The Impact of Classification of Interest on Predictive Toxicogenomics

The era of toxicogenomics has introduced a new way of monitoring the effect of environmental stressors and toxicants on biological systems via quantification of changes in gene expression. Because the liver is one of the major organs for synthesis and secretion of substances which metabolize endogenous and exogenous materials, there has been a great deal of interest in elucidating predictive and mechanistic genomic markers of hepatotoxicity. This mini-review will bring context to a limited number of toxicogenomics studies which used genomics to evaluate the transcriptional changes in blood and liver in response to acetaminophen (APAP) or other liver toxicants, but differed according to the classification of interest (COI), i.e., the partitioning of the samples a priori according to a common toxicological characteristic. The toxicogenomics studies highlighted are characterized by a classification of either no/low vs. high APAP dose exposure, none vs. observed necrosis, and severity of necrosis. The overlap or lack thereof between the gene classifiers and the modulated biological processes that are elucidated will be discussed to enhance the understanding of the effect of the particular COI model and experimental design used for prediction

Initial Development of a Patient-Reported Instrument Assessing Harm, Efficacy, and Misuse of Long-Term Opioid Therapy

Guidelines on long-term opioid therapy recommend frequent reassessment of harm, efficacy, and misuse of these potentially harmful and sometimes ineffective medications. In primary care, there is a need for a brief, patient-reported instrument. This report details the initial steps in the development of such an instrument. An interdisciplinary team of clinician-scientists performed four discrete steps in this study: (1) conceptualization of the purpose and function of the instrument, (2) assembly of an item pool, (3) expert rating on which items were most important to include in the instrument, and (4) modification of expert-selected items based on a reading level check and cognitive interviews with patients. A diverse panel of 47 subject matter experts was presented with 69 items to rate on a 1–9 scale in terms of importance for inclusion in the instrument. The panel highly rated 37 items: 8 related to harm, 4 related to efficacy, and 25 related to misuse. These 37 items were then tested for patient comprehension and modified as needed. Next steps in development will include further item reduction, testing against a gold standard, and assessment of the instrument’s effect on clinical outcomes

Strengthening the Synapse between Outpatient Neurological Care and Inpatient Referral

Objective The goal of this project is to investigate if established neurology patients are appropriately referred to the emergency room. We suspect that there are patients that could be more effectively triaged to prevent unnecessary visits to the emergency department. If this is the case, implementing an intervention such as offering expedited visits or contingency plan, may reduce non-emergent inpatient consultative services5. This would also improve outpatient communication and decrease utilization of both ER and patient resources

Scaffold-Based [Fe]-Hydrogenase Model: H\u3csub\u3e2\u3c/sub\u3e Activation Initiates Fe(0)-Hydride Extrusion and Non-Biomimetic Hydride Transfer

We report the synthesis and reactivity of a model of [Fe]-hydrogenase derived from an anthracene-based scaffold that includes the endogenous, organometallic acyl(methylene) donor. In comparison to other non-scaffolded acyl-containing complexes, the complex described herein retains molecularly well-defined chemistry upon addition of multiple equivalents of exogenous base. Clean deprotonation of the acyl(methylene) C-H bond with a phenolate base results in the formation of a dimeric motif that contains a new Fe-C(methine) bond resulting from coordination of the deprotonated methylene unit to an adjacent iron center. This effective second carbanion in the ligand framework was demonstrated to drive heterolytic H2 activation across the Fe(ii) center. However, this process results in reductive elimination and liberation of the ligand to extrude a lower-valent Fe-carbonyl complex. Through a series of isotopic labelling experiments, structural characterization (XRD, XAS), and spectroscopic characterization (IR, NMR, EXAFS), a mechanistic pathway is presented for H2/hydride-induced loss of the organometallic acyl unit (i.e. pyCH2-CO → pyCH3+CO). The known reduced hydride species [HFe(CO)4]– and [HFe3(CO)11]– have been observed as products by 1H/2H NMR and IR spectroscopies, as well as independent syntheses of PNP[HFe(CO)4]. The former species (i.e. [HFe(CO)4]–) is deduced to be the actual hydride transfer agent in the hydride transfer reaction (nominally catalyzed by the title compound) to a biomimetic substrate ([TolIm](BArF) = fluorinated imidazolium as hydride acceptor). This work provides mechanistic insight into the reasons for lack of functional biomimetic behavior (hydride transfer) in acyl(methylene)pyridine based mimics of [Fe]-hydrogenase

Factors influencing paternity in multiply mated female red-sided garter snakes and the persistent use of sperm stored over winter

