Integration of a clinical pharmacist practitioner-led pharmacogenomics service in a Veterans Affairs hematology/oncology clinic.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: This article describes the implementation and evaluation of pharmacogenomic testing within the hematology/oncology ambulatory care clinic at the William S. Middleton Memorial Veterans Hospital in Madison, WI. SUMMARY: The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for veterans nationally. Program implementation at the Madison Veterans Affairs site began in the hematology/oncology clinic with the goal of integrating the offer for pharmacogenomic testing, testing completion, and review of the results by the hematology/oncology clinical pharmacist practitioner (CPP) into current workflows to create a sustainable process for PHASER. The hematology/oncology CPP designed workflows outlining how testing would be offered to patients, how results would be reported and to whom, and how documentation would occur in the electronic medical record. Veterans are offered preemptive PHASER testing, before needing therapy requiring pharmacogenomic results. Exceptions to pharmacogenomic testing were patients with a history of liver or allogeneic hematopoietic stem cell transplantation. CONCLUSION: This article provides a summary of the role of the hematology/oncology CPP in the implementation of a pharmacogenomics service and the impact on medication management in a hematology/oncology clinic.

Noninvasive Bolus Transit Detection in Cervical Esophagus Utilizing Ultrasound Characteristics.

This pilot study aims to identify characteristic A-mode ultrasound features relevant to noninvasive detection of esophageal bolus transit in the proximal esophagus. Ultrasound signals at a lateral neck site were obtained via a single-element ultrasonic transducer with synchronous videofluoroscopic swallowing studies images of swallows of differing viscosities in 21 adult dysphagia outpatients. Characteristic ultrasound features were extracted to differentiate a bolus-filled from a collapsed esophagus. From 21 subjects, 412 swallows exhibited 4 reproducible waveform patterns associated with bolus transit as displayed in a heatmap: (1) Strong Reflectors; (2) Echo Shifts; (3) Distal Acoustic Enhancement; and (4) Speckling: One or more of these features were observed in the swallow series for all 21 subjects. Distinct acoustic waveform features acquired by single-element ultrasonic transducers can identify bolus transit through the cervical esophagus.

Feasibility of a centralized specialty biologic medication management clinic at a VA hospital.

BACKGROUND: Given the cost and complexity of home subcutaneous biologic use, a centralized specialty medication management (CSMM) service was developed utilizing clinical pharmacist practitioners (CPPs). OBJECTIVE: To determine the implementation feasibility of the CSMM service. PRACTICE DESCRIPTION: The CSMM service was implemented in a Veterans Health Administration (VHA) hospital. The VHA does not use dedicated specialty pharmacies. PRACTICE INNOVATION: The CSMM service was developed utilizing CPPs who operated as an advance practice provider under a national VHA scope of practice. The CPP staffing the CSMM service performed patient education, screened for medication appropriateness, and monitored for safety and efficacy via videoconference or telephone. All patients newly starting a home subcutaneous biologic were offered the service from allergy, cardiology, dermatology, gastroenterology, and rheumatology clinics, as appropriate. EVALUATION METHODS: A retrospective chart review was completed through the first year the service was offered, which included the recruitment and retention of patients, number of follow-up appointments, and interventions made. RESULTS: Of the 68 patients offered clinic enrollment, 54 were enrolled in the service (79.4%). Of the 44 who had completed an initial appointment with the CPP, 42 had either received an initial follow-up or were scheduled for a follow-up (95.5%). A total of 161 clinical outcomes have been performed by the CSMM CPP including administrative assistance (33.5%), initial patient education (17.4%), technique correction (7.5%), and medication changes or discontinuations (6.8%). CONCLUSION: Given the high rate of enrollment and retention, the implementation of the CSMM service at a VA hospital was feasible. The service contributed to safe and effective medication use for enrolled patients and continues to grow in both patient enrollment and services offered.

Characterization of the G protein-coupled receptor family SREB across fish evolution.

