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Very fast simulated reannealing in radiation therapy treatment plan optimization.

PURPOSE: Very Fast Simulated Reannealing is a relatively new (1989) and sophisticated algorithm for simulated annealing applications. It offers the advantages of annealing methods while requiring shorter execution times. The purpose of this investigation was to adapt Very Fast Simulated Reannealing to conformal treatment planning optimization. METHODS AND MATERIALS: We used Very Fast Simulated Reannealing to optimize treatments for three clinical cases with two different cost functions. The first cost function was linear (minimum target dose) with nonlinear dose-volume normal tissue constraints. The second cost function (probability of uncomplicated local control) was a weighted product of normal tissue complication probabilities and the tumor control probability. RESULTS: For the cost functions used in this study, the Very Fast Simulated Reannealing algorithm achieved results within 5-10% of the final solution (100,000 iterations) after 1000 iterations and within 3-5% of the final solution after 5000-10000 iterations. These solutions were superior to those produced by a conventional treatment plan based on an analysis of the resulting dose-volume histograms. However, this technique is a stochastic method and results vary in a statistical manner. Successive solutions may differ by up to 10%. CONCLUSION: Very Fast Simulated Reannealing, with modifications, is suitable for radiation therapy treatment planning optimization. It produced results within 3-10% of the optimal solution, produced using another optimization algorithm (Mixed Integer Programming), in clinically useful execution times.

Algorithms↗

Impact of "optimized" treatment planning for tandem and ring, and tandem and ovoids, using high dose rate brachytherapy for cervical cancer.

PURPOSE: Different treatment techniques are used in high dose rate (HDR) remote afterloading intracavitary brachytherapy for uterine cervical cancer. We have investigated the differences between "optimized" and "nonoptimized" therapy using both a tandem and ring (T/R) applicator, and a tandem and ovoids (T/O), applicator. METHODS AND MATERIALS: HDR afterloading brachytherapy using the Madison System for Stage IB cervical cancer was simulated for 10 different patients using both a T/R applicator and a T/O applicator. A treatment course consists of external beam irradiation and five insertions of HDR afterloading brachytherapy. Full dosimetry calculations were performed at the initial insertion for both applicators and used as a reference for the following four insertions of the appropriate applicator. Forty dosimetry calculations were performed to determine the dose delivered to Point M (similar to Point A), Point E (obturator lymph nodes), vaginal surface, bladder, and rectum. "Optimized" doses were specified to Point M and to the vaginal surface. "Nonoptimized" doses were specified to Point M only. Using the linear-quadratic equation, calculations have been performed to convert the delivered dose using HDR to the biologically equivalent doses at the conventional low dose rate (LDR) at 0.60 Gy/h. RESULTS: Major differences between "optimized" and "nonoptimized" LDR equivalent doses were found at the vaginal surface, bladder, and rectum. Overdoses at the vaginal surface, bladder, and rectum were calculated to be 208%, nil, and 42%, respectively, for the T/R applicator with "nonoptimization." However, for the T/O applicator, the overdoses were smaller, being nil, 32%, and 27%, respectively, with "nonoptimization." CONCLUSION: Doses given in high dose rate intracavitary brachytherapy border on tissue tolerance. "Optimization" of either applicator decreases the risk of a dose that may have potential for complications. Optimization of a tandem and ovoids best ensures that the doses are not diminished at the treatment sites, and that the potential for overdose is reduced.

Brachytherapy↗

Intraoperative optimization of needle placement and dwell times for conformal prostate brachytherapy.

PURPOSE: Traditionally, transperineal prostate brachytherapy has been heavily operator dependent. To overcome this limitation, a treatment planning method was developed for intraoperative planning, guidance, and evaluation. In this setting, reliability, speed, and ease of understanding are primary considerations. This planning method has been implemented for ultrasound guided implants of the prostate, but can be extended for use in other body sites. METHODS AND MATERIALS: The length and cross-section of the target (prostate) and location of urethra and rectum are determined intraoperatively from live ultrasound imaging. The planning program then automatically generates a "reference plan" containing needle locations, dwell times, and the resulting isodose distribution. As needles are placed, this information is corrected to account for any deviation of needle placement or movement of the prostate. Once all needles are in place, the normalization is adjusted to reconcile remaining hot-spots with coverage of the target volume. Optimization is performed in three separate stages. Each stage works to enhance only a subset of the implant parameters. (a) Pattern Optimization attempts to find the most appropriate placement for the needles or catheters. It is based on the transverse contour of the target volume. Needles are placed uniformly around the perimeter, and interior needle positions are determined from the cross-sectional area and shape. Critical structures such as the urethra are explicitly avoided. This step provides the overall framework for the implant, and is not generally repeated. (b) Relative Dwell Time Optimization selects relative dwell times that will give the best uniformity of dose. It works by setting the relative dwell time in each source position inversely proportional to the dose delivered to that point by the other source positions. It is used in the reference plan, and is repeated as each needle is inserted. This provides dosimetric feedback to the physician, who can judge the effect of deviations from the reference plan. (c) Relative Volume Optimization is an interactive method for fine tuning the normalization based upon volume analysis. The volume analysis is presented in tabular and graphical form, both being updated rapidly as the normalization is adjusted. The information is formatted to help the operator judge coverage and uniformity. Special functions are provided that allow the operator to "jump" to special normalization values based on several indices of uniformity or uniformity/coverage. RESULTS: This system overcomes some conventional brachytherapy limitations. Rather than depend on the operator's intuitive judgement of where the needles should be placed, a global plan is generated and validated with full dose calculations. Immediate feedback is provided concerning the adequacy of placement and avoidance of critical structures. This information is provided in terms of actual tissue doses to the target volume and critical structures using point doses, isodose distributions, and volume analysis. Since the new method was introduced in January 1994, 33 implants have been performed. The needle placement method has been reliable in the clinic, with different doctors producing similar results on subsequent fractions for the same patient. CONCLUSION: The method of decomposing the optimization problem into several simple steps is capable of rapidly, consistently, and reliably designing conformal treatment plans of high uniformity. Operator dependence has been significantly reduced. We are adapting the method for other anatomic sites.

Brachytherapy↗

Liquid chromatography solvent optimization: potential pitfalls when using a black box for developing a quality separation.

ICOS and DIAMOND are two commercially available, semi-automated HPLC solvent optimization software packages. The resultant optimized chromatographic separation is dependent on a combination of the operator's objective, the capability of the software system and the appropriateness of the data input. The latter contains components that represent the match between the requirements of the algorithms used and the information content of the data on which those algorithms operated. Knowledge about the sample content, stability and potential sample-solvent interactions can have a significant effect on the quality of the optimal solvent composition that is calculated. The results generated during the optimization of the separation of a mixture of U-83,757 and a variety of related compounds illustrate the need to consider the significance of the contribution to the calculated optimal separation of each of these potential pitfalls, both individually and in combination with the mode of operation of the relevant algorithms. Our results indicate that the quality of the final result is highly dependent on the intelligence content of the data used.

Acetonitriles↗

Optimal intensity of oral anticoagulant therapy after myocardial infarction.

OBJECTIVES: This study attempted to determine the optimal intensity of anticoagulant therapy in patients after myocardial infarction. BACKGROUND: Treatment with oral anticoagulant therapy entails a delicate balance between over- (risk of bleeding) and under-anticoagulation (risk of thromboemboli). The optimal intensity required to prevent the occurrence of either event (bleeding or thromboembolic) is not known. METHODS: A method was used to determine the optimal intensity of anticoagulant therapy by calculating incidence rates for either event associated with a specific international normalized ratio. The numerator included events occurring at given international normalized ratios, and the denominator comprised the total observation time. RESULTS: The study population included 3,404 myocardial infarction patients enrolled in the ASPECT (Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) trial. Total treatment was 6,918 patient-years. Major bleeding occurred in 57 patients (0.8/100 patient-years), and thromboembolic complications in 397 (5.7/100 patient-years). The incidence of the combined outcome (bleeding or thromboembolic complications) with international normalized ratio <2 was 8.0/100 patient-years (283 events in 3,559 patient-years), with international normalized ratios between 2 and 3, 3.9/100 patient-years (33 events in 838 patient-years); 3.2/100 patient-years (57 events in 1,775 patient-years) for international normalized ratios between 3 and 4; 6.6/100 patient-years (37 events in 564 patient-years) for international normalized ratios between 4 and 5; and 7.7/100 patient-years (14 events in 182 patient-years) for international normalized ratios >5. After adjustment for achieved international normalized ratio levels, significant predictors were higher levels of systolic blood pressure and age. CONCLUSIONS: If equal weight is given to hemorrhagic and thromboembolic complications, these results suggest that the optimal intensity of long-term anticoagulant therapy for myocardial infarction patients lies between 2.0 and 4.0 international normalized ratio, with a trend to suggest an optimal intensity of 3.0 to 4.0.

