Developing a Comprehensive Framework of Safeguarding Strategies to Address Anticipated Errors With Organizational High-Alert Medications.

Purpose: To describe the development of a comprehensive framework of safeguarding strategies to address observed/anticipated errors with organizational high-alert medications. Methods: Observed/anticipated errors were identified for organizational high-alert medications and medication classes based on a review of external literature and alerts as well as internal voluntary error reporting. Anticipated or frequently reported errors were categorized into common cause error types. Error reduction strategies to address each common cause error were identified in collaboration with medication safety specialists and specialty practice pharmacists. Results: The review of externally and internally reported errors identified 101 observed/anticipated common cause errors across the 19 high-alert medication classes (median 5 error types per medication class, interquartile range 3-6). Safeguarding strategies specific to high-alert medications were identified in the following domains: separate or sequestered storage; restricted ordering; active alerts; dispensing in patient-specific dosing, unit of use, or unit-dose packaging; dispensing from pharmacy only; auxiliary labeling; level of care restriction; required monitoring; independent double checks; certification/privileging of staff; specific guidelines for use/monitoring; and other/miscellaneous. Identification of the observed/anticipated errors and the associated safeguarding strategies facilitated the development of a comprehensive tool and visual framework for addressing common cause errors associated with organizational high-alert medications. Conclusion: A comprehensive framework of safeguarding strategies to address anticipated errors with organizational high-alert medications is proposed. Although individual safeguards are institution-specific, the framework can be leveraged by all hospitals in order to take inventory of error-reduction strategies and prospectively identify gaps to address common cause errors.

Customized Scaffolds for Direct Assembly of Functionalized DNA Origami.

Functional DNA origami nanoparticles (DNA-NPs) are used as nanocarriers in a variety of biomedical applications including targeted drug delivery and vaccine development. DNA-NPs can be designed into a broad range of nanoarchitectures in one, two, and three dimensions with high structural fidelity. Moreover, the addressability of the DNA-NPs enables the precise organization of functional moieties, which improves targeting, actuation, and stability. DNA-NPs are usually functionalized via chemically modified staple strands, which can be further conjugated with additional polymers and proteins for the intended application. Although this method of functionalization is extremely efficient to control the stoichiometry and organization of functional moieties, fewer than half of the permissible sites are accessible through staple modifications. In addition, DNA-NP functionalization rapidly becomes expensive when a high number of functionalizations such as fluorophores for tracking and chemical modifications for stability that do not require spatially precise organization are used. To facilitate the synthesis of functional DNA-NPs, we propose a simple and robust strategy based on an asymmetric polymerase chain reaction (aPCR) protocol that allows direct synthesis of custom-length scaffolds that can be randomly modified and/or precisely modified via sequence design. We demonstrated the potential of our strategy by producing and characterizing heavily modified scaffold strands with amine groups for dye functionalization, phosphorothioate bonds for stability, and biotin for surface immobilization. We further validated our sequence design approach for precise conjugation of biomolecules by synthetizing scaffolds including binding loops and aptamer sequences that can be used for direct hybridization of nucleic acid tagged biomolecules or binding of protein targets.

The potential for floral evolution in response to competing selection pressures following the loss of hawkmoth pollination in Ruellia humilis.

