Washout Time Research Articles

Biogeography Inspired Optimization Approaches for Optimal Sizing of PSS to Mitigate Electromechanical Mode Oscillations in Power System

This paper presents an application of biogeography inspired optimization methods to enhance the rotor angle stability by mitigating the electromechanical mode oscillations in the presence of Power System Stabilizer (PSS) with a proposed multi objective mathematical model of minimizing damping factor and maximizing the damping ratio in anelectric power system. Newly proposed meta-heuristic optimization techniques named as Biogeography Based Optimization (BBO) and Oppositional Biogeography Based Optimization (OBBO) are utilized to explore the optimal sizing of PSS parameters such as gain, lag-lead time constants and washout time constant. These advances are tested in two area four machine (kundur system) and typical New York-New England (NYNE) (16-machine, 68 buses) interconnected system at different scenarios to show the performance and effectiveness of the proposed methods. Results obtained for both eigenvalue analysis and nonlinear time domain transient analysis are reassuring the validity of the proposed methods for the effective mitigation of electromechanical mode oscillations compared with Genetic Algorithm (GA), Artificial Bee Colony (ABC), BBO and Sequential Quadratic Programming based ABC (ABC-SQP) approaches.

Comparison of functional ramp walk test and 6-min walk test in healthy volunteers: A new approach in functional capacity evaluation

Objective: Inclined surfaces or ramps are the common obstacles faced by elderly and cardiopulmonary disabled in accessing public amenities. Ramp walking is one of the most common functional demands to be met by a common man in the industrialized world. To assess the functional (uphill walking) capacity, we need a different functional stress test over the routinely used 6-min walk test (6MWT). Hence, a new 3-min steep ramp walk test (3MRWT) was constructed to meet the demands similar to an uphill walk and to provide more functional stress than routinely used 6MWT. Methodology: The observational, crossover study design was adopted for this study. Fifteen healthy participants (8 males, 7 females) performed both tests in a randomized order with a washout time of 6 h in between the tests. Walking distance to both ramp and ground, heart rate, blood pressure, saturation (SpO2), dyspnea, and fatigue with Borg exertion scale were compared prior and after the two walk tests. Results: The average distances covered in 6MWT were 510.5 ± 55.06 and 440.65 ± 25.08 meters and in 3MRWT were 270.18 ± 30.8, 230.05 ± 15.06 meters for male and female respectively. The difference between 3MRWT and 6MWT distances covered by the participants was statistically significant (t = 0.893). The mean difference between the heart rate, saturation and perceptions were highly significant (P < 0.001). Conclusion: The study results show that 3MRWT is valid over routinely administered 6MWT and may provide greater functional stress (uphill or ramp walk capacity) in a shorter duration in healthy individuals in assessing the maximal functional capacity in a ramp or uphill walking.

Bioequivalence of Two Prolonged-Release Diclofenac Sodium Formulations in Healthy Volunteers: A Randomized, Crossover, Double-Blind Study

Background: The implementation of generic drug development programs constitutes a basic component of the global health policy. The aim of this work is to determine the existence of bioequivalence between two prolonged release diclofenac sodium formulations in healthy volunteers. Methods: A phase I, randomized, crossover, double-blind clinical trial was conducted where pharmacokinetics in plasma and biological safety of Voltaren Retard® (reference formulation) and a generic prolonged-release Cuban diclofenac sodium formulation were compared. The sampling period was 24 hours, with a washout time of 15 days between each one. All subjects received, orally, a single dose of 100 mg (one tablet) of the corresponding formulation in each period. Results: Thirty-six volunteers, the half women, with a mean age of 33 years were included. White skin subjects were 56%. The quantification of diclofenac sodium in plasma by HPLC demonstrated a high similitude between formulations. The mean values of the pharmacokinetic parameters were: AUC24 (4924 vs. 4928 ng.h/mL), AUCinf (5046 vs. 5054 ng.h/mL), Cmax (1047 vs. 1042 μg/mL), t1/2 2.25 vs. 2.25 h), Median Tmax was 2 hours for both formulations. The preparations could be considered as bioequivalent according to ANOVA and 90% CI analysis. No formulation, period, sequential and residual effects were detected. The adverse events were mild, well tolerated, with a low frequency of onset. The most frequent events were hypertension, headache and increase in transaminases and urea values, registered in less than 10% of the subjects. Conclusion: Cuban prolonged-release diclofenac sodium formulation was bioequivalent with the commercial reference formulation Voltaren Retard®.

