invasion of Poa annua in Maritime Antarctica. Methods We explored the composition and diversity of fungal communities associated with different P. annua tissues (seeds, leaves and roots) and the soil. We also measured parameters including germination rate, above-ground biomass, reproductive structures, and the survival of invasive P. annua as well as of the native Colobanthus quitensis and Deschampsia antarctica grown from seeds with and without endophytes. Furthermore, we conducted inter- and intraspecific competition experiments among native and invasive plants, where chemically-mediated plant-to-plant interference (allelopathy) and plant growth rate were measured to calculate a relative competition index. Results We found that fungal endophyte taxa associated with P. annua tissues were very different from those in the soil. Fungal endophytes in P. annua differed among seed, root and shoot tissues, which suggests low transmission among different organs. The removal of endophytes from P. annua seeds was associated with reduced seed germination, plant growth and survivorship, while the competitive ability of P. annua (assessed by accumulated biomass) relative to native species, as well as levels of allelochemicals in soils, were higher in the presence of seed fungal endophytes. Conclusion Our results suggest that fungal endophyte

Im Rahmen der ISAR (“rISk strAtification in end stage Renal disease”) Studie wurde die Assoziation der EKG-LVH-Parameter Sokolow-Lyon, Cornell und Peguero-Lo Presti Index mit der kardiovaskulären Mortalität und Gesamtmortalität bei 308 Hämodialysepatienten untersucht. Sowohl der Cornell als auch der Peguero-Lo Presti Index, nicht aber der Sokolow-Lyon Index, waren auch nach Adjustierung auf verschiedene Risikomodelle signifikant mit der kardiovaskulären Mortalität assoziiert., As part of the ISAR (rISk strAtification in end stage Renal disease) study the association of the ECG-LVH criteria Sokolow-Lyon, Cornell and Peguero-Lo Presti Index with cardiovascular and all-cause mortality in 308 hemodialysis patients was investigated. Both the Cornell and Peguero-Lo Presti Index, but not the Sokolow-Lyon Index, were significantly associated with cardiovascular mortality even after adjustement for different risk models.

Antarctic plants have developed mechanisms to deal with one or more adverse factors which allow them to successfully survive such extreme environment. Certain effective mechanisms to face adverse stress factors can arise from the establishment of functional symbiosis with endophytic fungi. In this work, we explored the role of fungal endophytes on host plant performance under high level of UV-B radiation, a harmful factor known to damage structure and function of cell components. In order to unveil the underlying mechanisms, we characterized the expression of genes associated to UV-B photoreception, accumulation of key flavonoids, and physiological responses of Colobanthus quitensis plants with (E+) and without (E−) fungal endophytes, under contrasting levels of UV-B radiation. The deduced proteins of CqUVR8, CqHY5, and CqFLS share the characteristic domains and display high degrees of similarity with other corresponding proteins in plants. Endophyte symbiotic plants showed lower lipid peroxidation and higher photosynthesis efficiency under high UV-B radiation. In comparison with E−, E+ plants showed lower CqUVR8, CqHY5, and CqFLS transcript levels. The content of quercetin, a ROS-scavenger flavonoid, in leaves of E- plants exposed to high UV-B was almost 8-fold higher than that in E+ plants 48 h after treatment. Our results suggest that endophyte fungi minimize cell damage and boost physiological performance in the Antarctic plants increasing the tolerance to UV-B radiation. Fungal endophytes appear as fundamental biological partners for plants to cope with the highly damaging UV-B radiation of Antarctica.

