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In thoracic endovascular aortic repair (TEVAR), the left subclavian artery (LSA) is often occluded. Although most patients tolerate this, some develop ischemic symptoms to the brain or left upper extremity (LUE). A revascularization procedure may be associated with significant complications. The purpose of this review was to assess the incidence of LSA occlusion, resulting ischemic symptoms, and complications related to revascularization operations in trauma patients compared to non-trauma patients.Studies from 2010 to 2020 were fully reviewed if they discussed incidence of LSA coverage, LUE ischemia, carotid-subclavian bypass, or complications associated with carotid-subclavian bypass.Seventeen articles were included in this analysis. A total of 167 patients were identified as trauma cases. Incidence of LSA occlusion in trauma was 91/167 (54%) compared to 281/1446 (19%) in the population exclusive of trauma (p 0.001). Following LSA occlusion, the rate of LUE claudication/ischemia was 21/56 (38%) for trauma, compared to 12/193 (6%) in non-trauma cases (p 0.001). The overall complication rate after carotid-subclavian rescue bypass was 29.2% (33/112), with phrenic nerve palsy (24%), recurrent laryngeal nerve palsy (5%), and pseudoaneurysm (1.7%) being the most common.LSA coverage following TEVAR is common and associated with significant complications, often requiring operative management. The incidence of ischemic complications after occlusion of the LSA is significantly higher in the trauma population. Revascularization procedures to correct the occlusion have a high rate of complications.

We present the Indinavir Ligand Induced Transient Engagement switch (IDV LITE Switch), a fully synthetic Chemically Induced Dimerization (CID) system wherein two humanized antibody fragments are heterodimerized by the antiviral drug indinavir. The IDV LITE Switch represents the first CID system made from fully humanized protein components and dimerized by a clinically approved small molecule drug lacking a mammalian target, making it an ideal bioorthogonal molecular switch for application in small-molecule controlled therapeutics.

The Groningen gas field in the Netherlands is experiencing induced seismicity as a result of ongoing depletion. The physical mechanisms that control seismicity have been studied through rock mechanical experiments and combined physical-statistical models to support development of a framework to forecast induced-seismicity risks. To investigate whether machine learning techniques such as Random Forests and Support Vector Machines bring new insights into forecasts of induced seismicity rates in space and time, a pipeline is designed that extends time-series analysis methods to a spatiotemporal framework with a factorial setup, which allows probing a large parameter space of plausible modelling assumptions, followed by a statistical meta-analysis to account for the intrinsic uncertainties in subsurface data and to ensure statistical significance and robustness of results. The pipeline includes model validation using e.g. likelihood ratio tests against average depletion thickness and strain thickness baselines to establish whether the models have statistically significant forecasting power. The methodology is applied to forecast seismicity for two distinctly different gas production scenarios. Results show that seismicity forecasts generated using Support Vector Machines significantly outperform beforementioned baselines. Forecasts from the method hint at decreasing seismicity rates within the next 5 years, in a conservative production scenario, and no such decrease in a higher depletion scenario, although due to the small effective sample size no statistically solid statement of this kind can be made. The presented approach can be used to make forecasts beyond the investigated 5-years period, although this requires addition of limited physics-based constraints to avoid unphysical forecasts.

OBJECTIVE: Tori or exostoses are bony growths that appear in different oral regions. Torus palatinus, more specifically, develop in the palate midline and can impair proper word pronunciation and hinder the fabrication and use of dentures. Even though a multifactorial inheritance model has been suggested for torus palatinus appearance, precise genetic factors involved in its etiology remain unclear. Hence, in this study we aimed to identify variants across the genome of individuals from 46 Filipino families that associate with torus palatinus. DESIGN: All families were composed of fishermen or landless rural dwellers who provided blood samples for DNA extraction and genotyping. A total of 3,519 single nucleotide polymorphisms (SNPs) were analyzed through a transmission disequilibrium test in individuals affected by torus palatinus and their unaffected family members. RESULTS: Fourteen SNPs showed trends for associations to the level of p