The study on hepatic epithelioid hemangioendothelioma by contrast-enhanced ultrasound

Objective To investigate the value of contrast enhanced ultrasonography(CEUS) in the diagnosis of hepatic epithelioid hemangioendothelioma(HEHE). Methods The images of CEUS had been retrospectively evaluated in 21 lesions of HEHE which were confirmed by pathology. The perfusion patterns and time of enhancement were observed,including time to begin enhancement,time to peak enhancement,the washout time and the appearance of internal structures. Results The mean time of begin enhancement,time to peak,time to isoechogenity and hypoechogenity were (17.4±5.2)s,(22.0±7.2) s,(23.9±4.6)s and (42.2±13.7)s,respectively. During the arterial phase,8 lesions showed diffuse enhancement,7 lesions showed rim-like enhancement and 6 lesions showed branch enhancement. The inner margin in 6 lesions showed speculate enhancement. The central portion of the tumors was not enhanced in part lesions of 8 cases. As to time of peak enhancement,compared to the normal hepatic parenchyma,hypoenhancement,isoenhancement and hyperenhancement were observed in 10 lesions,6 lesions and 5 lesions respectively. Synchronous enhancement was observed in 11 lesions on CEUS,rapid enhancement was observed in 8 lesions and slow enhancement was observed in 2 lesions. Twenty-one lesions manifested hypoechoic mass in portal phase and delayed phase. The boundary of lesions was unclear on conventional ultrasound and became distinct after contrast injection in 21 lesions. Conclusions CEUS is useful for the diagnosis of HEHE. Key words: Contrast-enhanced ultrasound; Liver neoplasms; Hemangioendothelioma,epithelioid

Influence of Animal Heating on PET Imaging Quantification and Kinetics: Biodistribution of 18F-Tetrafluoroborate and 18F-FDG in Mice.

Different environmental conditions under anesthesia may lead to unstable homeostatic conditions in rodents and therefore may alter kinetics. In this study, the impact of different heating conditions on PET imaging quantification was evaluated. Methods: Two groups of 6 adult female BALB/c nude mice with subcutaneously implanted tumors underwent microPET imaging after injection of 18F-labeled tetrafluoroborate or 18F-FDG. Dynamic scans were acquired under optimal and suboptimal heating conditions. Time-activity curves were analyzed to calculate uptake and washout time constants. Results: With 18F-labeled tetrafluoroborate, optimal animal heating led to a stable heart rate during acquisition (515 ± 35 [mean ± SD] beats/min), whereas suboptimal heating led to a lower heart rate and a higher SD (470 ± 84 beats/min). Both uptake and washout time constants were faster (P < 0.01) in animals maintained with optimal heating. Conclusion: Although the difference in heart rates was slight, optimal heating yielded significantly faster uptake and washout kinetics than suboptimal heating in all organs for both tracers.

Numerical prediction of thrombus risk in an anatomically dilated left ventricle: the effect of inflow cannula designs.

BackgroundImplantation of a rotary blood pump (RBP) can cause non-physiological flow fields in the left ventricle (LV) which may trigger thrombosis. Different inflow cannula geometry can affect LV flow fields. The aim of this study was to determine the effect of inflow cannula geometry on intraventricular flow under full LV support in a patient specific model.MethodsComputed tomography angiography imaging of the LV was performed on a RBP candidate to develop a patient-specific model. Five inflow cannulae were evaluated, which were modelled on those used clinically or under development. The inflow cannulae are described as a crown like tip, thin walled tubular tip, large filleted tip, trumpet like tip and an inferiorly flared cannula. Placement of the inflow cannula was at the LV apex with the central axis intersecting the centre of the mitral valve. Full support was simulated by prescribing 5 l/min across the mitral valve. Thrombus risk was evaluated by identifying regions of stagnation. Rate of LV washout was assessed using a volume of fluid model. Relative haemolysis index and blood residence time was calculated using an Eulerian approach.ResultsThe inferiorly flared inflow cannula had the lowest thrombus risk due to low stagnation volumes. All cannulae had similar rates of LV washout and blood residence time. The crown like tip and thin walled tubular tip resulted in relatively higher blood damage indices within the LV.ConclusionChanges in intraventricular flow due to variances in cannula geometry resulted in different stagnation volumes. Cannula geometry does not appreciably affect LV washout rates and blood residence time. The patient specific, full support computational fluid dynamic model provided a repeatable platform to investigate the effects of inflow cannula geometry on intraventricular flow.

Parametric imaging with contrast-enhanced ultrasound for differentiating hepatocellular carcinoma from metastatic liver cancer.

