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DOE OSTI2015

Adverse Outcomes After Palliative Radiation Therapy for Uncomplicated Spine Metastases: Role of Spinal Instability and Single-Fraction Radiation Therapy

Purpose: Level I evidence demonstrates equivalent pain response after single-fraction (SF) or multifraction (MF) radiation therapy (RT) for bone metastases. The purpose of this study is to provide additional data to inform the incidence and predictors of adverse outcomes after RT for spine metastases. Methods and Materials: At a single institution, 299 uncomplicated spine metastases (without cord compression, prior RT, or surgery) treated with RT from 2008 to 2013 were retrospectively reviewed. The spinal instability neoplastic score (SINS) was used to assess spinal instability. The primary outcome was time to first spinal adverse event (SAE) at the site, including symptomatic vertebral fracture, hospitalization for site-related pain, salvage surgery, interventional procedure, new neurologic symptoms, or cord compression. Fine and Gray's multivariable model assessed associations of the primary outcome with SINS, SF RT, and other significant baseline factors. Propensity score matched analysis further assessed the relationship of SF RT to first SAEs. Results: The cumulative incidence of first SAE after SF RT (n=66) was 6.8% at 30 days, 16.9% at 90 days, and 23.6% at 180 days. For MF RT (n=233), the incidence was 3.5%, 6.4%, and 9.2%, respectively. In multivariable analysis, SF RT (hazard ratio [HR] = 2.8, 95% confidence interval [CI] 1.5-5.2, P=.001) and SINS ≥11 (HR=2.5 , 95% CI 1.3-4.9, P=.007) were predictors of the incidence of first SAE. In propensity score matched analysis, first SAEs had developed in 22% of patients with SF RT versus 6% of those with MF RT cases (HR=3.9, 95% CI 1.6-9.6, P=.003) at 90 days after RT. Conclusion: In uncomplicated spinal metastases treated with RT alone, spinal instability with SINS ≥11 and SF RT were associated with a higher rate of SAEs.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Optimizing Radiation Therapy Quality Assurance in Clinical Trials: A TROG 08.03 RAVES Substudy

Purpose: To explore site- and clinician-level factors associated with protocol violations requiring real-time-review (RTR) resubmission in a multicenter clinical trial to help tailor future quality assurance (QA) protocols. Methods and Materials: RAVES (Radiation Therapy–Adjuvant vs Early Salvage) (Trans-Tasman Radiation Oncology Group 08.03) is a randomized trial comparing adjuvant with early salvage radiation therapy in men with positive surgical margins or pT3 disease after prostatectomy. Quality assurance in RAVES required each clinician and site to submit a credentialing dummy run (DR) and for each patient's radiation therapy plan to undergo external RTR before treatment. Prospectively defined major violations from trial protocol required remedy and resubmission. Site and clinician factors associated with RTR resubmission were examined using hierarchical modeling. Results: Data were collected from 171 consecutive patients, treated by 46 clinicians at 32 hospitals. There were 47 RTR resubmissions (27%) due to 65 major violations. The relative rate of resubmission decreased by 29% per year as the study progressed (odds ratio OR. 0.71, P=.02). The majority of resubmissions were due to contouring violations (39 of 65) and dosimetric violations (22 of 65). For each additional patient accrued, significant decreases in RTR resubmission were seen at both clinician level (OR 0.75, P=.02) and site level (OR 0.72, P=.01). The rate of resubmission due to dosimetric violations was only 1.6% after the first 5 patients. Use of IMRT was associated with lower rates of resubmission compared with 3-dimensional conformal radiation therapy (OR 0.38, P=.05). Conclusion: Several low- and high-risk factors that may assist with tailoring future clinical trial QA were identified. Because the real-time resubmission rate was largely independent of the credentialing exercise, some form of RTR QA is recommended. The greatest benefit from QA was derived early in trial activation and clinician experience.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Association Between Geographic Access to Cancer Care and Receipt of Radiation Therapy for Rectal Cancer

