Dosimetric Performance and Planning/Delivery Efficiency of a Dual-Layer Stacked and Staggered MLC on Treating Multiple Small Targets: A Planning Study Based on Single-Isocenter Multi-Target Stereotactic Radiosurgery (SRS) to Brain Metastases.

Purpose: To evaluate the dosimetric performance and planning/delivery efficiency of a dual-layer MLC system for treating multiple brain metastases with a single isocenter. Materials and Methods: 10 patients each with 6-10 targets with volumes from 0.11 to 8.57 cc, and prescription doses from 15 to 24 Gy, were retrospectively studied. Halcyon has only coplanar delivery mode. Halcyon V1 MLC modulates only with the lower layer at 1 cm resolution, whereas V2 MLC modulates with both layers at an effective resolution of 0.5 cm. For each patient five plans were compared varying MLC and beam arrangements: the clinical plan using multi-aperture dynamic conformal arc (DCA) and non-coplanar arcs, Halcyon-V1 using coplanar-VMAT, Halcyon-V2 using coplanar-VMAT, HDMLC-0.25 cm using coplanar-VMAT, and HDMLC-0.25 cm using non-coplanar-VMAT. All same-case plans were generated following the same planning protocol and normalization. Conformity index (CI), gradient index (GI), V12Gy, V6Gy, V3Gy, and brain mean dose were compared. Results: All VMAT plans met clinical constraints for critical structures. For targets with diameter \u3c 1 cm, Halcyon plans showed inferior CI among all techniques. For targets with diameter \u3e1 cm, Halcyon VMAT plans had CI similar to non-coplanar VMAT plans, and better than non-coplanar clinical DCA plans. For GI, Halcyon MLC plans performed similarly to coplanar HDMLC plans and inferiorly compared to non-coplanar HDMLC plans. All coplanar VMAT plans (Halcyon MLC and HDMLC) and clinical DCA plans had similar V12Gy, but were inferior compared to non-coplanar VMAT plans. Halcyon plans had slightly reduced V3Gy and mean brain dose compared to HDMLC plans. The difference between Halcyon V1 and V2 is only significant in CI of tumors less than 1cm in diameter. Halcyon plans required longer optimization than Truebeam VMAT plans, but had similar delivery efficiency. Conclusion: For targets with diameter \u3e1 cm, Halcyon\u27s dual-layer stacked and staggered MLC is capable of producing similar dose conformity compared to HDMLC while reducing low dose spill to normal brain tissue. GI and V12Gy of Halcyon MLC plans were, in general, inferior to non-coplanar DCA or VMAT plans using HDMLC, likely due to coplanar geometry and wider MLC leaves. HDMLC maintained its advantage in CI for smaller targets with diameter \u3c1 cm. © 2019 Li, Irmen, Liu, Shi, Alonso-Basanta, Zou, Teo, Metz and Dong

Adaptive Evolution of Signaling Partners

Proteins that interact coevolve their structures. When mutation disrupts the interaction, compensation by the partner occurs to restore interaction otherwise counterselection occurs. We show in this study how a destabilizing mutation in one protein is compensated by a stabilizing mutation in its protein partner and their coevolving path. The pathway in this case and likely a general principle of coevolution is that the compensatory change must tolerate both the original and derived structures with equivalence in function and activity. Evolution of the structure of signaling elements in a network is constrained by specific protein pair interactions, by requisite conformational changes, and by catalytic activity. The heterotrimeric G protein-coupled signaling is a paragon of this protein interaction/function complexity and our deep understanding of this pathway in diverse organisms lends itself to evolutionary study. Regulators of G protein Signaling (RGS) proteins accelerate the intrinsic GTP hydrolysis rate of the Gα subunit of the heterotrimeric G protein complex. An important RGS-contact site is a hydroxyl-bearing residue on the switch I region of Gα subunits in animals and most plants, such as Arabidopsis. The exception is the grasses (e.g., rice, maize, sugarcane, millets); these plants have Gα subunits that replaced the critical hydroxyl-bearing threonine with a destabilizing asparagine shown to disrupt interaction between Arabidopsis RGS protein (AtRGS1) and the grass Gα subunit. With one known exception (Setaria italica), grasses do not encode RGS genes. One parsimonious deduction is that the RGS gene was lost in the ancestor to the grasses and then recently acquired horizontally in the lineage S. italica from a nongrass monocot. Like all investigated grasses, S. italica has the Gα subunit with the destabilizing asparagine residue in the protein interface but, unlike other known grass genomes, still encodes an expressed RGS gene, SiRGS1. SiRGS1 accelerates GTP hydrolysis at similar concentration of both Gα subunits containing either the stabilizing (AtGPA1) or destabilizing (RGA1) interface residue. SiRGS1 does not use the hydroxyl-bearing residue on Gα to promote GAP activity and has a larger Gα-interface pocket fitting to the destabilizing Gα. These findings indicate that SiRGS1 adapted to a deleterious mutation on Gα using existing polymorphism in the RGS protein population

Spine SBRT With Halcyon™: Plan Quality, Modulation Complexity, Delivery Accuracy, and Speed

Purpose: Spine SBRT requires treatment plans with steep dose gradients and tight limits to the cord maximal dose. A new dual-layer staggered 1-cm MLC in Halcyon™ treatment platform has improved leakage, speed, and DLG compared to 120-Millennium (0.5-cm) and High-Definition (0.25-cm) MLCs in the TrueBeam platform. Halcyon™ 2.0 with SX2 MLC modulates fluence with the upper and lower MLCs, while in Halcyon™ 1.0 with SX1 only the lower MLC modulates the fluence and the upper MLC functions as a back-up jaw. We investigated the effects of four MLC designs on plan quality for spine SBRT treatments.Methods: 15 patients previously treated at our institution were re-planned according to the NRG-BR-002 guidelines with a prescription of 3,000 cGy in 3 fractions, 6xFFF, 800 MU/min, and 3-arc VMAT technique. Planning objectives were adjusted manually by an experienced planner to generate optimal plans and kept the same for different MLCs within the same platform.Results: All treatment plans were able to achieve adequate target coverage while meeting NRG-BR002 dosimetric constraints. Planning parameters were evaluated including: conformity index, homogeneity index, gradient measure, and global point dose maximum. Delivery accuracy, modulation complexity, and delivery time were also analyzed for all MLCs.Conclusion: The Halcyon™ dual-layer MLC can generate comparable and clinically equivalent spine SBRT plans to TrueBeam plans with less rapid dose fall-off and lower conformity. MLC width leaf can impact maximum dose to organs at risk and plan quality, but does not cause limitations in achieving acceptable plans for spine SBRT treatments

Multi-Institutional Dosimetric Evaluation of Modern Day Stereotactic Radiosurgery (SRS) Treatment Options for Multiple Brain Metastases.

Purpose/Objectives: There are several popular treatment options currently available for stereotactic radiosurgery (SRS) of multiple brain metastases: 60Co sources and cone collimators around a spherical geometry (GammaKnife), multi-aperture dynamic conformal arcs on a linac (BrainLab Elements™ v1.5), and volumetric arc therapy on a linac (VMAT) calculated with either the conventional optimizer or with the Varian HyperArc™ solution. This study aimed to dosimetrically compare and evaluate the differences among these treatment options in terms of dose conformity to the tumor as well as dose sparing to the surrounding normal tissues. Methods and Materials: Sixteen patients and a total of 112 metastases were analyzed. Five plans were generated per patient: GammaKnife, Elements, HyperArc-VMAT, and two Manual-VMAT plans to evaluate different treatment planning styles. Manual-VMAT plans were generated by different institutions according to their own clinical planning standards. The following dosimetric parameters were extracted: RTOG and Paddick conformity indices, gradient index, total volume of brain receiving 12Gy, 6Gy, and 3Gy, and maximum doses to surrounding organs. The Wilcoxon signed rank test was applied to evaluate statistically significant differences (p \u3c 0.05). Results: For targets ≤ 1 cm, GammaKnife, HyperArc-VMAT and both Manual-VMAT plans achieved comparable conformity indices, all superior to Elements. However, GammaKnife resulted in the lowest gradient indices at these target sizes. HyperArc-VMAT performed similarly to GammaKnife for V12Gy parameters. For targets ≥ 1 cm, HyperArc-VMAT and Manual-VMAT plans resulted in superior conformity vs. GammaKnife and Elements. All SRS plans achieved clinically acceptable organs-at-risk dose constraints. Beam-on times were significantly longer for GammaKnife. Manual-VMATA and Elements resulted in shorter delivery times relative to Manual-VMATB and HyperArc-VMAT. Conclusion: The study revealed that Manual-VMAT and HyperArc-VMAT are capable of achieving similar low dose brain spillage and conformity as GammaKnife, while significantly minimizing beam-on time. For targets smaller than 1 cm in diameter, GammaKnife still resulted in superior gradient indices. The quality of the two sets of Manual-VMAT plans varied greatly based on planner and optimization constraint settings, whereas HyperArc-VMAT performed dosimetrically superior to the two Manual-VMAT plans

Acceptance of and Preference for COVID-19 Vaccination in India, the United Kingdom, Germany, Italy, and Spain: An International Cross-Sectional Study

Objective: India and Europe have large populations, a large number of Coronavirus disease 2019 (COVID-19) cases, and different healthcare systems. This study aims to investigate the differences between the hesitancy toward and preference for COVID-19 vaccines in India and four European countries, namely, the United Kingdom (UK), Germany, Italy, and Spain. Methodology: We conducted a cross-national survey for distribution in India, the UK, Germany, Italy, and Spain. More specifically, a discrete choice experiment (DCE) was conducted to evaluate vaccine preferences, and Likert scales were used to probe the underlying factors that contribute to vaccination acceptance. Propensity score matching (PSM) was performed to directly compare India and European countries. Results: A total of 2565 respondents (835 from India and 1730 from the specified countries in Europe) participated in the survey. After PSM, more than 82.5% of respondents from India positively accepted the COVID-19 vaccination, whereas 79.9% of respondents from Europe had a positive attitude; however, the proportion in Europe changed to 81.6% in cases in which the vaccine was recommended by friends, family, or employers. The DCE found that the COVID-19 vaccine efficacy was the most important factor for respondents in India and the four European nations (41.8% in India and 47.77% in Europe), followed by the vaccine cost (28.06% in India and 25.88% in Europe). Conclusion: Although most respondents in both regions showed high acceptance of COVID-19 vaccines, either due to general acceptance or acceptance as a result of social cues, the vaccination coverage rate shows apparent distinctions. Due to the differences in COVID-19 situations, public health systems, cultural backgrounds, and vaccine availability, the strategies for COVID-19 vaccine promotion should be nation-dependent