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To examine detail depth dose characteristics of ideal proton beams using the GATE Monte Carlo technique.
In this study, in order to improve simulation efficiency, we used pencil beam geometry instead of parallel broad-field geometry. Depth dose distributions for beam energies from 5 to 250 MeV in a water phantom were obtained. This study used parameters named Rpeak, R90, R80, R73, R50, full width at half maximum (FWHM), width of 80–20% distal fall-off (W(80–20)) and peak-to-entrance ratio to represent Bragg peak characteristics. The obtained energy–range relationships were fitted into third-order polynomial formulae. The present study also used the GATE Monte Carlo code to calculate the stopping power of proton pencil beams in a water cubic phantom and compared results with the National Institute of Standards and Technology (NIST) standard reference database.
The study results revealed deeper penetration, broader FWHM and distal fall-off and decreased peak-to-entrance dose ratio with increasing beam energy. Study results for monoenergetic proton beams showed that R73 can be a good indicator to characterise a range of incident beams. These also suggest FWHM is more sensitive than W(80–20) distal fall-off in finding initial energy spread. Furthermore, the difference between the obtained stopping power from simulation and NIST data almost in all energies was lower than 1%.
Detail depth dose characteristics for monoenergetic proton beams within therapeutic energy ranges were reported. These results can serve as a good reference for clinical practitioners in their daily practice.
Background: Challenges in predicting risk of recurrence for individual patients with meningioma limits appropriate selection of patients who may benefit from adjuvant radiation therapy to delay recurrence. Here, we aimed to develop and validate a combined clinicomolecular predictor of early recurrence for individual patients with meningiomas. Methods: A methylation-based predictor of 5-year recurrence-free-survival (RFS) was developed using DNA-methylation profiles from a training cohort of 228 patients. Model performance was compared to a standard-of-care histological-based model using three independent cohorts (N=54 ;N=140; N=64 patients). Subsequently, a nomogram that integrated the methylome-based predictor with prognostic clinical factors was developed and validated. Results: The methylome-based predictor of 5-year RFS performed favorably compared to a grade-based predictor when tested using the three validation cohorts (ΔAUC=0.10, 95%CI 0.03 – 0.018) and was independently associated with RFS on multivariable Cox regression analysis (HR=3.6, 95%CI 1.8–7.2, P<0.001). A nomogram combining the methylome-predictor with clinical factors demonstrated greater discrimination for recurrence than a nomogram using clinical factors alone (ΔAUC=0.25, 95%CI 0.22–0.27) and resulted in two risk groups with distinct recurrence patterns (HR=7.7, 95%CI 5.3–11.1, P<0.001) and clinical implications. Conclusions: Our validated models provide important novel prognostic information that could be used to individualize decisions regarding post-operative therapeutic interventions in meningioma.
Background: Molecular signatures are being increasing used to classify central nervous system (CNS) tumors with incorporation into World Health Organization (WHO) classifications. A recently published genome-wide DNA methylation-based CNS tumor classifier assisted in diagnostically challenging cases. However its impact on patient care has not been reported, limiting translation to other centres. Methods: All 55 challenging CNS tumour diagnoses over three years underwent DNA methylation profiling. Tumor classification along with copy number variant (CNV) plot results were integrated with histopathological findings to determine final diagnoses and corresponding clinical impact was assessed. Results: After methylation profiling 46/55 (84%) received clinically relevant diagnostic changes, 30 (55%) with a new diagnosis or resolved differential diagnosis and 16 (29%) with clinically important molecular diagnostic or subtyping changes. WHO grade changed in 15 (27%), with two-thirds upgraded. Nine new IDH mutations in gliomas, four new molecular subtypes in medulloblastomas/ependymomas, and three false positive 1p/19q codeletions were identified. Patient care was directly changed by methylation profiling in 7/47 (15%) followed-up cases to avoid unnecessary treatment in three, insufficient treatment in three, and medically assisted death in one. Conclusions: This real-world use of methylation-based CNS tumor classification substantially impacts patient care for diagnostically challenging tumors and also avoids misdiagnosis-related uncessary resource use.