To evaluate the diagnostic performance of parametric imaging with contrast-enhanced ultrasound(CEUS) for differentiating hepatocellular carcinoma(HCC) from metastatic liver cancer(MLC). 30 HCCs (mean diameter, 3.6±1.3 cm; range, 2.1-5.0 cm) and 30 MLCs (mean diameter, 2.8±1.5 cm; range, 1.2-5.0 cm) pathologically diagnosed or confirmed by clinical criteria that underwent CEUS were randomly included. CEUS was carried out using a multifrequency transducer (2-4 MHz) and a bolus injection of 2.4 mL SonoVue. The CEUS clips of the targeted lesion were recorded continuously for 6 minutes. By analyzing CEUS clips, parametric image could be obtained using the SonoLiver® software automatically. Quantitative parameters were compared between HCC and MLC groups. Receiver operating characteristic (ROC) curve analysis was further performed on parameters with significant difference between two groups. On parametric imaging, the maximum intensity, rise time, time to peak, mean transit time and washout time for HCC and MLC were 185.6±148.0 vs. 95.2±58.6 (P = 0.003), 25.7±6.3 s vs. 23.8±8.8 s (P = 0.341), 30.7±7.9 s vs. 27.8±10.5 s (P = 0.246), 90.2±45.7 s vs. 89.3±40.3 s (P = 0.805), 63.4±29.5 s vs. 37.2±33.8 s (P = 0.005), respectively. ROC analysis was further performed for washout time and it showed a cut-off point of 43.765 s for the differentiation between HCC and MLC, with the AUC value of 0.780 (95% CI: 0.646-0.914). The corresponding diagnostic specificity, sensitivity and accuracy were 72.0%, 84.6% and 78.4% respectively. Parametric imaging of CEUS can display perfusion effects of HCC and MLC objectively and visually and washout time may serve as a useful parameter on the differential diagnosis between HCC and MLC.

Clinical trial of modulatory effects of oxytocin treatment on higher-order social cognition in autism spectrum disorder: a randomized, placebo-controlled, double-blind and crossover trial.

BackgroundAutism spectrum disorders are neurodevelopmental conditions with severe impairments in social communication and interaction. Pioneering research suggests that oxytocin can improve motivation, cognition and attention to social cues in patients with autism spectrum disorder. The aim of this clinical trial is to characterize basic mechanisms of action of acute oxytocin treatment on neural levels and to relate these to changes in different levels of socio-affective and -cognitive functioning.MethodsThis clinical study is a randomized, double-blind, cross-over, placebo-controlled, multicenter functional magnetic resonance imaging study with two arms. A sample of 102 male autism spectrum disorder patients, diagnosed with Infantile Autistic Disorder (F84.0 according to ICD-10), Asperger Syndrome (F84.5 according to ICD-10), or Atypical Autism (F84.1 according to ICD-10) will be recruited and will receive oxytocin and placebo nasal spray on two different days. Autism spectrum disorder patients will be randomized to determine who receives oxytocin on the first and who on the second visit. Healthy control participants will be recruited and case-control matched to the autism spectrum disorder patients. The primary outcome will be neural network activity, measured with functional magnetic resonance imaging while participants perform socio-affective and -cognitive tasks. Behavioral markers such as theory of mind accuracy ratings and response times will be assessed as secondary outcomes in addition to physiological measures such as skin conductance. Trait measures for alexithymia, interpersonal reactivity, and social anxiety will also be evaluated. Additionally, we will analyze the effect of oxytocin receptor gene variants and how these potentially influence the primary and secondary outcome measures. Functional magnetic resonance imaging assessments will take place at two time points which will be scheduled at least two weeks apart to ensure a sufficient wash-out time after oxytocin treatment. The study has been approved by an ethical review board and the competent authority.DiscussionRevealing the mechanisms of acute oxytocin administration, especially on the socio-affective and -cognitive domains at hand, will be a further step towards novel therapeutic interventions regarding autism.Trial registrationGerman Clinical Trial Register DRKS00010053. The trial was registered on the 8th of April 2016

Slurry micro-sampling technique for use in argon-helium microwave induced plasma optical emission spectrometry

