1,460 research outputs found

    Sepsis target validation for repurposing and combining complement and immune checkpoint inhibition therapeutics

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    Introduction: Sepsis is a disease that occurs due to an adverse immune response to infection by bacteria, viruses and fungi and is the leading pathway to death by infection. The hallmarks for maladapted immune reactions in severe sepsis, which contribute to multiple organ failure and death, are bookended by the exacerbated activation of the complement system to protracted T-cell dysfunction states orchestrated by immune checkpoint control. Despite major advances in our understanding of the condition, there remains to be either a definitive test or an effective therapeutic intervention. Areas covered: The authors consider a combinational drug therapy approach using new biologics, and mathematical modeling for predicting patient responses, in targeting innate and adaptive immune mediators underlying sepsis. Special consideration is given for emerging complement and immune checkpoint inhibitors that may be repurposed for sepsis treatment. Expert opinion: In order to overcome the challenges inherent to finding new therapies for the complex dysregulated host response to infection that drives sepsis, it is necessary to move away from monotherapy and promote precision for personalized combinatory therapies. Notably, combinatory therapy should be guided by predictive systems models of the immune-metabolic characteristics of an individual’s disease progression

    Drivers of post-fire Nothofagus antarctica forest recovery in Tierra del Fuego, Argentina

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    Introduction: Large wildfires were historically absent in the forests of Tierra del Fuego, southern Argentina. This has changed in recent decades as humans have increased ignition sources, and warmer, drier periods have fueled large, severe wildfires. As a result of its location at an extreme southern latitude, Tierra del Fuego has very low tree species diversity. One of the region's dominant tree species, Nothofagus antarctica, is believed to have traits that may make it resilient to wildfire (e.g., the ability to resprout prolifically). Methods: This study examined post-fire N. antarctica regeneration across an environmental and time-since-fire gradient. Plots were established in burned areas (n = 160) and unburned controls (n = 32) in and around two wildfires that occurred circa 1940 and in 2019. Seedling/resprout and sapling regeneration densities, as well as site characteristics (e.g., slope) and fire-impacted variables (e.g., distance to mature live trees), were measured. Results: Seedling and resprout densities were lower in burned plots than in controls, with this trend being exacerbated in the 2019 fire with increasing distance from mature live trees. Regeneration generally occurs in clumps and principally through sprouting from live and top-killed trees, with not all top-killed trees having resprouted. Seedling and resprout densities were most strongly impacted by time since fire, distance to mature live trees and post-fire canopy cover. Sapling densities were modulated by slope, time since fire, and distance to mature live trees. Discussion: Despite lower regeneration densities in recently burned plots and less live basal area and canopy cover in older burned plots compared to unburned controls, burned stands may be on a trajectory to recover pre-fire characteristics, although this recovery is spatially variable. However, full recovery has not occurred 80 years after the 1940's fire. Currently, these burned areas resemble grasslands or savannas. They do not provide the habitat or ecosystem services that denser forests do and may require active restoration to fully recover their pre-fire characteristics.Fil: Ruggirello, Matthew. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Bustamante, Gimena Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Fulé, Peter Z.. Northern Arizona University.; Estados UnidosFil: Soler Esteban, Rosina Matilde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentin

    Mining sorghum biodiversity-potential of dual-purpose hybrids for bio-economy

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    Sweet, grain, and dual-purpose sorghums differ in a number of important traits, including biomass production, total solutes in the stem juice, and sugar accumulation across the stem. Ten dual-purpose hybrids, two sweet genotypes, and two grain landraces of sorghums were characterized under temperate environmental conditions to determine their potential for bioethanol production. Five sorghum hybrids (Ganymed, Hannibal, Tarzan, Merlin, and Zerberus) performed better with respect to cane yield, juice yield, potential sugar, and ethanol yields compared to sweet and grain genotypes. While the sweet genotype KIT1 produced the highest sugar concentration in the stem, the lowest concentration was produced by the grain landrace Razinieh. The study showed that plant height, leaf number, leaf weight, cane yield, and juice yield were positively correlated with the sugar yield in fresh stalk. Sugar accumulation was higher in the central internodes of all genotypes. Clustering analysis showed that sweet genotypes are located more closely to dual-purpose hybrids than grain landraces. We discuss the results with respect to the potential of dual-purpose sorghum hybrids for bio-economy in Germany

    Tunable and functional deep eutectic solvents for lignocellulose valorization

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    Stabilization of reactive intermediates is an enabling concept in biomass fractionation and depolymerization. Deep eutectic solvents (DES) are intriguing green reaction media for biomass processing; however undesired lignin condensation is a typical drawback for most acid-based DES fractionation processes. Here we describe ternary DES systems composed of choline chloride and oxalic acid, additionally incorporating ethylene glycol (or other diols) that provide the desired ‘stabilization’ function for efficient lignocellulose fractionation, preserving the quality of all lignocellulose constituents. The obtained ethylene-glycol protected lignin displays high β-O-4 content (up to 53 per 100 aromatic units) and can be readily depolymerized to distinct monophenolic products. The cellulose residues, free from condensed lignin particles, deliver up to 95.9 ± 2.12% glucose yield upon enzymatic digestion. The DES can be recovered with high yield and purity and re-used with good efficiency. Notably, we have shown that the reactivity of the β-O-4 linkage in model compounds can be steered towards either cleavage or stabilization, depending on DES composition, demonstrating the advantage of the modular DES composition