PREMISE: In the absence of hawkmoth pollinators, chasmogamous (CH) flowers of Ruellia humilis self-pollinate by two secondary mechanisms. Other floral visitors might exert selection on CH floral traits to restore outcrossing, but at the same time preferential predation of CH seeds generates selection to increase the allocation of resources to cleistogamous (CL) flowers. METHODS: To assess the potential for an evolutionary response to these competing selection pressures, we estimated additive genetic variances ( σ A 2 ${\sigma }_{{\rm{A}}}^{2}$ ) and covariances for 14 reproductive traits and three fitness components in a Missouri population lacking hawkmoth pollinators. RESULTS: We found significant σ A 2 ${\sigma }_{{\rm{A}}}^{2}$ for all 11 floral traits and two measures of resource allocation to CL flowers, indicating the potential for a short-term response to selection on most reproductive traits. Selection generated by seed predators is predicted to increase the percentage of CL flowers by 0.24% per generation, and mean stigma-anther separation is predicted to decrease as a correlated response, increasing the fraction of plants that engage in prior selfing. However, the initial response to this selection is opposed by strong directional dominance. CONCLUSIONS: The predicted evolutionary decrease in the number of CH flowers available for potential outcrossing, combined with the apparent preclusion of potential diurnal pollinators by the pollen-harvesting activities of sweat bees, suggest that 100% cleistogamy is the likely outcome of evolution in the absence of hawkmoths. However, rare mutations with large effects, such as delaying budbreak until after sunrise, could provide pathways for the restoration of outcrossing that are not reachable by gradual quantitative-genetic evolution.

Description of the role of pharmacist independent double checks during cognitive order verification of outpatient parenteral anti-cancer therapy.

INTRODUCTION: To describe pharmacist interventions as a result of an independent double check during cognitive order verification of outpatient parenteral anti-cancer therapy. METHODS: A single-center, retrospective analysis of all individual orders for outpatient, parenteral anti-cancer agents within a hematology/oncology infusion center during a 30 day period was conducted. The primary endpoint was error identification rates during first and second verification. Secondary endpoints included the type, frequency, and severity of errors identified during second verification using a modified National Coordinating Council for Medication Error Reporting and Prevention Index. RESULTS: A total of 1970 anti-cancer parenteral orders were screened, from which 1645 received an independent double check and were included. The number of errors identified during first and second verification were 30 (1.8%) and 10 (0.6%) respectively; second verification resulted in a 33.3% increase in corrected errors. The 10 errors identified during second verification included: four rate transcriptions to optimize pump interoperability, three rate and/or volume modifications, two dosage adjustments, and one treatment deferral due to toxicity. The severity was classified as Category A for four (40%), Category C for three (30%), and Category D for three (30%) errors. This correlated to a low capacity for harm for seven (70%) and a serious capacity for three (30%) errors. CONCLUSIONS: Second verification of outpatient, parenteral anti-cancer medication orders resulted in a 33.3% increase in corrected errors. Three errors detected during second verification were determined to have a serious capacity for harm, supporting the value of independent double checks during pharmacist cognitive order verification.

Prospective Study of a Novel Risk Stratification Process for Opioid-Related Harm Reduction in Cancer Patients Seen in an Outpatient Palliative Care Clinic.

Background: Oncologists and palliative specialists prescribe opioids for millions of cancer patients despite limited research on effective screening and mitigation strategies to reduce risk of opioid-related harm in that population. Objective: To evaluate the efficacy of a novel opioid risk stratification process for predicting significant aberrant behaviors (SABs) related to prescribed opioid medications. Design and Setting/Subjects: This is a prospective, longitudinal study of 319 consecutive patients referred to an outpatient palliative care clinic between 2010 and 2012, a period during which prescription opioid-related deaths began to increase in the United States. Measures: Patients completed a psychodiagnostic/substance use risk assessment with a licensed clinical psychologist or social worker at the initial palliative clinic visit. Patients were assigned to Low-, Moderate-, or High-Risk groups based on predetermined stratification criteria and were managed via an opioid harm reduction approach. The primary dependent measure was the presence of at least one SAB after the initial visit. Results: Eighteen percent of patients (n = 56) demonstrated at least one major aberrant behavior. Odds of future aberrant behavior was 15 times greater in the High-Risk versus the Low-Risk category. Five risk factors significantly enhanced our risk model: age 18 to 45 years, job instability, history of bipolar diagnosis, history of substance abuse, and theft. Conclusion: Our risk stratification process provides a useful model for predicting those at greatest risk of future aberrant behaviors and most in need of comanagement. We recommend additional studies to test our proposed streamlined risk stratification tool.

Visuomotor control of ankle joint using position vs. force.

