nus-tool: A unified program for generating and analyzing sample schedules for nonuniformly sampled NMR experiments.

Increases in digital resolution achieved by high-field NMR require increases in spectral width. Additionally, the ability to resolve two overlapping peaks requires a sufficiently long acquisition time. These constraints combine, so that achieving high resolution spectra on high-field magnets requires long experiment times when employing uniform sampling and Fourier Transform processing. These limitations may be addressed by using nonuniform sampling (NUS), but the complexity of the parameter space across the variety of available NUS schemes greatly hinders the establishment of optimal approaches and best practices. We address these challenges with nus-tool, which is a software package for generating and analyzing NUS schedules. The nus-tool software internally implements random sampling and exponentially biased sampling. Through pre-configured plug-ins, it also provides access to quantile sampling and Poisson gap sampling. The software computes the relative sensitivity, mean evolution time, point spread function, and peak-to-sidelobe ratio; all of which can be determined for a candidate sample schedule prior to running an experiment to verify expected sensitivity, resolution, and artifact suppression. The nus-tool package is freely available on the NMRbox platform through an interactive GUI and via the command line, which is especially useful for scripted workflows that investigate the effectiveness of various NUS schemes.

Levels and Characteristics of mRNAs in Spores of Firmicute Species.

Spores of firmicute species contain 100s of mRNAs, whose major function in Bacillus subtilis is to provide ribonucleotides for new RNA synthesis when spores germinate. To determine if this is a general phenomenon, RNA was isolated from spores of multiple firmicute species and relative mRNA levels determined by transcriptome sequencing (RNA-seq). Determination of RNA levels in single spores allowed calculation of RNA nucleotides/spore, and assuming mRNA is 3% of spore RNA indicated that only ∼6% of spore mRNAs were present at >1/spore. Bacillus subtilis, Bacillus atrophaeus, and Clostridioides difficile spores had 49, 42, and 51 mRNAs at >1/spore, and numbers of mRNAs at ≥1/spore were ∼10 to 50% higher in Geobacillus stearothermophilus and Bacillus thuringiensis Al Hakam spores and ∼4-fold higher in Bacillus megaterium spores. In all species, some to many abundant spore mRNAs (i) were transcribed by RNA polymerase with forespore-specific σ factors, (ii) encoded proteins that were homologs of those encoded by abundant B. subtilis spore mRNAs and are proteins in dormant spores, and (iii) were likely transcribed in the mother cell compartment of the sporulating cell. Analysis of the coverage of RNA-seq reads on mRNAs from all species suggested that abundant spore mRNAs were fragmented, as was confirmed by reverse transcriptase quantitative PCR (RT-qPCR) analysis of abundant B. subtilis and C. difficile spore mRNAs. These data add to evidence indicating that the function of at least the great majority of mRNAs in all firmicute spores is to be degraded to generate ribonucleotides for new RNA synthesis when spores germinate. IMPORTANCE Only ∼6% of mRNAs in spores of six firmicute species are at ≥1 molecule/spore, many abundant spore mRNAs encode proteins similar to B. subtilis spore proteins, and some abundant B. subtilis and C. difficile spore mRNAs were fragmented. Most of the abundant B. subtilis and other Bacillales spore mRNAs are transcribed under the control of the forespore-specific RNA polymerase σ factors, F or G, and these results may stimulate transcription analyses in developing spores of species other than B. subtilis. These findings, plus the absence of key nucleotide biosynthetic enzymes in spores, suggest that firmicute spores' abundant mRNAs are not translated when spores germinate but instead are degraded to generate ribonucleotides for new RNA synthesis by the germinated spore.

Merging NMR Data and Computation Facilitates Data-Centered Research.

