Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.

The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.

Continuous Thoracic Paravertebral Block to Treat Electrical Storm.

Continuous ganglion block is increasingly being used to help manage ventricular tachyarrhythmias. We present the cases of 2 patients in whom we used continuous left thoracic paravertebral block to achieve sympathetic denervation and improvement in drug-refractory ventricular tachyarrhythmias. Whether as destination therapy or bridging therapy, we conclude that the block is safe, improves patients' comfort, and is superior in several ways to stellate ganglion block and other single-injection techniques.

LC-MS/MS analysis of bisphenol S and five other bisphenols in total diet food samples.

It is already known that bisphenol S (BPS) has been used as a substitute for BPA in thermal papers in recent years. It is not clear, however, if BPS has also been used to replace BPA in can coatings as currently being speculated due to a lack of credible studies on migration of BPS from can coatings and occurrence data of BPS in foods. In this study, an LC-MS/MS method was developed for the analysis of BPS, along with several other bisphenols, and method detection limits for BPS varied from 0.0017 to 3.1 ng/g depending on the type of sample matrix and the amount of sample analysed. This method was used to analyse 159 different food composite samples from a recent Canadian total diet study. Bisphenol E (BPE), bisphenol B (BPB), and bisphenol AF (BPAF) were not detected in any of the 159 food composite samples, bisphenol F (BPF) was detected in only three samples (25-2360 ng/g), and bisphenol A (BPA) was detected in 10 samples (5.3-41 ng/g) which were all prepared from canned foods. BPS was not detected in any of the canned food composite samples but was detected in nine food composite samples prepared from meat and meat products (1.2-35 ng/g), indicating sources for BPS other than can coatings may be possible, which will be investigated in future studies.

Non-inferiority trial of a pedal controlled injection device: a step toward enhancing patient safety and operator independence during neural blockade.

BACKGROUND AND OBJECTIVES: Limitations in manpower in health care facilities, both in civilian and military settings, can severely affect patient safety as well as overall outcomes. Regional anesthesia via neural blockade is an effective means of managing uncontrolled acute pain, which has been associated with cardiopulmonary, endocrine, immunologic, and hematologic derangement in addition to the development of potentially life-threatening coagulopathy. We have designed a remote-controlled injection device that may expedite the performance of regional nerve blocks in these situations. METHODS: This work examines how the device affects the ability of the operator to act independently with respect to various block component times by statistically comparing device-assisted blockade with usual or clinically relevant techniques. The classic or two-person technique was compared with the foot-controlled technique. RESULTS: The results validated the hypothesis that the novel mechanism of performing a nerve block is not inferior to the classic technique with regard to the specified endpoints within our experimental design. CONCLUSION: This confirmation indicates that the use of this device may be feasible when the use of another technique could be cumbersome, or otherwise untenable.

The Evolution of Iliac Bone Graft Donor Site Analgesia in Cleft Patients: Transversus Abdominis Plane Block Is Safe and Efficacious.

BACKGROUND: The transversus abdominis plane (TAP) block has been increasingly used as a means of abdominal wall analgesia. This study aims to determine if TAP block analgesia provides a benefit in cleft patients undergoing alveolar bone grafting with iliac crest cancellous bone graft. METHODS: Two groups of 20 consecutive patients undergoing alveolar bone grafting with iliac crest cancellous bone with either TAP block or indwelling catheter pain pump were examined in a retrospective fashion. Demographic data, pharmacologic use, and hospital length of stay were examined. RESULTS: Mean lengths of stay were identical between both groups. Patients in both groups received similar cumulative doses of morphine equivalents, codeine, ibuprofen, and ondansetron at 6 and 24 hours postoperatively. Transversus abdominis plane block patients received greater amounts of Tylenol at both 6 and 24 hours (P = 0.0015 and P = 0.0106). Pain scores did not differ significantly across our groups at 6 or 24 hours postoperatively. No adverse events were reported with the TAP block procedure. CONCLUSIONS: Patients undergoing TAP blocks receive the benefit of a single stage procedure without an indwelling catheter and similar 6- and 24-hour morphine usage. Given the safety profile of the procedure, its effectiveness and comfort without indwelling catheter, we advocate for TAP block analgesia as an adjunct therapy in the management of postoperative pain in this population.

Comparison of single-injection ultrasound-guided approach versus multilevel landmark-based approach for thoracic paravertebral blockade for breast tumor resection: a retrospective analysis at a tertiary care teaching institution.

BACKGROUND: The role of thoracic paravertebral blockade (TPVB) in decreasing opioid requirements in breast cancer surgery is well documented, and there is mounting evidence that this may improve survival and reduce the rate of malignancy recurrence following cancer-related mastectomy. We compared the two techniques currently in use at our institution, the anatomic landmark-guided (ALG) multilevel versus an ultrasound-guided (USG) single injection, to determine an optimal technique. METHODS: We retrospectively reviewed records of patients who received TPVB from January 2013 to December 2014. Perioperative opioid use, post anesthesia care unit (PACU) pain scores and length of stay, block performance, and complications were compared between the two groups. RESULTS: We found no statistical difference between the two approaches in the studied outcomes. We did find that the number of times attending physicians in the ALG group took over the blocks from residents was significantly greater than that of the USG group (p=0.006) and more local anesthetic was used in the USG group (p=0.04). CONCLUSION: This study compared the ALG approach with the USG approach for patients undergoing mastectomy for breast cancer. Based on our observations, an attending physician is more likely to take over an ALG injection, and more local anesthetic is administered during USG single injection.