Ozonation is a common remediation approach to eliminate odors from mold, tobacco and fire damage in buildings. Little information exists to: 1) assess its effectiveness; 2) provide guidance on operation conditions; and 3) identify potential risks associated with the presence of indoor ozone and ozonation byproducts. The goal of this study is to evaluate chemical changes in thirdhand smoke (THS) aerosols induced by high levels of ozone, in comparison with THS aerosols aged under similar conditions in the absence of ozone. Samples representing different stages of smoke aging in the absence of ozone, including freshly emitted secondhand smoke (SHS) and THS, were collected inside an 18-m3 room-sized chamber over a period of 42 h after six cigarettes were consumed. The experiments involved collection and analysis of gas phase species including volatile organic compounds (VOCs), volatile carbonyls, semivolatile organic compounds (SVOCs), and particulate matter. VOC analysis was carried out by gas chromatography/mass spectrometry with a thermal desorption inlet (TD-GC/MS), and volatile carbonyls were analyzed by on-line derivatization with dinitrophenylhydrazine (DNPH), followed by liquid chromatography with UV/VIS detection. SVOCs were extracted from XAD-coated denuders and Teflon-coated fiberglass filters in the absence of ozone. In those extracts, tobacco-specific nitrosamines (TSNAs) and other SVOCs were analyzed by gas chromatography with positive chemical ionization-triple quadrupole mass spectrometric detection (GC/PCI-QQQ-MS), and polycyclic aromatic hydrocarbons (PAHs) were quantified by gas chromatography with ion trap mass spectrometric detection (GC/IT-MS) in selected ion monitoring mode. Particulate matter concentration was determined gravimetrically. In a second experiment, a 300 mg h-1 commercial ozone generator was operated during 1 h, one day after smoke was generated, to evaluate the remediation of THS by ozonation. VOCs and volatile c

Ozonation is a common remediation approach to eliminate odors from mold, tobacco and fire damage in buildings. Little information exists to: 1) assess its effectiveness; 2) provide guidance on operation conditions; and 3) identify potential risks associated with the presence of indoor ozone and ozonation byproducts. The goal of this study is to evaluate chemical changes in thirdhand smoke (THS) aerosols induced by high levels of ozone, in comparison with THS aerosols aged under similar conditions in the absence of ozone. Samples representing different stages of smoke aging in the absence of ozone, including freshly emitted secondhand smoke (SHS) and THS, were collected inside an 18-m3 room-sized chamber over a period of 42 h after six cigarettes were consumed. The experiments involved collection and analysis of gas phase species including volatile organic compounds (VOCs), volatile carbonyls, semivolatile organic compounds (SVOCs), and particulate matter. VOC analysis was carried out by gas chromatography/mass spectrometry with a thermal desorption inlet (TD-GC/MS), and volatile carbonyls were analyzed by on-line derivatization with dinitrophenylhydrazine (DNPH), followed by liquid chromatography with UV/VIS detection. SVOCs were extracted from XAD-coated denuders and Teflon-coated fiberglass filters in the absence of ozone. In those extracts, tobacco-specific nitrosamines (TSNAs) and other SVOCs were analyzed by gas chromatography with positive chemical ionization-triple quadrupole mass spectrometric detection (GC/PCI-QQQ-MS), and polycyclic aromatic hydrocarbons (PAHs) were quantified by gas chromatography with ion trap mass spectrometric detection (GC/IT-MS) in selected ion monitoring mode. Particulate matter concentration was determined gravimetrically. In a second experiment, a 300 mg h-1 commercial ozone generator was operated during 1 h, one day after smoke was generated, to evaluate the remediation of THS by ozonation. VOCs and volatile c

Remote ischaemic preconditioning reduces the risk of myocardial injury within 4 days of hip fracture surgery. We aimed to investigate the effect of remote ischaemic preconditioning on the incidence of major adverse cardiovascular events 1 year after hip fracture surgery. We performed a phase-2, multicentre, randomised, observer-blinded, clinical trial between February 2015 and September 2017. We studied patients aged ≥ 45 years with a hip fracture and a minimum of one cardiovascular risk factor. Patients were allocated randomly to remote ischaemic preconditioning applied just before surgery or no treatment (control group). Remote ischaemic preconditioning was performed on the upper arm with a tourniquet in four cycles of 5 min ischaemia and 5 min reperfusion. Primary outcome was the occurrence of major adverse cardiovascular events within 1 year of surgery. A total of 316 patients were allocated randomly to the remote ischaemic preconditioning group and 309 patients to the control group. Major adverse cardiovascular events occurred in 43 patients (13.6%) in the remote ischaemic preconditioning group compared with 51 patients (16.5%) in the control group (adjusted hazard ratio (95%CI) 0.83 (0.55–1.25); p = 0.37). Fewer patients in the remote ischaemic preconditioning group had a myocardial infarction (11 (3.5%) vs. 22 (7.1%); hazard ratio (95%CI) 0.48 (CI 0.23–1.00); p = 0.04). Remote ischaemic preconditioning did not reduce the occurrence of major adverse cardiovascular events within 1 year of hip fracture surgery. The effect of remote ischaemic preconditioning on clinical cardiovascular outcomes in non-cardiac surgery needs confirmation in appropriately powered randomised clinical trials.