The Biological Magnetic Resonance Data Bank (BMRB) has served the NMR structural biology community for 40 years, and has been instrumental in the development of many widely-used tools. It fosters the reuse of data resources in structural biology by embodying the FAIR data principles (Findable, Accessible, Inter-operable, and Re-usable). NMRbox is less than a decade old, but complements BMRB by providing NMR software and high-performance computing resources, facilitating the reuse of software resources. BMRB and NMRbox both facilitate reproducible research. NMRbox also fosters the development and deployment of complex meta-software. Combining BMRB and NMRbox helps speed and simplify workflows that utilize BMRB, and enables facile federation of BMRB with other data repositories. Utilization of BMRB and NMRbox in tandem will enable additional advances, such as machine learning, that are poised to become increasingly powerful.

NUScon: a community-driven platform for quantitative evaluation of nonuniform sampling in NMR.

Although the concepts of nonuniform sampling (NUS​​​​​​​) and non-Fourier spectral reconstruction in multidimensional NMR began to emerge 4 decades ago , it is only relatively recently that NUS has become more commonplace. Advantages of NUS include the ability to tailor experiments to reduce data collection time and to improve spectral quality, whether through detection of closely spaced peaks (i.e., "resolution") or peaks of weak intensity (i.e., "sensitivity"). Wider adoption of these methods is the result of improvements in computational performance, a growing abundance and flexibility of software, support from NMR spectrometer vendors, and the increased data sampling demands imposed by higher magnetic fields. However, the identification of best practices still remains a significant and unmet challenge. Unlike the discrete Fourier transform, non-Fourier methods used to reconstruct spectra from NUS data are nonlinear, depend on the complexity and nature of the signals, and lack quantitative or formal theory describing their performance. Seemingly subtle algorithmic differences may lead to significant variabilities in spectral qualities and artifacts. A community-based critical assessment of NUS challenge problems has been initiated, called the "Nonuniform Sampling Contest" (NUScon), with the objective of determining best practices for processing and analyzing NUS experiments. We address this objective by constructing challenges from NMR experiments that we inject with synthetic signals, and we process these challenges using workflows submitted by the community. In the initial rounds of NUScon our aim is to establish objective criteria for evaluating the quality of spectral reconstructions. We present here a software package for performing the quantitative analyses, and we present the results from the first two rounds of NUScon. We discuss the challenges that remain and present a roadmap for continued community-driven development with the ultimate aim of providing best practices in this rapidly evolving field. The NUScon software package and all data from evaluating the challenge problems are hosted on the NMRbox platform.

Analysis of 5'-NAD capping of mRNAs in dormant spores of Bacillus subtilis.

Spores of Gram-positive bacteria contain 10s-1000s of different mRNAs. However, Bacillus subtilis spores contain only ∼ 50 mRNAs at > 1 molecule/spore, almost all transcribed only in the developing spore and encoding spore proteins. However, some spore mRNAs could be stabilized to ensure they are intact in dormant spores, perhaps to direct synthesis of proteins essential for spores' conversion to a growing cell in germinated spore outgrowth. Recent work shows that some growing B. subtilis cell mRNAs contain a 5'-NAD cap. Since this cap may stabilize mRNA in vivo, its presence on spore mRNAs would suggest that maintaining some intact spore mRNAs is important, perhaps because they have a translational role in outgrowth. However, significant levels of only a few abundant spore mRNAs had a 5'-NAD cap, and these were not the most stable spore mRNAs and had likely been fragmented. Even higher levels of 5'-NAD-capping were found on a few low abundance spore mRNAs, but these mRNAs were present in only small percentages of spores, and had again been fragmented. The new data are thus consistent with spore mRNAs serving only as a reservoir of ribonucleotides in outgrowth.

Killing of bacterial spores by dodecylamine and its effects on spore inner membrane properties.

