Replication or exploration? Sequential design for stochastic simulation experiments

We investigate the merits of replication, and provide methods for optimal design (including replicates), with the goal of obtaining globally accurate emulation of noisy computer simulation experiments. We first show that replication can be beneficial from both design and computational perspectives, in the context of Gaussian process surrogate modeling. We then develop a lookahead based sequential design scheme that can determine if a new run should be at an existing input location (i.e., replicate) or at a new one (explore). When paired with a newly developed heteroskedastic Gaussian process model, our dynamic design scheme facilitates learning of signal and noise relationships which can vary throughout the input space. We show that it does so efficiently, on both computational and statistical grounds. In addition to illustrative synthetic examples, we demonstrate performance on two challenging real-data simulation experiments, from inventory management and epidemiology.Comment: 34 pages, 9 figure

Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

Polymer micelles with cross-linked ionic cores are shown here to improve the therapeutic performance of the platinum-containing anticancer compound cisplatin. Biodistribution, antitumor efficacy, and toxicity of cisplatin-loaded core cross-linked micelles of poly(ethylene glycol)-b-poly(methacrylic acid) were evaluated in a mouse ovarian cancer xenograft model. Cisplatin-loaded micelles demonstrated prolonged blood circulation, increased tumor accumulation, and reduced renal exposure. Improved antitumor response relative to free drug was seen in a mouse model. Toxicity studies with cisplatin-loaded micelles indicate a significantly improved safety profile and lack of renal abnormalities typical of free cisplatin treatment. Overall, the study supports the fundamental possibility of improving the potential of platinum therapy using polymer micelle-based drug delivery

Multi-output calibration of a honeycomb seal via on-site surrogates

We consider large-scale industrial computer model calibration, combining multi-output simulation with limited physical observation, involved in the development of a honeycomb seal. Toward that end, we adopt a localized sampling and emulation strategy called "on-site surrogates (OSSs)", designed to cope with the amalgamated challenges of high-dimensional inputs, large-scale simulation campaigns, and nonstationary response surfaces. In previous applications, OSSs were one-at-a-time affairs for multiple outputs leading to dissonance in calibration efforts for a common parameter set across outputs for the honeycomb. We demonstrate that a principal-components representation, adapted from ordinary Gaussian process surrogate modeling to the OSS setting, can resolve this tension. With a two-pronged - optimization and fully Bayesian - approach, we show how pooled information across outputs can reduce uncertainty and enhance efficiency in calibrated parameters and prediction for the honeycomb relative to the previous, "data-poor" univariate analog.Comment: 52 pages, 21 figure

Praziquantel analogs with activity against juvenile Schistosoma mansoni.

Six amide and four urea derivatives of praziquantel were synthesized and tested for antischistosomal activity against juvenile and adults stages of Schistosoma mansoni in infected mice. Only one of these had significant activity against adult worms, but, unlike praziquantel, six of these had low to modest activity against juvenile worms. A praziquantel ketone derivative had the best combination of activity against juveniles and adults, but it had no effect on the motility of adult S. mansoni in ex vivo culture. Cytochrome P450 metabolic stability data support the hypothesis that the major trans-cyclohexanol metabolite of praziquantel plays an important role in the antischistosomal activity of this drug

Characterizing Spatiotemporal Patterns of Snowfall in the Kaidu River Basin from 2000–2020 Using MODIS Observations

Characterizing spatiotemporal patterns of snowfall is essential for understanding cryosphere responses to warming climate stress. The changes in snowfall and topographic controls in mountain regions still need to be clarified. This study proposes a general parsimonious methodology to obtain the frequency of snowfall in mountainous areas. The methodology employed is easily transferable to any other mountain region. Utilizing daily MODIS observations from June 2000 to May 2020 and the snowfall event detection algorithm, we monitored the frequency of snowfall in a long time series in the Kaidu river basin. The results are as follows: (1) The method for detecting the frequency of snowfall has high accuracy. The annual detected results agreed with surface observations, with an R2 of 0.65 and RMSE of 3.39. (2) The frequency of snowfall events increased monotonically with elevation. The influence of slope angle on snowfall gradually decreased with increasing elevation. (3) The frequency of snowfall events in the Kaidu river basin was dominated by an increasing trend. The trends showed a pronounced topographic dependence. This study reveals the distribution characteristics and changing snowfall trends in mountain regions. The results provide a reference for snowfall research in mountainous areas

Enteric Polymer–Based Amorphous Solid Dispersions Enhance Oral Absorption of the Weakly Basic Drug Nintedanib via Stabilization of Supersaturation

The pH–induced crystallization of weakly basic drugs in the small intestine limits oral bioavailability. In this study, we investigated the solubilization and inhibitory effects on nintedanib in the presence of enteric polymers (HPMCAS LG, HPMCAS MG, Eudragit L100 55, and Eudragit L100). These polymers provided maintenance of supersaturation by increasing the solubility of nintedanib in PBS 6.8 in a concentration-dependent manner, and the improved ranking was as follows: Eudragit L100 > Eudragit L100 55 > HPMCAS MG > HPMCAS LG. After being formulated into amorphous solid dispersions (ASDs) by a solvent evaporation method, the drug exhibited an amorphous state. The pH shift dissolution results of polymer-ASDs demonstrated that four polymers could effectively maintain the drug supersaturation even at the lowest ratio of nintedanib and polymer (1:1, w/w). Eudragit L100–ASD could provide both acid resistance and the favorable mitigation of crystallization in GIF. In comparison to the coarse drug, the relative bioavailability of Eudragit L100–ASD was 245% after oral administration in rats, and Tmax was markedly delayed from 2.8 ± 0.4 h to 5.3 ± 2.7 h. Our findings indicate that enteric ASDs are an effective strategy to increase the intestinal absorption of nintedanib by improving physiologically generated supersaturation and subsequent crystallization

Detecting Snowfall Events over Mountainous Areas Using Optical Imagery

Snowfall over mountainous areas not only has important implications on the water cycle and the Earth’s radiation balance, but also causes potentially hazardous weather. However, snowfall detection remains one of the most difficult problems in modern hydrometeorology. We present a method for detecting snowfall events from optical satellite data for seasonal snow in mountainous areas. The proposed methodology is based on identifying expanded snow cover or suddenly declined snow grain size using time series images, from which it is possible to detect the location and time of snowfall events. The methodology was tested with Moderate Resolution Imaging Spectroradiometer (MODIS) daily radiance data for an entire hydrologic year from July 2014 to June 2015 in the mountainous area of the Manas River Basin, Northwest China. The study evaluated the recordings of precipitation events at eighteen meteorological stations in the study area prove the effectiveness of the proposed method, showing that there was more liquid precipitation in the second and third quarter, and more solid precipitation in the first and fourth quarter

Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion

TJ0711∙HCl, which is a novel α1/β1 adrenoceptor blocking agent with a ratio of 1:1 for α1/β1, is designed to treat and prevent perioperative hypertension. M1 and M3 were identified as important metabolites in vitro for either antihypertension activity or the major metabolite production. In order to obtain a pharmacokinetic profile of both TJ0711 and its metabolites, a rapid, selective, and reliable LC-MS/MS method was developed and validated for simultaneous determination of TJ0711 and two metabolites in beagle dog plasma via efficiently separating two interferential metabolites M16 and M4 from M1 and M3, respectively. Chromatographic separation was achieved on a Waters CORTECS C18+ column (2.1 × 100 mm, 2.7 μm). The mass spectrometric detection was carried out in positive ion MRM mode with ESI+ source. Protein precipitation was used in sample preparation and provided good recovery without a matrix effect. Good linearity was observed at the ranges of 0.5–100 ng/mL for TJ0711 and M3, 0.1–20 ng/mL for M1. Additional validation results were within the acceptance limits followed U.S. FDA guidelines for bioanalytical method validation. This method was successfully applied to an intravenous infusion pharmacokinetic study of TJ0711 at dosing rates of 3, 6, and 12 µg/kg/min in anesthetized beagle dogs for the first time. TJ0711 and its two metabolites exhibited effective proportionality in the dosage of 3 to 12 µg/kg/min. Neither TJ0711 nor its metabolites showed significant differences in pharmacokinetic parameters such as t1/2, CL, and Vss among three dose groups