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Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir (

Organ Procurement and Transplant Network (OPTN) pediatric policies on knowledge and skill requirements for key personnel failed to address the Director of Anesthesia for Pediatric Liver Transplantation. A Joint Committee representing the Society for the Advancement of Transplant Anesthesia and Society for Pediatric Anesthesia (SPA) surveyed all pediatric anesthesia liver transplant practices to determine if practices were aligned with policies and what changes would be needed for compliance.A survey of the Director or equivalent at each program collected data about specialized knowledge and skill sets. Questions focused on (1) skill and knowledge of the Director and team, (2) requirements for appointment, (3) experience in pediatrics, and (4) characteristics of the program including the availability of pediatric resources.Response rate was 73% (n = 63). Most responding programs had a Director (67%) with certification, selection committee, and continuing education credits outlined in existing policies. Team members met similar requirements. Alternate pathways for acquiring knowledge and skill sets were identified between programs.Pediatric liver transplant anesthesiologists use knowledge and skill pathways that align with the new pediatric policies. We suggest that collaborative work with oversight agencies is needed to resolve high case volume requirements originally designed for adult programs.Most pediatric liver transplant anesthesiologists in the US have specialized knowledge and skills for expert care consistent with current oversight policies. Differences in pathways to acquire knowledge and skill sets were still aligned with the new policies for pediatric transplant surgeons and bylaws for the Director of Transplant Anesthesia. We conclude that minimal changes in case volume requirements to the existing Pediatric Transplant Anesthesiology Directorship criteria that authenticates the pediatric anesthesia Director's position would improve the safety of care without limiting access to transplantation.

Perturbations in stoichiometry invariably induce topological defects in epoxy–amine systems which consequently affect properties. The present work elucidates the role played by topological defects on variations in properties with stoichiometry.

INTRODUCTION Liver transplant anesthesiology is an evolving and expanding subspecialty, and programs have, in the past, exhibited significant variations of practice at transplant centers across the United States. In order to explore current practice patterns, the Quality & Standards Committee from the Society for the Advancement of Transplant Anesthesia (SATA) undertook a survey of liver transplant anesthesiology program directors. METHODS Program directors were invited to participate in an online questionnaire. A total of 110 program directors were identified from the 2018 Scientific Registry of Transplant Recipients (SRTR) database. Replies were received from 65 programs (response rate of 59%). RESULTS Our results indicate an increase in transplant anesthesia fellowship training and advanced training in transesophageal echocardiography (TEE). We also find that the use of intraoperative TEE and viscoelastic testing is more common. However, there has been a reduction in the use of veno-venous bypass, routine placement of pulmonary artery catheters and the intraoperative use of anti-fibrinolytics when compared to prior surveys. CONCLUSION The results show considerable heterogeneity in practice patterns across the country that continues to evolve. However, there appears to be a movement towards the adoption of specific structural and clinical practices.

The effect of alkyl chain in the amidoamine crosslinker on the yield and post-yield behavior using non-equilibrium molecular dynamics simulation is studied in this work. Specifically the deformation behavior of two thermosets with and without the alkyl chain are simulated. The yield stress and strain hardening modulus were predicted. It was found that the thermoset with alkyl chain had lower yield stress and strain hardening modulus compared to the one without. Stress partitioning revealed that intermolecular Lennard-Jones (LJ) and covalent interactions contribute significantly to the yield stress and strain hardening modulus in these thermosets while the electrostatic interactions have no significant effect on both. The effect of methylene interactions on the yield and post-yield behavior were also investigated. It was found that the lower yield stress in the thermoset with alkyl chain is due to the dilution effect and the decrease in strain hardening modulus is due to both dilution effect and intramolecular LJ interactions of methylenes. Simulations reveal a trade off between dilution effect and covalent interactions of the system which can be utilized to tune the mechanical properties of thermosets. The major contribution of this work is the computational approach that can be used to discover the effect of additives or other molecular constituents on the deformation characteristics of a thermoset regardless of the deformation mode tensile or compressive.