AIMS: The objective of this study was to determine the effects of Ca-dipicolinic acid (CaDPA), cortex-lytic enzymes (CLEs), the inner membrane (IM) CaDPA channel and coat on spore killing by dodecylamine. METHODS AND RESULTS: Bacillus subtilis spores, wild-type, CaDPA-less due to the absence of DPA synthase or the IM CaDPA channel, or lacking CLEs, were dodecylamine-treated and spore viability and vital staining were all determined. Dodecylamine killed intact wild-type and CaDPA-less B. subtilis spores similarly, and also killed intact Clostridiodes difficile spores ± CaDPA, with up to 99% killing with 1 mol l-1 dodecylamine in 4 h at 45°C with spores at ~108  ml-1 . Dodecylamine killing of decoated wild type and CLE-less B. subtilis spores was similar, but ~twofold faster than for intact spores, and much faster for decoated CaDPA-less spores, with ≥99% killing in 5 min. Propidium iodide stained intact spores ± CaDPA minimally, decoated CaDPA-replete spores or dodecylamine-killed CLE-less spores peripherally, and cores of decoated CaDPA-less spores and dodecylamine-killed intact spores with CLEs. The IM of some decoated CaDPA-less spores was greatly reorganized. CONCLUSIONS: Dodecylamine spore killing does not require CaDPA channels, CaDPA or CLEs. The lack of CaDPA in decoated spores allowed strong PI staining of the spore core, indicating loss of these spores IM permeability barrier. SIGNIFICANCE AND IMPACT OF THE STUDY: This work gives new information on killing bacterial spores by dodecylamine, and how spore IM's relative impermeability is maintained.

DNA Damage Kills Bacterial Spores and Cells Exposed to 222-Nanometer UV Radiation.

This study examined the microbicidal activity of 222-nm UV radiation (UV222), which is potentially a safer alternative to the 254-nm UV radiation (UV254) that is often used for surface decontamination. Spores and/or growing and stationary-phase cells of Bacillus cereus, Bacillus subtilis, Bacillus thuringiensis, Staphylococcus aureus, and Clostridioides difficile and a herpesvirus were all killed or inactivated by UV222 and at lower fluences than with UV254B. subtilis spores and cells lacking the major DNA repair protein RecA were more sensitive to UV222, as were spores lacking their DNA-protective proteins, the α/ß-type small, acid-soluble spore proteins. The spore cores' large amount of Ca2+-dipicolinic acid (∼25% of the core dry weight) also protected B. subtilis and C. difficile spores against UV222, while spores' proteinaceous coat may have given some slight protection against UV222 Survivors among B. subtilis spores treated with UV222 acquired a large number of mutations, and this radiation generated known mutagenic photoproducts in spore and cell DNA, primarily cyclobutane-type pyrimidine dimers in growing cells and an α-thyminyl-thymine adduct termed the spore photoproduct (SP) in spores. Notably, the loss of a key SP repair protein markedly decreased spore UV222 resistance. UV222-treated B. subtilis spores germinated relatively normally, and the generation of colonies from these germinated spores was not salt sensitive. The latter two findings suggest that UV222 does not kill spores by general protein damage, and thus, the new results are consistent with the notion that DNA damage is responsible for the killing of spores and cells by UV222IMPORTANCE Spores of a variety of bacteria are resistant to common decontamination agents, and many of them are major causes of food spoilage and some serious human diseases, including anthrax caused by spores of Bacillus anthracis Consequently, there is an ongoing need for efficient methods for spore eradication, in particular methods that have minimal deleterious effects on people or the environment. UV radiation at 254 nm (UV254) is sporicidal and commonly used for surface decontamination but can cause deleterious effects in humans. Recent work, however, suggests that 222-nm UV (UV222) may be less harmful to people than UV254 yet may still kill bacteria and at lower fluences than UV254 The present work has identified the damage by UV222 that leads to the killing of growing cells and spores of some bacteria, many of which are human pathogens, and UV222 also inactivates a herpesvirus.

Developing nonuniform sampling strategies to improve sensitivity and resolution in 1,1-ADEQUATE experiments.