The Flow Focusing Pneumatic Nebulizer (FFPN) working at low liquid flow rates was evaluated for the elemental analysis in slurried samples by argon-helium microwave induced plasma optical emission spectrometry (MIP-OES). The obtained results achieved were compared with commercially available V-groove Babington type nebulizer (VBPN). A univariate approach and the simplex optimization procedure were used to achieve optimized conditions and derive analytical figures of merit.Analytical performance of the micro nebulization system was characterized by a determination of the limits of detection (LODs), the precision (RSDs) and the wash-out times for Ba, Ca, Cd, Cu, Fe, Mg, Mn, Pb and Sr. The experimental concentration detection limits for simultaneous determination, calculated as the concentration giving a signal equal to three times of the standard deviation of the blank (LOD, 3σblank criterion, peak height) were 0.9, 0.2, 0.3, 0.2, 0.3, 0.1, 0.2, 0.4, 0.4 and 0.3ngmL−1 for Ba, Ca, Cd, Cu, Fe, Mg, Mn, Pb and Sr, respectively. The method offers relatively good precision (RSD ranged from 5% to 8%) for micro-slurry sampling analysis. Analyses of the certified reference materials (NRCC DOLT-2, GBW 07302 and SRM 2710) were performed in order to determine the accuracy available with the presented nebulization systems. The measured contents of elements in the reference materials were in satisfactory agreement with the certified values. In addition, these elements were determined in two real samples.Slurry concentration up to 3% m/v (particles <20μm), prepared in 10% m/v HCl through the application of ultrasonic agitation, was used with calibration by the standard addition technique. An ultrasonic probe was used to homogenize the slurry in the polypropylene bottle just before its introduction into the nebulizer. The nebulizers exhibited no clogging problems.

Double-blind Randomized Controlled Trial of Intranasal Dexmedetomidine Versus Intranasal Midazolam as Anxiolysis Prior to Pediatric Laceration Repair in the Emergency Department.

The objective of this study was to compare anxiolysis with intranasal dexmedetomidine, an alpha-2 agonist, versus intranasal midazolam for pediatric laceration repairs. We performed a double-blind, randomized controlled trial of 40 patients 1-5years with lacerations requiring suture repair in an academic pediatric emergency department (ED). Patients were randomized to receive either intranasal dexmedetomidine or intranasal midazolam. Our primary outcome measure was the anxiety score at the time of patient positioning for the laceration repair. We chose this time point to isolate the anxiolysis from the medications prior to intervention. Patient encounters were videotaped and scored for anxiety at multiple time points using the modified Yale Preoperative Anxiety Scale. The scale is 23.3-100 with higher scores indicating higher anxiety. We also evaluated these scores as a secondary outcome by dichotomizing them into anxious versus not anxious with a previously validated score cutoff. Of the 40 patients enrolled, 20 in the dexmedetomidine group and 18 in the midazolam group completed the study and were included in the analysis. The median age was 3.3years (range=1.0-5.4years). The median baseline anxiety score was 48.3. The anxiety score at position for procedure for patients receiving dexmedetomidine was 9.2 points lower than those receiving midazolam (median difference=9.2, 95% confidence interval=5 to 13.3; median scorefor dexmedetomidine=23.3, median score for midazolam=36.3). The proportion of patients who were classified as not anxious at the position for procedure was significantly higher in the dexmedetomidine group (70%) versus the midazolam group (11%). The number needed to treat with dexmedetomidine instead of midazolam to obtain the result of a not anxious patient at this time point was 1.7 patients. There were also significantly more patients who were classified as not anxious at the time of wound washout in the dexmedetomidine group compared to the midazolam group (35% vs. 6%). Dexmedetomidine and midazolam performed similarly with respect to all other measures including anxiety at other time points, parental perceived anxiety, parent and proceduralist satisfaction, procedural success, complications, and time in the ED. There were no serious adverse events seen in either group. Intranasal dexmedetomidine is an alternative anxiolytic medication to intranasal midazolam for pediatric laceration repairs, performing similarly in our study, except that patients who received dexmedetomidine had less anxiety at the time of positioning for procedure.

