Ischemic injury of the upper gastrointestinal tract after out-of-hospital cardiac arrest: a prospective, multicenter study.

BACKGROUND: The consequences of cardiac arrest (CA) on the gastro-intestinal tract are poorly understood. We measured the incidence of ischemic injury in the upper gastro-intestinal tract after Out-of-hospital CA (OHCA) and determined the risk factors for and consequences of gastrointestinal ischemic injury according to its severity. METHODS: Prospective, non-controlled, multicenter study in nine ICUs in France and Belgium conducted from November 1, 2014 to November 30, 2018. Included patients underwent an esophago-gastro-duodenoscopy 2 to 4 d after OHCA if still intubated and the presence of ischemic lesions of the upper gastro-intestinal tract was determined by a gastroenterologist. Lesions were a priori defined as severe if there was ulceration or necrosis and moderate if there was mucosal edema or erythema. We compared clinical and cardiac arrest characteristics of three groups of patients (no, moderate, and severe lesions) and identified variables associated with gastrointestinal ischemic injury using multivariate regression analysis. We also compared the outcomes (organ failure during ICU stay and neurological status at hospital discharge) of the three groups of patients. RESULTS: Among the 214 patients included in the analysis, 121 (57%, 95% CI 50-63%) had an upper gastrointestinal ischemic lesion, most frequently on the fundus. Ischemic lesions were severe in 55/121 (45%) patients. In multivariate regression, higher adrenaline dose during cardiopulmonary resuscitation (OR 1.25 per mg (1.08-1.46)) was independently associated with increased odds of severe upper gastrointestinal ischemic lesions; previous proton pump inhibitor use (OR 0.40 (0.14-1.00)) and serum bicarbonate on day 1 (OR 0.89 (0.81-0.97)) were associated with lower odds of ischemic lesions. Patients with severe lesions had a higher SOFA score during the ICU stay and worse neurological outcome at hospital discharge. CONCLUSIONS: More than half of the patients successfully resuscitated from OHCA had upper gastrointestinal tract ischemic injury. Presence of ischemic lesions was independently associated with the amount of adrenaline used during resuscitation. Patients with severe lesions had higher organ failure scores during the ICU stay and a worse prognosis. Clinical Trial Registration NCT02349074 .

Biodistribution of Detonation Synthesis Nanodiamonds in Mice after Intravenous Administration and Some Biochemical Changes in Blood Plasma.

Biodistribution of nanodiamonds in mice after intravenous administration, activities of AST and ALT, and the level of bilirubin in the blood plasma were studied in 2.5 h and 10, 35, and 97 days after injection of nanodiamonds. In 2.5 h after intravenous injection, nanodiamonds mainly accumulate in the lungs and liver. Then, redistribution of nanodiamonds from all organs to the liver was observed. Activities of AST and ALT and the level of bilirubin in the blood increased after 2.5 h and then decreased to the initial values.

Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors.

BACKGROUND: This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules. PATIENTS AND METHODS: The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels. RESULTS: In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure. CONCLUSIONS: Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors. CLINICAL TRIAL NUMBER: NCT01362374.

Nematic Correlation Length in Iron-Based Superconductors Probed by Inelastic X-Ray Scattering.

Nematicity is ubiquitous in electronic phases of high-T_{c} superconductors, particularly in the Fe-based systems. We used inelastic x-ray scattering to extract the temperature-dependent nematic correlation length ξ from the anomalous softening of acoustic phonon modes in FeSe, underdoped Ba(Fe_{0.97}Co_{0.03})_{2}As_{2}, and optimally doped Ba(Fe_{0.94}Co_{0.06})_{2}As_{2}. In all cases, we find that ξ is well described by a power law (T-T_{0})^{-1/2} extending over a wide temperature range. Combined with the previously reported Curie-Weiss behavior of the nematic susceptibility, these results point to the mean-field character of the nematic transition, which we attribute to a sizable nematoelastic coupling that is likely detrimental to superconductivity.

Mutational Analysis of the Bovine Hepacivirus Internal Ribosome Entry Site.

