scholarly journals Relativistic Optimization Force Concept for gEUD Biological Optimization and Novel a-value Selection Viewpoint

Author(s):  
Yusuke Anetai ◽  
Hideki Takegawa ◽  
Yuhei Koike ◽  
Satoaki Nakamura ◽  
Noboru Tanigawa

Abstract Generalized equivalent uniform dose (gEUD) optimization is a biological optimization method used for intensity modulated radiation therapy (IMRT). Although parametric analyses have been widely reported, the use of parameter a-value in the optimization method remains elusive. This study aims to clarify the mathematical characteristics of the gEUD and to provide effective a-value selection. The gEUD is typically obtained using a differential dose volume histogram (DVH). This can be rewritten using a cumulative DVH (cDVH) and applied to variational analysis. The equivalence between the gEUD and the dose is then obtained; a low or high a-value corresponds to a wide or narrow dose range of optimization, respectively. Next, we focused on the gEUD curve behavior against a-value shifts and it retained its curve characteristics despite optimization. Using differential geometry, this curve shift can be considered as a geodesic deviation between pre- and post-optimization by a relativistic optimization force. The total action enacted by the force includes the curvature of the gEUD curve. This idea provides a novel viewpoint that the curvature of the gEUD curve is influenced by the optimization effect. The curvature stationary point of the gEUD curve (the vertex point, a = a_k) is expected to be a special point that leads to effective a-value selection. Eleven head and neck patient cases were used to verify the curvature effect. We used the Photon Optimizer (PO) of Eclipse for optimization and focused the upper gEUD to simplify the dose constraint for the organ at risk (OAR) that requires balancing of the overlapped planning target volume(PTV). Static seven-field IMRT was used for optimization, changing the a-value of the affected side of the parotid and retaining PTV D95% = 70Gy at the different a-value optimization. Finally, cDVH shift (ΔDVH), gEUD shift (ΔgEUD), their average values, and a_k were evaluated. The a = a_k optimization showed an intermediate effect of lower and higher a-values on ΔDVH, ΔgEUD, and their averages. “Lower” (a=0.5/1.0/2.0/3.0), “middle” (a=4.0/5.0/6.0/8.0/10/a_k), and “higher” (a=12/15/20/40) were defined using a=a_k as a base point. Lower a-value optimization was effective for the low-dose region and weakly affected the whole range of cDVH weight. In contrast, higher a-value optimization addressed the high-dose region and strongly affected the high-dose range of the cDVH weight as theoretically predicted. In addition, the middle range of the a-value optimization induced a decrease in the clinically important middle-to-high dose range, which retained the high dose of the PTV. Interestingly, the average ΔDVH and ΔgEUD corresponded exponentially to the curvature and the gradient of the gEUD curve. Using our relativistic optimization force concept, gEUD optimization is represented as a gEUD curve shift, highlighting that the curvature of the gEUD curve is the essence of gEUD optimization. The curvature stationary point (a = a_k), namely the vertex point of the gEUD curve, played an intermediate role in the low-to-high a-value condition. We can effectively select a lower/middle/higher a-value from a base point of a = a_k under clinically complex optimization situation.

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gertraud Eylert ◽  
Reinhard Dolp ◽  
Alexandra Parousis ◽  
Richard Cheng ◽  
Christopher Auger ◽  
...  

Abstract Background Multipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®. Methods We conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin. Result We found that the low dose range between 200 and 40,000 cells/cm2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000–400,000 cells/cm2 and a high dose of 2,000,000 cells/cm2. The low dose of 40,000 cells/cm2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control. Conclusion This regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome.