The SREB (Super-conserved Receptors Expressed in Brain) family of G protein-coupled receptors is highly conserved across vertebrates and consists of three members: SREB1 (orphan receptor GPR27), SREB2 (GPR85), and SREB3 (GPR173). Ligands for these receptors are largely unknown or only recently identified, and functions for all three are still beginning to be understood, including roles in glucose homeostasis, neurogenesis, and hypothalamic control of reproduction. In addition to the brain, all three are expressed in gonads, but relatively few studies have focused on this, especially in non-mammalian models or in an integrated approach across the entire receptor family. The purpose of this study was to more fully characterize sreb genes in fish, using comparative genomics and gonadal expression analyses in five diverse ray-finned (Actinopterygii) species across evolution. Several unique characteristics were identified in fish, including: (1) a novel, fourth euteleost-specific gene (sreb3b or gpr173b) that likely emerged from a copy of sreb3 in a separate event after the teleost whole genome duplication, (2) sreb3a gene loss in Order Cyprinodontiformes, and (3) expression differences between a gar species and teleosts. Overall, gonadal patterns suggested an important role for all sreb genes in teleost testicular development, while gar were characterized by greater ovarian expression that may reflect similar roles to mammals. The novel sreb3b gene was also characterized by several unique features, including divergent but highly conserved amino acid positions, and elevated brain expression in puffer (Dichotomyctere nigroviridis) that more closely matched sreb2, not sreb3a. These results demonstrate that SREBs may differ among vertebrates in genomic structure and function, and more research is needed to better understand these roles in fish.

Evaluation of the integrated riparian ecosystem response to future flow regimes on semiarid rivers in Colorado, USA.

Riparian ecosystems are shaped by interactions among streamflow, plants, and physical processes. Sustaining functioning riparian ecosystems in the face of climate change, growing human demands for water, and increasing water scarcity requires improved understanding of the sensitivity of riparian ecosystems to shifts in flow regimes and associated adaptive management strategies. We applied projected future flow regimes to an ecogeomorphic model of riparian and channel response to evaluate these interactions. We tested the hypothesis that components of the riparian ecosystem vary in their vulnerabilities to shifts in flow attributes and that changes in the representation of functional groups of plants result from interactions between ecological and physical drivers. Using the Yampa and Green Rivers in northwestern Colorado as our test system, we investigated ecogeomorphic response to (1) synthetic flow regimes representing continuous changes from baseline flows; and (2) future flow scenarios that incorporate changing climate, demand, and water-resource projects. For this region, we showed that riparian plant presence, composition, and cover are highly sensitive to the high flows that occur early in the growing season, but that shifts to low flows are also important, especially for determining the functional diversity of a riparian community. Future flow regimes are likely to induce vegetation encroachment on lower channel surfaces and to increase plant cover, which will be dominated by fewer functional groups. In particular, we predict a decrease in some mesic plants (shrubs and tall herbs) and an increase in presence and cover of late-seral, xeric shrubs, most of which are non-native species. Managing for high flows that occur early in the growing season must complement maintenance of adequate baseflows to maintain ecosystem functioning in the face of hydrologic alterations induced by climate change and human water demand.

Bolus Detection in the Proximal Esophagus Using Pulse-Echo Ultrasound: A Feasibility Study.

Here, the feasibility of using nonimaging pulse-echo ultrasound as a method of noninvasively detecting a bolus in the proximal esophagus was demonstrated. To accomplish this, patient swallows were recorded on a clinical ultrasound device with research interface that allowed for collection of the pulse-echo data. These ultrasound data of the proximal esophagus were processed with a series of signal processing techniques in both the temporal and spectral domains, which revealed characteristic signatures that were unique for both liquid and food boluses compared to the normal collapsed esophageal state. Since substantial amounts of laryngopharyngeal reflux are gaseous in nature, future work will revolve around expanding the data set to include boluses of gaseous refluxate, a standardized methodology for capturing bolus events; developing automated detection tools for identifying laryngopharyngeal reflux for an extended duration; and assessing technology limitations due to user error.

Conceptualizing Ecological Responses to Dam Removal: If You Remove It, What's to Come?

One of the desired outcomes of dam decommissioning and removal is the recovery of aquatic and riparian ecosystems. To investigate this common objective, we synthesized information from empirical studies and ecological theory into conceptual models that depict key physical and biological links driving ecological responses to removing dams. We define models for three distinct spatial domains: upstream of the former reservoir, within the reservoir, and downstream of the removed dam. Emerging from these models are response trajectories that clarify potential pathways of ecological transitions in each domain. We illustrate that the responses are controlled by multiple causal pathways and feedback loops among physical and biological components of the ecosystem, creating recovery trajectories that are dynamic and nonlinear. In most cases, short-term effects are typically followed by longer-term responses that bring ecosystems to new and frequently predictable ecological condition, which may or may not be similar to what existed prior to impoundment.

Spectrum of Off-Label Nitric Oxide Utilization After Pediatric Cardiac Surgery Among Centers of Varying Surgical Volume.

OBJECTIVE: Nitric oxide is utilized after pediatric cardiac surgery as an off-label medication without much evidence, is expensive, and varies among centers of varying surgical volume. The objective of our study was to describe the spectrum of nitric oxide utilization and to evaluate the effect of nitric oxide utilization on outcomes among patients cared for in centers of varying surgical volume using Pediatric Health Information system. METHODS: Patients aged ≤18 years undergoing heart surgery were included (2004-2015). Multivariable mixed-effects logistic regression models were fitted to evaluate association of center volume with odds of nitric oxide utilization among patients undergoing heart operations. Centers were classified into 3 volume categories based on tertiles of number of cardiopulmonary bypass cases performed (low volume: 34 792 patients, 21 centers; medium volume: 38 362 patients, 13 centers; high volume: 30 560 patients, 7 centers). RESULTS: A total of 103 714 patients from 41 hospitals were included. Of these, 15 708 (15.1%) patients received nitric oxide after cardiac surgery. Of the patients receiving nitric oxide, only 3936 (25.1%) patients were associated with a diagnosis of pulmonary hypertension. In adjusted models, low- and medium-volume centers were associated with higher nitric oxide utilization after heart operations as compared to high-volume centers (low vs high, odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.38-1.60; medium vs high, OR: 1.33, 95% CI: 1.26-1.41). Despite higher nitric oxide utilization, the mortality was worse among patients treated in low- and medium-volume centers, as compared to high-volume centers (low vs high, OR: 1.42, 95% CI: 1.26-1.60; medium vs high, OR: 1.14, 95% CI: 1.04-1.25). CONCLUSIONS: This study demonstrates variation in nitric oxide utilization after heart operations among centers of varying surgical volume. Further, it raises questions on the benefit of nitric oxide administration after pediatric cardiac surgery.

Solubility and Complexation of the Bismuthate Ion in Nitric Acid Systems.

The dissolution rate and solubility of NaBiO3 have been investigated in nitric acid systems ranging from 4 to 6 M HNO3 and were found to be 58-76 µg/cm2·d and 490-830 mM, respectively. The presence of 50 mM U(VI) drastically increased the solubility to 540-1200 mM, while rates of dissolution were relatively unchanged. The solubility of NaBiO3 increased with an increase in U(VI) concentrations at 4 M HNO3, with log-log analysis indicating a one-to-one complex between Bi and U and infrared spectroscopic evidence monitoring uranyl stretching, suggesting complex formation. Absorbance spectra were obtained experimentally and computationally with an absorbance band in the range of 450-600 nm that has been attributed to Bi(V). The ingrowth and decay of Bi(V) in solution was also studied as a function of mass of solid NaBiO3 present, acidity, and temperature. The activation energies of dissolution and decomposition were calculated to be 39 ± 4 and 61 ± 6 kJ/mol, respectively. These results indicate that dissolution of NaBiO3 into the respective Na+ and BiO3-occurs prior to undergoing reduction, a process which conventionally has been believed to occur in the reverse order.

Simple and inexpensive micromachined aluminum microfluidic devices for acoustic focusing of particles and cells.

