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Background: Recent studies have presented concerning data on the safety of cardioversion for acute atrial fibrillation and flutter. We conducted this meta-analysis to evaluate the effect of oral anticoagulation use on thromboembolic events post-cardioversion of low-risk acute atrial fibrillation and flutter patients of?<?48 h in duration. Methods: We searched MEDLINE, Embase, and Cochrane from inception through February 6, 2020 for studies reporting thromboembolic events post-cardioversion of acute atrial fibrillation and flutter. Main outcome was thromboembolic events within 30 days post-cardioversion. Primary analysis compared thromboembolic events based on oral anticoagulation use versus no oral anticoagulation use. Secondary analysis was based on baseline thromboembolic risk. We performed meta-analyses where 2 or more studies were available, by applying the DerSimonian-Laird random-effects model. Risk of bias was assessed with the Quality in Prognostic Studies tool. Results: Of 717 titles screened, 20 studies met inclusion criteria. Primary analysis of seven studies with low risk of bias demonstrated insufficient evidence regarding the risk of thromboembolic events associated with oral anticoagulation use (RR?=?0.82 where RR?<?1 suggests decreased risk with oral anticoagulation use; 95% CI 0.27 to 2.47; I2?=?0%). Secondary analysis of 13 studies revealed increased risk of thromboembolic events with high baseline thromboembolic risk (RR?=?2.25 where RR?>?1 indicates increased risk with higher CHADS2or CHA2DS2-VASc scores; 95% CI 1.25 to 4.04; I2?=?0%). Conclusion: Primary analysis revealed insufficient evidence regarding the effect of oral anticoagulation use on thromboembolic events post-cardioversion of low-risk acute atrial fibrillation and flutter, though the event rate is low in contemporary practice. Our findings can better inform patient-centered decision-making when considering 4-week oral anticoagulation use for acute atrial fibrillation and flutter patients.

•Total salt partitioning decreases with larger feed salinities but is unaffected by pressure.•Salt permeability trends differ at ultrahigh pressures compared to conventional operating conditions.•Ultrahigh pressures and salinities induce structural changes to the polyamide matrix.•Changes at ultrahigh pressures increase frictional forces, altering performance-based parameters.

High-resolution mass spectrometry (HRMS) is a very powerful technology for equine doping control analysis. The more recently developed hybrid type of Orbitrap-based HRMS instrument allows for both targeted and non-targeted screening analyses in a single liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) run. In the present study, an LC-HRMS/MS method was developed and validated to detect prohibited substances in equine sports. The substances were recovered from equine plasma by liquid–liquid extraction (LLE) using methyl tert-butyl ether and were separated on a C18 reversed-phase column using mobile phases of 5 mM ammonium formate and acetonitrile. A 7.5 min LC gradient was employed to elute substances and results indicated that the LC method generated sharp and symmetric chromatographic peaks. An in-house equine doping compound database and a spectral library were built to increase method specificity for substances of interest. Five criteria, i.e.accurate mass, retention time, isotope pattern, selected HRMS/MS fragment ions (compound database) and HRMS/MS spectra (spectral library), were employed for targeted screening. We utilized these criteria to validate targeted detection of 451 substances within our in-house equine doping compound database. By using all five criteria in screening, the false screening positive rate is significantly reduced. A screening strategy and a Microsoft Excel macro were developed to facilitate interpretation and reporting of results. As the simultaneous acquisition of the full scan HRMS data provides the opportunity for retrospective non-targeted analysis, our findings highlight the use of this novel methodology as a simple, rapid, and reliably reproducible strategy to meet the challenge of identifying an increasing number of doping substances that could potentially impact the integrity of the horse racing community.

