Multi-Institutional Audit of FLASH and Conventional Dosimetry With a 3D Printed Anatomically Realistic Mouse Phantom.

PURPOSE: We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3-dimensional (3D) printed mouse phantom. METHODS AND MATERIALS: A computed tomography (CT) scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm3) and polylactic acid (∼1.24 g/cm3) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm3). Hounsfield units (HU), densities, and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom and each institution performed 2 replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film. RESULTS: Compared with the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm3 for bone, 0.12 g/cm3 for lung, and 0.03 g/cm3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal effect on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3%-1.2%), and differences from the prescribed dose decreased for both CONV (3.6%-2.5%) and FLASH (6.4%-2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, although these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance. CONCLUSIONS: This study marks the first dosimetric audit for FLASH using a nonhomogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biologic findings.

Age-Specific Association of Co-Morbidity With Home-Time After Acute Stroke.

OBJECTIVE: To examine the association of co-morbidity with home-time after acute stroke and whether the association is influenced by age. METHODS: We conducted a province-wide study using linked administrative databases to identify all admissions for first acute ischemic stroke or intracerebral hemorrhage between 2007 and 2018 in Alberta, Canada. We used ischemic stroke-weighted Charlson Co-morbidity Index of 3 or more to identify those with severe co-morbidity. We used zero-inflated negative binomial models to determine the association of severe co-morbidity with 90-day and 1-year home-time, and logistic models for achieving ≥ 80 out of 90 days of home-time, assessing for effect modification by age and adjusting for sex, stroke type, comprehensive stroke center care, hypertension, atrial fibrillation, year of study, and separately adjusting for estimated stroke severity. We also evaluated individual co-morbidities. RESULTS: Among 28,672 patients in our final cohort, severe co-morbidity was present in 27.7% and was associated with lower home-time, with a greater number of days lost at younger age (-13 days at age < 60 compared to -7 days at age 80+ years for 90-day home-time; -69 days at age < 60 compared to -51 days at age 80+ years for 1-year home-time). The reduction in probability of achieving ≥ 80 days of home-time was also greater at younger age (-22.7% at age < 60 years compared to -9.0% at age 80+ years). Results were attenuated but remained significant after adjusting for estimated stroke severity and excluding those who died. Myocardial infarction, diabetes, and cancer/metastases had a greater association with lower home-time at younger age, and those with dementia had the greatest reduction in home time. CONCLUSION: Severe co-morbidity in acute stroke is associated with lower home-time, more strongly at younger age.

A clinical solution for non-toxic 3D-printed photon blocks in external beam radiation therapy.

PURPOSE: A well-known limitation of multi-leaf collimators is that they cannot easily form island blocks. This can be important in mantle region therapy. Cerrobend photon blocks, currently used for supplementary shielding, are labor-intensive and error-prone. To address this, an innovative, non-toxic, automatically manufactured photon block using 3D-printing technology is proposed, offering a patient-specific and accurate alternative. METHODS AND MATERIALS: The study investigates the development of patient-specific photon shielding blocks using 3D-printing for three different patient cases. A 3D-printed photon block shell filled with tungsten ball bearings (BBs) was designed to have similar dosimetric properties to Cerrobend standards. The generation of the blocks was automated using the Eclipse Scripting API and Python. Quality assurance was performed by comparing the expected and actual weight of the tungsten BBs used for shielding. Dosimetric and field geometry comparisons were conducted between 3D-printed and Cerrobend blocks, utilizing ionization chambers, imaging, and field geometry analysis. RESULTS: The quality assurance assessment revealed a -1.3% average difference in the mass of tungsten ball bearings for different patients. Relative dose output measurements for three patient-specific blocks in the blocked region agreed within 2% of each other. Against the Treatment Planning System (TPS), both 3D-printed and Cerrobend blocks agreed within 2%. For each patient, 6 MV image profiles taken through the 3D-printed and Cerrobend blocks agreed within 1% outside high gradient regions. Jaccard distance analysis of the MV images against the TPS planned images, found Cerrobend blocks to have 15.7% dissimilarity to the TPS, while that of the 3D-printed blocks was 6.7%. CONCLUSIONS: This study validates a novel, efficient 3D-printing method for photon block creation in clinical settings. Despite potential limitations, the benefits include reduced manual labor, automated processes, and greater precision. It holds potential for widespread adoption in radiation therapy, furthering non-toxic radiation shielding.