Background As the number of households with dogs in the United States has increased, so has the incidence of dog bites. Contemporary analysis of nationwide epidemiological data regarding such injuries is scarce. The purpose of this study is to describe dog bite injury patterns and related surgical interventions with a focus on differences between pediatric and adult age groups. Study Design This is a retrospective study (2015-2017) using the National Trauma Data Bank. 10 569 patients were included. Results Of these, 4729 (44.7%) qualified as pediatric (age ≤ 12 years) and 5840 (55.3%) qualified as adults (age ≥ 13 years). Pediatric patients were more frequently admitted with facial injuries (78.1% vs. 29.3%, P < .01) and facial fractures (4.8% vs. 2.5%, P < .01), and had a higher incidence of facial bone surgical procedures (1.3% vs. .5%, P < .01). Adult patients were more frequently admitted with upper extremity injuries (65.8% vs. 21.2%, P < .01) and upper extremity vascular arterial injuries (2.3% vs. .2%, P < .01) with a higher incidence of upper extremity arterial procedures (1.3% vs. .2%, P < .01). Conclusion This study demonstrates the contrast in injury patterns from dog bite between adults and children. These findings can dictate injury prevention policies and prepare clinicians to treat dog bite victims.

Many multivariate time series observed in practice are second order nonstationary, i.e. their covariance properties vary over time. In addition, missing observations in such data are encountered in many applications of interest, due to recording failures or sensor dropout, hindering successful analysis. This article introduces a novel method for data imputation in multivariate nonstationary time series, based on the so-called locally stationary wavelet modelling paradigm. Our methodology is shown to perform well across a range of simulation scenarios, with a variety of missingness structures, as well as being competitive in the stationary time series setting. We also demonstrate our technique on data arising in a health monitoring application.

Methods for the supervised classification of signals generally aim to assign a signal to one class for its entire time span. In this paper we present an alternative formulation for multivariate signals where the class membership is permitted to change over time. Our aim therefore changes from classifying the signal as a whole to classifying the signal at each time point to one of a fixed number of known classes. We assume that each class is characterised by a different stationary generating process, the signal as a whole will however be nonstationary due to class switching. To capture this nonstationarity we use the recently proposed Multivariate Locally Stationary Wavelet model. To account for uncertainty in class membership at each time point our goal is not to assign a definite class membership but rather to calculate the probability of a signal belonging to a particular class. Under this framework we prove some asymptotic consistency results. This method is also shown to perform well when applied to both simulated and accelerometer data. In both cases our method is able to place a high probability on the correct class for the majority of time points.

Premise of the study Plant pathogens that form persistent systemic infections within plants have the potential to affect multiple plant life history traits, yet we tend to focus only on visible symptoms. Anther smut of Silene latifolia caused by the fungus Microbotryum lychnidis-dioicae induces the anthers of its host to support fungal spore production instead of pollen, and the pathogen is primarily transmitted among flowering plants by pollinators. Nevertheless, most of its life cycle is spent in the asymptomatic vegetative phase, and spores falling on seedlings or nonflowering plants can also infect the host. The purpose of this study was to ask whether the fungus also had an effect on its host plant in the juvenile vegetative phase before flowering as this is important for the disease dynamics in species where infection of seedlings is commonplace. Methods Leaf length and leaf number of inoculated and uninoculated juvenile plants were compared in greenhouse experiments, and in one experiment, disease status of the plants at flowering was determined. Key results Inoculated plants had shorter but more leaves, and reduced root mass at the early juvenile (preflowering) stage. Some of these effects were detectable in plants that were inoculated but showed no disease symptoms at flowering. Conclusions These results show that pathogenic fungi can have endophyte-like effects even in the total absence of their typical and more charismatic symptoms, and conversely that the assessment of endophyte effects on the fitness of their hosts should include all stages of the host life cycle.

Objective To quantitatively measure tissue composition and hemodynamics during resuscitative endovascular balloon occlusion of the aorta (REBOA) in two tissue compartments using non-invasive two-channel broadband diffuse optical spectroscopy (DOS). Methods Tissue concentrations of oxy- and deoxyhemoglobin (HbO2 and HbR), water, and lipid were measured in a porcine model (n = 10) of massive hemorrhage (65% total blood volume over 1 h) and 30-min REBOA superior and inferior to the aortic balloon. Results After hemorrhage, hemoglobin oxygen saturation (StO2 = HbO2/[HbO2 + HbR]) at both sites decreased significantly (−29.9% and −42.3%, respectively). The DOS measurements correlated with mean arterial pressure (MAP) (R2 = 0.79, R2 = 0.88), stroke volume (SV) (R2 = 0.68, R2 = 0.88), and heart rate (HR) (R2 = 0.72, R2 = 0.88). During REBOA, inferior StO2 continued to decline while superior StO2 peaked 12 min after REBOA before decreasing again. Inferior DOS parameters did not associate with MAP, SV, or HR during REBOA. Conclusions Dual-channel regional tissue DOS measurements can be used to non-invasively track the formation of hemodynamically distinct tissue compartments during hemorrhage and REBOA. Conventional systemic measures MAP, HR, and SV are uncorrelated with tissue status in inferior (downstream) sites. Multi-compartment DOS may provide a more complete picture of the efficacy of REBOA and similar resuscitation procedures.