We introduce a new method to construct microfluidic devices especially useful for bulk acoustic wave (BAW)-based manipulation of cells and microparticles. To obtain efficient acoustic focusing, BAW devices require materials that have high acoustic impedance mismatch relative to the medium in which the cells/microparticles are suspended and materials with a high-quality factor. To date, silicon and glass have been the materials of choice for BAW-based acoustofluidic channel fabrication. Silicon- and glass-based fabrication is typically performed in clean room facilities, generates hazardous waste, and can take several hours to complete the microfabrication. To address some of the drawbacks in fabricating conventional BAW devices, we explored a new approach by micromachining microfluidic channels in aluminum substrates. Additionally, we demonstrate plasma bonding of poly(dimethylsiloxane) (PDMS) onto micromachined aluminum substrates. Our goal was to achieve an approach that is both low cost and effective in BAW applications. To this end, we micromachined aluminum 6061 plates and enclosed the systems with a thin PDMS cover layer. These aluminum/PDMS hybrid microfluidic devices use inexpensive materials and are simply constructed outside a clean room environment. Moreover, these devices demonstrate effectiveness in BAW applications as demonstrated by efficient acoustic focusing of polystyrene microspheres, bovine red blood cells, and Jurkat cells and the generation of multiple focused streams in flow-through systems. Graphical abstract The aluminum acoustofluidic device and the generation of multinode focusing of particles.

An Empirically Derived Pediatric Cardiac Inotrope Score Associated With Pediatric Heart Surgery.

We aimed to empirically derive an inotrope score to predict real-time outcomes using the doses of inotropes after pediatric cardiac surgery. The outcomes evaluated included in-hospital mortality, prolonged hospital length of stay, and composite poor outcome (mortality or prolonged hospital length of stay). The study population included patients <18 years of age undergoing heart operations (with or without cardiopulmonary bypass) of varying complexity. To create this novel pediatric cardiac inotrope score (PCIS), we collected the data on the highest doses of 4 commonly used inotropes (epinephrine, norepinephrine, dopamine, and milrinone) in the first 24 hours after heart operation. We employed a hierarchical framework by representing discrete probability models with continuous latent variables that depended on the dosage of drugs for a particular patient. We used Bayesian conditional probit regression to model the effects of the inotropes on the mean of the latent variables. We then used Markov chain Monte Carlo simulations for simulating posterior samples to create a score function for each of the study outcomes. The training dataset utilized 1030 patients to make the scientific model. An online calculator for the tool can be accessed at https://soipredictiontool.shinyapps.io/InotropeScoreApp. The newly proposed empiric PCIS demonstrated a high degree of discrimination for predicting study outcomes in children undergoing heart operations. The newly proposed empiric PCIS provides a novel measure to predict real-time outcomes using the doses of inotropes among children undergoing heart operations of varying complexity.

Mail-order pharmacy experience of veterans living with AIDS/HIV.

BACKGROUND: The VA system is the largest single provider of healthcare in the United States and to individuals infected with HIV specifically. High quality medication management is particularly important since HIV is a chronic infectious condition which requires taking multiple medications with strict requirements for adherence to medication regimens. Veterans Administration (VA) patients are required to obtain all chronic medications using the VA mail-order pharmacy system. OBJECTIVE: Drawing on Donabedian's Quality Improvement framework, this study sought to examine experiences that Veterans with HIV have with the Veterans Administration medication mail-order system, and to explore opportunities for quality improvement. METHODS: A sequential, explanatory mixed-methods design was used to interview Veterans receiving care at a Midwestern Veterans Administration Hospital using a mail-order experience survey followed by in-depth interviews. All 57 Veterans, out of 72, who were successfully contacted consented to participate. RESULTS: Overall, Veterans evaluated the mail-order service positively and valued the accuracy (correct medication delivery). However, a notable problem emerged with respect to assuring access to HIV medications with about half (47%) indicating running out of HIV medication. Respondents identified structural issues with respect to days covered by mailed medications (90 versus current 30 days) and process issues with scheduling new refills. Veterans also indicated the information sheets were too long, complex and not helpful for their queries. Patients were open to pharmacists playing an active role during clinic visits and felt this would help manage their conditions better. CONCLUSIONS: Veterans generally reported that the VA Mail-order service was of high quality. However, some findings indicate there are opportunities to improve this service to be more patient-centered particularly for vulnerable HIV patients.