Background: Endothelial dysfunction seems to play a role in the pathophysiology of myocardial injury after surgery. The aim of this randomised clinical trial was to examine whether remote ischaemic preconditioning in relation to hip fracture surgery ameliorates post-operative systemic endothelial dysfunction. Methods: This was a planned single-centre pilot sub-study of a multicentre, randomised clinical trial. Patients ≥45 years with a cardiovascular risk factor were randomised to remote ischaemic preconditioning (RIPC) or control (standard treatment) performed in relation with their hip fracture operation. RIPC consisted of four cycles of 5 minutes forearm ischaemia and reperfusion. The procedure was performed non-invasively with a tourniquet. The endothelial function was assessed with non-invasive digital pulse amplitude tonometry on post-operative day 1 and expressed as the reactive hyperaemia index (RHI). Endothelial dysfunction was defined as RHI < 1.22. Results: Between February 2015 and December 2016, 18 patients were allocated to the RIPC group and 20 patients to the control group. The endothelial function was impaired in both groups on post-operative day 1. RHI did not differ between the groups, 1.47 (95% CI 1.20-1.75) in the RIPC group vs. 1.54 (95% CI 1.17-1.91) in the control group, P =.76. Endothelial dysfunction was present in 3/18 patients (16.7%) in the RIPC group and 8/20 patients (40%) in the control group, P =.11. Conclusion: No beneficial effect of remote ischaemic preconditioning on the systemic endothelial dysfunction, assessed at a single time point on post-operative day one, was detected after hip fracture surgery.

Ziel/Aim The monoamine oxidase B (MAO B) isoenzyme is known to be involved in the oxidative deamination of biogenic amines. While the use of MAO B inhibitors is already well-established for the treatment of Parkinson’s disease, recent reports suggest its involvement in certain types of brain tumors.1 We herein aim at the synthesis and preclinical evaluation of fluorinated indanone-based derivatives targeting MAO B in the brain via positron emission tomography (PET). Methodik/Methods A small series of fluorinated indanone derivatives was obtained via the O-alkylation or esterification starting with the commercially available 6-hydroxy-2,3-dihydro-1H-inden-1-one in one or two steps. Binding affinities towards the human MAO isoenzymes were estimated in vitro by radioligand displacement. HL126 was selected for radiofluorination via its corresponding boronic acid pinacol ester. In vitro autoradiography of [18F]HL126 was performed in mice brain slices. In vivo evaluation of [18F]HL126 in CD-1 mice was carried out and metabolism studies were performed in plasma and brain samples via radio-HPLC. Ergebnisse/Results The fluorinated indanone derivatives were synthesized in yields ranging from 65-89 %. The fluorophenyl ether derivative, HL126, was further selected for radiofluorination based on its high binding affinity towards MAO B (Ki = 6.9 ± 5.3 nM). [18F]HL126 was obtained by an alcohol-enhanced copper-mediated approach via the corresponding boronic acid pinacol ester precursor with radiochemical yields of about 11 ± 3 %, high radiochemical purities (≥99 %) and molar activities in the range of 20 GBq/mmol. In vitro autoradiography showed a specific blockade with selective MAO-A/B inhibitors. PET/MRI analyses revealed that [18F]HL126 readily enters the brain. Some radiometabolites do cross the blood-brain barrier. Schlussfolgerungen/Conclusions Although metabolism studies with [18F] HL126 revealed the presence of radiometabolites in the brain, the high binding affinity towa