In recent years, hepatitis C virus (HCV)-related viruses were identified in several species, including dogs, horses, bats, and rodents. In addition, a novel virus of the genus Hepacivirus has been discovered in bovine samples and was termed bovine hepacivirus (BovHepV). Prediction of the BovHepV internal ribosome entry site (IRES) structure revealed strong similarities to the HCV IRES structure comprising domains II, IIIabcde, pseudoknot IIIf, and IV with the initiation codon AUG. Unlike HCV, only one microRNA-122 (miR-122) binding site could be identified in the BovHepV 5' nontranslated region. In this study, we analyzed the necessity of BovHepV IRES domains to initiate translation and investigated possible interactions between the IRES and core coding sequences by using a dual luciferase reporter assay. Our results suggest that such long-range interactions within the viral genome can affect IRES-driven translation. Moreover, the significance of a possible miR-122 binding to the BovHepV IRES was investigated. When analyzing translation in human Huh-7 cells with large amounts of endogenous miR-122, introduction of point mutations to the miR-122 binding site resulted in reduced translation efficiency. Similar results were observed in HeLa cells after substitution of miR-122. Nevertheless, the absence of pronounced effects in a bovine hepatocyte cell line expressing hardly any miR-122 as well suggests additional functions of this host factor in virus replication.IMPORTANCE Several members of the family Flaviviridae, including HCV, have adapted cap-independent translation strategies to overcome canonical eukaryotic translation pathways and use cis-acting RNA-elements, designated viral internal ribosome entry sites (IRES), to initiate translation. Although novel hepaciviruses have been identified in different animal species, only limited information is available on their biology on molecular level. Therefore, our aim was a fundamental analysis of BovHepV IRES functions. The findings which show that functional IRES elements are also crucial for BovHepV translation expand our knowledge on molecular mechanism of hepacivirus propagation. We also studied the possible effects of one major host factor implicated in HCV pathogenesis, miR-122. The results of mutational analyses suggested that miR-122 enhances virus translation mediated by BovHepV IRES.

Left ventricular systolic function evaluated by strain echocardiography and relationship with mortality in patients with severe sepsis or septic shock: a systematic review and meta-analysis.

BACKGROUND: Sepsis-induced myocardial dysfunction is associated with poor outcomes, but traditional measurements of systolic function such as left ventricular ejection fraction (LVEF) do not directly correlate with prognosis. Global longitudinal strain (GLS) utilizing speckle-tracking echocardiography (STE) could be a better marker of intrinsic left ventricular (LV) function, reflecting myocardial deformation rather than displacement and volume changes. We sought to investigate the prognostic value of GLS in patients with sepsis and/or septic shock. METHODS: We conducted a systematic review (PubMed and Embase up to 26 October 2017) and meta-analysis to investigate the association between GLS and mortality at longest follow up in patients with severe sepsis and/or septic shock. In the primary analysis, we included studies reporting transthoracic echocardiography data on GLS according to mortality. A secondary analysis evaluated the association between LVEF and mortality including data from studies reporting GLS. RESULTS: We included eight studies in the primary analysis with a total of 794 patients (survival 68%, n = 540). We found a significant association between worse LV function and GLS values and mortality: standard mean difference (SMD) - 0.26; 95% confidence interval (CI) - 0.47, - 0.04; p = 0.02 (low heterogeneity, I2 = 43%). No significant association was found between LVEF and mortality in the same population of patients (eight studies; SMD, 0.02; 95% CI - 0.14, 0.17; p = 0.83; no heterogeneity, I2 = 3%). CONCLUSIONS: Worse GLS (less negative) values are associated with higher mortality in patients with severe sepsis or septic shock, while such association is not valid for LVEF. More critical care research is warranted to confirm the better ability of STE in demonstrating underlying intrinsic myocardial disease compared to LVEF.

Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab.

BACKGROUND: Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. MATERIALS AND METHODS: An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. RESULTS: A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. CONCLUSIONS: Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

Tissue Doppler assessment of diastolic function and relationship with mortality in critically ill septic patients: a systematic review and meta-analysis.

