Optimal Exposures Research Articles

Pharmacodynamic Profiling of Antimicrobials against Gram-negative Respiratory Isolates from Canadian Hospitals

With diminishing antimicrobial potency, the choice of effective empirical therapy has become more challenging. Thus, the pharmacodynamic evaluation of potential therapies is essential to identify optimal agents, doses and administration strategies. Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. Minimum inhibitory concentrations were obtained for Escherichia coli (n=64 respiratory isolates), Enterobacter cloacae (n=53), Klebsiella pneumoniae (n=75) and Pseudomonas aeruginosa (n=273) throughout Canada. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. A CFR ≥90% was defined as optimal. All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. Prolonged infusion doripenem and meropenem 1 g and 2 g every 8 h, along with standard infusion doripenem and meropenem 2 g every 8 h, were the only regimens to attain optimal exposures against P aeruginosa. Ciprofloxacin had the lowest CFR against P aeruginosa, followed by cefepime. Among the P aeruginosa isolates collected in the intensive care unit (ICU) compared with the wards, differences of 0.5% to 10% were noted in favour of non-ICU isolates for all agents; however, marked differences (10% to 15%) in CFR were observed for ciprofloxacin in favour of ICU isolates. Standard dosing of cefepime, doripenem, ertapenem and meropenem has a high likelihood of obtaining optimal pharmacodynamic indexes against these Enterobacteriaceae. For P aeruginosa, aggressive treatment with high-dose and/or prolonged infusion regimens are likely required to address the elevated resistance rates of respiratory isolates from Canada.

Geometric Mean Maximization: An Overlooked Portfolio Approach?

Academics and practitioners usually optimize portfolios on the basis of mean and variance. They set the goal of maximizing risk-adjusted returns measured by the Sharpe ratio and thus determine their optimal exposures to the assets considered. However, there is an alternative criterion that has an equally plausible underlying idea. Geometric mean maximization aims to maximize the growth of the capital invested, thus seeking to maximize terminal wealth. This criterion has several attractive properties and is easy to implement, and yet it seems to have taken a back seat to the maximization of risk-adjusted returns. The ultimate goal of this article is to compare both criteria from an empirical perspective. The results reported and discussed leave the question posed in the title largely intact: Are academics and practitioners overlooking a useful portfolio approach? <b>TOPICS:</b>Portfolio construction, equity portfolio management, volatility measures

Portfolio Choice Under Cumulative Prospect Theory: An Analytical Treatment

We formulate and carry out an analytical treatment of a single-period portfolio choice model featuring a reference point in wealth, S-shaped utility (value) functions with loss aversion, and probability weighting under Kahneman and Tversky's cumulative prospect theory (CPT). We introduce a new measure of loss aversion for large payoffs, called the large-loss aversion degree (LLAD), and show that it is a critical determinant of the well-posedness of the model. The sensitivity of the CPT value function with respect to the stock allocation is then investigated, which, as a by-product, demonstrates that this function is neither concave nor convex. We finally derive optimal solutions explicitly for the cases when the reference point is the risk-free return and when it is not (while the utility function is piece-wise linear), and we employ these results to investigate comparative statics of optimal risky exposures with respect to the reference point, the LLAD, and the curvature of the probability weighting.

Earning the Right Premium on the Right Factor in Portfolio Planning

The optimal portfolio as well as the utility from trading stocks and derivatives depends on the risk factors and on their market prices of risk. We analyze this dependence for a CRRA investor in a model setup with stochastic volatility and stochastic jumps in the stock price and its volatility. We find that both the decomposition of the variance and the decomposition of the equity risk premium into a diffusion component and a jump risk component matter. We furthermore show that the same holds true for the compartment of the latter into its various elements. Additionally, we show that the structure of the optimal exposures to jump risk crucially depends on which elements of jump risk are priced. In a complete market, changing the assumption on whether jump intensity risk, jump size risk, or jump variance risk are priced reverses the dependence of the optimal jump risk exposures on the jump size (in the stock price) completely. The function changes from flat to increasing to (inversely) U-shaped.

Trading strategies with partial access to the derivatives market

This research analyzes trading strategies with derivatives when there are several assets and risk factors. We investigate portfolio improvement if investors have full and partial access to the derivatives markets, i.e. situations in which derivatives are written on some but not all stocks or risk factors traded on the market. The focus is on markets with jump risk. In these markets the choice of optimal exposures to jump and diffusion risk is linked. In a numerical application we study the potential benefit from adding derivatives to the market. It turns out that e.g. diffusion correlation and volatility or jump sizes may have a significant impact on the benefit of a new derivative product even if market prices of risk remain unchanged. Given the structure of risk investors may have different preferences for making risk factors tradable. Utility gains provided by new derivatives may be both increasing or decreasing depending on the type of contract added.

Portfolio Choice Under Cumulative Prospect Theory: An Analytical Treatment

We formulate and carry out an analytical treatment of a single-period portfolio choice model featuring a reference point in wealth, S-shaped utility (value) functions with loss aversion, and probability weighting under Kahneman and Tversky's cumulative prospect theory (CPT). We introduce a new measure of loss aversion for large payoffs, called the large-loss aversion degree (LLAD), and show that it is a critical determinant of the well-posedness of the model. The sensitivity of the CPT value function with respect to the stock allocation is then investigated, which, as a by-product, demonstrates that this function is neither concave nor convex. We finally derive optimal solutions explicitly for the cases in which the reference point is the risk-free return and those in which it is not (while the utility function is piecewise linear), and we employ these results to investigate comparative statics of optimal risky exposures with respect to the reference point, the LLAD, and the curvature of the probability weighting. This paper was accepted by Wei Xiong, finance.

Alzheimer Disease Aβ Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts

Alzheimer disease beta-amyloid (Abeta) peptides are generated via sequential proteolysis of amyloid precursor protein (APP) by BACE1 and gamma-secretase. A subset of BACE1 localizes to cholesterol-rich membrane microdomains, termed lipid rafts. BACE1 processing in raft microdomains of cultured cells and neurons was characterized in previous studies by disrupting the integrity of lipid rafts by cholesterol depletion. These studies found either inhibition or elevation of Abeta production depending on the extent of cholesterol depletion, generating controversy. The intricate interplay between cholesterol levels, APP trafficking, and BACE1 processing is not clearly understood because cholesterol depletion has pleiotropic effects on Golgi morphology, vesicular trafficking, and membrane bulk fluidity. In this study, we used an alternate strategy to explore the function of BACE1 in membrane microdomains without altering the cellular cholesterol level. We demonstrate that BACE1 undergoes S-palmitoylation at four Cys residues at the junction of transmembrane and cytosolic domains, and Ala substitution at these four residues is sufficient to displace BACE1 from lipid rafts. Analysis of wild type and mutant BACE1 expressed in BACE1 null fibroblasts and neuroblastoma cells revealed that S-palmitoylation neither contributes to protein stability nor subcellular localization of BACE1. Surprisingly, non-raft localization of palmitoylation-deficient BACE1 did not have discernible influence on BACE1 processing of APP or secretion of Abeta. These results indicate that post-translational S-palmitoylation of BACE1 is not required for APP processing, and that BACE1 can efficiently cleave APP in both raft and non-raft microdomains.

Variable payout annuities and dynamic portfolio choice in retirement

AbstractMany retirees hope to continue earning capital market rewards on their saving while avoiding outliving their funds during retirement. We model a dynamic utility maximizing investor who seeks to benefit from holding both equity and longevity insurance. She is free to adjust her portfolio allocation of her financial wealth as well as of the annuity over time, and she can purchase variable payout annuities any time and incrementally. In this setting, we show that the retiree will not fully annuitize even without bequests; rather, she will combine variable annuities with withdrawals from her liquid financial wealth so as to match her desired consumption profile. Optimal stock exposures decrease over time, both within the variable annuity and the withdrawal plan. Welfare gains from this strategy can amount to 40% of financial wealth, depending on risk parameters and other resources; additionally, many retirees will do almost as well as the fully optimized outcome if they hold variable annuities invested 60/40 in stocks/bonds.

Comparative pharmacodynamics for intravenous antibiotics against Gram-negative bacteria in Europe between 2002 and 2006: a report from the OPTAMA program

The Optimizing Pharmacodynamic Target Attainment using the MYSTIC Antibiogram (OPTAMA) Program has been used globally to estimate antimicrobial exposures for either targeted pathogens or disease states. Herein, we utilised this methodology to determine antimicrobial exposures of cefepime, ceftazidime, ciprofloxacin, imipenem, meropenem and piperacillin/tazobactam against European-derived isolates of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa obtained in 2006 and compared these with results from 2002. All regimens, except ciprofloxacin, provided optimal pharmacodynamic exposures against E. coli, whereas more regional differences were noted with K. pneumoniae. For K. pneumoniae, the carbapenems provided the highest likelihood of optimal exposures. Ciprofloxacin exposures were also noted to be low for both P. aeruginosa and A. baumannii. Moreover, for these two organisms higher doses and/or prolonged infusion of the studied β-lactams was necessary to obtain the desired pharmacodynamic targets. These data reveal regional differences in the probability of pharmacodynamic optimisation as well as the potential utility of employing regimens utilising higher doses and/or prolonged infusion techniques when directing therapy against P. aeruginosa and A. baumannii.

Strategic Asset Allocation with Relative Performance Concerns

This article analyzes the dynamic portfolio choice implications of strategic interaction among money managers. The strategic interaction is modelled as managers' having relative performance concerns in their objectives, either due to money flows or behavioral considerations. We provide tractable formulations of relative performance concerns between two risk averse managers in a continuous-time setting, and solve for their equilibrium policies in closed-form. Under a formulation with relative performance concerns smoothly affecting the managers at all levels of wealth, we obtain a unique Nash equilibrium. We demonstrate that much of the novel investment behavior depends on whether a manager is a chaser, increasing investments in response to the other's increasing hers, or a contrarian. The managers are chasers for empirically plausible parameters and increase their optimal risk exposures due to the presence of strategic interaction. We then consider a formulation with asymmetric relative performance concerns, where a manager gets money flows, and hence displays relative concerns, only if her relative return is above a performance threshold. Such relative concerns induce the manager to engage in risk shifting around the threshold, so as to either end up as a winner (getting money flows) or a loser (no flows). Here, we do not always obtain a Nash equilibrium since the managers cannot agree on the winner. For sufficiently similar managers, we obtain equilibria, but multiple, since managers care only about the total number of winning states. We recover a unique equilibrium, however, with a sufficiently high threshold, where the managers' risk aversion prevents them from taking huge gambles, leading both to be losers around the threshold.

Pharmacodynamic Target Attainment of Oral β-Lactams for the Empiric Treatment of Acute Otitis Media in Children

To determine the probability of oral beta-lactam regimens achieving bactericidal pharmacodynamic exposure against pathogens causing acute otitis media (AOM) given contemporary prevalence and resistance rates. A 5000-patient Monte Carlo simulation was used to recreate steady-state concentration-time profiles for oral drug administration regimens of amoxicillin, amoxicillin/clavulanic acid, cefpodoxime, cefprozil, ceftibuten, and cefuroxime in a population of 12.5-month-old children. The percent of simulated children in whom free drug concentrations above the minimum inhibitory concentration (MIC) for 50% of the drug administration interval (50% fT>MIC) were achieved was determined; 180 middle ear fluid isolates (56 Haemophilus influenzae and 124 Streptococcus pneumoniae) collected during the 2004 Global Respiratory Antimicrobial Surveillance Project (GRASP) were used. The cumulative fraction of response (CFR) was calculated and weighted against the prevalence of organisms causing AOM extrapolated from the literature. The contribution of a 'Pollyanna phenomenon' for each organism was also incorporated to estimate clinical effectiveness. Against S. pneumoniae isolates, amoxicillin 30 mg/kg every 8 hours (84.7%) achieved the greatest CFR followed by amoxicillin/clavulanic acid and the other amoxicillin-based regimens. Against H. influenzae isolates, cefpodoxime, ceftibuten, and amoxicillin/clavulanic acid each achieved a CFR of >90%. When weighted by the prevalence of AOM-causing pathogens, CFR was highest for cefpodoxime (87.5%), amoxicillin/clavulanic acid (85.7%), and amoxicillin 30 mg/kg every 8 hours (70.8%). The contribution of a 'Pollyanna phenomenon' increased the probability of clinical effectiveness for all agents, with amoxicillin/clavulanic acid (90.2%) and cefpodoxime (90.1%) having the highest weighted CFR. Based on the recent epidemiologic and resistance profiles of S. pneumoniae and H. influenzae, amoxicillin/clavulanic acid (45 mg/kg every 12 hours) and cefpodoxime (5 mg/kg every 12 hours) provide the greatest likelihood of achieving optimal pharmacodynamic exposures empirically in children with AOM.

