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Short-term improvement in submaximal exercise capacity by optimized therapy with ACE inhibitors and beta blockers in heart failure patients is associated with restoration of peripheral endothelial function.

BACKGROUND: Improved exercise capacity in chronic heart failure (CHF) has been attributed to restoration of endothelial function. ACE inhibitors as well as beta blockers have previously been shown to enhance endothelial function and exercise capacity. The aim of this study was to determine whether short-term improvement in submaximal exercise capacity induced by optimized therapy with ACE inhibitors in combination with beta blockers is associated with restoration of endothelial function in CHF patients. METHODS: Thirty-three patients with CHF were evaluated: six-minute walk test, NYHA class, brain natriuretic peptide (BNP), big Endothelin-1 (bigET-1) and flow-mediated vasodilation (FMD) of the brachial artery were assessed at baseline and after a 3-month period of optimized neurohormonal therapy. Two groups were formed retrospectively based on the changes in submaximal exercise capacity (responders and non-responders). RESULTS: Optimization of neurohormonal therapy was comparable between groups. Responders (n=17) revealed a significant increase in walking distance (304+/-109 to 441+/-75 m; p<0.01), which was paralleled by a decrease in NYHA class (2.7+/-0.6 to 2.0+/-0.4; p<0.01), BNP (484+/-454 to 243+/-197 pg/ml; p<0.01), and bigET-1 (2.0+/-0.9 vs. 1.5+/-0.6 fmol/ml; p=0.04). By contrast, the latter variables did not change in non-responders. Improvement in functional capacity in responders was associated with an increase in FMD (8.2+/-3.9% to 11.0+/-5.6%; p<0.05). Increments in FMD were directly correlated with increases in walking distance (r=0.34; p<0.05). CONCLUSION: Short-term improvement of submaximal exercise capacity in CHF patients following optimized therapy with ACE inhibitors and beta blockers is associated with restoration of endothelial function in conduit arteries.

Adrenergic beta-Antagonists↗

Beneficial effects of high doses of growth hormone in the introduction and optimization of medical treatment in decompensated congestive heart failure.

BACKGROUND: Optimizing oral therapy in patients with unstable decompensated and/or dobutamine-dependent congestive heart failure (CHF) is a challenge. METHODS AND RESULTS: We investigated the effects of high doses of recombinant human growth hormone (GH) in 6 patients with cardiac cachexia and unstable decompensated CHF (5 dobutamine-dependent), including its influence in the optimization of oral CHF treatment. Patients received 8 IU of subcutaneous GH per day for median 26 (range 61) days. GH improved the systolic systemic blood pressure (SSBP, in mm Hg) from median 85 (range 34) to 100 (20) (p<.01), and the left ventricular (LV) ejection fraction (in %) from median 23 (range 22) (pretreatment) to 28 (18) (posttreatment) and 38 (28) (later) (p<.007). The NYHA functional class improved from IV to I in 2 patients, from IV to II in 3, and from IV to II-III in one. All patients were discharged from the hospital. It was possible in the hospital to initiate and after discharge to optimize long-term CHF treatment from 37.5 to 50 mg of carvedilol in 5 patients and with higher doses of captopril (from 50 to 150 mg) in all patients. Three patients are alive after 67, 75, and 11 months of follow-up. The remaining 3 patients died from a pulmonary abscess at 9 months, septicemia at 21 months, and progressive heart failure due to unplanned withdrawal of carvedilol at 36 months. CONCLUSION: The use of GH in patients with decompensated CHF and cardiac cachexia provided clinical stability without the need for inotropic drugs permitting introduction of nonpreviously tolerated drugs. This could represent a new option for optimizing long-term CHF therapy and discharging hospitalized patients who are dobutamine-dependent.

Adult↗

Application of experimental design methodology in development and optimization of drug release method.

The aim of our research was to apply experimental design methodology in the development and optimization of drug release methods. Diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid monosodium salt) was selected as a model drug and Naklofen retard prolonged release tablets, containing 100 mg of diclofenac sodium, were chosen as a model prolonged release system. On the basis of previous results, a three-level three-factorial Box-Behnken experimental design was used to characterize and optimize three physicochemical parameters, i.e. rotation speeds of the stirring elements, pH, and ionic strengths of the dissolution medium, affecting the release of diclofenac sodium from the tablets. The chosen dependent variables (responses) were a cumulative percentage of dissolved diclofenac sodium in 2, 6, 12 and 24 h. For estimation of coefficients in the approximating polynomial function, the least square regression method was applied. Afterwards, the information about the model reliability was verified by using the analysis of variance (ANOVA). The estimation of model factors' significance was performed by Student's t-test. For investigation of the shape of the predicted response surfaces and for model optimization, the canonical analysis was applied. Our study proved that experimental design methodology could efficiently be applied for characterization and optimization of analytical parameters affecting drug release and that it is an economical way of obtaining the maximum amount of information in a short period of time and with the fewest number of experiments.

Analysis of Variance↗

Optimization of dose distribution for HDR brachytherapy of the prostate using Attraction-Repulsion Model.

PURPOSE: To optimize dose distribution for high-dose-rate brachytherapy for prostate cancer, we have developed a new algorithm named Attraction-Repulsion Model (ARM). In this study, we compared the ARM with geometric optimization (GO). METHODS AND MATERIALS: The ARM was used to optimize the dose distribution by finding the best dwell time combination. ARM requires grids inside the clinical target volume (CTV) and critical organs. These grids generate attraction or repulsion based on specific dose constraints. After calculations were performed repeatedly until the attraction and repulsion forces reached equilibrium, the optimal dwell time distribution was established. We compared the ARM with GO for 10 patients using dose-volume histograms. RESULTS: The CTV ranged from 23 to 48 cc, and the CTV V150 ranged from 52% to 79%, and 23% to 44% for GO and ARM, respectively. This indicates that the dose homogeneity indices, as well as the conformal indices, were higher for ARM than for GO. The urethra V150 was 0-99% and 0-1% for GO and ARM, respectively. CONCLUSION: The ARM proved to be superior to GO in minimizing the dose to normal structures and in improving dose homogeneity for the target while reducing the dose to normal tissues.

Algorithms↗

Multiple fields may offer better esophagus sparing without increased probability of lung toxicity in optimized IMRT of lung tumors.

PURPOSE: To evaluate whether increasing numbers of intensity-modulated radiation therapy (IMRT) fields enhance lung-tumor dose without additional predicted toxicity for difficult planning geometries. METHODS AND MATERIALS: Data from 8 previous three dimensional conformal radiation therapy (3D-CRT) patients with tumors located in various regions of each lung, but with planning target volumes (PTVs) overlapping part of the esophagus, were used as input. Four optimized-beamlet IMRT plans (1 plan that used the 3D-CRT beam arrangement and 3 plans with 3, 5, or 7 axial, but predominantly one-sided, fields) were compared. For IMRT, the equivalent uniform dose (EUD) in the whole PTV was optimized simultaneously with that in a reduced PTV exclusive of the esophagus. Normal-tissue complication probability-based costlets were used for the esophagus, heart, and lung. RESULTS: Overall, IMRT plans (optimized by use of EUD to judiciously allow relaxed PTV dose homogeneity) result in better minimum PTV isodose surface coverage and better average EUD values than does conformal planning; dose generally increases with the number of fields. Even 7-field plans do not significantly alter normal-lung mean-dose values or lung volumes that receive more than 13, 20, or 30 Gy. CONCLUSION: Optimized many-field IMRT plans can lead to escalated lung-tumor dose in the special case of esophagus overlapping PTV, without unacceptable alteration in the dose distribution to normal lung.

Esophagus↗

Beam angle optimization and reduction for intensity-modulated radiation therapy of non-small-cell lung cancers.

