Complex circular subsidence structures in tephra deposited on large blocks of ice: Varða tuff cone, Öræfajökull, Iceland

Several broadly circular structures up to 16 m in diameter, into which higher strata have sagged and locally collapsed, are present in a tephra outcrop on southwest Öræfajökull, southern Iceland. The tephra was sourced in a nearby basaltic tuff cone at Varða. The structures have not previously been described in tuff cones, and they probably formed by the melting out of large buried blocks of ice emplaced during a preceding jökulhlaup that may have been triggered by a subglacial eruption within the Öræfajökull ice cap. They are named ice-melt subsidence structures, and they are analogous to kettle holes that are commonly found in proglacial sandurs and some lahars sourced in ice-clad volcanoes. The internal structure is better exposed in the Varða examples because of an absence of fluvial infilling and reworking, and erosion of the outcrop to reveal the deeper geometry. The ice-melt subsidence structures at Varða are a proxy for buried ice. They are the only known evidence for a subglacial eruption and associated jökulhlaup that created the ice blocks. The recognition of such structures elsewhere will be useful in reconstructing more complete regional volcanic histories as well as for identifying ice-proximal settings during palaeoenvironmental investigations

Monte Carlo Investigation of Diffusion of Receptors and Ligands that Bind Across Opposing Surfaces

Studies of receptor diffusion on a cell surface show a variety of behaviors, such as diffusive, sub-diffusive, or super-diffusive motion. However, most studies to date focus on receptor molecules diffusing on a single cell surface. We have previously studied receptor diffusion to probe the molecular mechanism of receptor clustering at the cell–cell junction between two opposing cell surfaces. Here, we characterize the diffusion of receptors and ligands that bind to each other across two opposing cell surfaces, as in cell–cell and cell–bilayer interactions. We use a Monte Carlo method, where receptors and ligands are simulated as independent agents that bind and diffuse probabilistically. We vary receptor–ligand binding affinity and plot the molecule-averaged mean square displacement (MSD) of ligand molecules as a function of time. Our results show that MSD plots are qualitatively different for flat and curved interfaces, as well as between the cases of presence and absence of directed transport of receptor–ligand complexes toward a specific location on the interface. Receptor–ligand binding across two opposing surfaces leads to transient sub-diffusive motion at early times provided the interface is flat. This effect is entirely absent if the interface is curved, however, in this instance we observe sub-diffusive motion. In addition, a decrease in the equilibrium value of the MSD occurs as affinity increases, something which is absent for a flat interface. In the presence of directed transport of receptor–ligand complexes, we observe super-diffusive motion at early times for a flat interface. Super-diffusive motion is absent for a curved interface, however, in this case we observe a transient decrease in MSD with time prior to equilibration for high-affinity values

Patterns of primary care and mortality among patients with schizophrenia or diabetes: a cluster analysis approach to the retrospective study of healthcare utilization

Abstract Background Patients with schizophrenia have difficulty managing their medical healthcare needs, possibly resulting in delayed treatment and poor outcomes. We analyzed whether patients reduced primary care use over time, differentially by diagnosis with schizophrenia, diabetes, or both schizophrenia and diabetes. We also assessed whether such patterns of primary care use were a significant predictor of mortality over a 4-year period. Methods The Veterans Healthcare Administration (VA) is the largest integrated healthcare system in the United States. Administrative extracts of the VA's all-electronic medical records were studied. Patients over age 50 and diagnosed with schizophrenia in 2002 were age-matched 1:4 to diabetes patients. All patients were followed through 2005. Cluster analysis explored trajectories of primary care use. Proportional hazards regression modelled the impact of these primary care utilization trajectories on survival, controlling for demographic and clinical covariates. Results Patients comprised three diagnostic groups: diabetes only (n = 188,332), schizophrenia only (n = 40,109), and schizophrenia with diabetes (Scz-DM, n = 13,025). Cluster analysis revealed four distinct trajectories of primary care use: consistent over time, increasing over time, high and decreasing, low and decreasing. Patients with schizophrenia only were likely to have low-decreasing use (73% schizophrenia-only vs 54% Scz-DM vs 52% diabetes). Increasing use was least common among schizophrenia patients (4% vs 8% Scz-DM vs 7% diabetes) and was associated with improved survival. Low-decreasing primary care, compared to consistent use, was associated with shorter survival controlling for demographics and case-mix. The observational study was limited by reliance on administrative data. Conclusion Regular primary care and high levels of primary care were associated with better survival for patients with chronic illness, whether psychiatric or medical. For schizophrenia patients, with or without comorbid diabetes, primary care offers a survival benefit, suggesting that innovations in treatment retention targeting at-risk groups can offer significant promise of improving outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/78274/1/1472-6963-9-127.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78274/2/1472-6963-9-127.pdfPeer Reviewe

Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial

BACKGROUND: Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer. METHODS: JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III-IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed. FINDINGS: Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1-14·9); 11·1 months (7·0-15·3) for the avelumab maintenance group, 11·0 months (7·4-14·5) for the avelumab combination group, and 10·2 months (6·7-14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5-not estimable [NE]) with avelumab maintenance, 18·1 months (14·8-NE) with avelumab combination treatment, and NE (18·2 months-NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05-1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83-1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3-4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (<1%) patient in the avelumab maintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumab combination group (due to disease progression). INTERPRETATION: Although no new safety signals were observed, results do not support the use of avelumab in the frontline treatment setting. Alternative treatment regimens are needed to improve outcomes in patients with advanced epithelial ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany

Nano-mechanical properties of Fe-Mn-Al-C lightweight steels

High Al Low-density steels could have a transformative effect on the light-weighting of steel structures for transportation and achieving the desired properties with the minimum amount of Ni is of great interest from an economic perspective. In this study, the mechanical properties of two duplex low-density steels, Fe-15Mn-10Al-0.8C-5Ni and Fe-15Mn-10Al-0.8C (wt.%) were investigated through nano-indentation and simulation through utilization of ab initio formalisms in Density Functional Theory (DFT) in order to establish the hardness resulting from two critical structural features (ߢ-carbides and B2 intermetallic) as a function of annealing temperature (500 − 1050 ℃) and the addition of Ni. In the Ni-free sample, the calculated elastic properties of kappa-carbides were compared with those of the B2 intermetallic Fe3Al − L12, and the role of Mn in the kappa structure and its elastic properties were studied. The Ni-containing samples were found to have a higher hardness due to the B2 phase composition being NiAl rather than FeAl, with Ni-Al bonds reported to be stronger than the Fe-Al bonds. In both samples, at temperatures of 900 ℃ and above, the ferrite phase contained nano-sized discs of B2 phase, wherein the Ni-containing samples exhibited higher hardness, attributed again to the stronger Ni-Al bonds in the B2 phase. At 700 ℃ and below, the nano-sized B2 discs were replaced by micrometre sized needles of kappa in the Ni-free sample resulting in a lowering of the hardness. In the Ni-containing sample, the entire alpha phase was replaced by B2 stringers, which had a lower hardness than the Ni-Al nano-discs due to a lower Ni content in B2 stringer bands formed at 700 ℃ and below. In addition, the hardness of needle-like kappa-carbides formed in alpha phase was found to be a function of Mn content. Although it was impossible to measure the hardness of cuboid kappa particles in gamma phase because of their nano-size, the hardness value of composite phases, e.g. gamma + kappa was measured and reported. All the hardness values were compared and rationalized by bonding energy between different atoms

Behavior of a Metabolic Cycling Population at the Single Cell Level as Visualized by Fluorescent Gene Expression Reporters

BACKGROUND: During continuous growth in specific chemostat cultures, budding yeast undergo robust oscillations in oxygen consumption that are accompanied by highly periodic changes in transcript abundance of a majority of genes, in a phenomenon called the Yeast Metabolic Cycle (YMC). This study uses fluorescent reporters of genes specific to different YMC phases in order to visualize this phenomenon and understand the temporal regulation of gene expression at the level of individual cells within the cycling population. METHODOLOGY: Fluorescent gene expression reporters for different phases of the YMC were constructed and stably integrated into the yeast genome. Subsequently, these reporter-expressing yeast were used to visualize YMC dynamics at the individual cell level in cultures grown in a chemostat or in a microfluidics platform under varying glucose concentrations, using fluorescence microscopy and quantitative Western blots. CONCLUSIONS: The behavior of single cells within a metabolic cycling population was visualized using phase-specific fluorescent reporters. The reporters largely recapitulated genome-specified mRNA expression profiles. A significant fraction of the cell population appeared to exhibit basal expression of the reporters, supporting the hypothesis that there are at least two distinct subpopulations of cells within the cycling population. Although approximately half of the cycling population initiated cell division in each permissive window of the YMC, metabolic synchrony of the population was maintained. Using a microfluidics platform we observed that low glucose concentrations appear to be necessary for metabolic cycling. Lastly, we propose that there is a temporal window in the oxidative growth phase of the YMC where the cycling population segregates into at least two subpopulations, one which will enter the cell cycle and one which does not

Tissue Doppler Imaging can be useful to distinguish pathological from physiological left ventricular hypertrophy: a study in master athletes and mild hypertensive subjects

