How did we reform our out of control massive transfusion protocol program?

BACKGROUND: The massive transfusion protocol (MTP) is designed to quickly provide blood products at a fixed ratio for the exsanguinating patient. At our academic medical center, the frequency of MTP activation increased over 10-fold between 2008 and 2015, putting inordinate stress on our transfusion service. STUDY DESIGN AND METHODS: Gathering a large number of relevant stakeholders, we performed a multidisciplinary root cause analysis (RCA) in response to the acute clinical need to reform our MTP. RESULTS: Through the RCA, we identified four principal opportunities for improvement (OFI) associated with our MTP: education, stewardship, process improvement, and communication. Through the deployment of new approaches to each of these OFI, we reduced MTP activations, blood product waste, and transfusion service technologist stress. CONCLUSION: The MTP is amenable to improvement, and, although time intensive, the RCA process yields significant favorable effects: improving communication with colleagues, reducing stress within the transfusion service, and improving resource utilization. Activation of the MTP at our institution is now more aligned with its primary purpose: rapidly providing large quantities of blood products to exsanguinating patients.

Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.

We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.

Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.

Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects.

Multiple endogenous compounds have been proposed as candidate biomarkers to monitor organic anion transporting polypeptide (OATP) function in preclinical species or humans. Previously, we demonstrated that coproporphyrins (CPs) I and III are appropriate clinical markers to evaluate OATP inhibition and recapitulate clinical drug-drug interactions (DDIs). In the present study, we investigated bile acids (BAs) dehydroepiandrosterone sulfate (DHEAS), hexadecanedioate (HDA), and tetradecanedioate (TDA) in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs. All probes were determined in samples from a single study that examined their behavior and their association with rosuvastatin (RSV) pharmacokinetics after administration of an OATP inhibitor rifampin (RIF) in healthy subjects. Among endogenous probes examined, RIF significantly increased maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC)(0-24h) of fatty acids HDA and TDA by 2.2- to 3.2-fold. For the 13 bile acids in plasma examined, no statistically significant changes were detected between treatments. Changes in plasma DHEAS did not correlate with OATP1B inhibition by RIF. On the basis of the magnitude of effects for the endogenous compounds that demonstrated significant changes from baseline over interindividual variations, the overall rank order for the AUC change was found to be CP I > CP III > HDA ≈ TDA ≈ RSV > > BAs. Collectively, these results reconfirmed that CPs are novel biomarkers suitable for clinical use. In addition, HDA and TDA are useful for OATP functional assessment. Since these endogenous markers can be monitored in conjunction with pharmacokinetics analysis, the CPs and fatty acid dicarboxylates, either alone or in combination, offer promise of earlier diagnosis and risk stratification for OATP-mediated DDIs.

The utility of stable isotope labeled (SIL) analogues in the bioanalysis of endogenous compounds by LC-MS applied to the study of bile acids in a metabolomics assay.

The growing field of biomarker bioanalysis by liquid chromatography mass spectrometry (LC-MS) is challenged with the selection of suitable matrices to construct relevant and valid calibration curves resulting in not only precise but also accurate data. Because surrogate matrices are often employed with the associated concerns about the accuracy of the obtained data, here we present an assay using surrogate analytes in naive biological matrices. This approach is illustrated with the analysis of endogenous bile acids (e-BAs) in serum and plasma using stable isotope-labeled (SIL) analogues as calibration standards to address the matrix concerns. Several deuterated BAs (d-BAs) were used as standards representing respectively grouped e-BAs with structural similarity allowing for the simultaneous bioanalysis of 16 e-BA. The utility of this LC-MS assay employing d-BAs is demonstrated with the analysis of samples resultant of a controlled metabolomics study where a cohort of rats was fed/fasted to investigate the change of e-BAs dependent on food consumption and fasting time.

Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box.

Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.

Difluorocyclobutylacetylenes as positive allosteric modulators of mGluR5 with reduced bioactivation potential.

Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.

Efficient multiframe super-resolution for imagery with lateral shifts.

Trade studies used to design optical imaging systems frequently result in systems being undersampled. The resolution of such systems is limited by the finite size of the detector pixels rather than the cutoff spatial frequency of the optical system. Multiframe super-resolution techniques can be used to combine a number of spatially displaced images from such systems into a single, high-resolution image. Nonlinear optimization techniques have frequently been used to solve this problem. Such techniques define an objective function and use numerical optimization methods to obtain a solution. These numerical methods are often more efficient when derivatives of the objective function with respect to the variables can be calculated analytically rather than numerically. We demonstrate for the simple motion model of pure lateral translation that the derivatives of the objective function with respect to the image lateral shifts can be calculated analytically to speed optimization calculations.

Allograft swelling after preparation during ACL reconstruction: do we need to upsize tunnels?

The purpose of this study was to determine whether the pull-through force of soft-tissue allografts increases over time after being hydrated with saline-soaked sponges. Eighteen aseptic soft-tissue, fresh-frozen anterior tibialis allograft specimens were thawed and sized using standard sizing guides. After sizing, initial pull-through force was measured using an Instron Model 5865 machine. Grafts were randomized to soak in saline sponges for 20, 40, or 60 min. After soaking, pull-through force was again assessed. Pre- and post-soaking pull-through forces were compared using a paired t test. The effect of time on pull-through force was evaluated using an ANOVA and Tukey post hoc test. Two allografts had initial pull-through forces outside the inclusion criteria and were excluded. The average pull-through force for the remaining 16 allografts pre-soaking was 43.0 N and post-soaking was 81.7 N, for an increase of 90 % (P < 0.001). Longer hydration time in the saline soaked sponges was not correlated with higher pull-through force (P = 0.724). Pull-through force post-hydration was not related to the allograft diameter (P = 0.641). Post-hydration, 33 % of grafts that had soaked for 20 min and 40 % of grafts that had soaked for 40 or 60 min required greater than 100 N pull-through force. Our data supports the hypothesis that soft-tissue allografts swell as a result of being stored in saline-soaked sponges, resulting in greater pull-through forces during graft passage. Surgeons should bear in mind that allografts swell when stored in saline-soaked gauze and should size their tunnels accordingly.

Phase diversity with undersampled systems via superresolution preprocessing.

Phase diversity algorithms allow a wavefront to be reconstructed from through-focus measurements of a point source or extended scene. These algorithms have traditionally been limited to systems that are Nyquist sampled. Many optical systems for remote sensing applications are designed to be undersampled, however. One approach to phase diversity with undersampled systems is to employ superresolution techniques to first create properly sampled scenes. This is demonstrated experimentally for a point object, but is applicable to extended scenes as well.

Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties.

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.

Discovery of Indole- and Indazole-acylsulfonamides as Potent and Selective NaV1.7 Inhibitors for the Treatment of Pain.

3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder.

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

Have the focus and sophistication of research in health education changed?

This study assessed the types of research and the statistical methods used in three representative health education journals from 1994 through 2003. Editorials, commentaries, program/practice notes, and perspectives represent 17.6% of the journals' content. The most common types of articles are cross-sectional studies (27.5%), reviews (23.2%), and analytic studies (i.e., case-control, cohort, and experimental studies) (18.4%). The estimated annual percentage change across the study period in these types of articles was 3.3, -9.3, and 5.5, respectively. A significant increase was observed in use of descriptive statistics (estimated annual percentage change = 2.4), parametric test statistics (4.4), nonparametric test statistics (3.5), epidemiologic statistics (10.3), generalized linear models (6.8), validation statistics (6.7), and other statistics (8.2). Movement toward increasing use of cross-sectional studies, analytic study designs, and statistical methods--representing greater emphasis on needs assessment for health education, health education program development, and program evaluation--indicates the need for better quantitatively trained health educators.

Role of regional absorption and gastrointestinal motility on variability in oral absorption of a model drug.

Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration. The effect of BMS-955829 on gastric emptying and intestinal motility was investigated by radiography after co-administration of barium. BMS-955829 exhibited species dependent oral bioavailability, with high variability in monkeys. During regional absorption studies, highest rate of drug absorption was observed after direct intraduodenal administration. Radiography studies indicated that BMS-955829 slowed gastric emptying and intestinal motility. The effect of rate and site of drug release on oral exposure was studied using different drug product formulations. Reducing the rate of drug release reduced oral exposure variability without compromising exposure in cynomolgus monkeys. This effect was likely mediated by avoidance of rapid initial absorption and drug effect on gastric emptying and intestinal transit within the biorelevant timeframe. Thus, drug release rate can modulate the effect of physiological factors on variability in the oral absorption of sensitive compounds.

Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5.

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

Climate conditions and physical activity in the United States.

OBJECTIVE: To identify the influence season and climate have on physical activity among US adults. METHODS: Seven weather classifications from 255 weather stations were linked with 355 counties covered by the 2003 BRFSS. RESULTS: The percentage meeting the recommendations for physical activity ranged from 30.9% in Puerto Rico to 60.9% in Montana and significantly varied across seasons: 44.6% in winter, 46.2% in spring, 48.4% in summer, and 45.8% in fall. Counties in the top 25% meeting the recommendations for physical activity had the highest percentage of days with dry moderate conditions. Counties in the bottom 25% had the highest percentage of days with moist tropical conditions. CONCLUSION: Season and climate significantly influence physical activity in the United States.

Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus.

The long lasting antidepressant response seen following acute, i.v. ketamine administration in patients with treatment-resistant depression (TRD) is thought to result from enhanced synaptic plasticity in cortical and hippocampal circuits. Using extracellular field recordings in rat hippocampal slices, we show that a single dose of the non-selective NMDA receptor antagonist ketamine or CP-101,606, a selective antagonist of the NR2B subunit of the NMDA receptor, enhances hippocampal synaptic plasticity induced with high frequency stimulation (HFS) 24h after dosing - a time at which plasma concentrations of the drug are no longer detectable in the animal. These results indicate that acute inhibition of NMDA receptors containing the NR2B subunit can lead to long-lasting changes in hippocampal plasticity.

Understanding why adult participants at the World Senior Games choose a healthy diet.

BACKGROUND: Identifying those seniors most likely to adopt a healthy diet, the relative importance they place on certain perceived benefits associated with a healthy diet, and whether these perceived benefits are associated with selected demographic, lifestyle, and health history variables is important for directing effective dietary health promotion programs. METHODS: Analyses are based on a cross-sectional convenience sample of 670 seniors aged 50 years and older at the 2002 World Senior Games in St. George, Utah. Data are assessed using frequencies, bivariate analysis, analysis of variance, and multiple logistic regression analysis. RESULTS: Fruit and vegetable consumption was significantly higher in individuals aged 70-79, in women, in those not overweight or obese, and in those with excellent overall health. Dietary fiber consumption was significantly higher in former or never smokers, current and previous alcohol drinkers, in those not overweight or obese, and in those with excellent health. The strongest motivating factors identified for adopting a healthy diet were to improve the quality of life, to increase longevity, and to prevent disease. Of intermediate importance were the need to feel a sense of control and to satisfy likes or dislikes. Least important were the desire to experience a higher level of spirituality, social reasons, and peer acceptance. CONCLUSION: Seniors who have adopted a healthy diet are more likely to have chosen that behavior because of perceived health benefits than for personal and social benefits. Overweight or obese individuals and those in poor health were less likely to be engaged in healthy eating behavior and require special attention by dieticians and public health professionals.

Outcome expectations that motivate physical activity among world senior games participants.

This study validates a questionnaire which examines the role of selected outcome expectations from physical activity on motivating regular physical activity among a group of older adults. Data were obtained from a cross-sectional survey of 675 participants in the 2002 World Senior Games. Factor analysis identified four clusters among 14 outcome expectation items, which were labeled Recreation and Social, Physical Health, Mental Health, and Self-image. The percentage agreeing that the selected items motivated physical activity were calculated and ranked from 1 (high) to 14 (low). The average ranking in each of the four factors was 4.7 for Recreation and Social, 5.8 for Physical Health, 10.5 for Self-image, and 11.7 for Mental Health. The ranks of items did not significantly differ across categories of sex, age, marital status, education, smoking, alcohol drinking, and disease history. However, the ranking did significantly differ between individuals who considered themselves to be physically active versus sedentary. Physically active individuals were most likely to agree that recreational enjoyment or fun motivated physical activity, whereas sedentary individuals were most likely to agree that improving the quality of life motivated physical activity.