Changes in Pharmacodynamic Target Attainment for Antimicrobials Over a 2-Year Period

The Optimizing Pharmacodynamic Target Attainment using a Microbiology Antibiogram (OPTAMA) program aims to determine the likelihood that specific antibiotic regimens will achieve bactericidal pharmacodynamic exposures against common nosocomial pathogens. The pharmacokinetic profiles of 5000 subjects were simulated to determine the bactericidal cumulative fraction of response (CFR) for commonly used intravenous β-lactams and ciprofloxacin against Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella species, isolated during the 2004 Meropenem Yearly Susceptibility Test Information Collection surveillance study in North America. Bactericidal CFRs were compared with 2002 OPTAMA results to assess for trends. Compared with 2002 results, declines in susceptibility, with a corresponding decrease in CFR, were observed for many agents against P. aeruginosa and A. baumannii, and for ciprofloxacin against E. coli. Conversely, discordance was observed with ciprofloxacin against Klebsiella species. Among this current population of nosocomial-acquired Gram negatives, the ability to achieve optimal pharmacodynamic exposures is becoming more difficult because of increasing resistance; therefore, continual evaluation of optimal dosing strategies will be necessary.

Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux pumps

To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and ΔK767 (knockout strain). Efficacy (Δ log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10 5 CFU/thigh) and high (10 7 CFU/thigh) inoculums. At 10 5 CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (−2.82, −1.88) and K767+ (−2.24, −2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (−2.74 and −2.19, respectively). Similar magnitudes of kill were observed at the 10 7 inocula. Except for ΔK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against ΔK767. ΔK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on β-lactam agents in vivo warrant further research.

Effects of imaging system and exposure on accurate detection of the second mesio-buccal canal in maxillary molar teeth

The objectives of this study were to determine observer ability to detect the second mesio-buccal canal (MB2) in maxillary molars using analog film, CMOS, and photostimulable phosphor x-ray detectors across a wide range of radiation exposures and to determine the optimal exposures for these modalities accurately detecting presence of the MB2. Using 6 experimental models with 2 maxillary molars in each, images were generated with the 3 detector modalities at nominal x-ray beam angulations of 0 degrees and 10 degrees across a range of radiation exposures. Observers independently assessed presence of the MB2 in images presented in random order. Horizontal root sections were then evaluated to determine true MB2 presence. For single images at optimal exposures, the correct number of mesiobuccal canals could be identified 55% of the time for CMOS (RVG 6000), 44% of the time for analog x-ray film (InSight), and 39% of the time for photostimulable phosphor (DenOptix). Statistically significant differences were observed between the imaging modalities (chi2 = 23.4, crucial value = 5.99, P < or = .05). RVG 6000 CMOS outperformed both DenOptix photostimulable phosphor (z score = -5.5) and InSight analog direct exposure x-ray film (z score = 4). Exposure affected the rate of accuracy for MB2 detection across the exposure range tested for RVG 6000 and for film, but not to any appreciable degree for DenOptix. The CMOS detector (RVG-6000) performed best for evaluating presence of the MB2. This was the only modality to exceed 50% reliability with optimal exposure when single images were considered.

Increased Bioavailability of Intravenous Versus Oral CI-1033, a Pan erbB Tyrosine Kinase Inhibitor: Results of a Phase I Pharmacokinetic Study

In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability. Fifty-three patients with advanced nonhematologic malignancies received i.v. CI-1033 via 30-minute infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental analysis. Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The maximum administered dose was 500 mg, whereas the maximum tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were observed. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. C(max) was noted with a 3-fold increase in AUC compared with oral CI-1033 at equivalent doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen. CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired.

Empiric Treatment of Multidrug‐Resistant Burkholderia cepacia Lung Exacerbation in a Patient with Cystic Fibrosis: Application of Pharmacodynamic Concepts to Meropenem Therapy

A 31-year-old man with cystic fibrosis was diagnosed with multidrug-resistant Burkholderia cepacia pneumonia. Meropenem 2000 mg every 8 hours was administered as a 3-hour infusion to maximize pharmacodynamic exposure; oral minocycline 100 mg twice/day was also given. Blood samples were collected to confirm meropenem concentrations. Concentrations above the mimimum inhibitory concentration (MIC) of 8 microg/ml were achieved for 52% of the dosing interval, which is greater than what is required for a bactericidal effect. The patient's condition improved, he was discharged, and completed a 3-week course of the antibiotic regimen. After 6 months, he had remained at his baseline level of health. This case demonstrates that pharmacodynamic principles can be used to design an antibiotic dosing regimen that can achieve optimal exposures when the MIC is above that considered susceptible to conventional dosing strategies.

Robustness and Ambiguity Aversion in General Equilibrium

We analyze the empirical predictions arising from settings of ambiguity aversion in intertemporal heterogenous agents economies. We study equilibria for two tractable wealth-homothetic settings of ambiguity aversion in continuous time. Such settings are motivated by a different robust control optimization problem. We show that ambiguity aversion affects optimal portfolio exposures in a way that is similar to an increase in risk aversion. A distinct property of the second of our settings of ambiguity aversion is that such increase is state-dependent and highly pronounced at moderate portfolio exposures. This feature causes quite prudent levels of equity market participation over a nontrivial set of states of the economy. In general equilibrium, ambiguity aversion tends to induce a higher equilibrium equity premium and lower interest rates. A distinct feature of the second of our settings of ambiguity aversion is that the equity premium part due to ambiguity aversion dominates when the exogenous random factors in the economy have low volatility. Thus, such setting can account for some distinct empirical predictions - like a limited equity market participation and ambiguity equity premia that dominate equity premia for small equity volatilities - which are unavailable under the first of our settings of ambiguity aversion.

An Empirical Study of Portfolio Selection for Optimally Hedged Portfolios

This paper reports a study into the performance of currency-hedged portfolios constructed using mean-variance optimization methods. The method is to carry out optimization relative to a benchmark portfolio, which consists of the real assets, and simultaneously to determine the optimal exposures to each currency future. This is done at various levels of risk along the efficient frontier. A study into a portfolio of international stock and bond indices viewed from a US Dollar perspective indicates that, for the period studied, optimal currency hedging has the potential to add value in terms of additional expected return and excess return on a risk-adjusted basis. The results also demonstrate the superiority of strategies in which the hedge ratio is optimally determined over those with a fixed hedge ratio.

Use of hop ( Humulus lupulus) agricultural by-products for the reduction of aqueous lead(II) environmental health hazards

The agricultural by-products of the hop plant ( Humulus lupulus L.) were investigated to determine their potential for use in the removal of heavy lead(II) ions from contaminated aqueous solutions. Separate batch laboratory experiments were performed to establish the optimal binding pH, time exposures, and capacity of the metal adsorption for lead(II) ions by dried and ground hop leaves and stems biomass. Results from these studies have shown a pH dependent binding trend from pH 2–6, with optimum binding occurring around pH 5.0. Time dependency experiments showed a rapid adsorption of lead(II) ions within the first 5 min of contact. Binding capacity experiments demonstrated that 74.2 mg of lead(II) were bound per gram of leaf biomass. Similarly overall capacity was seen for the leaves and stems. Desorption of 99% of the bound lead(II) ions was achieved by exposing the metal laden biomass to 0.5 M sodium citrate. Further experiments were performed with silica-immobilized hop tissues to determine the lead(II) binding ability under flow conditions. Comparison studies were performed with ion-exchange resins to evaluate the binding ability and to gain further insight into the metal binding mechanism. X-ray absorption spectroscopy experiments were also utilized to gain further insight into the possible lead(II) binding mechanism by the hop plant tissue. Results from these studies indicate that carboxyl ligands are involved in the binding of lead(II) from aqueous solution. These findings show that the use of hop agricultural waste products may be a viable alternative, for the removal and recovery of aqueous lead(II) ions from contaminated waters.

Currency Hedging and the Risk of Loss

The most commonly cited argument against currency hedging is the assertion that foreign exchange risk washes out over the long run. But even if we set aside these facts and accept the view that foreign exchange risk washes out over long horizons, it does not necessarily follow that we should ignore the volatility introduced by currency exposure. It depends critically on how we perceive risk. This study reviews currency arithmetic and shows explicitly how exchange rate fluctuations affect a foreign asset9s risk. It also contains a derivation of the minimum risk and optimal exposures to currency forward contracts. The article presents two alternative approaches for measuring risk of loss, and it shows the effect of currency exposure on these two measures of risk of loss.