<p>Abstract</p> <p>Background</p> <p>Transthoracic echocardiography left ventricular wall thickness is often increased in master athletes and it results by intense physical training. Left Ventricular Hypertrophy can also be due to a constant pressure overload. Conventional Pulsed Wave (PW) Doppler analysis of diastolic function sometimes fails to distinguish physiological from pathological LVH.</p> <p>The aim of this study is to evaluate the role of Pulsed Wave Tissue Doppler Imaging in differentiating pathological from physiological LVH in the middle-aged population.</p> <p>Methods</p> <p>we selected a group of 80 master athletes, a group of 80 sedentary subjects with essential hypertension and an apparent normal diastolic function at standard PW Doppler analysis. The two groups were comparable for increased left ventricular wall thickness and mass index (134.4 ± 19.7 vs 134.5 ± 22.1 gr/m2; p > .05). Diastolic function indexes using the PW technique were in the normal range for both.</p> <p>Results</p> <p>Pulsed Wave TDI study of diastolic function immediately distinguished the two groups. While in master athletes the diastolic TDI-derived parameters remained within normal range (E' 9.4 ± 3.1 cm/sec; E/E' 7.8 ± 2.1), in the hypertensive group these parameters were found to be constantly altered, with mean values and variation ranges always outside normal validated limits (E' 7.2 ± 2.4 cm/sec; E/E' 10.6 ± 3.2), and with E' and E/E' statistically different in the two groups (p < .001).</p> <p>Conclusion</p> <p>Our study showed that the TDI technique can be an easy and validated method to assess diastolic function in differentiating normal from pseudonormal diastolic patterns and it can distinguish physiological from pathological LVH emphasizing the eligibility certification required by legal medical legislation as in Italy.</p

Isothiocyanates are detected in human synovial fluid following broccoli consumption and can affect the tissues of the knee joint

Osteoarthritis is a major cause of disability and there is no current pharmaceutical treatment which can prevent the disease or slow its progression. Dietary advice or supplementation is clearly an attractive option since it has low toxicity and ease of implementation on a population level. We have previously demonstrated that sulforaphane, a dietary isothiocyanate derived from its glucosinolate precursor which is found in broccoli, can prevent cartilage destruction in cells, in in vitro and in vivo models of osteoarthritis. As the next phase of this research, we enrolled 40 patients with knee osteoarthritis undergoing total knee replacement into a proof-of-principle trial. Patients were randomised to either a low or high glucosinolate diet for 14 days prior to surgery. We detected ITCs in the synovial fluid of the high glucosinolate group, but not the low glucosinolate group. This was mirrored by an increase in ITCs and specifically sulforaphane in the plasma. Proteomic analysis of synovial fluid showed significantly distinct profiles between groups with 125 differentially expressed proteins. The functional consequence of this diet will now be tested in a clinical trial

Study of the decays B->D_s1(2536)+ anti-D(*)

We report a study of the decays B -> D_s1(2536)+ anti-D(*), where anti-D(*) is anti-D0, D- or D*-, using a sample of 657 x 10^6 B anti-B pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider. The branching fractions of the decays B+ -> D_s1(2536)+ anti-D0, B0 -> D_s1(2536)+ D- and B0 -> D_s1(2536)+ D*- multiplied by that of D_s1(2536)+ -> (D*0K+ + D*+K0) are found to be (3.97+-0.85+-0.56) x 10^-4, (2.75+-0.62+-0.36) x 10^-4 and (5.01+-1.21+-0.70) x 10^-4, respectively.Comment: 6 pages, 2 figues, submitted to PRD (RC

A Non Membrane-Targeted Human Soluble CD59 Attenuates Choroidal Neovascularization in a Model of Age Related Macular Degeneration

Age related macular degeneration (AMD) is the most common cause of blindness amongst the elderly. Approximately 10% of AMD patients suffer from an advanced form of AMD characterized by choroidal neovascularization (CNV). Recent evidence implicates a significant role for complement in the pathogenesis of AMD. Activation of complement terminates in the incorporation of the membrane attack complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels of MAC have been documented on choroidal blood vessels and retinal pigment epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound inhibitor of MAC formation. Previously we have shown that membrane bound human CD59 delivered to the RPE cells of mice via an adenovirus vector can protect those cells from human complement mediated lysis ex vivo. However, application of those observations to choroidal blood vessels are limited because protection from MAC- mediated lysis was restricted only to the cells originally transduced by the vector. Here we demonstrate that subretinal delivery of an adenovirus vector expressing a transgene for a soluble non-membrane binding form of human CD59 can attenuate the formation of laser-induced choroidal neovascularization and murine MAC formation in mice even when the region of vector delivery is distal to the site of laser induced CNV. Furthermore, this same recombinant transgene delivered to the intravitreal space of mice by an adeno-associated virus vector (AAV) can also attenuate laser-induced CNV. To our knowledge, this is the first demonstration of a non-membrane targeting CD59 having biological potency in any animal model of disease in vivo. We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD