Dynamic Aortic Pressure Augmentation as a Novel Method of Swine Terminal Blood Extraction.

INTRODUCTION: Uncontrolled hemorrhage models require sufficient quantities of donor blood products to support resuscitation. To that end, we describe a novel method of whole blood extraction from donor swine using resuscitative endovascular balloon occlusion of the aorta (REBOA) to support hemodynamics during terminal blood extraction and its impact on the quality of banked blood. METHODS: Ten adult Yorkshire-cross swine were anesthetized and instrumented with an REBOA catheter, femoral multistage venous cannula, and proximal/distal blood pressure monitoring. Hemodynamics during terminal blood extraction was supported with hand-titrated partial REBOA. Blood samples were taken at set time points for analysis. RESULTS: The median collected blood volume was 3912 mL, with all animals surviving through the planned blood collection of 60% estimated total blood volume (ETBV). Median lactate and potassium levels remained within normal limits for swine through collection of 40% of the ETBV. Median hemoglobin through collection of 40% ETBV did not significantly change from values measured at the start of hemorrhage. CONCLUSIONS: This method of whole blood extraction provided sufficient blood volume and blood quality appropriate for transfusion through 40% ETBV, with remaining collected blood likely still acceptable for allogeneic transfusion despite increased lactate levels. This method of whole blood extraction can efficiently provide a large volume of quality blood to support resuscitation for subsequent uncontrolled hemorrhage models.

Supervised discretization for decluttering classification models.

Presented here is the first demonstration of supervised discretization to 'declutter' multivariate classification data in chemical sensor applications. The performance of multivariate classification models is often limited by the non-informative chemical variance within each target class; decluttering methods seek to reduce within-class variance while retaining between-class variance. Supervised discretization is shown to declutter classes in a manner that is superior to the state-of-the-art External Parameter Orthogonalization (EPO) by constructing a more parsimonious model with fewer parameters to optimize and is, consequently, less susceptible to overfitting and information loss. The comparison of supervised discretization and EPO is performed on three classification applications: X-ray fluorescence spectra of pine ash where the pine was grown in three distinct soil types, laser induced breakdown spectroscopy of colored artisanal glasses, and laser induced breakdown spectroscopy of exotic hardwood species.

Endovascular Perfusion Augmentation After Resuscitative Endovascular Balloon Occlusion of the Aorta Improves Renal Perfusion and Decreases Vasopressors.

INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) causes a severe ischemia-reperfusion injury. Endovascular Perfusion Augmentation for Critical Care (EPACC) has emerged as a hemodynamic/mechanical adjunct to vasopressors and crystalloid for the treatment of post-REBOA ischemia-reperfusion injury. The objective of the study is to examine the impact of EPACC as a tool for a wean from complete REBOA compared to standard resuscitation techniques. METHODS: Nine swine underwent anesthesia and then a controlled 30% blood volume hemorrhage with 30 min of supraceliac total aortic occlusion to create an ischemia-reperfusion injury. Animals were randomized to standardized critical care (SCC) or 90 min of EPACC followed by SCC. The critical care phase lasted 270 min after injury. Hemodynamic markers and laboratory values of ischemia were recorded. RESULTS: During the first 90 min the intervention phase SCC spent 60% (54%-73%) and EPACC spent 91% (88%-92%) of the time avoiding proximal hypotension (<60 mm Hg), P = 0.03. There was also a statistically significant decrease in cumulative norepinephrine dose at the end of the experiment between SCC (80.89 mcg/kg) versus EPACC (22.03 mcg/kg), P = 0.03. Renal artery flow during EPACC was similar compared to SCC during EPACC, P = 0.19. But during the last hour of the experiment (after removal of aortic balloon) the renal artery flow in EPACC (2.9 mL/kg/min) was statistically significantly increased compared to SCC (1.57 mL/min/kg), P = 0.03. There was a statistically significant decrease in terminal creatinine in the EPACC (1.7 mg/dL) compared to SCC (2.1 mg/dL), P = 0.03. CONCLUSIONS: The 90 min of EPACC as a weaning adjunct in the setting of a severe ischemia-reperfusion injury after complete supraceliac REBOA provides improved renal flow with improvement in terminal creatinine compared to SCC with stabilized proximal hemodynamics and decreased vasopressor dose.

Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells.

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) 'knockout' (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid ß-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including 'respiratory electron transport' and 'formation of ATP by chemiosmotic coupling' increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII2/CIV and CI/CIII2/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency.

Selective Lobe Ventilation and a Novel Platform for Pulmonary Drug Delivery.

The current methods of mechanical ventilation and pulmonary drug delivery do not account for the heterogeneity of acute respiratory distress syndrome or its dependence on gravity. The severe lung disease caused by severe acute respiratory distress syndrome coronavirus 2, coronavirus disease 2019, is one of the many causes of acute respiratory distress syndrome. Severe acute respiratory distress syndrome coronavirus 2 has caused more than three million deaths worldwide and has challenged all therapeutic options for mechanical ventilation. Thus, new therapies are necessary to prevent deaths and long-term complications of severe lung diseases and prolonged mechanical ventilation. The authors of the present report have developed a novel device that allows selective lobe ventilation and selective lobe recruitment and provides a new platform for pulmonary drug delivery. A major advantage of separating lobes that are mechanically heterogeneous is to allow for customization of ventilator parameters to match the needs of segments with similar compliance, a better overall ventilation perfusion relationship, and prevention of ventilator-induced lung injury of more compliant lobes. This device accounts for lung heterogeneity and is a potential new therapy for acute lung injury by allowing selective lobe mechanical ventilation using two novel modes of mechanical ventilation (differential positive end-expiratory pressure and asynchronous ventilation), and two new modalities of alveolar recruitment (selective lobe recruitment and continuous positive airway pressure of lower lobes with continuous ventilation of upper lobes). Herein the authors report their initial experience with this novel device, including a brief overview of device development; the initial in vitro, ex vivo, and in vivo testing; layout of future research; potential benefits and new therapies; and expected challenges before its uniform implementation into clinical practice.

Pediatric orbital floor fractures and the oculocardiac reflex: Experience from a level I trauma center.

PURPOSE: The purpose of this study is to determine whether bradycardia associated with the oculocardiac reflex is a significant source of morbidity in the post injury period following orbital floor fractures in children. MATERIALS/METHODS: A retrospective review of all pediatric patients who presented to our emergency department with an orbital floor fracture from May 1, 2016 to June 1, 2018 were included. Basic demographic data was collected as well as mechanism of injury, presence of bradycardia, and time to operating room. Morbidity was based on the need for medications to treat bradycardia. RESULTS: Thirty-five pediatric patients with orbital floor fractures were reviewed. 6 (17.1%) patients had post injury bradycardia, with one patient requiring medication to stabilize their heart rate. There was no statistically significant difference in sex, race/ethnicity, or age in patients with or without bradycardia (p > 0.05) however there was a significant relationship between bradycardia and need for operative repair (X2 = 7.88, df = 1, p = 0.005). The most common mechanism of injury was motor vehicle collision (45.7%). The average time to the operating room was 145 h (6.04 days). CONCLUSIONS: While activation of the oculocardiac reflex is a legitimate concern in the post injury period, there is unlikely to be significant morbidity due to bradycardia, and the greater concern should be for the ischemic muscle injury incurred from the fracture.

Assessing utility of handheld laser induced breakdown spectroscopy as a means of Dalbergia speciation.

Many species of Dalbergia are prized hardwoods, generally referred to as 'Rosewood,' and used in high-end products due to their distinctive hue and scent. Despite more than 58 species of Dalbergia being listed as endangered in Appendix 1 of The Convention on International Trade in Endangered Species of Fauna and Flora (CITES), the illegal logging and trade of this timber is ongoing. In this work, a handheld laser induced breakdown spectrometer (LIBS) was used to analyze seven Dalbergia species and two other exotic hardwood species to evaluate the ability of handheld LIBS for rapid classification of Dalbergia in the field. The KNN model of the classification presented 80% to 90% sensitivity for discriminating between Dalbergia species in the training set. PLS-DA models were based on a binary decision tree structure. Cumulatively, the PLS-DA decision tree model showed greater than 97% sensitivity and 99% selectivity for prediction of Dalbergia species included in the training set. The data presented in the following study are promising for the use of handheld LIBS devices and both KNN and PLS-DA models for applications in customs screenings at the port of entry of hard woods, among others.

dbl-1/TGF-ß and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest.

Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-ß, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-ß and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-ß, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-ß and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-ß and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

Changes in illicit cocaine hydrochloride processing identified and revealed through multivariate analysis of cocaine signature data.

For nearly 30years, the methods utilized in illicit cocaine hydrochloride production have remained relatively consistent. Cocaine hydrochloride is typically produced one kilogram at a time. As a result, each individual kilogram is unique and distinct from other kilograms in any particular seizure based on the total alkaloid profile, occluded solvent profile, and isotopic signature. Additionally, multi-kilogram cocaine seizures are often comprised of cocaine from several different coca growing regions. There has been a documented shift in this type of processing based on the recent analysis of a large cocaine seizure in the Eastern Pacific. Signature analyses of samples from 21kg randomly selected from a 517kg seizure were virtually identical. Triplicate analyses of each sample via gas chromatography with flame ionization detection, static headspace gas chromatography mass spectrometry, and isotope ratio mass spectrometry were completed. An initial outlier evaluation of the data and an in-depth univariate analysis indicated there was no statistically significant difference among the 21 samples at the 95% confidence interval. Principal components analysis did reveal consistent minor deviations between the samples and known authentic data from the Nariño coca growing region of Colombia. These deviations were only observed on the latter principal components and could be explained by differences in solvent selection during cocaine hydrochloride processing. Chemical analyses in addition to a thorough statistical evaluation suggest a shift in the traditional small-batch method of cocaine processing to a multi-kilogram, high throughput approach.

Timing of adding blood to prime affects inflammatory response to neonatal cardiopulmonary bypass.

Complications from systemic inflammation are reported in neonates following exposure to cardiopulmonary bypass. Although the use of asanguinous primes can reduce these complications, in neonates, this can result in significant haemodilution, requiring addition of blood. This study investigates whether the addition of blood after institution of bypass alters the inflammatory response compared with a blood prime. Neonatal swine were randomised into four groups: blood prime, blood after bypass but before cooling, blood after cooling but before low flow, and blood after re-warming. All groups were placed on central bypass, cooled, underwent low flow, and then re-warmed for a total bypass time of 2 hours. Although haematocrit values between groups varied throughout bypass, all groups ended with a similar value. Although they spent time with a lower haematocrit, asanguinous prime groups did not have elevated lactate levels at the end of bypass compared with blood prime. Asanguinous primes released less tumour necrosis factor α than blood primes (p=0.023). Asanguinous primes with blood added on bypass produced less interleukin 10 and tumour necrosis factor α (p=0.006, 0.019). Animals receiving blood while cool also showed less interleukin 10 and tumour necrosis factor α production than those that received blood warm (p=0.026, 0.033). Asanguinous primes exhibited less oedema than blood primes, with the least body weight gain noted in the end cool group (p=0.011). This study suggests that using an asanguinous prime for neonates being cooled to deep hypothermia is practical, and the later addition of blood reduces inflammation.

Mechanical tissue resuscitation (MTR): a nonpharmacological approach to treatment of acute myocardial infarction.

BACKGROUND AND AIM: Myocardial ischemia-reperfusion injury is known to trigger an inflammatory response involving edema, apoptosis, and neutrophil activation/accumulation. Recently, mechanical tissue resuscitation (MTR) was described as a potent cardioprotective strategy for reduction of myocardial ischemia-reperfusion injury. Here, we further describe the protective actions of MTR and begin to define its therapeutic window. METHODS: A left ventricular, free-wall ischemic area was created in anesthetized swine for 85 minutes and then reperfused for three hours. Animals were randomized to two groups: (1) untreated controls (Control) and (2) application of MTR that was delayed 90 minutes after the initiation of reperfusion (D90). Hemodynamics and regional myocardial blood flow were assessed at multiple time points. Infarct size and neutrophil accumulation were assessed following the reperfusion period. In separate cohorts, the effect of MTR on myocardial interstitial water (MRI imaging) and blood flow was examined. RESULTS: Both groups had similar areas at risk (AAR), hemodynamics, and arterial blood gas values. MTR, even when delayed 90 minutes into reperfusion (D90, 29.2 ± 5.0% of AAR), reduced infarct size significantly compared to Controls (51.9 ± 2.7%, p = 0.006). This protection was associated with a 33% decrease in neutrophil accumulation (p = 0.047). Improvements in blood flow and interstitial water were also observed. Moreover, we demonstrated that the therapeutic window for MTR lasts for at least 90 minutes following reperfusion. CONCLUSIONS: This study confirms our previous observations that MTR is an effective therapeutic approach to reducing reperfusion injury with a clinically useful treatment window.

Succinylated octopamine ascarosides and a new pathway of biogenic amine metabolism in Caenorhabditis elegans.

The ascarosides, small-molecule signals derived from combinatorial assembly of primary metabolism-derived building blocks, play a central role in Caenorhabditis elegans biology and regulate many aspects of development and behavior in this model organism as well as in other nematodes. Using HPLC-MS/MS-based targeted metabolomics, we identified novel ascarosides incorporating a side chain derived from succinylation of the neurotransmitter octopamine. These compounds, named osas#2, osas#9, and osas#10, are produced predominantly by L1 larvae, where they serve as part of a dispersal signal, whereas these ascarosides are largely absent from the metabolomes of other life stages. Investigating the biogenesis of these octopamine-derived ascarosides, we found that succinylation represents a previously unrecognized pathway of biogenic amine metabolism. At physiological concentrations, the neurotransmitters serotonin, dopamine, and octopamine are converted to a large extent into the corresponding succinates, in addition to the previously described acetates. Chemically, bimodal deactivation of biogenic amines via acetylation and succinylation parallels posttranslational modification of proteins via acetylation and succinylation of L-lysine. Our results reveal a small-molecule connection between neurotransmitter signaling and interorganismal regulation of behavior and suggest that ascaroside biosynthesis is based in part on co-option of degradative biochemical pathways.

Mechanical tissue resuscitation protects against myocardial ischemia-reperfusion injury.

BACKGROUND AND AIM: Reperfusion injury is a complex inflammatory response involving numerous mechanisms and pathways. Mechanical tissue resuscitation is a newly described therapeutic strategy that reduces reperfusion injury. This study further investigates potential mechanisms for the protective effects of mechanical tissue resuscitation while utilizing a bio-absorbable matrix. METHODS: Anesthetized swine were subjected to 80 minutes of coronary ischemia and three hours of reperfusion. An absorbable matrix was used to cover the ischemic-reperfused myocardium and apply the mechanical tissue resuscitation (-50 mmHg) throughout reperfusion. Infarct size, myocardial blood flow (microspheres), apoptosis, edema, and hemodynamics were analyzed. RESULTS: Both control and treated groups displayed similar hemodynamics and physiologic parameters. Mechanical tissue resuscitation significantly reduced early infarct size (16.6 ± 3.8% vs. 27.3 ± 2.5% of area at risk, p < 0.05). This reduction of infarct size was accompanied by reduced edema formation in both epicardial (27% reduction) and endocardial (58% reduction) samples. Histological examination of both epicardial and endocardial tissues also revealed a reduction in apoptosis (80% and 44% reductions) in MTR-treated hearts. CONCLUSIONS: Treatment with mechanical tissue resuscitation during reperfusion reduces both early cell death and the delayed, programmed cell death after ischemia-reperfusion. This cardioprotection is also associated with a significant reduction in interstitial water. Additional cardioprotection may be derived from mechanical tissue resuscitation-induced increased blood flow. Mechanical tissue resuscitation, particularly with a resorbable device, is a straightforward and efficacious mechanical strategy for decreasing cardiomyocyte death following myocardial infarction as an adjunctive therapy to surgical revascularization.

Evaluation of a software system for estimating planned dose error in patients, based on planar IMRT QA measurements.

BACKGROUND: Intensity modulated radiation therapy (IMRT) dosimetry verification is routinely conducted via integrated or individual field dosimetry using film or a matrix of detectors. Techniques and software systems are commercially available which use individual field dosimetry measurements as input into algorithms that estimate 3D patient dose distributions on CT scan derived target volumes and organs at risk (OARs), thus allowing direct dose-volume histogram (DVH) analysis vs. treatment planning system (TPS) DVH. The purpose of this work is to present a systematic benchmarking technique to evaluate the accuracy and consistency of such a software system. METHODS: A MapCheck2 diode array and 3DVH™ software from Sun Nuclear were used for this study. Delivered planar dose was measured with the diode array as an input to 3DVH™ software that was used to estimate the 3D dose matrix. Accuracy of the output of 3DVH™ is tested by comparing measured planar doses over a range of depths to the same planes reconstructed by 3DVH™. Different fields from complex IMRT cases were selected and examined in this study. The sensitivity to depth of measurement was evaluated. RESULTS: The Gamma Index analysis, comparing calculated 3D dose with measured 3D dose with 2% and 2mm distance-to-agreement (DTA) criteria returned a pass rate of > 90% for all patient cases calculated by the treatment planning system and it returned a pass rate of > 96% in 9 out of 10 cases calculated by 3DVH™. Extracted computed dose planes with 3DVH™ software at different depths in the flat phantom passed all gamma evaluation analyses when compared to measured planes at different depths using MapCheck2. CONCLUSIONS: Studying complex head and neck IMRT fields, it was shown that the 3D dose distribution predicted by the planned dose perturbation (PDP) algorithm is both accurate and consistent.

First Dorsal Compartment Release During Volar Approach for Distal Radius Fracture Fixation Reduces Symptoms in Patients With Pre-Existing De Quervain Disease.

Purpose: Release of the first dorsal compartment is a described technique during volar approach for distal radius fracture fixation. Our objective was to determine whether release of the first dorsal compartment during volar approach for distal radius fracture fixation impacted corresponding symptoms in pre-existing de Quervain disease. Methods: A prospective, randomized cohort study was performed with patients grouped for release (release group) or no release (control group) of the first dorsal compartment during volar approach for distal radius fracture fixation. Inclusion required a confirmed diagnosis of de Quervain disease within the 12 months preceding a distal radius fracture. Results: Patients in the release group were significantly less symptomatic than those in the control group at 3 and 6 months after surgery. Lateral pinch strength in the release group was significantly greater than that in the control group at 3 and 6 months after surgery. Conclusions: The current results demonstrated a significantly greater reduction in de Quervain disease symptoms in the release group compared with the no release group during the short-term follow-up. This indicates that routine first dorsal compartment release during distal radius fracture fixation may expedite symptom relief in patients with de Quervain disease. Type of study/level of evidence: Therapeutic I.

INVESTIGATING THE RELATIONSHIP BETWEEN BLEEDING, CLOTTING, AND COAGULOPATHY DURING AUTOMATED PARTIAL REBOA STRATEGIES IN A HIGHLY LETHAL PORCINE HEMORRHAGE MODEL.

ABSTRACT: Background: Death due to hemorrhagic shock, particularly, noncompressible truncal hemorrhage, remains one of the leading causes of potentially preventable deaths. Automated partial and intermittent resuscitative endovascular balloon occlusion of the aorta (i.e., pREBOA and iREBOA, respectively) are lifesaving endovascular strategies aimed to achieve quick hemostatic control while mitigating distal ischemia. In iREBOA, the balloon is titrated from full occlusion to no occlusion intermittently, whereas in pREBOA, a partial occlusion is maintained. Therefore, these two interventions impose different hemodynamic conditions, which may impact coagulation and the endothelial glycocalyx layer. In this study, we aimed to characterize the clotting kinetics and coagulopathy associated with iREBOA and pREBOA, using thromboelastography (TEG). We hypothesized that iREBOA would be associated with a more hypercoagulopathic response compared with pREBOA due to more oscillatory flow. Methods: Yorkshire swine (n = 8/group) were subjected to an uncontrolled hemorrhage by liver transection, followed by 90 min of automated pREBOA, iREBOA, or no balloon support (control). Hemodynamic parameters were continuously recorded, and blood samples were serially collected during the experiment (i.e., eight key time points: baseline (BL), T0, T10, T30, T60, T90, T120, T210 min). Citrated kaolin heparinase assays were run on a TEG 5000 (Haemonetics, Niles, IL). General linear mixed models were employed to compare differences in TEG parameters between groups and over time using STATA (v17; College Station, TX), while adjusting for sex and weight. Results: As expected, iREBOA was associated with more oscillations in proximal pressure (and greater magnitudes of peak pressure) because of the intermittent periods of full aortic occlusion and complete balloon deflation, compared to pREBOA. Despite these differences in acute hemodynamics, there were no significant differences in any of the TEG parameters between the iREBOA and pREBOA groups. However, animals in both groups experienced a significant reduction in clotting times (R time: P < 0.001; K time: P < 0.001) and clot strength (MA: P = 0.01; G: P = 0.02) over the duration of the experiment. Conclusions: Despite observing acute differences in peak proximal pressures between the iREBOA and pREBOA groups, we did not observe any significant differences in TEG parameters between iREBOA and pREBOA. The changes in TEG profiles were significant over time, indicating that a severe hemorrhage followed by both pREBOA and iREBOA can result in faster clotting reaction times (i.e., R times). Nevertheless, when considering the significant reduction in transfusion requirements and more stable hemodynamic response in the pREBOA group, there may be some evidence favoring pREBOA usage over iREBOA.

Insulin/IGF-dependent Wnt signaling promotes formation of germline tumors and other developmental abnormalities following early-life starvation in Caenorhabditis elegans.

The Developmental Origins of Health and Disease hypothesis postulates that early-life stressors can predispose people to disease later in life. In the roundworm Caenorhabditis elegans, prolonged early-life starvation causes germline tumors, uterine masses, and other gonad abnormalities to develop in well-fed adults. Reduction of insulin/insulin-like growth factor (IGF) signaling (IIS) during larval development suppresses these starvation-induced abnormalities. However, molecular mechanisms at play in formation and suppression of starvation-induced abnormalities are unclear. Here we describe mechanisms through which early-life starvation and reduced IIS affect starvation-induced abnormalities. Transcriptome sequencing revealed that expression of genes in the Wnt signaling pathway is upregulated in adults starved as young larvae, and that knockdown of the insulin/IGF receptor daf-2/InsR decreases their expression. Reduction of Wnt signaling through RNAi or mutation reduced starvation-induced abnormalities, and hyperactivation of Wnt signaling produced gonad abnormalities in worms that had not been starved. Genetic and reporter-gene analyses suggest that Wnt signaling acts downstream of IIS in the soma to cell-nonautonomously promote germline hyperproliferation. In summary, this work reveals that IIS-dependent transcriptional regulation of Wnt signaling promotes starvation-induced gonad abnormalities, illuminating signaling mechanisms that contribute to adult pathology following early-life starvation.

Early-life starvation alters lipid metabolism in adults to cause developmental pathology in Caenorhabditis elegans.

Early-life malnutrition increases adult disease risk in humans, but the causal changes in gene regulation, signaling, and metabolism are unclear. In the roundworm Caenorhabditis elegans, early-life starvation causes well-fed larvae to develop germline tumors and other gonad abnormalities as adults. Furthermore, reduced insulin/IGF signaling during larval development suppresses these starvation-induced abnormalities. How early-life starvation and insulin/IGF signaling affect adult pathology is unknown. We show that early-life starvation has pervasive effects on adult gene expression which are largely reversed by reduced insulin/IGF signaling following recovery from starvation. Early-life starvation increases adult fatty-acid synthetase fasn-1 expression in daf-2 insulin/IGF signaling receptor-dependent fashion, and fasn-1/FASN promotes starvation-induced abnormalities. Lipidomic analysis reveals increased levels of phosphatidylcholine in adults subjected to early-life starvation, and supplementation with unsaturated phosphatidylcholine during development suppresses starvation-induced abnormalities. Genetic analysis of fatty-acid desaturases reveals positive and negative effects of desaturation on development of starvation-induced abnormalities. In particular, the ω3 fatty-acid desaturase fat-1 and the Δ5 fatty-acid desaturase fat-4 inhibit and promote development of abnormalities, respectively. fat-4 is epistatic to fat-1, suggesting that arachidonic acid-containing lipids promote development of starvation-induced abnormalities, and supplementation with ARA enhanced development of abnormalities. This work shows that early-life starvation and insulin/IGF signaling converge on regulation of adult lipid metabolism, affecting stem-cell proliferation and tumor formation.

Investigating the variability in pressure-volume relationships during hemorrhage and aortic occlusion.

Introduction: The pressure-volume (P-V) relationships of the left ventricle are the classical benchmark for studying cardiac mechanics and pumping function. Perturbations in the P-V relationship (or P-V loop) can be informative and guide the management of heart failure, hypovolemia, and aortic occlusion. Traditionally, P-V loop analyses have been limited to a single-beat P-V loop or an average of consecutive P-V loops (e.g., 10 cardiac cycles). While there are several algorithms to obtain single-beat estimations of the end-systolic and end-diastolic pressure-volume relations (i.e., ESPVR and EDPVR, respectively), there remains a need to better evaluate the variations in P-V relationships longitudinally over time. This is particularly important when studying acute and transient hemodynamic and cardiac events, such as active hemorrhage or aortic occlusion. In this study, we aim to investigate the variability in P-V relationships during hemorrhagic shock and aortic occlusion, by leveraging on a previously published porcine hemorrhage model. Methods: Briefly, swine were instrumented with a P-V catheter in the left ventricle of the heart and underwent a 25% total blood volume hemorrhage over 30 min, followed by either Zone 1 complete aortic occlusion (i.e., REBOA), Zone 1 endovascular variable aortic control (EVAC), or no occlusion as a control, for 45 min. Preload-independent metrics of cardiac performance were obtained at predetermined time points by performing inferior vena cava occlusion during a ventilatory pause. Continuous P-V loop data and other hemodynamic flow and pressure measurements were collected in real-time using a multi-channel data acquisition system. Results: We developed a custom algorithm to quantify the time-dependent variance in both load-dependent and independent cardiac parameters from each P-V loop. As expected, all pigs displayed a significant decrease in the end-systolic pressures and volumes (i.e., ESP, ESV) after hemorrhage. The variability in response to hemorrhage was consistent across all three groups. However, upon introduction of REBOA, we observed significantly high levels of variability in both load-dependent and independent cardiac metrics such as ESP, ESV, and the slope of ESPVR (Ees). For instance, pigs receiving REBOA experienced a 342% increase in ESP from hemorrhage, while pigs receiving EVAC experienced only a 188% increase. The level of variability within the EVAC group was consistently less than that of the REBOA group, which suggests that the EVAC group may be more supportive of maintaining healthier cardiac performance than complete occlusion with REBOA. Discussion: In conclusion, we successfully developed a novel algorithm to reliably quantify the single-beat and longitudinal P-V relations during hemorrhage and aortic occlusion. As expected, hemorrhage resulted in smaller P-V loops, reflective of decreased preload and afterload conditions; however, the cardiac output and heart rate were preserved. The use of REBOA and EVAC for 44 min resulted in the restoration of baseline afterload and preload conditions, but often REBOA exceeded baseline pressure conditions to an alarming level. The level of variability in response to REBOA was significant and could be potentially associated to cardiac injury. By quantifying each P-V loop, we were able to capture the variability in all P-V loops, including those that were irregular in shape and believe that this can help us identify critical time points associated with declining cardiac performance during hemorrhage and REBOA use.

Increased warm water intrusions could cause mass loss in East Antarctica during the next 200 years.

The East Antarctic Ice Sheet (EAIS) is currently surrounded by relatively cool water, but climatic shifts have the potential to increase basal melting via intrusions of warm modified Circumpolar Deep Water (mCDW) onto the continental shelf. Here we use an ice sheet model to show that under the current ocean regime, with only limited intrusions of mCDW, the EAIS will likely gain mass over the next 200 years due to the increased precipitation from a warming atmosphere outweighing increased ice discharge due to ice-shelf melting. However, if the ocean regime were to become dominated by greater mCDW intrusions, the EAIS would have a negative mass balance, contributing up to 48 mm of SLE over this time period. Our modelling finds George V Land to be particularly at risk to increased ocean induced melting. With warmer oceans, we also find that a mid range RCP4.5 emissions scenario is likely to result in a more negative mass balance than a high RCP8.5 emissions scenario, as the relative difference between increased precipitation due to a warming atmosphere and increased ice discharge due to a warming ocean is more negative in the mid range RCP4.5 emission scenario.