Bakgrund: Psykisk ohälsa är en folkhälsosjukdom i Sverige som ökat kraftigt de senaste tio åren med ökade sjukskrivningar och förskrivningar av antidepressiva läkemedel som följd. Hästunderstödda insatser (HUI) är en ickemedicinsk omvårdnadsåtgärd som till viss del används som komplement inom psykoterapi och psykosocial behandling. HUI kan i vissa kommuner förskrivas via Fysisk aktivitet på recept (FaR) men detta är i nuläget ej vedertaget i hela Sverige. Hästar har egenskaper som speglar människors känsloyttringar, detta har visat sig vara användbart inom psykoterapin. Syfte: Syftet var att beskriva patienters erfarenheter av hästunderstödda insatser som omvårdnadsåtgärd vid psykisk ohälsa. Metod: Litteraturstudie baserad på åtta kvalitativa, vetenskapliga studier från databaserna Pubmed och Psycinfo. Studierna är granskade med granskningsmall för kvalitativa studier. Tematisk analys utfördes och gav tre teman samt åtta subteman. Resultat: Deltagarna i studierna beskrev erfarenheter som positiva känslor, relation till hästen samt personlig utveckling. Diskussion: Resultatets teman diskuteras utifrån vilka möjligheter och hinder som finns för att HUI ska kunna användas som icke medicinsk omvårdnadsåtgärd.

Industrial facilities consist of the primary load-carrying structure and various process engineering components (secondary structures), which under seismic loading, may exhibit significant damage that may threaten their structural integrity with severe consequences on the population, the environment and the economy. Structures in industrial facilities vary widely from flexible piping to rigid machining tools, and from small precision equipment to large cranes. Most machine installations have specific functions, including manufacturing precision, number of revolutions, production efficiency, and supply capacity, thus the functional failure is as important as structural failure. The paper presents the shaking table tests in the framework of the SPIF (Seismic Performance of multi-component systems in special risk Industrial Facilities) project. Special attention has been paid to the interactions between the primary structure and components as well as between the components among themselves. The steel structure of three stories has been designed, with the vessels on the first and second storey connected with the pipes. The structure has been planned for testing in two configurations: as fully fixed and with base isolation at the bottom. The focus is placed on the behaviour of the vessels and seismic performance of the pipes and connections has for the purpose of derivation of the design recommendations. Measuring accelerations, relative displacements of the components and pipe sections for different levels of peak ground acceleration is planned. The results will be used to increase the knowledge on definition of damage levels, limit states and performance for industrial facilities.

In this review, we examine the functional roles of microbial symbionts in plant tolerance to cold and freezing stresses. The impacts of symbionts on antioxidant activity, hormonal signaling and host osmotic balance are described, including the effects of the bacterial endosymbionts Burkholderia, Pseudomonas and Azospirillum on photosynthesis and the accumulation of carbohydrates such as trehalose and raffinose that improve cell osmotic regulation and plasma membrane integrity. The influence of root fungal endophytes and arbuscular mycorrhizal fungi on plant physiology at low temperatures, for example their effects on nutrient acquisition and the accumulation of indole‐3‐acetic acid and antioxidants in tissues, are also reviewed. Meta‐analyses are presented showing that aspects of plant performance (shoot biomass, relative water content, sugar and proline concentrations and Fv/Fm) are enhanced in symbiotic plants at low (−1 to 15 °C), but not at high (20–26 °C), temperatures. We discuss the implications of microbial symbionts for plant performance at low and sub‐zero temperatures in the natural environment and propose future directions for research into the effects of symbionts on the cold and freezing tolerances of plants, concluding that further studies should routinely incorporate symbiotic microbes in their experimental designs.

Background and purposeBrain MRI-derived lesions and atrophy are related to multiple sclerosis (MS) disability. In the Serially Unified Multicenter MS Investigation (SUMMIT), from Brigham and Women's Hospital (BWH) and University of California, San Francisco (UCSF), we assessed whether MRI methodologic heterogeneity may limit the ability to pool multisite data sets to assess 5-year clinical-MRI associations.MethodsPatients with relapsing-remitting (RR) MS (n = 100 from each site) underwent baseline brain MRI and baseline and 5-year clinical evaluations. Patients were matched on sex (74 women each), age, disease duration, and Expanded Disability Status Scale (EDSS) score. MRI was performed with differences between sites in both acquisition (field strength, voxel size, pulse sequences), and postprocessing pipeline to assess brain parenchymal fraction (BPF) and T2 lesion volume (T2LV).ResultsThe UCSF cohort showed higher correlation than the BWH cohort between T2LV and disease duration. UCSF showed a higher inverse correlation between BPF and age than BWH. UCSF showed a higher inverse correlation than BWH between BPF and 5-year EDSS score. Both cohorts showed inverse correlations between BPF and T2LV, with no between-site difference. The pooled but not individual cohort data showed a link between a lower baseline BPF and the subsequent 5-year worsening in disability in addition to other stronger relationships in the data.ConclusionsMRI acquisition and processing differences may result in some degree of heterogeneity in assessing brain lesion and atrophy measures in patients with MS. Pooling of data across sites is beneficial to correct for potential biases in individual data sets.