BACKGROUND: Myocardial dysfunction may contribute to circulatory failure in sepsis. There is growing evidence of an association between left ventricular diastolic dysfunction (LVDD) and mortality in septic patients. Utilizing echocardiography, we know that tissue Doppler imaging (TDI) variables e' and E/e' are reliable predictors of LVDD and are useful measurements to estimate left ventricular (LV) filling pressures. METHODS: We conducted a systematic review and meta-analysis to investigate the association of e' and E/e' with mortality of patients with severe sepsis or septic shock. In the primary analysis, we included studies providing transthoracic TDI data for e' and E/e' and their association with mortality. Subgroup analyses were conducted according to myocardial regional focus of TDI assessment (septal, lateral or averaged). Three secondary analyses were performed: one included data from a transoesophageal study, another excluded studies reporting data at a very early (<6 h) or late (>48 h) stage following diagnosis, and the third pooled data only from studies excluding patients with heart valve disease. RESULTS: The primary analysis included 16 studies with 1507 patients with severe sepsis and/or septic shock. A significant association was found between mortality and both lower e' [standard mean difference (SMD) 0.33; 95% confidence interval (CI): 0.05, 0.62; P=0.02] and higher E/e' (SMD -0.33; 95% CI: -0.57, -0.10; P=0.006). In the subgroup analyses, only the lateral TDI values showed significant association with mortality (lower e' SMD 0.45; 95% CI: 0.11, 0.78; P=0.009; higher E/e' SMD -0.49; 95% CI: -0.76, -0.22; P=0.0003). The findings of the primary analysis were confirmed by all secondary analyses. CONCLUSIONS: There is a strong association between both lower e' and higher E/e' and mortality in septic patients.

Detection of nanodiamonds in biological samples by EPR spectrometry.

In model experiments in vitro, the applicability of the EPR spectrometry method for the detection of modified nanodiamonds (MNDs) in blood and homogenates of mouse organs has been established. A characteristic signal (g = 2.003, ΔH ≈ 10 G) is observed in the samples of biomaterials containing MNDs, the intensity of which increases linearly with the concentration of nanoparticles in the range of 1.6-200 µg MNDs per 1 mL of the sample. The EPR method in biomaterials reveals the presence of intrinsic paramagnetic centers, signals from which are superimposed on the signal from the MNDs. However, the intensity of these signals is small, which makes it possible to register the MNDs using EPR spectrometry with the necessary accuracy. The data obtained open up the prospects of using the EPR method for studies of the interorgan distribution, accumulation, and elimination of MNDs during their intravenous injection into experimental animals.

Adsorption of viral particles from the blood plasma of patients with viral hepatitis on nanodiamonds.

Adsorption of viral particles from the blood plasma of patients with viral hepatitis B and C on modified nanodiamonds (MNDs) was shown in the in vitro experiments. PCR method showed the treatment of plasma with MNDs leads to a decrease in the viral load by 2-3 orders of magnitude or more in both cases studied. These results make it possible to predict the applicability of MNDs for the development of new technologies of hemodialysis and plasmapheresis for binding and removal of viral particles from the blood of infected patients.

Passive absorption in a classical photonic crystal-based organic solar cell.

We study the light trapping efficiency of a bidimensional photonic crystal (PC) integrated in a classical organic multilayer solar cell. The role of the PC is to enhance light absorption in the active layer by leveraging resonant mode excitation. However the light trapping efficiency is drastically inhibited by the overall absorption of the entire multilayer, which includes absorption by the passive layers that do not contribute to the photocurrent. This study focuses on the impact of passive absorption in ITO and PEDOT, which is often neglected in the study of light trapping organic solar cell systems, despite the significant role it plays in highly absorbing devices. Indeed, we show here that the absorption enhancement in the active layer can vary between 23% and 46% depending on the optical properties of the passive layers, which are dependent on fabrication conditions. We also detail how the PC behaves with coupled parameters such as the optical indices of the passive layers, as well as the period and the air filling fraction of the PC.

Designing a reusable system based on nanodiamonds for biochemical determination of urea.

A reusable system including urease covalently bound to the surface of modified nanodiamonds (MNDs) has been developed for the multiple determination of urea. The immobilized enzyme exhibits functional activity and catalyzes the hydrolysis of urea to yield ammonia. The presence of ammonia is confirmed by the formation of a colored product after the addition of chemical reagents. It was shown that the MNDs-urease complex can function in a wide range of temperatures and pH as well as in deionized water. The complex provides a linear yield of the product at low analyte concentrations and allows the multiple determination of urea in vitro.

