Traumatic Brain Injury (TBI) and persistent post-concussion syndrome (PCS) including chronic migraine (CM) are major health issues for civilians and the military. It is important to understand ...underlying biochemical mechanisms of these conditions, and be able to monitor them in an accurate and minimally invasive manner. This study describes the initial use of a novel serum analytical platform to help distinguish TBI patients, including those with post-traumatic headache (PTH), and to help identify phenotypes at play in these disorders. The hypothesis is that physiological responses to disease states like TBI and PTH and related bodily stresses are reflected in biomolecules in the blood in disease-specific manner. Leave one out (serum sample) cross validations (LOOCV) and sample randomizations were utilized to distinguished serum samples from the following TBI patient groups: TBI +PTSD + CM + severe depression (TBI "most affected" group) vs healthy controls, TBI "most affected" vs TBI, TBI vs controls, TBI + CM vs controls, and TBI + CM vs TBI. Inter-group discriminatory p values were ≤ 10-10, and sample group randomizations resulted in p non-significant values. Peptide/protein identifications of discriminatory mass peaks from the TBI "most affected" vs controls and from the TBI plus vs TBI minus CM groups yielded information of the cellular/molecular effects of these disorders (immune responses, amyloidosis/Alzheimer's disease/dementia, neuronal development). More specific biochemical disease effects appear to involve blood brain barrier, depression, migraine headache, autoimmunity, and autophagy pathways. This study demonstrated the ability for the first time of a novel, accurate, biomarker platform to monitor these conditions in serum, and help identify biochemical relationships leading to better understanding of these disorders and to potential therapeutic approaches.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A search for millicharged particles, a simple extension of the standard model, has been performed with the ArgoNeuT detector exposed to the Neutrinos at the Main Injector beam at Fermilab. The ...ArgoNeuT liquid argon time projection chamber detector enables a search for millicharged particles through the detection of visible electron recoils. We search for an event signature with two soft hits (MeV-scale energy depositions) aligned with the upstream target. For an exposure of the detector of 1.0×10^{20} protons on target, one candidate event has been observed, compatible with the expected background. This search is sensitive to millicharged particles with charges between 10^{-3}e and 10^{-1}e and with masses in the range from 0.1 to 3 GeV. This measurement provides leading constraints on millicharged particles in this large unexplored parameter space region.
AbstractBackgroundRecent policy developments and journal articles have emphasized a divergence: when interventions are found to be cost-effective but unaffordable. This apparent paradox reflects a ...conventional practice of cost-effectiveness analysis that does not properly evaluate the opportunity costs of an intervention that imposes non-marginal costs on the healthcare system. ObjectiveTaking the perspective of an exogenously resource constrained decision maker, this paper presents a framework by which concerns for affordability can be appropriately incorporated within cost-effectiveness analysis. MethodsA net benefit framework is proposed where health opportunity costs are estimated for each simulation iteration within each time period. The framework is applied to a hypothetical case study based on the recent experience of the English NHS with new hepatitis C drugs. ResultsUnder the proposed framework, but not under conventional cost-effectiveness analysis, estimates of health opportunity costs differ between scenarios involving different profiles of budget impact even when their net present value, or expected value, are the same. ConclusionsThe framework presented here reflects the importance of the scale of budget impacts along with their uncertainty distribution and time profile. In doing so it resolves issues with the conduct of conventional cost-effectiveness analysis where affordability concerns are not explicitly incorporated.