2021 ◽  
Author(s):  
Zuzanna Kabacińska ◽  
Alida Timar-Gabor ◽  
Benny Guralnik

<p>Thermally activated processes can be described mathematically by the Arrhenius equation. The Meyer-Neldel Rule (MNR), or compensation law, linearly relates the pre-exponent term to the logarithm of the excitation enthalpy for processes that are thermally driven in an Arrhenian manner. This empirical rule was observed in many areas of materials science, in physics, chemistry, and biology. In geosciences it was found to uphold in hydrogen diffusion (Jones 2014a) and proton conduction (Jones 2014b) in minerals.</p><p>Trapped charge dating methods that use electron spin resonance (ESR) or optically or thermally stimulated luminescence (OSL and TL) are based on the dose-dependent accumulation of defects in minerals such as quartz and feldspar. The thermal stability of these defects in the age range investigated is a major prerequisite for accurate dating, while the accurate determination of the values of the trap depths and frequency factors play a major role in thermochronometry applications. </p><p>The correlation of kinetic parameters for diffusion has been very recently established for irradiated oxides (Kotomin et al. 2018). A correlation between the activation energy and the frequency factor that satisfied the Meyer–Neldel rule was reported when the thermal stability of [AlO<sub>4</sub>/h<sup>+</sup>]<sup>0</sup> and [TiO<sub>4</sub>/M<sup>+</sup>]<sup>0</sup> ESR signals in quartz was studied as function of dose (Benzid and Timar-Gabor 2020). Here we compiled the optically stimulated luminescence (OSL) data published so far in this regard, and investigated experimentally the thermal stability of OSL signals for doses ranging from 10 to 10000 Gy in sedimentary quartz samples. We report a linear relationship between the natural logarithm of the preexponent term (the frequency factor) and the activation energy E, corresponding to a Meyer-Neldel energy of 45 meV, and a deviation from first order kinetics in the high dose range accompanied by an apparent decrease in thermal stability. The implications of these observations and the atomic and physical mechanisms are currently studied.</p><p> </p><p><strong>References</strong></p><p>Benzid, K., Timar Gabor, A. 2020. The compensation effect (Meyer–Neldel rule) on [AlO<sub>4</sub>/h<sup>+</sup>]<sup>0</sup> and [TiO<sub>4</sub>/M<sup>+</sup>]<sup>0</sup> paramagnetic centers in irradiated sedimentary quartz. <em>AIP Advance</em>s 10, 075114.</p><p>Kotomin, E., Kuzovkov, V., Popov, A. I., Maier, J., and Vila, R. 2018. Anomalous kinetics of diffusion-controlled defect annealing in irradiated ionic solids. <em>J. Phys. Chem. A</em> 122(1), 28–32</p><p>Jones, A. G. (2014a), Compensation of the Meyer-Neldel Compensation Law for H diffusion in minerals, <em>Geochem. Geophys. Geosyst.</em>, 15, 2616–2631</p><p>Jones, A. G. (2014b), Reconciling different equations for proton conduction using the Meyer-Neldel compensation rule, <em>Geochem. Geophys. Geosyst</em>., 15, 337–349</p>


2021 ◽  
pp. 1-8
Author(s):  
Yuki Furukawa ◽  
Tasnim Hamza ◽  
Andrea Cipriani ◽  
Toshi A. Furukawa ◽  
Georgia Salanti ◽  
...  

Background Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear. Aims To find the optimal dosage of aripiprazole augmentation. Method Multiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose–effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: ≥50% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4–12 weeks). Results Ten studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose–efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15–1.85) and 5 mg (OR = 1.93, 95% CI 1.33–2.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52–2.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate. Conclusions Low-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.


2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Naomi Even-Zohar ◽  
Yael Sofer ◽  
Iris Yaish ◽  
Merav Serebro ◽  
Karen Tordjman ◽  
...  

Abstract Introduction : Transgender women with intact gonads receive lifelong hormonal treatment in order to suppress physiologic androgen production. Cyproterone acetate (CA) is the most comon antiandrogenic drug prescribed for this indication in Europe, with a dose range between 25-100 mg/day. Aim: To assess the effectiveness and safety of low dose (<20 mg/day), compared with high dose (>50 mg/day) CA treatment. Methods: Historical cohort study of transgender women treated in our department between January 2000 and October 2018. Results: There were 42 transgender women in the low dose group (LDG) and 32 in the high dose group (HDG). Age (27.9 ± 1.6 vs.28.9 ± 1.7 years) and follow up time (16.2 ± 2.2 vs. 20.1 ± 2.1 months) were similar in the LDG and HDG, respectively. At the last available visit, testosterone levels were effectively and similarly suppressed in both treatment groups (0.6 ± 0.1 vs 0.8 ± 0.3 nmol/l; p=0.37, for LDG and HDG respectively). Prolactin (659 ± 64 vs 486 ± 42 mIU/ml, p=0.02), LDL cholesterol (96.1 ± 5 vs 78.5 ± 4 mg/dl, p= 0.02) and triglycerides (93.3 ± 9 vs 69 ± 5 mg/dl; p=0.02) were higher in the HDG compared with LDG respectively. Side effects were common in the HDG (four cases of increased liver enzymes, one case of pulmonary embolism and one case of sudden death). Conclusion: We show for the first time that anti-androgenic treatment of transgender women with low dose CA is as effective as high dose treatment, but safer. We suggest incorporation of this observation in future guidelines.


2019 ◽  
Vol 107 (6) ◽  
pp. 523-529 ◽  
Author(s):  
Mohamad Bekhit ◽  
Asmaa Sobhy ◽  
Zakaria I. Ali ◽  
Sameh M. Gafar

Abstract A novel high-dose dosimeter based on γ radiation reduction of copper ions and formation of copper metal inside polymer matrix were investigated. γ radiation induced synthesis of copper nanoparticles (CuNPs) in poly vinyl alcohol films were studied by UV-Visible Spectrophotometer, X-ray diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR). The optical absorption spectra showed that the Cu/PVA nanocomposite films have surface plasmon resonance (SPR) of copper nanoparticles which depending on irradiation doses. Upon γ irradiation these films turns its color from faint blue to deep reddish brown depending on metal ion concentration. The XRD pattern and FTIR spectrum confirm the formation of the CuNPs. The response of Cu/PVA nanocomposite dosimeters depends on both the irradiation doses and concentration of copper precursor. The dose range for these films was from 50 to 650 kGy, revealing its important applications for high dose dosimetry. Cu/PVA nanocomposites films exhibit good post-irradiation stability in dark and light.


2020 ◽  
Vol 9 (11) ◽  
pp. 3747
Author(s):  
Lisa Goudman ◽  
Ann De Smedt ◽  
Patrice Forget ◽  
Maarten Moens

The Medication Quantification Scale III (MQS) is a tool to represent the negative impact of medication. A reduction in medication can serve as an indicator to evaluate treatment success. However, no cut-off value has yet been determined to evaluate whether a decrease in medication is clinically relevant. Therefore, the objective is to estimate the thresholds for the MQS and morphine milligram equivalents (MMEs) that best identify a clinically relevant important improvement for patients. Data from the Discover registry, in which patients with failed back surgery syndrome were treated with high-dose spinal cord stimulation, were used. Patient satisfaction was utilized to evaluate a clinically important outcome 12 months after stimulation. Anchor-based and distribution-based methods were applied to determine the minimal clinical important difference (MCID). Distribution-based methods revealed a value of 4.28 for the MQS and 33.61 for the MME as MCID. Anchor-based methods indicated a percentage change score of 41.2% for the MQS and 28.2% for the MME or an absolute change score of 4.72 for the MQS and 22.65 for the MME. For assessing a treatment outcome, we recommend using the percentage change score, which better reflects a clinically important outcome and is not severely influenced by high medication intake at baseline.