    Refined heart failure detection algorithm for improved clinical reliability of OptiVol alerts in CRT-D recipients

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       Background: The reliability of intrathoracic impedance monitoring for prediction of heart failure (HF) by implantable cardiac devices is controversial. Despite using additional device-based parameters described in the PARTNERS HF study, such as new onset of arrhythmias, abnormal autonomics, low biventricular pacing rate or patient activity level, the predictive power of device diagnostic algorithm is still in doubt. The objective of this study was to compare the device diagnostic algorithm described in the PARTNERS HF study to a newly developed algorithm applying refined diagnostic criteria. Methods: Fourty two patients were prospectively enrolled who had been implanted with an intrathoracic impedance and remote monitoring capable implantable cardiac defibrillator with a cardiac resychroniza­tion therapy (CRT-D) device in this observational study. If a remote OptiVolTM alert occurred, patients were checked for presence of HF symptoms. A new algorithm was derived from the original PARTNERS HF criteria, considering more sensitive cut-offs and changes of patterns of the device-based parameters. Results: During an average follow-up of 38 months, 722 remote transmissions were received. From the total of 128 transmissions with OptiVol alerts, 32 (25%) corresponded to true HF events. Upon multivariate discriminant analysis, low patient activity, high nocturnal heart rate, and low CRT pacing (< 90%) proved to be independent predictors of true HF events (all p < 0.01). Incorporating these three refined criteria in a new algorithm, the diagnostic yield of OptiVol was improved by increasing specific­ity from 37.5% to 86.5%, positive predictive value from 34.1% to 69.8% and area under the curve from 0.787 to 0.922 (p < 0.01), without a relevant loss in sensitivity (96.9% vs. 93.8%). Conclusions: A refined device diagnostic algorithm based on the parameters of low activity level, high nocturnal heart rate, and suboptimal biventricular pacing might improve the clinical reliability of OptiVol alerts.  

    Enhancing physical activity and reducing symptoms of patients with osteoarthritis of the knee: a randomized controlled trial of the PrevOP-Psychological Adherence Program

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    Background This primary analysis evaluated the “PREVenting the impairment of primary Osteoarthritis by high-impact long-term Physical exercise regimen—Psychological Adherence Program” (PrevOP-PAP), designed to support patients with osteoarthritis of the knee (OAK) to engage in regular moderate-to-vigorous physical activity (MVPA) to reduce OAK symptoms (WOMAC scores). Theory-based on the health action process approach (HAPA), the intervention targeted volitional precursors of MVPA change: action and coping planning, maintenance and recovery self-efficacy, action control, and social network formation. We hypothesized that compared to an active control condition, increases in MVPA at the end of the 12-month intervention would translate into lower WOMAC scores at 24 months in the intervention condition. Methods Participants with radiographically verified moderate OAK (N = 241; 62.66% female; M(SD) = 65.60(7.61) years) were randomly assigned to the intervention (51%) or the active control condition. WOMAC scores (24 months) were the primary -, accelerometer-assessed MVPA (12 months) the key secondary outcomes. The PrevOP-PAP was a 12-month intervention with computer-assisted face-to-face and phone-based sessions designed to increase HAPA-proposed volitional precursors of MVPA change (up to 24 months; secondary outcomes). Intent-to-treat analyses included multiple regression and manifest path models. Results MVPA (12 months) did not mediate effects of the PrevOP-PAP on WOMAC scores (24 months). Compared to the active control condition, WOMAC scores (24 months) were lower in the intervention condition, but this effect did not remain stable in sensitivity analyses (b(SE) = -8.41(4.66), 95%-CI [-17.53; 0.71]). However, exploratory analyses revealed significantly stronger reductions in WOMAC-pain (24 months) in the intervention condition (b(SE) = -2.99(1.18), 95%-CI [-5.36; -0.63]). Groups did not differ in MVPA at 12 months (b(SE) = -3.78(3.42), 95%-CI [-10.80; 2.58]). Of the proposed precursors of MVPA change, action planning was higher in the intervention than in the control condition (24 months; b(SE) = 0.64(0.26), 95%-CI [0.14; 1.15]). Conclusions Compared to an active control condition, the PrevOP-PAP did not produce reliable effects on WOMAC scores and none on preceding MVPA. Of the HAPA-proposed volitional precursors, only action planning was sustainably increased. Future interventions should use m-health applications to digitally support long-term changes in proposed volitional precursors of MVPA change. Trial registration German Clinical Trials Register; https://drks.de/search/de/trial/DRKS00009677; also available at http://apps.who.int/trialsearch/; registration number: DRKS00009677; date of registration: 26/01/2016
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