Adaptive and maladaptive introgression in grapevine domestication.

Domesticated grapevines spread to Europe around 3,000 years ago. Previous studies have revealed genomic signals of introgression from wild to cultivated grapes in Europe, but the time, mode, genomic pattern, and biological effects of these introgression events have not been investigated. Here, we studied resequencing data from 345 samples spanning the distributional range of wild (Vitis vinifera ssp. sylvestris) and cultivated (V. vinifera ssp. vinifera) grapes. Based on machine learning-based population genetic analyses, we detected evidence for a single domestication of grapevine, followed by continuous gene flow between European wild grapes (EU) and cultivated grapes over the past ~2,000 y, especially from EU to wine grapes. We also inferred that soft-selective sweeps were the dominant signals of artificial selection. Gene pathways associated with the synthesis of aromatic compounds were enriched in regions that were both selected and introgressed, suggesting EU wild grapes were an important resource for improving the flavor of cultivated grapes. Despite the potential benefits of introgression in grape improvement, the introgressed fragments introduced a higher deleterious burden, with most deleterious SNPs and structural variants hidden in a heterozygous state. Cultivated wine grapes have benefited from adaptive introgression with wild grapes, but introgression has also increased the genetic load. In general, our study of beneficial and harmful effects of introgression is critical for genomic breeding of grapevine to take advantage of wild resources.

Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.

[Figure: see text].

Association of sedation and anesthesia on cognitive outcomes in very premature infants: a retrospective observational study.

PURPOSE: Cognitive outcomes in preterm infants may be adversely affected by use of sedation and anesthetic agents. We investigated the associations between anesthetics/sedatives and full-scale intelligence quotient (FSIQ) measured at 36 months corrected age (CA) in very preterm infants (born < 29 weeks gestational age). METHODS: This retrospective cohort study included preterm infants born at < 29 weeks of gestation between 1 January 2006 and 31 December 2012, whose cognitive outcomes were assessed at 36 months CA. Imputed and complete case univariable and adjusted multivariable linear regressions were used to investigate the associations between FSIQ [standardized to mean (standard deviation) 100 (15)] and exposure to volatile anesthetics, propofol, benzodiazepines, barbiturates, and ketamine. These agents were the subject of a 2016 warning from regulatory authorities in the USA recommending caution for administration to children and pregnant women. RESULTS: A total of 731 infants met the inclusion criteria. Unadjusted associations were -7 (95% confidence interval [CI], -10 to -4; P < 0.001) and -6 (95% CI, -10 to -3; P < 0.001) FSIQ points with exposure to warned medications using imputed and complete case analyses, respectively. Imputed and complete case adjusted associations between FSIQ and warned medications were -3 (95% CI, -7 to 0; P = 0.045) and -4 (95% CI, -8 to 0; P = 0.071) FSIQ points, respectively. Adjusted associations between volatile anesthetic exposure only and FSIQ were -3 (95% CI, -6 to 0; P = 0.072) and -5 (95% CI, -9 to -2; P = 0.004) FSIQ points using imputed and complete case data sets, respectively. FSIQ was not associated with opioid exposure. CONCLUSION: Exposure of very preterm infants to anesthetics/sedatives on the United States Food and Drug Administration warning list was associated with a decrease in FSIQ points at 36 months CA. There was no association between opioid exposure and FSIQ.

RéSUMé: OBJECTIF : L'utilization d'agents sédatifs et anesthésiques pourrait avoir une incidence défavorable sur l'évolution cognitive des nourrissons prématurés. Nous avons analysé les associations existantes entre les anesthésiques/sédatifs et le quotient d'intelligence global (QIg) mesuré à 36 mois d'âge corrigé (AC) chez des enfants nés grands prématurés (nés < 29 semaines d'âge gestationnel). MéTHODES: Cette étude de cohorte rétrospective a inclus des nourrissons prématurés nés avant 29 semaines d'âge gestationnel entre le 1er janvier 2006 et le 31 décembre 2012 et dont les critères d'évaluation cognitifs ont été évalués à 36 mois d'AC. Des régressions linéaires à une seule variable et multivariables ajustée, sur les cas imputés et sur les cas complets, ont été utilisées pour rechercher les associations entre le QIg (standardisé à la moyenne 100 [± écart-type] [15]) et l'exposition à des anesthésiques volatils, du propofol, des benzodiazépines, des barbituriques et de la kétamine. Ces molécules ont fait l'objet d'une mise en garde en 2016 par les autorités de réglementation aux États-Unis, recommandant la prudence concernant leur administration à des enfants et à des femmes enceintes. RéSULTATS: Un total de 731 nourrissons présentait les critères d'inclusion. Les associations non ajustées ont été de -7 (intervalle de confiance [IC] à 95 % : -10 à -4; P < 0,001) et -6 (IC à 95 % : -10 à -3; P < 0,001) points de QIg avec l'exposition aux médicaments sous avertissement en utilisant, respectivement, des analyses de cas imputés et de cas complets. Les associations ajustées de cas imputés et complets entre le QIg et les médicaments sous avertissement ont été, respectivement, de -3 (IC à 95 % : -7 à 0; P = 0,045) et -4 (IC à 95 % : -8 à 0; P = 0,071) points de QIg. Les associations ajustées entre l'exposition aux anesthésiques volatiles, uniquement, et le QIg ont été de -3 (IC à 95 % : -6 à 0; P = 0,072) et -5 (IC à 95 % : -9 à 2; P = 0,004) points de QIg en utilisant, respectivement, les ensembles de données des cas imputés et des cas complets. Le QIg n'a pas été associé à une exposition aux opioïdes. CONCLUSION: L'exposition des nourrissons grands prématurés aux anesthésiques/sédatifs figurant sur la liste d'avertissement de la Food and Drug Administration des États-Unis a été associée à une diminution des points de QIg à 36 mois d'AC. Il n'y a pas eu d'association entre l'exposition aux opioïdes et le QIg.

Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop.

RATIONALE: In the endothelium, insulin stimulates endothelial NO synthase (eNOS) to generate the antiatherosclerotic signaling radical NO. Insulin-resistant type 2 diabetes mellitus is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. OBJECTIVE: To answer this question, we generated a mouse with endothelial cell (EC)-specific overexpression of the human insulin receptor (hIRECO) using the Tie2 promoter-enhancer. METHODS AND RESULTS: hIRECO demonstrated significant endothelial dysfunction measured by blunted endothelium-dependent vasorelaxation to acetylcholine, which was normalized by a specific Nox2 NADPH oxidase inhibitor. Insulin-stimulated phosphorylation of protein kinase B was increased in hIRECO EC as was Nox2 NADPH oxidase-dependent generation of superoxide, whereas insulin-stimulated and shear stress-stimulated eNOS activations were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of proline-rich tyrosine kinase 2 that phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of proline-rich tyrosine kinase 2 improved insulin-induced and shear stress-induced eNOS activation in hIRECO EC. CONCLUSIONS: Enhancing insulin sensitivity specifically in EC leads to a paradoxical decline in endothelial function, mediated by increased tyrosine phosphorylation of eNOS and excess Nox2-derived superoxide. Increased EC insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide. Inhibition of proline-rich tyrosine kinase 2 restores insulin-induced and shear stress-induced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide.

Anesthetic Neuroprotection in Experimental Stroke in Rodents: A Systematic Review and Meta-analysis.

BACKGROUND: Patients undergoing endovascular therapy for acute ischemic stroke may require general anesthesia to undergo the procedure. At present, there is little clinical evidence to guide the choice of anesthetic in this acute setting. The clinical implications of experimental studies demonstrating anesthetic neuroprotection are poorly understood. Here, the authors evaluated the impact of anesthetic treatment on neurologic outcome in experimental stroke. METHODS: Controlled studies of anesthetics in stroke using the filament occlusion model were identified in electronic databases up to December 15, 2015. The primary outcome measures, infarct volume, and neurologic deficit score were used to calculate the normalized mean difference for each comparison. Meta-analysis of normalized mean difference values provided estimates of neuroprotection and contributions of predefined factors: study quality, the timing of treatment, and the duration of ischemia. RESULTS: In 80 retrieved publications anesthetic treatment reduced neurologic injury by 28% (95% CI, 24 to 32%; P < 0.0001). Internal validity was high: publication bias enhanced the effect size by 4% or less, effect size increased with study quality (P = 0.0004), and approximately 70% of studies were adequately powered. Apart from study quality, no predefined factor influenced neuroprotection. Neuroprotection failed in animals with comorbidities. Neuroprotection by anesthetics was associated with prosurvival mechanisms. CONCLUSIONS: Anesthetic neuroprotection is a robust finding in studies using the filament occlusion model of ischemic stroke and should be assumed to influence outcomes in studies using this model. Neuroprotection failed in female animals and animals with comorbidities, suggesting that the results in young male animals may not reflect human stroke.

Grapevine species from varied native habitats exhibit differences in embolism formation/repair associated with leaf gas exchange and root pressure.

Drought induces xylem embolism formation, but grapevines can refill non-functional vessels to restore transport capacity. It is unknown whether vulnerability to embolism formation and ability to repair differ among grapevine species. We analysed in vivo embolism formation and repair using x-ray computed microtomography in three wild grapevine species from varied native habitats (Vitis riparia, V. arizonica, V. champinii) and related responses to measurements of leaf gas exchange and root pressure. Vulnerability to embolism formation was greatest in V. riparia, intermediate in V. arizonica and lowest in V. champinii. After re-watering, embolism repair was rapid and pronounced in V. riparia and V. arizonica, but limited or negligible in V. champinii even after numerous days. Similarly, root pressure measured after re-watering was positively correlated with drought stress severity for V. riparia and V. arizonica (species exhibiting embolism repair) but not for V. champinii. Drought-induced reductions in transpiration were greatest for V. riparia and least in V. champinii. Recovery of transpiration after re-watering was delayed for all species, but was greatest for V. champinii and most rapid in V. arizonica. These species exhibit varied responses to drought stress that involve maintenance/recovery of xylem transport capacity coordinated with root pressure and gas exchange responses.

Restoring Akt1 activity in outgrowth endothelial cells from South Asian men rescues vascular reparative potential.

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented re-endothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.

Ultrasound assessment of gastric volume in the fasted pediatric patient undergoing upper gastrointestinal endoscopy: development of a predictive model using endoscopically suctioned volumes.

BACKGROUND: Aspiration of gastric contents can be a serious anesthetic-related complication. Gastric antral sonography prior to anesthesia may have a role in identifying pediatric patients at risk of aspiration. We examined the relationship between sonographic antral area and endoscopically suctioned gastric volumes, and whether a 3-point qualitative grading system is applicable in pediatric patients. METHODS: Fasted patients presenting to a pediatric hospital for upper gastrointestinal endoscopy were included in the study. Sonographic measurement of the antral cross-sectional area (CSA) in supine (supine CSA) and right lateral decubitus (RLD CSA) position was completed, and the antrum was designated as empty or nonempty. Gastric contents were endoscopically suctioned and measured. Multiple regression analysis was used to fit a mathematical model to estimate gastric volume. RESULTS: One hundred patients (aged 11-216 months) were included. The gastric antrum was measured in 94% and 99% of patients in the supine and RLD positions, respectively. Gastric antral CSA correlated with total gastric volume in both supine (ρ = 0.63) and RLD (ρ = 0.67) positions. A mathematical model incorporating RLD CSA and age (R(2)  = 0.60) was determined as the best-fit model to predict gastric volumes. Increasing gastric antral grade (0-2) was associated with increasing gastric fluid volume. CONCLUSION: The results suggest that sonographic assessment of the gastric antrum provides useful information regarding gastric content (empty versus nonempty) and volume (ml·kg(-1) ) in pediatric patients. Results suggest that the three-point grading system may be a valuable tool to assess gastric 'fullness' based on a qualitative exam of the antrum.

Discriminatory ability of perioperative heart rate variability in predicting postoperative complications in major urologic surgery: a prospective cohort study.

We aimed to determine if continuous perioperative heart rate variability (HRV) monitoring could improve risk stratification compared to a short preoperative measurement in radical cystectomy patients. Electrocardiography (ECG) recordings were collected continuously preoperatively to discharge in 83 patients. Two, 5-min ECG signal segments (preoperative and at 24-h post ECG placement) were analyzed offline to extract HRV metrics. HRV metric discriminatory ability to identify patients with 30-day postoperative complications were analyzed using receiver operating characteristics curves. Sixty participants were included for analysis of which 27 (45%) developed a complication within 30 days postoperative. HRV was reduced in patients with complications. Postoperative standard deviation NN intervals and root mean square of successive differences had area under the curves (AUC) of 0.67 (95% CI 0.54 to 0.81) and 0.68 (95% CI 0.54 to 0.82), respectively. Significant discriminatory abilities were also reported for postoperative frequency metrics of absolute low frequency (LF) [AUC = 0.65 (95% CI 0.51 to 0.79)] and high frequency (HF) powers [AUC = 0.69 (95% CI 0.55 to 0.83)] and total power [AUC = 0.66 (95% CI 0.53 to 0.80)]. Postoperative acquired HRV metrics demonstrated improved discriminatory ability. Our findings suggest that longer-term perioperative HRV monitoring presents with superior ability to stratify complication risk.

Overexpression of facilitative glucose transporter-3 and membrane procoagulation in maternal platelets of preeclamptic pregnancy.

BACKGROUND: Preeclampsia (PE) is a hypertensive disorder during pregnancy that results in significant adverse maternal and neonatal outcomes. Platelet activation is present in PE and contributes to the thrombo-hemorrhagic states of the disorder. However, the mechanisms that initiate and/or sustain platelet activation in PE are ill-defined. OBJECTIVES: We aimed to characterise this mechanism and the procoagulant potentials of platelets in PE. METHODS: In this quantitative observational study, we analyzed platelet procoagulant membrane dynamics in patients with PE (n = 21) compared with age-matched normotensive pregnancies (n = 20), gestational hypertension (n = 10), and non-pregnant female controls (n = 19). We analyzed fluorescently labeled indicators of platelet activation, bioenergetics, and procoagulation (phosphatidylserine exposure and thrombin generation), coupled with high-resolution imaging and thrombelastography. We then validated our findings using flow cytometry, immunoassays, classical pharmacology, and convolutional neural network analysis. RESULTS: PE platelets showed significant ultra-structural remodeling, are more extensively preactivated than in healthy pregnancies and can circulate as microaggregates. Preactivated platelets of PE externalized phosphatidylserine and thrombin formed on the platelet membranes. Platelets' expression of facilitative glucose transporter-1 increased in all pregnant groups. However, PE platelets additionally overexpress glucose transporter-3 to enhance glucose uptake and sustain activation and secretion events. Although preeclampsia platelets exposed to subendothelial collagen showed incremental activation, the absolute hemostatic response to collagen was diminished, and likely contributed to greater blood loss perioperatively. CONCLUSIONS: We revealed 2 bioenergetic mediators in the mechanism of sustained platelet procoagulation in preeclampsia. Although glucose transporter-1 and glucose transporter-3 remain elusive antiprocoagulant targets, they may be sensitive monitors of PE onset and progression.

The viscous behaviour of HES 130/0.4 (Voluven®) and HES 260/0.45 (Pentaspan®).

PURPOSE: Several fluids are available for volume therapy to address hypovolemia. We focus on two hydroxyethyl starches (HES) available for volume expansion in Canada, HES 130/0.4 (Voluven®) and HES 260/0.45 (Pentaspan®). Although information is available regarding their pharmacokinetic and risk/benefit profiles, this paper examines their viscous properties. METHODS: Dynamic viscosities of HES 130/0.4 and HES 260/0.45 were measured through capillary viscometry at 21°C and 37°C. The viscosities of the solutions were then measured through a closed flow loop at room temperature across physiologically relevant flow rates that maintained a laminar flow regime. RESULTS: Measured dynamic viscosity through capillary viscometry for HES 130/0.4 and HES 260/0.45 was 2.76 centipoises (cP) and 7.62 cP, respectively, at 21°C decreasing to 1.74 cP and 4.25 cP, respectively, at 37°C. Pipe flow analysis found that HES 130/0.4 (expiry 02/13) and HES 260/0.45 (expiry 10/10) displayed marginal variation in viscosity suggesting Newtonian behaviour. However, a sample of HES 130/0.4 (expiry 10/10) displayed an appreciable increase in viscosity (13%) at higher flow rates suggesting shear thickening behaviour. CONCLUSION: This study represents an innovative characterization of not only the viscosity of two commonly utilized HES solutions but also their viscous behaviour across physiologically relevant flow rates. The shear thickening behaviour of a sample of HES 130/0.40 (expiry 10/10) at high flow rates was not expected, and the effect this result may have on endothelial cell function is unknown.

The quantification of hemodynamic parameters downstream of a Gianturco Zenith stent wire using newtonian and non-newtonian analog fluids in a pulsatile flow environment.

Although deployed in the vasculature to expand vessel diameter and improve blood flow, protruding stent struts can create complex flow environments associated with flow separation and oscillating shear gradients. Given the association between magnitude and direction of wall shear stress (WSS) and endothelial phenotype expression, accurate representation of stent-induced flow patterns is critical if we are to predict sites susceptible to intimal hyperplasia. Despite the number of stents approved for clinical use, quantification on the alteration of hemodynamic flow parameters associated with the Gianturco Z-stent is limited in the literature. In using experimental and computational models to quantify strut-induced flow, the majority of past work has assumed blood or representative analogs to behave as Newtonian fluids. However, recent studies have challenged the validity of this assumption. We present here the experimental quantification of flow through a Gianturco Z-stent wire in representative Newtonian and non-Newtonian blood analog environments using particle image velocimetry (PIV). Fluid analogs were circulated through a closed flow loop at physiologically appropriate flow rates whereupon PIV snapshots were acquired downstream of the wire housed in an acrylic tube with a diameter characteristic of the carotid artery. Hemodynamic parameters including WSS, oscillatory shear index (OSI), and Reynolds shear stresses (RSS) were measured. Our findings show that the introduction of the stent wire altered downstream hemodynamic parameters through a reduction in WSS and increases in OSI and RSS from nonstented flow. The Newtonian analog solution of glycerol and water underestimated WSS while increasing the spatial coverage of flow reversal and oscillatory shear compared to a non-Newtonian fluid of glycerol, water, and xanthan gum. Peak RSS were increased with the Newtonian fluid, although peak values were similar upon a doubling of flow rate. The introduction of the stent wire promoted the development of flow patterns that are susceptible to intimal hyperplasia using both Newtonian and non-Newtonian analogs, although the magnitude of sites affected downstream was appreciably related to the rheological behavior of the analog. While the assumption of linear viscous behavior is often appropriate in quantifying flow in the largest arteries of the vasculature, the results presented here suggest this assumption overestimates sites susceptible to hyperplasia and restenosis in flow characterized by low and oscillatory shear.

Preventing persistent postsurgical pain: A systematic review and component network meta-analysis.

BACKGROUND AND OBJECTIVES: Evidence for perioperative methods to prevent persistent postsurgical pain (PPP) is uncertain, in part because few treatments have been directly compared. Here we have used component network meta-analysis (cNMA) to incorporate both direct and indirect evidence in the evaluation of the efficacy and tolerability of pharmacological and neural block treatments. DATABASES AND DATA TREATMENT: We searched the Cochrane Central Registry of Controlled Trials, Embase, MEDLINE, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry up to January 2021 for randomized, double-masked, controlled trials that reported the prevalence of PPP. We assessed trial quality with the Cochrane risk of bias tool (RoB 2.0). We analysed the results with frequentist cNMA models. The primary outcome was the relative risk (RR) of PPP. We assessed efficacy in relation to a clinically important effect size of RR = 0.9, which is a 10% improvement with treatment. RESULTS: The analysis included 107 trials (13,553 participants) of 13 treatments. The effects of complex interventions were the multiplicative effects of their components. Compared with placebo, serotonin-norepinephrine reuptake inhibitors (SNRIs), neural block alone, or in combination with NMDA receptor blockers or gabapentanoids were effective. Treatments with benefit in the immediate post-operative period predicted a reduced risk of PPP. CONCLUSIONS: Several treatments and treatment combinations effectively reduce PPP prevalence. Pain outcomes in the immediate postoperative period are an important mediator of PPP. Multimodal interventions can be analysed using cNMA. SIGNIFICANCE: Systematic reviews of PPP prevention usually focus on the efficacy of specific treatments in comparison with control interventions. In this study we used component network meta-analysis to compare interventions to each other, including both pharmacological and neural block techniques, and multimodal interventions. Interventions that are not effective alone may improve the efficacy of multimodal interventions that include neural block techniques. Immediate postoperative benefit was an important mediator for reduction of PPP. STUDY REGISTRATION: PROSPERO: CRD42018085570 https://www.crd.york.ac.uk/prospero/.

Introgression among North American wild grapes (Vitis) fuels biotic and abiotic adaptation.

BACKGROUND: Introgressive hybridization can reassort genetic variants into beneficial combinations, permitting adaptation to new ecological niches. To evaluate evolutionary patterns and dynamics that contribute to introgression, we investigate six wild Vitis species that are native to the Southwestern United States and useful for breeding grapevine (V. vinifera) rootstocks. RESULTS: By creating a reference genome assembly from one wild species, V. arizonica, and by resequencing 130 accessions, we focus on identifying putatively introgressed regions (pIRs) between species. We find six species pairs with signals of introgression between them, comprising up to ~ 8% of the extant genome for some pairs. The pIRs tend to be gene poor, located in regions of high recombination and enriched for genes implicated in disease resistance functions. To assess potential pIR function, we explore SNP associations to bioclimatic variables and to bacterial levels after infection with the causative agent of Pierce's disease (Xylella fastidiosa). pIRs are enriched for SNPs associated with both climate and bacterial levels, suggesting that introgression is driven by adaptation to biotic and abiotic stressors. CONCLUSIONS: Altogether, this study yields insights into the genomic extent of introgression, potential pressures that shape adaptive introgression, and the evolutionary history of economically important wild relatives of a critical crop.

Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis.

Endothelial insulin receptors (Insr) promote sprouting angiogenesis, although the underpinning cellular and molecular mechanisms are unknown. Comparing mice with whole-body insulin receptor haploinsufficiency (Insr+/-) against littermate controls, we found impaired limb perfusion and muscle capillary density after inducing hind-limb ischemia; this was in spite of increased expression of the proangiogenic growth factor Vegfa. Insr+/- neonatal retinas exhibited reduced tip cell number and branching complexity during developmental angiogenesis, which was also found in separate studies of mice with endothelium-restricted Insr haploinsufficiency. Functional responses to vascular endothelial growth factor A (VEGF-A), including in vitro angiogenesis, were also impaired in aortic rings and pulmonary endothelial cells from Insr+/- mice. Human umbilical vein endothelial cells with shRNA-mediated knockdown of Insr also demonstrated impaired functional angiogenic responses to VEGF-A. VEGF-A signaling to Akt and endothelial nitric oxide synthase was intact, but downstream signaling to extracellular signal-reduced kinase 1/2 (ERK1/2) was impaired, as was VEGF receptor-2 (VEGFR-2) internalization, which is required specifically for signaling to ERK1/2. Hence, endothelial insulin receptors facilitate the functional response to VEGF-A during angiogenic sprouting and are required for appropriate signal transduction from VEGFR-2 to ERK1/2.

Association of heart failure and its comorbidities with loss of life expectancy.

OBJECTIVE: Estimating survival can aid care planning, but the use of absolute survival projections can be challenging for patients and clinicians to contextualise. We aimed to define how heart failure and its major comorbidities contribute to loss of actuarially predicted life expectancy. METHODS: We conducted an observational cohort study of 1794 adults with stable chronic heart failure and reduced left ventricular ejection fraction, recruited from cardiology outpatient departments of four UK hospitals. Data from an 11-year maximum (5-year median) follow-up period (999 deaths) were used to define how heart failure and its major comorbidities impact on survival, relative to an age-sex matched control UK population, using a relative survival framework. RESULTS: After 10 years, mortality in the reference control population was 29%. In people with heart failure, this increased by an additional 37% (95% CI 34% to 40%), equating to an additional 2.2 years of lost life or a 2.4-fold (2.2-2.5) excess loss of life. This excess was greater in men than women (2.4 years (2.2-2.7) vs 1.6 years (1.2-2.0); p<0.001). In patients without major comorbidity, men still experienced excess loss of life, while women experienced less and were non-significantly different from the reference population (1 year (0.6-1.5) vs 0.4 years (-0.3 to 1); p<0.001). Accrual of comorbidity was associated with substantial increases in excess lost life, particularly for diabetes, chronic kidney and lung disease. CONCLUSIONS: Comorbidity accounts for the majority of lost life expectancy in people with heart failure. Women, but not men, without comorbidity experience survival close to reference controls.

Quality improvement assessment of a bianchi-technique pediatric orchiopexy perioperative pain management pathway.

BACKGROUND: Surgical correction of undescended testes is a common surgical procedure which can be performed via a two-incision technique or a single high scrotal incision (Bianchi technique). The Bianchi technique requires less surgical time and may be associated with less pain in the initial postoperative period, however it has been adopted slowly due to a lack of familiarity and perceived technical challenges of the technique. Traditionally postoperative orchiopexy pain is managed with a caudal or ilioinguinal/iliohypogastric nerve block. As urologists at our site adopted the Bianchi technique, the anesthesiologists stopped performing caudals or ilioinguinal/iliohypogastric nerve blocks as local infiltration appeared sufficient. Therefore, this quality improvement (QI) project endeavoured to assess Alberta Children's Hospital's care pathway in its effectiveness to control pain in the first 24 h following pediatric orchiopexy using the Bianchi technique. METHODS: We completed a prospective QI project examining a care pathway for patients undergoing orchiopexy using the Bianchi technique. Eligible patients were healthy and aged 6 months to 12 years. A multimodal analgesic approach including local anesthetic surgical infiltration was used. Pain scores (FLACC) were recorded for up to 2 h postoperatively and a PPPM was completed at 24 h postoperatively. RESULTS: Sixty-four patients were included in the final analysis. The median discharge FLACC score was 0 (range 0-2) (Table 2). Median intraoperative morphine administered was 0.09 mg/kg with no significant correlations between the amount of morphine administered and postoperative pain measures. Median PPPM scores were 4 and 3.5 for unilateral and bilateral procedures, respectively. CONCLUSIONS: We have demonstrated that orchiopexies repaired using the Bianchi technique following the care pathway established at Alberta Children's Hospital are associated with minimal pain scores. Our QI project suggests that combining a Bianchi technique with a simple multimodal analgesic approach including local infiltration, negates the need for regional anesthesia techniques, yet still provides adequate analgesia.