Background Due to the life-threatening consequences that a failed tracheal intubation entails, many efforts have been made to identify specific patient features, which may predict difficulty during tracheal intubation. In addition, debate exists as to whether or not video-assisted laryngoscopy (VAL) should replace direct laryngoscopy and if airway practitioners will lose their skills associated with direct laryngoscopy, now that VAL use has increased in clinical practice. Aim This study was designed to determine the first attempt success rate of tracheal intubation with the McGRATH™ MAC laryngoscope using direct visualization in patients with known difficult airways, as well as exploring the possibility of identifying a particular direct Cormack-Lehane (C-L) grade view where indirect (video) visualization can be most beneficial during laryngoscopy and intubation. Methods Following IRB/ethical board approval and written informed consent, 100 adult patients (age > 18 years) with an ASA status I-III and a BMI 2 who met ≥ 2 of the following inclusion criteria: Mallampatti class: III-IV, reduced mouth opening 40 cm for females, > 43 cm for males), thyromental distance Results Out of the 94 patients that were included in the data analysis, 72 (76.6%) were successfully intubated via direct laryngoscopy and 16 (17%) were successfully intubated via indirect (video) laryngoscopy on the first attempt with the McGRATH™ MAC ( P = 0.59). This translates to an overall first-attempt success rate of 96.15% (n = 88). Six patients required a second attempt for tracheal intubation, in which indirect (video) laryngoscopy was then performed, representing an 83% second attempt success rate (n = 5; 5.3%). One patient (1.1%) required a third intubation attempt and an alternative device was used to secure the airway (n = 1; Table 1). The most common initial C-L grade view during the first attempt was a 2b (28.7%), which accounted for 36.1% of the 72 patients that were successfully intubated via direct laryngoscopy (n = 26). A noticeable C-L grade view improvement was observed with the use of the McGRATH™ MAC using the indirect view. Thus, the most common initial indirect C-L grade view during the first attempt was a 1 (54.3%), which accounted for 65.3% of the 72 patients that were successfully intubated via direct laryngoscopy (n = 47). Conclusion The McGRATH™ MAC is a versatile laryngoscope that allows both direct and indirect (video) laryngoscopy to be performed, simultaneously if needed, with a favorable chance of successful intubation during the first attempt. VAL with the McGRATH™ MAC exhibited an enhanced glottic view and served as a successful rescue airway device during inadequate glottic visualization and/or unsuccessful tracheal intubation, after failing with the same device when direct laryngoscopy was performed.

To verify that temporal artery (TA) temperature measured in the postanesthesia care unit (PACU) in noncardiac surgical patients is a valid reflection of core temperature, a prospective, observational, institutional review board–approved study was conducted in a large, academic tertiary care hospital. The study developed from an initial quality improvement project. A total of 276 patients who had an indwelling bladder catheter as standard of care were enrolled when a research student was available over a 6-month period in 2015. Infrared TA temperature was measured (average of three readings) simultaneously with bladder temperature on PACU arrival. Mean temperature in the bladder and TA groups was >36°C with a clinically negligible difference (0.125°C; 90% confidence interval, 0.059–0.192). Agreement between bladder and TA temperatures, as well as between bladder and last operating room temperatures, was >95% by Bland-Altman analysis. A properly performed TA temperature measure on PACU arrival is an acceptable representation of core temperature for purposes of quality assessment, patient comfort, and regulatory requirements.

Given potential disparity and limited allocation of deceased donor kidneys for transplantation, a new federal kidney allocation system was implemented in 2014. Donor organ function and estimated recipient survival in this system has implications for perioperative management of kidney transplant recipients. Early analysis suggests that many of the anticipated goals are being attained. For anesthesiologists, implications of increased dialysis duration and burdens of end-stage renal disease include increased cardiopulmonary disease, challenging fluid, hemodynamic management, and central vein access. With no recent evidence to guide anesthesia care within this new system, we describe the kidney allocation system, summarize initial data, and briefly review organ systems of interest to anesthesiologists. As additional invasive and echocardiographic monitoring may be indicated, one consideration may be development of a dedicated anesthesiology team experienced in management and monitoring of complex patients, in a similar manner as has been done for liver transplant recipients.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an endovascular technique that allows for temporary occlusion of the aorta in patients with severe, life-threatening, trauma-induced noncompressible hemorrhage arising below the diaphragm. REBOA utilizes a transfemoral balloon catheter inserted in a retrograde fashion into the aorta to provide inflow control and support blood pressure until definitive hemostasis can be achieved. Initial retrospective and registry clinical data in the trauma surgical literature demonstrate improvement in systolic blood pressure with balloon inflation and improved survival compared to open aortic cross-clamping via resuscitative thoracotomy. However, there are no significant reports of anesthetic implications and perioperative management in this challenging cohort. In this narrative, we review the principles, technique, and logistics of REBOA deployment, as well as initial clinical outcome data from our level-1 American College of Surgeons-verified trauma center. For anesthesiologists who may not yet be familiar with REBOA, we make several suggestions and recommendations for intraoperative management based on extrapolation from these initial surgical-based reports, opinions from a team with increasing experience, and translated experience from emergency aortic vascular surgical procedures. Further prospective data will be necessary to conclusively guide anesthetic management, especially as potential complications and implications for global organ function, including cerebral and renal, are recognized and described.

Rat is commonly used for pharmacokinetic screening during pharmaceutical lead optimization. To handle the large number of compounds, rats with a single jugular vein cannulation are commonly utilized for intravenous pharmacokinetic studies, where the same cannula is used both for dose administration and blood sampling. We demonstrate that the single cannula method is not suitable for all compounds, especially for high logP compounds. We propose an alternative dual cannulation technique in which two cannulas are placed in the same jugular vein, thus avoiding an additional surgery. Compounds were administered orally or via intravenous infusion to compare PK parameters, including bioavailability, using both procedures. For itraconazole and amiodarone, known to bind to the cannula, the measured plasma exposures were substantially higher in the single cannulated rats than those from dual cannulated rats. Area under the plasma concentration time curve differed by 79% and 74% for itraconazole and amiodarone, respectively. When compared to the single cannulation approach, clearance, volume of distribution and bioavailability determined by dual cannulation were 39%, 60% and 38% higher for itraconazole, and 46%, 34% and 42% higher for amiodarone, respectively. In contrast, all pharmacokinetic parameters were similar between single and dual-cannulated rats for the hydrophilic compound atenolol. Based on these results, we recommend the use of dual cannulated rats for intravenous pharmacokinetic studies when testing a series of hydrophobic compounds that may be prone to non-specific binding to the cannula. If single cannulated model is selected for pharmacokinetic screening, we recommend a bridging study with dual cannulated rats with representative compounds of a given chemical series.

There are disparities in liver transplant anesthesia team (LTAT) care across the United States. However, no policies address essential resources for liver transplant anesthesia services similar to other specialists. In response, the Society for the Advancement of Transplant Anesthesia appointed a task force to develop national recommendations. The Conditions of Transplant Center Participation were adapted to anesthesia team care and used to develop Delphi statements. A Delphi panel was put together by enlisting 21 experts from the fields of liver transplant anesthesiology and surgery, hepatology, critical care, and transplant nursing. Each panelist rated their agreement with and the importance of 17 statements. Strong support for the necessity and importance of 13 final items were as follows: resources, including preprocedure anesthesia assessment, advanced monitoring, immediate availability of consultants, and the presence of a documented expert in liver transplant anesthesia credentialed at the site of practice; call coverage, including schedules to assure uninterrupted coverage and methods to communicate availability; and characteristics of the team, including membership criteria, credentials at the site of practice, and identification of who supervises patient care. Unstructured comments identified competing time obligations for anesthesia and transplant services as the principle reason that the remaining recommendations to attend integrative patient selection and quality review committees were reduced to a suggestion rather than being a requirement. This has important consequences because deficits in team integration cause higher failure rates in service quality, timeliness, and efficiency. Solutions are needed that remove the time-related financial constraints of competing service requirements for anesthesiologists. In conclusion, using a modified Delphi technique, 13 recommendations for the structure of LTATs were agreed upon by a multidisciplinary group of experts.