Ankle joint plays a critical role in daily activities involving interactions with environment using force and position control. Neuromechanical dysfunctions (e.g., due to stroke or brain injury), therefore, have a major impact on individuals' quality of life. The effective design of neuro-rehabilitation protocols for robotic rehabilitation platforms relies on understanding the control characteristics of the ankle joint in interaction with external environment using force and position, as the findings in upper limb may not be generalizable to the lower limb. This study aimed to characterize the skilled performance of ankle joint in visuomotor position and force control. A two-degree-of-freedom (DOF) robotic footplate was used to measure individuals' force and position. Healthy individuals (n = 27) used ankle force or position for point-to-point and tracking control tasks in 1-DOF and 2-DOF virtual game environments. Subjects' performance was quantified as a function of accuracy and completion time. In contrast to comparable performance in 1-DOF control tasks, the performance in 2-DOF tasks was different and had characteristic patterns in the position and force conditions, with a significantly better performance for position. Subjective questionnaires on the perceived difficulty matched the objective experimental results, suggesting that the poor performance in force control was not due to experimental set-up or fatigue but can be attributed to the different levels of challenge needed in neural control. It is inferred that in visuomotor coordination, the neuromuscular specialization of ankle provides better control over position rather than force. These findings can inform the design of neuro-rehabilitation platforms, selection of effective tasks and therapeutic protocols.

Evaluation of QTc Interval Prolongation Among Patients With Cancer Using Enteral Methadone.

CONTEXT:: The effect of methadone on corrected QT interval (QTc) in patients with cancer pain is not well-known. OBJECTIVES:: To describe and characterize the effect of low-, moderate-, and high-dose enteral methadone on QTc interval in patients with cancer. METHODS:: Retrospective cohort study including patients prescribed enteral methadone during the 27-month study period. Participants were divided into 3 methadone daily dose groups: <30 (low dose), 30 to 59 (moderate dose), ≥60 (high dose) mg. The primary outcome was the incidence of QTc prolongation (>450 ms for females and >430 ms for males). Secondary outcomes included the magnitude of change in QTc after starting methadone, the incidence of clinically significant QTc prolongation (>500 ms) and the prevalence of torsades de pointes and syncope. RESULTS:: Two hundred three patients met study inclusion criteria: 91 (45%) low dose, 52 (26%) moderate dose, and 60 (29%) high dose. Incidence of QTc prolongation for low-, moderate-, and high-dose groups was 50 (55%), 37 (71%), and 43 (72%), respectively ( P = .039, low vs high dose). Incidence of clinically significant QTc prolongation was 10 (11%), 4 (8%), and 7 (12%) for low-, moderate-, and high-dose groups. For patients without QTc prolongation prior to initiating methadone, 62% of moderate-dose patients and 67% of high-dose patients had QTc prolongation, while taking methadone. CONCLUSION:: This study found a notably high incidence of QTc prolongation in patients with cancer using enteral methadone. Future studies should aim to determine the risk of adverse cardiac effects in the cancer population and determine appropriate monitoring of methadone for pain management.

Pharmacogenomics of sickle cell disease: steps toward personalized medicine.

Sickle cell disease (SCD) is a monogenetic disease but has a wide range of phenotypic expressions. Some of these differences in phenotype can be explained by genetic polymorphisms in the human globin gene. These polymorphisms can result in different responses to typical treatment, sometimes leading to inadequate therapeutics. Research is revealing more polymorphisms, and therefore, new targets for intervention to improve outcomes in SCD. This area of pharmacogenomics is continuing to develop. We provide a brief review of the current literature on pharmacogenomics in SCD and possible targets for intervention.

Evaluation of Emergency Department Management of Opioid-Tolerant Cancer Patients With Acute Pain.

