Design of a supervisory predictive controller and its application to thermal power plants

The optimization at supervisory level of thermal power plant controls is investigated. The design of a predictive supervisory controller that optimizes an objective function in order to determine the set‐points for a given regulatory level is described. The objective function includes both an economic criterion and a regulatory criterion. The proposed supervisory controller is applied to the gas turbine of a thermal power plant and it is compared with the control strategy for constant optimum set‐points. Copyright © 2005 John Wiley & Sons, Ltd.     

Computational Opioid Prescribing: A Novel Application of Clinical Pharmacokinetics

ABSTRACT

We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist prescribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety.     

全程优化护理对老年慢性阻塞性肺病患者的影响观察

目的探讨本院全程优化护理对老年慢性阻塞性肺病（COPD）患者的舒适度、治疗遵从性及心理状态的影响。方法选取本院2011年2月～2012年8月入院治疗的66例老年COPD患者的相关临床资料进行回顾性分析。结果实施不同护理后,实验组患者的舒适度、治疗遵从性及心理状态均显著优于对照组患者。结论本院针对老年COPD患者所采用的全程优化护理措施的效果显著,有效地提高了患者的舒适度、改善了治疗遵从性和患者的心理状态。     

HIFU treatment time reduction through heating approach optimisation

Purpose: This study evaluated the HIFU treatment time reductions attainable for several scan paths when optimising the heating approach used (single, discrete pulses versus volumetric scanning) and the paths’ focal zone heating locations’; number (N_FZL), spacings, sequencing order, number of heating cycles (N_CYCLES), and heating times. Also evaluated were the effects of focal zone size, increased tissue absorptivity due to heating, and optimisation technique.

Materials and methods: Treatments of homogeneous constant property tumours were simulated for several simple generic tumour shapes and sizes. The concentrated heating approach (which delivered the desired thermal dose to each location in one discrete heating pulse (N_CYCLES?=?1)) was compared to the fractionated heating approach (which dosed the tumour using multiple, shorter pulses repeatedly scanned around the heating path (i.e. ‘volumetric scanning’ with N_CYCLES?>?1)). Treatment times were minimised using both simultaneous, collective pulse optimisation (which used full a priori knowledge of the interacting effects of all pulses) and sequential, single pulse optimisation (which used only the information from previous pulses and cooling of the current pulse).

Results: Optimised concentrated heating always had shorter treatment times than optimised fractionated heating, and concentrated heating resulted in less normal tissue heating. When large, rapid tissue absorptivity changes were present (doubled or quadrupled immediately after heating) the optimal ordering of the scan path's sequence of focal zone locations changed.

Conclusions: Concentrated heating yields significant treatment time reductions and less normal tissue heating when compared to all fractionated scanning approaches, e.g. volumetric scanning.     

Optimization of hyperthermia with CT scanning

In a prospective study CT scanning was used to evaluate the precision of thermometry catheter placement in tumours in the head and neck or on the chest wall in 30 consecutive patients prior to hyperthemia treatment. Patients had variable-sized tumours from several primary sites. Thermometry catheter placement was guided by palpation with or without a prior CT scan. Catheter placement was confirmed by CT. All lesions were less than 8×8×6 cm (L×W×D) in size. A mean of 4.2±0-2 (±1 SEM, range 2–7) closed-end polyurethane catheters were inserted orthogonally by the same experienced radiation oncologist. Horizontal thermometry catheters were intended to traverse the centre and base of the tumour mass, and a vertical catheter was often inserted to intersect a horizontal catheter. After catheter placement, wire cables with 1 cm spacings were inserted into the catheters and positions determined using orthogonal films and CT scans. The success of catheter placement was judged on the following criteria: (1) catheter distribution factor (CDF=proportion of tumour CT slices transected by at least one catheter); (2) catheter hit ratio (CHR=average number of catheters in tumour per CT slice); (3) catheter miss factor (CMF=average number of catheters out of tumour per CT slice); (4) catheter placement index, CPI = [(CHR)(CDF)] -CMF; and (5) distance of nearest catheter from the visually estimated centre of tumour in the most central tumour CT scan. In the first seven lesions with 3–6 cm depth catheter insertion was guided by palpation only. In the next 23 lesions catheter insertion was guided by a prior CT scan. In the latter group, 15 lesions had depth 3–6 cm while eight lesions had depth ≤3 cm. Catheter placement by palpation only, without the benefit of CT scan, was much less accurate in terms of the nearest catheter to the centre of the tumour (p= awl), the proportion of CT slices with catheter in tumour (CDF, p=0–04) and the probability of a catheter being outside the tumour (CMF, p=0.01). The catheter placement index (CPI) was a good measure of the accuracy and adequacy of catheter placement in large tumours (p=0.04). Displacement of normal tissue structures by tumour precluded accurate catheter placement and led to a low CPI. It was difficult to accurately instrument lesions ≤3 cm depth even with the benefit of a prior CT scan. In summary a simple method for quantifying temperature catheter placement is proposed, and with its use it is shown that a prior CT scan greatly increases the accuracy and adequacy of tumour catheter insertion, thus proving that a CT scan is essential for documentation of tumour temperature catheter placement.     

Discordant Left and Right Ventricular Optimal Atrioventricular and Interventricular Delays during Biventricular Pacemaker Optimization

Echocardiography‐guided optimization of atrioventricular (AV) delay (AVD) improves left ventricular (LV) filling, and optimized interventricular delay (VVD) leads to further improvement in cardiac output in patients with biventricular (Biv) pacing. Investigators use LV filling and ejection to optimize AV and VV delay in patients with Biv pacing. Effect of such optimization on right‐sided hemodynamics remains unknown. In our experience, few patients experience worsening of right ventricle (RV) hemodynamics when LV parameters are optimized. We present a series of cases where we observed suboptimal RV filling or ejection at optimal AVD and VVD for LV. This RV‐LV discordance may contribute to nonresponder rate to cardiac resynchronization therapy (CRT) and should be evaluated in a consecutive series of CRT nonresponder patients to help improve CRT response.     

“Real-time” disintegration analysis and D-optimal experimental design for the optimization of diclofenac sodium fast-dissolving films

The objective of this work was to study the dissolution and mechanical properties of fast-dissolving films prepared from a tertiary mixture of pullulan, polyvinylpyrrolidone and hypromellose. Disintegration studies were performed in real-time by probe spectroscopy to detect the onset of film disintegration. Tensile strength and elastic modulus of the films were measured by texture analysis. Disintegration time of the films ranged from 21 to 105 seconds whereas their mechanical properties ranged from approximately 2 to 49?MPa for tensile strength and 1 to 21 MPa% for young’s modulus. After generating polynomial models correlating the variables using a D-Optimal mixture design, an optimal formulation with desired responses was proposed by the statistical package. For validation, a new film formulation loaded with diclofenac sodium based on the optimized composition was prepared and tested for dissolution and tensile strength. Dissolution of the optimized film was found to commence almost immediately with 50% of the drug released within one minute. Tensile strength and young’s modulus of the film were 11.21?MPa and 6, 78 MPa%, respectively. Real-time spectroscopy in conjunction with statistical design were shown to be very efficient for the optimization and development of non-conventional intraoral delivery system such as fast dissolving films.     

rG17PE38, a novel immunotoxin target to gastric cancer with overexpressed CCK-2R

Abstract

Background: Gastrin/cholecystokinin subtype 2 receptor (CCK2R) is overexpressed in several types of tumors. Gastrin-17 (G17) peptide has a high affinity with CCK2R. These characters suggest that G17 may be useful for target cancer therapy.

Purpose: Construct a new immunotoxin (IT) targeting of CCK2R overexpressed gastric cancer.