Eravacycline is an investigational, synthetic fluorocycline antibacterial agent that is structurally similar to tigecycline with two modifications to the D-ring of its tetracycline core: a fluorine ...atom replaces the dimethylamine moiety at C-7 and a pyrrolidinoacetamido group replaces the 2-tertiary-butyl glycylamido at C-9. Like other tetracyclines, eravacycline inhibits bacterial protein synthesis through binding to the 30S ribosomal subunit. Eravacycline demonstrates broad-spectrum antimicrobial activity against Gram-positive, Gram-negative, and anaerobic bacteria with the exception of
Pseudomonas aeruginosa
. Eravacycline is two- to fourfold more potent than tigecycline versus Gram-positive cocci and two- to eightfold more potent than tigecycline versus Gram-negative bacilli. Intravenous eravacycline demonstrates linear pharmacokinetics that have been described by a four-compartment model. Oral bioavailability of eravacycline is estimated at 28 % (range 26–32 %) and a single oral dose of 200 mg achieves a maximum plasma concentration (
C
max
) and area under the plasma concentration-time curve from 0 to infinity (AUC
0–∞
) of 0.23 ± 0.04 mg/L and 3.34 ± 1.11 mg·h/L, respectively. A population pharmacokinetic study of intravenous (IV) eravacycline demonstrated a mean steady-state volume of distribution (
V
ss
) of 320 L or 4.2 L/kg, a mean terminal elimination half-life (
t
½
) of 48 h, and a mean total clearance (CL) of 13.5 L/h. In a neutropenic murine thigh infection model, the pharmacodynamic parameter that demonstrated the best correlation with antibacterial response was the ratio of area under the plasma concentration-time curve over 24 h to the minimum inhibitory concentration (AUC
0–24h
/MIC). Several animal model studies including mouse systemic infection, thigh infection, lung infection, and pyelonephritis models have been published and demonstrated the in vivo efficacy of eravacycline. A phase II clinical trial evaluating the efficacy and safety of eravacycline in the treatment of community-acquired complicated intra-abdominal infection (cIAI) has been published as well, and phase III clinical trials in cIAI and complicated urinary tract infection (cUTI) have been completed. The eravacycline phase III program, known as IGNITE (Investigating Gram-Negative Infections Treated with Eravacycline), investigated its safety and efficacy in cIAI (IGNITE 1) and cUTI (IGNITE 2). Eravacycline met the primary endpoint in IGNITE 1, while data analysis for IGNITE 2 is currently ongoing. Common adverse events reported in phase I–III studies included gastrointestinal effects such as nausea and vomiting. Eravacycline is a promising intravenous and oral fluorocycline that may offer an alternative treatment option for patients with serious infections, particularly those caused by multidrug-resistant Gram-negative pathogens.
The role of fluids in trauma resuscitation is controversial. We compared resuscitation with 0.9% saline vs hydroxyethyl starch, HES 130/0.4, in severe trauma with respect to resuscitation, fluid ...volume, gastrointestinal recovery, renal function, and blood product requirements.
Randomized, controlled, double-blind study of severely injured patients requiring>3 litres of fluid resuscitation. Blunt and penetrating trauma were randomized separately. Patients were followed up for 30 days.
A total of 115 patients were randomized; of which, 109 were studied. For patients with penetrating trauma (n=67), the mean (sd) fluid requirements were 5.1 (2.7) litres in the HES group and 7.4 (4.3) litres in the saline group (P<0.001). In blunt trauma (n=42), there was no difference in study fluid requirements, but the HES group required significantly more blood products packed red blood cell volumes 2943 (1628) vs 1473 (1071) ml, P=0.005 and was more severely injured than the saline group (median injury severity score 29.5 vs 18; P=0.01). Haemodynamic data were similar, but, in the penetrating group, plasma lactate concentrations were lower over the first 4 h (P=0.029) and on day 1 with HES than with saline 2.1 (1.4) vs 3.2 (2.2) mmol litre−1; P=0.017. There was no difference between any groups in time to recovery of bowel function or mortality. In penetrating trauma, renal injury occurred more frequently in the saline group than the HES group (16% vs 0%; P=0.018). In penetrating trauma, maximum sequential organ function scores were lower with HES than with saline (median 2.4 vs 4.5, P=0.012). No differences were seen in safety measures in the blunt trauma patients.
In penetrating trauma, HES provided significantly better lactate clearance and less renal injury than saline. No firm conclusions could be drawn for blunt trauma.
Study registration: ISRCTN 42061860.