Survival benefit of repeat liver transplantation in the United States: a serial MELD analysis by hepatitis C status and donor risk index.

Survival benefit (SB) for first liver transplantation (LT) is favorable at Model for End-Stage Liver Disease (MELD)≥15. Herein, we identify the MELD threshold for SB from repeat liver transplantation (ReLT) by recipient hepatitis C virus (HCV) status and donor risk index (DRI). We analyzed lab MELD scores in new United Network for Organ Sharing registrants for ReLT from March 2002 to January 2010. Risk of ReLT graft failure≤1 year versus waitlist mortality was calculated using Cox regression, adjusting for recipient characteristics. Of 3057 ReLT candidates, 54% had HCV and 606 died while listed. There were 1985 ReLT recipients, 52% had HCV and 567 ReLT graft failures by 1 year. Unadjusted waitlist mortality and post-ReLT graft failure rates were 416 (95% confidence interval [CI] 384-450) and 375 (95% CI 345-407) per 1000 patient-years, respectively. Waitlist mortality was higher with increasing waitlist MELD (p<0.001). The MELD for SB from ReLT overall was 21 (21 in non-HCV and 24 in HCV patients). MELD for SB varied by DRI in HCV patients (MELD 21, 24 and 27 for low, medium and high DRI, respectively) but did not vary for non-HCV patients. Compared to first LT, ReLT requires a higher MELD threshold to achieve an SB resulting in a narrower therapeutic window to optimize the utility of scarce liver grafts.

Evaluation of pulse pressure variation validity criteria in critically ill patients: a prospective observational multicentre point-prevalence study.

BACKGROUND: Respiratory variation in pulse pressure (ΔPP) is commonly used to predict the fluid responsiveness of critically ill patients. However, some researchers have demonstrated that this measurement has several limitations. The present study was designed to evaluate the proportion of patients satisfying criteria for valid application of ΔPP at a given time-point. METHODS: A 1 day, prospective, observational, point-prevalence study was performed in 26 French intensive care units (ICUs). All patients hospitalized in the ICUs on the day of the study were included. The ΔPP validity criteria were recorded prospectively and defined as follows: (i) mechanical ventilation in the absence of spontaneous respiration; (ii) regular cardiac rhythm; (iii) tidal volume ≥8 ml kg(-1) of ideal body weight; (iv) a heart rate/respiratory rate ratio >3.6; (v) total respiratory system compliance ≥30 ml cm H2O(-1); and (vi) tricuspid annular peak systolic velocity ≥0.15 m s(-1). RESULTS: The study included 311 patients with a Simplified Acute Physiology Score II of 41 (39-43). Overall, only six (2%) patients satisfied all validity criteria. Of the 170 patients with an arterial line in place, only five (3%) satisfied the validity criteria. During the 24 h preceding the study time-point, fluid responsiveness was assessed for 79 patients. ΔPP had been used to assess fluid responsiveness in 15 of these cases (19%). CONCLUSIONS: A very low percentage of patients satisfied all criteria for valid use of ΔPP in the evaluation of fluid responsiveness. Physicians must consider limitations to the validity of ΔPP before using this variable.

Coupling light into a slow-light photonic-crystal waveguide from a free-space normally-incident beam.

We present a coupler design allowing normally-incident light coupling from free-space into a monomode photonic crystal waveguide operating in the slow-light regime. Numerical three-dimensional calculations show that extraction efficiencies as high as 80% can be achieved for very large group indices up to 100. We demonstrate experimentally the device feasibility by coupling and extracting light from a photonic crystal waveguide over a large group-index range (from 10 to 60). The measurements are in good agreement with theoretical predictions. We also study numerically the impact of various geometrical parameters on the coupler performances.

A novel tridentate bis(phosphinic acid)phosphine oxide based europium(III)-selective Nafion membrane luminescent sensor.