2018 ◽  
Vol 103 (2) ◽  
pp. e1.9-e1
Author(s):  
Christiansen Nanna ◽  
Ashraf Saleha

AimsPatients with cystic fibrosis (CF) require supplementation of fat-soluble vitamins due to the effects of the disease on the pancreas and the resulting inability of absorb fat effectively.1The study aimed to assess the effectiveness of current of vitamin D supplementation to achieve adequate serum Vitamin D (25OHD) levels in paediatric CF patients.2 Secondly, this study assessed the effectiveness of ‘Stoss’ therapy (a high dose vitamin D therapy administered every three months) as an alternative to daily vitamin D supplementation for patients with known poor compliance.3MethodsVitamin D doses and serum 25OHD levels between January and December 2016 were reviewed for paediatric CF patients at a UK centre. Data was collected for 138 paediatric patients. The ‘clinical record summary’ system was used to extract the data which included age, hospital number, weight in 2015 and 2016, 25OHD levels from 2015 and 2016, vitamin D dose before each level and pancreatic status.Data was entered onto Statistical Package for the Social Sciences (SPSS) system for analysis. A paired T-test was conducted to ascertain if there was a significant difference in weekly/kg doses between patients that were sufficient (25OHD>50 nmol/L) and insufficient (25OHD<50 nmol/L).ResultsData was collected for a total of 138 patients. The data from only 70 patients was analysed when investigating the first objective, as all other patients did not have 25OHD levels available for both 2015 and 2016. A further five patients wereexcluded and analysed seperately due to receiving Stoss therapy. The weekly Vitamin D dose range was very wide for both years with 43% (n=40) of patients requiring additional vitamin D in addition to Aquadeks (CF multivitamin preparation). There was no significant difference in Vitamin D doses between patients with sufficient and insufficient 25OHD levels. This was thecase for both 2015 (p=0.432) and 2016 (p=0.192). The daily supplementation doses were successful at maintaining vitamin D sufficiency for 83% of patients in 2015 and 93% in 2016.Out of the 5 patients who received ‘Stoss’ therapy, 3 had an increase in 25OHD levels. However, only one of the patients had a significant increase leading to sufficient 25OHD levels. In 2 cases there was actually a 60%–68% decrease in 25OHD levels, which lead to these patients developing vitamin D deficiency.ConclusionThis study was useful in determining the effectiveness of current Vitamin D dosing. The results suggest that patients having insufficient 25OHD levels may not be due to an inadequacy of doses provided in the current guideline, as there was no significant difference in dose between patients with sufficient and insufficient 25OHD levels. Given the patient group, the difference could be attributable to a lack of compliance to daily therapies in the patients with insufficient 25OHD levels or even differences in individual responses to therapy.In this sample, ‘Stoss’ therapy is not effective in maintaining sufficient 25OHD levels. Although the data for this part of the study was very limited, it identifies a need to investigate the effectiveness of ‘Stoss’ therapy further.ReferencesFerguson JH, Chang AB. Vitamin D supplementation for cystic fibrosis. Cochrane Database of Syst Rev [Internet] 2014. http://onlinelibrary.wiley.com/ & doi:10.1002/14651858.CD007298.pub3/pdf [Available: 2017April 12].Green D, Carson K, Leonard A, et al. Current treatment recommendations for correcting vitamin D deficiency in paediatric patients with cystic fibrosis is inadequate. J Pediatr2008;4:554–559.Shepherd D, Belessis Y, Katz, et al. Single high-dose oral vitamin D3 (stoss) therapy: A solution to vitamin D deficiency in children with cystic fibrosis?J Cyst Fibros2013;2:177–182.


2017 ◽  
Vol 36 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Madhav G. Paranjpe ◽  
Jessica Belich ◽  
Tom J. Vidmar ◽  
Reem H. Elbekai ◽  
Marie McKeon ◽  
...  

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.


2019 ◽  
Vol 60 (3) ◽  
pp. 298-307 ◽  
Author(s):  
Ryo Saga ◽  
Yusuke Matsuya ◽  
Rei Takahashi ◽  
Kazuki Hasegawa ◽  
Hiroyuki Date ◽  
...  

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