ABSTRACTBackgroundPrognosis and disposition among older emergency department (ED) patients with suspected infection remains challenging. Frailty is increasingly recognized as a predictor of poor prognosis among critically ill patients; however, its association with clinical outcomes among older ED patients with suspected infection is unknown.MethodsWe conducted a multicenter prospective cohort study at two tertiary care EDs. We included older ED patients (≥75 years) with suspected infection. Frailty at baseline (before index illness) was explicitly measured for all patients by the treating physicians using the Clinical Frailty Scale (CFS). We defined frailty as a CFS 5–8. The primary outcome was 30-day mortality. We used multivariable logistic regression to adjust for known confounders. We also compared the prognostic accuracy of frailty with the Systemic Inflammatory Response Syndrome (SIRS) and Quick Sequential Organ Failure Assessment (qSOFA) criteria.ResultsWe enrolled 203 patients, of whom 117 (57.6%) were frail. Frail patients were more likely to develop septic shock (adjusted odds ratio [aOR], 1.83; 95% confidence interval [CI], 1.08–2.51) and more likely to die within 30 days of ED presentation (aOR 2.05; 95% CI, 1.02–5.24). Sensitivity for mortality was highest among the CFS (73.1%; 95% CI, 52.2–88.4), compared with SIRS ≥ 2 (65.4%; 95% CI, 44.3–82.8) or qSOFA ≥ 2 (38.4; 95% CI, 20.2–59.4).ConclusionsFrailty is a highly prevalent prognostic factor that can be used to risk-stratify older ED patients with suspected infection. ED clinicians should consider screening for frailty to optimize disposition in this population.

Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced β cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca2+-binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca2+overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca2+entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca2+flux in β cells and in their capacity to adapt to metabolic stress.

This paper studies the market phenomenon of non-convergence between futures and spot prices in the grains market. We postulate that the positive basis observed at maturity stems from the futures holder's timing options to exercise the shipping certificate delivery item and subsequently liquidate the physical grain. In our proposed approach, we incorporate stochastic spot price and storage cost, and solve an optimal double stopping problem to give the optimal strategies to exercise and liquidate the grain. Our new models for stochastic storage rates lead to explicit no-arbitrage prices for the shipping certificate and associated futures contract. We calibrate our models to empirical futures data during the periods of observed non-convergence, and illustrate the premium generated by the shipping certificate.

Because of a limited volume of urine that can be collected from a mouse, it is very difficult to apply the common strategy of using multiple analytical techniques to analyze the metabolites to increase the metabolome coverage for mouse urine metabolomics. We report an enabling method based on differential isotope labeling liquid chromatography mass spectrometry (LC–MS) for relative quantification of over 950 putative metabolites using 20 μL of urine as the starting material. The workflow involves aliquoting 10 μL of an individual urine sample for 12C-dansylation labeling that target amines and phenols. Another 10 μL of aliquot was taken from each sample to generate a pooled sample that was subjected to 13C-dansylation labeling. The 12C-labeled individual sample was mixed with an equal volume of the 13C-labeled pooled sample. The mixture was then analyzed by LC–MS to generate information on metabolite concentration differences among different individual samples. The interday repeatability for the LC–MS runs was assessed, and the median relative standard deviation over 4 days was 5.0%. This workflow was then applied to a metabolomic biomarker discovery study using urine samples obtained from the TgCRND8 mouse model of early onset familial Alzheimer’s disease (FAD) throughout the course of their pathological deposition of beta amyloid (Aβ). It was showed that there was a distinct metabolomic separation between the AD prone mice and the wild type (control) group. As early as 15–17 weeks of age (presymptomatic), metabolomic differences were observed between the two groups, and after the age of 25 weeks the metabolomic alterations became more pronounced. The metabolomic changes at different ages corroborated well with the phenotype changes in this transgenic mice model. Several useful candidate biomarkers including methionine, desaminotyrosine, taurine, N1-acetylspermidine, and 5-hydroxyindoleacetic acid were identified. Some of them were found in previous metabolomics studies in human cerebrospinal fluid or blood samples. This work illustrates the utility of this isotope labeling LC–MS method for biomarker discovery using mouse urine metabolomics.

We report what we believe to be the first near-infrared pH-sensitive fluorescence lifetime molecular probe suitable for biological applications in physiological range. Specifically, we modified a known fluorophore skeleton, hexamethylindotricarbocyanine, with a tertiary amine functionality that was electronically coupled to the fluorophore, to generate a pH-sensitive probe. The pKaof the probe depended critically on the location of the amine. Peripheral substitution at the 5-position of the indole ring resulted in a compound with pKa∼ 4.9 as determined by emission spectroscopy. In contrast, substitution at the meso-position shifted the pKato 5.5. The resulting compound, LS482, demonstrated steady-state and fluorescence-lifetime pH-sensitivity. This sensitivity stemmed from distinct lifetimes for protonated (∼1.16 ns in acidic DMSO) and deprotonated (∼1.4 ns in basic DMSO) components. The suitability of the fluorescent dyes for biological applications was demonstrated with a fluorescence-lifetime tomography system. The ability to interrogate cellular processes and subsequently translate the findings in living organisms further augments the potential of these lifetime-based pH probes.

The contrast mechanisms used for photoacoustic tomography (PAT) and fluorescence imaging differ in subtle, but significant, ways. The design of contrast agents for each or both modalities requires an understanding of the spectral characteristics as well as intra- and intermolecular interactions that occur during formulation. We found that fluorescence quenching that occurs in the formulation of near-infrared (NIR) fluorescent dyes in nanoparticles results in enhanced contrast for PAT. The ability of the new PAT method to utilize strongly absorbing chromophores for signal generation allowed us to convert a highly fluorescent dye into an exceptionally high PA contrast material. Spectroscopic characterization of the developed NIR dye-loaded perfluorocarbon-based nanoparticles for combined fluorescence and PA imaging revealed distinct dye-dependent photophysical behavior. We demonstrate that the enhanced contrast allows detection of regional lymph nodes of rats in vivowith time-domain optical and photoacoustic imaging methods. The results further show that the use of fluorescence lifetime imaging, which is less dependent on fluorescence intensity, provides a strategic approach to bridge the disparate contrast reporting mechanisms of fluorescence and PA imaging methods.

Age of bloodstains: Determining the age of a bloodstain at a crime scene is one of the greatest and oldest challenges in forensic science. The results presented herein, with dog blood as a model, indicate a highly reproducible correlation between the fluorescence lifetime and the age of the bloodstain (see figure). The time‐dependent changes in fluorescence lifetime were attributed to the alteration of tryptophan.

Fluorescence lifetime (FLT) properties of organic molecules provide a new reporting strategy for molecular imaging in the near infrared (NIR) spectral region. Unfortunately, most of the NIR fluorescent dyes have short FLT typically clustered below 1.5 ns. In this study, we demonstrate that a new class of NIR fluorescent dyes, pyrrolopyrrole cyanine dyes, have exceptionally long FLTs ranging from 3 to 4 ns, both in vitro (dimethyl sulfoxide and albumin/water solutions) and in vivo (mice). These results provide a new window for imaging molecular processes, rejecting backscattered light and autofluorescence, and multiplexing imaging information with conventional NIR fluorescent dyes that absorb and emit light at similar wavelengths.

This paper examines the main drivers of the returns of gold miner stocks and ETFs during 2006–2017. We solve a combined optimal control and stopping problem to demonstrate that gold miner equities behave like real options on gold. Inspired by our proposed model, we construct a method to dynamically replicate gold miner stocks using two factors: the spot gold ETF and market equity portfolio. Furthermore, through each firm’s factor loadings on the replicating portfolio, we dynamically infer the firm’s implied leverage parameters of our model using the Kalman Filter. We find that our approach can explain a significant portion of the drivers of firm implied gold leverage. We posit that gold miner companies hold additional real options which help mitigate firm downside volatility, but these real options contribute to lower returns relative to the replicating portfolio when gold returns are positive.

We present a novel, dual modality gadolinium based MRI/near-infrared optical probe. Utilizing a fluorescent dye as a scaffold with attached Gd-chelating moiety, we demonstrated a substantial shortening of T1 relaxation time of water protons in vitro. The probe was compared to the commonly used MRI Gd-based contrast agents Magnevist® and Multihance® and showed superior contrast properties. The enhancement was due to strong albumin binding of the hydrophobic fluorophore and overall rigidification of the contrast agent. Due to the near-infrared optical properties of the probe and excellent MRI activity the proposed construct can be potentially utilized as a dual probe in multimodal MRI/NIR optical imaging.