A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.

Highlights • Primary breast leiomyosarcoma is a rare disease with unclear diagnosis, management and prognosis. • We present a case of primary breast leiomyosarcoma metastases to the lung in a young adult female. • We provide a complete list and discussion of 68 documented cases of primary breast leiomyosarcoma. • Treatment of breast leiomyosarcoma should include surveillance for lung metastases., Introduction Primary leiomyosarcomas of the breast are extremely rare. Because of this rarity, only a small number of studies have been published about the disease; diagnosis, treatment, and prognosis are not well-described. Our work has been reported in line with the SCARE criteria. Presentation of case We present a 20-year-old female with primary breast leiomyosarcoma who despite mastectomy, developed lung metastases three years later. Discussion We discuss the rarity of breast leiomyosarcoma and risk of metastatic disease even with treatment. We review the literature and provide an outline of available data to shed light on the best strategies to manage this aggressive disease. Conclusion Physicians and surgeons treating breast leiomyosarcoma must be vigilant of potential lung metastases in order to optimize short- and long-term oncologic outcomes.

Cells in the solid tumor microenvironment are frequently exposed to hypoxic conditions, necessitating molecular adaptations for survival. Of particular importance are transcriptional changes mediated by heterodimeric Hypoxia-Inducible Factor (HIF) proteins that consist of an oxygen-regulated α monomer (either HIF-1α, -2α, and -3α) coupled to a constitutively expressed β monomer (HIF-1β/ARNT). In normal oxygen conditions, HIF-2α is degraded following ubiquitination by the von Hippel-Lindau (pVHL) E3-ubiquitin ligase complex. Exposure to hypoxia, VHL mutation, or epigenetic silencing of pVHL leads to HIF-2α stabilization and transcription of pro-tumorigenic gene sets in both cancer and non-cancer cells. Inhibition of HIF-2α has been shown clinically to be an effective strategy to mitigate tumor growth, particularly in patients suffering from VHL disease or clear cell renal cell carcinoma (ccRCC), a cancer that has a particularly high prevalence of pVHL dysfunction. Applying a pharmacophore mapping and structure-based design approach, we identified a novel and potent small molecule HIF-2α inhibitor, AB521. AB521 avidly binds the HIF-2α PAS-B domain, preventing HIF-2α-mediated gene transcription. AB521 is characterized by a favorable preclinical pharmacokinetic profile and is projected to be suitable for once-daily dosing in humans. When delivered orally in mice, AB521 significantly regressed established 786-O xenograft tumors and decreased pharmacodynamic markers associated with HIF-2α in a dose-dependent manner. In vitro, AB521 potently inhibited HIF-2α-specific luciferase reporter transcription under high-serum conditions, VEGF protein secretion, colony formation in soft agar, and did not exhibit off-target cytotoxicity in 786-O cells. AB521 selectively inhibited HIF-2α-, but not HIF-1α-, mediated gene expression in hypoxic Hep3B hepatocellular carcinoma cells. AB521 also inhibited the transcriptional activity of endogenous HIF-2α in relevant human primary cell types, including endothelial cells and pro-tumorigenic M2-polarized macrophages. Importantly, inhibiting HIF-2α did not impact functionality of activated hypoxic human T cells, suggesting that AB521 would be favorable combination partner for I-O therapeutic agents. Indeed, expression of CD73, the primary enzyme responsible for synthesis of the immunosuppressive metabolite adenosine, was highly correlated with hypoxic signatures across several indications in publicly available bioinformatic datasets, suggesting combinations with adenosine pathway antagonists in ccRCC and beyond. In summary, AB521 is a novel and selective HIF-2α inhibitor with potent anti-tumor activity. Clinical evaluation of this molecule is expected to begin in the latter part of 2021. Citation Format: Kelsey E. Sivick Gauthier, Dana Piovesan, Soonweng Cho, Kenneth V. Lawson, Patrick G. Schweickert, Alejandra Lopez, Suan Liu, Timothy Park, Artur Mailyan, Jeremy T. A. Fournier, Joel W. Beatty, Samuel L. Drew, Jarek Kalisiak, Balint Gal, Guillaume Mata, Zhang Wang, Brandon R. Rosen, Clayton Hardman, Matthaw P. Epplin, Kai Yu, Karl T. Haelsig, Lixia Jin, Elaine Ginn, Jennie Au, Cesar A. Meleza, Joel Tencer, Amber Pham, Hyock J. Kwon, Stephen W. Young, Manmohan Leleti, Jay P. Powers, Matthew J. Walters. AB521 potently and selectively inhibits pro-tumorigenic gene transcription by Hypoxia-Inducible Factor (HIF)-2α in vitro and in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P206.

A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.

Distributed acoustic sensing technology is increasingly being used to support production and well management within the oil and gas sector, for example to improve flow monitoring and production profiling. This sensing technology is capable of recording substantial data volumes at multiple depths within an oil well, giving unprecedented insights into production behaviour. However the technology is also prone to recording periods of anomalous behaviour, where the same physical features are concurrently observed at multiple depths. Such features are called ‘stripes’ and are undesirable, detrimentally affecting well performance modelling. This paper focuses on the important challenge of developing a principled approach to identifying such anomalous periods within distributed acoustic signals. We extend recent work on classifying locally stationary wavelet time series to an online setting and, in so doing, introduce a computationally-efficient online procedure capable of accurately identifying anomalous regions within multivariate time series.

Within the Oil and Gas industry the use of Acoustics data for flow rate estimation is increasingly being explored. One technique is to consider the total spectral power of the signal within a specific frequency range, known as an FBE. The FBE, along with measured Flow rates, can then be used to build a simple regression model to estimate the flow rate. We collect acoustic data using Distributed Acoustic Sensing, DAS, and find that the recorded FBE generally contains some corrupted data and outliers. This may be due to well shut-in periods or other physical phenomena, or it may be due to issues in the DAS recording itself. These outliers can have a detrimental effect on the calibration of any predictive model and lead to biased flow predictions. We combat this by calibrating out model using Robust Regression techniques, such as Least Absolute Deviation, which are less influenced by outliers. Another practical concern is choosing the correct frequency band for the FBE. This can be done by evaluating the model performance on a training set, however we find that the signal quality within a band can diminish over time necessitating a change in the band used. Our challenge is to find a way to identify when a band is likely to be giving poor predictions. We do this by looking at the ratios between different FBE bands, we find that under normal conditions these are highly correlated, however for certain bands this correlation is lost over time. This can be used to determine when it is time to switch to use a different band. This paper contains the motivation and results of these techniques as they are applied to flow prediction in a gas producing well which has been part of a long-term flow monitoring project.

Long-term collection of data and samples appears critical to contribute to our understanding of the impacts of fisheries and climate change on the marine ecosystems, and for the implementation of management measures for sustainable use of the resources. In the western and central Pacific Ocean, the source of 50% of the worldwide tuna catches, several tools have been implemented to monitor the fisheries and the tuna pelagic ecosystem. Since the 1990’s fisheries observers of 15 Pacific Island countries, which are now operating under a regional standardised framework, collect data on fishing effort, catch and bycatch to monitor, among others, changes in biodiversity. This network of 800 observers also collect biological samples (stomachs, muscles, otoliths…) that constitute a biological tissue bank of pelagic fish with more than 95000 samples available to scientists for biological studies. Since the 1970’s tuna tagging programmes have been implemented to monitor the fishing pressure and tuna movements and growth. Fishing-independent data have also been collected during scientific cruises to monitor the lower levels of the trophic web. These multiple initiatives at the scale of half of the Pacific represent a unique opportunity to understand the impact of fisheries and climate change on the tuna ecosystem.

Operators of Oil & Gas assets have long struggled with the issue of managing so-called "safety stocks" of spare part inventory. Within Shell, this problem sits within the materials management discipline whichcovers the ordering, storage and utilisation of material assets such as subsea facility equipment or pipeline parts. Across all assets globally, Shell carries a huge stock of such items which ties up large quantities of working capital. Observations over time have noted significant issues such as unrealistic supplier lead times, rising inventory levels and associated carrying cost for some assets, andincreasing demands on warehouse space in certain locations. In response to these challenges, over the past 2 years an interdisciplinary project team has produced a tool, based on advanced analytical methods, that helps assets optimise stock levels and purchase strategies. This approach reduces the risk of deferment due to stock outs and prevents excessive stock carrying costs. It also supports on-time execution of maintenance schedules and so helps to maximise asset uptime.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is less invasive than emergency department thoracotomy for the treatment of massive hemorrhage. We evaluated the effects of REBOA on carotid blood flow (Qcarotid) in a porcine model of massive hemorrhage. We hypothesized that REBOA restores Qcarotid faster than reinfusion of blood.Spontaneously breathing sedated Sinclair pigs underwent exponential hemorrhage of 65% total blood volume in 1 hour. They were randomized into three groups. Positive control (PC, n = 7) underwent immediate transfusion of shed blood. REBOA (n = 21) received a novel 7 Fr ER-REBOA catheter (Pryor Medical, Arvada, CO) placed into aortic Zone 1 via a femoral artery introducer for 30 minutes or 60 minutes, with transfusion either after deflation or midway through inflation. Negative control (n = 7) received no resuscitation. Qcarotid was recorded continuously using an ultrasonic flow probe. Survival and time between Qcarotid, min and both a stable maximal value (Qcarotid, max) and restoration of baseline flow (Qcarotid, new BL) were compared by Kaplan-Meier analysis.Median time to Qcarotid, max was 3.0 minutes in the REBOA group versus 9.6 minutes in the control group (p = 0.006). Median time to Qcarotid, new BL was 6.0 minutes in the REBOA group versus 20.5 minutes in the PC group (p = 0.11). Slope of the linear regression between Qcarotid, min and Qcarotid, new BL was 16.7 in REBOA and 10.4 in PC (p = 0.31). Four-hour survival was 95% (20 of 21) in the REBOA group versus 71% (5 of 7) in the PC group (p = 0.06) and 0% in the negative control group.REBOA resulted in the restoration of Qcarotid ("cerebrovascular resuscitation") at least as rapidly as retransfusion of shed blood, with equivalent 4-hour survival. Further studies of REBOA, to include mitigation of end-organ effects and longer follow-up, are needed.

In this paper, we will share the recent work that was done to understand how bulk flow rates and fluid composition may be derived in single-phase and multi-phase flow by tracking the slopes (velocities) of coherent features detected using Distributed Acoustic Sensing (DAS). Both laboratory experiments and real field examples will be presented to demonstrate how velocity features can be detected and attributed to events such as slug flow or sound waves. Speed of Sound (SoS) analysis can in principle be used for determining changes in the fluid composition in multiphase flows, which provides opportunities to detect fluid interfaces and water or gas breakthrough. On the other hand, slowly moving features such as slugs or turbulent eddies can be used to derive bulk flow velocities, which may be used for injection or production profiling. The evaluation method directly derives velocities by Fourier transforming the raw DAS data in the temporal and spatial domains without applying any calibration steps. It can therefore be used to monitor flow in wells on a drive-by or continuous basis without a need for reference flow data.

We consider the problem of estimating time-localized cross-dependence in a collection of nonstationary signals. To this end, we develop the multivariate locally stationary wavelet framework, which provides a time-scale decomposition of the signals and, thus, naturally captures the time-evolving scale-specific cross-dependence between components of the signals. Under the proposed model, we rigorously define and estimate two forms of cross-dependence measures: wavelet coherence and wavelet partial coherence. These dependence measures differ in a subtle but important way. The former is a broad measure of dependence, which may include indirect associations, i.e., dependence between a pair of signals that is driven by another signal. Conversely, wavelet partial coherence measures direct linear association between a pair of signals, i.e., it removes the linear effect of other observed signals. Our time-scale wavelet partial coherence estimation scheme thus provides a mechanism for identifying hidden dynamic relationships within a network of nonstationary signals, as we demonstrate on electroencephalograms recorded in a visual–motor experiment.

BACKGROUND: Recently, automated alerts have been used to identify patients with respiratory failure based on set criteria, which can be gleaned from the electronic medical record (EMR). Such an approach may also be useful for identifying patients with severe adult respiratory distress syndrome (ARDS) who may benefit from extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (iNO) is a common rescue therapy for severe ARDS which can be easily tracked in the EMR, and some patients started on iNO may have indications for initiating ECMO. This case series summarizes our experience with using automated electronic alerts for ECMO team activation focused particularly on an alert triggered by the initiation of iNO. METHODS: After a brief trial evaluation, our Smart Alert system generated an automated page and e-mail alert to ECMO team members whenever a nonzero value for iNO appeared in the respiratory care section of our EMR. If iNO was initiated for severe respiratory failure, a detailed evaluation by the ECMO team determined if ECMO was indicated. For those patients managed with ECMO, we tabulated baseline characteristics, indication for ECMO, and outcomes. RESULTS: From September 2012 to July 2013, 45 iNO alerts were generated on 42 unique patients. Six patients (14%) met criteria for ECMO. Of these, four were identified exclusively by the iNO alert. At the time of the alert, the median PaO2-to-FIO2 ratiowas 64 mm Hg (range, 55-107 mm Hg), the median age-adjusted oxygenation index was 73 (range, 51-96), and the median Murray score was 3.4 (range, 3-3.75), indicating severe respiratory failure. Median time from iNO alert to ECMO initiation was 81 hours (range, -2 to 292 hours). Survival to hospital discharge was 83% in those managed with ECMO. CONCLUSION: Automated alerts may be useful for identifying patients with severe ARDS who may be ECMO candidates.

Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy but cause high incidence of angioedema. We examined whether dual inhibition of angiotensin AT1 receptor (ARB) and NEP (ARB-NEPI, valsartan-candoxatril) provides similar efficacy to omapatrilat without the risk of angioedema. Activity of test compounds at the targets was assayed using fluorescence-based enzyme assays (ACE, NEP, aminopeptidase P) or competition binding assays (AT1). Target engagement in vivo (ACE, AT1, and NEP) was quantified by measuring inhibition of angiotensin-pressor responses and potentiation of atrial natriuretic peptide-induced urinary cyclic guanosine monophosphate (cGMP) output in rats. Tracheal plasma extravasation (TPE) was used as a surrogate to assess propensity of compounds to promote upper airway angioedema. Antihypertensive efficacy in renin-dependent and -independent states was measured in spontaneously hypertensive rats and deoxycorticosterone acetate salt hypertensive rats, respectively. Administration of omapatrilat and coadministration of valsartan and candoxatril blocked angiotensin induced vasopressor responses and potentiated atrial natriuretic peptide-induced increase in urinary cGMP output. In spontaneously hypertensive rats, valsartan, omapatrilat, and valsartan-candoxatril combination all produced reduction in blood pressure to a similar extent, whereas candoxatril was ineffective. In deoxycorticosterone acetate rats, omapatrilat, candoxatril, and valsartan-candoxatril combination but not valsartan produced reduction in blood pressure. Antihypertensive doses of omapatrilat produced robust increases in TPE; by contrast, valsartan, candoxatril, or their combination did not increase TPE. Pretreatment with icatibant, a bradykinin B2 antagonist, abolished omapatrilat-induced TPE but not its antihypertensive effects. On the background of NEP inhibition, suppression of the renin-angiotensin system through ARB and ACE inhibition shows a similar antihypertensive efficacy but exerts differential effects on bradykinin metabolism and TPE indicative of reduced risk of angioedema. Thus, dual AT1 receptor blockade and NEP inhibition is potentially an attractive approach to retain the excellent antihypertensive effects of omapatrilat but with a superior safety profile.

Learning Objectives: Heart-rate-complexity (HRC) calculated off-line was associated with injury severity, mortality, and the performance of life-saving interventions in animal and human studies. We hypothesized that real-time automatic HRC measurements by the Aesculon monitor (Cardiotronic-Osypka Medical, USA) are associated with hemodynamic status and mortality. Methods: Spontaneously breathing consciously sedated swine were shed 65% of blood volume over 1 hour, then were randomized to 3 groups: control (C, n=7); transfusion of shed blood (TSB, n=7); or endovascular balloon occlusion of the aorta (REBOA) (Pryor Medical, Arvada, CO) for up to 60 minutes followed by TSB (n=21). Epinephrine boluses were given if mean arterial pressure (MAP) 40 mmHg in the TSB and REBOA groups. After resuscitative interventions, animals were followed for 240 min or death. Aesculon monitor performed continuous, real-time measurements of HRC, i.e. sample entropy (SampEn) and multiscale entropy (MSE). At 30 minutes after all interventions, heart rate (HR), MAP, Lactate (Lac), and HRC metrics were assessed for their association with death using logistic regression and receiver-operating-characteristic (ROC) curve analysis. Results: All animals died in group C, 2/7 in group TSB, and 1/21 in group REBOA. SampEn and MSE decreased with hemorrhage and increased after interventions (TSB or REBOA+TSB). After resuscitative interventions, HRC metrics individually were associated with death: SampEn p=0.0002, area under the curve (AUC) =.88; MSE p=0.002, AUC=.83; both SampEn and MSE together p=0.0005, AUC=.90. Traditional vital signs were also associated with death: HR, p=0.02, AUC .72; MAP, p=0.01, AUC .85; Lac p=0.05, AUC=.69; and for all three metrics together p0.03, AUC=0.85. When traditional and HRC variables were combined into a single model the overall AUC was .93, p=0.003.

Learning Objectives: Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) using generic balloon catheters placed into the descending aorta under fluoroscopy has been used to treat hemorrhagic shock in animal models. We tested a new non-image guided 7F ER-REBOA catheter (Pryor Medical Arvada, CO) for its potential to improve survival in a 100% lethal model of hemorrhagic shock. We hypothesized that ER-REBOA, placed without fluoroscopic guidance, improves survival. Methods: Spontaneously breathing, consciously sedated, sexually mature male Sinclair pigs undergone computerized exponential hemorrhage of 65% of their blood volume over 1 hour via an arterial line. Animals were then randomized into groups of 7 animals each including: negative control (NC), no resuscitation; positive control (PC), immediate transfusion of shed blood (TSB); ER30; 30 min of ERREBOA then TSB; ER60, 60 min of ER-REBOA then TSB; ER, 60 min of ERREBOA with TSB after 30 min of REBOA. After balloon deflation, epinephrine was given if mean arterial pressure was under 40 mm Hg. Up to 20 min of mechanical ventilation (FiO2 .21, RR 12, TV 10 ml/kg, ZEEP) was provided if animal suffered respiratory arrest. Animals were monitored for 240 min post-hemorrhage or until death. Survival was assessed via Kaplan-Meier analysis. Balloon placement was verified via post-mortem CT scan and at necropsy. Results: ER-REBOA was placed successfully in 100% of cases without fluoroscopy. Survival in the NC and PC groups was 0 and 71% respectively. Analysis showed significantly higher survival in the ER-REBOA groups: 100% in ER30 and ER60 groups and 86% in ER (p0.001). Epinephrine was given to 4/7 PC animals and to 6/7, 7/7, and 2/7 animals in ER30, ER60, and ER groups respectively. Ventilation support was given to 1/7, 2/7, and 3/7 in the ER30, ER60, and ER groups and to 2/7 in the PC group respectively.

We report a case of diffuse endobronchial polyps contributing to continued respiratory failure in a patient 5 wk after titanium tetrachloride inhalation injury. After the institution of corticosteroid therapy, the total number and size of remaining polyps were markedly reduced at which time the subject was successfully weaned from the ventilator. Follow-up bronchoscopy at 2 months, 5 months, and 1 yr postinjury revealed gradual but complete resolution of all polyps accompanied by improvement in the patient’s obstructive airways disease. This delayed complication of inhalation injury has been previously reported as a complication of thermal respiratory injury, and may be an important contributing factor in prolonged or late respiratory failure in burn patients.

The rise of super-centers and the entry of Wal-Mart into food retailing have dramatically altered the competitive environment in the industry. This paper explores the impact of such changes on the labor market practices of traditional food retailers. We use longitudinal data on workers and firms to construct new measures of compensation and employment, and examine how these measures evolve within and across firms in response to changes in product market structure. An additional feature of the analysis is to combine rich case study knowledge about the retail food industry with the new matched employer-employee data from the Census Bureau.