Nonuniform sampling (NUS) strategies are developed for acquiring highly resolved 1,1-ADEQUATE spectra, in both conventional and homodecoupled (HD) variants with improved sensitivity. Specifically, the quantile-directed and Poisson gap methods were critically compared for distributing the samples nonuniformly, and the quantile schedules were further optimized for weighting. Both maximum entropy and iterative soft thresholding spectral estimation algorithms were evaluated. All NUS approaches were robust when the degree of data reduction is moderate, on the order of a 50% reduction of sampling points. Further sampling reduction by NUS is facilitated by using weighted schedules designed by the quantile method, which also suppresses sampling noise well. Seed independence and the ability to specify the sample weighting in quantile scheduling are important in optimizing NUS for 1,1-ADEQUATE data acquisition. Using NUS yields an improvement in sensitivity, while also making longer evolution times accessible that would be difficult or impractical to attain by uniform sampling. Theoretical predictions for the sensitivity enhancements in these experiments are in the range of 5-20%; NUS is shown to disambiguate weak signals, reveal some n JCC correlations obscured by noise, and improve signal strength relative to uniform sampling in the same experimental time. This work presents sample schedule development for applying NUS to challenging experiments. The schedules developed here are made available for general use and should facilitate the broader utilization of ADEQUATE experiments (including 1,1-, 1,n-, and HD- variants) for challenging structure elucidation problems.

The influence of the probability density function on spectral quality in nonuniformly sampled multidimensional NMR.

The goal of nonuniform sampling (NUS) is to select a subset of free induction decays (FIDs) from the conventional, uniform grid in a manner that sufficiently samples short evolution times needed for improved sensitivity and long evolution times needed for enhanced resolution. In addition to specifying the number of FIDs to be collected from a uniform grid, NUS schemes also specify the distribution of the selected FIDs, which directly impacts sampling-induced artifacts. Sampling schemes typically address these heuristic guidelines by utilizing a probability density function (PDF) to bias the distribution of sampled evolution times. Given this common approach, schemes differentiate themselves by how the evolution times are distributed within the envelope of the PDF. Here, we employ maximum entropy reconstruction and utilize in situ receiver operating characteristic (IROC) to conduct a critical comparison of the sensitivity and resolution that can be achieved by three types of biased sampling schemes: exponential (PDF is exponentially decaying), Poisson-gap (PDF derived from a sine function), and quantile-directed (PDF defined by simple polynomial decay). This methodology reveals practical insights and trends regarding how the sampling schemes and bias can provide the highest sensitivity and resolution for two nonuniformly sampled dimensions in a three-dimensional biomolecular NMR experiment. The IROC analysis circumvents the limitations of common metrics when used with nonlinear spectral estimation (a characteristic of all methods used with NUS) by quantifying the spectral quality via synthetic signals that are added to the empirical dataset. Recovery of these synthetic signals provides a proxy for the quality of the empirical portion of the spectrum. The central finding is that differences in spectral quality are primarily driven by the strength of bias in the PDF. In addition, a sampling coverage threshold is observed that appears to be connected to the dependence of each NUS method on its random seed. The differences between sampling schemes and biases are most relevant below 20% coverage where seed-dependence is high, whereas at higher coverages, the performance metrics for all of the sampling schemes begin to converge and approach a seed-independent regime. The results presented here show that aggressive sampling at low coverage can produce high-quality spectra by employing a sampling scheme that adheres to a decaying PDF with a bias to a broad range of short evolution times and includes relatively few FIDs at long evolution times.

An open-source platform for interactive collision prevention in photon and particle beam therapy treatment planning.

We present an open-source platform to aid medical dosimetrists in preventing collisions between gantry head and patient or couch during photon or particle beam therapy treatment planning. This generic framework uses the native scripting interface of the particular planning software to import STL files of the treatment machine elements. These are visualized in 3D together with the contoured or scanned patient surface. A graphical dialog with sliders allows the interactive rotation of the gantry and couch, with real-time feedback. To prevent a future replanning, treatment planners can assess in advance and exclude beam angles resulting in a potential risk of collision. The software platform is publicly available on GitHub and has been validated for RayStation with actual patient plans. Furthermore, the incorporation of the complete patient geometry was tested with a 3D surface scan of a full-body phantom performed with a handheld smartphone. With this study, we aim at minimizing the risk of replanning due to collisions and thus of treatment delays and unscheduled consumption of manpower. The clinical workflow can be streamlined at no cost already at the treatment planning stage. By ensuring a real-time verification of the plan feasibility, the script might boost the use of optimal couch angles that a planner might shy away from otherwise.

Impact of setup and range uncertainties on TCP and NTCP following VMAT or IMPT of oropharyngeal cancer patients.

Setup and range uncertainties compromise radiotherapy plan robustness. We introduce a method to evaluate the clinical effect of these uncertainties on the population using tumor control probability (TCP) and normal tissue complication probability (NTCP) models. Eighteen oropharyngeal cancer patients treated with curative intent were retrospectively included. Both photon (VMAT) and proton (IMPT) plans were created using a planning target volume as planning objective. Plans were recalculated for uncertainty scenarios: two for range over/undershoot (IMPT) or CT-density scaling (VMAT), six for shifts. An average shift scenario ([Formula: see text]) was calculated to assess random errors. Dose differences between nominal and scenarios were translated to TCP (2 models) and NTCP (15 models). A weighted average (W_Avg) of the TCP\NTCP based on Gaussian distribution over the variance scenarios was calculated to assess the clinical effect of systematic errors on the population. TCP/NTCP uncertainties were larger in IMPT compared to VMAT. Although individual perturbations showed risks of plan deterioration, the [Formula: see text] scenario did not show a substantial decrease in any of the TCP endpoints suggesting evaluated plans in this cohort were robust for random errors. Evaluation of the W_Avg scenario to assess systematic errors showed in VMAT no substantial decrease in TCP endpoints and in IMPT a limited decrease. In IMPT, the W_Avg scenario had a mean TCP loss of 0%-2% depending on plan type and primary or nodal control. The W_Avg for NTCP endpoints was around 0%, except for mandible necrosis in IMPT (W_Avg: 3%). The estimated population impact of setup and range uncertainties on TCP/NTCP following VMAT or IMPT of oropharyngeal cancer patients was small for both treatment modalities. The use of TCP/NTCP models allows for clinical interpretation of the population effect and could be considered for incorporation in robust evaluation methods. Highlights: - TCP/NTCP models allow for a clinical evaluation of uncertainty scenarios. - For this cohort, in silico-PTV based IMPT plans and VMAT plans were robust for random setup errors. - Effect of systematic errors on the population was limited: mean TCP loss was 0%-2%.

Nonuniform sampling by quantiles.

A flexible strategy for choosing samples nonuniformly from a Nyquist grid using the concept of statistical quantiles is presented for broad classes of NMR experimentation. Quantile-directed scheduling is intuitive and flexible for any weighting function, promotes reproducibility and seed independence, and is generalizable to multiple dimensions. In brief, weighting functions are divided into regions of equal probability, which define the samples to be acquired. Quantile scheduling therefore achieves close adherence to a probability distribution function, thereby minimizing gaps for any given degree of subsampling of the Nyquist grid. A characteristic of quantile scheduling is that one-dimensional, weighted NUS schedules are deterministic, however higher dimensional schedules are similar within a user-specified jittering parameter. To develop unweighted sampling, we investigated the minimum jitter needed to disrupt subharmonic tracts, and show that this criterion can be met in many cases by jittering within 25-50% of the subharmonic gap. For nD-NUS, three supplemental components to choosing samples by quantiles are proposed in this work: (i) forcing the corner samples to ensure sampling to specified maximum values in indirect evolution times, (ii) providing an option to triangular backfill sampling schedules to promote dense/uniform tracts at the beginning of signal evolution periods, and (iii) providing an option to force the edges of nD-NUS schedules to be identical to the 1D quantiles. Quantile-directed scheduling meets the diverse needs of current NUS experimentation, but can also be used for future NUS implementations such as off-grid NUS and more. A computer program implementing these principles (a.k.a. QSched) in 1D- and 2D-NUS is available under the general public license.

Traumatic wound microbiome workshop.

On May 9-10, 2011, the Walter Reed Army Institute of Research, as the Army Center of Excellence for Infectious Disease, assembled over a dozen leaders in areas related to research into the communities of microorganisms which colonize and infect traumatic wounds. The objectives of the workshop were to obtain guidance for government researchers, to spur research community involvement in the field of traumatic wound research informed by a microbiome perspective, and to spark collaborative efforts serving the Wounded Warriors and similarly wounded civilians. During the discussions, it was made clear that the complexity of these infections will only be met by developing a new art of clinical practice that engages the numerous microbes and their ecology. It requires the support of dedicated laboratories and technologists who advance research methods such as community sequencing, as well as the kinds of data analysis expertise and facilities. These strategies already appear to be bearing fruit in the clinical management of chronic wounds. There are now funding announcements and programs supporting this area of research open to extramural collaborators.

Malignant peripheral nerve sheath tumour of the urinary bladder in a cat.

A 14-year-old domestic shorthair cat presented with a 5-month history of urinary incontinence and inappro-priate elimination. Ultrasonography revealed a well-marginated, vascular mass of mixed echogenicity ex-tending from the dorsal wall of the urinary bladder into the lumen. Partial cystectomy was performed for re-moval of the urinary bladder mass; histopathological evaluation revealed a spindle cell neoplasm with a prominent palisading pattern. Histomorphologic features and immunohistochemical demonstration of vimentin, glial fibrillary acidic protein and S-100 protein, combined with negativity for smooth muscle actin and desmin were consistent with malignant peripheral nerve sheath tumour. This case report describes a novel location of malignant peripheral nerve sheath tumour; to the authors' knowledge, the bladder has not been described as a site of origin in the cat or any other domestic species.

Molecular analysis of imipenem-resistant Acinetobacter baumannii isolated from US service members wounded in Iraq, 2003-2008.

Global dissemination of imipenem-resistant (IR) clones of Acinetobacter baumannii - A. calcoaceticus complex (ABC) have been frequently reported but the molecular epidemiological features of IR-ABC in military treatment facilities (MTFs) have not been described. We characterized 46 IR-ABC strains from a dataset of 298 ABC isolates collected from US service members hospitalized in different US MTFs domestically and overseas during 2003-2008. All IR strains carried the bla(OXA-51) gene and 40 also carried bla(OXA-23) on plasmids and/or chromosome; one carried bla(OXA-58) and four contained ISAbal located upstream of bla(OXA-51). Strains tended to cluster by pulsed-field gel electrophoresis profiles in time and location. Strains from two major clusters were identified as international clone I by multilocus sequence typing.

SU-E-T-615: Quantifying the Benefit of Adaptive Fractionation.

PURPOSE: To quantify the benefit of adaptive fractionation, through both theoretical test cases and patient data. METHODS: We consider the effect of delivering a different fraction size based on the changes observed in the patient anatomy. Given that a fixed prescription dose must be delivered to the tumor over the course of the treatment, we find that adaptively varying the fraction size results in a lower cumulative dose to a primary organ-at-risk (OAR). We construct a one dimensional theoretical example by randomly varying the distance between the tumor and OAR, and simulate the benefit of adaptive fractionation in such a setting. Next, we test our methodology using contoured daily CT images from 5 prostate patients. RESULTS: For the theoretical example, we found about a 10% decrease in dose to the OAR when using a uniformly distributed motion model and a 20% daily fraction size deviation. In general, the amount of decrease in dose to the OAR varied significantly (5-85%) for these theoretical test cases depending on the amount of motion in the anatomy, the number of fractions, and the range of fraction sizes allowed. Preliminary results from the prostate patients indicate an average reduction in dose to the rectum of 1.4%, 3.5%, and 7.0% when using 20%, 50%, and 100% daily fraction size deviations, respectively. CONCLUSIONS: Qualitatively, the theoretical example indicates that adaptive fractionation is beneficial for disease sites in which there is significant inter-fractional motion. We also expect greater benefit when using many fractions and allowing for large daily fraction size deviations. For the prostate disease site in particular, we find that adaptive fractionation is beneficial only when allowing large daily fraction size deviations. Further research quantifying the gain for disease sites that exhibit significant inter-fractional motion, such as rectal and cervical cancers, would be useful. Partially supported by Siemens.