Objective: To summarize the findings of randomized controlled trials (RCTs) on the efficacy and safety of vitamins and minerals for migraine prophylaxis. Methods: We systematically searched bibliographic databases and relevant websites for parallel and crossover RCTs reporting efficacy and/or safety of vitamins and/or minerals for migraine prophylaxis. Our primary outcomes were migraine frequency (number of attacks) and duration (hours). Secondary outcomes were severity (intensity), days with migraine, and adverse events. Meta-analysis was conducted when analyzable data were available from at least two trials. Results: Eighteen placebo-controlled trials met our eligibility criteria. Only coenzyme Q10 and magnesium contributed to meta-analyses. In adults, compared with placebo, coenzyme Q10 did not significantly decrease migraine frequency (mean difference (MD) −0.44 (−2.14 to 1.26); I2 53%; 2 trials; 97 participants; moderate strength of the evidence), duration (MD −1.97 (−4.82 to 0.87); I2 0%; 2 trials; 97 participants; moderate strength of the evidence), or severity (ratio of means (RoM) −0.05 (−0.20 to 0.11); I2 0%; 2 trials; 97 participants). In adults, compared with placebo, magnesium did not significantly decrease migraine severity (RoM −0.17 (−0.36 to 0.02); I2 48%; 3 trials; 226 participants; low strength of the evidence). Meta-analysis of other vitamins and minerals, and other outcomes were not feasible due to a lack of sufficiently reported data. Conclusions: Based on insufficient evidence, it is unknown if coenzyme Q10 and magnesium are effective for migraine prophylaxis in adults. High-quality, adequately powered RCTs are needed to fully evaluate the efficacy and safety of vitamins and minerals for migraine prophylaxis.
In this study, polyploidy level was determined by flow cytometry analysis. The effect of polyploidy by colchicine treatment was examined on the growth parameters, malondealdehyde (MDA), as well as activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) in response to different levels of salinity in Dunaliella salina. The results of algal growth indicated that 3 M NaCl was the optimal concentration of salt, since the highest enhancement in fresh and dry weight, chlorophyll and carotenoids, soluble sugar, glycerol, protein and starch content was observed in comparison to other concentrations. The amount of these metabolites declined in the concentrations under optimum salinity. The least and highest amounts of MDA were observed at 1 and 4 M NaCl respectively. Polyploidy in optimum concentration of salt, caused further increment of the above growth parameters. In relation to this, in most cases, treatment of 0.1% colchicine was most effective. The beneficial effects of polyploidy in non-optimal conditions were also found in some parameters such as biomass, chlorophyll, carotenoids, proteins and starch. Furthermore, the activity of antioxidant enzymes CAT, SOD and POD showed a positive significant correlation with salt stress and these were maximized at 4 M NaCl. Polyploidy (especially colchicine 0.1%) affected activity of these antioxidant enzymes in some concentrations of salt. Overall, our results suggest that the microalgae has significantly different responses to salt stress based on ploidy levels.
To validate the Geant4 Application for Tomographic Emission (GATE) Monte Carlo simulation code by calculating the proton beam range in the therapeutic energy range.
Materials and methods
In this study, the GATE code which is based on Geant4 was used for simulation. The proton beams in the therapeutic energy range (5–250 MeV) were simulated in a water medium, and then compared with the data from National Institute of Standards and Technology (NIST) in order to investigate the accuracy of different physics list available in the GATE code. In addition, the optimal value of SetCut was assessed.
In all energy ranges, the QBBC physics had a greater deviation in the ranges relative to the NIST data. With respect to the range calculation accuracy, the QGSP_BIC_EMY and QGSP_BERT_HP_EMY physics were in the range of statistical uncertainty; however, QGSP_BIC_EMY produced better results using the least squares. Based on an investigation into the range calculation precision and simulation efficiency, the optimal SetCut was set at 0·1 mm.
Based on an investigation into the range calculation precision and simulation yield, the QGSP_BIC_EMY physics and the optimal SetCut was recommended to be 0·1 mm.
A time-optimal problem for redundantly actuated robots moving on a specified path is a challenging problem. Although the problem is well explored and there are proposed solutions based on phase plane analysis, there are still several unresolved issues regarding calculation of solution curves. In this paper, we explore the characteristics of the maximum velocity curve and propose an efficient algorithm to establish the solution curve. Then we propose a straightforward method to calculate the maximum or minimum possible acceleration on the path based on the pattern of saturated actuators, which substantially reduces the computational cost. Two numerical examples are provided to illustrate the issues and the solutions.
The present study proposed and tested a revision of the self-guides outlined in the L2 motivational self system (Dörnyei, 2005, 2009). Covering the previous conceptualization and measurement issues, ideal L2 self and ought-to L2 self were bifurcated by own and other standpoints, and reoperationalized based on the fundamental tenets of self-discrepancy theory (Higgins, 1987) and regulatory focus theory (Higgins, 1997). Confirmatory factor analysis supported the fitness of the model and its superiority over three alternative models based on data collected from 257 international students learning English as a second language at a major North American university. Multiple regression results showed that ought L2 self/own was the strongest predictor of motivated behavior. Ideal L2 self/own, ought L2 self/other, and ideal L2 self/other were the next predictors in order of strength. Furthermore, ideal L2 self/own predicted an eager strategic inclination in L2 behavior, whereas ought L2 self/own predicted a vigilant strategic inclination, supporting the core principle of the regulatory focus theory that individuals with different regulatory orientations pursue their goals in qualitatively different manners.
BACKGROUND: Meningiomas are the most common primary benign brain tumors in adults. Given the extended life expectancy of most meningiomas, consideration of quality of life (QOL) is important when selecting the optimal management strategy. There is currently a dearth of meningioma-specific QOL tools in the literature. OBJECTIVE: In this systematic review, we analyze the prevailing themes and propose toward building a meningioma-specific QOL assessment tool. METHODS: A systematic search was conducted, and only original studies based on adult patients were considered. QOL tools used in the various studies were analyzed for identification of prevailing themes in the qualitative analysis. The quality of the studies was also assessed. RESULTS: Sixteen articles met all inclusion criteria. Fifteen different QOL assessment tools assessed social and physical functioning, psychological, and emotional well-being. Patient perceptions and support networks had a major impact on QOL scores. Surgery negatively affected social functioning in younger patients, while radiation therapy had a variable impact. Any intervention appeared to have a greater negative impact on physical functioning compared to observation. CONCLUSION: Younger patients with meningiomas appear to be more vulnerable within social and physical functioning domains. All of these findings must be interpreted with great caution due to great clinical heterogeneity, limited generalizability, and risk of bias. For meningioma patients, the ideal QOL questionnaire would present outcomes that can be easily measured, presented, and compared across studies. Existing scales can be the foundation upon which a comprehensive, standard, and simple meningioma-specific survey can be prospectively developed and validated.
Glioblastomas are the most frequent and aggressive primary brain tumor in adults and despite recent therapeutic advances, they are resistant to treatment. Increasing malignancy of gliomas correlates with an increase in cellularity and a poorly organized tumor vasculature, leading to insufficient blood supply, hypoxic areas, and ultimately to the formation of necrosis. Hypoxia induces direct or indirect changes in the biology of solid tumor and their microenvironment through the activation of HIF transcription factors, leading to increased aggressiveness and tumor resistance to therapy. Not much is known about the epigenetic alterations induced by hypoxia and how they could alter tumor biology. In the present study, we have utilized PIMO as a specific marker of hypoxia in glioblastoma patients, treated with PIMO preoperatively. We have estimated PIMO positivity in each tumor (5-45%) and determined that it positively correlates with the hypoxia marker CA IX (r=0.57). In addition, 10 surgical PIMO cases were dissociated, immune labeled using PIMO antibody, followed by DNA isolation and methylation profiling. Our analysis of differentially top 4000 differentially methylated probes suggests that PIMO-positive (hypoxic) cells are differentially methylated compared to the PIMO-negative cells and these changes are associated with genes involved in hypoxic cellular response. We will validate these findings in additional glioblastoma cases and assess the mechanism of these epigenetic alterations in vitro in glioma stem cell culture conditions and upon exposure of the cells hypoxic conditions.