Administration, Oral↗

An optimized examination protocol for contrast-enhanced cervical and mediastinal CT.

We compared an optimized contrast-enhanced CT technique for the neck and upper mediastinum with a conventional technique and with nonenhanced images, using densitometric measurements. The optimized protocol included slice thickness, infusion rate, postural maneuvers, and manipulation of the gantry tilt. Densitometric evaluation showed significantly higher enhancement values in vessels and metastases with the optimized protocol than with conventional technique, without significant enhancement in muscle. Semiquantitative assessment demonstrated significantly better image quality with the optimized protocol. The optimized technique has been implemented into routine use.

Absorptiometry, Photon↗

Optimization of a polypyrrole glucose oxidase biosensor.

An amperometric glucose biosensor was fabricated by the electrochemical polymerization of pyrrole onto a platinum electrode in the presence of the enzyme glucose oxidase in a KCl solution at a potential of +0.65 V versus SCE. The enzyme was entrapped into the polypyrrole film during the electropolymerization process. Glucose responses were measured by potentiostating the enzyme electrode at a potential of +0.7 V versus SCE in order to oxidize the hydrogen generated by the oxidation of glucose by the enzyme in the presence of oxygen. Experiments were performed to determine the optimal conditions of the polypyrrole glucose oxidase film preparation (pyrrole and glucose oxidase concentrations in the plating solution) and the response to glucose from such electrodes was evaluated as a function of film thickness, pH and temperature. It was found that a concentration of 0.3 M pyrrole in the presence of 65 U/ml of glucose oxidase in 0.01 M KCl were the optimal parameters for the fabrication of the biosensor. The optimal response was obtained for a film thickness of 0.17 microns (75 mC/cm2) at pH 6 and at a temperature of 313 K. The temperature dependence of the amperometric response indicated an activation energy of 41 kJ/mole. The linearity of the enzyme electrode response ranged from 1.0 mM to 7.5 mM glucose and kinetic parameters determined for the optimized biosensors were 33.4 mM for the Km and 7.2 microA for the Imax. It was demonstrated that the internal diffusion of hydrogen peroxide through the polypyrrole layer to the platinum surface was the main limiting factor controlling the magnitude of the response of the biosensor to glucose. The response was directly related to the enzyme loading in the polypyrrole film. The shelf life and the operational stability of the optimized biosensor exceed 500 days and 175 assays, respectively. The substrate specificity of the entrapped glucose oxidase was not altered by the immobilization procedure.

Biosensing Techniques↗

Wide range for optimal concentration of folinic acid in fluorouracil modulation--experimental data on human tumour cell lines.

The clinical use of the fluorouracil (FU)-folinic acid (FA) combination is hampered by the still open choice of the optimal schedule, with marked controversy as concerns the optimal FA dose. This in vitro study on FU-FA combinations in 17 human cancer cell lines, representative of tumour types responding to FU-FA treatment, reassesses the notion of the optimal FA concentration. Cells were exposed for 5 days to various FU-FA concentrations (0.07-77 microM, 14 concentrations, for FU; and 0.0025-100 microM for FA). The growth inhibition was assessed by the MTT test. The investigated cell lines exhibited FU IC50 ranging from 0.4 to 38.9 microM (median 3.7 microM). In six out of 17 cell lines investigated, the addition of FA did not result in a substantial enhancement of FU cytotoxicity (group 1). For the remaining 11 cell lines responding to FA supplementation (group 2), the maximal enhancement factor ranged from 3 to 8, meaning that in the presence of optimal FA concentration, the efficient FU concentration (IC50) was reduced by between 3 and 8 as compared to the efficient FU concentration without FA supplementation. For cell lines responding to FA supplementation, the optimal FA concentrations ranged from 10(-7) to 4 x 10(-4) M (4000-fold range) with a median value at 9.6 x 10(-7) M. Distribution of cell doubling time was not significantly different between group 1 and group 2. In contrast, the FU IC50 were significantly different (P = 0.02) between group 1 (median 7.4 microM) and group 2 (median 2.2 microM), thus indicating that cell lines with the greatest FU cytotoxicity enhancement by FA were those intrinsically sensitive to FU and vice versa.