Methods: Two ITs were generated using forward and reverse G17 peptides fused with PE38. To get a high yield, codon optimized gene and optimized fermentation parameters were used in large-scale protein expression. An immunoaffinity technique was introduced into pseudomonas exotoxin (PE)-derived IT purification procedure. G17 competition, GST pull-down and indirect immunoflourescence assays were carried out to confirm the interaction between rG17 and CCK2R. Then, several cytotoxic assays were carried out on 18 cell lines, and an in vivo antitumor activity experiment was tested in nude mice.

Results: The rG17PE38 showed specific cytotoxicity on three gastric cancer cells, while G17PE38 did not. After optimization, the expression level reached about 40% in medium deprived of NaCl. Next, 15–27.5?mg of pure rG17PE38 per 1?L of cultures was obtained. Results of G17 competition, GST pull-down and indirect immunoflourescence assays demonstrated that rG17 have a specific interact with CCK2R. Purified rG17PE38 showed high cytotoxicity on gastric cancer cell lines with the IC₅₀ value of 0.6–4?ng?·?mL^?1. Treatment of nude mice inoculated with BGC-823 tumor xenografts with rG17PE38 efficiently inhibited tumor size.

Conclusions and discussion: The present study demonstrates that reversed G17 could be used as target moiety of PE-derived IT and the rG17PE38 could be developed as a new immunotherapy agent. Codon optimized gene could increase the rG17PE38 expression level in E. coli and furthermore NaCl inhibits the rG17PE38 expression in large scale. Meanwhile, our present study inducts an immunoaffinity method in the IT purification procedure, which could purify the PE-derived ITs in native form.     

A Study of the Impact of Freezing on the Lyophilization of a Concentrated Formulation with a High Fill Depth

The objective of this study was to evaluate the impact of freezing on the lyophilization of a concentrated formulation with a high fill depth. A model system consisting of a 15-mL fill of 15% (w/w) sulfobutylether 7-beta-cyclodextrin (SBECD) solution in a 30-mL vial was selected for this study. Various freezing methods including single-step freezing, two-step freezing with a super-cooling holding, annealing, vacuum-induced freezing, changing ice habit using tert-butyl-alcohol (TBA), ice nucleation with silver iodide (AgI), as well as combinations of some of the methods, were used in the lyophilization of this model system. This work demonstrated that the freezing process had a significant impact on primary drying rate and product quality of a concentrated formulation with a high fill depth. Annealing, vacuum-induced freezing, and addition of either TBA or an ice nucleating agent (AgI) to the formulation accelerated the subsequent ice sublimation process. Two-step freezing or addition of TBA improved the product quality by eliminating vertical heterogeneity within the cake. The combination of two-step freezing in conjunction with an annealing step was shown to be a method of choice for freezing in the lyophilization of a product with a high fill depth. In addition to being an effective method of freezing, it is most applicable for scaling up. An alternative approach is to add a certain amount of TBA to the formulation, if the TBA-formulation interaction or regulatory concerns can be demonstrated as not being an issue. An evaluation of vial size performed in this study showed that although utilizing large-diameter vials to reduce the fill depth can greatly shorten the cycle time of a single batch, it will substantially decrease the product throughput in a large-scale freeze-dryer.     

Optimization of stealth adeno-associated virus vectors by randomization of immunogenic epitopes

Therapeutic gene transfer by adeno-associated virus of serotype 2 (AAV-2) vectors is hampered in patients with pre-existing immunity. Molecular engineering was recently used to identify key immunogenic amino acid residues of the viral capsid and generate mutants with decreased antibody recognition. Here we explored the importance of finely tuning amino acid identity at immunogenic sites to optimize vector phenotype. A capsid library was generated by codon randomization at five positions where substitutions were shown to yield antibody evading phenotypes. Screening this library to isolate immune-escaping mutants allowed an exhaustive scan of combinations of the 20 natural amino acids at each position and yielded variants that remained infectious when incubated with serum or IVIG concentrations that completely neutralize AAV-2. Clones obtained replacing different residues at the same positions displayed strikingly different phenotypes, demonstrating that a precise choice of amino acid substitutions is fundamental to optimize immune-escaping, packaging ability, infectivity and tropism.