Reducing COPD Readmission Rates: Using a COPD Care Service During Care Transitions.

A chronic obstructive pulmonary disease care service improves timely access to follow-up care and patient education at the time of transition from hospital to home.

Characterizing cardiac arrest in children undergoing cardiac surgery: A single-center study.

OBJECTIVES: To characterize cardiac arrest in children undergoing cardiac surgery using single-center data from the Society of Thoracic Surgeons and Pediatric Advanced Life Support Utstein-Style Guidelines. METHODS: Patients aged 18 years or less having a cardiac arrest for 1 minute or more during the same hospital stay as heart operation qualified for inclusion (2002-2014). Patients having a cardiac arrest both before or after heart operation were included. Heart operations were classified on the basis of the first cardiovascular operation of each hospital admission (the index operation). The primary outcome was survival to hospital discharge. RESULTS: A total of 3437 children undergoing at least 1 heart operation were included. Overall rate of cardiac arrest among these patients was 4.5% (n = 154) with survival to hospital discharge of 84 patients (66.6%). Presurgery cardiac arrest was noted among 28 patients, with survival of 21 patients (75%). Among the 126 patients with postsurgery cardiac arrest, survival was noted among 84 patients (66.6%). Regardless of surgical case complexity, the median days between heart operation and cardiac arrest, duration of cardiac arrest, and survival after cardiac arrest were similar. The independent risk factors associated with improved chances of survival included shorter duration of cardiac arrest (odds ratio, 1.12; 95% confidence interval, 1.05-1.20; P = .01) and use of defibrillator (odds ratio, 4.51; 95% confidence interval, 1.08-18.87; P = .03). CONCLUSIONS: This single-center study demonstrates that characterizing cardiac arrest in children undergoing cardiac surgery using definitions from 2 societies helps to increase data granularity and understand the relationship between cardiac arrest and heart operation in a better way.

Impact of varied center volume categories on volume-outcome relationship in children receiving ECMO for heart operations.

To study the volume-outcome relationship among children receiving extracorporeal membrane oxygenation (ECMO), different studies from different databases use different volume categories. The objective of this study was to evaluate if different center volume categories impact the volume-outcome relationship among children receiving ECMO for heart operations. We performed a post hoc analysis of data from an existing national database, the Pediatric Health Information System. Centers were classified into five different volume categories using different cut-offs and different variables. Mortality rates were compared between the varied volume categories using a mixed effects logistic regression model after adjusting for patient- and center-level risk factors. Data collection included demographic information, baseline characteristics, pre-ECMO risk factors, operation details, patient diagnoses, and center data. In unadjusted analysis, there was a significant relationship between center volume and mortality, with low-and medium-volume centers associated with higher mortality rates compared to high-volume centers in all volume categories, except the hierarchical clustering volume category. In contrast, there was no significant association between center-volume and mortality among all volume categories in adjusted analysis. We concluded that high-volume centers were not associated with improved outcomes for the majority of the categorization schemes despite using different cut-offs and different variables for volume categorization.

Potential enhancement of degradation of the nematicides aldicarb, oxamyl and fosthiazate in UK agricultural soils through repeated applications.

BACKGROUND: The potential for enhanced degradation of the carbamoyloxime nematicides aldicarb and oxamyl and the organophosphate fosthiazate was investigated in 35 UK agricultural soils. Under laboratory conditions, soil samples received three successive applications of nematicide at 25 day intervals. RESULTS: The second and third applications of aldicarb were degraded at a faster rate than the first application in six of the 15 aldicarb-treated soils, and a further three soils demonstrated rapid degradation of all three applications. High organic matter content and low pH had an inhibitory effect on the rate of aldicarb degradation. Rapid degradation was observed in nine out of the ten soils treated with oxamyl. In contrast, none of the fosthiazate-treated soils demonstrated enhanced degradation. CONCLUSION: The potential for enhanced degradation of aldicarb and oxamyl was demonstrated in nine out of 15 and nine out of ten soils respectively that had previously been treated with these active substances. Degradation of fosthiazate occurred at a much slower rate, with no evidence of enhanced degradation. Fosthiazate may provide a useful alternative in cases where the efficacy of aldicarb and oxamyl has been reduced as a result of enhanced degradation.

