Feasibility of linking violent death decedents to prior-month emergency department visits in North Carolina, 2019-2020.

OBJECTIVE: Linking data between violent death decedents and other sources can provide valuable insight, highlighting opportunities for prevention of violent injury. This study investigated the feasibility of linking North Carolina Violent Death Reporting System (NC-VDRS) records with North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT) emergency department (ED) visit data to identify prior-month ED visits among this population. METHODS: NC-VDRS death records from 2019 through 2020 were linked to NC DETECT ED visit data from December 2018 through 2020 using a probabilistic linkage approach. Linkage variables included date of birth, age, sex, zip code and county of residence, date of event (death/ED visit) and mechanism of injury. Potential linkable ED visits were filtered to those occurring in the month prior to death and manually reviewed for validity. Linked records were compared with the NC-VDRS study population to assess linkage performance and generalisability. RESULTS: Among the 4768 violent deaths identified, we linked 1340 NC-VDRS records to at least one ED visit in the month prior to death. A higher proportion of decedents dying in medical facilities (ED/outpatient, hospital inpatient, hospice or nursing/long-term care facility) linked to a prior-month visit (80%) relative to those dying in other locations (12%). When stratified by place of death, linked decedents demographically resembled the overall NC-VDRS study population. CONCLUSIONS: Though resource intensive, an NC-VDRS-to-NC DETECT linkage was successful in identifying prior-month ED visits among violent death decedents. This linkage should be leveraged to further analyse ED utilisation prior to violent death, expanding the knowledge base surrounding prevention opportunities for violent injuries.

Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses.

Circulating monocytes carrying human CMV (HCMV) migrate into tissues, where they differentiate into HCMV-infected resident macrophages that upon interaction with bacterial products may potentiate tissue inflammation. In this study, we investigated the mechanism by which HCMV promotes macrophage-orchestrated inflammation using a clinical isolate of HCMV (TR) and macrophages derived from primary human monocytes. HCMV infection of the macrophages, which was associated with viral DNA replication, significantly enhanced TNF-α, IL-6, and IL-8 gene expression and protein production in response to TLR4 ligand (LPS) stimulation compared with mock-infected LPS-stimulated macrophages during a 6-d in vitro infection. HCMV infection also potentiated TLR5 ligand-stimulated cytokine production. To elucidate the mechanism by which HCMV infection potentiated inducible macrophage responses, we show that infection by HCMV promoted the maintenance of surface CD14 and TLR4 and TLR5, which declined over time in mock-infected macrophages, and enhanced both the intracellular expression of adaptor protein MyD88 and the inducible phosphorylation of IκBα and NF-κB. These findings provide additional information toward elucidating the mechanism by which HCMV potentiates bacteria-induced NF-κB-mediated macrophage inflammatory responses, thereby enhancing organ inflammation in HCMV-infected tissues.

A New Database Facilitates Characterization of Flavonoid Intake, Sources, and Positive Associations with Diet Quality among US Adults.

BACKGROUND: Epidemiologic studies demonstrate inverse associations between flavonoid intake and chronic disease risk. However, lack of comprehensive databases of the flavonoid content of foods has hindered efforts to fully characterize population intakes and determine associations with diet quality. OBJECTIVES: Using a newly released database of flavonoid values, this study sought to describe intake and sources of total flavonoids and 6 flavonoid classes and identify associations between flavonoid intake and the Healthy Eating Index (HEI) 2010. METHODS: One day of 24-h dietary recall data from adults aged ≥ 20 y (n = 5420) collected in What We Eat in America (WWEIA), NHANES 2007-2008, were analyzed. Flavonoid intakes were calculated using the USDA Flavonoid Values for Survey Foods and Beverages 2007-2008. Regression analyses were conducted to provide adjusted estimates of flavonoid intake, and linear trends in total and component HEI scores by flavonoid intake were assessed using orthogonal polynomial contrasts. All analyses were weighted to be nationally representative. RESULTS: Mean intake of flavonoids was 251 mg/d, with flavan-3-ols accounting for 81% of intake. Non-Hispanic whites had significantly higher (P < 0.001) intakes of total flavonoids (275 mg/d) than non-Hispanic blacks (176 mg/d) and Hispanics (139 mg/d). Tea was the primary source (80%) of flavonoid intake. Regardless of whether the flavonoid contribution of tea was included, total HEI score and component scores for total fruit, whole fruit, total vegetables, greens and beans, seafood and plant proteins, refined grains, and empty calories increased (P < 0.001) across flavonoid intake quartiles. CONCLUSIONS: A new database that permits comprehensive estimation of flavonoid intakes in WWEIA, NHANES 2007-2008; identification of their major food/beverage sources; and determination of associations with dietary quality will lead to advances in research on relations between flavonoid intake and health. Findings suggest that diet quality, as measured by HEI, is positively associated with flavonoid intake.