Abstract CT149: Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study

Abstract Veliparib is a potent oral poly(ADP-ribose) polymerase inhibitor that impairs DNA damage repair and shows single-agent activity in tumors with homologous recombination repair defects as well as in combination with DNA-damaging chemotherapies. Nonclinical studies suggested a potential risk of QT prolongation at the peak plasma concentration (Cmax) achieved at the maximum tolerated dose for veliparib monotherapy (400 mg twice daily). This phase 1, single-dose, double-blind, placebo (PBO)-controlled, randomized crossover study (NCT02009631) evaluated the effect of veliparib on corrected QT (QTc) interval in patients (pts) with relapsed/refractory solid tumors. Methods: Eligible pts (?18 years) with metastatic or unresectable solid tumors and ECOG PS ?1 received single-dose oral veliparib (200 mg [V200], 400 mg [V400]) or PBO in a 6-sequence, 3-period crossover design, with ?3-day interperiod washout time. The primary objective was to assess the effect of veliparib on QT interval with Fridericia's correction (QTcF). Lack of clinically relevant effect on QTc interval was shown if the 95% upper confidence bound (UCB) for the maximum baseline-adjusted QTcF difference between veliparib and PBO (??QTcF) for the 400 mg dosing was &amp;lt;10 msec (ICH E14 guidelines). Pharmacokinetics and safety were also evaluated. Results: Forty-seven pts (85% female; median age 58 years) were enrolled and analyzed. After single-dose administration, maximum ??QTcF of V400 compared to PBO was 6.4 msec with a 95% UCB of 8.9 msec; for V200 the maximum ??QTcF was 3.6 msec, with a 95% UCB of 6.1 msec. Mean time to maximum plasma concentration (Tmax) was similar for V200 (2.4 ± 0.7 h) and V400 (2.5 ± 0.6 h). Mean Cmax was 1.32 ± 0.38 μg/mL and 2.61 ± 0.85 μg/mL, and total exposure (AUC?) was 12.0 ± 3.98 μg•h/mL and 25.5 ± 8.37 μg•h/mL, for V200 and V400, respectively. Treatment-emergent adverse events (TEAEs) were experienced by 36.2%, 48.9%, and 47.8% of pts while receiving V200, V400, and placebo, respectively. Most common TEAEs were nausea (12.8%) and myalgia (8.5%) while receiving V200; nausea (8.5%) and vomiting (8.5%) while receiving V400; and nausea (6.5%) while receiving PBO. TEAEs were mainly grade 1/2, with grade 3 vomiting and depression experienced by 1 pt each. The most common TEAE possibly related to study drug was nausea (19.1%), reported in 8.5%, 6.4%, and 4.3% of pts while receiving V200, V400, and PBO, respectively. One pt discontinued treatment after the V200-V400 sequence due to study drug-unrelated AEs. There were no deaths or serious AEs. Conclusions: Single-dose veliparib (200 or 400 mg) did not exhibit clinically relevant QT prolongation greater than the 10 msec threshold per ICH E14 guideline. Citation Format: Wijith Munasinghe, Anthony Tolcher, Emiliano Calvo, Michael Gordon, Mathilde Jalving, Judith de Vos-Geelen, Diane M. Medina, Dennis M. Bergau, Silpa Nuthalapati, David M. Hoffman, Stacie L. Shepherd, Hao Xiong. Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT149.

Isocapnic hyperventilation shortens washout time for sevoflurane - an experimental in vivo study.

Isocapnic hyperventilation (IHV) is a method that fastens weaning from inhalation anaesthesia by increasing airway concentration of carbon dioxide (CO2 ) during hyperventilation (HV). In an animal model, we evaluated a technique of adding CO2 directly to the breathing circuit of a standard anaesthesia apparatus. Eight anaesthetised pigs weighing 28 ± 2 kg were intubated and mechanically ventilated. From a baseline ventilation of 5 l/min, HV was achieved by doubling minute volume and fresh gas flow. Respiratory rate was increased from 15 to 22/min. The CO2 absorber was disconnected and CO2 was delivered (DCO2 ) to the inspiratory limb of a standard breathing circuit via a mixing box. Time required to decrease end-tidal sevoflurane concentration from 2.7% to 0.2% was defined as washout time. Respiration and haemodynamics were monitored by blood gas analysis, spirometry, electric impedance tomography and pulse contour analysis. A DCO2 of 261 ± 19 ml/min was necessary to achieve isocapnia during HV. The corresponding FICO2 -level remained stable at 3.1 ± 0.3%. During IHV, washout of sevoflurane was three times faster, 433 ± 135 s vs. 1387 ± 204 s (P < 0.001). Arterial CO2 tension and end-tidal CO2 , was 5.2 ± 0.4 kPa and 5.6 ± 0.4%, respectively, before IHV and 5.1 ± 0.3 kPa and 5.7 ± 0.3%, respectively, during IHV. In this experimental in vivo model of isocapnic hyperventilation, the washout time of sevoflurane anaesthesia was one-third compared to normal ventilation. The method for isocapnic hyperventilation described can potentially be transferred to a clinical setting with the intention to decrease emergence time from inhalation anaesthesia.

Modelling levels of nitrous oxide exposure for healthcare professionals during EMONO usage.

BackgroundComputational fluid dynamics (CFD) has been used to compute nitrous oxide (N2O) levels within a room during the administration of an equimolar mix of N2O/oxygen (EMONO) in the clinical setting. This study modelled realistic scenarios of EMONO usage in hospital or primary care, in order to estimate the potential N2O exposure of healthcare professionals (HCP) with routine EMONO use and to provide guidance for EMONO users.MethodsSixteen scenarios were defined by carrying out a survey of practitioners. CFD simulations were performed for each scenario and N2O concentrations over time were calculated. N2O exposures (time-weighted average of concentration over 8 h [TWA-8 h]) were calculated at the HCPs’ mouth to be compared with a predefined occupational exposure limit (OEL).ResultsAdministration duration and ventilation type were the main factors influencing N2O levels; ventilation type also influenced wash-out time between EMONO administrations. N2O concentration showed a plume distribution towards the ceiling and was highly heterogeneous, highlighting the importance of measurement location. Although estimated TWA-8 h varied widely, 13 of the 16 scenarios had an N2O TWA-8 h of <100 parts per million.ConclusionsData demonstrate that EMONO usage in well ventilated rooms – as recommended – helps to ensure that N2O exposure does not exceed the OEL and does not signal any major risks for HCPs when recommendations are followed. Although these data are numerical simulations and should be considered as such, they can provide guidance for EMONO users.

Hydrophilic trans-Cyclooctenylated Noncanonical Amino Acids for Fast Intracellular Protein Labeling.

Introduction of bioorthogonal functionalities (e.g., trans-cyclooctene-TCO) into a protein of interest by site-specific genetic encoding of non-canonical amino acids (ncAAs) creates uniquely targetable platforms for fluorescent labeling schemes in combination with tetrazine-functionalized dyes. However, fluorescent labeling of an intracellular protein is usually compromised by high background, arising from the hydrophobicity of ncAAs; this is typically compensated for by hours-long washout to remove excess ncAAs from the cellular interior. To overcome these problems, we designed, synthesized, and tested new, hydrophilic TCO-ncAAs. One derivative, DOTCO-lysine was genetically incorporated into proteins with good yield. The increased hydrophilicity shortened the excess ncAA washout time from hours to minutes, thus permitting rapid labeling and subsequent fluorescence microscopy.

The Effect of Valve-in-Valve Implantation Height on Sinus Flow.

Valve-in-valve transcatheter aortic valve replacement (VIV-TAVR) has proven to be a successful treatment for high risk patients with failing aortic surgical bioprostheses. However, thrombus formation on the leaflets of the valve has emerged as a major issue in such procedures, posing a risk of restenosis, thromboembolism, and reduced durability. In this work we attempted to understand the effect of deployment position of the transcatheter heart valve (THV) on the spatio-temporal flow field within the sinus in VIV-TAVR. Experiments were performed in an in vitro pulsatile left heart simulator using high-speed Particle Image Velocimetry (PIV) to measure the flow field in the sinus region. The time-resolved velocity data was used to understand the qualitative and quantitative flow patterns. In addition, a particle tracking technique was used to evaluate relative thrombosis risk via sinus washout. The velocity data demonstrate that implantation position directly affects sinus flow patterns, leading to increased flow stagnation with increasing deployment height. The particle tracking simulations showed that implantation position directly affected washout time, with the highest implantation resulting in the least washout. These results clearly demonstrate the flow pattern and flow stagnation in the sinus is sensitive to THV position. It is, therefore, important for the interventional cardiologist and cardiac surgeon to consider how deployment position could impact flow stagnation during VIV-TAVR.

Using Monte Carlo simulation to determine optimal dosing regimen for cefetamet sodium for injection

The objective of the study was to use Monte Carlo simulation to determine the optimal treatment dosing regimen of the cefetamet sodium for injection by analysing the pharmacokinetics (PK) parameters in healthy Chinese volunteers, and antibacterial activity in vitro was also examined. A three-cross Latin square single-dose PK study was designed. Twelve healthy volunteers were randomized to receive 500, 1000, and 2000 mg of cefetamet sodium for IV infusion over 30 minutes in three periods sequentially; and the washout time in between periods was 3 days. The drug concentrations in plasma were analysed by high-performance liquid chromatography, and the PK parameters were calculated using DAS2.0 PK software. The peak concentrations (Cmax) at 0.5 hours were 37.78±7.29, 76.18±12.81, and 149.32±29.94 mg/l, the areas under concentration–time curve (AUC0–t) were 69.75±14.44, 139.06±22.62, and 278.54±53.12 mg h/l, and the elimination half-life (t1/2) were 1.69±0.19, 1.69±0.27, and 1.81±0.23 hours for 500, 1000, and 2000 mg of cefetamet sodium for injection, respectively. The disposition of cefetamet was appear to fit a two-compartment model with linear kinetics. Antibacterial activity in vitro showed that most Gram-negative bacteria, including non-extended-spectrum beta-lactamases (ESBL)-producing Enterobacter, Haemophilus influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae, were sensitive to cefetamet. The result of Monte Carlo simulation showed that the probability of target attainment for bactericidal response (%fT>MIC≧50%) for susceptible bacteria was reached at all three dosing regimens of 500 mg, q6h, 1000 and 2000 mg, q8h and q6h. Considering the efficacy, safety, and pharmacoeconomy comprehensively, we recommended the dosing regimen of 500 mg, q6h for further clinical treatment based on the principle of minimum daily dosage.