Background and purposeMR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations.Materials and methodsTwenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM.ResultsThe orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions.ConclusionsNODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

Background and purposeThe quantification of spinal cord (SC) atrophy by MRI has assumed an important role in assessment of neuroinflammatory/neurodegenerative diseases and traumatic SC injury. Recent technical advances make possible the quantification of gray matter (GM) and white matter tissues in clinical settings. However, the goal of a reliable diagnostic, prognostic or predictive marker is still elusive, in part due to large intersubject variability of SC areas. Here, we investigated the sources of this variability and explored effective strategies to reduce it.MethodsOne hundred twenty-nine healthy subjects (mean age: 41.0 ± 15.9) underwent MRI on a Siemens 3T Skyra scanner. Two-dimensional PSIR at the C2-C3 vertebral level and a sagittal 1 mm3 3D T1-weighted brain acquisition extended to the upper cervical cord were acquired. Total cross-sectional area and GM area were measured at C2-C3, as well as measures of the vertebra, spinal canal and the skull. Correlations between the different metrics were explored using Pearson product-moment coefficients. The most promising metrics were used to normalize cord areas using multiple regression analyses.ResultsThe most effective normalization metrics were the V-scale (from SienaX) and the product of the C2-C3 spinal canal diameters. Normalization methods based on these metrics reduced the intersubject variability of cord areas of up to 17.74%. The measured cord areas had a statistically significant sex difference, while the effect of age was moderate.ConclusionsThe present work explored in a large cohort of healthy subjects the source of intersubject variability of SC areas and proposes effective normalization methods for its reduction.

Bakgrund: Psykisk ohälsa är en folkhälsosjukdom i Sverige som ökat kraftigt de senaste tio åren med ökade sjukskrivningar och förskrivningar av antidepressiva läkemedel som följd. Hästunderstödda insatser (HUI) är en ickemedicinsk omvårdnadsåtgärd som till viss del används som komplement inom psykoterapi och psykosocial behandling. HUI kan i vissa kommuner förskrivas via Fysisk aktivitet på recept (FaR) men detta är i nuläget ej vedertaget i hela Sverige. Hästar har egenskaper som speglar människors känsloyttringar, detta har visat sig vara användbart inom psykoterapin. Syfte: Syftet var att beskriva patienters erfarenheter av hästunderstödda insatser som omvårdnadsåtgärd vid psykisk ohälsa. Metod: Litteraturstudie baserad på åtta kvalitativa, vetenskapliga studier från databaserna Pubmed och Psycinfo. Studierna är granskade med granskningsmall för kvalitativa studier. Tematisk analys utfördes och gav tre teman samt åtta subteman. Resultat: Deltagarna i studierna beskrev erfarenheter som positiva känslor, relation till hästen samt personlig utveckling. Diskussion: Resultatets teman diskuteras utifrån vilka möjligheter och hinder som finns för att HUI ska kunna användas som icke medicinsk omvårdnadsåtgärd.