Adjunctive steroid therapy for managing pulmonary tuberculosis.

BACKGROUND: Tuberculosis causes approximately 8.6 million disease episodes and 1.3 million deaths worldwide per year. Although curable with standardized treatment, outcomes for some forms of tuberculosis are improved with adjunctive corticosteroid therapy. Whether corticosteroid therapy would be beneficial in treating people with pulmonary tuberculosis is unclear. OBJECTIVES: To evaluate whether adjunctive corticosteroid therapy reduces mortality, accelerates clinical recovery or accelerates microbiological recovery in people with pulmonary tuberculosis. SEARCH METHODS: We identified studies indexed from 1966 up to May 2014 by searching: Cochrane Infectious Diseases Group's trials register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and LILACS using comparative search terms. We handsearched reference lists of all identified studies and previous reviews and contacted relevant researchers, organizations and companies to identify grey literature. SELECTION CRITERIA: Randomized controlled trials and quasi-randomized control trials of recognized antimicrobial combination regimens and corticosteroid therapy of any dose or duration compared with either no corticosteroid therapy or placebo in people with pulmonary tuberculosis were included. DATA COLLECTION AND ANALYSIS: At least two investigators independently assessed trial quality and collected data using pre-specified data extraction forms. Findings were reported as narrative or within tables. If appropriate, Mantel-Haenszel meta-analyses models were used to calculate risk ratios. MAIN RESULTS: We identified 18 trials, including 3816 participants, that met inclusion criteria. When compared to taking placebo or no steroid, corticosteroid use was not shown to to reduce all-cause mortality, or result in higher sputum conversion at 2 months or at 6 months (mortality: RR 0.77, 95%CI 0.51 to 1.15, 3815 participants, 18 studies, low quality evidence; sputum conversion at 2 months RR 1.03, 95%CI 0.97 to 1.09, 2750 participants, 12 studies; at 6 months; RR1.01, 95%CI 1.01, 95%CI 0.98 to 1.04, 2150 participants, 9 studies, both low quality evidence). However, corticosteroid use was found to increase weight gain (data not pooled, eight trials, 1203 participants, low quality evidence), decrease length of hospital stay (data not pooled, three trials, participants 379, very low quality of evidence) and increase clinical improvement within one month (RR 1.16, 95% CI 1.09 to 1.24; five trials, 497 participants, low quality evidence). AUTHORS' CONCLUSIONS: It is unlikely that adjunctive corticosteroid treatment provides major benefits for people with pulmonary tuberculosis. Short term clinical benefits found did not appear to be maintained in the long term. However, evidence available to date is of low quality. In order to evaluate whether adjunctive corticosteroids reduce mortality, or accelerate clinical or microbiological recovery in people with pulmonary tuberculosis further large randomized control trials sufficiently powered to detect changes in such outcomes are needed.

Designing clinical trials for patients who are not average.

The heterogeneity inherent in cancer means that even a successful clinical trial merely results in a therapeutic regimen that achieves, on average, a positive result only in a subset of patients. The only way to optimize an intervention for an individual patient is to reframe their treatment as their own, personalized trial. Toward this goal, we formulate a computational framework for performing personalized trials that rely on four mathematical techniques. First, mathematical models that can be calibrated with patient-specific data to make accurate predictions of response. Second, digital twins built on these models capable of simulating the effects of interventions. Third, optimal control theory applied to the digital twins to optimize outcomes. Fourth, data assimilation to continually update and refine predictions in response to therapeutic interventions. In this perspective, we describe each of these techniques, quantify their "state of readiness", and identify use cases for personalized clinical trials.

Transgenic songbirds offer an opportunity to develop a genetic model for vocal learning.

Zebra finches are widely used for studying the basic biology of vocal learning. The inability to introduce genetic modifications in these animals has substantially limited studies on the molecular biology of this behavior, however. We used an HIV-based lentivirus to produce germline transgenic zebra finches. The lentivirus encoded the GFP regulated by the human ubiquitin-C promoter [Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D (2002) Science 295:868-872], which is active in a wide variety of cells. The virus was injected into the very early embryo (blastodisc stage) to target the primordial germline cells that later give rise to sperm and eggs. A total of 265 fertile eggs were injected with virus, and 35 hatched (13%); 23 of these potential founders (F0) were bred, and three (13%) produced germline transgenic hatchlings that expressed the GFP protein (F1). Two of these three founders (F0) have produced transgenic young at a rate of 12% and the third at a rate of 6%. Furthermore, two of the F1 generation transgenics have since reproduced, one having five offspring (all GFP positive) and the other four offsping (one GFP positive).

An investigation into factors affecting electron density calibration for a megavoltage cone-beam CT system.

There is a growing interest in the use of megavoltage cone-beam computed tomography (MV CBCT) data for radiotherapy treatment planning. To calculate accurate dose distributions, knowledge of the electron density (ED) of the tissues being irradiated is required. In the case of MV CBCT, it is necessary to determine a calibration-relating CT number to ED, utilizing the photon beam produced for MV CBCT. A number of different parameters can affect this calibration. This study was undertaken on the Siemens MV CBCT system, MVision, to evaluate the effect of the following parameters on the reconstructed CT pixel value to ED calibration: the number of monitor units (MUs) used (5, 8, 15 and 60 MUs), the image reconstruction filter (head and neck, and pelvis), reconstruction matrix size (256 by 256 and 512 by 512), and the addition of extra solid water surrounding the ED phantom. A Gammex electron density CT phantom containing EDs from 0.292 to 1.707 was imaged under each of these conditions. The linear relationship between MV CBCT pixel value and ED was demonstrated for all MU settings and over the range of EDs. Changes in MU number did not dramatically alter the MV CBCT ED calibration. The use of different reconstruction filters was found to affect the MV CBCT ED calibration, as was the addition of solid water surrounding the phantom. Dose distributions from treatment plans calculated with simulated image data from a 15 MU head and neck reconstruction filter MV CBCT image and a MV CBCT ED calibration curve from the image data parameters and a 15 MU pelvis reconstruction filter showed small and clinically insignificant differences. Thus, the use of a single MV CBCT ED calibration curve is unlikely to result in any clinical differences. However, to ensure minimal uncertainties in dose reporting, MV CBCT ED calibration measurements could be carried out using parameter-specific calibration measurements.

Repeatability and reproducibility of magnetic resonance imaging-based radiomic features in rectal cancer.

Purpose: Radiomics of magnetic resonance images (MRIs) in rectal cancer can non-invasively characterize tumor heterogeneity with potential to discover new imaging biomarkers. However, for radiomics to be reliable, the imaging features measured must be stable and reproducible. The aim of this study is to quantify the repeatability and reproducibility of MRI-based radiomic features in rectal cancer. Approach: An MRI radiomics phantom was used to measure the longitudinal repeatability of radiomic features and the impact of post-processing changes related to image resolution and noise. Repeatability measurements in rectal cancers were also quantified in a cohort of 10 patients with test-retest imaging among two observers. Results: We found that many radiomic features, particularly from texture classes, were highly sensitive to changes in image resolution and noise. About 49% of features had coefficient of variations ≤ 10 % in longitudinal phantom measurements. About 75% of radiomic features in in vivo test-retest measurements had an intraclass correlation coefficient of ≥ 0.8 . We saw excellent interobserver agreement with mean Dice similarity coefficient of 0.95 ± 0.04 for test and retest scans. Conclusions: The results of this study show that even when using a consistent imaging protocol many radiomic features were unstable. Therefore, caution must be taken when selecting features for potential imaging biomarkers.