In some species, sperm is stored within the female reproductive tract for months to years, and yet remains viable to fertilize eggs and produce offspring. Female red-sided garter snakes store sperm for over seven months of winter dormancy. In previous work we demonstrated that these stored sperm account for an average of 25% paternity of a litter when the female mates with a male at spring emergence. Here we tested whether last-male sperm precedence was prevalent when a female mates with two males during the spring. On average, paternity was shared equally among the first (P₁ proportion of paternity of the first male to mate) and second male (P₂) to mate in the spring, and stored sperm (P[subscript ss]), but the variance in paternity was high. Thus, last male sperm precedence may diminish when a female has more than two mates. Male size did not affect paternity, but as the interval between matings increased, P₁ increased at the expense of P[subscript ss]. Interestingly, as the second spring male’s copulation duration increased, P₁ also increased at the expense of P₂. This result suggests that female influence over sperm and/or copulatory plug transfer during matings may also affect which male fathers her offspring in response to coercive matings as we assisted females to mate for their second mating. Finally, all females were spring “virgins”, consequently sperm stored from autumn matings (and/or previous spring matings) remain competitive even when faced with two rivals in sperm competition and is likely the driver of the evolution of sperm longevity.Keywords: Sperm competition, Stored sperm, Mating interval, Sperm precedence, Mate-orde

Testing implementation facilitation of a primary care-based collaborative care clinical program using a hybrid type III interrupted time series design: a study protocol

Abstract Background Dissemination of evidence-based practices that can reduce morbidity and mortality is important to combat the growing opioid overdose crisis in the USA. Research and expert consensus support reducing high-dose opioid therapy, avoiding risky opioid-benzodiazepine combination therapy, and promoting multi-modal, collaborative models of pain care. Collaborative care interventions that support primary care providers have been effective in medication tapering. We developed a patient-centered Primary Care-Integrated Pain Support (PIPS) collaborative care clinical program based on effective components of previous collaborative care interventions. Implementation facilitation, a multi-faceted and dynamic strategy involving the provision of interactive problem-solving and support during implementation of a new program, is used to support key organizational staff throughout PIPS implementation. The primary aim of this study is to evaluate the effectiveness of the implementation facilitation strategy for implementing and sustaining PIPS in the Veterans Health Administration (VHA). The secondary aim is to examine the effect of the program on key patient-level clinical outcomes—transitioning to safer regimens and enhancing access to complementary and integrative health treatments. The tertiary aim is to determine the categorical costs and ultimate budget impact of PIPS implementation. Methods This multi-site study employs an interrupted time series, hybrid type III design to evaluate the effectiveness of implementation facilitation for a collaborative care clinical program—PIPS—in primary care clinics in three geographically diverse VHA health care systems (sites). Participants include pharmacists and allied staff involved in the delivery of clinical pain management services as well as patients. Eligible patients are prescribed either an outpatient opioid prescription greater than or equal to 90 mg morphine equivalent daily dose or a combination opioid-benzodiazepine regimen. They must also have an upcoming appointment in primary care. The Consolidated Framework for Implementation Research will guide the mixed methods work across the formative evaluation phases and informs the selection of activities included in implementation facilitation. The RE-AIM framework will be used to assess Reach, Effectiveness, Adoption, Implementation, and Maintenance of PIPS. Discussion This implementation study will provide important insight into the effectiveness of implementation facilitation to enhance uptake of a collaborative care program in primary care, which targets unsafe opioid prescribing practices.https://deepblue.lib.umich.edu/bitstream/2027.42/146542/1/13012_2018_Article_838.pd

Remote Infrared Imaging of the Space Shuttle During Hypersonic Flight: HYTHIRM Mission Operations and Coordination

The Hypersonic Thermodynamic Infrared Measurements (HYTHIRM) project has been responsible for obtaining spatially resolved, scientifically calibrated in-flight thermal imagery of the Space Shuttle Orbiter during reentry. Starting with STS-119 in March of 2009 and continuing through to the majority of final flights of the Space Shuttle, the HYTHIRM team has to date deployed during seven Shuttle missions with a mix of airborne and ground based imaging platforms. Each deployment of the HYTHIRM team has resulted in obtaining imagery suitable for processing and comparison with computational models and wind tunnel data at Mach numbers ranging from over 18 to under Mach 5. This paper will discuss the detailed mission planning and coordination with the NASA Johnson Space Center Mission Control Center that the HYTHIRM team undergoes to prepare for and execute each mission

HyperCP: A high-rate spectrometer for the study of charged hyperon and kaon decays

The HyperCP experiment (Fermilab E871) was designed to search for rare phenomena in the decays of charged strange particles, in particular CP violation in $\Xi$ and $\Lambda$ hyperon decays with a sensitivity of $10^{-4}$. Intense charged secondary beams were produced by 800 GeV/c protons and momentum-selected by a magnetic channel. Decay products were detected in a large-acceptance, high-rate magnetic spectrometer using multiwire proportional chambers, trigger hodoscopes, a hadronic calorimeter, and a muon-detection system. Nearly identical acceptances and efficiencies for hyperons and antihyperons decaying within an evacuated volume were achieved by reversing the polarities of the channel and spectrometer magnets. A high-rate data-acquisition system enabled 231 billion events to be recorded in twelve months of data-taking.Comment: 107 pages, 45 Postscript figures, 14 tables, Elsevier LaTeX, submitted to Nucl. Instrum. Meth.