Ziel/Aim The monoamine oxidase B (MAO B) isoenzyme is known to be involved in the oxidative deamination of biogenic amines. While the use of MAO B inhibitors is already well-established for the treatment of Parkinson’s disease, recent reports suggest its involvement in certain types of brain tumors.1 We herein aim at the synthesis and preclinical evaluation of fluorinated indanone-based derivatives targeting MAO B in the brain via positron emission tomography (PET). Methodik/Methods A small series of fluorinated indanone derivatives was obtained via the O-alkylation or esterification starting with the commercially available 6-hydroxy-2,3-dihydro-1H-inden-1-one in one or two steps. Binding affinities towards the human MAO isoenzymes were estimated in vitro by radioligand displacement. HL126 was selected for radiofluorination via its corresponding boronic acid pinacol ester. In vitro autoradiography of [18F]HL126 was performed in mice brain slices. In vivo evaluation of [18F]HL126 in CD-1 mice was carried out and metabolism studies were performed in plasma and brain samples via radio-HPLC. Ergebnisse/Results The fluorinated indanone derivatives were synthesized in yields ranging from 65-89 %. The fluorophenyl ether derivative, HL126, was further selected for radiofluorination based on its high binding affinity towards MAO B (Ki = 6.9 ± 5.3 nM). [18F]HL126 was obtained by an alcohol-enhanced copper-mediated approach via the corresponding boronic acid pinacol ester precursor with radiochemical yields of about 11 ± 3 %, high radiochemical purities (≥99 %) and molar activities in the range of 20 GBq/mmol. In vitro autoradiography showed a specific blockade with selective MAO-A/B inhibitors. PET/MRI analyses revealed that [18F]HL126 readily enters the brain. Some radiometabolites do cross the blood-brain barrier. Schlussfolgerungen/Conclusions Although metabolism studies with [18F] HL126 revealed the presence of radiometabolites in the brain, the high binding affinity towa

In this review, we examine the functional roles of microbial symbionts in plant tolerance to cold and freezing stresses. The impacts of symbionts on antioxidant activity, hormonal signaling and host osmotic balance are described, including the effects of the bacterial endosymbionts Burkholderia, Pseudomonas and Azospirillum on photosynthesis and the accumulation of carbohydrates such as trehalose and raffinose that improve cell osmotic regulation and plasma membrane integrity. The influence of root fungal endophytes and arbuscular mycorrhizal fungi on plant physiology at low temperatures, for example their effects on nutrient acquisition and the accumulation of indole‐3‐acetic acid and antioxidants in tissues, are also reviewed. Meta‐analyses are presented showing that aspects of plant performance (shoot biomass, relative water content, sugar and proline concentrations and Fv/Fm) are enhanced in symbiotic plants at low (−1 to 15 °C), but not at high (20–26 °C), temperatures. We discuss the implications of microbial symbionts for plant performance at low and sub‐zero temperatures in the natural environment and propose future directions for research into the effects of symbionts on the cold and freezing tolerances of plants, concluding that further studies should routinely incorporate symbiotic microbes in their experimental designs.

Past earthquakes demonstrated the high vulnerability of industrial facilities equipped with complex process technologies leading to serious damage of the process equipment and multiple and simultaneous release of hazardous substances in industrial facilities. Nevertheless, the design of industrial plants is inadequately described in recent codes and guidelines, as they do not consider the dynamic interaction between the structure and the installations and thus the effect of seismic response of the installations on the response of the structure and vice versa. The current code-based approach for the seismic design of industrial facilities is considered not enough for ensure proper safety conditions against exceptional event entailing loss of content and related consequences. Accordingly, SPIF project (Seismic Performance of Multi- Component Systems in Special Risk Industrial Facilities) was proposed within the framework of the European H2020 - SERA funding scheme (Seismology and Earthquake Engineering Research Infrastructure Alliance for Europe). The objective of the SPIF project is the investigation of the seismic behavior of a representative industrial structure equipped with complex process technology by means of shaking table tests. The test structure is a three-story moment resisting steel frame with vertical and horizontal vessels and cabinets, arranged on the three levels and connected by pipes. The dynamic behavior of the test structure and installations is investigated with and without base isolation. Furthermore, both firmly anchored and isolated components are taken into account to compare their dynamic behavior and interactions with each other. Artificial and synthetic ground motions are applied to study the seismic response at different PGA levels. After each test, dynamic identification measurements are carried out to characterize the system condition. The contribution presents the numerical simulations to calibrate the tests on the prototype, the exper