Breast Neoplasms↗

Automatic selection of the optimal cardiac phase for gated three-dimensional coronary x-ray angiography.

RATIONALE AND OBJECTIVES: For the reconstruction of the coronary arteries from rotational angiography data, a crucial point is the selection of the optimal cardiac phase for data reconstruction. To avoid time-consuming interactive selection of the optimal cardiac phase by visual inspection of multiple high-resolution data sets reconstructed at different cardiac phases, an automatic approach for deriving optimal reconstruction windows is attractive. MATERIALS AND METHODS: This paper presents a new approach to fully automatic selection of the optimal cardiac phase for image reconstruction. It is based on the analysis of a four-dimensional data set of the region of interest reconstructed at low-spatial resolution utilizing an image quality index, which quantifies the image quality of a single three-dimensional reconstructed volume. The derived image quality index utilizes the histogram information of a single temporal snapshot as a quality measure for the vessel reconstruction. The proposed technique was applied to 16 projection data sets obtained in eight pigs. RESULTS: Experiments to evaluate the proposed method based on user-defined image quality parameters serving as ground truth, showed a relatively high correlation (>84%) for high-quality (c(phi) > 0.95) images. CONCLUSION: An image-based technique is introduced, which is able to determine the optimal cardiac phase for 3D-RCA fully automatically. The proposed method was successfully applied to 16 data sets obtained in a total of 8 porcine models.

Algorithms↗

On the correlation between genomic G+C content and optimal growth temperature in prokaryotes: data quality and confounding factors.

The correlation between genomic G+C content and optimal growth temperature in prokaryotes has gained renewed interest after Musto et al. [H. Musto, H. Naya, A. Zavala, H. Romero, F. Alvarex-Valin, G. Bernardi, Correlations between genomic GC levels and optimal growth temperatures in prokaryotes, FEBS Lett. 573 (2004) 73-77], reported that positive correlations exist in 15 families studied. We have reanalyzed their data and found that when genome size and data quality were adjusted for, there was no significant evidence of relationship between optimal temperature and GC content for two of the families that had previously shown strongly significant correlations. Using updated temperature optima for Halobacteriaceae species we found the correlation is insignificant in this family. For the family Enterobacteriaceae when genome size and optimal temperature are included in a multiple linear regression, only genome size is significant as a predictor of GC content. We showed that more profound statistical methods than simple two factor correlation analysis should be used for analyzing complex intrinsic and extrinsic factors that affect genomic GC content. We further found that a positive correlation between temperature and genomic GC is only evident in free-living species of low optimal growth temperatures.

Base Composition↗

Optimization of 25 kDa linear polyethylenimine for efficient gene delivery.

A 25-kDa linear polyethylenimine (25 kDa L-PEI) has proven to be efficient and versatile agent for gene delivery. Therefore, we determined the optimal transfection conditions of 25 kDa L-PEI and examined whether it has comparable transfection efficiency with other commercially available reagents, ExGen 500, LipofectAMINE 2000, and Effectene by using EGFP expression vector in different cell lines. Transfection efficiency and cytotoxicity were measured by flow cytometry. First of all, we determined the optimal ratio of nitrogen to phosphorous (N/P) and DNA concentration. With the increase of N/P ratio and DNA amounts, transfection efficiency increased with a slight variation in cell types. The optimal amounts of 25 kDa L-PEI were determined at N/P ratio 40 and DNA concentration varied among the cell types. In addition, 25 kDa L-PEI worked efficiently and was less toxic than other reagents. However, the efficiency and toxicity of all these reagents varied according to cell types as well as the ratio of DNA to reagents and the amounts of DNA. Our finding illustrates the importance of optimal transfection conditions of 25 kDa L-PEI to obtain maximal transgene expression with less cytotoxicity. Importantly, the optimization of those conditions may make possible to perform transfection cost-effectively and efficiently.

Animals↗

Optimization of fibrin scaffolds for differentiation of murine embryonic stem cells into neural lineage cells.

The objective of this research was to determine the appropriate cell culture conditions for embryonic stem (ES) cell proliferation and differentiation in fibrin scaffolds by examining cell seeding density, location, and the optimal concentrations of fibrinogen, thrombin, and aprotinin (protease inhibitor). Mouse ES cells were induced to become neural progenitors by adding retinoic acid for 4 days to embryoid body (EB) cultures. For dissociated EBs, the optimal cell seeding density and location was determined to be 250,000 cells/cm(2) seeded on top of fibrin scaffolds. For intact EBs, three-dimensional (3D) cultures with one EB per 400 microL fibrin scaffold resulted in greater cell proliferation and differentiation than two-dimensional (2D) cultures. Optimal concentrations for scaffold polymerization were 10mg/mL of fibrinogen and 2 NIH units/mL of thrombin. The optimal aprotinin concentration was determined to be 50 microg/mL for dissociated EBs (2D) and 5 microg/mL for intact EBs in 3D fibrin scaffolds. Additionally, after 14 days in 3D culture EBs differentiated into neurons and astrocytes as indicated by immunohistochemisty. These conditions provide an optimal fibrin scaffold for evaluating ES cell differentiation and proliferation in culture, and for use as a platform for neural tissue engineering applications, such as the treatment for spinal cord injury.

Animals↗

Response surface optimization of the critical medium components for carbonyl reductase production by Candida viswanathii MTCC 5158.

Culture conditions were optimized for the growth and carbonyl reductase production by a novel yeast strain Candida viswanathii. Response surface methodology was applied for the critical medium components (initial pH, mannitol, yeast extract and calcium chloride) identified earlier by one-factor-at-a-time approach. Central composite design was used for the optimization studies. Using this methodology, the optimal values for the concentration of mannitol, initial pH, yeast extract and calcium chloride were 1.9, 7.5, 1.6 and 4, respectively. This medium was projected to produce, theoretically, growth having an optical density of 1.1 (600 nm) and an enzyme activity of 81.5 U/ml. Using this optimized medium, an experimental growth of 1.1 OD (600 nm) and enzyme activity 80.9 U/ml verified the applied methodology. This approach for medium optimization led to an enhancement of the growth and enzyme activity by 1.3 and 2.3 times higher, respectively, as compared to the unoptimized media.

Alcohol Oxidoreductases↗

Whole genome analysis of non-optimal codon usage in secretory signal sequences of Streptomyces coelicolor.

Non-optimal (rare) codons have been suggested to reduce translation rate and facilitate secretion in Escherichia coli. In this study, the complete genome analysis of non-optimal codon usage in secretory signal sequences and non-secretory sequences of Streptomyces coelicolor was performed. The result showed that there was a higher proportion of non-optimal codons in secretory signal sequences than in non-secretory sequences. The increased tendency was more obvious when tested with the experimental data of secretory proteins from proteomics analysis. Some non-optimal codons for Arg (AGA, CGU and CGA), Ile (AUA) and Lys (AAA) were significantly over presented in the secretary signal sequences. It may reveal that a balanced non-optimal codon usage was necessary for protein secretion and expression in Streptomyces.

Base Sequence↗

Optimization of the capillary zone electrophoresis method for Huperzine A determination using experimental design and artificial neural networks.

Huperzine A, natural product from Huperzia serrata, is quite an important compound used to treat the Alzheimer's disease as a food supplement and also proposed as a prospective and prophylactic antidote against organophosphate poisoning. In this work, simple and fast capillary electrophoresis (CE) procedure with UV detection (at 230 nm) for determination of Huperzine A was developed and optimized. Capillary electrophoresis determination of Huperzine A was optimized using a combination of the experimental design (ED) and the artificial neural networks (ANN). In the first stage of optimization, the experiments were done according to the appropriate ED. Data evaluated by ANN allowed finding the optimal values of several analytical parameters (peak area, peak height, and analysis time). Optimal conditions found were 50 mM acetate buffer, pH 4.6, separation voltage 10 kV, hydrodynamic injection time 10 s and temperature 25 degrees C. The developed method shows good repeatability as relative standard division (R.S.D. = 0.9%) and it has been applied for determination of Huperzine A in various pharmaceutical products and in biological liquids. The limit of detection (LOD) in aqueous media was 0.226 ng/ml and 0.233 ng/ml for determination in the serum.

Alkaloids↗

A better global resolution function and a novel iterative stochastic search method for optimization of high-performance liquid chromatographic separation.

HPLC optimization strategy consists of four elements; experimental design, retention modeling, quality criteria function, and optimum search method. In this paper we present a simple, superior alternative to general classes of classical resolution functions (S function) and a novel optimum search algorithm (iterative stochastic search, ISS) for HPLC optimization. Comparison of S with general classes of resolution-based quality criteria functions (Rs, Rp, and Rmin) shows superior features such as correct assessment of favorable separation conditions, preservation of peak pair contributions, elimination of arbitrary cut-off values, and a unique capability to interpret absolute significance of function values through a simple inequality. The proposed ISS algorithm is more robust than standard methods and it is easily applicable to hyperdimensional optimization. ISS also shows clear advantages in its ability to correctly identify the global optimum (instead of local optimum), with higher precision, with more efficient use of computation cycles, and with easier implementation. Successful application of S and ISS to HPLC optimization was demonstrated in the separation of representative functionalities (sugars, alcohols, and organic acids) present in microbial fermentations. Both the optimal and pathological (worst) conditions were successfully predicted and experimentally verified.

Algorithms↗

Effect of mobile phase composition on the SMB processes efficiency. Stochastic optimization of isocratic and gradient operation.

The solvent composition was adjusted in a theoretical study in order to maximize the efficiency of a simulated moving bed (SMB) process. The isocratic realization of the process as well as the solvent gradient mode were considered. The solvent composition and the flow rates were used as decision variables in a random search optimization algorithm known to be a reliable tool for nonlinear programming problems. The results of the optimization indicate that the optimal composition of the mobile phase depends strongly on the feed concentration. The asymmetry of the internal concentration profiles, which has a negative effect on the separation efficiency, can be partly damped by an increase of the solvent strength. In the cases studied the optimal solvent strength determined for concentrated feed streams is higher than that for diluted ones. Moreover, the optimum is strongly influenced by the value of the selectivity factor and its dependency on the mobile phase composition. Different results were obtained for cases, in which the separation factor increases with increasing the modifier concentration, than for cases, in which the separation factor decreases with increasing the modifier concentration. A similar analysis was performed for a solvent gradient SMB process, in which different solvents are used at the two inlet ports: a weak solvent in the feed stream and a strong solvent in the desorbent stream. Again the optimal mobile phase composition was strongly affected by the type of the isotherms and their non-linearity. The potential of a gradient SMB process in terms of increasing the productivity and reducing the eluent consumption is exemplified.

Chromatography, Liquid↗

Perspective: How to evaluate studies on peri-operative nutrition? Considerations about the definition of optimal nutrition for patients and its key role in the comparison of the results of studies on nutritional intervention.

Different nutritional outcome studies on the same subject can have vast differences in composition of the chosen food without justification, suggesting that the composition of "optimal" nutrition in patients is not known or that optimal nutrition does not exist. The result will be negative studies which reinforces the existing impression that nutritional intervention is of limited value in every day's patient care. This perspective will put arguments forward that optimal nutrition exists and that the definition of optimal nutrition should be the base of future nutrition intervention studies. This perspective aims at providing a definition of optimal nutrition and consequently a basis to critically appraise the literature upon nutritional interventions in disease states.

Critical Illness↗