Citations

Abstract Background and Aims The long-term efficacy and safety of upadacitinib in patients with moderate to severe Crohn’s disease (CD) were evaluated in the U-ENDURE Long-Term Extension (LTE) study. Here we report the results after 2 years of total maintenance treatment. Methods U-ENDURE is an ongoing 240-week LTE study conducted at 243 sites across 43 countries (first patient enrolled in LTE 21 March 2019). Patients who completed the 52-week maintenance study continued their previously assigned treatment, once-daily upadacitinib 15 mg or upadacitinib 30 mg. Efficacy was analyzed at week 48 of the LTE; safety was analyzed in the cumulative study population (combined 52 week maintenance and 48 week LTE) and the LTE study population only (cutoff date: 19 December 2023). Results From LTE week 0 to week 48, as-observed efficacy rates for clinical remission (per stool frequency/abdominal pain score, upadacitinib 15 mg: 78.3% to 82.9%; upadacitinib 30 mg: 84.7% to 76.6%; per CD Activity Index, upadacitinib 15 mg: 81.3% to 83.1%; upadacitinib 30 mg: 86.1% to 86.8%), endoscopic response (upadacitinib 15 mg: 59.6% to 67.1%; upadacitinib 30 mg: 71.2% to 69.6%), inflammatory biomarkers, and quality-of-life outcomes remained stable. The safety profile of the cumulative maintenance population observed through LTE week 48 was consistent with previous trials in the upadacitinib CD program. Treatment-emergent adverse event rates for the cumulative maintenance population were 283.1 and 273.4 events/100 patient-years for upadacitinib 15 mg and upadacitinib 30 mg, respectively. Event rates of serious treatment-­emergent adverse events were 16.0 events/100 patient-years for upadacitinib 15 mg and 14.6 events/100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest (≥ 5.0 events/100 patient-years) were hepatic disorder, lymphopenia, creatine phosphokinase elevation, herpes zoster, and anemia. There was 1 treatment-emergent adverse event of suicide leading to death. Conclusion Sustained clinical, endoscopic, quality-of-life, and biomarker outcomes were observed in patients who were initial responders to upadacitinib and completed 2 years of maintenance therapy, with no new safety signals identified. Clinical trial identifier U-ENDURE; ClinicalTrials.gov number, NCT03345823.

Abstract Background and Aims There is a paucity of data on arrhythmia burden in patients with congenitally corrected transposition of the great arteries (ccTGAs). The present study sought to quantify the incidence of atrial arrhythmia (AA), ventricular arrhythmia (VA), and complete atrioventricular block (CAVB) in patients with ccTGA and identify associated factors. Methods An international, multi-centre, retrospective cohort study was conducted in 29 tertiary hospitals (six countries) between 1990 and 2018. Primary analyses consisted of determining the incidence of a combined outcome consisting of AA, VA, or CAVB, along with its individual components. Factors associated with the different types of arrhythmias were assessed by uni-variable and multi-variable Cox regression analyses. Results A total of 1131 patients with ccTGA were followed for 9.0 (interquartile range 4.0–17.2) years. Cumulative rates of the primary endpoint at 10, 15, and 20 years were 44.5%, 51.0%, and 58.8%, respectively. AA, VA, and CAVB occurred in 2.1, 1.4, and 2.0 cases per 100 person-years, respectively. In multi-variable analyses, surgery/intervention conferred a greater than three-fold higher risk of AA [hazard ratio (HR) 3.01, 95% confidence interval (CI) 1.90–4.78, P < .001]. Furthermore, surgery/intervention was significantly associated with a greater risk of VA (HR 1.73, 95% CI 0.98–3.05, P = .003) and CAVB (HR 3.65, 95% CI 2.20–6.05, P < .001). The left bundle branch block was associated with a higher risk of VA (HR 4.03, 95% CI 1.59–10.23, P = .003) and the right bundle branch block with a higher risk of CAVB (HR 3.71, 95% CI 1.81–7.63, P < .001). Conclusions The arrhythmia burden in patients with ccTGA is substantial, with a high incidence of AA, VA, and CAVB.

Abstract Background & Aims Pregnancy can be a complex and risk-filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process was used when sufficient published data were available and the RAND (Research and Development) process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

Abstract Introduction While randomized clinical trials (RCT) confirmed superiority of Mepitel film (MF) in reducing acute radiation dermatitis (ARD) compared to standard-of-care (SoC), the incremental cost difference has limited its use. A cost-effectiveness analysis (CEA) was conducted from a Canadian healthcare payer’s perspective to guide policy decisions. Methods: A decision model was constructed to perform a CEA for MF compared to SoC (moisturisers) for prevention of grade 2 or higher ARD following adjuvant hypo-fractionated whole-breast radiotherapy (RT) based on a Canadian multicentre RCT. Direct and indirect cost data were collected from two oncology centres in Canada. Quality-of-life (QoL) utility values were derived from mapping Dermatology Life Quality Index (DLQI) scores for patients with grade 2 or higher ARD at week 6 of RT to EQ-5D. A willingness-to-pay (WTF) threshold of CAD 50,000 per quality-adjusted life years (QALY) gained was used. One-way sensitivity analysis was performed to account for uncertainty in decision model assumptions. Results: Base case analysis demonstrated that MF is cost-effective in preventing grade 2 or higher ARD as compared with SoC with an incremental cost-effectiveness ratio (ICER) of CAD 3,366 per QALY gained. When nursing costs were included, MF resulted in an ICER of CAD 2,823 per QALY gained. One-way sensitivity analysis showed that the results were most sensitive to the QoL utility value for ARD. All sensitivity variations remained well below the WTP threshold. Conclusions: MF is a cost-effective intervention for preventing high-grade ARD and should be recommended for patients with breast cancer undergoing adjuvant RT.