Purpose: Trimodality therapy (chemoradiation and surgery) is the standard of care for stage II/III rectal cancer but nearly one third of patients do not receive radiation therapy (RT). We examined the relationship between the density of radiation oncologists and the travel distance to receipt of RT. Methods and Materials: A retrospective study based on the National Cancer Data Base identified 26,845 patients aged 18 to 80 years with stage II/III rectal cancer diagnosed from 2007 to 2010. Radiation oncologists were identified through the Physician Compare dataset. Generalized estimating equations clustering by hospital service area was used to examine the association between geographic access and receipt of RT, controlling for patient sociodemographic and clinical characteristics. Results: Of the 26,845 patients, 70% received RT within 180 days of diagnosis or within 90 days of surgery. Compared with a travel distance of <12.5 miles, patients diagnosed at a reporting facility who traveled ≥50 miles had a decreased likelihood of receipt of RT (50-249 miles, adjusted odds ratio 0.75, P<.001; ≥250 miles, adjusted odds ratio 0.46; P=.002), all else being equal. The density level of radiation oncologists was not significantly associated with the receipt of RT. Patients who were female, nonwhite, and aged ≥50 years and had comorbidities were less likely to receive RT (P<.05). Patients who were uninsured but self-paid for their medical services, initially diagnosed elsewhere but treated at a reporting facility, and resided in Midwest had an increased the likelihood of receipt of RT (P<.05). Conclusions: An increased travel burden was associated with a decreased likelihood of receiving RT for patients with stage II/III rectal cancer, all else being equal; however, radiation oncologist density was not. Further research of geographic access and establishing transportation assistance programs or lodging services for patients with an unmet need might help decrease geographic barriers and improve the quality of rectal cancer care.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non–Small Cell Lung Cancer

Radiation dose escalation has been shown to improve local control and survival in patients with non–small cell lung cancer in some studies, but randomized data have not supported this premise, possibly owing to adverse effects. Because of the physical characteristics of the Bragg peak, proton therapy (PT) delivers minimal exit dose distal to the target volume, resulting in better sparing of normal tissues in comparison to photon-based radiation therapy. This is particularly important for lung cancer given the proximity of the lung, heart, esophagus, major airways, large blood vessels, and spinal cord. However, PT is associated with more uncertainty because of the finite range of the proton beam and motion for thoracic cancers. PT is more costly than traditional photon therapy but may reduce side effects and toxicity-related hospitalization, which has its own associated cost. The cost of PT is decreasing over time because of reduced prices for the building, machine, maintenance, and overhead, as well as newer, shorter treatment programs. PT is improving rapidly as more research is performed particularly with the implementation of 4-dimensional computed tomography–based motion management and intensity modulated PT. Given these controversies, there is much debate in the oncology community about which patients with lung cancer benefit significantly from PT. The Particle Therapy Co-operative Group (PTCOG) Thoracic Subcommittee task group intends to address the issues of PT indications, advantages and limitations, cost-effectiveness, technology improvement, clinical trials, and future research directions. This consensus report can be used to guide clinical practice and indications for PT, insurance approval, and clinical or translational research directions.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Single-Fraction Versus Multifraction (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of Radiation-Induced Brain Necrosis

Purpose: To investigate the local control and radiation-induced brain necrosis in patients with brain metastases >2 cm in size who received single-fraction or multifraction stereotactic radiosurgery (SRS); factors associated with clinical outcomes and the development of brain radionecrosis were assessed. Methods and Materials: Two hundred eighty-nine consecutive patients with brain metastases >2.0 cm who received SRS as primary treatment at Sant'Andrea Hospital, University of Rome Sapienza, Rome, Italy, were analyzed. Cumulative incidence analysis was used to compare local control and radiation-induced brain necrosis between groups from the time of SRS. To achieve a balanced distribution of baseline covariates between treatment groups, a propensity score analysis was used. Results: The 1-year cumulative local control rates were 77% in the single-fraction SRS (SF-SRS) group and 91% in the multifraction SRS (MF-SRS) group (P=.01). Recurrences occurred in 25 and 11 patients who received SF-SRS or MF-SRS (P=.03), respectively. Thirty-one patients (20%) undergoing SF-SRS and 11 (8%) subjected to MF-SRS experienced brain radionecrosis (P=.004); the 1-year cumulative incidence rate of radionecrosis was 18% and 9% (P=.01), respectively. Significant differences between the 2 groups in terms of local control and risk of radionecrosis were maintained after propensity score adjustment. Conclusions: Multifraction SRS at a dose of 27 Gy in 3 daily fractions seems to be an effective treatment modality for large brain metastases, associated with better local control and a reduced risk of radiation-induced radionecrosis as compared with SF-SRS.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

The Curie–Da Vinci Connection: 5-Years' Experience With Laparoscopic (Robot-Assisted) Implantation for High-Dose-Rate Brachytherapy of Solitary T2 Bladder Tumors

Purpose: To report experience and early results of laparoscopic implantation for interstitial brachytherapy (BT) of solitary bladder tumors and the feasibility of a high-dose-rate (HDR) schedule. Methods and Materials: From December 2009 to April 2015, 57 patients with a T2 solitary bladder tumor were treated in Arnhem with transurethral bladder resection followed by external beam irradiation, applied to the bladder and regional iliac lymph nodes, 40 Gy in 20 fractions, 5 fractions per week, and within 1 week interstitial HDR BT, in selected cases combined with partial cystectomy and lymph node dissection. The BT catheters were placed via a transabdominal approach with robotic assistance from a Da Vinci robot after a successful initial experience with a nonrobotic laparoscopic approach. The fraction schedule for HDR was 10 fractions of 2.5 Gy, 3 fractions per day. This was calculated to be equivalent to a reference low-dose-rate schedule of 30 Gy in 60 hours. Data for oncologic outcomes and toxicity (Common Toxicity Criteria version 4) were prospectively collected. Results: These modifications resulted in an average postoperative hospitalization of 6 days, minimal blood loss, and no wound healing problems. Two patients had severe acute toxicity: 1 pulmonary embolism grade 4 and 1 cardiac death. Late toxicity was mild (n=2 urogenital grade 3 toxicity). The median follow-up was 2 years. Using cumulative incidence competing risk analysis, the 2-year overall, disease-free, and disease-specific survival and local control rates were 59%, 71%, 87%, and 82%, respectively. Conclusions: The benefits of minimally invasive surgery for implantation of BT catheters and the feasibility of HDR BT in bladder cancer are documented. The patient outcome and adverse events are comparable to the best results published for a bladder-sparing approach.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Validation of the Web-Based IBTR! 2.0 Nomogram to Predict for Ipsilateral Breast Tumor Recurrence After Breast-Conserving Therapy

Purpose: To evaluate the IBTR! 2.0 nomogram, which predicts 10-year ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy with and without radiation therapy for breast cancer, by using a large, external, and independent cancer center database. Methods and Materials: We retrospectively identified 1898 breast cancer cases, treated with breast-conserving therapy and radiation therapy at the University Hospital Leuven from 2000 to 2007, with requisite data for the nomogram variables. Clinicopathologic factors were assessed. Two definitions of IBTR were considered where simultaneous regional or distant recurrence were either censored (conform IBTR! 2.0) or included as event. Validity of the prediction algorithm was tested in terms of discrimination and calibration. Discrimination was assessed by the concordance probability estimate and Harrell's concordance index. The mean predicted and observed 10-year estimates were compared for the entire cohort and for 4 risk groups predefined by nomogram-predicted IBTR risks, and a calibration plot was drawn. Results: Median follow-up was 10.9 years. The 10-year IBTR rates were 1.3% and 2.1%, according to the 2 definitions of IBTR. The validation cohort differed from the development cohort with respect to the administration of hormonal therapy, surgical section margins, lymphovascular invasion, and tumor size. In univariable analysis, younger age (P=.002) and a positive nodal status (P=.048) were significantly associated with IBTR, with a trend for the omission of hormonal therapy (P=.061). The concordance probability estimate and concordance index varied between 0.57 and 0.67 for the 2 definitions of IBTR. In all 4 risk groups the model overestimated the IBTR risk. In particular, between the lowest-risk groups a limited differentiation was suggested by the calibration plot. Conclusions: The IBTR! 2.0 predictive model for IBTR in breast cancer patients shows substandard discriminative ability, with an overestimation of the risk in all subgroups.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

The Radiation Oncology Job Market: The Economics and Policy of Workforce Regulation

Examinations of the US radiation oncology workforce offer inconsistent conclusions, but recent data raise significant concerns about an oversupply of physicians. Despite these concerns, residency slots continue to expand at an unprecedented pace. Employed radiation oncologists and professional corporations with weak contracts or loose ties to hospital administrators would be expected to suffer the greatest harm from an oversupply. The reduced cost of labor, however, would be expected to increase profitability for equipment owners, technology vendors, and entrenched professional groups. Policymakers must recognize that the number of practicing radiation oncologists is a poor surrogate for clinical capacity. There is likely to be significant opportunity to augment capacity without increasing the number of radiation oncologists by improving clinic efficiency and offering targeted incentives for geographic redistribution. Payment policy changes significantly threaten radiation oncologists' income, which may encourage physicians to care for greater patient loads, thereby obviating more personnel. Furthermore, the implementation of alternative payment models such as Medicare's Oncology Care Model threatens to decrease both the utilization and price of radiation therapy by turning referring providers into cost-conscious consumers. Medicare funds the vast majority of graduate medical education, but the extent to which the expansion in radiation oncology residency slots has been externally funded is unclear. Excess physician capacity carries a significant risk of harm to society by suboptimally allocating intellectual resources and creating comparative shortages in other, more needed disciplines. There are practical concerns associated with a market-based solution in which medical students self-regulate according to job availability, but antitrust law would likely forbid collaborative self-regulation that purports to restrict supply. Because Congress is unlikely to create one central body to govern residency controls for all specialties, we recommend better reporting of program-specific employment metrics and careful, intellectually honest re-evaluation of existing Accreditation Council for Graduate Medical Education accreditation standards.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2017

Nation-Scale Adoption of Shorter Breast Radiation Therapy Schedules Can Increase Survival in Resource Constrained Economies: Results From a Markov Chain Analysis

Purpose: Hypofractionated whole breast irradiation and accelerated partial breast irradiation (APBI) offer women options for shorter courses of breast radiation therapy. The impact of these shorter schedules on the breast cancer populations of emerging economies with limited radiation therapy resources is unknown. We hypothesized that adoption of these schedules would improve throughput in the system and, by allowing more women access to life-saving treatments, improve patient survival within the system. Methods and Materials: We designed a Markov chain model to simulate the different health states that a postlumpectomy or postmastectomy patient could enter over the course of a 20-year follow-up period. Transition rates between health states were adapted from published data on recurrence rates. We used primary data from a tertiary care hospital in Lahore, Pakistan, to populate the model with proportional use of mastectomy versus breast conservation and to estimate the proportion of patients suitable for APBI. Sensitivity analyses on the use of APBI and relative efficacy of APBI were conducted to study the impact on the population. Results: The shorter schedule resulted in more women alive and more women remaining without evidence of disease (NED) compared with the conventional schedule, with an absolute difference of about 4% and 7% at 15 years, respectively. Among women who had lumpectomies, the chance of remaining alive and with an intact breast was 62% in the hypofractionation model and 54% in the conventional fractionation model. Conclusions: Increasing throughput in the system can result in improved survival, improved chances of remaining without evidence of disease, and improved chances of remaining alive with a breast. These findings are significant and suggest that adoption of hypofractionation in emerging economies is not simply a question of efficiency and cost but one of access to care and patient survivorship.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

First Results of a Phase 2 Trial of Once-Weekly Hypofractionated Breast Irradiation (WHBI) for Early-Stage Breast Cancer