SU-E-T-630: MCO-Informed VMAT Planning for Prostate Cancer.

PURPOSE: To develop a VMAT optimization procedure using information from Multi-Criteria Optimization of IMRT plans and to perform a treatment planning comparison for prostate cancer patients. METHODS: IMRT plans using Multi-Criteria Optimization (MCO), 6 MV photons, 20 and 7 treatment fields were generated for 10 prostate patients in the RayStation treatment planning system (Version 2.2.13, Raysearch Laboratories, Stockholm, Sweden). The prescription dose was 7560 cGy to the prostate PTV and 5796 cGy to the seminal vesicles, using a simultaneous integrated boost technique. The resulting DVH parameters of the 20 field IMRT-MCO plan were used as initial optimization parameters for VMAT planning. The initial VMAT plan for each patient was further optimized by adjusting the optimization objectives/constraints. Final plan quality was compared using a homogeneity index (HI) and D98 for PTV-prostate, V70 and V75 for anterior rectum and V70 for bladder. Moreover, delivery efficiency of VMAT and the 7 field MCO-IMRT plans was also evaluated. RESULTS: All plans fulfilled the standard clinical objectives. The average HI of the PTV-prostate was 0.11 for VMAT, 0.13 for 20 field IMRT-MCO and 0.12 for 7 field IMRT-MCO, respectively. Average D98 values were 7191, 7294 and 7305 cGy for VMAT, 20 field IMRT-MCO and 7 field IMRT-MCO, respectively. For organ-at-risk (OAR), V70 and V75 for anterior rectum and V70 for bladder were within 3%. Analysis of delivery efficiency shows the estimated delivery time of VMAT is less than 2 minutes, while it is 7 min for 7 field IMRT-MCO. CONCLUSIONS: MCO-informed VMAT optimization is a useful way to generate optimal VMAT plans. The resulting VMAT plan quality essentially matched the MCO-IMRT plan but with a shorter delivery time. Dose homogeneity of VMAT is slight superior compared to IMRT-MCO while the cold spots are slightly inferior. Furthermore, there is no clinically significant difference in OAR sparing. Funding support provided by NCI Federal Share Proton Beam Program Income Grant and Raysearch Laboratories.

SU-E-T-627: Optimal Partial Arcs in VMAT Planning.

PURPOSE: To describe a method for producing minimal delivery time partial arc VMAT plans. METHODS: We begin with the assumption that dose quality is the primary treatment planning goal. Therefore the first step in the partial arc computation is a 180 beam equi-spaced IMRT multi-criteria optimized treatment plan, which serves as an ideal plan, along with a set of user- specified allowable deviations from this plan. This defines a set of target coverage and healthy organ sparing constraints. We then seek a partial arc plan which recovers this ideal plan but is minimal in delivery time. The search for the optimal partial arc which fulfills the hard constraints is done by wrapping a VMAT fluence map optimization/merging/simplification algorithm called VMERGE. The search is performed over all possible partial arcs, with start and end locations discretized to 20 degree increments, and respecting that the gantry cannot pass underneath the couch. This results in 169 partial arcs. For the ones that yield feasible plans, the complete VMERGE algorithm is run, which minimizes the delivery time for that arc. The minimal delivery time plan that fulfills the dosimetric requirements is returned. RESULTS: We apply the method to a lung and liver case. The time savings are as follows: (full arc time, optimal partial arc time): lung (185 s, 94 s), liver (263 s, 165 s). The optimal arc for the lung lesion, a left anterior target, is 140 degrees centered at 50 degrees. The optimal arc for the liver lesion is 160 degrees centered at -90 degrees. CONCLUSIONS: By wrapping a fast VMAT optimization/sequencing routine by an exhaustive search over 169 possible partial arcs, we are able to determine the fastest delivery partial arc. The use of partial arcs can significantly shorten delivery time in VMAT delivery. The project described was supported by Award Number R01CA103904 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the ocial views of the National Cancer Institute or the National Institutes of Health.