Repeatability of radiotherapy dose-painting prescriptions derived from a multiparametric magnetic resonance imaging model of glioblastoma infiltration.

Background and purpose: Glioblastoma (GBM) patients have a dismal prognosis. Tumours typically recur within months of surgical resection and post-operative chemoradiation. Multiparametric magnetic resonance imaging (mpMRI) biomarkers promise to improve GBM outcomes by identifying likely regions of infiltrative tumour in tumour probability (TP) maps. These regions could be treated with escalated dose via dose-painting radiotherapy to achieve higher rates of tumour control. Crucial to the technical validation of dose-painting using imaging biomarkers is the repeatability of the derived dose prescriptions. Here, we quantify repeatability of dose-painting prescriptions derived from mpMRI. Materials and methods: TP maps were calculated with a clinically validated model that linearly combined apparent diffusion coefficient (ADC) and relative cerebral blood volume (rBV) or ADC and relative cerebral blood flow (rBF) data. Maps were developed for 11 GBM patients who received two mpMRI scans separated by a short interval prior to chemoradiation treatment. A linear dose mapping function was applied to obtain dose-painting prescription (DP) maps for each session. Voxel-wise and group-wise repeatability metrics were calculated for parametric, TP and DP maps within radiotherapy margins. Results: DP maps derived from mpMRI were repeatable between imaging sessions (ICC > 0.85). ADC maps showed higher repeatability than rBV and rBF maps (Wilcoxon test, p = 0.001). TP maps obtained from the combination of ADC and rBF were the most stable (median ICC: 0.89). Conclusions: Dose-painting prescriptions derived from a mpMRI model of tumour infiltration have a good level of repeatability and can be used to generate reliable dose-painting plans for GBM patients.

An investigation of the conformity, feasibility, and expected clinical benefits of multiparametric MRI-guided dose painting radiotherapy in glioblastoma.

Background: New technologies developed to improve survival outcomes for glioblastoma (GBM) continue to have limited success. Recently, image-guided dose painting (DP) radiotherapy has emerged as a promising strategy to increase local control rates. In this study, we evaluate the practical application of a multiparametric MRI model of glioma infiltration for DP radiotherapy in GBM by measuring its conformity, feasibility, and expected clinical benefits against standard of care treatment. Methods: Maps of tumor probability were generated from perfusion/diffusion MRI data from 17 GBM patients via a previously developed model of GBM infiltration. Prescriptions for DP were linearly derived from tumor probability maps and used to develop dose optimized treatment plans. Conformity of DP plans to dose prescriptions was measured via a quality factor. Feasibility of DP plans was evaluated by dose metrics to target volumes and critical brain structures. Expected clinical benefit of DP plans was assessed by tumor control probability. The DP plans were compared to standard radiotherapy plans. Results: The conformity of the DP plans was >90%. Compared to the standard plans, DP (1) did not affect dose delivered to organs at risk; (2) increased mean and maximum dose and improved minimum dose coverage for the target volumes; (3) reduced minimum dose within the radiotherapy treatment margins; (4) improved local tumor control probability within the target volumes for all patients. Conclusions: A multiparametric MRI model of GBM infiltration can enable conformal, feasible, and potentially beneficial dose painting radiotherapy plans.

Prioritising public health: a qualitative study of decision making to reduce health inequalities.

BACKGROUND: The public health system in England is currently facing dramatic change. Renewed attention has recently been paid to the best approaches for tackling the health inequalities which remain entrenched within British society and across the globe. In order to consider the opportunities and challenges facing the new public health system in England, we explored the current experiences of those involved in decision making to reduce health inequalities, taking cardiovascular disease (CVD) as a case study. METHODS: We conducted an in-depth qualitative study employing 40 semi-structured interviews and three focus group discussions. Participants were public health policy makers and planners in CVD in the UK, including: Primary Care Trust and Local Authority staff (in various roles); General Practice commissioners; public health academics; consultant cardiologists; national guideline managers; members of guideline development groups, civil servants; and CVD third sector staff. RESULTS: The short term target- and outcome-led culture of the NHS and the drive to achieve "more for less", combined with the need to address public demand for acute services often lead to investment in "downstream" public health intervention, rather than the "upstream" approaches that are most effective at reducing inequalities. Despite most public health decision makers wishing to redress this imbalance, they felt constrained due to difficulties in partnership working and the over-riding influence of other stakeholders in decision making processes. The proposed public health reforms in England present an opportunity for public health to move away from the medical paradigm of the NHS. However, they also reveal a reluctance of central government to contribute to shifting social norms. CONCLUSIONS: It is vital that the effectiveness and cost effectiveness of all new and existing policies and services affecting public health are measured in terms of their impact on the social determinants of health and health inequalities. Researchers have a vital role to play in providing the complex evidence required to compare different models of prevention and service delivery. Those working in public health must develop leadership to raise the profile of health inequalities as an issue that merits attention, resources and workforce capacity; and advocate for central government to play a key role in shifting social norms.

The Patient Protection and Affordable Care Act of 2010 (PL 111-148): an analysis of maternal-child health home visitation.

On March 23, 2010, President Obama signed the Patient Protection and Affordable Care Act, setting in motion a historic and, for many, a long-awaited radical change to the current American health care system. Section 2951 of the PPACA addresses provision and funding of maternal, infant, and early childhood home visiting programs. The purpose of this article is to acquaint the reader with the legislative odyssey of home visitation services to at-risk prenatal and postpartum women and children as delineated in the PPACA and to discuss the nursing practice and research implications of this landmark legislation. Few question the need for more rigorous methodology in all phases of home visitation research. Public health nursing may provide the comprehensive approach to evaluating effective home visitation programs.

Comparing Two Days of Dietary Intake in What We Eat in America (WWEIA), NHANES, 2013-2016.

The objective of this research is to compare the Day 1 and Day 2 dietary intakes of adults in What We Eat in America, National Health and Nutrition Examination Survey (WWEIA, NHANES) 2013-2016. Dietary recalls of males (n = 2599) and females (n = 2624) 20+ years who had both a Day 1 and Day 2 recall and reported their intake as usual on both days in WWEIA, NHANES 2013-2016 were examined. Mean (±SE) energy intake for males was 2425 ± 26 kcal for Day 1 and 2334 ± 32 kcal for Day 2 (p = 0.004). For females, 1832 ± 18 kcal and 1775 ± 26 kcal were reported for Day 1 and 2, respectively (p = 0.020). There were no significant differences between energy intake on Day 1 and Day 2 within males and females by ten-year age groups. Comparing 20 year age groups for males and females by race/ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic) and income (<131%, 131-350%, and >350% of poverty level) also showed no significant differences in energy intake between Day 1 and Day 2. Mean energy intake of adults was not statistically different between the two days of recall by sex, race/ethnicity or income within selected age groups. Overall, the difference in energy intake was less than 4% for both males and females.

Combining Kangaroo Care and Live-Performed Music Therapy: Effects on Physiological Stability and Neurological Functioning in Extremely and Very Preterm Infants.

Interventions such as kangaroo care (KC) and live-performed music therapy (LPMT), are increasingly used to facilitate stress reduction in neonates. This study aims to investigate the effect of combining the two on physiological responses and neurological functioning in very preterm infants. Infants received six sessions of LPMT. KC was added to one LPMT session. Physiological responses included heart rate, respiratory rate and oxygen saturation. We videotaped infants for 30 min before and after two sessions to assess general movements (GMs). We included 17 infants, gestational age median 26.0 weeks (IQR 25.6-30.6 weeks), of whom six were males. Combined interventions showed a decrease in heart rate from mean 164 bpm before to 157 bpm during therapy, p = 0.001. Oxygen saturation levels increased during combination therapy from median 91.4% to 94.5%, p = 0.044. We found no effects of LPMT or combined interventions on GMs. Infants with a postnatal age (PNA) <7 days generally seem to display less optimal GMs after therapy compared with infants with a PNA >7 days. In conclusion, combining interventions is equally beneficial for physiological stability and neurological functioning as LPMT alone. Future studies should focus on the effects of this combination on parent-infant bonding.

Measurements of human tolerance to horizontal rotation within an MRI scanner: Towards gantry-free radiation therapy.

INTRODUCTION: Recent advances in image guidance and adaptive radiotherapy could enable gantry-free radiotherapy using patient rotation. Gantry-free radiotherapy could substantially reduce the cost of radiotherapy systems and facilities. MRI guidance complements a gantry-free approach because of its ability to visualise soft tissue deformation during rotation. A potential barrier to gantry-free radiotherapy is patient acceptability, especially when combined with MRI. This study investigates human experiences of horizontal rotation within an MRI scanner. METHODS: Ten healthy human participants and nine participants previously treated with radiotherapy were rotated within an MRI scanner. Participants' anxiety and motion sickness was assessed before being rotated in 45-degree increments and paused, representing a multi-field intensity-modulated radiotherapy treatment. An MR image was acquired at each 45-degree angle. Following imaging, anxiety and motion sickness were re-assessed, followed by a comfort questionnaire and exit interview. The significance of the differences in anxiety and motion sickness pre- versus post-imaging was assessed using Wilcoxon signed-rank tests. Content analysis was performed on exit interview transcripts. RESULTS: Eight of ten healthy and eight of nine patient participants completed the imaging session. Mean anxiety scores before and after imaging were 7.9/100 and 11.8/100, respectively (P = 0.26), and mean motion sickness scores were 5.3/100 and 13.7/100, respectively (P = 0.02). Most participants indicated likely acceptance of rotation if MRI were to be used in a hypothetical treatment. Physical discomfort was reported to be the biggest concern. CONCLUSIONS: Horizontal rotation within an MRI scanner was acceptable for most (17/19) participants.

Self-blame, self-forgiveness, and spirituality in breast cancer survivors in a public sector setting.

Cognitive appraisal affects adjustment to breast cancer. A self-forgiving attitude and spirituality may benefit breast cancer survivors who blame themselves for their cancer. One hundred and eight women with early breast cancers completed questionnaires assessing self-blame, self-forgiveness, spirituality, mood and quality of life (QoL) in an outpatient breast clinic. Women who blamed themselves reported more mood disturbance (p < 0.01) and poorer QoL (p < 0.01). Women who were more self-forgiving and more spiritual reported less mood disturbance and better QoL (p's < 0.01). Interventions that reduce self-blame and facilitate self-forgiveness and spirituality could promote better adjustment to breast cancer.

Multicenter evaluation of MRI-based radiomic features: A phantom study.

INTRODUCTION: This work describes the development of a novel radiomics phantom designed for magnetic resonance imaging (MRI) that can be used in a multicenter setting. The purpose of this study is to assess the stability and reproducibility of MRI-based radiomic features using this phantom across different MRI scanners. METHODS & MATERIALS: A set of phantoms were three-dimensional (3D) printed using MRI visible materials. One set of phantoms were imaged on seven MRI scanners and one was imaged on one MRI scanner. Radiomics analysis of the phantoms, which included first-order features, shape and texture features was performed. Intraclass correlation coefficient (ICC) was used to assess the stability of radiomic features across eight scanners and the reproducibility of two printed models on one scanner. Coefficient of variation (COV) was used to assess the reproducibility of radiomics measurements in the phantom on a single scanner. RESULTS: The phantom models provide sufficient signal-to-noise and contrast in all the tumor models permitting robust automatic segmentation. During a 12-month period of monitoring, the phantom material was stable with T1 and T2 of 150.7 ± 6.7 ms and 56.1 ± 3.9 ms, respectively. Of all the radiomic features computed, 34 of 69 had COV < 10%. Features from first-order statistics were the most robust in stability across the eight scanners with eight of 12 (67%) having high stability. About 29 of 50 (58%) texture features had high stability and no shape features had high stability features across the eight scanners. CONCLUSION: A novel MRI radiomics phantom has been developed to assess the reproducibility and stability of MRI-based radiomic features across multiple institutions. The variation in radiomic feature stability demonstrates the need for caution when interpreting these features for clinical studies.

Increased Dose to Organs in Urinary Tract Associates With Measures of Genitourinary Toxicity in Pooled Voxel-Based Analysis of 3 Randomized Phase III Trials.

Purpose: Dose information from organ sub-regions has been shown to be more predictive of genitourinary toxicity than whole organ dose volume histogram information. This study aimed to identify anatomically-localized regions where 3D dose is associated with genitourinary toxicities in healthy tissues throughout the pelvic anatomy. Methods and Materials: Dose distributions for up to 656 patients of the Trans-Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar CT dataset. Voxel- based multiple comparison permutation dose difference testing, Cox regression modeling and LASSO feature selection were used to identify regions where 3D dose-increase was associated with late grade ≥ 2 genitourinary dysuria, incontinence and frequency, and late grade ≥ 1 haematuria. This was externally validated by registering dose distributions from the RT01 (up to n = 388) and CHHiP (up to n = 247) trials onto the same exemplar and repeating the voxel-based tests on each of these data sets. All three datasets were then combined, and the tests repeated. Results: Voxel-based Cox regression and multiple comparison permutation dose difference testing revealed regions where increased dose was correlated with genitourinary toxicity. Increased dose in the vicinity of the membranous and spongy urethra was associated with dysuria for all datasets. Haematuria was similarly correlated with increased dose at the membranous and spongy urethra, for the RADAR, CHHiP, and combined datasets. Some evidence was found for the association between incontinence and increased dose at the internal and external urethral sphincter for RADAR and the internal sphincter alone for the combined dataset. Incontinence was also strongly correlated with dose from posterior oblique beams. Patients with fields extending inferiorly and posteriorly to the CTV, adjacent to the membranous and spongy urethra, were found to experience increased frequency. Conclusions: Anatomically-localized dose-toxicity relationships were determined for late genitourinary symptoms in the urethra and urinary sphincters. Low-intermediate doses to the extraprostatic urethra were associated with risk of late dysuria and haematuria, while dose to the urinary sphincters was associated with incontinence.

Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials.

PURPOSE: Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by using high-quality prostate radiation therapy clinical trial data to identify anatomically localized regions where dose variation is associated with prostate-specific antigen progression (PSAP). METHODS AND MATERIALS: Planned dose distributions for 683 patients of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (RADAR) trial were deformably registered onto a single exemplar computed tomography data set. These were divided into high-risk and intermediate-risk subgroups for analysis. Three independent voxel-based statistical tests, using permutation testing, Cox regression modeling, and least absolute shrinkage selection operator feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk RADAR subgroup were externally validated by registering dose distributions from the RT01 (n = 388) and Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer Trial (CHHiP) (n = 253) trials onto the same exemplar and repeating the tests on each of these data sets. RESULTS: Voxel-based Cox regression revealed regions where reduced dose was correlated with increased prostate-specific androgen progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate, and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for RADAR and RT01 patients, but not for CHHiP patients. Reduced dose to the seminal vesicle region was also associated with increased PSAP for RADAR intermediate-risk patients. CONCLUSIONS: Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the seminal vesicles), where aggressive cancer spread may be occurring, may improve tumor control. It is recommended that particular care be taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients.