Fire management alters the thermal landscape and provides multi-scale thermal options for a terrestrial turtle facing a changing climate.

As effects of climate change intensify, there is a growing need to understand the thermal properties of landscapes and their influence on wildlife. A key thermal property of landscapes is vegetation structure and composition. Management approaches can alter vegetation and consequently the thermal landscape, potentially resulting in underappreciated consequences for wildlife thermoregulation. Consideration of spatial scale can clarify how management overlaid onto existing vegetation patterns affects thermal properties of landscapes relevant to wildlife. We examined effects of temperature, fire management, and vegetation structure on multi-scale habitat selection of an ectothermic vertebrate (the turtle Terrapene carolina triunguis) in the Great Plains of the central United States by linking time-since-fire data from 18 experimental burn plots to turtle telemetry locations and thermal and vegetation height data. Within three 60-ha experimental landscapes, each containing six 10-ha sub-blocks that are periodically burned, we found that turtles select time-since-fire gradients differently depending on maximum daily ambient temperature. At moderate temperatures, turtles selected sub-blocks with recent (<1 year) time-since-fire, but during relatively hot and cool conditions, they selected sub-blocks with later (2-3 year) time-since-fire that provided thermal buffering compared with recently burned sub-blocks. Within 10-ha sub-blocks, turtles selected locations with taller vegetation during warmer conditions that provided thermal buffering. Thermal performance curves revealed that turtle activity declined as temperatures exceeded ~24-29°C, and on "heat days" (≥29°C) 73% of turtles were inactive compared with 37% on non-heat days, emphasizing that thermal extremes may lead to opportunity costs (i.e., foregone benefits turtles could otherwise accrue if active). Our results indicate that management approaches that promote a mosaic of vegetation heights, like spatiotemporally dynamic fire, can provide thermal refuges at multiple spatial scales and thus be an actionable way to provide wildlife with multiple thermal options in the context of ongoing and future climate change.

Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation.

We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 µg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 µg/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft.

Morphometric analysis of the human common hepatic artery reveals a rich and accessible target for sympathetic liver denervation.

This study quantified the distribution of nerves and adjacent anatomies surrounding human common hepatic artery (CHA) as guidance for catheter based denervation. CHA collected from cadaveric human donors (n = 20) were histologically evaluated and periarterial dimensions and distributions of nerves, lymph nodes, pancreas and blood vessels quantified by digital morphometry. Nerve abundance decreased significantly with distance from the aortic ostium (P < 0.0001) and was higher in the Superior/Inferior compared to the Anterior/Posterior quadrants (P = 0.014). In each locational group, nerves were absent from the artery wall, and starting 0.5-1.0 mm from the lumen exhibited a first order dependence on radial distance, fully defined by the median distance. Median subject-averaged nerve distance to the lumen was 2.75 mm, ranging from 2.1-3.1 mm in different arterial segments and quadrants and 2.0-3.5 mm in individuals. Inter-individual variance was high, with certain individuals exhibiting 50th and 75th nerve distances of, respectively, 3.5 and 6.5 mm The pancreas rarely approached within 4 mm of the lumen proximally and 2.5 mm more distally. The data indicate that the CHA is a rich and accessible target for sympathetic denervation regardless of sex and diabetes, with efficacy and safety most optimally balanced proximally.

Calcified plaque modification alters local drug delivery in the treatment of peripheral atherosclerosis.