Background: Venous thromboembolism (VTE) is a serious complication following severe TBI, however, anticoagulant prophylaxis is often withheld over concerns of intracranial hemorrhage (ICH) progression. We analyzed practice patterns and outcomes among severe TBI patients and systematically reviewed the literature for studies of anticoagulant prophylaxis after severe TBI. Methods: We prospectively screened consecutive patients with severe TBI (highest GCS≤8 from time of injury to ICU admission) admitted to a Level-I trauma centre between Oct 1,2015–Sept 30,2016 to assess type/timing of anticoagulant prophylaxis, rates of new VTE and ICH progression. Results: We identified 64 eligible patients with severe TBI. Most (53;83%) received anticoagulant prophylaxis, initiated ≥3d after TBI in 67%. Ten (16%) developed VTE during hospitalization; 8 started prophylaxis prior to VTE. No significant difference was observed in VTE incidence or ICH progression between patients with early prophylaxis (<3d) vs.later (≥3d). Our systematic review identified 5 studies of heterogeneous quality/design, with reported VTE incidence of 11-30% in patients without anticoagulant prophylaxis and 5-10% in patients with prophylaxis. Conclusions: VTE is a common complication after severe TBI despite routine use of anticoagulant prophylaxis. Anticoagulant prophylaxis is often started late (≥3d) post-injury. The relative benefits of early prophylaxis versus possible risks of ICH progression should be directly compared in an appropriately powered RCT.
Observational studies reported potential associations between different dietary patterns and the risk of metabolic syndrome (MetS); however, a consistent perspective has not been established to date. The current systematic review and meta-analysis aimed to evaluate the relationship between a posteriori dietary patterns and MetS by pooling available data.
MEDLINE and EMBASE databases were searched for relevant articles published up to July 2015 with no time restriction and with English language restriction. Two independent reviewers completed study selection and data extraction. Random-effects models (DerSimonian–Laird method) were used to pool effect sizes of eligible studies. The potential sources of heterogeneity were assessed using the I2 statistic.
Nineteen papers that identified dietary patterns using an a posteriori method were selected and included in the meta-analysis. The ‘Healthy/Prudent’ dietary pattern was inversely associated with risk of MetS (OR=0·89; 95 % CI 0·84, 0·94, P=0·002). In contrast, the ‘Unhealthy/Western’ dietary pattern had a significant positive association with risk of MetS (OR=1·16; 95 % CI 1·11, 1·22, P<0·001).
Our findings provide evidence that greater adherence to a healthy/prudent dietary pattern is associated with a lower risk of MetS, while an unhealthy/Western dietary pattern is associated with increased risk of MetS. These data suggest that a diet based on healthy food choices is also beneficial for prevention of MetS.
There is conflict regarding the relative abilities of Bos indicus and Bos taurus cattle to digest the feedstuffs. Part of this conflict may have arisen because a wide variety of diets have been fed at different range of intakes and only digestibility in whole tract measured. Generally no attempts have been made to partition rumen and post-rumen digestion or to assess the relative importance of rumen digestion and clearance between diets and between genotypes. Nitrogen (N) is frequently a major limiting nutrient for ruminants specially when they are given diets of mature herbage. On the other hand the extent to which cattle are able to recycle urea-N from blood to rumen for utilization in production of microbial protein could have an important influence on animal survival under condition of severe N limitation. The present experiment was designed to compare rumen microbial population and the end products of rumen fermentation between Sistani (Bos indicus) and Holstein (Bos taurus) breeds.
Background: Neurofibromatosis type 1 (NF1) is a common single-gene disorder. A multidisciplinary approach to the management of NF1 patients is necessitated by the heterogeneity of clinical manifestations. Although multidisciplinary paediatric clinics have been well established, there is a dearth of such resources for adults with NF1. Herein we report our one-year institutional experience with a multidisciplinary adult NF1 clinic. Methods: A multidisciplinary team was assembled, and an NF Patient Registry Initiative questionnaire was adapted to collect patient-reported data during clinics. Multiple databases were searched to identify publications pertaining to the experience of other multidisciplinary NF1 clinics focusing on adult patients. Data on patient epidemiology and clinical staff were compared to our data. Results: A total of 77 patients were scheduled, and 68 attended the clinic, of whom 66 completed the intake questionnaire. The demographic and clinical data from this Canadian population are mostly consistent with previous reports, with some exceptions. Clinical data related to immune system involvement such as asthma, airway/breathing-related difficulties or allergies were striking in our NF1 population. Six relevant published reports of other NF1 clinics were identified. Reports from these studies pertained to periods ranging from 10 to 38 months, and the number of adults assessed ranged from 19 to 177 patients. Conclusions: The structure of our clinic and the patient volume are comparable to those of other established centres found in the literature. Our data offer valuable cross-sectional prevalence statistics in the Canadian population. The patient-reported data concerning involvement of the immune system contribute to an emerging recognized medical concern within the NF1 population and warrant further clinical and basic investigation.
Objectives: To summarize the clinical characteristics and outcomes of pediatric sports-related concussion (SRC) patients who were evaluated and managed at a multidisciplinary pediatric concussion program and examine the healthcare resources and personnel required to meet the needs of this patient population. Methods: We conducted a retrospective review of all pediatric SRC patients referred to the Pan Am Concussion Program from September 1st, 2013 to May 25th, 2015. Initial assessments and diagnoses were carried out by a single neurosurgeon. Return-to-Play decision-making was carried out by the multidisciplinary team. Results: 604 patients, including 423 pediatric SRC patients were evaluated at the Pan Am Concussion Program during the study period. The mean age of study patients was 14.30 years (SD: 2.32, range 7-19 years); 252 (59.57%) were males. Hockey (182; 43.03%) and soccer (60; 14.18%) were the most commonly played sports at the time of injury. Overall, 294 (69.50%) of SRC patients met the clinical criteria for concussion recovery, while 75 (17.73%) were lost to follow-up, and 53 (12.53%) remained in active treatment at the end of the study period. The median duration of symptoms among the 261 acute SRC patients with complete follow-up was 23 days (IQR: 15, 36). Overall, 25.30% of pediatric SRC patients underwent at least one diagnostic imaging test and 32.62% received referral to another member of our multidisciplinary clinical team. Conclusion: Comprehensive care of pediatric SRC patients requires access to appropriate diagnostic resources and the multidisciplinary collaboration of experts with national and provincially-recognized training in TBI.
Background: Despite the critical role played by neurosurgeons in performing radiosurgery, neurosurgery residents in Canada have limited exposure to radiosurgery during their training. A survey of neurosurgery residents and faculty along with radiation oncology faculty was conducted to analyze perspectives regarding incorporating formal radiosurgery training into the neurosurgery residency curriculum Methods: An online survey platform was employed. Descriptive statistics were used to summarize center and respondent characteristics. Categorical variables were compared using odds ratios and corresponding 95% confidence intervals. The chi-squared test was utilized to assess statistical significance. A value of p<0.05 was considered significant Results: The response rate was 31% (119/381); 87% (102/119) of respondents were from the neurosurgical specialty and 13% (17/119) from radiation oncology. Some 46% of residents (18/40) were “very uncomfortable” with radiosurgery techniques, and 57% of faculty (42/73) believed that dedicated radiosurgery training would be beneficial though impractical. No respondents felt that “no training” would be beneficial. A total of 46% of residents (19/41) felt that this training would be beneficial and that time should be taken away from other rotations, if needed, while 58% of faculty (42/73) and 75% (28/41) of residents believed that either 1 or 1-3 months of time dedicated to training in radiosurgery would suffice Conclusions: Canadian neurosurgeons are actively involved in radiosurgery. Despite residents anticipating a greater role for radiosurgery in their future, they are uncomfortable with the practice. With the indications for radiosurgery expanding, this training gap can have serious adverse consequences for patients. Considerations regarding the incorporation and optimal duration of dedicated radiosurgery training into the Canadian neurosurgery residency curriculum are necessary.
The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently down-regulated in a variety of malignancies. We characterized the role of Dicer in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells to form tumors in a mouse model of GB. DICER silencing in glioma stem-like cells (GSCs) reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER affects the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB.