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PubMed2004

Does inverse planning applied to Iridium192 high dose rate prostate brachytherapy improve the optimization of the dose afforded by the Paris system?

BACKGROUND AND PURPOSE: The purpose of the work is to analyse for 192Ir prostate brachytherapy (BT) some of the different steps in optimizing the dose delivered to the CTV, urethra and rectum. MATERIALS AND METHODS: Between 07/1998 and 12/2001, 166 patients were treated with 192Ir wires providing a low dose rate, according to the Paris system philosophy and with the 2D version of the treatment planning IsisR. 40-45 Gy were delivered after an external beam radiotherapy of 40 Gy. The maximum tolerable doses for BT were 25 Gy to the anterior third of the rectum on the whole length of the implant (R dose) and 52 Gy to the urethra on a 1cm length (Umax). A Umax/CTV dose ratio >1.3 represented a pejorative value as the planned dose of 40-45 Gy could not be achieved. On the other side a ratio 1.25 decreased significantly with optimization required on CTV contours and additional constraints on urethra while the R/CTV ratio was maintained under 0.55. For initial Umax/CTV >1.3 or >1.25 but <or=1.3 indeed, the mean respective values of 1.41+/-0.16 and 1.28+/-0.01 decreased to 1.28+/-0.24 and 1.17+/-0.09 (P<0.001), allowing to increase the total dose to the CTV by 4 Gy. CONCLUSIONS: The Paris system which assumes a homogeneous distribution of a minimum number of catheters inside the CTV allowed to anticipate a satisfactory dosimetry in 82% of cases. However, this precision rate could be improved until 95% with an optimization approach based on an inverse planning philosophy. These new 3D optimization methods, ideally based on good quality implants at first allow to deliver the highest doses with minimal probability of creating cold spots inside the CTV or unacceptable hot spots outside.

Adenocarcinoma↗

PubMed2006

The optimization of dose delivery for intraoperative high-dose-rate radiation therapy using curved HAM applicators.

BACKGROUND AND PURPOSE: To determine the effect of the curvature of Harrison-Anderson-Mick applicators on the dose distribution in high-dose-rate intraoperative radiation therapy (HDR-IORT). MATERIAL AND METHODS: Treatment planning was performed with flat applicators using (192)Ir as the radioactive source, and dwell times were optimized using dose-point optimization techniques. These optimized dwell times were then used for the curved applicators, and the dose distributions that would actually be delivered to patients were determined. RESULTS: The dose directly below the central catheter was strongly dependent on the curvature of the applicator. Steep parabolic curves caused underdoses of as much as 19% at a point 1cm from the convex side of the applicator. The rate of dose reduction with increasing distance from the applicator surface was also a function of the curvature of the applicator. CONCLUSIONS: The curvature of the applicator profoundly affects dosimetry and can be exploited to optimize coverage of the target during HDR-IORT procedures. To ensure accurate dose delivery, these dose perturbations must be accounted for in the planning process. We recommend maintaining a dosimetry atlas of various applicator sizes and curvatures in addition to one for flat applicators.

Brachytherapy↗

PubMed2006

Optimal diving behaviour and respiratory gas exchange in birds.

This review discusses the advancements in our understanding of the physiology and behaviour of avian diving that have been underpinned by optimal foraging theory and the testing of optimal models. To maximise their foraging efficiency during foraging periods, diving birds must balance numerous factors that are directly or indirectly related to the replenishment of the oxygen stores and the removal of excess carbon dioxide. These include (1) the time spent underwater (which diminishes the oxygen supply, increases carbon dioxide levels and may even include a build up of lactate due to anaerobic metabolism), (2) the time spent at the surface recovering from the previous dive and preparing for the next (including reloading their oxygen supply, decreasing their carbon dioxide levels and possibly also metabolising lactate) and (3) the trade-off between maximising oxygen reserves for consumption underwater by taking in more air to the respiratory system, and minimising the energy costs of positive buoyancy caused by this air, to maximise the time available underwater to forage. Due to its importance in avian diving, replenishment of the oxygen stores has become integral to models of optimal diving, which predict the time budgeting of animals foraging underwater. While many of these models have been examined qualitatively, such tests of predictive trends appear fallible and only quantifiable support affords strong evidence of their predictive value. This review describes how the quantification of certain optimal diving models, using tufted ducks, indeed demonstrates some predictive success. This suggests that replenishment of the oxygen stores and removal of excess carbon dioxide have significant influences on the duration of the surface period between dives. Nevertheless, present models are too simplistic to be robust predictors of diving behaviour for individual animals and it is proposed that they require refinement through the incorporation of other variables that also influence diving behaviour such as, perhaps, prey density and predator avoidance.