Purpose: To report early outcome analysis of a prospective institutional phase 2 trial of weekly hypofractionated breast irradiation (WHBI) for patients undergoing breast-conserving surgery (BCS). Methods and Materials: Patients who underwent BCS for American Joint Committee on Cancer stage 0, I, or II breast cancer with negative surgical margins received whole-breast radiation therapy to 30 or 28.5 Gy in 5 weekly fractions with or without an additional boost. The eligibility criteria were the same as for NSABP (National Surgical Adjuvant Breast and Bowel Project) B39/RTOG (Radiation Therapy Oncology Group) 0413, and there were no restrictions on age, breast size, tumor grade, receptor status, or the use of cytotoxic chemotherapy for otherwise eligible patients. The primary endpoint was ipsilateral breast tumor recurrence. Patients were also evaluated for acute toxicity (Common Terminology Criteria for Adverse Events version 3.0), cosmesis (Harvard Scale), development of distant metastatic disease, and overall survival. Results: Between January 2011 and October 2015, 158 eligible patients underwent WHBI immediately following BCS. The median age was 60 years (range, 30-84 years), and the median follow-up period was 3 years. Ipsilateral breast tumor recurrence developed in a total of 2 patients (1.3%), 1 in conjunction with widespread metastatic disease. Distant metastatic disease developed in 4 patients (2.5%), and the 3-year disease-free survival and overall survival rates were 97.5% and 96.2%, respectively. The most common grade 1 or 2 acute toxicities were breast pain, radiation dermatitis, and fatigue. There were 2 grade 3 events (1.3%): pain requiring narcotic analgesics (1) and posttreatment infection requiring hospitalization (1). The rate of excellent or good cosmesis versus fair or poor cosmesis was 82.3% versus 17.7%. The rate of significant cosmetic change from baseline to last follow-up (dropping from excellent or good to fair or poor) was 11.6%. Conclusions: Early outcomes after WHBI are favorable and parallel those seen with daily hypofractionated whole-breast irradiation. With broader entry criteria than all previous reports of WHBI, this study will facilitate comparison to the results of NSABP B39/RTOG 0413. With continued follow-up, future reports will assess cosmetic stability and disease-specific outcomes.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Patterns of Care in Adjuvant Therapy for Resected Oral Cavity Squamous Cell Cancer in Elderly Patients

Purpose: To characterize the patterns of care and potential barriers to access to care for elderly patients with oral cavity cancer in the adjuvant setting. Methods and Materials: We performed a retrospective cohort study using the National Cancer Data Base and identified patients with resected oral cavity squamous cell carcinoma diagnosed between 2004 and 2012, who survived for ≥3 months after surgery. We used logistic regression models to assess the association between age (<70, 70-79, and ≥80 years) and the receipt of adjuvant therapy within 3 months of surgery. We additionally assessed the association between patient and tumor characteristics and the receipt of adjuvant therapy among those aged ≥70 years. Results: A total of 25,829 patients were included in the study. Compared with those aged <70 years, older patients were more likely to have no neck dissection or have fewer lymph nodes dissected and were less likely to receive adjuvant therapy than younger patients. Among our cohort, 11,361 patients (44%) had pathologic T3-T4 disease or N2-N3 disease, and 4185 patients (16%) had extracapsular nodal extension or positive surgical margins. In multivariate analyses controlling for comorbidity and demographic characteristics, older age was independently associated with lower odds of receiving adjuvant radiation therapy in the subgroup with T3 or T4 disease or N2 or N3 disease and adjuvant chemoradiation therapy in the positive extracapsular nodal extension or positive surgical margin subgroup. Among elderly patients, both greater patient distance from reporting facility and older age were associated with lower odds of receiving both adjuvant radiation therapy (odds ratio 0.66; 95% confidence interval, 0.55-0.81) and chemoradiation therapy (odds ratio 0.56; 95% confidence interval, 0.40-0.79). Conclusions: In a national hospital-based cohort of patients with oral cavity cancer, elderly patients were less likely to receive adjuvant radiation or chemoradiation therapy. Greater patient distance from reporting facility, in addition to older age, was associated with lower odds of receiving both adjuvant radiation therapy and adjuvant chemoradiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Predicting Patient-specific Dosimetric Benefits of Proton Therapy for Skull-base Tumors Using a Geometric Knowledge-based Method

Purpose: To predict the organ at risk (OAR) dose levels achievable with proton beam therapy (PBT), solely based on the geometric arrangement of the target volume in relation to the OARs. A comparison with an alternative therapy yields a prediction of the patient-specific benefits offered by PBT. This could enable physicians at hospitals without proton capabilities to make a better-informed referral decision or aid patient selection in model-based clinical trials. Methods and Materials: Skull-base tumors were chosen to test the method, owing to their geometric complexity and multitude of nearby OARs. By exploiting the correlations between the dose and distance-to-target in existing PBT plans, the models were independently trained for 6 types of OARs: brainstem, cochlea, optic chiasm, optic nerve, parotid gland, and spinal cord. Once trained, the models could estimate the feasible dose–volume histogram and generalized equivalent uniform dose (gEUD) for OAR structures of new patients. The models were trained using 20 patients and validated using an additional 21 patients. Validation was achieved by comparing the predicted gEUD to that of the actual PBT plan. Results: The predicted and planned gEUD were in good agreement. Considering all OARs, the prediction error was +1.4 ± 5.1 Gy (mean ± standard deviation), and Pearson's correlation coefficient was 93%. By comparing with an intensity modulated photon treatment plan, the model could classify whether an OAR structure would experience a gain, with a sensitivity of 93% (95% confidence interval: 87%-97%) and specificity of 63% (95% confidence interval: 38%-84%). Conclusions: We trained and validated models that could quickly and accurately predict the patient-specific benefits of PBT for skull-base tumors. Similar models could be developed for other tumor sites. Such models will be useful when an estimation of the feasible benefits of PBT is desired but the experience and/or resources required for treatment planning are unavailable.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Process mining for healthcare: Characteristics and challenges

Process mining techniques can be used to analyse business processes using the data logged during their execution. These techniques are leveraged in a wide range of domains, including healthcare, where it focuses mainly on the analysis of diagnostic, treatment, and organisational processes. Despite the huge amount of data generated in hospitals by staff and machinery involved in healthcare processes, there is no evidence of a systematic uptake of process mining beyond targeted case studies in a research context. When developing and using process mining in healthcare, distinguishing characteristics of healthcare processes such as their variability and patient-centred focus require targeted attention. Against this background, the Process-Oriented Data Science in Healthcare Alliance has been established to propagate the research and application of techniques targeting the data-driven improvement of healthcare processes. This paper, an initiative of the alliance, presents the distinguishing characteristics of the healthcare domain that need to be considered to successfully use process mining, as well as open challenges that need to be addressed by the community in the future.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

“I'm Just Guessing These Answers!” An Evaluation of the (In)Accuracy of Patient-Reported Medical History Collected as Part of a Breast Imaging Program

Hundreds of thousands of Ontario women receive breast screening imaging each year. The patient's medical history is a vital tool used to personalize breast screening approaches. This study evaluated the accuracy of self-reported medical and imaging history in patients about to receive breast imaging procedures in a large urban Canadian hospital. The patient experience with using a blank screening form vs. a novel prefilled screening form was also evaluated.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Clostridium difficile toxin glucosyltransferase domains in complex with a non-hydrolyzable UDP-glucose analogue

Clostridium difficile is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis worldwide. The organism produces two homologous toxins, TcdA and TcdB, which enter and disrupt host cell function by glucosylating and thereby inactivating key signalling molecules within the host. As a toxin-mediated disease, there has been a significant interest in identifying small molecule inhibitors of the toxins’ glucosyltransferase activities. This study was initiated as part of an effort to identify the mode of inhibition for a small molecule inhibitor of glucosyltransferase activity called apigenin. In the course of trying to get co-crystals with this inhibitor, we determined five different structures of the TcdA and TcdB glucosyltransferase domains and made use of a non-hydrolyzable UDP-glucose substrate. While we were able to visualize apigenin bound in one of our structures, the site was a crystal packing interface and not likely to explain the mode of inhibition. Nevertheless, the structure allowed us to capture an apo-state (one without the sugar nucleotide substrate) of the TcdB glycosyltransferase domain that had not been previously observed. Additionally, comparison of this structure with structures obtained in the presence of a non-hydrolyzable UDP-glucose analogue have allowed us to document multiple conformations of a C-terminal loop important for catalysis. We present our analysis of these five new structures with the hope that it will advance inhibitor design efforts for this important class of biological toxins.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Association Between Dispatch Complaint and Critical Prehospital Time Intervals in Suspected Stroke 911 Activations in the National Emergency Medical Services Information System, 2012–2016

Emergency Medical Services can help improve stroke outcomes by recognizing stroke symptoms, establishing response priority for 911 calls, and minimizing prehospital delays. This study examines 911 stroke events and evaluates associations between events dispatched as stroke and critical EMS time intervals. Data from the National Emergency Medical Services Information System, 2012 to 2016, were analyzed. Activations from 911 calls with a primary or secondary provider impression of stroke were included for adult patients transported to a hospital destination. Three prehospital time intervals were evaluated: (1) response time (RT) ≤8 min, (2) on-scene time (OST) ≤15 min, and (3) transport time (TT) ≤12 min. Associations between stroke dispatch complaint and prehospital time intervals were assessed using multivariate regression to estimate adjusted risk ratios (ARR) and 95% confidence intervals (CIs). Approximately 37% of stroke dispatch complaints were identified by EMS as a suspected stroke. Compared to stroke events without a stroke dispatch complaint, median OST was shorter for events with a stroke dispatch (16 min vs. 14 min, respectively). In adjusted analyses, events dispatched as stroke were more likely to meet the EMS time benchmark for OST ≤15 min (OST, 1.20 [1.20–1.21]), but not RT or TT (RT, [1.00–1.01]; TT, 0.95 [0.94–0.95]). Furthermore, our results indicate that dispatcher recognition of stroke symptoms reduces the time spent on-scene by EMS personnel. These findings can inform future EMS stroke education and quality improvement efforts to emphasize dispatcher recognition of stroke signs and symptoms, as EMS dispatchers play a crucial role in optimizing the prehospital response.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Sepsis reconsidered: Identifying novel metrics for behavioral landscape characterization with a high-performance computing implementation of an agent-based model

Objectives: Sepsis affects nearly 1 million people in the United States per year, has a mortality rate of 28–50% and requires more than $20 billion a year in hospital costs. Over a quarter century of research has not yielded a single reliable diagnostic test or a directed therapeutic agent for sepsis. Central to this insufficiency is the fact that sepsis remains a clinical/physiological diagnosis representing a multitude of molecularly heterogeneous pathological trajectories. Advances in computational capabilities offered by High Peformance Computing (HPC) platforms call for an evolution in the investigation of sepsis to attempt to define the boundaries of traditional research (bench, clinical and computational) through the use of computational proxy models. We present a novel investigatory and analytical approach, derived from how HPC resources and simulation are used in the physical sciences, to identify the epistemic boundary con- ditions of the study of clinical sepsis via the use of a proxy agent-based model of systemic inflammation. Design: Current predictive models for sepsis use correlative methods that are limited by patient heterogeneity and data sparseness. We address this issue by using an HPC version of a system-level validated agent-based model of sepsis, the Innate Immune Response ABM (IIRBM), as a proxy system in order to identify boundary conditions for the possible behavioral space for sepsis. We then apply advanced analysis derived from the study of Random Dynamical Systems (RDS) to identify novel means for characterizing system behavior and providing insight into the tractability of traditional investigatory methods. Results: The behavior space of the IIRABM was examined by simulating over 70 million sepsis patients for up to 90 days in a sweep across the following parameters: cardio-respiratory-metabolic resilience; microbial invasiveness; microbial toxigenesis; and degree of nosocomial exposure. In addition to using established methods for describing parameter space, we developed two novel methods for characterizing the behavior of a RDS: Probabilistic Basins of Attraction (PBoA) and Stochastic Trajectory Analysis (STA). Computationally generated behavioral landscapes demonstrated attractor structures around stochastic re- gions of behavior that could be described in a complementary fashion through use of PBoA and STA. The stochasticity of the boundaries of the attractors highlights the challenge for correlative attempts to characterize and classify clinical sepsis. Conclusions: HPC simulations of models like the IIRABM can be used to generate approximations of the behavior space of sepsis to both establish “boundaries of futility” with respect to existing investi- gatory approaches and apply system engineering principles to investigate the general dynamic properties of sepsis to provide a pathway for developing control strategies. Here, the issues that bedevil the study and treatment of sepsis, namely clinical data sparseness and inadequate experimental sampling of system behavior space, are fundamental to nearly all biomedical research, manifesting in the “Crisis of Reproducibility” at all levels. HPC-augmented simulation-based research offers an investigatory strategy more consistent with that seen in the physical sciences (which combine experiment, theory and simulation), and an opportunity to utilize the leading advances in HPC, namely deep machine learning and evolutionary computing, to form the basis of an iterative scientific process to meet the full promise of Precision Medicine (right drug, right patient, right time).

59 BASIC BIOLOGICAL SCIENCES↗