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Objective To evaluate whether prophylactic administration of oxytocin plus ergonovine or oxytocin plus carboprost is more effective than oxytocin alone in reducing the need for additional uterotonics among women undergoing cesarean delivery for labor arrest. Methods In this double-blind, three-arm randomized controlled trial, participants were assigned to receive either oxytocin 5 units intravenous alone, or with ergonovine 0.25 mg intravenous or carboprost 0.25 mg intramuscular immediately after delivery, followed with maintenance infusion of oxytocin 40 milliunits/minute in all groups. Uterine tone was assessed at 3, 5, and 10 minutes after delivery, and additional uterotonics were administered if deemed necessary. The primary outcome was intraoperative need for additional uterotonics. Secondary outcomes included uterine tone, calculated blood loss, and side effects. A sample size of 34 per group (n=102), based on the null hypothesis that there is no association between treatment assignment and the need for additional uterotonics, permitted independent post hoc pairwise comparisons between oxytocin plus ergonovine, oxytocin plus carboprost, and oxytocin alone using an adjusted P-value of .025. The association between the need for additional uterotonics and treatment group was assessed using the χ2 test. Results From June 2013 through July 2019, 105 participants were randomized (35 per group) and data from 100 participants were analyzed: oxytocin (n=35), oxytocin plus ergonovine (n=33), and oxytocin plus carboprost (n=32). There was no difference in the requirement of additional intraoperative uterotonics across groups (oxytocin [37%] vs oxytocin plus ergonovine [33%] vs oxytocin plus carboprost [34%], P=.932). Uterine tone and calculated blood loss were similar across groups. Incidence of nausea or vomiting was higher in oxytocin plus ergonovine (85%; odds ratio [OR] 5.3, 95% CI 1.7-16.9, P=.003) and oxytocin plus carboprost (72%; OR 2.4, 95% CI 0.9-6.7, P=.086) compared with the oxytocin (51%) group. Conclusion Compared with oxytocin alone, prophylactic use of a combination of uterotonic drugs did not reduce the need for additional uterotonics at cesarean delivery for labor arrest. Clinical trial registration ClinicalTrials.gov, NCT01869556.

The distribution of hydrogen across different crystallographic sites and point defects in forsterite determines how many properties, such as rheology, conductivity and diffusion are affected by water. In this study, we use lattice dynamics and Density Functional Theory (DFT) to build a thermodynamic model of H-bearing defects in Al,Ti bearing forsterite. From this, the distribution of hydrogen in forsterite as a function of pressure (P), temperature (T), water, Al and Ti concentration is determined. Primarily, hydrogen distribution in forsterite is complex and highly varied in different P, T and composition regimes. Therefore, extrapolation of properties that depend upon water between these different regimes is non-trivial. This extrapolation has often been done by determining exponents which describe how defect-specific defect concentrations or properties dependent upon them vary with water concentration/fugacity. We show here that these exponents can vary radically across common experimental and geophysical P, T and [H2O]bulk ranges as the favoured hydrogen-bearing defects change. In general, at low pressures hydrogen favours Mg vacancies (high temperatures) or complexes with titanium (low temperatures) whilst at high pressures, hydrogen favours Si vacancies regardless of all other conditions. Higher values of [H2O]bulk also favours hydrated Si vacancies. We evaluate these distributions along geotherms and find that hydrogen distribution and thus its effect on forsterite properties is highly varied across the expected conditions of the upper mantle and thus cannot be simply represented. No such distribution of hydrogen has been previously constructed and it is essential to consider this hydrogen distribution when considering the properties of a wet mantle.

Earth's core has produced a global magnetic field for the last 4 Gyrs, presently sustained by inner core growth.Models of the core with high thermal conductivity suggest potentially insufficient power available for the geodynamo prior to inner core formation ~1 Ga.Precipitation of SiO2 from the liquid core might offer an alternative power source for the magnetic field before inner core growth, however, no estimates of partition coefficient exist for conditions of the early core.We present the first determination of the silicon partition coefficient at core-mantle boundary conditions and use these results to build a thermodynamic model that is integrated into a model of coupled core-mantle thermal evolution.We show that models including precipitation of silicon can satisfy constraints of inner core size, mantle convective heat flux, mantle temperature and a persistent ancient geodynamo whilst those excluding fail.Successful power from precipitation favours an oxygen poor initial core composition.

Background Hemodynamic instability is commonly seen during carotid angioplasty and stenting. Although prophylactic treatment with anticholinergics is beneficial, selected use in high-risk patients is desirable. This study examines whether plaque characteristics on computed tomography angiography in addition to demographic factors improve predictive capability. Methods We retrospectively collected information from 298 carotid angioplasty procedures between January 2013 and December 2018. Nine individuals were excluded due to a previous ipsilateral endarterectomy. Our primary outcome was a decrease of 20% or more in heart rate or blood pressure at angioplasty. Data were analyzed using χ tests and regression statistics. Results Of the 289 patients included for analysis, 57 had intraoperative instability and 26 had postoperative instability. Radiologist interpretation was found to have a risk ratio of 1.63 (95% confidence interval: 1.00-2.65) for intraoperative instability (P=0.080). Intraoperative instability was significantly associated with subsequent postoperative instability (P=0.005). Our regression model included previous endarterectomy and diabetes as predictive factors with a sensitivity of 11.3% and a specificity of 100.0%. Anticholinergic usage was associated with hypotension without coexisting bradycardia with a risk ratio of 2.36 (95% confidence interval: 1.06-5.26; P=0.047). Conclusions Individuals without a previous contralateral endarterectomy and/or history of diabetes are at lower risk of hemodynamic instability. The addition of computed tomography angiographic variables does not improve this prediction. Future prospective, randomized work is required to improve our ability to identify and treat individuals at high risk of instability during carotid angioplasty and stenting.

Background Determining an optimal location within the right atrium (RA) for placement of the distal ventriculoatrial (VA) shunt catheter offer several operative challenges that place patients at risk for perioperative complications and downstream VA shunt failure. Utilizing transesophageal echocardiography (TEE) guidance to place distal VA shunt catheters may help to circumvent these risks. Objective To review our current practice of VA shunt insertion using TEE guidance. Methods A retrospective review of all consecutive patients who underwent VA shunt procedures between December 19, 2016 and January 22, 2019, during which time intraoperative TEE was used for shunt placement was performed. Data on the time required for shunt placement and total procedure time, baseline echocardiography findings, and short- and long-term complications of shunt placement were assessed. Results A total of 33 patients underwent VA shunt procedures, with a median follow-up time of 250 (88-412) d. The only immediate complication related to shunt placement or TEE use was transient ectopy in 1 patient. The mean time for atrial catheter insertion was 12.6 ± 4.8 min. Right-heart catheters were inserted between the RA-superior vena cava junction and 22 mm within the RA in all but 3 procedures. A total of 7/33 patients (21%) underwent shunt revision. Indications for revisions included distal clots, proximal obstruction, positive blood culture, and shunt valve revision. No other complications of VA shunt insertion were reported. Conclusion VA shunt insertion using TEE allows for precise distal catheter placement. Early patient experience confirms this technique has a low complication rate.

Anesthesia-related complications in obstetric patients could be catastrophic and impact the lives of both the parturient and the neonate. The objective of this study was to determine the frequency, temporal trend, and risk factors of anesthesia-related adverse events during hospitalization for delivery in Canada. This retrospective population-based study utilized the hospitalization database of the Canadian Institute for Health Information for all parturients (gestation ≥ 20 weeks) in Canada (except Quebec) hospitalized for childbirth from April 2004 to March 2017. Complications were identified by the enhanced Canadian version of the tenth revision of the International Statistical Classification of Diseases and Related Health Problems codes. Data were summarized with descriptive statistics. Associations between hospitalizations with an anesthesia-related adverse event and patient characteristics, delivery method, and modality of anesthesia were assessed using multivariate logistic regression. Among 2,601,034 hospitalizations (3,194,875 interventions), 8,361 anesthesia-related adverse events occurred over a 13-year period (262 per 100,000 interventions; 95% confidence interval [CI], 256 to 267), with a significant decline over time (P < 0.001). These were two-fold and seven-fold higher per 100,000 interventions with general (488; 95% CI, 438 to 542) and general plus neuraxial (1,476; 95% CI, 1,284 to 1,689) anesthesia compared with neuraxial anesthesia alone (225; 95% CI, 219 to 230). Serious adverse events constituted 9% of all adverse events. The most common adverse event was spinal and epidural anesthesia-induced headache (6,908/8,361; 83%); the overall rate of failed or difficult intubations was low (201/8,361; 2%). Anesthesia-related events were more likely in those who had a Cesarean delivery compared with vaginal delivery (odds ratio [OR], 1.12; 95% CI, 1.06 to 1.18) and general anesthesia compared with neuraxial anesthesia (OR, 1.71; 95% CI, 1.53 to 1.93). Noteworthy associations were found between any anesthesia-related adverse events and cardiomyopathy (OR, 8.34; 95% CI, 2.59 to 26.83), eclampsia (OR, 3.11; 95% CI, 1.95 to 4.97), and obstructive sleep apnea (OR, 1.91; 95% CI, 1.66 to 2.19). The incidence of anesthesia-related adverse events in obstetric patients in Canada is low and declining. High vigilance is required in parturients undergoing Cesarean delivery, receiving general anesthesia, and those with pre-existing medical conditions.

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.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.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.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.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.PROSPERO: CRD42018085570 https://www.crd.york.ac.uk/prospero/.

Background Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is beneficial in peritoneal carcinomatosis. Epidurals provide excellent pain relief for laparotomies. Coagulopathy (platelet count 1.5 or PTT >45) occurs with CRS and HIPEC, increasing risk for bleeding complications with epidurals. This prospective study characterizes clot kinetics with thromboelastography (TEG) to determine suitability for epidural analgesia. Methods After Research Ethics approval, thirty consented patients had blood collected. Primary data collected included TEG and conventional coagulation measures (platelets, PTT and INR). Secondary data collected included demographics, disease, surgical, intraoperative factors and complications from epidural placement. Results Of 30 patients analyzed, two had incomplete data. Four developed abnormal coagulation between the second and fifth post-operative day. For all patients, TEG values remained normal. Postoperative INR was elevated until day 3 (all INR Conclusions In this study CRS and HIPEC do not contribute to the conventional definition of clinical coagulopathy. Clot kinetics indicate that epidural catheters may be recommended for post-operative analgesia.

Purpose Enteral access via nasogastric tube (NGT) placement can be essential in the provision of care in pediatric patients. Methods exist to confirm correct placement with success rates between 80% and 85%. Radiographic confirmation remains the "gold-standard," however; it exposes patients to ionizing radiation and fails to provide "real-time" information. In this study, we determined the feasibility of using sonography to assist in the placement of NGT insertions in pediatric patients that have difficulty cooperating. Methods Thirty patients requiring NGT placement were stratified into three age groups. Upon NGT insertion, transverse and longitudinal ultrasound images were acquired to visualize tube progression through the esophagus. Subsequently, a focused ultrasonographic exam of the gastric antrum and body were performed. If amenable, an air bolus (1 mL/kg) was injected in the stomach if the NGT was not directly visualized. Following intubation, standard guidelines for NGT position confirmation were performed. Results The NGT was visualized in all esophageal views and 52% of gastric views. Subgroup analysis showed that successful visualization of tube placement in the stomach ranged from 40% (7-18 years) to 70% (3-6 years). Eighty percentage of air boluses injected were visualized. Conclusion The use of ultrasonography may assist NGT placement in pediatric patients and reduce the incidence of suboptimal placement during insertion. We demonstrated successful NGT visualization through the esophagus regardless of age. NGT visualization in the stomach was challenging; however, injection of an air bolus may improve visualization. Further studies are required to improve the success rate of obtaining gastric views of the NGT.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) benefit patients with peritoneal carcinomatosis. Nevertheless, this therapy is associated with considerable postoperative pain due to the extensive abdominal incision. While epidural analgesia offers efficacious pain control, CRS and HIPEC therapy is associated with perioperative coagulopathy that may impact its use. The purpose of this retrospective study is to characterize the postoperative coagulopathy in this patient subset and to develop a model that will help predict those at risk. Our database of patients treated with CRS and HIPEC (n = 171) was reviewed to assess perioperative changes in platelet count, international normalized ratio (INR), and partial thromboplastin time (PTT). Abnormal coagulation was defined by platelet count 2.0, and/or PTT > 60 sec. A logistic regression model was developed to determine if patient, disease, and/or surgical factor(s) were associated with the development of postoperative coagulopathy. Epidural catheter management in this patient population was also reviewed. Significant differences (adjusted P < 0.007) were noted between median preoperative and postoperative platelet and INR values on postoperative days (POD) 0 through 6 and days 0 through 3, respectively. Highest observed median differences between preoperative and postoperative values showed a decrease in platelet count of 94 × 10−9·L−1 (POD 2 and POD 3), an increase in INR of 0.2 (POD 0 to POD 2), and a decrease in PTT of 3.1 sec (POD 5). Coagulopathy and severe coagulopathy occurred in 38% and 4.7% of patients, respectively. Predictors of coagulopathy included intraoperative transfusion of packed red blood cells (PRBCs) and perhaps the peritoneal carcinomatosis index (PCI). Epidural catheters were inserted in 26 patients for a median [IQR] duration of 7.0 [5.0-7.0] days without complication. At the time of their removal, no blood products were required to correct abnormal coagulation values. Altered coagulation may appear during the postoperative period in approximately 40% of our patients treated with CRS and HIPEC. Intraoperative transfusion of RBCs and possibly increased PCI are associated with abnormal postoperative coagulation. Close monitoring of coagulation parameters is required to help ensure safe removal of an epidural catheter.

Summary 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. Summary Table . Median [min–max] post-operative FLACC scores for all patients and stratified by unilateral or bilateral orchiopexy procedures. 15-min FLACC 30-min FLACC Discharge FLACC P-value All patients (N = 64) 0 [0–10] a 0 [0–8] b 0 [0–2] a b Unilateral orchiopexy (N = 19) 1 [0–10] a 0 [0–4] 0 [0–2] a 0.001 Bilateral orchiopexy (N = 45) 0 [0–10] a 0 [0–8] b 0 [0–2] a b 0.001 FLACC = Face, Legs, Activity, Cry, Consolability Scale; N = Number of Patients. a Significant difference P b Significant difference P

To assess the effects of a real-time feedback device and refresher sessions in acquiring and retaining chest compression skills.Healthcare providers participated in refresher sessions at 3-time points (blocks) over 1-year. At each block, chest compression (CC) skills were assessed on an infant and adult task trainer, in one 2-min trial without feedback (blinded), and up to three 2-min trials with feedback (unblinded). Skills retention over time was explored at three time lags: 1-3, 3-6,6 months. Data collected included chest compression rate (100-120/min), depth (4 cm for infants and 5 cm for adults), and recoil between compressions.Among 194 participants, achievement of excellent CC (≥90% of adequate compressions for all parameters) increased with feedback. Linear mixed models found significant (p 0.05) improvement in rate, depth, and recoil. Performance between last unblinded trial in block 1 with the following blinded trial in block 2 significantly decayed in rate on both task trainers irrespective of time passed, while depth and recoil performance were maintained only for infants.A real-time visual feedback device improved CC skills with better results in infants. Skills decayed over time despite two refresher sessions with feedback.

Anaesthetic neuroprotection in the setting of traumatic brain injury (TBI) remains unproved and is based upon the results in preclinical experiments. Here, we sought to synthesise the results in rodent models of TBI, and to evaluate the effects of publication bias, experimental manipulation, and poor study quality on the effect estimates.After a systematic review, we used pairwise meta-analysis to estimate the effect of anaesthetics, opioids, and sedative-hypnotics on neurological outcome, and network meta-analysis to compare their relative efficacy. We sought evidence of bias related to selective publication, experimental manipulation, and study quality.Sixteen studies, involving 32 comparisons, were included (546 animals). The treatment improved the neurological outcomes by 35%; 95% confidence interval: 26-44%; P0.001. The statistical heterogeneity was small (12%), but the 95% prediction interval for the estimate was wide (15-56%). The statistical power was low: 61% (90% confidence interval: 22-86%). The small sample size in the studies was a serious shortcoming reducing the statistical heterogeneity and obscuring differences in outcome between drugs and between experimental conditions.Anaesthetics do provide neuroprotection in rodent models of TBI. The effect-size estimates do not appear to be exaggerated by selective publication, experimental manipulation, or study design. The main shortcoming of the included studies were small sample sizes leading to low power and imprecision, which precluded the network meta-analysis from providing a meaningful ranking for efficacy amongst the drugs. Reliable preclinical investigations of neuroprotection by anaesthetics will require larger sample sizes.

SummaryBackground 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 (R2 = 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.

The primary aim of this study is to show the non-inferiority of 15mg intraoperative dose of ketorolac as compared to the standard 30mg ketorolac by looking at the visual analog scale pain (VAS) scores 4h after an adult spine surgery.The study design is a prospective randomized non-inferiority clinical trial looking at non-inferiority of intraoperative 15mg ketorolac from the standard 30mg dose.Quaternary care center.50 adult (18-65years of age) undergoing lumbar decompression spine surgery.Group A received a single intraoperative dose of 15mg ketorolac at the end of surgery and group B received single intraoperative dose of 30mg ketorolac.The primary outcome was the visual analog scale (VAS) pain scores 4h after an adult spine surgery. Secondary measures were morphine usage in the first 8 and 24h postoperatively, numeric rating scores (NRS) up to 24h, sedation, nausea, vomiting, respiratory depression, pruritus and bleeding complications.Intention to treat analysis showed a mean increase in 4h VAS pain score of 7.9mm (95% CI: -4.5mm to 20.4mm) in patients administered 15mg ketorolac. This difference was neither statistically (P=0.207) nor clinically significant (18mm on VAS scale). A similar increase in the 15mg group was noted through a per protocol analysis, 6.9mm (95% CI: -6.6mm to 20.5mm, P=0.307) greater in the 15mg group. Non-inferiority of 15mg was not confirmed. No significant difference was found in secondary endpoints.Ketorolac 30mg intravenous was not superior to 15mg intravenous for post-operative pain management after spine surgery. However, 15mg failed to meet the pre-specified criteria for non-inferiority to the 30mg dose.

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.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.In 80 retrieved publications anesthetic treatment reduced neurologic injury by 28% (95% CI, 24 to 32%; P0.0001). 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.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.

BACKGROUND: Although a blood analog of aqueous glycerol and xanthan gum was found to replicate the viscoelastic behavior of blood, measurements were restricted to laminar flow. OBJECTIVE: To expand the characterization of a non-Newtonian blood analog of aqueous glycerol and xanthan gum to transitional Reynolds numbers to quantify its behavior as a function of both natural and shear-layer-induced mechanisms. METHODS: A Newtonian analog and a shear-thinning aqueous glycerol, xanthan gum solution were circulated through an in vitro flow loop replicating both a straight and obstructed artery where transition was initiated through natural and shearlayer-induced mechanisms respectively. Steady and pulsatile pressure drop measurements for both fluids were acquired across a range of Reynolds numbers up to 7600 and Womersley numbers of 4 and 6. RESULTS: In steady and pulsatile straight flow, the non-Newtonian analog presented with reduced pressure drops and prolonged laminar flow to Reynolds numbers of 3200 and 3800 respectively. Upon blockage inclusion, non-Newtonian minor losses were comparable to Newtonian in steady flow and greater in pulsatile flow suggesting an elongation of downstream non-Newtonian recirculation. Although non-Newtonian total system pressure drops in both straight and obstructed flows were lower, the ratio of pressure drop difference between the two fluids decreased through shear-layer-induced transition. CONCLUSIONS: These findings not only demonstrated the suitability of using a xanthan gum analog to model blood flow in transitional regimes, but also presented the respective differences in analog behavior as a function of transition mechanism.

Particle image velocimetry (PIV) was used to investigate the influence of a non-Newtonian blood analog of aqueous xanthan gum on flow separation in laminar and transitional environments and in both steady and pulsatile flow. Initial steady pressure drop measurements in laminar and transitional flow for a Newtonian analog showed an extension of laminar behavior to Reynolds number (Re) ~ 2900 for the non-Newtonian case. On a macroscale level, this showed good agreement with porcine blood. Subsequently, PIV was used to measure flow patterns and turbulent statistics downstream of an axisymmetric stenosis in the aqueous xanthan gum solution and for a Newtonian analog at Re ~ 520 and Re ~ 1250. The recirculation length for the non-Newtonian case was reduced at Re ~ 520 resultant from increased viscosity at low shear strain rates. At Re ~ 1250, peak turbulent intensities and turbulent shear stresses were dampened by the non-Newtonian fluid in close proximity to the blockage outlet. Although the non-Newtonian case's recirculation length was increased at peak pulsatile flow, turbulent shear stress was found to be elevated for the Newtonian case downstream from the blockage, suggesting shear layer fragmentation and radial transport. Our findings conclude that the xanthan gum elastic polymer prolongs flow stabilization, which in turn emphasizes the importance of non-Newtonian blood characteristics on the resulting flow patterns in such cardiovascular environments.

Although information pertaining to the viscous characterization of HES 130/0.4 Voluven® and HES 260/0.45 Pentaspan® is available, quantification is limited to 100% concentrations. We focus here on the quantification of their viscous behavior along with HES 130/0.4 Volulyte® in a shear thinning non-Newtonian blood analog of aqueous xanthan gum and glycerol. Dynamic viscosities of multiple batches of HES fluids were measured through capillary viscometry. The viscous behavior of 100%, 25% and 12.5% concentrations were then measured through a closed flow loop across physiologically relevant flow rates. Measured viscosities were 2.57 millipascal second (mPa·s) 6.52 mPa·s and 2.48 mPa·s for HES 130/0.4 Voluven®, HES 260/0.45 and HES 130/0.4 Volulyte®, respectively. Pipe flow analysis found that all HES fluids displayed Newtonian behavior at 100% concentrations. 25% concentrations of both HES 130/0.4 fluids decreased analog viscosity 23%-29% at a flow rate of 1.0 ml/s and 16%-21% at a flow rate of 22.5 ml/s. At a flow rate of 22.5 ml/s, 25% and 12.5% concentrations of HES 260/0.45 resulted in analog viscosity changes of 3.9%-4.5%. Capillary viscosity reductions of approximately 7% and 14.5% in HES 130/0.4 Voluven® and HES 260/0.45 suggest changes in molecular composition to batches previously measured. Maintenance of analog viscosity suggests that HES 260/0.45 would be suitable as a high viscosity plasma expander in extreme hemodilution through preservation of microcirculatory function and wall shear stress (WSS).

Array-based comparative genome hybridization (aCGH) is a powerful, data-intensive technique used to identify genomic copy number variation throughout the human genome. The use of aCGH clinically to identify pathogenic copy number aberrations is becoming common, and the statistical and mathematical algorithms used in aCGH data analysis play an important role in determining the performance of these platforms. Interpretation of aCGH data can be complicated by a platform-independent technical artifact described as GC-waves, which are wave patterns in CGH data correlating to regional GC-content of the human genome that can reduce the clinical specificity and sensitivity of aCGH platforms. We describe an automated GC-wave correction algorithm and techniques to understand how the correction affects the analytical performance of aCGH. This GC-correction algorithm was effective at mitigating GC-wave effects. After correction, array data were measurably improved by the algorithm, demonstrating improvements in specificity and sensitivity and in overall data quality.

Objective. There is increasing evidence of adverse outcomes associated with blood transfusions for adult traumatic brain injury patients. However, current evidence suggests that pediatric traumatic brain injury patients may respond to blood transfusions differently on a vascular level. This study examined the influence of blood transfusions and anemia on the outcome of pediatric traumatic brain injury patients.Design. A retrospective cohort analysis of severe pediatric traumatic brain injury (TBI) patients was undertaken to investigate the association between blood transfusions and anemia on patient outcomes.Measurements and Main Results. One hundred and twenty patients with severe traumatic brain injury were identified and included in the analysis. The median Glasgow Coma Scale (GCS) was 6 and the mean hemoglobin (Hgb) on admission was 115.8 g/L. Forty-three percent of patients (43%) received at least one blood transfusion and the mean hemoglobin before transfusion was 80.1 g/L. Multivariable regression analysis revealed that anemia and the administration of packed red blood cells were not associated with adverse outcomes. Factors that were significantly associated with mortality were presence of abusive head trauma, increasing PRISM score, and low GCS after admission.Conclusion. In this single centre retrospective cohort study, there was no association found between anemia, blood transfusions, and hospital mortality in a pediatric traumatic brain injury patient population.

Background: Spinal muscular atrophy (SMA) is the most common inherited lethal disease of children. Various genetic deletions involving the bi-allelic loss of SMN1 exon 7 are reported to account for 94% of affected individuals. Published literature places the carrier frequency for SMN1 mutations between 1 in 25 and 1 in 50 in the general population. Although SMA is considered to be a pan-ethnic disease, carrier frequencies for many ethnicities, including most ethnic groups in North America, are unknown. Objectives and methods: To provide an accurate assessment of SMN1 mutation carrier frequencies in African American, Ashkenazi Jewish, Asian, Caucasian, and Hispanic populations, more than 1000 specimens in each ethnic group were tested using a clinically validated, quantitative real-time polymerase chain reaction (PCR) assay that measures exon 7 copy number. Results: The observed one-copy genotype frequency was 1 in 37 (2.7%) in Caucasian, 1 in 46 (2.2%) in Ashkenazi Jew, 1 in 56 (1.8%) in Asian, 1 in 91 (1.1%) in African American, and 1 in 125 (0.8%) in Hispanic specimens. Additionally, an unusually high frequency of alleles with multiple copies of SMN1 was identified in the African American group (27% compared to 3.3–8.1%). This latter finding has clinical implications for providing accurate adjusted genetic risk assessments to the African American population. Conclusions: Differences in the frequency of SMA carriers were significant among several ethnic groups. This study provides an accurate assessment of allele frequencies and estimates of adjusted genetic risk that were previously unavailable to clinicians and patients considering testing.

The quantification of Lagrangian coherent structures (LCS) has been investigated using an algorithm based on the tesselation of unstructured data points. The applicability of the algorithm in resolving an LCS was tested using a synthetically generated unsteady double-gyre flow and experimentally in a nominally two-dimensional free shear flow. The effects of two parameters on LCS identification were studied: the threshold track length used to quantify the LCS and resulting effective seeding density upon applying the threshold. At lower threshold track lengths, increases in the threshold track length resulted in finite-time Lyapunov exponent (FTLE) field convergence towards the expected LCS ridge of the double-gyre flow field at several effective seeding densities. However, at higher track lengths, further increases to the threshold track length failed to improve convergence at low effective seeding densities. The FTLE of the experimental data set was well-resolved using moderate threshold track lengths that achieved field convergence but maintained a sufficiently high seeding density. In contrast, the use of lower or higher track lengths produced an FTLE field characterized by an incoherent LCS ridge. From the analytical and experimental results, recommendations are made for future experiments for identifying LCS directly from unstructured data.

Gene expression profiling was performed on central nervous system (CNS) tissue from neonatal mice carrying the T9H translocation and maternal or paternal duplication of proximal Chromosomes 7 and 15. Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the Prader-Willi/Angelman Syndrome (PW/AS) locus. The transcripts were termed Pec2 and Pec3, for paternally expressed in the CNS. Imprinting of these transcripts was confirmed by sequencing of RT-PCR products in F(1) hybrids between Mus musculus musculus C57BL/6 and Mus musculus castaneus, following identification of single nucleotide polymorphisms between the two strains. Imprinting of Pec2 was also confirmed by Northern blot analysis. The two transcripts are separated by 0.5 Mb and are transcribed in the same orientation. They are located in a long interspersed transposable element (LINE)-rich region midway between the PW/AS imprinting center and the paternally expressed genes Ndn, Magel2, and Mkrn3, which are under imprinting center control. Our analysis also revealed imprinting of Magel2, Mkrn3, Ndn, Ube3a, and Usp29, as well as Pec2 and Pec3, in embryonic brain 15.5 dpc, and provided a survey of biallelically expressed genes on proximal Chrs 7 and 15 in embryonic and neonatal CNS.

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.

Echo particle image velocimetry (Echo PIV) presents itself as an attractive in vivo flow quantification technique to traditional approaches. Promising results have been acquired; however, limited quantification and validation is available for post-stenotic flows. We focus here on the comprehensive evaluation of in vitro downstream stenotic flow quantified by Echo PIV and validated in relation to digital particle image velocimetry (DPIV). A Newtonian blood analog was circulated through a closed flow loop and quantified immediately downstream of a 50 % axisymmetric blockage at two Reynolds numbers (Re) using time-averaged Echo PIV and DPIV. Centerline velocities were in good agreement at all Re; however, Echo PIV measurements presented with elevated standard deviation (SD) at all measurements points. SD was improved using increased line density (LD); however, frame rate or field of view (FOV) is compromised. Radial velocity profiles showed close agreement with DPIV with the largest disparity in the shear layer and near-wall recirculation. Downstream recirculation zones were resolved by Echo PIV at both Re; however, magnitude and spatial coverage was reduced compared to DPIV that coincided with reduced contrast agent penetration beyond the shear layer. Our findings support the use of increased LD at a cost to FOV and highlight reduced microbubble penetration beyond the shear layer. High local SD at near-wall measurements suggests that further refinement is required before proceeding to in vivo quantification studies of wall shear stress in complex flow environments.

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.

The leukocyte common antigen (CD45) is alternatively spliced, generating various isoforms expressed on hemopoietic cells. The splicing pattern of CD45 in T cells is altered in some individuals who show abnormal expression of high molecular weight isoforms containing exon A. The variant splicing pattern was shown to be associated with heterozygosity for a silent point mutation within CD45 exon A. This C to G transition is located 77 nucleotides downstream of the splice acceptor junction of exon A (198 bp total length). Here we report that this mutation is the cause of abnormal splicing. To isolate the mutant gene, somatic cell hybrids of lymphocytes with a CD45 splicing defect and a mouse lymphoid line were produced and clones expressing different isoforms of CD45 were isolated. Expression of the high molecular weight isoform containing exon A was associated with the mutation within exon A. All hybrids expressing the low molecular weight isoforms lacking exon A contained the normal allele of CD45 only. In addition, minigenes including this mutation were constructed and transfected into various cell lines (COS-7, HeLa, CHO). Semi-quantitative reverse transcription polymerase chain reaction showed an increase of more than tenfold in splicing to CD45RA (concomitant with a decrease in splicing to CD45RO) when compared with the normal minigene. Taken together, these results demonstrate a causal relationship between the mutation in CD45 exon A and the variant splicing pattern observed. The involvement of trans-acting splicing factors that interact with this region of CD45 pre-mRNA is currently under investigation.

The assumption of Newtonian behavior to characterize circulating blood is applicable to large, healthy, arteries of the vasculature. However, at low shear strain rates, blood displays marked non-Newtonian behavior resulting from red blood cell adhesion. Consequently, the consideration of non-linear viscous behavior may be of critical importance to accurately quantify critical hemodynamic parameters in separated flow regimes associated with low shear strain rates (1). Walker et al. (1) measured noteworthy reductions in the propagation of negative axial velocities and oscillatory shear patterns downstream of a stent wire using a non-Newtonian blood analog while Choi and Barakat (2) used CFD to predict non-Newtonian reductions in recirculation length downstream of a backward facing step.Copyright © 2013 by ASME

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.

A case of acute myelogenous leukemia (AML) French-American-British (FAB)-type M5b is described, secondary to myelodysplastic syndrome (MDS), in which a primary clone containing a dup (1)(p22p36) and a subclone containing dup(1)(p22p36), dup(1)(p22p36), were identified. This is believed to be a novel mutation in AML.

Stent strut configuration has been found to alter local fluid flow and wall shear stress (WSS) patterns that can promote intimal hyperplasia. To quantify these alterations, we used particle image velocimetry (PIV) to investigate local fluid dynamics distal to a deployed stent within an acrylic tube. A blood analogue mixture of glycerol and water was pumped through a flow loop in both steady and pulsatile conditions. Steady and pulsatile velocity profiles and near WSS (NWSS) predicted by PIV were in good agreement with the Poiseuille and Womersley estimations. Introduction of a Palmaz balloon expanded slotted tube stent increased centerline velocities between 6.9% and 9% and decreased NWSS distal from the stent outlet by > 40%. Peak normalized vorticity was similar between non-stented and stented flows, although spatial coverage of higher vorticity was increased upon stent introduction. Future work will incorporate Echo PIV to complement PIV findings on how strut configuration affects flow dynamics.Copyright © 2012 by ASME

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. 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. 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. 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 intravenous fluid of choice for acute blood volume replacement remains controversial. We focus here on the two hydroxyethyl (HES) available in Canada: HES 130/0.40 (Voluven®) and HES 260/0.45 (Pentaspan®). Although information regarding their pharmacokinetic and risk/benefit profiles are available, how the infusion of these fluids could affect blood viscosity and vascular endothelial function in humans is largely unknown. Dynamic viscosity was measured at 21°C and 37°C through capillary viscometry. The HES solutions were driven through a closed flow loop at room temperature (21°C). Viscosity at 21°C was 7.62 centipoise (cP) for HES 260/0.45 and 2.73 cP for HES 130/0.40 decreasing to 4.23 cP for HES 260/0.45 and 1.72 cP for HES 130/0.40 at 37°C. Analysis of viscous behaviour through pipe flow found that HES 260/0.45 displayed marginal variations in viscosity suggesting Newtonian behaviour across our range of Re measured. HES 130/0.40 displayed an appreciable increase in viscosity at higher Re suggesting the presence of shear thickening behaviour. Human aortic endothelial cells (HAEC) and human microvascular endothelial cells (HMVEC) were exposed to the HES solutions and saline to identify chemical effects on vascular endothelium. Western blot quantification showed that E-selectin was the leukocyte adhesion receptor that was most strongly affected, and this was not dose dependent. Interestingly, HAEC and HMVEC had different responses to HES treatment, suggesting that different vascular tissues may have different outcomes to HES infusion. Protein expression in HMVEC decreased when exposed to both HES solutions.Copyright © 2010 by ASME