SU-E-T-634: Convex Direct Aperture Optimization for Sliding Window IMRT.

PURPOSE: To introduce a convex Direct Aperture Optimization (DAO) technique for sliding window IMRT. This method combines the accuracy of aperture-based dose calculations, which include leaf end effect, scatter, and leakage, with the convexity, and hence efficient solvability, of classic two phase IMRT optimization (fluence map optimization followed by sliding window leaf sequencing). METHODS: Artificial pencil beam profiles used in fluence map optimization are replaced with sigmoid-like profiles representing the dose "blocked" by a leaf while at some incremental position, per MU. More precisely, the profiles represent the dose from photons blocked minus that from photons leaked through or scattered by the leaf. These profiles can be computed by any clinically validated IMRT dose engine, and the scatter component for an individual leaf can be accurately included to the extent that it is independent of positions of other leaves. Variables of the resulting convex optimization are the MUs delivered while each leaf is at each incremental position. All constraints necessary to ensure a deliverable sliding window solution, such as those preventing leaf collision, are linear. Thus, provided the dose objective functions are convex, the entire IMRT optimization is convex, and therefore can be efficiently solved to provable optimality. RESULTS: Our derivations prove that DAO is convex for sliding window IMRT, and we demonstrate the technique on a clinical prostate case. CONCLUSIONS: By moving from the standard idealized fluence beamlet approach to a'fluence blocked by a leaf at position x' approach, we fully convexify the sliding window IMRT optimization problem, and thus avoid the dose degradation observed in two-step IMRT optimization and the non-convexity of the traditionally posed DAO problem.

SU-E-T-619: A Network-Flow Solution Approach to VMAT Treatment Plan Optimization.

PURPOSE: To add mathematical rigor to the merging phase of the recently published two-stage VMAT optimization method called VMERGE. Using an exact merging method, we are able to better characterize the tradeoff between delivery efficiency and dose quality. METHODS: VMERGE begins with an IMRT plan that uses 180 equi-spaced beams and yields the "ideal" dose. Neighboring fluence maps are successively merged, meaning they are added together and delivered as one map. The merging process improves the delivery time at the expense of deviating from the initial high-quality dose distribution. We replace the original heuristic merging method by considering the merging problem as a bi-criteria optimization problem: maximize treatment efficiency and minimize the deviation from the ideal dose. We formulate this using a network-flow model where nodes represent the beam angles along with the starting MLC leaf position and arcs represent the possible merges. Since the problem is non-convex, we employ a customized box algorithm to obtain the Pareto approximation. We also evaluate the performance of several simple heuristics. RESULTS: We test our exact and heuristic solution approaches on a pancreas and a prostate case. For both cases, the shape of the Pareto frontier suggests that starting from a high quality plan, we can obtain efficient VMAT plans through merging neighboring arcs without substantially deviating from the initial dose distribution. The trade-off curves obtained by the various heuristics are contrasted and shown to all be equally capable of initial plan simplifications, but to deviate in quality for more drastic efficiency improvements. CONCLUSIONS: This work presents a bi-criteria network-flow solution approach to the merging problem. The obtained Pareto-frontier approximation is used as a benchmark to evaluate the performance of the proposed merging heuristics. The results validate that one of the heuristics in particular can achieve high-quality solutions.