CONTEXT: There are no previously published studies examining opioid doses administered to opioid-tolerant cancer patients during emergency department (ED) encounters. OBJECTIVES: To determine if opioid-tolerant cancer patients presenting with acute pain exacerbations receive adequate initial doses of as needed (PRN) opioids during ED encounters based on home oral morphine equivalent (OME) use. METHODS: We performed a retrospective cohort study of opioid-tolerant cancer patients who received opioids in our ED over a two-year period. The percentage of patients who received an adequate initial dose of PRN opioid (defined as ≥10% of total 24-hour ambulatory OME) was evaluated. Logistic regression was used to establish the relationship between 24-hour ambulatory OME and initial ED OME to assess whether higher home usage was associated with higher likelihood of being undertreated. RESULTS: Out of 216 patients, 61.1% of patients received an adequate initial PRN dose of opioids in the ED. Of patients taking <200 OMEs per day at home, 77.4% received an adequate initial dose; however, only 3.2% of patients taking >400 OMEs per day at home received an adequate dose. Patients with ambulatory 24-hour OME greater than 400 had 99% lower odds of receiving an adequate initial dose of PRN opioid in the ED compared to patients with ambulatory 24-hour OME less than 100 (OR <0.01, CI 0.00-0.02, P < 0.001). CONCLUSIONS: Patients with daily home use less than 200 OMEs generally received adequate initial PRN opioid doses during their ED visit. However, patients with higher home opioid usage were at increased likelihood of being undertreated.

Diltiazem for the management of malignancy-associated perineal pain and tenesmus.

BACKGROUND: Perineal pain is a frequent complaint of patients with advanced cancer (colorectal, genitourinary, prostate), and often quite difficult to manage with significant impact on quality of life. Calcium channel blockers (CCBs) are potent inhibitors of intestinal smooth muscle contraction and have been shown to impact tone and motility of the gastrointestinal tract. As such, they have been used in various pain syndromes of the lower gastrointestinal tract, such as chronic anal fissure, to promote healing and improve pain. Here we describe two cases using oral diltiazem for malignancy-associated perineal pain and tenesmus. DISCUSSION: The first case describes an elderly male with advanced urothelial cancer post surgical resection and chemoradiation who suffered from rectal pain described as "sitting on a football" despite nerve blocks and oral opioids. He experienced dramatic improvement in pain scores and daily requirements of oral analgesics after starting oral diltiazem. The second case describes a middle-aged female with rectal cancer post surgical resection and chemoradiation who suffered from quality-of-life-limiting rectal pain and pressure despite oral opioids. She experienced dramatic improvement in the "pressure-type" pain after adding oral diltiazem. CONCLUSION: Based on our experience with these two cases, we propose oral diltiazem for use as an adjunct therapy for management of chronic malignancy-associated perineal pain, specifically with characteristics of pressure-type pain and tenesmus.

Position versus force control: using the 2-DOF robotic ankle trainer to assess ankle's motor control.

An estimated of 2,000,000 acute ankle sprains occur annually in the United States. Furthermore, ankle disabilities are caused by neurological impairments such as traumatic brain injury, cerebral palsy and stroke. The virtually interfaced robotic ankle and balance trainer (vi-RABT) was introduced as a cost-effective platform-based rehabilitation robot to improve overall ankle/balance strength, mobility and control. The system is equipped with 2 degrees of freedom (2-DOF) controlled actuation along with complete means of angle and torque measurement mechanisms. Vi-RABT was used to assess ankle strength, flexibility and motor control in healthy human subjects, while playing interactive virtual reality games on the screen. The results suggest that in the task with 2-DOF, subjects have better control over ankle's position vs. force.

Introducing W.A.T.E.R.S.: a workflow for the alignment, taxonomy, and ecology of ribosomal sequences.