Hemodynamic instability and Horner's syndrome following a labour lumbar neuraxial block: A warning sign of a potentially lethal event?

The development of Horner's syndrome during routine neuraxial anaesthesia suggests anatomic, technical or physiologic variance. Even more importantly, it warrants immediate cessation of the anaesthetic intervention.

Data generated from three quantitative mass spectral methods for the analysis of trivalent influenza vaccine antigens are compared.

Herein we present the data necessary for generation of alternative means to produce equimolar mixtures of peptides ("Design and Expression of a QconCAT Protein to Validate Hi3 Protein Quantification of Influenza Vaccine Antigens" (D.G.S. Smith, G. Gingras, Y. Aubin, T.D. Cyr, 2016) [1]), such as QConCAT ("Trends in QconCATs for targeted proteomics" (J. Chen, I.V. Turko, 2014) [2] , "Natural flanking sequences for peptides included in a quantification concatamer internal standard" (C.S. Cheung, K.W. Anderson, M. Wang, I.V. Turko, 2015) [3]) and SpikeTides versus the label free Hi3 approach. The experimental design and the interpretation of results are discussed in the original article [1].

Design and expression of a QconCAT protein to validate Hi3 protein quantification of influenza vaccine antigens.

UNLABELLED: Quantification of the antigens hemagglutinin and neuraminidase in influenza vaccines has been reported using an antibody-free liquid chromatography-mass spectrometry (LC-MS) based method known as MS(E) "Hi3". This approach is based on the average signal intensity of the three most intense tryptic peptides relative to a primary standard. This strategy assumes that the Hi3 signal responses are consistent for all proteins, and therefore comparable to a spiked reference for absolute quantification. This method is much faster than the current standard methods; however, the results can vary significantly which brought the method's accuracy into question. To address this question we generated synthetic proteins comprising a concatenation of the peptides used to quantify the proteins of interest (QconCAT). Complete tryptic digestion of a QconCAT protein produces equal molar peptide amounts, allowing verification of equal signal response of Hi3 peptides for the proteins of interest. The generation of an intact, stable, QconCAT protein that digest completely is challenging. We have designed and analyzed five QconCAT proteins with unique design elements to address these challenges. We conclude that a suitable QconCAT protein can be produced and that the results obtained reinforce the validity of the Hi3 approach for quantifying proteins in annual influenza vaccine formulations. SIGNIFICANCE: The advances in quantitative proteomics have allowed the adaptation and application of these methods to numerous fields. In this paper we have validated a Hi3 approach to augment the antigen quantification for influenza vaccines injected into many millions annually. This methodology allows analysis of multiple antigens simultaneously without the need to generate antibodies. Key circumstances where this is advantageous are for quantitation of very similar antigens, such as the new quadravalent products and when time is critical such as in a flu pandemic.

Epidural Catheter Migration in a Patient with Severe Spinal Stenosis.

Establishment of appropriate neuraxial catheter positioning is typically a straightforward procedural undertaking. It can, however, lead to deception of even the most experienced clinician and occur despite the most meticulous attention to detail. Written and verbal consent were obtained from the patient to prepare, discuss, and publish this case report; we describe the occurrence of what we believe was the intraoperative migration of an epidural catheter in the setting of significant tissue changes resulting from a previous spinal fusion.

The Evolution of an Innovative Community-Engaged Health Navigator Program to Address Social Determinants of Health.

BACKGROUND: Health navigators and other types of community health workers (CHWs) have become recognized as essential components of quality care, and key for addressing health disparities owing to the complex health care services landscape presents almost insurmountable challenges for vulnerable individuals. Bernalillo County, New Mexico, has high rates of uninsurance, poverty, and food insecurity. OBJECTIVES: The design of the Pathways to a Healthy Bernalillo County Program (BP) has evolved innovations that are unique in terms of program stability and security, expansive reach, and community capacity across six domains: sustainable public mechanism for program funding, involvement of community organizations in designing the program, expanded focus to address the broader social determinants of health with targeted outreach, an integrated, community-based implementation structure, an outcomes-based payment structure, and using an adaptive program design that actively incorporates navigators in the process. METHODS: In 2008, the Pathways to a Healthy Bernalillo County Program (BP), located in the Albuquerque metropolitan area in central New Mexico, was established to provide navigation and support for the most vulnerable county residents. BP is funded through a 1% carve out of county mill levy funds. RESULTS: The pathways model is an outcome-based approach for health and social services coordination that uses culturally competent CHW as "navigators" trained to connect at-risk individuals to needed health and social services. CONCLUSIONS: One of the important innovations of the pathways approach is a shift in focus from merely providing discrete services to confirming healthy outcomes for the individual patient.

Data set for mass spectrometric analysis of recombinant human serum albumin from various expression systems.

Human serum albumin (HSA) is a versatile and important protein for the pharmaceutical industry (Fanali et al., Mol. Aspects Med. 33(3) (2012) 209-290). Due to the potential transmission of pathogens from plasma sourced albumin, numerous expression systems have been developed to produce recombinant HSA (rHSA) (Chen et al., Biochim. Biophys. Acta (BBA)-Gen. Subj. 1830(12) (2013) 5515-5525; Kobayashi, Biologicals 34(1) (2006) 55-59). Based on our previous study showing increased glycation of rHSA expressed in Asian rice (Frahm et al., J. Phys. Chem. B 116(15) (2012) 4661-4670), both supplier-to-supplier and lot-to-lot variability of rHSAs from a number of expression systems were evaluated using reversed phase liquid chromatography linked with MS and MS/MS analyses. The data are associated with the research article 'Determination of Supplier-to-Supplier and Lot-to-Lot Variability in Glycation of Recombinant Human Serum Albumin Expressed in Oryza sativa' where further analysis of rHSA samples with additional biophysical methods can be found (Frahm et al., PLoS ONE 10(9) (2014) e109893). We determined that all rHSA samples expressed in rice showed elevated levels of arginine and lysine hexose glycation compared to rHSA expressed in yeast, suggesting that the extensive glycation of the recombinant proteins is a by-product of either the expression system or purification process and not a random occurrence.

Trial ultrasound-guided continuous left stellate ganglion blockade before surgical gangliolysis in a patient with a left ventricular assist device and intractable ventricular tachycardia: a pain control application to a complex hemodynamic condition.

Stellate ganglion blockade for cardiac dysrhythmia is a well-described technique but infrequently used to manage ventricular tachycardia (VT). In patients with left ventricular assist devices (LVADs), these dysrhythmias cause increased morbidity because of right ventricular dysfunction, and often severe discomfort. Continuous stellate ganglion blockade may yield valuable information on a diagnostic and therapeutic basis in preparation for definitive, permanent interventions. We describe the successful management of intractable VT with continuous left stellate ganglion blockade, followed by surgical gangliolysis in a patient with an LVAD.

Treatment of acute flares of chronic pancreatitis pain with ultrasound guided transversus abdominis plane block: a novel application of a pain management technique in the acute care setting.

The use of transversus abdominis plane (TAP) block to provide either analgesia or anesthesia to the anterior abdominal wall is well described. The technique yields high analgesic effectiveness and is opioid sparing and potentially of long duration with reported analgesia lasting up to 36 hours. When compared to neuraxial analgesia, TAP blocks are associated with a lower incidence of hypotension and motor blockade. TAP blocks are typically described as providing somatic analgesia only without any effect on visceral pain. There may be, however, certain conditions in which TAP blocks can provide effective analgesia in pain of visceral or mixed somatic and visceral origin. We describe two cases in which TAP blockade provided complete control of pain considered to be of visceral origin.

Determination of supplier-to-supplier and lot-to-lot variability in glycation of recombinant human serum albumin expressed in Oryza sativa.

The use of different expression systems to produce the same recombinant human protein can result in expression-dependent chemical modifications (CMs) leading to variability of structure, stability and immunogenicity. Of particular interest are recombinant human proteins expressed in plant-based systems, which have shown particularly high CM variability. In studies presented here, recombinant human serum albumins (rHSA) produced in Oryza sativa (Asian rice) (OsrHSA) from a number of suppliers have been extensively characterized and compared to plasma-derived HSA (pHSA) and rHSA expressed in yeast (Pichia pastoris and Saccharomyces cerevisiae). The heterogeneity of each sample was evaluated using size exclusion chromatography (SEC), reversed-phase high-performance liquid chromatography (RP-HPLC) and capillary electrophoresis (CE). Modifications of the samples were identified by liquid chromatography-mass spectrometry (LC-MS). The secondary and tertiary structure of the albumin samples were assessed with far U/V circular dichroism spectropolarimetry (far U/V CD) and fluorescence spectroscopy, respectively. Far U/V CD and fluorescence analyses were also used to assess thermal stability and drug binding. High molecular weight aggregates in OsrHSA samples were detected with SEC and supplier-to-supplier variability and, more critically, lot-to-lot variability in one manufactures supplied products were identified. LC-MS analysis identified a greater number of hexose-glycated arginine and lysine residues on OsrHSA compared to pHSA or rHSA expressed in yeast. This analysis also showed supplier-to-supplier and lot-to-lot variability in the degree of glycation at specific lysine and arginine residues for OsrHSA. Both the number of glycated residues and the degree of glycation correlated positively with the quantity of non-monomeric species and the chromatographic profiles of the samples. Tertiary structural changes were observed for most OsrHSA samples which correlated well with the degree of arginine/lysine glycation. The extensive glycation of OsrHSA from multiple suppliers may have further implications for the use of OsrHSA as a therapeutic product.