Identifying gaps in the photographic record of the vascular plant flora of the Americas.

Field photographs of plant species are crucial for research and conservation, but the lack of a centralized database makes them difficult to locate. We surveyed 25 online databases of field photographs and found that they harboured only about 53% of the approximately 125,000 vascular plant species of the Americas. These results reflect the urgent need for a centralized database that can both integrate and complete the photographic record of the world's flora.

Economic outcomes with the conversion of insulin delivery methods in hospitals.

PURPOSE: To evaluate the insulin wastage and associated acquisition costs when switching from individual patient supply (IPS) of 3-mL pens of rapid-acting insulin (RAI) aspart to floor stock (FS) dispensing of 3-mL vials of RAI lispro, and with conversion from IPS of 3-mL pens to centralized unit dose (CUD) of 10-mL vials of basal insulin detemir. METHODS: Data from September 2010 to December 2012 from three hospitals in the Roper St. Francis Healthcare (RSFH) were used: Roper Hospital (368 beds), Bon Secours St. Francis Hospital (204 beds), and Roper St. Francis Mt. Pleasant Hospital (85 beds). Insulin wastage and associated acquisition costs were estimated using regression models. RESULTS: The conversion from IPS of 3-mL pens of insulin aspart to FS of 3-mL vials of lispro was associated with a significant decrease in insulin wastage (204,042 IUs; p < .001) and equated to an average savings of $106.40 per patient at all three hospitals combined (p < .001). For basal insulin, conversion from IPS of 3-mL pens of insulin detemir to CUD of 10-mL vials was associated with a significant decrease in insulin wastage at Roper and St. Francis Hospitals (p < .001). For Mt. Pleasant Hospital, the decrease was not statistically significant. The predicted average reduction in insulin wastage per month was 52,542.9 IUs (p < .001) at all three hospitals combined. CONCLUSIONS: Switching RAI from IPS of 3-mL pens of insulin aspart to one-time unit dose insulin lispro dispensed from FS 3-mL vials as needed significantly reduced insulin wastage and associated acquisition costs at the three combined hospitals. Conversion of basal insulin from IPS of 3-mL pens of insulin detemir to CUD of 10-mL vials of insulin detemir was associated with a significant reduction in insulin wastage and associated acquisition costs at three hospitals combined.

Association of Anticholinergic Burden with Cognitive Impairment and Health Care Utilization Among a Diverse Ambulatory Older Adult Population.

STUDY OBJECTIVE: To determine the association between Anticholinergic Cognitive Burden (ACB) score and both cognitive impairment and health care utilization among a diverse ambulatory older adult population. DESIGN: Retrospective cohort study. DATA SOURCE: Medication exposure and other clinical data were extracted from the Regenstrief Medical Record System (RMRS), and cognitive diagnosis was derived from a dementia screening and diagnosis study. PATIENTS: A total of 3344 community-dwelling older adults (age 65 yrs and older) who were enrolled in a previously published dementia screening and diagnosis study; of these, 3127 were determined to have no cognitive impairment, and 217 were determined to have cognitive impairment. MEASUREMENTS AND MAIN RESULTS: The study followed a two-phase screening and comprehensive neuropsychiatric examination to determine a cognitive diagnosis, which defined cognitive impairment as dementia or mild cognitive impairment. The ACB scale was used to identify anticholinergics dispensed in the 12 months prior to screening. A total daily ACB score was calculated by using pharmacy dispensing data from RMRS; each anticholinergic was multiplied by 1, 2, or 3 consistent with anticholinergic burden defined by the ACB scale. The sum of all ACB medications was divided by the number of days with any medication dispensed to achieve the total daily ACB score. Health care utilization included visits to inpatient, outpatient, and the emergency department, and it was determined by using visit data from the RMRS. The overall population had a mean age of 71.5 years, 71% were female, and 58% were African American. Each 1-point increase in mean total daily ACB score was associated with increasing risk of cognitive impairment (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.004-1.27, p=0.043). Each 1-point increase in mean total daily ACB score increased the likelihood of inpatient admission (OR 1.11, 95% CI 1.02-1.29, p=0.014) and number of outpatient visits after adjusting for demographic characteristics, number of chronic conditions, and prior visit history (estimate 0.382, standard error [SE] 0.113; p=0.001). The number of visits to the emergency department was also significantly different after similar adjustments (estimate 0.046, SE 0.023, p=0.043). CONCLUSION: Increasing total ACB score was correlated with an increased risk for cognitive impairment and more frequent health care utilization. Future work should study interventions that safely reduce ACB and evaluate the impact on brain health and health care costs.

Estimated Budget Impact of Increased Use of Mirabegron, A Novel Treatment for Overactive Bladder.

BACKGROUND: Oral pharmacological treatment for overactive bladder (OAB) consists of antimuscarinics and the beta-3 adrenergic agonist mirabegron. Antimuscarinic adverse events (AEs) such as dry mouth, constipation, and blurry vision can result in frequent treatment discontinuation rates, leaving part of the OAB population untreated. Antimuscarinics also contribute to a patient's anticholinergic cognitive burden (ACB), so the Beers Criteria recommends cautious use of antimuscarinics in elderly patients who take multiple anticholinergic medications or have cognitive impairment. Since mirabegron does not affect the cholinergic pathways, it is unlikely to contribute to a patient's ACB. OBJECTIVE: To estimate the health care costs associated with the pharmacological treatment of OAB with mirabegron and antimuscarinics from U.S. commercial payer and Medicare Advantage perspectives, using a budget impact model. METHODS: For this budget impact model, 2 analyses were performed. The primary analysis estimated the budgetary impact of increasing the use of mirabegron in a closed patient cohort treated with oral pharmacological treatments. The secondary analysis modeled the economic impact in an open cohort by allowing untreated patients to begin treatment with mirabegron after potential contraindication, intolerance, or lack of effectiveness of antimuscarinics. The analyses were performed over a 3-year time horizon. The economic impact of increased mirabegron use was quantified using direct medical costs, including prescription costs and health resource utilization (HRU) costs. Costs of comorbidities included pharmacy and medical costs of treating OAB-related urinary tract infections (UTI), skin rashes, and depression. An analysis of a large single-site integrated health network database was commissioned to quantify ACB-related HRU in terms of the increases in yearly outpatient and emergency department visits. Based on this analysis, the model associated each unit increase in ACB score with increased HRU and probability of mild cognitive impairment. Clinical outcomes of increased use of mirabegron were presented as the number of AEs and comorbidity episodes that could be avoided. One-way sensitivity analyses were performed to quantify the expected budget impact over the range of uncertainty for the key input variables. RESULTS: Primary analysis calculated the impact of increasing the use of mirabegron from 4.5% to 5.3%, 7.1%, and 9.4% in years 1, 2, and 3, respectively, among oral pharmacological OAB treatments that included generic and branded antimuscarinics: oxybutynin, tolterodine, trospium, darifenacin, fesoterodine, and solifenacin. For a 1 million-member U.S. commercial payer plan, the total prescription costs increased, and the total medical costs decreased during the 3-year time horizon, yielding increases of $0.005, $0.016, and $0.031 from current per member per month (PMPM) costs and $0.90, $2.92, and $5.53 from current per treated member per month (PTMPM) costs, an average of less than 2% of current OAB treatment costs. For the Medicare Advantage plan, the resulting incremental PMPM costs were $0.010, $0.034, and $0.065, and the incremental PTMPM costs were $0.93, $3.04, and $5.76; all were less than 4% of the current cost. The secondary analysis estimated the budgetary effects of reducing the untreated population by 1% annually by initiating treatment with mirabegron. For a commercial payer, this resulted in PMPM cost increases of $0.156, $0.311, and $0.467 from the current value, while the incremental PTMPM cost increased by $6.17, $11.67, and $16.61. For the Medicare Advantage plan, the incremental increases in PMPM costs were $0.277, $0.553, and $0.830, and in PTMPM costs were $6.42, $12.15, and $17.29. Clinically, treating more OAB patients resulted in fewer OAB-related comorbidities from both health plan perspectives, since most events associated with nontreatment could be avoided. In the Medicare Advantage population of the secondary analysis, the total numbers of avoided events were predicted as 452 UTIs, 2,598 depression diagnoses, and 3,020 skin rashes during the time horizon of the model. CONCLUSIONS: Mirabegron addresses an unmet need for therapy for certain OAB patients, for whom antimuscarinics are not recommended because of a risk of cognitive impairment and who are intolerant to the anticholinergic AEs. Using mirabegron involves moderate additional economic cost to a commercial or Medicare Advantage health plan for which medical cost savings can offset a substantial part of increased pharmacy costs. DISCLOSURES: Funding for this study was provided by Astellas. Perk, Wielage, T. Klein, and R. Klein are employed by Medical Decision Modeling, a contract research company that was paid to perform the described outcomes research and build the model contained in this study. Campbell and Perkins are employed by the Regenstrief Institute, which conducted a database analysis for this research. Campbell reports consultancy fees from Astellas, as well as pending grants from Merck, Sharpe, and Dohme Corp. Posta, Yuran, and Ng are employed by Astellas Pharma Global Development, the developer of mirabegron. Study concept and design were contributed by Perk, Wielage, R. Klein, and Ng. Campbell, T. Klein, and Perkins took the lead in data collection, assisted by Perk, Wielage, and Ng. Data interpretation was performed by Posta and Yuran, along with Perk, Wielage, R. Klein, Ng, Campbell, and Perkins. The manuscript was written by Perk and R. Klein, along with Wielage, T. Klein, Posta, Yuran, and Ng, and revised by all the authors.

Mirabegron for the treatment of overactive bladder: cost-effectiveness from US commercial health-plan and Medicare Advantage perspectives.

BACKGROUND AND OBJECTIVE: The first class of oral pharmacologic treatments for overactive bladder (OAB) are antimuscarinics that are associated with poor persistence, anticholinergic adverse events, and increased anticholinergic burden (ACB) with risk of cognitive impairment. Mirabegron, a ß3-adrenoceptor agonist, is an oral treatment that does not contribute to ACB and has early evidence of improved persistence. The objective of the analysis was to assess the cost-effectiveness of mirabegron for OAB vs six antimuscarinics in the US. METHODS: A Markov state-transition model assessed US commercial health-plan and Medicare Advantage perspectives over a 3-year time horizon in an OAB patient population. Transition probabilities between five micturition and five incontinence severity states were derived from a network meta-analysis of 44 trials of oral OAB treatments. Therapy beginning with an oral OAB agent could discontinue or switch to another oral agent and could be followed by tibial nerve stimulation, sacral neuromodulation, or onabotulinumtoxinA. The primary outcome was cost per quality-adjusted life year (QALY). Utilities were mapped from incontinence and micturition frequencies as well as demographics. Based on analysis of data from a large healthcare system, elevated ACB was associated with increased healthcare utilization and probability of cognitive impairment. RESULTS: From both commercial and Medicare Advantage perspectives, mirabegron was the most clinically effective treatment, while oxybutynin was the least expensive. Tolterodine immediate release (IR) was also on the cost-effectiveness frontier. The analysis estimated costs per QALY of $59,690 and $66,347 for mirabegron from commercial health plan and Medicare Advantage perspectives, respectively, compared to tolterodine IR. Other antimuscarinics were dominated. CONCLUSIONS: This analysis estimated that mirabegron is a cost-effective treatment for OAB from US commercial health plan and Medicare Advantage perspectives, due to fewer projected adverse events and comorbidities, and data suggesting better persistence.

Enhancing the Budget Impact Model for Institutional Use: A Tool with Practical Applications for the Hospital Oncology Pharmacy.

BACKGROUND: The cost of cancer care is increasing, and tools are needed to understand the economic impact of new drugs on the hospital pharmacy budget. OBJECTIVE: To develop an interactive budget impact model (BIM) through a collaborative effort of industry, academia, and modeling experts to evaluate the use of a new agent in non-small cell lung cancer (NSCLC); this BIM included an institutional module specific to the needs of practices that purchase medications for use in institutional settings. METHODS: Treatment regimens, doses, duration of therapy, toxicity, and cost data are from published sources. All input data may be modified to match the local population. Outputs include cost of care, reimbursement, and margin overall and by treatment regimen. RESULTS: The base case assumes 20 NSCLC patients progressing after initial therapy (3 receiving ramucirumab+docetaxel, 2 bevacizumab+erlotinib, 3 docetaxel, 6 erlotinib, and 6 pemetrexed), wholesale acquisition cost (WAC) purchase price, and reimbursement at WAC+4.3%. The model estimated the total cost and reimbursement for the institutional oncology pharmacy to be $699,413 and $729,487, respectively, resulting in a margin of $30,075 (difference due to rounding) for the year for regimens utilized in the treatment of NSCLC in the post-progression setting. Results will vary depending on the input data. CONCLUSIONS: There is an increasing need for institutional pharmacies to plan ahead and anticipate the impact of new drugs on their oncology budgets. This interactive Excel-based institutional BIM may provide evidence-based support for pharmacy decision making.

Evaluation of a patient self-directed mealtime insulin titration algorithm: a US payer perspective.

Objective To model the potential economic impact of implementing the AUTONOMY once daily (Q1D) patient self-titration mealtime insulin dosing algorithm vs standard of care (SOC) among a population of patients with Type 2 diabetes living in the US. Methods Three validated models were used in this analysis: The Treatment Transitions Model (TTM) was used to generate the primary results, while both the Archimedes (AM) and IMS Core Diabetes Models (IMS) were used to test the veracity of the primary results produced by TTM. Models used data from a 'real world' representative sample of patients (2012 US National Health and Nutrition Examination Survey) that matched the characteristics of US patients enrolled in the randomized controlled trial 'AUTONOMY' cohort. The base-case time horizon was 10 years. Results The modeling results from TTM demonstrated that total costs in the base-case were reduced by $1732, with savings predicted to occur as early as year 1. Results from the three models were consistent, showing a reduction in total costs for all sensitivity analyses. Limitations Data from short-term clinical trials were used to develop long-term projections. The nature of such extrapolation leads to increased uncertainty. Conclusion The results from all three models indicate that the AUTONOMY Q1D algorithm has the potential to abate total costs as early as the first year.

Machine perfusion enhances hepatocyte isolation yields from ischemic livers.

BACKGROUND: High-quality human hepatocytes form the basis of drug safety and efficacy tests, cell-based therapies, and bridge-to-transplantation devices. Presently the only supply of cells derives from an inadequate pool of suboptimal disqualified donor livers. Here we evaluated whether machine perfusion could ameliorate ischemic injury that many of these livers experience prior to hepatocyte isolation. METHODS: Non-heparinized female Lewis rat livers were exposed to an hour of warm ischemia (34°C) and then perfused for 3h. Five different perfusion conditions that utilized the cell isolation apparatus were investigated, namely: (1) modified Williams Medium E and (2) Lifor, both with active oxygenation (95%O(2)/5%CO(2)), as well as (3) Lifor passively oxygenated with ambient air (21%O(2)/0.04%CO(2)), all at ambient temperatures (20 ± 2°C). At hypothermic temperatures (5 ± 1°C) and under passive oxygenation were (4) University of Wisconsin solution (UW) and (5) Vasosol. Negative and positive control groups comprised livers that had ischemia (WI) and livers that did not (Fresh) prior to cell isolation, respectively. RESULTS: Fresh livers yielded 32 ± 9 million cells/g liver while an hour of ischemia reduced the cell yield to 1.6 ± 0.6 million cells/g liver. Oxygenated Williams Medium E and Lifor recovered yields of 39 ± 11 and 31 ± 2.3 million cells/g liver, respectively. The passively oxygenated groups produced 15 ± 7 (Lifor), 13 ± 7 (Vasosol), and 10 ± 6 (UW)million cells/g liver. Oxygenated Williams Medium E was most effective at sustaining pH values, avoiding the accumulation of lactate, minimizing edematous weight gain and producing bile during perfusion. CONCLUSIONS: Machine perfusion results in a dramatic increase in cell yields from livers that have had up to an hour of warm ischemia, but perfusate choice significantly impacts the extent of recovery. Oxygenated Williams Medium E at room temperature is superior to Lifor, UW and Vasosol, largely facilitated by its high oxygen content and low viscosity.

Collective and individual migration following the epithelial-mesenchymal transition.

During cancer progression, malignant cells in the tumour invade surrounding tissues. This transformation of adherent cells to a motile phenotype has been associated with the epithelial-mesenchymal transition (EMT). Here, we show that EMT-activated cells migrate through micropillar arrays as a collectively advancing front that scatters individual cells. Individual cells with few neighbours dispersed with fast, straight trajectories, whereas cells that encountered many neighbours migrated collectively with epithelial biomarkers. We modelled these emergent dynamics using a physical analogy to phase transitions during binary-mixture solidification, and validated it using drug perturbations, which revealed that individually migrating cells exhibit diminished chemosensitivity. Our measurements also indicate a degree of phenotypic plasticity as cells interconvert between individual and collective migration. The study of multicellular behaviours with single-cell resolution should enable further quantitative insights into heterogeneous tumour invasion.

A fitness index for transplantation of machine-perfused cadaveric rat livers.

BACKGROUND: The 110,000 patients currently on the transplant waiting list reflect the critical shortage of viable donor organs. However, a large pool of unused organs, from donors after cardiac death (DCD) that are disqualified because of extensive ischemic injury, may prove transplantable after machine perfusion treatment, fundamentally impacting the availability of treatment for end-stage organ failure. Machine perfusion is an ex-vivo organ preservation and treatment procedure that has the capacity to quantitatively evaluate and resuscitate cadaveric organs for transplantation. METHODS: To diagnose whether an organ was fresh or ischemic, an initial assessment of liver quality was conducted via dynamic discriminant analysis. Subsequently, to determine whether the organs were sufficiently viable for successful implantation, fitness indices for transplantation were calculated based on squared prediction errors (SPE) for fresh and ischemic livers. RESULTS: With just three perfusate metabolites, glucose, urea and lactate, the developed MPLSDA model distinguished livers as fresh or ischemic with 90% specificity. The SPE analyses revealed that fresh livers with SPE(F) < 10.03 and WI livers with SPE(WI) < 3.92 yield successful transplantation with 95% specificity. CONCLUSIONS: The statistical methods used here can discriminate between fresh and ischemic livers based on simple metabolic indicators measured during perfusion. The result is a predictive fitness index for transplantation of rat livers procured after cardiac death. The translational implications of this study are that any donor organ procured from controlled, but most especially from uncontrolled cardiac death donors, will be objectively assessed and its recovery monitored over time, minimizing the critical loss of otherwise viable organs.

A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers.

With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD). A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD), recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP), and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE) as log(SPE) >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.

Preliminary phenotypic characterization of newly isolated halophilic microorganisms by footprinting: a rapid metabolome analysis.

The emerging need for rapid screening and identification methods for microbiological purposes necessitates the combined uses of high-tech instruments. In this work, electrospray ionization mass spectrometry was used to visualize the relation of ten newly isolated moderately halophilic microorganisms, to Halomonas salina DSMZ 5,928 and Halomonas halophila DSMZ 4,770. The method was based on the global analysis of the metabolites in culture media and is termed as metabolic footprinting. Since it was not possible to gain insight into the similarities solely based on the visual inspection of the chromatograms, principal component (PC) analysis was applied on the data. Three PCs alone were able to explain 99% of the information in the data set. The score plots revealed the relation of the new isolates to the two type strains whereas the loading plots gave important clues on the significant ions responsible for the observed clustering. Loading plots also indicated inversely correlated ions that give clues on differing metabolic pathways. The work described here offers a potentially useful way for preliminary rapid phenotypic characterization of new and closely related isolates and a method for screening of similar microorganisms for different and valuable secondary metabolites.

Monte Carlo sampling and principal component analysis of flux distributions yield topological and modular information on metabolic networks.

The work presented here uses Monte Carlo random sampling combined with flux balance analysis and linear programming to analyse the steady-state flux distributions on the surface of the glucose-ammonia phenotypic phase plane of an Escherichia coli system grown on glucose-minimal medium. The distribution of allowable glucose and ammonia uptake rates showed a triangular shape, the apex corresponding to maximum growth rate. The exact shape, e.g. the diagonal boundary is determined by the relative amounts of nutrients required for growth. The logarithm of flux values has a normal distribution, e.g. there is a log normal distribution, and most of the reactions have an order of magnitude between 10(-1) and 1. The increase in the number of blocked reactions as growth switched from aerobic to micro-aerobic phase and the presence of alternate networks for a single optimal solution were both reflections of the variability of pathway utilization for survival and growth. Principal component analysis (PCA) provided us with significant clues on the correlations between individual reactions and correlations between sets of reactions. Furthermore, PCA identified the most influential reactions of the system. The PCA score plots clearly distinguish two different growth phases, micro-aerobic and aerobic. The loading plots for each growth phase showed both the impact of the reactions on the model and the clustering of reactions that are highly correlated. These results have proved that PCA is a promising way to analyse correlations in high-dimensional solution spaces and to detect modular patterns among reactions in a network.