Citations

In Radiation Therapy Oncology Group 90-05, the maximum tolerated dose of single-fraction radiosurgery (SRS) for brain metastases of 21–30 mm was 18 Gy (biologically effective dose (BED) 45 Gy12). Since the patients in this study received prior brain irradiation, tolerable BED may be >45 Gy12 for de novo lesions. We investigated SRS and fractionated stereotactic radiotherapy (FSRT) with a higher BED for radiotherapy-naive lesions. Patients receiving SRS (19–20 Gy) and patients treated with FSRT (30–48 Gy in 3–12 fractions) with BED > 49 Gy12 for up to 4 brain metastases were compared for grade ≥ 2 radiation necrosis (RN). In the entire cohort (169 patients with 218 lesions), 1-year and 2-year RN rates were 8% after SRS vs. 2% and 13% after FSRT (p = 0.73) in per-patient analyses, and 7% after SRS vs. 7% and 10% after FSRT (p = 0.59) in per-lesion analyses. For lesions ≤ 20 mm (137 patients with 185 lesions), the RN rates were 4% (SRS) vs. 0% and 15%, respectively, (FSRT) (p = 0.60) in per-patient analyses, and 3% (SRS) vs. 0% and 11%, respectively, (FSRT) (p = 0.80) in per-lesion analyses. For lesions > 20 mm (32 patients with 33 lesions), the RN rates were 50% (SRS) vs. 9% (FSRT) (p = 0.012) in both per-patient and per-lesion analyses. In the SRS group, a lesion size > 20 mm was significantly associated with RN; in the FSRT group, lesion size had no impact on RN. Given the limitations of this study, FSRT with BED > 49 Gy12 was associated with low RN risk and may be safer than SRS for brain metastases > 20 mm.

Abstract Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients because of mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered before transplant, at day +7 and +30 to 80 pediatric and young adult patients who received allogeneic HSCT. Lactulose and rhamnose were detected using urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and enzyme-linked immunosorbent assay analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at day +7 but returned to baseline at day +30 in most patients (P = .014). Conditioning regimen intensity did not affect the trajectory of L:R (P = .39). Baseline L:R ratios did not vary with diagnosis. L:R correlated with LBP levels (r2 = 0.208; P = .0014). High L:R ratios were associated with lower microbiome diversity (P = .035), loss of anaerobic organisms (P = .020), and higher plasma LBP (P = .0014). No adverse gastrointestinal effects occurred because of LR. Intestinal permeability as measured through L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The LR assay is well-tolerated and may identify transplant recipients who are more likely to experience adverse outcomes.

Objective Ceramides have been associated with several ageing-related conditions but have not been studied as a general biomarker of multimorbidity (MM). Therefore, we determined whether ceramide levels are associated with the rapid development of MM. Design Retrospective cohort study. Setting Mayo Clinic Biobank. Participants 1809 persons in the Mayo Clinic Biobank ≥65 years without MM at the time of enrolment, and with ceramide levels assayed from stored plasma. Primary outcome measure Persons were followed for a median of 5.7 years through their medical records to identify new diagnoses of 20 chronic conditions. The number of new conditions was divided by the person-years of follow-up to calculate the rate of accumulation of new chronic conditions. Results Higher levels of C18:0 and C20:0 were associated with a more rapid rate of accumulation of chronic conditions (C18:0 z score RR: 1.30, 95% CI: 1.10 to 1.53; C20:0 z score RR: 1.26, 95% CI: 1.07 to 1.49). Higher C18:0 and C20:0 levels were also associated with an increased risk of hypertension and coronary artery disease. Conclusions C18:0 and C20:0 were associated with an increased risk of cardiometabolic conditions. When combined with biomarkers specific to other diseases of ageing, these ceramides may be a useful component of a biomarker panel for predicting accelerated ageing.

Abstract Resilience, which relates to one's ability to respond to stressors, typically declines with age and the development of comorbid conditions in older organisms. Although progress has been made to improve our understanding of resilience in older adults, disciplines have employed different frameworks and definitions to study various aspects of older adults' response to acute or chronic stressors. “Overview of the Resilience World: State of the Science,” a bench‐to‐bedside conference on October 12–13, 2022, was sponsored by the American Geriatrics Society and National Institute on Aging. This conference, summarized in this report, explored commonalities and differences among the frameworks of resilience most commonly used in aging research in the three domains of resilience: physical, cognitive, and psychosocial. These three main domains are intertwined, and stressors in one domain can lead to effects in other domains. The themes of the conference sessions included underlying contributors to resilience, the dynamic nature of resilience throughout the life span, and the role of resilience in health equity. Although participants did not agree on a single definition of “resilience(s),” they identified common core elements of a definition that can be applied to all domains and noted unique features that are domain specific. The presentations and discussions led to recommendations for new longitudinal studies of the impact of exposures to stressors on resilience in older adults, the use of new and existing cohort study data, natural experiments (including the COVID‐19 pandemic), and preclinical models for resilience research, as well as translational research to bring findings on resilience to patient care.

AbstractBackgroundSmall coronary arteries containing stents pose a challenge in CT imaging due to metal‐induced blooming artifact. High spatial resolution imaging capability is as the presence of highly attenuating materials limits noninvasive assessment of luminal patency.PurposeThe purpose of this study was to quantify the effective lumen diameter within coronary stents using a clinical photon‐counting‐detector (PCD) CT in concert with a convolutional neural network (CNN) denoising algorithm, compared to an energy‐integrating‐detector (EID) CT system.MethodsSeven coronary stents of different materials and inner diameters between 3.43 and 4.72 mm were placed in plastic tubes of diameters 3.96–4.87 mm containing 20 mg/mL of iodine solution, mimicking stented contrast‐enhanced coronary arteries. Tubes were placed parallel with or perpendicular to the scanner's z‐axis in an anthropomorphic phantom emulating an average‐sized patient and scanned with a clinical EID‐CT and PCD‐CT. EID scans were performed using our standard coronary computed tomography angiography (cCTA) protocol (120 kV, 180 quality reference mAs). PCD scans were performed using the ultra‐high‐resolution (UHR) mode (120 × 0.2 mm collimation) at 120 kV with tube current adjusted so that CTDIvol was matched to that of EID scans. EID images were reconstructed per our routine clinical protocol (Br40, 0.6 mm thickness), and with the sharpest available kernel (Br69). PCD images were reconstructed at a thickness of 0.6 mm and a dedicated sharp kernel (Br89) which is only possible with the PCD UHR mode. To address increased image noise introduced by the Br89 kernel, an image‐based CNN denoising algorithm was applied to the PCD images of stents scanned parallel to the scanner's z‐axis. Stents were segmented based on full‐width half maximum thresholding and morphological operations, from which effective lumen diameter was calculated and compared to reference sizes measured with a caliper.ResultsSubstantial blooming artifacts were observed on EID Br40 images, resulting in larger stent struts and reduced lumen diameter (effective diameter underestimated by 41% and 47% for parallel and perpendicular orientations, respectively). Blooming artifacts were observed on EID Br69 images with 19% and 31% underestimation of lumen diameter compared to the caliper for parallel and perpendicular scans, respectively. Overall image quality was substantially improved on PCD, with higher spatial resolution and reduced blooming artifacts, resulting in the clearer delineation of stent struts. Effective lumen diameters were underestimated by 9% and 19% relative to the reference for parallel and perpendicular scans, respectively. CNN reduced image noise by about 50% on PCD images without impacting lumen quantification (<0.3% difference).ConclusionThe PCD UHR mode improved in‐stent lumen quantification for all seven stents as compared to EID images due to decreased blooming artifacts. Implementation of CNN denoising algorithms to PCD data substantially improved image quality.

Abstract Background and Aims To evaluate the effect of mirikizumab, a p19-targeted anti-interleukin-23, on histological and/or endoscopic outcomes in moderately-to-severely active ulcerative colitis [UC]. Methods Endoscopic remission [ER], histological improvement [HI], histological remission [HR], histological-endoscopic mucosal improvement [HEMI], and histological-endoscopic mucosal remission [HEMR] were assessed at Week [W]12 [LUCENT-1: N = 1162, induction] and W40 [LUCENT-2: N = 544, maintenance] for patients randomised to mirikizumab or placebo. Analyses were performed to evaluate predictors of: HEMI at W12 with mirikizumab and HEMR at W40 in patients re-randomised to subcutaneous [SC] mirikizumab; associations between W12 histological/endoscopic endpoints and W40 outcomes in mirikizumab responders re-randomised to mirikizumab SC; and associations between W40 endoscopic normalisation [EN] with/without HR. Results Significantly more patients treated with mirikizumab achieved HI, HR, ER, HEMI, and HEMR vs placebo [p &lt;0.001], irrespective of prior biologic/tofacitinib failure [p &lt;0.05]. Lower clinical baseline disease activity, female sex, no baseline immunomodulator use, and no prior biologic/tofacitinib failure were predictors of HEMI at W12 [p &lt;0.05]. Corticosteroid use and longer disease duration were negative predictors of achieving HEMR at W40 [p &lt;0.05]. W12 HI, HR, or ER was associated with W40 HEMI or HEMR [p &lt;0.05]; ER at W12 was associated with clinical remission [CR] [p &lt;0.05] and corticosteroid-free remission [CSFR] at W40 [p = 0.052]. HR and HEMR at W12 were associated with CSFR, CR, and symptomatic remission at W40. Alternate HEMR [EN + HR] at W40 was associated with bowel urgency remission at W40 [p &lt;0.05]. Conclusions Early resolution of endoscopic and histological inflammation with mirikizumab is associated with better UC outcomes. Clinicaltrials.gov: LUCENT-1, NCT03518086; LUCENT-2, NCT03524092.