We perform a comprehensive study of Milky Way (MW) satellite galaxies to constrain the fundamental properties of dark matter (DM). This analysis fully incorporates inhomogeneities in the spatial ...distribution and detectability of MW satellites and marginalizes over uncertainties in the mapping between galaxies and DM halos, the properties of the MW system, and the disruption of subhalos by the MW disk. Our results are consistent with the cold, collisionless DM paradigm and yield the strongest cosmological constraints to date on particle models of warm, interacting, and fuzzy dark matter. At 95% confidence, we report limits on (i) the mass of thermal relic warm DM, m_{WDM}>6.5 keV (free-streaming length, λ_{fs}≲10h^{-1} kpc), (ii) the velocity-independent DM-proton scattering cross section, σ_{0}<8.8×10^{-29} cm^{2} for a 100 MeV DM particle mass DM-proton coupling, c_{p}≲(0.3 GeV)^{-2}, and (iii) the mass of fuzzy DM, m_{ϕ}>2.9×10^{-21} eV (de Broglie wavelength, λ_{dB}≲0.5 kpc). These constraints are complementary to other observational and laboratory constraints on DM properties.
Natural biological suppression of soil-borne diseases is a function of the activity and composition of soil microbial communities. Soil microbe and phytopathogen interactions can occur prior to crop ...sowing and/or in the rhizosphere, subsequently influencing both plant growth and productivity. Research on suppressive microbial communities has concentrated on bacteria although fungi can also influence soil-borne disease. Fungi were analyzed in co-located soils 'suppressive' or 'non-suppressive' for disease caused by Rhizoctonia solani AG 8 at two sites in South Australia using 454 pyrosequencing targeting the fungal 28S LSU rRNA gene. DNA was extracted from a minimum of 125 g of soil per replicate to reduce the micro-scale community variability, and from soil samples taken at sowing and from the rhizosphere at 7 weeks to cover the peak Rhizoctonia infection period. A total of ∼ 994,000 reads were classified into 917 genera covering 54% of the RDP Fungal Classifier database, a high diversity for an alkaline, low organic matter soil. Statistical analyses and community ordinations revealed significant differences in fungal community composition between suppressive and non-suppressive soil and between soil type/location. The majority of differences associated with suppressive soils were attributed to less than 40 genera including a number of endophytic species with plant pathogen suppression potentials and mycoparasites such as Xylaria spp. Non-suppressive soils were dominated by Alternaria, Gibberella and Penicillum. Pyrosequencing generated a detailed description of fungal community structure and identified candidate taxa that may influence pathogen-plant interactions in stable disease suppression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Many of our actions require visual information, and for this it is important to direct the eyes to the right place at the right time. Two or three times every second, we must decide both when and ...where to direct our gaze. Understanding these decisions can reveal the moment-to-moment information priorities of the visual system and the strategies for information sampling employed by the brain to serve ongoing behavior. Most theoretical frameworks and models of gaze control assume that the spatial and temporal aspects of fixation point selection depend on different mechanisms. We present a single model that can simultaneously account for both when and where we look. Underpinning this model is the theoretical assertion that each decision to move the eyes is an evaluation of the relative benefit expected from moving the eyes to a new location compared with that expected by continuing to fixate the current target. The eyes move when the evidence that favors moving to a new location outweighs that favoring staying at the present location. Our model provides not only an account of when the eyes move, but also what will be fixated. That is, an analysis of saccade timing alone enables us to predict where people look in a scene. Indeed our model accounts for fixation selection as well as (and often better than) current computational models of fixation selection in scene viewing.
The East Antarctic Ice Sheet (EAIS) is currently surrounded by relatively cool water, but climatic shifts have the potential to increase basal melting via intrusions of warm modified Circumpolar Deep ...Water (mCDW) onto the continental shelf. Here we use an ice sheet model to show that under the current ocean regime, with only limited intrusions of mCDW, the EAIS will likely gain mass over the next 200 years due to the increased precipitation from a warming atmosphere outweighing increased ice discharge due to ice-shelf melting. However, if the ocean regime were to become dominated by greater mCDW intrusions, the EAIS would have a negative mass balance, contributing up to 48 mm of SLE over this time period. Our modelling finds George V Land to be particularly at risk to increased ocean induced melting. With warmer oceans, we also find that a mid range RCP4.5 emissions scenario is likely to result in a more negative mass balance than a high RCP8.5 emissions scenario, as the relative difference between increased precipitation due to a warming atmosphere and increased ice discharge due to a warming ocean is more negative in the mid range RCP4.5 emission scenario.
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