Real-World Patterns and Economic Burden Associated With Treatment Failure With Advanced Therapies in Patients With Moderate-to-Severe Ulcerative Colitis.

Background: Some patients lose response during treatment for moderate-to-severe ulcerative colitis (UC). We aimed to characterize real-world treatment failure patterns and associated economic burdens during use of first-line advanced therapies for UC. Methods: IBM MarketScan Commercial and Medicare Supplemental Databases were used to identify adults initiating ≥ 1 advanced therapy for UC (January 1, 2010-September 30, 2019). Treatment failure was defined as augmentation with non-advanced therapy, discontinuation, dose escalation/interval shortening, failure to taper corticosteroids, UC-related surgery, or UC-related urgent care ≤ 12 months after treatment initiation. The index date was the date of treatment failure (treatment failure cohort) or 12 months after treatment initiation (persistent cohort). Treatment failure rates were assessed using Kaplan-Meier analyses. All-cause and UC-related healthcare resource utilization (HCRU) and costs 12 months post-index were also assessed. Results: Analysis of treatment failure patterns included data from 6745 patients; HCRU and cost analyses included data from 5302 patients (treatment failure cohort, n = 4295; persistent cohort, n = 1007). In the overall population, 75% experienced treatment failure within the first 12 months (median: 5.1 months). Augmentation with non-advanced therapy (39%) was the most common first treatment failure event. The treatment failure cohort had significantly (P < .001) higher mean costs than the persistent cohort (all-cause, $74 995 vs $56 169; UC-related, $57 096 vs $47 347) mainly attributed to inpatient admissions and outpatient visits. Dose escalation/interval shortening accounted for the highest total costs ($101 668) across treatment failure events. Conclusions: Advanced therapies for moderate-to-severe UC are associated with high rates of treatment failure and significant economic burden. More efficacious and durable treatments are needed.

Clinical physicists' perceptions of weekly chart checks and the potential role for automated image review assessed by structured interviews.

BACKGROUND: This study utilizes interviews of clinical medical physicists to investigate self-reported shortcomings of the current weekly chart check workflow and opportunities for improvement. METHODS: Nineteen medical physicists were recruited for a 30-minute semi-structured interview, with a particular focus placed on image review and the use of automated tools for image review in weekly checks. Survey-type questions were used to gather quantitative information about chart check practices and importance placed on reducing chart check workloads versus increasing chart check effectiveness. Open-ended questions were used to probe respondents about their current weekly chart check workflow, opinions of the value of weekly chart checks and perceived shortcomings, and barriers and facilitators to the implementation of automated chart check tools. Thematic analysis was used to develop common themes across the interviews. RESULTS: Physicists ranked highly the value of reducing the time spent on weekly chart checks (average 6.3 on a scale from 1 to 10), but placed more value on increasing the effectiveness of checks with an average of 9.2 on a 1-10 scale. Four major themes were identified: (1) weekly chart checks need to adapt to an electronic record-and-verify chart environment, (2) physicists could add value to patient care by analyzing images without duplicating the work done by physicians, (3) greater support for trending analysis is needed in weekly checks, and (4) automation has the potential to increase the value of physics checks. CONCLUSION: This study identified several key shortcomings of the current weekly chart check process from the perspective of the clinical medical physicist. Our results show strong support for automating components of the weekly check workflow in order to allow for more effective checks that emphasize follow-up, trending, failure modes and effects analysis, and allow time to be spent on other higher value tasks that improve patient safety.

Results of an Artificial Intelligence-Based Image Review System to Detect Patient Misalignment Errors in a Multi-institutional Database of Cone Beam Computed Tomography-Guided Radiation Therapy.

PURPOSE: Present knowledge of patient setup and alignment errors in image guided radiation therapy (IGRT) relies on voluntary reporting, which is thought to underestimate error frequencies. A manual retrospective patient-setup misalignment error search is infeasible owing to the bulk of cases to be reviewed. We applied a deep learning-based misalignment error detection algorithm (EDA) to perform a fully automated retrospective error search of clinical IGRT databases and determine an absolute gross patient misalignment error rate. METHODS AND MATERIALS: The EDA was developed to analyze the registration between planning scans and pretreatment cone beam computed tomography scans, outputting a misalignment score ranging from 0 (most unlikely) to 1 (most likely). The algorithm was trained using simulated translational errors on a data set obtained from 680 patients treated at 2 radiation therapy clinics between 2017 and 2022. A receiver operating characteristic analysis was performed to obtain target thresholds. DICOM Query and Retrieval software was integrated with the EDA to interact with the clinical database and fully automate data retrieval and analysis during a retrospective error search from 2016 to 2017 and from 2021 to 2022 for the 2 institutions, respectively. Registrations were flagged for human review using both a hard-thresholding method and a prediction trending analysis over each individual patient's treatment course. Flagged registrations were manually reviewed and categorized as errors (>1 cm misalignment at the target) or nonerrors. RESULTS: A total of 17,612 registrations were analyzed by the EDA, resulting in 7.7% flagged events. Three previously reported errors were successfully flagged by the EDA, and 4 previously unreported vertebral body misalignment errors were discovered during case reviews. False positive cases often displayed substantial image artifacts, patient rotation, and soft tissue anatomy changes. CONCLUSIONS: Our results validated the clinical utility of the EDA for bulk image reviews and highlighted the reliability and safety of IGRT, with an absolute gross patient misalignment error rate of 0.04% ± 0.02% per delivered fraction.

Clinical Long-Term Outcomes of Patient-Reported Outcomes in the Prospective Real-World Tofacitinib Response in Ulcerative Colitis Registry.

INTRODUCTION: We previously reported the results of tofacitinib induction therapy in the prospective multisite US real-world Tofacitinib Response in Ulcerative Colitis registry. We now assessed patient-reported outcomes (PROs) and predictors of success during tofacitinib maintenance therapy. METHODS: Tofacitinib Response in Ulcerative Colitis included 103 patients with refractory ulcerative colitis (UC); 67% had failed ≥ 2 biologics. Patients reported the Simple Clinical Colitis Activity Index (SCCAI), Patient-Reported Outcome Measurement Information System measures for anxiety, depression, social satisfaction, and adverse events between weeks 8 and 52 using a web-based system. Paired t test and P for trend were used to compare changes in PRO measures over time. Bivariate analyses and logistic regression models were used to determine factors associated with response (SCCAI <5) or remission (SCCAI <2) at week 52. RESULTS: Of 103 patients, 82.5% entered the maintenance phase and 43.7% remained on tofacitinib at week 52. Tofacitinib de-escalation to 5 mg BID occurred in 15% of patients. At week 52, 42.7% and 31.1% of all patients reported an SCCAI <5 and SCCAI ≤2, respectively. Normalization of bowel frequency, rectal bleeding, and urgency occurred in 79%, 61%, and 48% of patients remaining on maintenance therapy. Social satisfaction improved significantly ( P < 0.001), while anxiety and depression scores only numerically improved. No consistent predictors for tofacitinib long-term treatment efficacy were identified, and safety findings were consistent with the known safety profile of tofacitinib. DISCUSSION: Tofacitinib is an effective maintenance therapy in patients with refractory UC. Dose reductions infrequently occurred during maintenance. Unmet needs in UC maintenance include improvement of urgency and psychosocial factors (NCT03772145).

Proof-of-concept study of artificial intelligence-assisted review of CBCT image guidance.

PURPOSE: Automation and computer assistance can support quality assurance tasks in radiotherapy. Retrospective image review requires significant human resources, and automation of image review remains a noteworthy missing element in previous work. Here, we present initial findings from a proof-of-concept clinical implementation of an AI-assisted review of CBCT registrations used for patient setup. METHODS: An automated pipeline was developed and executed nightly, utilizing python scripts to interact with the clinical database through DICOM networking protocol and automate data retrieval and analysis. A previously developed artificial intelligence (AI) algorithm scored CBCT setup registrations based on misalignment likelihood, using a scale from 0 (most unlikely) through 1 (most likely). Over a 45-day period, 1357 pre-treatment CBCT registrations from 197 patients were retrieved and analyzed by the pipeline. Daily summary reports of the previous day's registrations were produced. Initial action levels targeted 10% of cases to highlight for in-depth physics review. A validation subset of 100 cases was scored by three independent observers to characterize AI-model performance. RESULTS: Following an ROC analysis, a global threshold for model predictions of 0.87 was determined, with a sensitivity of 100% and specificity of 82%. Inspecting the observer scores for the stratified validation dataset showed a statistically significant correlation between observer scores and model predictions. CONCLUSION: In this work, we describe the implementation of an automated AI-analysis pipeline for daily quantitative analysis of CBCT-guided patient setup registrations. The AI-model was validated against independent expert observers, and appropriate action levels were determined to minimize false positives without sacrificing sensitivity. Case studies demonstrate the potential benefits of such a pipeline to bolster quality and safety programs in radiotherapy. To the authors' knowledge, there are no previous works performing AI-assisted assessment of pre-treatment CBCT-based patient alignment.

Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases: results from the phase 2, randomised, double-blind, placebo-controlled MANTA and MANTA-RAy studies.

OBJECTIVES: The phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases. METHODS: MANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition. In each study, participants were randomised 1:1 to receive once-daily, double-blind filgotinib 200 mg or placebo for 13 weeks for pooled analysis of the primary endpoint (proportion of participants with a ≥50% decrease from baseline in sperm concentration at week 13). Participants who met the primary endpoint were monitored over an additional 52 weeks for 'reversibility'. Secondary endpoints included change from baseline to week 13 in: sperm concentration, total motility, normal morphology, total count and ejaculate volume. Sex hormones (luteinising hormone, follicle stimulating hormone, inhibin B and total testosterone) and reversibility were exploratory endpoints. RESULTS: Across both studies, 631 patients were screened, and 248 were randomised to filgotinib 200 mg or placebo. Baseline demographics and characteristics were similar within indications between treatment groups. Numerically similar proportions of filgotinib-treated versus placebo-treated patients met the primary endpoint (8/120 (6.7%) vs 10/120 (8.3%)), Δ-1.7% (95% CI -9.3% to 5.8%)). There were no clinically relevant changes from baseline to week 13 in semen parameters or sex hormones, or patterns of reversibility between treatment groups. Filgotinib was well tolerated, with no new safety events. CONCLUSIONS: Results suggest that once daily filgotinib 200 mg for 13 weeks has no measurable impact on semen parameters or sex hormones in men with active IBD or inflammatory rheumatic diseases.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Multimetallic glycerolate as a precursor template of spherical porous high-entropy oxide microparticles.

High-entropy materials have received notable attention concern on account of their unique structure, tunable properties, and unprecedented potential applications in many fields. In this work, for the first time a NiCoMnZnMg-containing high-entropy glycerolate (HE-Gly) particles has been synthesized using a scalable solvothermal method. The HE-Gly particles were used as a precursor in design of porous high-entropy oxide (HEO) microparticles. The morphological and structural characterizations demonstrate that the temperature of the annealing process, and the composition of the metal ions in the HE-Gly precursors play important roles in determining porosity, crystallinity, and phase separation in HEOs. In fact, HE-Gly exhibited a porous structure of spinel HEOs with secreted MgO phase after annealing process at 800 °C, while the annealing process at 400 °C led to a low-crystallinity spinel phase without phase segregation. Overall, this work describes HE-Gly as a new precursor for altering the composition, crystallinity, and porosity of HEOs. This strategy is scalable for potential high mass productions, paving a new path toward industrial application of high-entropy materials.

Enhanced Bacterial Growth by Polyelemental Glycerolate Particles.

While polyelemental alloys are shown to be promising for healthcare applications, their effectiveness in promoting bacterial growth remains unexplored. In the present work, we evaluated the interaction of polyelemental glycerolate particles (PGPs) with Escherichia coli (E. coli) bacteria. PGPs were synthesized using the solvothermal route, and nanoscale random distribution of metal cations in the glycerol matrix of PGPs was confirmed. We observed 7-fold growth of E. coli bacteria upon 4 h of interaction with quinary glycerolate (NiZnMnMgSr-Gly) particles in comparison to control E. coli bacteria. Nanoscale microscopic studies on bacteria interactions with PGPs showed the release of metal cations in the bacterium cytoplasm from PGPs. The electron microscopy imaging and chemical mapping indicated bacterial biofilm formation on PGPs without causing significant cell membrane damage. The data showed that the presence of glycerol in PGPs is effective in controlling the release of metal cations, thus preventing bacterial toxicity. The presence of multiple metal cations is expected to provide synergistic effects of nutrients needed for bacterial growth. The present work provides key microscopic insights of mechanisms by which PGPs enhance biofilm growth. This study opens the door for future applications of PGPs in areas where bacterial growth is essential including healthcare, clean energy, and the food industry.

Tofacitinib Response in Ulcerative Colitis (TOUR): Early Response After Initiation of Tofacitinib Therapy in a Real-world Setting.

BACKGROUND: Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Using a novel electronic reporting tool, we aimed to prospectively describe the onset of tofacitinib efficacy during induction therapy in a real-world study. METHODS: Patient-reported outcome data (PROs) including the simple clinical colitis activity index (SCCAI), PRO Measurement Identification Systems (PROMIS) measures, and adverse events were collected daily for the first 14 days and at day 28 and 56. Paired t tests and P for trend were utilized to compare changes in SCCAI over time. Bivariate analyses and logistic regression models were performed to describe response (SCCAI <5) and remission (SCCAI ≤2) by clinical factors. RESULTS: Of all included patients (n = 96), 67% had failed ≥2 biologics, and 61.5% were on concomitant steroids. Starting at day 3, PROs showed significant and persistent decline of the mean SCCAI (-1.1, P < 000.1) including significantly lower SCCAI subscores for stool frequency (-0.3; P < .003), bleeding (-0.3; P < .0002) and urgency (-0.2; P < .001). Steroid-free remission at day 14, 28, and 56 was achieved in 25%, 30.2%, and 29.2% of patients, respectively. Neither prior biologics nor endoscopic severity were independently predictive of response or remission in multivariate models. Numeric improvements in all PROMIS measures (anxiety, depression, social satisfaction) were seen through day 56. Rates of discontinuation due to adverse events were low. CONCLUSIONS: In this prospective real-world study, tofacitinib resulted in a rapid and persistent improvement in UC disease activity PROs. The safety findings were consistent with the established safety profile of tofacitinib.

Rapid and Sustained Symptom Relief in Patients With Ulcerative Colitis Treated With Filgotinib: Data From the Phase 2b/3 SELECTION Trial.

INTRODUCTION: Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed. METHODS: In these post hoc analyses of the double-blinded, randomized, placebo-controlled 58-week SELECTION trial (NCT02914522), rectal bleeding and stool frequency diary data on days 1-15 and pMCS remission and response at multiple time points including weeks 10 and 58 were evaluated. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire at weeks 10 and 58. RESULTS: Filgotinib 200 mg relative to placebo improved rectal bleeding and stool frequency within 7 days ( P < 0.05). By week 2, greater proportions of filgotinib 200 mg-treated patients than placebo-treated patients achieved pMCS remission (biologic-naive, 15.1% vs 8.0%, P = 0.0410; biologic-experienced, 10.3% vs 4.2%, P = 0.0274). A similar treatment effect was observed at week 58 ( P < 0.0001). Day 7 rectal bleeding and stool frequency subscores were associated with the Mayo Clinic Score response at weeks 10 and 58. Patients in pMCS remission at weeks 10 and 58 had greater improvements in the Inflammatory Bowel Disease Questionnaire score than those not in pMCS remission. DISCUSSION: Filgotinib 200 mg daily resulted in rapid and sustained improvements in both UC symptoms and HRQoL.

AAPM MEDICAL PHYSICS PRACTICE GUIDELINE 5.b: Commissioning and QA of treatment planning dose calculations-Megavoltage photon and electron beams.

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: Must and Must Not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. While must is the term to be used in the guidelines, if an entity that adopts the guideline has shall as the preferred term, the AAPM considers that must and shall have the same meaning. Should and Should Not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances.

Appropriate cleaning reduces potential risk of spore transmission from patients with Clostridioides difficile infection treated in outpatient infusion centers.

OBJECTIVES: Patients with Clostridioides difficile infection (CDI) who receive treatment at outpatient infusion centers (OICs) pose a risk for spore transmission. We investigated C. difficile contamination in the environment of CDI and non-CDI patients and evaluated the effectiveness of standard cleaning. METHODS: This is a multicenter, non-conventional study including 8 OICs between October 2019 and December 2020. Samples were collected at baseline, after infusion, and after cleaning CDI and non-CDI areas. Cleaning was performed using hypochlorite and non-hypochlorite products for CDI and non-CDI, respectively. Samples were cultured for toxigenic C. difficile and strain-typed via fluorescent PCR ribotyping and whole-genome sequencing. RESULTS: The overall C. difficile contamination rate was 7.9% (156/1969) with 8.1% in patient and 5.6% in non-patient care areas, respectively. For CDI areas, contamination rates were 5.9% at baseline, 15.0% after infusion, and significantly reduced to 6.2% after cleaning (P = 0.004). For non-CDI areas, contamination was similar at baseline (9.5%), after infusion (7.6%), and after cleaning (4.3%). The difference in C. difficile-positive samples after infusion was significant for CDI vs. non-CDI (15.0% vs. 7.6%, P = 0.004). Overall contamination was 11.5% for floors, 7.9% for infusion chairs, and 3.8% for equipment (P = 0.001). The most frequent ribotypes were F014-020 (42.6%), F106 (15.6%), F255 (6.1%), F001 (5.2%) and F027 (3.5%). Cleaning resulted in elimination of F106, F255, F001, F027 and partial reduction of F014-020. CONCLUSIONS: Environmental C. difficile contamination was increased after CDI infusions and significantly reduced after cleaning with a hypochlorite solution, reducing the potential risk of spore transmission to others.

Development and interinstitutional validation of an automatic vertebral-body misalignment error detector for cone-beam CT-guided radiotherapy.

BACKGROUND: In cone-beam computed tomography (CBCT)-guided radiotherapy, off-by-one vertebral-body misalignments are rare but serious errors that lead to wrong-site treatments. PURPOSE: An automatic error detection algorithm was developed that uses a three-branch convolutional neural network error detection model (EDM) to detect off-by-one vertebral-body misalignments using planning computed tomography (CT) images and setup CBCT images. METHODS: Algorithm training and test data consisted of planning CTs and CBCTs from 480 patients undergoing radiotherapy treatment in the thoracic and abdominal regions at two radiotherapy clinics. The clinically applied registration was used to derive true-negative (no error) data. The setup and planning images were then misaligned by one vertebral-body in both the superior and inferior directions, simulating the most likely misalignment scenarios. For each of the aligned and misaligned 3D image pairs, 2D slice pairs were automatically extracted in each anatomical plane about a point within the vertebral column. The three slice pairs obtained were then inputted to the EDM that returned a probability of vertebral misalignment. One model (EDM1 ) was trained solely on data from institution 1. EDM1 was further trained using a lower learning rate on a dataset from institution 2 to produce a fine-tuned model, EDM2 . Another model, EDM3 , was trained from scratch using a training dataset composed of data from both institutions. These three models were validated on a randomly selected and unseen dataset composed of images from both institutions, for a total of 303 image pairs. The model performances were quantified using a receiver operating characteristic analysis. Due to the rarity of vertebral-body misalignments in the clinic, a minimum threshold value yielding a specificity of at least 99% was selected. Using this threshold, the sensitivity was calculated for each model, on each institution's test set separately. RESULTS: When applied to the combined test set, EDM1 , EDM2 , and EDM3 resulted in an area under curve of 99.5%, 99.4%, and 99.5%, respectively. EDM1 achieved a sensitivity of 96% and 88% on Institution 1 and Institution 2 test set, respectively. EDM2 obtained a sensitivity of 95% on each institution's test set. EDM3 achieved a sensitivity of 95% and 88% on Institution 1 and Institution 2 test set, respectively. CONCLUSION: The proposed algorithm demonstrated accuracy in identifying off-by-one vertebral-body misalignments in CBCT-guided radiotherapy that was sufficiently high to allow for practical implementation. It was found that fine-tuning the model on a multi-facility dataset can further enhance the generalizability of the algorithm.

Recurrent Clostridioides difficile infection worsens anxiety-related patient-reported quality of life.

BACKGROUND: Clostridioides difficile infection (CDI) is associated with high recurrence rates impacting health-related quality of life (HrQOL). However, patient-reported data are lacking particularly in the outpatient setting. We assessed changes in HrQOL over time in patients treated with bezlotoxumab at US infusion centers and determined clinical factors associated with HrQOL changes. METHODS: The HrQOL survey was conducted in adult patients with CDI, who received bezlotoxumab in 25 US outpatient infusion centers. The survey was adapted from the Cdiff32 instrument to assess anxiety-related changes to HrQOL and completed on the day of infusion (baseline) and at 90 days post bezlotoxumab (follow-up). Demographics, disease history, CDI risk factors, and recurrence of CDI (rCDI) at 90-day follow-up were collected. Changes in HrQOL scores were calculated and outcomes assessed using a multivariable linear regression model with P < 0.05 defined as statistically significant. RESULTS: A total of 144 patients (mean age: 68 ± 15 years, 63% female, median Charlson index: 4, 15.9% rCDI) were included. The overall mean baseline and follow-up HrQOL scores were 26.4 ± 11.5 and 56.4 ± 25.0, respectively. At follow-up, this score was significantly higher for patients who had primary CDI (34.5 ± 21.7) compared to those with multiple rCDI (24.7 ± 21.0; P = 0.039). The mean HrQOL change at follow-up was significantly higher for patients without rCDI (34.1 ± 28.8 increase) compared to patients with rCDI (6.7 ± 19.5 increase; P < 0.001), indicating improvement in anxiety. CONCLUSIONS: Using the Cdiff32 instrument, we demonstrated that HrQOL worsened significantly in patients with further rCDI. These findings support the use of Cdiff32 in assessing CDI-related humanistic outcomes.

MANTA and MANTA-RAy: Rationale and Design of Trials Evaluating Effects of Filgotinib on Semen Parameters in Patients with Inflammatory Diseases.

INTRODUCTION: The phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters in men with active inflammatory diseases. Here we describe the methods and rationale for these studies. METHODS AND RATIONALE: The MANTA and MANTA-RAy studies included men (aged 21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases, respectively. Participants had no history of reproductive health issues, and the following semen parameter values (≥ 5th percentile of World Health Organization reference values) at baseline: semen volume ≥ 1.5 mL, total sperm/ejaculate ≥ 39 million, sperm concentration ≥ 15 million/mL, sperm total motility ≥ 40% and normal sperm morphology ≥ 30%. Each trial included a 13-week, randomized, double-blind, placebo-controlled period (filgotinib 200 mg vs placebo, up to N = 125 per arm), for pooled analysis of the week-13 primary endpoint (proportion of participants with ≥ 50% decrease from baseline in sperm concentration). All semen assessments were based on two samples (≤ 14 days apart) to minimize effects of physiological variation; stringent standardization processes were applied across assessment sites. From week 13, MANTA and MANTA-RAy study designs deviated owing to disease-specific considerations. All subjects with a ≥ 50% decrease in sperm parameters continued the study in the monitoring phase until reversibility, or up to a maximum of 52 weeks, with standard of care as treatment. Overall conclusions from MANTA and MANTA-RAy will be based on the totality of the data, including secondary/exploratory measures (e.g. sperm motility/morphology, sex hormones, reversibility of any effects on semen parameters). CONCLUSIONS: Despite the complexities, the MANTA and MANTA-RAy studies form a robust trial programme that is the first large-scale, placebo-controlled evaluation of potential impacts of an advanced IBD and rheumatic disease therapy on semen parameters. TRIAL REGISTRATION: EudraCT numbers 2017-000402-38 and 2018-003933-14; ClinicalTrials.gov identifiers NCT03201445 and NCT03926195.

Filgotinib is a treatment for patients with ulcerative colitis and rheumatoid arthritis, and is being studied in other inflammatory diseases. Filgotinib works by blocking Janus kinase 1, an intracellular protein involved in inflammatory signalling processes. We designed the MANTA and MANTA-RAy trials with global health agencies to find out if filgotinib decreases the quality of semen in men with active inflammatory bowel disease (ulcerative colitis or Crohn's disease) (MANTA) or rheumatic disease (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or non-radiographic axial spondylitis) (MANTA-RAy). This paper describes the design of the two trials.Patients had normal sperm measurements and could not have had previous reproductive health issues. Nearly 250 patients were included in each trial. In both MANTA and MANTA-RAy, half of the patients were treated with 200 mg of filgotinib once a day for 13 weeks, and the other half with placebo. We determined if any patients had a decrease in number of sperm cells per millilitre (sperm concentration) by at least half after 13 weeks of treatment. We then monitored any patients who had such a decrease in sperm concentration for up to 52 weeks (while they received standard of care treatment) or until the decrease was reversed.The conclusions from the trials will be in a different paper and will be based on all the final data, including changes in sex hormones. This is the first large-scale clinical trial programme to measure the effect of a treatment on sperm in men with inflammatory bowel disease or rheumatic diseases.

Proactive infliximab optimisation using a pharmacokinetic dashboard versus standard of care in patients with Crohn's disease: study protocol for a randomised, controlled, multicentre, open-label study (the OPTIMIZE trial).

INTRODUCTION: Preliminary data indicates that proactive therapeutic drug monitoring (TDM) is associated with better outcomes compared with empiric dose escalation and/or reactive TDM, and that pharmacokinetic (PK) modelling can improve the precision of individual dosing schedules in Crohn's disease (CD). However, there are no data regarding the utility of a proactive TDM combined PK-dashboard starting early during the induction phase, when disease activity and drug clearance are greatest. The aim of this randomised, controlled, multicentre, open-label trial is to evaluate the efficacy and safety of a proactive TDM combined PK dashboard-driven infliximab dosing compared with standard of care (SOC) dosing in patients with moderately to severely active CD. METHODS AND ANALYSIS: Eligible adolescent and adult (aged ≥16-80 years) patients with moderately to severely active CD will be randomised 1:1 to receive either infliximab monotherapy with proactive TDM using a PK dashboard (iDose, Projections Research) or SOC infliximab therapy, with or without a concomitant immunomodulator (IMM) (thiopurine or methotrexate) at the discretion of the investigator. The primary outcome of the study is the proportion of subjects with sustained corticosteroid-free clinical remission and no need for rescue therapy from week 14 throughout week 52. Rescue therapy is defined as any IFX dose escalation other than what is forecasted by iDose either done empirically or based on reactive TDM; addition of an IMM after week 2; reintroduction of corticosteroids after initial tapering; switch to another biologic or need for CD-related surgery. The secondary outcomes will include both efficacy and safety end points, such as endoscopic and biological remission, durability of response and CD-related surgery and hospitalisation. ETHICS AND DISSEMINATION: The protocol has been approved by the Institutional Review Board Committee of the Beth Israel Deaconess Medical Center (IRB#:2021P000391). Results will be disseminated in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT04835506.