PURPOSE: To optimize beam angles and reduce the number of beams used for intensity-modulated radiation therapy (IMRT) of non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: An exhaustive search scheme was used to perform beam angle optimization (BAO) for IMRT of NSCLC. This approach involved intercomparison of all possible beam angle combinations and selection of the best angles based on the scores or costs of the objective functions used in the treatment plan optimization. Ten Stage III NSCLC cases were selected to evaluate the BAO algorithm and dosimetry benefits of IMRT-BAO. IMRT plans using five or seven coplanar beams were optimized and compared with those using nine equal-spaced beams. Results of BAO were also compared between plans using different numbers of beams with or without fluence modulation. RESULTS: Each anatomic structure, e.g., tumor or lung, had its own preferred beam angles. Thus, BAO required appropriate balance of competing objective functions. Plans using fewer angles (five or seven beams) could achieve plan quality similar to those using nine equal-spaced beams, however with reduced monitor units and field segments. The number of beams used for the treatment (five vs. seven) and the fluence modulation (open or IMRT beams) did not have a significant impact on the results of the BAO. CONCLUSIONS: Use of fewer beams (e.g., five) for lung IMRT could result in acceptable plan quality but improved treatment efficiency. A multiresolution search scheme could be developed for BAO using fewer and nonmodulated beams to reduce the computation cost of BAO.

Algorithms↗

Optimal number of beams for stereotactic body radiotherapy of lung and liver lesions.

PURPOSE: The aim of this study was to determine the optimal number of coplanar and noncoplanar external beams in the setting of stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Spherical targets were delineated within 2 separate extracranial sites, the lung and liver, with diameters varying from 2 cm to 7 cm to cover the range of volumes used in SBRT. Treatment plans were created for all target volumes using 5 to 15 geometrically optimized coplanar and noncoplanar conformal beams. Dose gradient and normal tissue complication probability (NTCP) were evaluated for each set of beam configurations and for each target size. RESULTS: For all lung and liver target volumes, the dose gradient improved with an increase in beam number from 5 to 15 for both coplanar and noncoplanar beam configurations. NTCP decreased as the beam number increased from 5 to 9 beams for all target sizes for both coplanar and noncoplanar beams. There is no significant improvement in NTCP when more than 9 beams were used for treatment planning regardless of target size. CONCLUSION: Based on dosimetric criteria, the optimal number of external beams is 13 to 15 for SBRT using either coplanar or noncoplanar beam bouquets. Simple biologic models indicate that the optimal number of beams is 9 for SBRT of lung and liver lesions >2 cm, whereas smaller lesions may benefit from plans using up to 13 beams.

Algorithms↗

Optimal glycemic control is associated with a lower rate of target vessel revascularization in treated type II diabetic patients undergoing elective percutaneous coronary intervention.

OBJECTIVES: We examined the association between glycemic control determined by preprocedural hemoglobin A1c (A1c) and the incidence of target vessel revascularization (TVR) in diabetic patients undergoing elective percutaneous coronary intervention (PCI). BACKGROUND: Patients with diabetes mellitus (DM) have increased rates of restenosis and a worse clinical outcome after PCI than patients without DM. METHODS: A total of 239 patients (60 without DM and 179 with DM) were enrolled in this study. Optimal glycemic control was defined as A1c < or =7%, and suboptimal control was defined as A1c >7%. Follow-up was performed at six and 12 months after the index intervention. RESULTS: Diabetic patients with optimal glycemic control had a rate of 12-month TVR similar to that of nondiabetic patients (15% vs. 18%, p = NS). Diabetic patients with A1c >7% had a significantly higher rate of TVR than those with A1c <7% (34% vs. 15%, p = 0.02). In a multiple logistic regression analysis, A1c >7% was a significant independent predictor of TVR (odds ratio 2.87, 95% confidence interval 1.13 to 7.24; p = 0.03). Optimal glycemic control was associated with a lower rate of cardiac rehospitalization (15% vs. 31%, p = 0.03) and recurrent angina (13% vs. 37%, p = 0.002) at 12-month follow-up. CONCLUSIONS: In diabetic patients undergoing elective PCI, optimal glycemic control (A1c < or =7%) is associated with a lower rate of TVR, cardiac rehospitalization, and recurrent angina. These data suggest that aggressive treatment of DM to achieve A1c < or =7% is beneficial in improving the clinical outcome after PCI.

Aged↗

Linear programming to optimize performance in a department of surgery.

BACKGROUND: Linear programming is an analytic method that can be used to develop models for health care that optimize distribution of resources through mathematical means. STUDY DESIGN: The linear programming model contained objective, decision, and constraint elements. The objective was to optimize financial outcomes for both the hospital and physicians in the Department of Surgery. The decision concerns procedure mix or the number of each type of surgical procedure. Constraints apply to resources that are consumed during the course of the patient's surgical encounter. RESULTS: The optimal solution produced an increase in professional payments of 3.6% and an increase in hospital total margin of 16.1%. This solution favored surgical procedures that require inpatient care; these patients had greater comorbidity, reflected in a higher case-mix index of 3.74 compared to 2.97. Substantial differences were noted in use of general care and ICU days, and in consumption of preoperative, intraoperative, and recovery room time. CONCLUSIONS: Aligning quality surgical care with optimal financial performance may be assisted by mathematical models such as linear programming.

Comorbidity↗

Significant parameters in the optimization of MALDI-TOF-MS for synthetic polymers.

One of the most significant issues in any analytical practice is optimization. Optimization and calibration are key factors in quantitation. In matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), instrument optimization is a limitation restricting quantitation. An understanding of the parameters that are most influential and the effects of these parameters on the mass spectrum is required for optimization. This understanding is especially important when characterizing synthetic polymers by MALDI-TOF-MS, due to the breadth of the polymer molecular mass distribution (MMD). Two considerations are important in quantitation, additivity of signal and signal-to-noise (S/N). In this study, the effects of several instrument parameters were studied using an orthogonal experimental design to understand effects on the signal-to-noise (S/N) of a polystyrene distribution. The instrument parameters examined included detector voltage, laser energy, delay time, extraction voltage, and lens voltage. Other parameters considered were polymer concentration and matrix. The results showed detector voltage and delay time were the most influential of the instrument parameters for polystyrene using all trans-retinoic acid (RA) as the matrix. These parameters, as well as laser energy, were most influential for the polystyrene with dithranol as the matrix.

Journal Article↗

Determination of patient-specific multi-joint kinematic models through two-level optimization.

Dynamic patient-specific musculoskeletal models have great potential for addressing clinical problems in orthopedics and rehabilitation. However, their predictive capability is limited by how well the underlying kinematic model matches the patient's structure. This study presents a general two-level optimization procedure for tuning any multi-joint kinematic model to a patient's experimental movement data. An outer level optimization modifies the model's parameters (joint position and orientations) while repeated inner level optimizations modify the model's degrees of freedom given the current parameters, with the goal of minimizing errors between model and experimental marker trajectories. The approach is demonstrated by fitting a 27 parameter, three-dimensional, 12 degree-of-freedom lower-extremity kinematic model to synthetic and experimental movement data for isolated joint (hip, knee, and ankle) and gait (full leg) motions. For noiseless synthetic data, the approach successfully recovered the known joint parameters to within an arbitrarily tight tolerance. When noise was added to the synthetic data, root-mean-square (RMS) errors between known and recovered joint parameters were within 10.4 degrees and 10 mm. For experimental data, RMS marker distance errors were reduced by up to 62% compared to methods that estimate joint parameters from anatomical landmarks. Optimized joint parameters found using a loaded full-leg gait motion differed significantly from those found using unloaded individual joint motions. In the future, this approach may facilitate the creation of dynamic patient-specific musculoskeletal models for predictive clinical applications.

Biomechanical Phenomena↗

Constraining spine stability levels in an optimization model leads to the prediction of trunk muscle cocontraction and improved spine compression force estimates.

A major limitation of optimization models of the spine has been the inability to accurately predict trunk muscle co-activity. Antagonist muscle activity is thought to be necessary to maintain adequate levels of spine stability but, in turn, creates increased loading on the spine. It is thus hypothesized that the CNS attempts to optimize the relationship between spine loading and spine stability in determining muscular activation patterns. This study presents an optimization model of the spine in which stability was constrained to target levels predicted from regression equations of independent loading variables. Objective functions were set to either minimize the sum of the cubed muscle forces or minimize the sum of the squared intervertebral forces at the L4-L5 disc level. Results demonstrate that the inclusion of stability constraints in optimization simulations produced realistic predictions of antagonist muscle activity and predictions of spine compression levels that agree more closely with EMG-based estimates, compared to simulations in which stability was unconstrained. It was concluded that spinal stability is a vital consideration for the CNS when dictating trunk muscle recruitment patterns.

Adult↗

Optimization model predictions for postural coordination modes.

This paper examines the ability of the dynamic optimization model to predict changes between in-phase and anti-phase postural modes of coordination and to evaluate influence of two particular environmental and intentional constraints on postural strategy. The task studied was based on an experimental paradigm that consisted in tracking a target motion with the head. An original optimal procedure was developed for cyclic problems to calculate hip and ankle angular trajectories during postural sway with a minimum torque change criterion. Optimization results give a good description of the sudden bifurcation phase between in-phase and anti-phase postural coordination modes in visual target tracking. Transition frequency and predicted effects of environmental and intentional constraints are also in line with experimental observations described in existing literature. In particular, these investigations pointed out that postural planning process can be related to the minimization of a dynamic cost criterion with an equilibrium constraint. In conclusion, the optimization technique is well suited for the prediction of postural modes of coordination and seems to offer many opportunities for better comprehension of neuromuscular movement control.

Ankle↗

Multi-criterion optimization for heel-toe running.

This paper presents an optimization procedure for multi-criterion analysis essential in many biomechanical studies. The optimization is illustrated with a heel-toe running analysis wherein the rate of load and the passive load on support leg are minimized concurrently. The goal of multi-criterion optimization is achieved by incorporating the criterion of Pareto optimality in the genetic algorithm. The proposed procedure can replace the popular weighted-sum approach for problems with multiple objectives. The selection of a final design from the Pareto optimum points (non-dominated designs) can be determined, based on the min-max objective deviation criterion. Nevertheless, a different decision can be made in the final selection without incurring recalculations. The scheme is readily adoptable for parallel computing, which deserves further study to reduce the execution time in a complex biomechanical analysis.

Algorithms↗

An optimized protocol for hip joint centre determination using the functional method.

The functional method identifies the hip joint centre (HJC) as the centre of rotation of the femur relative to the pelvis during an ad hoc movement normally recorded using stereophotogrammetry. This method may be used for the direct determination of subject-specific HJC coordinates or for creating a database from which regression equations may be derived that allow for the prediction of those coordinates. In order to contribute to the optimization of the functional method, the effects of the following factors were investigated: the algorithm used to estimate the HJC coordinates from marker coordinates, the type and amplitude of the movement of the femur relative to the pelvis, marker cluster location and dimensions, and the number of data samples. This was done using a simulation approach which, in turn, was validated using experiments made on a physical analogue of the pelvis and femur system. The algorithms used in the present context were classified and, in some instances, modified in order to optimize both accuracy and computation time, and submitted to a comparative evaluation. The type of movement that allowed for the most accurate results consisted of several flexion-extension/abduction-adduction movements performed on vertical planes of different orientations, followed by a circumduction movement. The accuracy of the HJC estimate improved, with an increasing rate, as a function of the amplitude of these movements. A sharp improvement was found as the number of the photogrammetric data samples used to describe the movement increased up to 500. For optimal performance with the recommended algorithms, markers were best located as far as possible from each other and with their centroid as close as possible to the HJC. By optimizing the analytical and experimental protocol, HJC location error not caused by soft tissue artefacts may be reduced by a factor of ten with a maximal expected value for such error of approximately 1mm.

Biomechanical Phenomena↗

The effect of three-dimensional shape optimization on the probabilistic response of a cemented femoral hip prosthesis.

Probabilistic analyses allow the effect of uncertainty in system parameters on predicted model performance measures to be determined. Furthermore, using performance functions to describe a failure event, the probability of failure can be quantified. The effect of three-dimensional prosthesis shape optimization on the probabilistic response and failure probability of a cemented hip prosthesis system is investigated. Random variables include joint and muscle loading, cortical and cancellous bone and PMMA bone cement elastic properties, and strength parameters describing failure of the bone cement and the prosthesis-bone cement interface. Several performance functions describing the bone cement and prosthesis-cement interface are used to compute the probability of failure. When evaluated deterministically, most performance functions indicated a safe design, with the exception of interface tensile failure. However, when evaluated probabilistically, finite probabilities of failure were computed, some significant. The most likely mode of failure before shape optimization was prosthesis-bone cement interface tensile failure with a predicted probability of failure of 97.9%. Deterministic prosthesis shape optimization reduced the probability of failure for all performance functions and reduced prosthesis-bone cement interface tensile failure by 31.7%. Probability sensitivity factors indicate that the uncertainty in the joint loading, cement strength, and implant-cement interface strength have the greatest effect on the computed probability of failure. Implant shape optimization results in a more robust implant design that is less sensitive to uncertainties in joint loading, which cannot be easily controlled, and more sensitive to cement and interface properties, which are easier to modify.

Cementation↗

Dynamic optimization of bioprocesses: efficient and robust numerical strategies.

The dynamic optimization (open loop optimal control) of non-linear bioprocesses is considered in this contribution. These processes can be described by sets of non-linear differential and algebraic equations (DAEs), usually subject to constraints in the state and control variables. A review of the available solution techniques for this class of problems is presented, highlighting the numerical difficulties arising from the non-linear, constrained and often discontinuous nature of these systems. In order to surmount these difficulties, we present several alternative stochastic and hybrid techniques based on the control vector parameterization (CVP) approach. The CVP approach is a direct method which transforms the original problem into a non-linear programming (NLP) problem, which must be solved by a suitable (efficient and robust) solver. In particular, a hybrid technique uses a first global optimization phase followed by a fast second phase based on a local deterministic method, so it can handle the nonconvexity of many of these NLPs. The efficiency and robustness of these techniques is illustrated by solving several challenging case studies regarding the optimal control of fed-batch bioreactors and other bioprocesses. In order to fairly evaluate their advantages, a careful and critical comparison with several other direct approaches is provided. The results indicate that the two-phase hybrid approach presents the best compromise between robustness and efficiency.

Algorithms↗

Optimization of culture conditions and medium composition for the production of micrococcin GO5 by Micrococcus sp. GO5.

To enhance the production of micrococcin GO5, a bacteriocin produced by Micrococcus sp. GO5, cultivation conditions and medium composition were optimized. The optimal initial pH and temperature for bacteriocin production were 7.0-9.0 and 37 degrees C, respectively. Micrococcus sp. GO5 displayed the highest micrococcin GO5 activity when grown in modified MRS medium that contained lactose or sucrose, rather than glucose, as a carbon source. The maximum bacteriocin activity was obtained in modified MRS medium containing 0.5% tryptone and 1.0% yeast extract as nitrogen sources instead of the other nitrogen sources present in MRS medium. Bacteriocin production was greatly affected by the concentration of K(2)HPO(4); strain GO5 produced eight-fold more bacteriocin in medium containing 2.0-2.5% K(2)HPO(4) than in medium containing 0.2% K(2)HPO(4). The optimal concentration of MgSO(4).7H(2)O for bacteriocin production was 0.5%. The production of micrococcin GO5 was increased 32-fold in shake flask culture and 16-fold in a bioreactor using the optimized medium (TY medium), compared with culturing in MRS medium.

Bacteriocins↗