A Couch Mounted Smartphone-based Motion Monitoring System for Radiation Therapy.

PURPOSE: Surface-guided radiation-therapy (SGRT) systems are being adopted into clinical practice for patient setup and motion monitoring. However, commercial systems remain cost prohibitive to resource-limited clinics around the world. Our aim is to develop and validate a smartphone-based application using LiDAR cameras (such as on recent Apple iOS devices) for facilitating SGRT in low-resource centers. The proposed SGRT application was tested at multiple institutions and validated using phantoms and volunteers against various commercial systems to demonstrate feasibility. METHODS AND MATERIALS: An iOS application was developed in Xcode and written in Swift using the Augmented-Reality (AR) Kit and implemented on an Apple iPhone 13 Pro with a built-in LiDAR camera. The application contains multiple features: 1) visualization of both the camera and depth video feeds (at a ∼60Hz sample-frequency), 2) region-of-interest (ROI) selection over the patient's anatomy where motion is measured, 3) chart displaying the average motion over time in the ROI, and 4) saving/exporting the motion traces and surface map over the ROI for further analysis. The iOS application was tested to evaluate depth measurement accuracy for: 1) different angled surfaces, 2) different field-of-views over different distances, and 3) similarity to a commercially available SGRT systems (Vision RT AlignRT and Varian IDENTIFY) with motion phantoms and healthy volunteers across 3 institutions. Measurements were analyzed using linear-regressions and Bland-Altman analysis. RESULTS: Compared with the clinical system measurements (reference), the iOS application showed excellent agreement for depth (r = 1.000, P < .0001; bias = -0.07±0.24 cm) and angle (r = 1.000, P < .0001; bias = 0.02±0.69°) measurements. For free-breathing traces, the iOS application was significantly correlated to phantom motion (institute 1: r = 0.99, P < .0001; bias =-0.003±0.03 cm; institute 2: r = 0.98, P < .0001; bias = -0.001±0.10 cm; institute 3: r = 0.97, P < .0001; bias = 0.04±0.06 cm) and healthy volunteer motion (institute 1: r = 0.98, P < .0001; bias = -0.008±0.06 cm; institute 2: r = 0.99, P < .0001; bias = -0.007±0.12 cm; institute 3: r = 0.99, P < .0001; bias = -0.001±0.04 cm). CONCLUSIONS: The proposed approach using a smartphone-based application provides a low-cost platform that could improve access to surface-guided radiation therapy accounting for motion.

Rib Fragility Fractures and Chest Wall Hematoma After Cardiopulmonary Resuscitation Training: A Case Report.

Fragility fractures commonly manifest as complications in individuals with diminished bone mineral density and other risk factors. The hip, vertebral body, and wrist are the most documented locations of fragility fractures among patients with osteoporosis or osteopenia. This report presents a rare case of multiple fragility fractures of the right ribs accompanied by an adjacent right chest wall hematoma in an otherwise healthy 60-year-old woman after participating in cardiopulmonary resuscitation (CPR) training. Upon further workup, a diagnosis of osteopenia was established. This report aims to underscore a potential complication in those performing CPR and outline the clinicoradiological presentations, diagnostic workup, and treatment of fragility fractures in patients with no history of prior underlying skeletal conditions or malignancy.

Tungsten Filled 3-Dimensional Printed Lung Blocks for Total Body Irradiation.

PURPOSE: Lung blocks for total-body irradiation are commonly used to reduce lung dose and prevent radiation pneumonitis. Currently, molten Cerrobend containing toxic materials, specifically lead and cadmium, is poured into molds to construct blocks. We propose a streamlined method to create 3-dimensional (3D)-printed lung block shells and fill them with tungsten ball bearings to remove lead and improve overall accuracy in the block manufacturing workflow. METHODS AND MATERIALS: 3D-printed lung block shells were automatically generated using an inhouse software, printed, and filled with 2 to 3 mm diameter tungsten ball bearings. Clinical Cerrobend blocks were compared with the physician drawn blocks as well as our proposed tungsten filled 3D-printed blocks. Physical and dosimetric comparisons were performed on a linac. Dose transmission through the Cerrobend and 3D-printed blocks were measured using point dosimetry (ion-chamber) and the on-board Electronic-Portal-Imaging-Device (EPID). Dose profiles from the EPID images were used to compute the full-width-half-maximum and to compare with the treatment-planning-system. Additionally, the coefficient-of-variation in the central 80% of full-width-half-maximum was computed and compared between Cerrobend and 3D-printed blocks. RESULTS: The geometric difference between treatment-planning-system and 3D-printed blocks was significantly lower than Cerrobend blocks (3D: -0.88 ± 2.21 mm, Cerrobend: -2.28 ± 2.40 mm, P = .0002). Dosimetrically, transmission measurements through the 3D-printed and Cerrobend blocks for both ion-chamber and EPID dosimetry were between 42% to 48%, compared with the open field. Additionally, coefficient-of-variation was significantly higher in 3D-printed blocks versus Cerrobend blocks (3D: 4.2% ± 0.6%, Cerrobend: 2.6% ± 0.7%, P < .0001). CONCLUSIONS: We designed and implemented a tungsten filled 3D-printed workflow for constructing total-body-irradiation lung blocks, which serves as an alternative to the traditional Cerrobend based workflow currently used in clinics. This workflow has the capacity of producing clinically useful lung blocks with minimal effort to facilitate the removal of toxic materials from the clinic.

Long non-coding RNA generated from CDKN1A gene by alternative polyadenylation regulates p21 expression during DNA damage response.

Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DDR-activated APA event occurs in the first intron of CDKN1A, inducing an alternate last exon-containing lncRNA. We named this lncRNA SPUD (Selective Polyadenylation Upon DNA Damage). SPUD localizes to polysomes in the cytoplasm and is detectable as multiple isoforms in available high-throughput studies. SPUD has low abundance compared to the CDKN1A full-length isoform under non-stress conditions, and SPUD is induced in cancer and normal cells under a variety of DNA damaging conditions in part through p53. The RNA binding protein HuR binds to and promotes the stability of SPUD precursor RNA. SPUD induction increases p21 protein, but not mRNA levels, affecting p21 functions in cell-cycle, CDK2 expression and cell growth. Like CDKN1A full-length isoform, SPUD can bind two competitive p21 translational regulators, the inhibitor calreticulin and the activator CUGBP1; SPUD alters their association with CDKN1A full-length in a DDR-dependent manner, promoting CDKN1A translation. Together, these results show a new regulatory mechanism by which a lncRNA controls p21 expression post-transcriptionally, highlighting lncRNA relevance in DDR progression and cell-cycle.

FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates.

BACKGROUND AND PURPOSE: The impact of radiotherapy (RT) at ultra high vs conventional dose rate (FLASH vs CONV) on the generation and repair of DNA double strand breaks (DSBs) is an important question that remains to be investigated. Here, we tested the hypothesis as to whether FLASH-RT generates decreased chromosomal translocations compared to CONV-RT. MATERIALS AND METHODS: We used two FLASH validated electron beams and high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), employing S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs) in HEK239T cells, to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated after various irradiation doses, dose rates and oxygen tensions (normoxic, 21% O2; physiological, 4% O2; hypoxic, 2% and 0.5% O2). Electron irradiation was delivered using a FLASH capable Varian Trilogy and the eRT6/Oriatron at CONV (0.08-0.13 Gy/s) and FLASH (1x102-5x106 Gy/s) dose rates. Related experiments using clonogenic survival and γH2AX foci in the 293T and the U87 glioblastoma lines were also performed to discern FLASH-RT vs CONV-RT DSB effects. RESULTS: Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Furthermore, RT dose rate modality on U87 cells did not change γH2AX foci numbers at 1- and 24-hours post-irradiation nor did this affect 293T clonogenic survival. CONCLUSION: Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

Shaping success: clinical implementation of a 3D-printed electron cutout program in external beam radiation therapy.

Purpose: The integration of 3D-printing technology into radiation therapy (RT) has allowed for a novel method to develop personalized electron field-shaping blocks with improved accuracy. By obviating the need for handling highly toxic Cerrobend molds, the clinical workflow is significantly streamlined. This study aims to expound upon the clinical workflow of 3D-printed electron cutouts in RT and furnish one year of in-vivo dosimetry data. Methods and materials: 3D-printed electron cutouts for 6x6 cm, 10x10 cm, and 15x15 cm electron applicators were designed and implemented into the clinical workflow after dosimetric commissioning to ensure congruence with the Cerrobend cutouts. The clinical workflow consisted of four parts: i) the cutout aperture was extracted from the treatment planning system (TPS). A 3D printable cutout was then generated automatically through custom scripts; ii) the cutout was 3D-printed with PLA filament, filled with tungsten ball bearings, and underwent quality assurance (QA) to verify density and dosimetry; iii) in-vivo dosimetry was performed with optically stimulated luminescence dosimeters (OSLDs) for a patient's first treatment and compared to the calculated dose in the TPS; iv) after treatment completion, the 3D-printed cutout was recycled. Results: QA and in-vivo OSLD measurements were conducted (n=40). The electron cutouts produced were 6x6 cm (n=3), 10x10 cm (n=30), and 15x15 cm (n=7). The expected weight of the cutouts differed from the measured weight by 0.4 + 1.1%. The skin dose measured with the OSLDs was compared to the skin dose in the TPS on the central axis. The difference between the measured and TPS doses was 4.0 + 5.2%. Conclusion: The successful clinical implementation of 3D-printed cutouts reduced labor, costs, and removed the use of toxic materials in the workplace while meeting clinical dosimetric standards.

Trends and Prescriber Variation in the Duration of Oxaliplatin-Containing Adjuvant Chemotherapy for Stage III Colon Cancer From 2007 to 2019: A Population-Based Retrospective Cohort Study.

INTRODUCTION: The International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration in 2017 established 3 months of adjuvant therapy as an alternative to 6 months of therapy for stage III colon cancer. We determined the association between the IDEA publication, changes in clinical practice, and prescriber variation. PATIENTS AND METHODS: Using linked databases, we identified Ontarians aged ≥18 years at diagnosis of stage III colon cancer between 2007 and 2019 who received oxaliplatin-containing adjuvant therapy. The outcome was duration of therapy, categorized as ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% of a 6-month course of therapy to approximate treatment durations in the IDEA collaboration. We examined trends in duration over time using an interrupted time series regression model. We analyzed treatment duration after accounting for patient and prescriber characteristics, using multivariable mixed effects logistic regression models to quantify between-prescriber variation. RESULTS: We included 4695 patients with stage III colon cancer who received oxaliplatin-containing adjuvant chemotherapy, of whom 77.5% initiated treatment pre-IDEA and 22.5% initiated treatment post-IDEA. Post-IDEA, there was a 16.4% (95% CI, 12.5%-20.3%) absolute increase in the proportion of patients treated with ≤50% of a maximal course of therapy. This trend was greatest among patients with low-risk tumors. Prescriber variation increased pre-IDEA to 15.6% post-IDEA (variance partition coefficient 5.4% pre-IDEA and 15.6% post-IDEA). CONCLUSION: The publication of IDEA was associated with increases in short duration adjuvant therapy and prescriber-level practice variation for stage III colon cancer. Clinicians should be better supported to make consistent recommendations about adjuvant duration under conditions of uncertainty and trade-offs.

Racial and Ethnic Distribution in Diabetic Macular Edema Clinical Trials in the United States (2002-2021).

PURPOSE: Diabetic macular edema (DME), the leading cause of vision loss among patients with diabetes mellitus, disproportionately affects Black and Hispanic patients. Currently, non-White racial and ethnic subgroups are frequently underrepresented in clinical trials, limiting the application of results to the most pertinent patient populations. Thus, we aimed to characterize the trajectory of racial reporting as well as changes and disparities in racial and ethnic distribution among participants of DME clinical trials. DESIGN: This is a cross-sectional retrospective study. SUBJECTS: Patients enrolled in United States (US)-based clinical trials for DME. METHODS: We examined the racial and ethnic demographic distribution of participants in clinical trials related to DME across a 20-year period from 2002 to 2021. Clinical trials were screened from ClinicalTrials.gov for DME, US trial location, study completion, and > 50 patient enrollment. Descriptive statistics, proportions, odds ratios (ORs), and chi-square tests were reported and compared with 2021 US Census demographic data and diagnosed patients with diabetes demographic data. MAIN OUTCOME MEASURES: Change in racial reporting and race/ethnicity across 2 decades and comparison of racial/ethnic distribution with 2021 US Census demographics and diagnosed patients with diabetes. RESULTS: There was an increase in race reporting from January 2002 to December 2011 (8 trials [40%]) versus January 2012 to December 2021 (20 trials [87%]; OR, 10.00; 95% confidence interval [CI], 2.21-45.16; P = 0.0032). Across the 2 decades, the proportion of Asian patients enrolled increased from 2.4% to 8.0% (OR, 3.47; 95% CI, 2.64-4.56; P < 0.0001). Similarly, the proportion of enrolled Hispanic patients increased from 13.4% to 19.5% (OR, 1.56; 95% CI, 1.37-1.78; P < 0.0001). Compared with diabetes prevalence, many minority groups are underrepresented in the total enrollment of DME clinical trial patients (Black [z = -18.51, P < 0.001]; Asian [z = -5.11, P < 0.0001]; Hispanic [chi-square = 274.7, df = 1, P < 0.0001]). CONCLUSIONS: In the past 2 decades, there has been a trend of increased racial reporting and minority patient enrollment in DME clinical trials. However, Black, Asian, and Hispanic patients remain significantly underrepresented among the DME clinical trial patient population based on diabetes prevalence. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Association of Oxaliplatin-Containing Adjuvant Chemotherapy Duration with Overall and Cancer-Specific Mortality in Individuals with Stage III Colon Cancer: A Population-Based Retrospective Cohort Study.

PURPOSE: Few studies have examined the relationship between duration of oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer and mortality in routine practice. We examined the association between treatment with 50% versus >85% of a maximal course of adjuvant therapy (eight cycles of CAPOX, twelve cycles of FOLFOX) and mortality in stage III colon cancer. METHODS: Using linked databases, we identified Ontarians aged ≥18 years at diagnosis of stage III colon cancer between 2007 and 2019. In the primary comparison, we compared patients who received 50% or >85% of a maximal course of adjuvant therapy; in a secondary comparison, we evaluated a dose effect across patients who received FOLFOX in one-cycle increments from six to ten cycles against >85% (more than ten cycles) of a maximal course of FOLFOX. The main outcomes were overall and cancer-specific mortality. Follow-up began 270 days after adjuvant treatment initiation and terminated at the first of the outcome of interest, loss of eligibility for Ontario's Health Insurance Program, or study end. Overlap propensity score weights accounted for baseline between-group differences. We determined the hazard ratio, estimating the association between mortality and treatment. Non-inferiority was concluded in the primary comparison for either outcome if the upper limit of the two-sided 95% CI was ≤1.11, which is the margin used in the International Duration Evaluation of Adjuvant Chemotherapy Collaboration. RESULTS: We included 3546 patients in the analysis of overall mortality; 486 (13.7%) received 50% and 3060 (86.3%) received >85% of a maximal course of therapy. Median follow-up was 5.4 years, and total follow-up was 20,510 person-years. There were 833 deaths. Treatment with 50% of a maximal course of adjuvant therapy was associated with a hazard ratio of 1.13 (95% CI 0.88 to 1.47) for overall mortality and a subdistribution hazard ratio of 1.31 (95% CI 0.91 to 1.87) for cancer-specific mortality versus >85% of a maximal course of therapy. In the secondary comparison, there was a trend toward higher overall mortality in patients treated with shorter durations of therapy, though confidence intervals overlapped considerably. CONCLUSION: We could not conclude that treatment with 50% of a maximal course is non-inferior to >85% of a maximal course of adjuvant therapy for mortality in stage III colon cancer. Clinicians and patients engaging in decision-making around treatment duration in this context should carefully consider the trade-off between treatment effectiveness and adverse effects of treatment.

An Affordable Platform for Virtual Reality-Based Patient Education in Radiation Therapy.

PURPOSE: The goal of this study was to develop and assess the effectiveness of an affordable smartphone-based virtual reality (VR) patient education platform with 360-degree videos produced depicting a first-person patient perspective during the radiation therapy (RT) care path to reduce patient anxiety. METHODS AND MATERIALS: Three disease site-specific (breast, pelvis, head and neck) VR videos were filmed using a 360-degree camera to portray the first-person perspective of a patient's standard RT appointments, including a computed tomography simulation and the first RT treatment session. Instruction is given for possible clinical implementation. Patient participation was divided into 2 groups: (1) Group A (n = 28) included patients participating before simulation and later after the first treatment, and (2) Group B (n = 33) included patients participating only while undergoing treatment. Patients viewed their disease site-specific video using an inexpensive cardboard VR viewer and their smartphone, emulating an expensive VR-headset. Surveys were administered assessing patient anxiety, comfort, satisfaction, and knowledge of RT on a 5-point Likert-type scale. RESULTS: Patients in Group A and Group B while undergoing treatment both indicated that their anxiety "decreased a little" in the survey, after watching the VR video (Group A, median on a 5-point Likert-type scale, 4 [IQR, 4-5]; Group B, 4 [IQR, 4-4]). The VR aspect of the videos was especially liked by patients while undergoing treatment, with 96.4% in Group A and 90.9% in Group B reporting that the VR aspect of the videos was helpful. All Group A participants believed that the VR videos would be beneficial to new patients. CONCLUSIONS: Our affordable VR patient education platform effectively immerses a patient in their care path from simulation through initial treatment delivery, reducing anxiety and increasing familiarity with the treatment process.

Randomised controlled trials of non-pharmacological interventions to improve patient-reported outcomes of colonoscopy: a scoping review.

BACKGROUND AND AIMS: Non-pharmacological interventions to improve patient-reported outcomes of colonoscopy may be effective at mitigating negative experiences and perceptions of the procedure, but research to characterise the extent and features of studies of these interventions is limited. METHODS: We conducted a scoping review searching multiple databases for peer-reviewed publications of randomised controlled trials conducted in adults investigating a non-pharmacological intervention to improve patient-reported outcomes of colonoscopy. Study characteristics were tabulated and summarised narratively and graphically. RESULTS: We screened 5939 citations and 962 full texts, and included 245 publications from 39 countries published between 1992 and 2022. Of these, 80.8% were full publications and 19.2% were abstracts. Of the 41.9% of studies reporting funding sources, 11.4% were unfunded. The most common interventions were carbon dioxide and/or water insufflation methods (33.9%), complementary and alternative medicines (eg, acupuncture) (20.0%), and colonoscope technology (eg, magnetic scope guide) (21.6%). Pain was as an outcome across 82.0% of studies. Studies most often used a patient-reported outcome examining patient experience during the procedure (60.0%), but 42.9% of studies included an outcome without specifying the time that the patient experienced the outcome. Most intraprocedural patient-reported outcomes were measured retrospectively rather than contemporaneously, although studies varied in terms of when outcomes were assessed. CONCLUSION: Research on non-pharmacological interventions to improve patient-reported outcomes of colonoscopy is unevenly distributed across types of intervention and features high variation in study design and reporting, in particular around outcomes. Future research efforts into non-pharmacological interventions to improve patient-reported outcomes of colonoscopy should be directed at underinvestigated interventions and developing consensus-based guidelines for study design, with particular attention to how and when outcomes are experienced and measured. PROSPERO REGISTRATION NUMBER: 42020173906.

Real-World Experience With Tofacitinib Dose De-Escalation in Patients With Moderate and Severe Ulcerative Colitis.

BACKGROUND & AIMS: Tofacitinib is associated with sustained steroid-free remission in patients with ulcerative colitis (UC), with the lowest effective dose recommended for maintenance therapy. However, there are limited real-world data to guide decisions on the optimal maintenance regimen. We aimed to evaluate predictors and outcomes of disease activity after tofacitinib dose de-escalation in this population. METHODS: Included were adults with moderate-severe UC treated with tofacitinib between June 2012 and January 2022. The primary outcome was evidence of UC disease activity-related events: hospitalization/surgery, corticosteroid initiation, tofacitinib dose increase, or therapy switch. RESULTS: Among 162 patients, 52% continued 10 mg twice daily while 48% underwent dose de-escalation to 5 mg twice daily. Cumulative incidence rates of UC events at 12 months were similar in patients with and without dose de-escalation (56% vs 58%; P = .81). In univariable Cox regression among patients with dose de-escalation, an induction course with 10 mg twice daily for more than 16 weeks was protective of UC events (hazard ratio [HR], 0.37; 95% CI, 0.16-0.85) while ongoing severe disease (Mayo 3) was associated with UC events (HR, 6.41; 95% 95% CI, 2.23-18.44), which remained significant after adjusting for age, sex, duration of induction course, and corticosteroid use at dose de-escalation (HR, 6.05; 95% CI, 2.00-18.35). Twenty-nine percent of patients with UC events had their dose re-escalated to 10 mg twice daily, with only 63% able to recapture clinical response at 12 months. CONCLUSIONS: In this real-world cohort, we observed a 56% cumulative incidence of UC events at 12 months in patients with tofacitinib dose de-escalation. Observed factors associated with UC events after dose de-escalation included induction course for fewer than 16 weeks and active endoscopic disease 6 months after initiation.

FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates.

The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV-RT) radiotherapy dose-rate remain to be elucidated. However, attenuated DNA damage and transient oxygen depletion are among several proposed models. Here, we tested whether FLASH-RT under physioxic (4% O 2 ) and hypoxic conditions (≤2% O 2 ) reduces genome-wide translocations relative to CONV-RT and whether any differences identified revert under normoxic (21% O 2 ) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing ( HTGTS-JoinT-seq ), using S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs), to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated by electron beam CONV-RT (0.08-0.13Gy/s) and FLASH-RT (1×10 2 -5×10 6 Gy/s), under varying ionizing radiation (IR) doses and oxygen tensions. Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Thus, Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

3D printing in brachytherapy: A systematic review of gynecological applications.

PURPOSE: To provide a systematic review of the applications of 3D printing in gynecological brachytherapy. METHODS: Peer-reviewed articles relating to additive manufacturing (3D printing) from the 34 million plus biomedical citations in National Center for Biotechnology Information (NCBI/PubMed), and 53 million records in Web of Science (Clarivate) were queried for 3D printing applications. The results were narrowed sequentially to, (1) all literature in 3D printing with final publications prior to July 2022 (in English, and excluding books, proceedings, and reviews), and then to applications in, (2) radiotherapy, (3) brachytherapy, (4) gynecological brachytherapy. Brachytherapy applications were reviewed and grouped by disease site, with gynecological applications additionally grouped by study type, methodology, delivery modality, and device type. RESULTS: From 47,541 3D printing citations, 96 publications met the inclusion criteria for brachytherapy, with gynecological clinical applications compromising the highest percentage (32%), followed by skin and surface (19%), and head and neck (9%). The distribution of delivery modalities was 58% for HDR (Ir-192), 35% for LDR (I-125), and 7% for other modalities. In gynecological brachytherapy, studies included design of patient specific applicators and templates, novel applicator designs, applicator additions, quality assurance and dosimetry devices, anthropomorphic gynecological applicators, and in-human clinical trials. Plots of year-to-year growth demonstrate a rapid nonlinear trend since 2014 due to the improving accessibility of low-cost 3D printers. Based on these publications, considerations for clinical use are provided. CONCLUSIONS: 3D printing has emerged as an important clinical technology enabling customized applicator and template designs, representing a major advancement in the methodology for implantation and delivery in gynecological brachytherapy.

Clinical Linear Accelerator-Based Electron FLASH: Pathway for Practical Translation to FLASH Clinical Trials.

PURPOSE: Ultrahigh-dose-rate (UHDR) radiation therapy (RT) has produced the FLASH effect in preclinical models: reduced toxicity with comparable tumor control compared with conventional-dose-rate RT. Early clinical trials focused on UHDR RT feasibility using specialized devices. We explore the technical feasibility of practical electron UHDR RT on a standard clinical linear accelerator (LINAC). METHODS AND MATERIALS: We tuned the program board of a decommissioned electron energy for UHDR electron delivery on a clinical LINAC without hardware modification. Pulse delivery was controlled using the respiratory gating interface. A short source-to-surface distance (SSD) electron setup with a standard scattering foil was configured and tested on an anthropomorphic phantom using circular blocks with 3- to 20-cm field sizes. Dosimetry was evaluated using radiochromic film and an ion chamber profiler. RESULTS: UHDR open-field mean dose rates at 100, 80, 70, and 59 cm SSD were 36.82, 59.52, 82.01, and 112.83 Gy/s, respectively. At 80 cm SSD, mean dose rate was ∼60 Gy/s for all collimated field sizes, with an R80 depth of 6.1 cm corresponding to an energy of 17.5 MeV. Heterogeneity was <5.0% with asymmetry of 2.2% to 6.2%. The short SSD setup was feasible under realistic treatment conditions simulating broad clinical indications on an anthropomorphic phantom. CONCLUSIONS: Short SSD and tuning for high electron beam current on a standard clinical LINAC can deliver flat, homogenous UHDR electrons over a broad, clinically relevant range of field sizes and depths with practical working distances in a configuration easily reversible to standard clinical use.

Top Ten Tips Palliative Care Clinicians Should Know about Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative condition of the central nervous system, with distinct challenges due to its heterogeneous presentation, prognostic uncertainty, and variable clinical course of neurological and non-neurological symptoms and disability. Although there have been significant advances in management of MS, many patients experience disability progression. Despite MS being a frequent cause of neurological disability, particularly in young persons, involvement of palliative care physicians in the care of patients with MS has been limited. This article provides ten tips for palliative clinicians for caring for patients with MS and their care partners.

Effects of a Province-wide Triaging System for TIA: The ASPIRE Intervention.

BACKGROUND AND OBJECTIVES: Urgent transient ischemic attack (TIA) management to reduce stroke recurrence is challenging, particularly in rural and remote areas. In Alberta, Canada, despite an organized stroke system, data from 1999 to 2000 suggested that stroke recurrence after TIA was as high as 9.5% at 90 days. Our objective was to determine whether a multifaceted population-based intervention resulted in a reduction in recurrent stroke after TIA. METHODS: In this quasi-experimental health services research intervention study, we implemented a TIA management algorithm across the entire province, centered around a 24-hour physician's TIA hotline and public and health provider education on TIA. From administrative databases, we linked emergency department discharge abstracts to hospital discharge abstracts to identify incident TIAs and recurrent strokes at 90 days across a single payer system with validation of recurrent stroke events. The primary outcome was recurrent stroke; with a secondary composite outcome of recurrent stroke, acute coronary syndrome, and all-cause death. We used an interrupted time series regression analysis of age-adjusted and sex-adjusted stroke recurrence rates after TIA, incorporating a 2-year preimplementation period (2007-2009), a 15-month implementation period, and a 2-year postimplementation period (2010-2012). Logistic regression was used to examine outcomes that did not fit the time series model. RESULTS: We assessed 6,715 patients preimplementation and 6,956 patients postimplementation. The 90-day stroke recurrence rate in the pre-Alberta Stroke Prevention in TIA and mild Strokes (ASPIRE) period was 4.5% compared with 5.3% during the post-ASPIRE period. There was neither a step change (estimate 0.38; p = 0.65) nor slope change (parameter estimate 0.30; p = 0.12) in recurrent stroke rates associated with the ASPIRE intervention implementation period. Adjusted all-cause mortality (odds ratio 0.71, 95% CI 0.56-0.89) was significantly lower after the ASPIRE intervention. DISCUSSION: The ASPIRE TIA triaging and management interventions did not further reduce stroke recurrence in the context of an organized stroke system. The apparent lower mortality postintervention may be related to improved surveillance after events identified as TIAs, but secular trends cannot be excluded. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a standardized population-wide algorithmic triage system for patients with TIA did not reduce recurrent stroke rate.