Study Objective To assess reliability and reproducibility of a recently instituted anesthesiology resident applicant interview scoring system at our own institution. Design Retrospective evaluation of 2 years of interview data with a newly implemented scoring system using randomly assigned interviewing faculty. Setting Interview scoring evaluations were completed as standard practice in a large academic anesthesiology department. Subjects All anesthesiology resident applicants interviewed over the 2013/14 and 2014/15 seasons by a stable cohort of faculty interviewers. Data collection blinded for both interviewers and interviewees. Interventions None for purposes of study – collation of blinded data already used as standard practice during interview process and analysis. Measurements None specific to study. Main Results Good inter-rater faculty reliability of interview scoring (day-of) and excellent inter-faculty reliability of application review (pre-interview). Conclusions Development of a department-specific interview scoring system including many elements beyond traditional standardized tests shows good-excellent reliability of faculty scoring of both the interview itself (including non-technical skills) and the application resume.

We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 in vivo.

After a hiatus of several decades, the concept of cold whole blood (WB) is being reintroduced into acute clinical trauma care in the United States. Initial implementation experience and data grew from military medical applications, followed by more recent development and data acquisition in civilian institutions. Anesthesiologists, especially those who work in acute trauma facilities, are likely to be presented with patients either receiving WB from the emergency department or may have WB as a therapeutic option in massive transfusion situations. In this focused review, we briefly discuss the historical concept of WB and describe the characteristics of WB, including storage, blood group compatibility, and theoretical hemolytic risks. We summarize relevant recent retrospective military and preliminary civilian efficacy as well as safety data related to WB transfusion, and describe our experience with the initial implementation of WB transfusion at our level 1 trauma hospital. Suggestions and collective published experience from other centers as well as ours may be useful to those investigating such a program. The role of WB as a significant therapeutic option in civilian trauma awaits further prospective validation.

HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.

Perioperative organ injury has a significant impact on surgical outcomes and presents a leading cause of death in the United States. Recent research has pointed out an important role of hypoxia signaling in the protection from organ injury, including for example myocardial infarction, acute respiratory distress syndrome, acute kidney, or gut injury. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), thereby leading to the induction of HIF target genes, which facilitates adaptive responses to low oxygen. In this review, we focus on current therapeutic strategies targeting hypoxia signaling in various organ injury models and emphasize potential clinical approaches to integrate these findings into the care of surgical patients. Conceptually, there are 2 options to target the HIF pathway for organ protection. First, drugs became recently available that promote the stabilization of HIFs, most prominently via inhibition of prolyl hydroxylase. These compounds are currently trialed in patients, for example, for anemia treatment or prevention of ischemia and reperfusion injury. Second, HIF target genes (such as adenosine receptors) could be activated directly. We hope that some of these approaches may lead to novel pharmacologic strategies to prevent or treat organ injury in surgical patients.

We report dramatic changes in bilateral cerebral tissue oxygenation in a patient undergoing an orthotopic liver transplant coincident with clamping and subsequent restoration of flow through the inferior vena cava. Although hemodynamic stability was maintained with low-dose vasopressor support, cardiac output was decreased, suggesting preload dependence of the measured cerebral oxygenation. Further investigation is warranted in patients with end-stage liver disease and interruption of venous return.

Background Assessment of the potentially difficult airway (DA) is a critical aspect of resident education. We investigated the impact of a new assessment form on airway prediction and management by anaesthesia residents. We hypothesized that residents would demonstrate improvement in evaluation of DAs over the study duration. Methods After IRB approval, anaesthesia residents were randomized into two groups: control (existing form) and experimental (new form). Data were collected prospectively from August 2008 to May 2010 on all non-obstetric adult patients undergoing non-emergent surgery. Results Eight thousand three hundred and sixty-four independent preoperative assessments were collected and 8075 were analysed. The experimental group had the higher completion rate than the control group (94.3% vs 84.3%, P=0.001). DA prediction was higher for the control group (71.2%) compared with the experimental group (69.1%; P=0.032). A significant improvement in prediction rates was found over time for the experimental group (likelihood estimate=0.00068, P=0.031). Conclusions The use of a comprehensive airway assessment did not improve resident ability to predict a DA in an academic, tertiary-based hospital, anaesthesiology residency training programme.