Animals↗

PubMed2006

Freezing response and optimal cooling rates for cryopreserving sperm cells of striped bass, Morone saxatilis.

This study explored the optimization of techniques for sperm cryopreservation of an economically important fish species, the striped bass Morone saxatilis. The volumetric shrinkage or the water transport response during freezing of sperm cells was obtained using a differential scanning calorimeter (DSC) technique. Water transport was obtained in the presence of extracellular ice at a cooling rate of 20 degrees C/min in two different media: (1) without cryoprotective agents (CPAs), and (2) with 5% (v/v) dimethyl sulfoxide (DMSO). The sperm cell was modeled as a cylinder of length of 22.8 microm and diameter 0.288 microm and was assumed to have an osmotically inactive cell volume (V(b)) of 0.6 V(0), where V(0) is the isotonic or initial cell volume. By fitting a model of water transport to the experimentally determined water transport data, the best fit membrane permeability parameters (reference membrane permeability to water, L(pg) or L(pg)[cpa] and the activation energy, E(Lp) or E(Lp)[cpa]) were determined and ranged from L(pg)=0.011-0.001 microm/min-atm, and E(Lp)=40.2-9.2 kcal/mol). The parameters obtained in this study suggested that the optimal rate of cooling for striped bass sperm cells in the presence and absence of DMSO range from 14 to 20 degrees C/min. These theoretically predicted rates of optimally freezing M. saxatilis sperm compared quite closely with independent and experimentally determined optimal rates of cooling striped bass sperm.

Animals↗

PubMed2004

Genetic details, optimization and phage life histories.

Optimality models assume that phenotypes evolve by natural selection largely independently of underlying genetic mechanisms. This neglect of genetic mechanisms is considered an advantage by some evolutionary biologists but a fatal flaw by others. The controversy has gone unresolved, in part, from a lack of complex phenotypes that meet optimality criteria and for which the underlying genetic mechanisms are known. Here, we look at both perspectives for lysis time in bacteriophages. We find that the basic assumptions of the optimality model are compatible with the genetic details, but the optimality model is limited in its ability to accommodate lysis time plasticity because the mechanistic underpinnings of plasticity are poorly known.

Journal Article↗

PubMed2005

Optimal immune responses: immunocompetence revisited.

The function of the immune system of an animal is to provide defence against infection, in order to maximize fitness. Understanding this and, particularly, how limiting resources are traded off between costly immune responses and other physiological demands, is central to properly understanding life-history traits and their evolution. Here, we propose that functional (rather than immunological) measures of immune responses should be used when investigating this. We further suggest that optimal immune responses are context specific, rather than generic; that is, a maximum immune response is not necessarily optimal. The nature of an optimal immune response will depend on the specific circumstances and infection status of the animal. Identifying and understanding such optimality requires that the effects of different immune strategies on fitness be considered.

Journal Article↗

PubMed2005

Optimization of point spread function in ultrasound arrays.

The design of aperture weightings in ultrasound arrays is a multi-objective optimization problem, involving parameters such as delays, aperture size, focal depth, operating frequency and beam properties. Besides, apodization causes the SNR in array output to be decreased. We introduce an analytic expression of the lateral point spread function and a model for SNR as nonlinear functions of weights, based on which, a new aperture design method is established, resulting in an optimal set of weights. These weights provide a point spread function having the predetermined peak sidelobe level, while the SNR in array output is optimized. Optimization results from a linear array with M=128 elements equally spaced at one wavelength, center frequency f0=3.5 MHz and 50% relative bandwidth, have shown that decreasing the peak sidelobe level, decreases the SNR. Therefore, an array designer can select a proper set of weights according to its application, using a SNR curve versus to the peak sidelobe level. In addition, the method can maintain the same beam properties over a long range with low variations in the SNR. Simulation results have shown only 1 dB variations in the SNR for depths from 20 mm to 120 mm, which is a longer range and better SNR performance than the conventional methods.

Journal Article↗

PubMed2006

Multiobjective optimization of an ultrasonic transducer using NIMBUS.

The optimal design of an ultrasonic transducer is a multiobjective optimization problem since the final outcome needs to satisfy several conflicting criteria. Simulation tools are often used to avoid expensive and time-consuming experiments, but even simulations may be inefficient and lead to inadequate results if they are based only on trial and error. In this work, the interactive multiobjective optimization method NIMBUS is applied in designing a high-power ultrasonic transducer. The performance of the transducer is simulated with a finite element model, and three design goals are formulated as objective functions to be minimized. To find an appropriate compromise solution, additional preference information is needed from a decision maker, who in our case is an expert in transducer design. A realistic design problem is formulated, and an interactive solution process is described. Our findings demonstrate that interactive multiobjective optimization methods, combined with numerical simulation models, can efficiently help in finding new solution approaches and possibilities as well as new understanding of real-life problems as entirenesses. In this case, the decision maker found a solution that was better with respect to all three objectives than the conventional unoptimized design.

Journal Article↗

PubMed2004

Independent but not synergistic enhancement to the immunogenicity of DNA vaccine expressing HIV-1 gp120 glycoprotein by codon optimization and C3d fusion in a mouse model.

The ability to elicit humoral and cell-mediated immune (CMI) responses from DNA immunization by combinational use of codon optimization and C3d component of complement was evaluated in this study. DNA vaccines that express either the wild type or the codon optimized gp120 gene coding for the envelope (Env) glycoprotein of human immunodeficiency virus (HIV-1) from the primary isolate JR-FL strain were compared to the same forms fused to three tandem copies of the murine C3d genes. Either codon optimization or C3d fusion alone was effective at generating early appearance, higher binding and neutralizing antibody responses. We also observed that cell-mediated immune responses against HIV Env could also be enhanced by C3d fusion. However, for both humoral and CMI responses, there were no synergistic effects when the combination of codon optimization and C3d fusion was employed.

AIDS Vaccines↗

PubMed2006

Novel codon-optimized GM-CSF gene as an adjuvant to enhance the immunity of a DNA vaccine against HIV-1 Gag.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent immunomodulatory cytokine. Here we generated a novel codon-optimized murine GM-CSF gene as an adjuvant. The codon-optimized GM-CSF gene significantly increased protein expression levels in all cells tested. Although injection of the wild-type GM-CSF plasmids adjuvanted HIV-1 Gag DNA vaccine induced detectable immune responses, co-administration of plasmids encoding the codon-optimized GM-CSF sequence with the DNA vaccine resulted in a strong antibody and CTL responses and a protective immune response against infection with recombinant vaccinia virus expressing HIV-1 Gag. This novel codon-optimized GM-CSF gene offers a practical molecular strategy for potentiating immune responses to vaccines as well as other immunotherapeutic strategies.

AIDS Vaccines↗

PubMed2006

Optimization of conditions for in vitro production of radical oxygen species and expression of tissue factor by canine mononuclear cells and granulocytes for use in high-throughput assays.