Industrial facilities consist of the primary load-carrying structure and various process engineering components (secondary structures), which under seismic loading, may exhibit significant damage that may threaten their structural integrity with severe consequences on the population, the environment and the economy. Structures in industrial facilities vary widely from flexible piping to rigid machining tools, and from small precision equipment to large cranes. Most machine installations have specific functions, including manufacturing precision, number of revolutions, production efficiency, and supply capacity, thus the functional failure is as important as structural failure. The paper presents the shaking table tests in the framework of the SPIF (Seismic Performance of multi-component systems in special risk Industrial Facilities) project. Special attention has been paid to the interactions between the primary structure and components as well as between the components among themselves. The steel structure of three stories has been designed, with the vessels on the first and second storey connected with the pipes. The structure has been planned for testing in two configurations: as fully fixed and with base isolation at the bottom. The focus is placed on the behaviour of the vessels and seismic performance of the pipes and connections has for the purpose of derivation of the design recommendations. Measuring accelerations, relative displacements of the components and pipe sections for different levels of peak ground acceleration is planned. The results will be used to increase the knowledge on definition of damage levels, limit states and performance for industrial facilities.

Plants harbor a wide diversity of microorganisms in their tissues. Some of them have a longco-evolutionary history with their hosts, likely playing a pivotal role in regulating the plantinteraction with other microbes such as pathogens. Some cool-season grasses are symbi-otic withEpichlo€efungal endophytes that grow symptomless and systemically in above-ground tissues. Among the many benefits that have been ascribed to endophytes, theirrole in mediating plant interactions with pathogens has been scarcely developed. Here,we explored the effects ofEpichlo€efungal endophytes on the interaction of host grasseswith fungal pathogens. We made a meta-analysis that covered a total of 18 host grass spe-cies, 11 fungal endophyte species, and 22 fungal pathogen species. We observedendophyte-mediated negative effects on pathogensin vitroandin planta. Endophyte nega-tive effects on pathogens were apparent not only in laboratory but also in greenhouse andfield experiments.Epichlo€efungal endophytes had negative effects on pathogen growth andspores’ germination. On living plants, endophytes reduced both severity and incidence ofthe disease as well as colonization and subsequent infection of seeds. Symbiosis with en-dophytes showed an inhibitory effect on debilitator and killer pathogens, but not on castra-tors, and this effect did not differ among biotrophic or necrotrophic lifestyles. We foundthat this protection can bedirectthrough the production of fungistatic compounds, thecompetition for a common resource, or the induction of plant defenses, andindirectasso-ciated with endophyte-generated changes in the abiotic or the biotic environment. Severalmechanisms operate simultaneously and contribute differentially to the reduction of dis-ease within grass populations.

ObjectiveRates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.MethodsDisability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.ResultsRelapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).InterpretationLong-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.

This chapter reviews recent research on speakers’ referential choices in discourse. It focuses on the choice to mention a certain referent first on the one hand, and to produce a pronoun or more elaborate noun phrase on the other. Whereas traditional theories have relied mainly on influence of linguistic context to explain these choices, recent psycholinguistic studies have started investigating the effect of non-linguistic factors as well. Results of these studies suggest that the two referential choices (choice of referent and choice of referring expression) are largely driven by different sets of factors, contrary to the claim that both are related to accessibility of mental representations in memory. The chapter concludes that these findings are best explained by assuming referents can be accessible on different levels: a local and a more global discourse level. Referential choices may be influenced by both levels of accessibility, but with different probabilities for different choices.

Luana Roberta Michels,1 Tamara Ramos Maciel,1 Kelly Ayumi Nakama,1 Flavia Elizabete Guerra Teixeira,1 Felipe Barbosa de Carvalho,1 André Gundel,2 Bibiana Verlindo de Araujo,3 Sandra Elisa Haas1 1Pharmaceutical Sciences Post Graduate Program, Pharmacy Course, Federal University of Pampa, UNIPAMPA, Uruguaiana, RS, Brazil; 2Campus Bagé, Federal University of Pampa, UNIPAMPA, Bagé, RS 1650, Brazil; 3Pharmaceutical Sciences Post Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 2752, BrazilCorrespondence: Sandra Elisa HaasCurso de Farmácia, Universidade Federal do Pampa, UNIPAMPA, Uruguaiana, BrazilTel +55 55 39110200Email sandrahaas@unipampa.edu.brIntroduction: The surface charge of nanoparticles, such as nanospheres (NS) and nanocapsules (NC), has been studied with the purpose of improving the in vivo performance of drugs. The aim of this study was to develop, characterize, and evaluate the in vitro antimalarial efficacy of NCP80 and NSP80 (polysorbate coated) or NCEUD and NSEUD (prepared with Eudragit RS 100) loading quinine (QN).Methods: Formulations were prepared by the nanoprecipitation method, followed by wide physicochemical characterization. Antimalarial activity in Plasmodium berghei-infected mice and populational pharmacokinetics (PopPK) in rats were evaluated.Results: The formulations showed a nanometric range (between 138 ± 3.8 to 201 ± 23.0 nm), zeta potential (mV) of −33.1 ± 0.7 (NCP80), −30.5 ± 1 (UNCP80), −25.5 ± 1 (NSP80), −20 ± 0.3 (UNSP80), 4.61 ± 1 (NCEUD), 14.1 ± 0.9 (UNCEUD), 2.86 ± 0.3 (NSEUD) and 2.84 ± 0.6 (UNSEUD), content close to 100%, and good QN protection against UVA light. There was a twofold increase in the penetration of QN into infected erythrocytes with NC compared to that with NS. There was a sign

ObjectiveRates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.MethodsDisability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.ResultsRelapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).InterpretationLong-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.

BackgroundThe benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear.MethodsWe randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days.ResultsThe trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, -0.3 percentage points; 95% confidence interval, -6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months.ConclusionsAmong patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortalit

Luana Roberta Michels,1 Tamara Ramos Maciel,1 Kelly Ayumi Nakama,1 Flavia Elizabete Guerra Teixeira,1 Felipe Barbosa de Carvalho,1 André Gundel,2 Bibiana Verlindo de Araujo,3 Sandra Elisa Haas1 1Pharmaceutical Sciences Post Graduate Program, Pharmacy Course, Federal University of Pampa, UNIPAMPA, Uruguaiana, RS, Brazil; 2Campus Bagé, Federal University of Pampa, UNIPAMPA, Bagé, RS 1650, Brazil; 3Pharmaceutical Sciences Post Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 2752, BrazilCorrespondence: Sandra Elisa HaasCurso de Farmácia, Universidade Federal do Pampa, UNIPAMPA, Uruguaiana, BrazilTel +55 55 39110200Email sandrahaas@unipampa.edu.brIntroduction: The surface charge of nanoparticles, such as nanospheres (NS) and nanocapsules (NC), has been studied with the purpose of improving the in vivo performance of drugs. The aim of this study was to develop, characterize, and evaluate the in vitro antimalarial efficacy of NCP80 and NSP80 (polysorbate coated) or NCEUD and NSEUD (prepared with Eudragit RS 100) loading quinine (QN).Methods: Formulations were prepared by the nanoprecipitation method, followed by wide physicochemical characterization. Antimalarial activity in Plasmodium berghei-infected mice and populational pharmacokinetics (PopPK) in rats were evaluated.Results: The formulations showed a nanometric range (between 138 ± 3.8 to 201 ± 23.0 nm), zeta potential (mV) of −33.1 ± 0.7 (NCP80), −30.5 ± 1 (UNCP80), −25.5 ± 1 (NSP80), −20 ± 0.3 (UNSP80), 4.61 ± 1 (NCEUD), 14.1 ± 0.9 (UNCEUD), 2.86 ± 0.3 (NSEUD) and 2.84 ± 0.6 (UNSEUD), content close to 100%, and good QN protection against UVA light. There was a twofold increase in the penetration of QN into infected erythrocytes with NC compared to that with NS. There was a sign

This chapter reviews recent research on speakers’ referential choices in discourse. It focuses on the choice to mention a certain referent first on the one hand, and to produce a pronoun or more elaborate noun phrase on the other. Whereas traditional theories have relied mainly on influence of linguistic context to explain these choices, recent psycholinguistic studies have started investigating the effect of non-linguistic factors as well. Results of these studies suggest that the two referential choices (choice of referent and choice of referring expression) are largely driven by different sets of factors, contrary to the claim that both are related to accessibility of mental representations in memory. The chapter concludes that these findings are best explained by assuming referents can be accessible on different levels: a local and a more global discourse level. Referential choices may be influenced by both levels of accessibility, but with different probabilities for different choices.