Telomerase-dependent and -independent chromosome healing in mouse embryonic stem cells.

Telomeres play an important role in protecting the ends of chromosomes and preventing chromosome fusion. We have previously demonstrated that double-strand breaks near telomeres in mammalian cells result in either the addition of a new telomere at the site of the break, termed chromosome healing, or sister chromatid fusion that initiates chromosome instability. In the present study, we have investigated the role of telomerase in chromosome healing and the importance of chromosome healing in preventing chromosome instability. In embryonic stem cell lines that are wild type for the catalytic subunit of telomerase (TERT), chromosome healing at I-SceI-induced double-strand breaks near telomeres accounted for 22 of 35 rearrangements, with the new telomeres added directly at the site of the break in all but one instance. In contrast, in two TERT-knockout embryonic stem cell lines, chromosome healing accounted for only 1 of 62 rearrangements, with a 23 bp insertion at the site of the sole chromosome-healing event. However, in a third TERT-knockout embryonic stem cell line, 10PTKO-A, chromosome healing was a common event that accounted for 20 of 34 rearrangements. Although this chromosome healing also occurred at the I-SceI site, differences in the microhomology at the site of telomere addition demonstrated that the mechanism was distinct from that in wild-type embryonic stem cell lines. In addition, the newly added telomeres in 10PTKO-A shortened with time in culture, eventually resulting in either telomere elongation through a telomerase-independent mechanism or loss of the subtelomeric plasmid sequences entirely. The combined results demonstrate that chromosome healing can occur through both telomerase-dependent and -independent mechanisms, and that although both mechanisms can prevent degradation and sister chromatid fusion, neither mechanism is efficient enough to prevent sister chromatid fusion from occurring in many cells experiencing double-strand breaks near telomeres.

Aromatic plant production on metal contaminated soils.

Field and container experiments were conducted to assess the feasibility of growing aromatic crops in metal contaminated areas and the effect of metals on herbage and oil productivity. The field experiments were conducted in the vicinities of the Non-Ferrous Metals Combine (Zn-Cu smelter) near Plovdiv, Bulgaria using coriander, sage, dill, basil, hyssop, lemon balm, and chamomile grown at various distances from the smelter. Herbage essential oil yields of basil, chamomile, dill, and sage were reduced when they were grown closer to the smelter. Metal removal from the site with the harvestable plant parts was as high as 180 g ha(-1) for Cd, 660 g ha(-1) for Pb, 180 g ha(-1) for Cu, 350 g ha(-1) for Mn, and 205 g ha(-1) for Zn. Sequential extraction of soil demonstrated that metal fractionation was affected by the distance to the smelter. With decreasing distance to the smelter, the transfer factor (TF) for Cu and Zn decreased but increased for Cd, while the bioavailability factor (BF) for Cd, Pb, Cu, Mn, and Zn decreased. Scanning electron microscopy and X-ray microanalyses of contaminated soil verified that most of the Pb, Cd, Mn, Cu, and Zn were in the form of small (<1 microm) particles, although there were larger particles (1-5 microm) with high concentrations of individual metals. This study demonstrated that high concentrations of heavy metals in soil or growth medium did not result in metal transfer into the essential oil. Of the tested metals, only Cu at high concentrations may reduce oil content. Our results demonstrated that aromatic crops may not have significant phytoremediation potential, but growth of these crops in metal contaminated agricultural soils is a feasible alternative. Aromatic crops can provide economic return and metal-free final product, the essential oil.

Regulation of extranuclear PtdIns5P production by phosphatidylinositol phosphate 4-kinase 2alpha.

Cellular levels of the phosphoinositide PtdIns5P are regulated by agonist stimulation, but the mechanisms controlling turnover of this lipid, and the subcellular location of the regulated PtdIns5P pool(s), remain poorly understood. Here we show that enhanced tyrosine phosphorylation robustly increases cellular PtdIns5P levels. Moreover, unlike PtdIns5P production enhanced by cell stress, we show that this pool of PtdIns5P is specifically regulated by the inositol lipid kinase PIP4K2a.