The purpose of this study was to optimize conditions for high throughput measurement of radical oxygen species (ROS) production and expression of tissue factor, also termed procoagulant activity, by canine leukocytes. Granulocytes and mononuclear cells were separated by density gradient centrifugation from peripheral blood collected on several occasions from three healthy large breed dogs. To determine optimal conditions for ROS production, granulocytes were incubated for 1 or 3h in PBG (PBS containing 0.5% BSA and 5mM glucose) or RPMI containing 10% fetal bovine serum (FBS); lipopolysaccharide (LPS), zymosan, peptidoglycan (PGN) and phorbol myristate acetate (PMA) were used as stimuli. ROS was assessed by conversion of the nonfluorescent dye dihydrorhodamine 123 to fluorescent rhodamine 123 by radical species released into the media. To identify optimal conditions for expression of tissue factor, mononuclear cells were incubated for 5h in RPMI containing different concentrations of heat-inactivated FBS (HI-FBS), and LPS, zymosan, PGN or PMA as stimuli. Expression of tissue factor was determined using a one-stage recalcification assay performed in an automated nephelometric coagulation analyzer. Neither LPS nor zymosan increased ROS production by granulocytes incubated in PBG media. In contrast, granulocytes incubated in RPMI had dose-dependent increases in ROS production in response to zymosan and PGN. ROS production was significantly increased by incubation with concentrations of LPS of 0.01microg/ml or greater, and by zymosan concentrations of 0.1microg/ml or greater. ROS production in response to incubation with PMA was significantly increased starting at 10(-7)M, and was significantly greater for cells incubated in RPMI than cells incubated in PBG. LPS-, zymosan- and PGN-stimulated procoagulant activity increased in a dose-dependent manner, whereas PMA-stimulated procoagulant activity peaked at 10(-7)M. Increasing concentrations of HI-FBS significantly increased LPS-, zymosan- and PGN-induced procoagulant activity of mononuclear cells. Results obtained in this study indicate production of ROS by canine granulocytes is optimal when these cells are incubated for 3h in RPMI with LPS (0.1microg/ml), zymosan (10 microg/ml), PGN (10 microg/ml), and PMA (10(-7)M). Furthermore, canine mononuclear cells express procoagulant activity in response to LPS, zymosan, PGN, and PMA, and responses to LPS, zymosan and PGN are enhanced by the addition of HI-FBS. These findings suggest that HI-FBS retains important serum proteins that facilitate interactions between each of these bacterial or yeast derived products and the mononuclear cells. Consequently, future studies regarding the regulation of procoagulant activity by canine mononuclear cells should be performed in the presence of HI-FBS. Both assays utilized in this study allow high throughput of samples, and therefore are appropriate choices for rapid screening of conditions and/or therapeutic interventions affecting the canine inflammatory system.

Animals↗

PubMed2006

Optimal bulking agent particle size and usage for heat retention and disinfection in domestic wastewater sludge composting.

Composting of two types of sludge produced in wastewater treatment plants, raw sludge (RS) and anaerobically digested sludge (ADS), has been systematically studied by means of the experimental design technique. The results have been analyzed using a full factorial experimental design in order to determine the optimal conditions for composting such sludges in terms of bulking agent particle size and bulking agent:sludge volumetric ratio, two of the key parameters to ensure an optimal performance of the composting process. The objective function selected was a simulated death kinetics of Salmonella, which was chosen as a model pathogen microorganism to represent the disinfection of the material. For both types of sludge, optimal values were found at 5mm bulking agent particle size and 1:1 bulking agent:sludge volumetric ratio when a Gaussian function was fitted to the experimental data. Pilot scale experiments using optimal values obtained were successfully undertaken and confirmed a full disinfection of the sludge by means of the composting process. A mathematical model to simulate the disinfection performance of a composting material is presented. The model can be applied to simulate the disinfection performance of a given pathogen.

Disinfection↗

PubMed2004

Drug sensitivity-related benefit of systematic lymphadenectomy during cytoreductive surgery in optimally debulked stages IIIc and IV ovarian cancer.

OBJECTIVE: The purpose of this study is to assess the survival experience following systematic lymphadenectomy (LNX) in conjunction with primary but optimal cytoreductive surgery in advanced epithelial ovarian cancer (OC) patients when followed by intensive chemotherapy. METHODS: This is a retrospective analysis of all women with OC who were treated in our institution between 1992 and 2000. A total of 98 patients with stages IIIc-IV of OC underwent primary cytoreductive surgery which was 'optimal' (<1 cm residual disease). All patients subsequently received postoperative platinum-containing chemotherapy. Group I, consisting of 51 patients underwent LNX; Group II, consisting of 47 patients did not undergo LNX. The percentage of patients failing to respond to chemotherapy in each group was similar. Each group had statistically equivalent age, stage, regimens of chemotherapy performed, and all other known prognostic factors. RESULTS: No survival benefit could be seen in platinum-sensitive patients. However, in patients who failed to respond to chemotherapy, the 2-year progression-free survival (PFS) (42.8% vs. 14.3%) and overall survival (OS) (51.2% vs. 28.8%) was quite different. LNX significantly improved those of drug-resistant patients when optimal cytoreductive surgery was performed [P = 0.008, risk ratio (rr) = 2.675, 95% confidence interval (CI) = 1.251-5.724]. Cox's proportional analysis shows that LNX was one of the three most significant covariate with the tumor grade and the number of postoperative residual lesions. CONCLUSIONS: The results show that LNX might be of benefit in patients who have optimal primary cytoreductive surgery and who do not respond to platinum-based chemotherapy.

Adult↗

PubMed2005

Development of a metabolic network design and optimization framework incorporating implementation constraints: a succinate production case study.

We have developed a pathway design and optimization scheme that accommodates genetically and/or environmentally derived operational constraints. We express the full set of theoretically optimal pathways in terms of the underlying elementary flux modes and then examine the sensitivity of the optimal yield to a wide class of physiological perturbations. Though the scheme is general it is best appreciated in a concrete context: we here take succinate production as our model system. The scheme produces novel pathway designs and leads to the construction of optimal succinate production pathway networks. The model predictions compare very favorably with experimental observations.

Computer Simulation↗

PubMed2000

Rationale and design of the OPTIME CHF trial: outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure.

BACKGROUND: The optimal management of an acute exacerbation of chronic heart failure (CHF) is uncertain. There is little randomized evidence available to support the various treatment strategies for patients hospitalized with an exacerbation of CHF. Inotropic agents may produce beneficial hemodynamic effects, and although they are currently used in these patients, their effect on clinical response and impact on clinical outcome is unclear. We present a unique and simple study designed to determine whether a treatment strategy for CHF exacerbations that includes an intravenous agent with inotropic properties can reduce hospital length of stay and lead to improved patient outcome. METHODS: The OPTIME CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) trial is an ongoing multicenter, randomized, placebo-controlled trial of a treatment strategy for patients with acute exacerbations of CHF. The design of this study provides a novel approach to the evaluation of treatment strategies in the care of this population. The OPTIME CHF design uses early initiation of intravenous milrinone as both an adjunct to the best the medical therapy and to facilitate optimal dosing of standard oral therapy for heart failure. Patients with known systolic heart failure requiring hospital admission for a CHF exacerbation are randomly assigned within 48 hours of admission to receive a 48-hour infusion of either intravenous milrinone or placebo. The primary end point of this design is a reduction in the total hospital days for cardiovascular events within 60 days after therapy. Enrollment of 1000 patients began July 7, 1997, at 80 US centers and is projected to conclude in late 1999.

Adolescent↗

PubMed2000

Optimally deployed stents in the treatment of restenotic versus de novo lesions.

Results from earlier trials performed before the implementation of optimal stent deployment techniques suggest that stenting for restenotic lesions may be associated with a higher risk of restenosis when compared with de novo lesions. The aim of this study was to compare the short- and long-term outcome of optimal stent deployment in restenotic versus de novo lesions. In all, 1,865 consecutive patients with 2,707 de novo lesions and 489 patients with 633 restenotic lesions underwent intravascular ultrasound-guided optimal stent deployment. In-hospital outcome was similar for both groups, except for a higher incidence of non-Q-wave myocardial infarction in the de novo group (14.6% vs 8.6%, p = 0.001). At 12-month follow-up, there was no statistical significant difference in the incidence of death or myocardial infarction, but event-free survival was better in the de novo lesion group of patients (74.5% vs 63.7%, p = 0.001). There was a higher incidence of target lesion revascularization in the restenosis group (25.1% vs 13.0%, p = 0.001). By multivariate analysis, restenotic lesions, vein graft lesions, and diabetes mellitus were strong determinants of repeat revascularization, whereas larger preprocedural reference vessel minimal lumen diameter and larger final minimal lumen diameter were associated with a reduced chance of restenosis and increased event-free survival. This study shows that optimal stent deployment for restenotic and de novo lesions has favorable short- and long-term outcome. However, the incidence of target lesion revascularization was significantly greater in restenotic lesions. Saphenous vein graft lesions and diabetes mellitus were confirmed as other independent risk factors for clinical restenosis.