Quantifying fatty acid synthesis using heavy water: Enabling back‐to‐back studies

Studies aimed at modulating the contribution of de novo lipogenesis (DNL) to lipid homeostasis are of interest. For example, there appears to be an increased contribution of DNL in cases of dyslipidemia and adipose accretion suggesting that the inhibition of fatty acid synthesis may affect clinical phenotypes. Unfortunately, it is unclear whether inhibition of one specific step in the lipogenic pathway is more important than another. Heavy water (D2O) is generally considered to be a reliable isotopic tracer for quantifying DNL. In contrast to other tracers, D2O yields a homogeneous and quantifiable precursor labeling. However, a drawback of using D2O centers on the relatively long half‐life of water implying that one must wait a substantial time before performing repeat studies in the same subjects; this can create a bottleneck in the development and evaluation of novel therapeutics for inhibiting DNL especially in cases where one aims to use subjects as their own controls. We previously demonstrated the ability to perform back‐to‐back studies of glucose and cholesterol flux by administering multiple doses of D2O and therein circumvent an extensive washout time; presumably these “tricks” can help minimize resources and decrease the turnaround time when testing hypotheses. Herein we now demonstrate the ability to perform back‐to‐back studies of DNL using D2O. However, we have identified special circumstances that limit some aspects of the data analysis, i.e. it is possible to obtain what appear to be negative values for DNL. Using a rodent model we have identified the physiological mechanism that explains the data. We show that one can use D2O to test inhibitors of DNL by performing back‐to‐back studies in higher species (i.e. treat non‐human primates with platensimycin, an inhibitor of fatty acid synthase).Support or Funding InformationAll authors were employed by Merck while this work was being done.

MP32-14 CYSTOSCOPY AND BLADDER WASHOUT FOR RECURRENT URINARY TRACT INFECTIONS IN RENAL TRANSPLANT RECIPIENTS

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation & Vascular Surgery II1 Apr 2016MP32-14 CYSTOSCOPY AND BLADDER WASHOUT FOR RECURRENT URINARY TRACT INFECTIONS IN RENAL TRANSPLANT RECIPIENTS Andre Thomas, Benjamin Sherer, and Oyedolamu Olaitan Andre ThomasAndre Thomas More articles by this author , Benjamin ShererBenjamin Sherer More articles by this author , and Oyedolamu OlaitanOyedolamu Olaitan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1309AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urinary tract infection (UTI) is the most common infection in renal transplant recipients (RTRs) and a major cause of morbidity; it is associated with the development of impaired allograft function, allograft loss and increased mortality. The aim of this study is to assess the effect of cystoscopy with bladder washout on the incidence of UTI in RTRs with recurrent complicated urinary tract infections. METHODS We offered cystoscopy with bladder washout to RTRs with recurrent UTIs (confirmed by positive urine culture) who had previously failed at least 2 courses of culture specific antibiotics. Bladder washout was performed via rigid cystourethroscopy under Monitored Anesthesia Care. The bladder was filled to capacity and emptied multiple times with a total of six liters of 0.9% sodium chloride irrigation fluid. We then evaluated for the number of UTIs in the six months pre and post bladder washout. RESULTS Thirty eight (29 female, 9 male) RTRs underwent cystoscopy with bladder washout performed by a single proceduralist between December 2013 and January of 2015. Mean age was 47.8 years. Mean time of bladder washout after renal transplantation was 3.65 years (range 9 months to 14 years). 17 patients (45%) were diabetic. All were on standard immunosuppression and PCP prophylaxis (with trimethoprim/sulfamethoxazole or diaminodiphenyl sulfone). None had a chronic ureteral stent in place. Post-procedurally, patients were followed with monthly urinalysis and culture. The number of UTI's in the 6 months prior to bladder washout (109) significantly decreased by 45% to 60 UTI's in the six months after bladder washout (p<0.02 via Wilcoxon signed rank test) CONCLUSIONS Cystoscopy with bladder washout appears to be effective method to decrease the frequency of UTI's in RTRs. Larger, controlled trials are necessary to confirm these findings. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e433 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Andre Thomas More articles by this author Benjamin Sherer More articles by this author Oyedolamu Olaitan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

New time-saving predictor algorithm for multiple breath washout in adolescents.