A new europium(III) membrane luminescent sensor based on a new tridentate bis(phosphinic acid)phosphine oxide (3) system has been developed. The synthesis of this new ligand is described and its full characterization by NMR, IR and elemental analyses is provided. The luminescent complex formed between europium(III) chloride and ligand 3 was evaluated in solution, observing that its spectroscopic and chemical characteristics are excellent for measuring in polymer inclusion membranes. Included in a Nafion membrane, all the parameters (ligand and ionic additives) that can affect the sensitivity and selectivity of the sensing membrane as well as the instrumental conditions were carefully optimized. The best luminescence signal (λexc = 229.06 nm and λem = 616.02 nm) was exhibited by the sensing film having a Nafion : ligand composition of 262.3 : 0.6 mg mL(-1). The membrane sensor showed a short response time (t95 = 5.0 ± 0.2 min) and an optimum working pH of 5.0 (25 mM acetate buffer solution). The membrane sensor manifested a good selectivity toward europium(III) ions with respect to other trivalent metals (iron, chromium and aluminium) and lanthanide(III) ions (lanthanum, samarium, terbium and ytterbium), although a small positive interference of terbium(III) ions was observed. It provided a linear range from 1.9 × 10(-8) to 5.0 × 10(-6) M with a very low detection limit (5.8 × 10(-9) M) and sensitivity (8.57 × 10(-7) a.u. per M). The applicability of this sensing film has been demonstrated by analyzing different kinds of spiked water samples obtaining recovery percentages of 95-97%.

Novel imino sugar α-glucosidase inhibitors as antiviral compounds.

Deoxynojirimycin (DNJ) based imino sugars display antiviral activity in the tissue culture surrogate model of Hepatitis C (HCV), bovine viral diarrhoea virus (BVDV), mediated by inhibition of ER α-glucosidases. Here, the antiviral activities of neoglycoconjugates derived from deoxynojirimycin, and a novel compound derived from deoxygalactonojirimycin, by click chemistry with functionalised adamantanes are presented. Their antiviral potency, in terms of both viral infectivity and virion secretion, with respect to their effect on α-glucosidase inhibition, are reported. The distinct correlation between the ability of long alkyl chain derivatives to inhibit ER α-glucosidases and their anti-viral effect is demonstrated. Increasing alkyl linker length between DNJ and triazole groups increases α-glucosidase inhibition and reduces the production of viral progeny RNA and the maturation of the envelope polypeptide. Disruption to viral glycoprotein processing, with increased glucosylation on BVDV E2 species, is representative of α-glucosidase inhibition, whilst derivatives with longer alkyl linkers also show a further decrease in infectivity of secreted virions, an effect proposed to be distinct from α-glucosidase inhibition.

Effects of modified detonation nanodiamonds on the biochemical composition of human blood.

In vitro experiments showed that protein and non-protein components of human blood serum could be absorbed on the surface of modified nanodiamonds obtained by detonation synthesis. The prospects of using nanodiamond as a new absorbent for hemodialysis, plasmapheresis, and laboratory diagnostics are discussed.

[The effect of modified nano-diamonds of detonation synthesis on the protein fractions of human blood].

It is established that the modified nano-diamonds of detonation synthesis are able to bind serum proteins of human blood. The relative selectivity is established concerning the effect of modified nano-diamonds of detonation synthesis on beta2- and gamma-globulin fractions of serum. The evidence of concentration dependence of effect of modified nano-diamonds of detonation synthesis from serum proteins is established. The study results make it possible to consider modified nano-diamonds of detonation synthesis as a potential sorbent in technologies of hemodialysis, plasmapheresis, isolation of blood proteins and as a foundation for development of new systems of laboratory diagnostic.

Collective excitations in a melt of fast phase change material GeCu2Te3.

Inelastic x-ray scattering measurements have been carried out to investigate atomic dynamics in a melt of fast phase change material GeCu2Te3. The dynamic structure factor was analysed using the model function with three damped harmonic oscillator components. By investigating the correlation between the excitation energy and the linewidth, and that between the excitation energy and the intensity on contour maps of a relative approximate probability distribution function proportional toexp(-χ2/N), we could judge the reliability of each inelastic excitation in the dynamic structure factor. The results indicate that there are two inelastic excitation modes besides the longitudinal acoustic one in the liquid. The lower energy excitation could be assigned to the transverse acoustic one whereas the higher energy one disperses like fast sound. The latter result may imply that the liquid ternary alloy exhibits a microscopic phase separation tendency.