A fundamental task in many image processing applications is image registration. Image registration can be defined as the process of aligning or matching two images such that the two images can be transformed into one coordinate system. The images can be from different viewpoints, different time and also from different sensors, sensing different regions across the electromagnetic spectrum. Image registration algorithms defined in literature have been very specific to an application and hence most surveys conducted revolve around a particular application. The need of the hour is an image registration technique which is universal, accurate, robust and yet be computationally efficient. This dissertation accomplishes a survey of existing image registration techniques for both two dimensional and three dimensional image processing applications and presents a qualitative and quantitative analysis on a range of test data to determine the generalization aspects of these registration techniques. The dissertation also explores an important class of applications requiring the three dimensional image registration process known as the 3D volume reconstruction. The dissertation proposes a technique to compute the real-world volume of an object from its three dimensional model. This has far ranging applications from healthcare to interactive gaming. For example in a hospital, when the patient is immobile and his/her weight has to be recorded and traditional techniques may be intrusive. Therefore, a non-intrusive approach is highly desirable and this dissertation proposes an approach for the volume generation of an object from its 3D model. The dissertation also documents the important challenges which have to be overcome to obtain a robust and accurate volume estimate of the 3D model. Master of Science (Signal Processing)

Cervical spine injury (CSI) creates a special problem in airway management. The cervical spine is comprised of seven vertebrae that are uniquely configured and house the spinal cord at the center. The configuration of the cervical spine allows specific movements of the head and neck in a limited fashion. Cervical instability is a serious concern and occurs when movement in the spine is greater than normal, possibly placing the spinal cord at risk. Spinal cord injury is the primary concern when considering CSI, and can occur in a number of scenarios and pathologies, the most worrisome of which are direct injury and spinal cord compression. Evaluation and initial management of CSI should include radiographic assessment in patients at particular risk, early cervical immobilization, and potentially elective intubation. Recognition of CSI in association with other traumatic injuries is critical. When approaching the airway of a CSI patient, recognition of injury and timely intubation are critical. Direct laryngoscopy with manual in-line stabilization (MILS) is the most commonly practiced technique and is considered safe; other options for intubation include flexible fiberoptic intubation, video laryngoscopy, laryngeal mask airway (LMA) use, and nasal intubation. Regardless of the modality used, airway management must be conducted with regard for securing the airway as quickly and safely as possible while maintaining cervical immobilization.

The role of uptake transporter (organic anion–transporting polypeptide [Oatp]) in the disposition of a P-glycoprotein (P-gp) substrate (digoxin) at the barriers of central nervous system, namely, the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and brain-cerebrospinal fluid barrier (BCSFB), was studied using rat as a preclinical species. In vivo chemical inhibition of P-gp and Oatp was achieved using elacridar and rifampicin, respectively. Our findings show that (1) digoxin had a low brain-to-plasma concentration ratio (B/P) (0.07) in rat; (2) in the presence of elacridar, the B/P of digoxin increased by about 12-fold; (3) rifampicin administration alone did not change the digoxin B/P significantly when compared with digoxin B/P alone; (4) rifampicin administration along with elacridar resulted only in 6-fold increase in the B/P of digoxin; (5) similar fold changes and trends were seen with the spinal cord-to-plasma concentration ratio of digoxin, indicating the similarity between BBB and the BSCB; and (6) unlike BBB and BSCB, the presence of rifampicin further increased the cerebrospinal fluid-to-plasma concentration ratio (CSF/P) for digoxin, suggesting a differential orientation of the uptake transporters at the BCSFB (CSF to blood) compared with the BBB (blood to brain). The observations for digoxin uptake, at least at the BBB and the BSCB, advocate the importance of uptake transporters (Oatps). However, the activity of such uptake transporters became evident only after inhibition of the efflux transporter (P-gp).

Figure 1: A non-invasive Respiratory Volume Monitor (RVM, ExSpiron, Respiratory Motion, Inc.) that provides continuous, real-time, non-invasive measurements of MV, TV and RR. Figure shows standard electrode placement. One electrode is placed at the sternal notch, another is placed on the xiphoid and the third is placed in the right mid-axillary line at the level of the xiphoid. Post-operative respiratory depression (PORD) and sleep disordered breathing, including obstructive sleep apnea (OSA) are well-established risk factors for post-operative respiratory complications, with increased prevalence in the obese population. Current post-operative monitoring does not provide quantitative measurements of ventilation, and the true incidences of PORD and post-operative apnea (POA) remain unknown. Because these incidences often increase with opioid use, accurately determining the risk associated with both PORD and POA is especially important given the prevalent use of opioids and other respiratory depressants in post-operative analgesia.