Multiple breath washout (MBW) is an informative but time-consuming test. This study evaluates the uncertainty of a time-saving predictor algorithm in adolescents. Adolescents were recruited from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC2000) birth cohort. MBW trials were performed at 13 y of age with Innocor model Inn00400 using sulfur hexafluoride (SF6) as tracer gas. Measurements were analyzed using a mixed model focusing on two prediction points doubling (t5%) and quadrupling (t10%) the standard end point (t2.5%). One hundred and seventy-two MBW trials conducted in 78 adolescents with and without asthma from COPSAC2000 were included. At t10%, the washout time (WoT) was reduced by 41%, and an uncertainty of 0.159 lung clearance index (LCI) units was introduced (±2 SD), ±1.27). At t5%, the WoT was reduced by 25%, with an uncertainty of 0.083 LCI units (±0.558). The optimal prediction point, which led to most saved time and least uncertainty was t5%. The predictor algorithm is capable of shortening the MBW test time but introduces an increasing uncertainty with earlier prediction points. This first-of-a-kind prediction algorithm holds promise in shortening the MBW test in children but should be used with caution in subjects with normal LCI values.

Abstract P6-13-22: Pharmacodynamics and consequences of PI3K inhibition in ER+ breast tumors

Abstract PI3K inhibitors have shown promise for the treatment of anti-estrogen-resistant ER+ breast cancers. Current PI3K inhibitor treatment regimens may incompletely and transiently inhibit the pathway in carcinomas, and are accompanied by significant adverse effects in patients. We hypothesized that short-term, complete inhibition of PI3K will have a greater anti-tumor effect and reduce systemic toxicity compared to chronic, partial inhibition. Pharmacokinetic analysis of the orally available pan-PI3K inhibitor GDC-0941 at low (100 mg/kg) and high (800 mg/kg) doses in mice revealed that plasma levels peaked after 15-30 min, and decreased below the limit of detection within 24 h (low dose) and 72 h (high dose), respectively. Administering 2 doses at 100 mg/kg 12 h apart provided continuous drug exposure. Drug pharmacokinetics in MCF-7 tumors was similar. Mice bearing s.c. MCF-7 tumors were treated with the anti-estrogen fulvestrant (fulv; 5 mg/wk) three days before GDC-0941 treatment to assess pharmacodynamic effects. Phospho-AKT and -S6 levels (markers of PI3K and mTORC1 activities, respectively) were inversely correlated with tumor drug concentrations. Mice bearing MCF-7, fulv-resistant T47D/FR, or HCC-003 patient-derived xenografts were treated with vehicle, fulv, GDC-0941 (100 mg/kg QD 5 d/wk; 100 mg/kg BID 3 d on/4 d off; 800 mg/kg QW), or combinations. Tumor growth curves indicated that different schedules of PI3K inhibition with fulv similarly induced tumor regression. Molecular analysis of MCF-7 tumors showed that fulv plus GDC-0941 QW induced 30.14% apoptosis (assessed by TUNEL) at 48 h, which dropped to baseline (2.72%) at 72 h. Fulv plus GDC-0941 BID induced 18.27% apoptosis at 24 h, and maintained apoptosis rate near 10% until 96 h (when GDC-0941 washed out), which is a rate similar to that observed with fulv plus GDC-0941 QD. Fulv plus GDC-0941 QW decreased cell proliferation (assessed by geminin and Ki67 staining) from 34.89% (baseline) to 11.46%, which rebounded to 60.54% at the time of GDC-0941 washout (at 96 h). Fulv plus GDC-0941 QD or BID modestly decreased cell proliferation to 28.84% and 24.32%, respectively, after 24 h, which returned to baseline after 36 h and 72 h, respectively, then maintained the level for a week. Temporal analysis of PI3K signaling revealed that fulv plus GDC-0941 QW and BID maximally decreased phospho-AKT levels after 3 h, which returned to baseline within 48 h and 72 h, respectively. With fulv + GDC-0941 QD, phospho-AKT levels decreased after 3 h, but rebounded to baseline within 24 h. These results indicate that 2 approaches to PI3K inhibition provide similar anti-tumor efficacy: 1) complete/intermittent (QW) PI3K inhibition induces a burst of apoptosis with a rebound in cell proliferation after drug clearance; and 2) metronomic/repeated (QD) PI3K inhibition repeatedly induces a smaller amount of apoptosis without significantly affecting cell proliferation. These findings may inform clinical testing of PI3K inhibitors to maximize therapeutic index. Citation Format: Yang W, Bean J, Hosford S, Lloye D, Liu S, Salphati L, Pang J, Zhang X, Nannini M, Miller TW. Pharmacodynamics and consequences of PI3K inhibition in ER+ breast tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-22.