Abstract Purpose To describe the creation and clinical deployment of an integrated stand‐alone hybrid automated chart review platform that is comprised of a database, oncology information system (OIS) interfaces, and a user interface (UI). Methods A consensus checklist was developed to homogenize the practices of clinical physics staff and physics residents for all plan types. Critical review of the single checklist's items led to the creation of a new concept, the “plan attribute,” which permits specialization of the final checklist based on the characteristics of a particular plan. Only relevant and applicable tests are automatically populated to form a plan checklist based on plan attributes. Each populated checklist in this hybrid automation platform includes elements of full automation, steps or functions that use automation to augment a human input or effort, as well as steps completed by humans. Logging and categorizing of deficiencies found during the chart check was also implemented. Results Chart check data was analyzed for an over 4‐year time span starting from the clinical deployment of the tool in October 2020. This analysis included a total of 427 073 tests spread among 7882 initial chart checks. The recorded deficiencies at three triage levels showed 7116 minor errors, 679 major errors, and 71 plan rejections. The plan rejection level is the highest chart deficiency, which required the plan to be rejected and sent back for serious remediation and/or new plan generation. Conclusion This report describes the successful development and implementation of a hybrid‐automated chart checking program. The software leverages modern database and software design to improve the per case performance and experience of a multi‐user group. Chart check database permits high‐level review and improvement in all aspects of plan check and user performance.

Introduction Despite growing evidence to characterise cancer-associated cognitive decline (CACD) in women with breast cancer, interventions to mitigate CACD are limited. Emerging evidence suggests aerobic exercise may enhance cognition after breast cancer diagnosis and treatment; yet, CACD remains an understudied outcome of exercise, and few high-quality studies have been conducted. In addition to knowledge gaps in effectiveness, the translation of exercise interventions to community settings remains challenging. The Breast cancer Reasoning and Activity INtervention (BRAIN) investigates the effectiveness of aerobic exercise training, delivered in a community-based setting, for improving cognitive function in women with breast cancer and gathers information on the implementation success of the intervention. Methods and analysis This Hybrid Type I effectiveness–implementation study is conducted at an academic medical centre in the southwestern United States in partnership with a non-profit, community health and wellness organisation. The study enrols 160 women diagnosed with stage I–IIIa breast cancer and within 3–36 months of treatment completion into a 1:1 randomised controlled trial. Individuals randomised to the exercise group receive a 6-month, individually tailored aerobic exercise programme delivered by exercise trainers employed at local community fitness centres. The programme is progressive in nature and designed to help participants achieve aerobic exercise levels consistent with guidelines for cancer survivors. Individuals randomise to the control group receive a 6-month health education control intervention delivered virtually by hospital-based health educators. Cognitive performance (primary), self-reported cognition, patient-reported outcomes, physical activity and cardiorespiratory fitness are measured at baseline, 6 months (postintervention) and 12 months (follow-up). Brain structure and function are measured via magnetic resonance imaging (MRI) at baseline and 6 months. Implementation outcomes are defined by the RE-AIM framework, which includes reach, effectiveness, adoption, implementation and maintenance. RE-AIM outcomes are measured at baseline, 6 months, 12 months and ongoing during the study. Ethics and dissemination This study was approved by the Mayo Clinic Institutional Review Board (#23-000020). All participants provide informed consent prior to participation. Findings will be disseminated to scientific, clinical and community audiences through manuscripts, presentations and newsletters. Trial registration number NCT04816006.

ABSTRACT 3‐hydroxy acylcarnitines (3‐OH‐ACs) are key biomarkers for screening of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase and trifunctional protein deficiencies (LCHADD/TFPD). The utility of this biomarker for disease monitoring in identified patients remains debated, and recent suggestions have highlighted the potential use of lipidomics for diagnosis, monitoring, prognosis, and/or identification of new biomarkers. We evaluated the use of omics in LCHADD/TFPD patients by analyzing plasma acylcarnitine profiles, metabolomics, and lipidomics, combined with genotype, visual assessments, and dietary records. Fasting plasma from 39 participants with LCHADD/TFPD and 32 control subjects were analyzed through untargeted metabolomic and lipidomic analyses. In LCHADD/TFPD participants, acylcarnitine profiling, visual and retinal function assessments were performed, and 3‐day diet records were collected. Relationships between acylcarnitines, metabolomics, lipidomics, along with visual outcomes and dietary intake were investigated. Plasma of LCHADD/TFPD participants exhibited elevated 3‐OH‐ACs, which correlated with genotype and visual outcomes. Metabolomics successfully distinguished LCHADD/TFPD from controls, and the biggest divergence was observed in lipid pathways. Metabolomic profiles tightly correlated with 3‐OH‐ACs, genotype, and visual outcomes. Lower concentrations of total lipids and some individual lipid species such as phosphoethanolamines (PE) were detected in LCHADD/TFPD, except for elevations in several certain triglycerides. LCHADD/TFPD participants followed a diet low in long‐chain fat (LCFA) as recommended. LCFA intake did not correlate with either plasma 3‐OH‐ACs or metabolomics. 3‐OH‐ACs are strong consistent biomarkers of LCHADD/TFPD that are associated with clinical parameters of vision and genotype. We did not observe a relationship between dietary LCFA intake and 3‐OH‐ACs.

Radiation segmentectomy is a dynamic image-guided therapy for hepatic malignancies that uses yttrium 90 transarterial radioembolization to deliver high radiation doses to targeted hepatic segments, achieving high and sustained response rates.