BACKGROUND: For more than two decades microbiologists have used a highly conserved microbial gene as a phylogenetic marker for bacteria and archaea. The small-subunit ribosomal RNA gene, also known as 16 S rRNA, is encoded by ribosomal DNA, 16 S rDNA, and has provided a powerful comparative tool to microbial ecologists. Over time, the microbial ecology field has matured from small-scale studies in a select number of environments to massive collections of sequence data that are paired with dozens of corresponding collection variables. As the complexity of data and tool sets have grown, the need for flexible automation and maintenance of the core processes of 16 S rDNA sequence analysis has increased correspondingly. RESULTS: We present WATERS, an integrated approach for 16 S rDNA analysis that bundles a suite of publicly available 16 S rDNA analysis software tools into a single software package. The "toolkit" includes sequence alignment, chimera removal, OTU determination, taxonomy assignment, phylogentic tree construction as well as a host of ecological analysis and visualization tools. WATERS employs a flexible, collection-oriented 'workflow' approach using the open-source Kepler system as a platform. CONCLUSIONS: By packaging available software tools into a single automated workflow, WATERS simplifies 16 S rDNA analyses, especially for those without specialized bioinformatics, programming expertise. In addition, WATERS, like some of the newer comprehensive rRNA analysis tools, allows researchers to minimize the time dedicated to carrying out tedious informatics steps and to focus their attention instead on the biological interpretation of the results. One advantage of WATERS over other comprehensive tools is that the use of the Kepler workflow system facilitates result interpretation and reproducibility via a data provenance sub-system. Furthermore, new "actors" can be added to the workflow as desired and we see WATERS as an initial seed for a sizeable and growing repository of interoperable, easy-to-combine tools for asking increasingly complex microbial ecology questions.

Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation.

Consumption of diets high in fat and calories leads to hyperphagia and obesity, which is associated with chronic "low-grade" systemic inflammation. Ingestion of a high-fat diet alters the gut microbiota, pointing to a possible role in the development of obesity. The present study used Sprague-Dawley rats that, when fed a high-fat diet, exhibit either an obesity-prone (DIO-P) or obesity-resistant (DIO-R) phenotype, to determine whether changes in gut epithelial function and microbiota are diet or obese associated. Food intake and body weight were monitored daily in rats maintained on either low- or high-fat diets. After 8 or 12 wk, tissue was removed to determine adiposity and gut epithelial function and to analyze the gut microbiota using PCR. DIO-P but not DIO-R rats exhibit an increase in toll-like receptor (TLR4) activation associated with ileal inflammation and a decrease in intestinal alkaline phosphatase, a luminal enzyme that detoxifies lipopolysaccharide (LPS). Intestinal permeability and plasma LPS were increased together with phosphorylation of myosin light chain and localization of occludin in the cytoplasm of epithelial cells. Measurement of bacterial 16S rRNA showed a decrease in total bacterial density and an increase in the relative proportion of Bacteroidales and Clostridiales orders in high-fat-fed rats regardless of phenotype; an increase in Enterobacteriales was seen in the microbiota of DIO-P rats only. Consumption of a high-fat diet induces changes in the gut microbiota, but it is the development of inflammation that is associated with the appearance of hyperphagia and an obese phenotype.

The complete genome sequence of Haloferax volcanii DS2, a model archaeon.

BACKGROUND: Haloferax volcanii is an easily culturable moderate halophile that grows on simple defined media, is readily transformable, and has a relatively stable genome. This, in combination with its biochemical and genetic tractability, has made Hfx. volcanii a key model organism, not only for the study of halophilicity, but also for archaeal biology in general. METHODOLOGY/PRINCIPAL FINDINGS: We report here the sequencing and analysis of the genome of Hfx. volcanii DS2, the type strain of this species. The genome contains a main 2.848 Mb chromosome, three smaller chromosomes pHV1, 3, 4 (85, 438, 636 kb, respectively) and the pHV2 plasmid (6.4 kb). CONCLUSIONS/SIGNIFICANCE: The completed genome sequence, presented here, provides an invaluable tool for further in vivo and in vitro studies of Hfx. volcanii.

Human gut microbiome adopts an alternative state following small bowel transplantation.