BACKGROUND: Calcific atherosclerosis is a major challenge to intraluminal drug delivery in peripheral artery disease (PAD). OBJECTIVES: We evaluated the effects of orbital atherectomy on intraluminal paclitaxel delivery to human peripheral arteries with substantial calcified plaque. METHODS: Diagnostic angiography and 3-D rotational imaging of five fresh human lower limbs revealed calcification in all main arteries. The proximal or distal segment of each artery was treated using an orbital atherectomy system (OAS) under simulated blood flow and fluoroscopy. Explanted arterial segments underwent either histomorphometric assessment of effect or tracking of 14C-labeled or fluorescent-labeled paclitaxel. Radiolabeled drug quantified bulk delivery and fluorescent label established penetration of drug over finer spatial domain in serial microscopic sections. Results were interpreted using a mathematical model of binding-diffusion mediated arterial drug distribution. RESULTS: Lesion composition affected paclitaxel absorption and distribution in cadaveric human peripheral arteries. Pretreatment imaging calcium scores in control femoropopliteal arterial segments correlated with a log-linear decline in the bulk absorption rate-constant of 14C-labeled, declining 5.5-fold per calcified quadrant (p=0.05, n=7). Compared to controls, OAS-treated femoropopliteal segments exhibited 180µm thinner intima (p<0.001), 45% less plaque calcification, and 2 log orders higher paclitaxel bulk absorption rate-constants. Correspondingly, fluorescent paclitaxel penetrated deeper in OAS-treated femoropopliteal segments compared to controls, due to a 70% increase in diffusivity (p<0.001). CONCLUSIONS: These data illustrate that calcified plaque limited intravascular drug delivery, and controlled OAS treatment of calcific plaques resulted in greater drug permeability and improved adjunct drug delivery to diseased arteries.

Relative costs of anesthesiologist prepared, hospital pharmacy prepared and outsourced anesthesia drugs.

BACKGROUND: Anesthesia drugs can be prepared by anesthesia providers, hospital pharmacies or outsourcing facilities. The decision whether to outsource all or some anesthesia drugs is challenging since the costs associated with different anesthesia drug preparation methods remain poorly described. METHODS: The costs associated with preparation of 8 commonly used anesthesia drugs were analyzed using a budget impact analysis for 4 different syringe preparation strategies: (1) all drugs prepared by anesthesiologist, (2) drugs prepared by anesthesiologist and hospital pharmacy, (3) drugs prepared by anesthesiologist and outsourcing facility, and (4) all drugs prepared by outsourcing facility. MAIN RESULTS: A strategy combining anesthesiologist and hospital pharmacy prepared drugs was associated with the lowest estimated annual cost in the base-case budget impact analysis with an annual cost of $225 592, which was lower than other strategies by a margin of greater than $86 000. CONCLUSION: A combination of anesthesiologist and hospital pharmacy prepared drugs resulted in the lowest annual cost in the budget impact analysis. However, the cost of drugs prepared by an outsourcing facility maybe lower if the capital investment needed for the establishment and maintenance of the US Pharmacopeial Convention Chapter <797> compliant facility is included in the budget impact analysis.

Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients.

Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral busulfan to lower rates of rejection, nonrelapse mortality, and relapse. Using the candidate gene approach, the authors evaluated whether busulfan clearance was associated with polymorphisms in the genes regulating the predominant metabolizing enzymes involved in busulfan conjugation, specifically glutathione S-transferase (GST) isoenzymes A1 (GSTA1) and M1 (GSTM1). Busulfan clearance was estimated after the morning dose on days 1, 2, and 3; each patient's average clearance was used for analyses. The average (± standard deviation) busulfan clearance was 3.2 ± 0.56 mL/min/kg in the separate population of 95 patients who received oral busulfan and 103 ± 24 ml/min/m(2) in the 57 patients who received IV busulfan. Oral busulfan clearance was associated with GSTA1 (P = .008) but not GSTM1 (P = .57) genotypes. However, among the GSTA1 haplotypes (ie, *A*A, *A*B, *B*B), there was significant overlap in the observed oral busulfan clearance and similar rates of achieving the target busulfan exposure. Clearance of IV busulfan was not associated with GSTA1 (P = .21) or GSTM1 (P = .99). These data suggest that personalizing either IV or oral busulfan dosing cannot be simplified on the basis of GSTA1 or GSTM1 genotype.