Aged↗

PubMed2002

Optimizing treatment of choroidal neovascularization feeder vessels associated with age-related macular degeneration.

PURPOSE: To optimize the method of treating choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). DESIGN: Experimental study and interventional case series. METHODS: The parameters associated with locating and then photocoagulating CNV feeder vessels were identified and optimized using published data and data derived from modeling the choroidal vasculature. Based on these optimized parameters, a prototype diagnostic/treatment system was designed that captures high-speed indocyanine green (ICG) angiogram images and facilitates analysis of the images by enhancing visualization of dye movement through CNV feeder vessels (FVs). The system also permits precise aiming and delivery of 810- nm wavelength photocoagulation laser energy to target FVs on a real-time ICG angiogram image of the choroidal vasculature. Target FVs are tracked by a joy-stick controlled laser aiming beam until an intravenously-injected high-concentration ICG dye bolus is observed to enter the target vessel, at which time the laser is fired. Proof of principle of the combined diagnosis/treatment system design for performing dye-enhanced photocoagulation (DEP) in the clinical setting and determination of the minimum DEP laser energy needed to close CNV FVs was made in 11 AMD patients requiring treatment of CNV, but for whom other treatment was not appropriate. RESULTS: Using ICG-DEP, CNV feeder vessels were closed with single pulse laser energy, delivering as little as 0.6 to 1.8 J of energy to the fundus, producing no visible change in the fundus. Successful FV closure was usually indicated immediately by presence of incarcerated ICG dye in the vessel adjacent to the burn site. The prototype system proved relatively easy to operate. After acquiring and interpreting diagnostic angiograms and repositioning a patient in front of the device, feeder vessel DEP and treatment evaluation required 15 to 20 minutes. CONCLUSIONS: Indocyanine green dye-enhanced photocoagulation of CNV feeder vessels, facilitated by use of a device that permits real-time visualization of the choroidal circulation while aiming the treatment laser beam, appears to minimize the amount of energy applied to the fundus and the volume of fundus tissue affected by treatment, compared with other treatment modalities. The combination diagnosis/treatment device should be useful in optimizing FV treatment and in refining and evaluating the efficacy of DEP in future clinical trials.

Aged↗

PubMed1997

Reduction of the fatigue-induced force decline in human skeletal muscle by optimized stimulation trains.

OBJECTIVE: To identify the stimulation pattern that optimizes the force-time integral produced during isometric contractions of fatigued human skeletal muscle. DESIGN: Twelve healthy subjects with no history of lower extremity orthopedic problems voluntarily participated. RESULTS: The primary findings were that (1) the optimized trains showed augmentation only from fatigued muscles and (2) a simple stimulation pattern, containing one brief (5msec) initial interpulse interval, produced the greatest force-time integrals and rates of rise of force. With muscle fatigue, the rate of rise of force of the constant-frequency train slowed, whereas the rate of rise of force of the optimized trains remained unchanged. This difference in the rate of rise of force may explain why the optimized trains, which take advantage of the catchlike property of skeletal muscle, are able to augment forces from fatigued muscles when compared with the constant-frequency train. CONCLUSIONS: These results may have important clinical implications when using brief trains of electric stimulation to aid patients in performing functional movements and contribute to our understanding of the relationship between the activation pattern of a muscle and the force output produced.

Adult↗