Small bowel transplants provide an exceptional opportunity for long-term study of the microbial ecology of the human small bowel. The ileostomy created at time of transplant for ongoing monitoring of the allograft provides access to samples of ileal effluent and mucosal biopsies. In this study, we used qPCR to assay the bacterial population of the small bowel lumen of 17 small bowel transplant patients over time. Surprisingly, the posttransplant microbial community was found to be dominated by Lactobacilli and Enterobacteria, both typically facultative anaerobes. This represents an inversion of the normal community that is dominated instead by the strictly anaerobic Bacteroides and Clostridia. We found this inverted community also in patients with ileostomies who did not receive a transplant, suggesting that the ileostomy itself is the primary ecological determinant shaping the microbiota. After surgical closure of the ileostomy, the community reverted to the normal structure. Therefore, we hypothesized that the ileostomy allows oxygen into the otherwise anaerobic distal ileum, thus driving the transition from one microbial community structure to another. Supporting this hypothesis, metabolomic profiling of both communities demonstrated an enrichment for metabolites associated with aerobic respiration in samples from patients with open ileostomies. Viewed from an ecological perspective, the two communities constitute alternative stable states of the human ileum. That the small bowel appears to function normally despite these dramatic shifts suggests that its ecological resilience is greater than previously realized.

An automated phylogenetic tree-based small subunit rRNA taxonomy and alignment pipeline (STAP).

Comparative analysis of small-subunit ribosomal RNA (ss-rRNA) gene sequences forms the basis for much of what we know about the phylogenetic diversity of both cultured and uncultured microorganisms. As sequencing costs continue to decline and throughput increases, sequences of ss-rRNA genes are being obtained at an ever-increasing rate. This increasing flow of data has opened many new windows into microbial diversity and evolution, and at the same time has created significant methodological challenges. Those processes which commonly require time-consuming human intervention, such as the preparation of multiple sequence alignments, simply cannot keep up with the flood of incoming data. Fully automated methods of analysis are needed. Notably, existing automated methods avoid one or more steps that, though computationally costly or difficult, we consider to be important. In particular, we regard both the building of multiple sequence alignments and the performance of high quality phylogenetic analysis to be necessary. We describe here our fully-automated ss-rRNA taxonomy and alignment pipeline (STAP). It generates both high-quality multiple sequence alignments and phylogenetic trees, and thus can be used for multiple purposes including phylogenetically-based taxonomic assignments and analysis of species diversity in environmental samples. The pipeline combines publicly-available packages (PHYML, BLASTN and CLUSTALW) with our automatic alignment, masking, and tree-parsing programs. Most importantly, this automated process yields results comparable to those achievable by manual analysis, yet offers speed and capacity that are unattainable by manual efforts.

Genetic and physical mapping of DNA replication origins in Haloferax volcanii.

The halophilic archaeon Haloferax volcanii has a multireplicon genome, consisting of a main chromosome, three secondary chromosomes, and a plasmid. Genes for the initiator protein Cdc6/Orc1, which are commonly located adjacent to archaeal origins of DNA replication, are found on all replicons except plasmid pHV2. However, prediction of DNA replication origins in H. volcanii is complicated by the fact that this species has no less than 14 cdc6/orc1 genes. We have used a combination of genetic, biochemical, and bioinformatic approaches to map DNA replication origins in H. volcanii. Five autonomously replicating sequences were found adjacent to cdc6/orc1 genes and replication initiation point mapping was used to confirm that these sequences function as bidirectional DNA replication origins in vivo. Pulsed field gel analyses revealed that cdc6/orc1-associated replication origins are distributed not only on the main chromosome (2.9 Mb) but also on pHV1 (86 kb), pHV3 (442 kb), and pHV4 (690 kb) replicons. Gene inactivation studies indicate that linkage of the initiator gene to the origin is not required for replication initiation, and genetic tests with autonomously replicating plasmids suggest that the origin located on pHV1 and pHV4 may be dominant to the principal chromosomal origin. The replication origins we have identified appear to show a functional hierarchy or differential usage, which might reflect the different replication requirements of their respective chromosomes. We propose that duplication of H. volcanii replication origins was a prerequisite for the multireplicon structure of this genome, and that this might provide a means for chromosome-specific replication control under certain growth conditions. Our observations also suggest that H. volcanii is an ideal organism for studying how replication of four replicons is regulated in the context of the archaeal cell cycle.