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Abstract Background and Aims Previously published long-term safety data reported a favourable ustekinumab safety profile for the treatment of inflammatory bowel disease [IBD]. We present the final cumulative safety data from pooled ustekinumab IBD phase 2/3 clinical studies through 5 years in Crohn’s disease [CD] and 4 years in ulcerative colitis [UC]. Methods In phase 3 studies, patients received a single intravenous placebo or ustekinumab [130 mg or ~6 mg/kg] induction dose followed by subcutaneous maintenance doses of placebo or ustekinumab [90 mg q8w or q12w]. Analyses included all patients who received one dose of study treatment and included patients who were biologic-naïve and patients with a history of biologic failure. Safety outcomes are summarized and presented using number of events per 100 patient-years of follow-up and corresponding 95% confidence intervals. Results In this final pooled safety analysis, 2575 patients were treated with ustekinumab with 4826 patient-years of follow-up. Rates of key safety events, including major adverse cardiac events and malignancies, were similar between placebo and ustekinumab or not higher for ustekinumab. Opportunistic infections, including tuberculosis, and malignancies were reported infrequently. Rates of key safety events in the IBD group were no higher in the ustekinumab group than in the placebo group for both patients who were biologic-naïve or who had a history of biologic failure. No lymphomas or cases of posterior reversible encephalopathy syndrome [formerly known as reversible posterior leukoencephalopathy syndrome] were reported. Conclusion The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo and continue to support the well-established safety profile across all approved indications. Clinical trials.gov numbers NCT00265122, NCT00771667, NCT01369329, NCT01369342, NCT01369355, NCT02407236

AbstractBackgroundObjective and quantitative evaluation for low‐contrast detectability that correlates with human observer performance is lacking for routine CT quality control testing. Channelized Hotelling observer (CHO) is considered a strong candidate to fill the need but has long been deemed impractical to implement due to its requirement of a large number of repeated scans in order to provide accurate and precise estimates of index of detectability (d’). In our previous work, we optimized a CHO model observer on the American College of Radiology (ACR) CT accreditation phantom and achieved accurate measurement of d’ with only 1–3 repeat scans.PurposeIn this work, we aim to validate the repeatability of the proposed CHO‐based low‐contrast evaluation on four scanner models using the ACR CT accreditation phantom.MethodsThe repeatability test was performed on four different scanners from two major CT manufacturers: Siemens Force and Alpha; Canon Prism and Prime SP. An ACR CT phantom was scanned 10 times, each time after repositioning of the phantom. For each repositioning, 3 repeated scans were acquired at 24, 12, and 6 mGy on all four scanner models. CHO was applied at the measured dose levels for different low‐contrast object sizes (4–6 mm). The CHO was also applied to images created using deep learning‐based reconstructions on Canon Prism and to four different scan/reconstruction modes on the Siemens Alpha, a photon‐counting‐detector (PCD)‐CT. The repeatability was evaluated by the probability that a measurement would fall within the ±15% tolerance (P<15%).ResultsWith the CHO setting optimized for the ACR phantom and the use of 3 repeated scans and 9 non‐overlapping slices per scan, the CHO measurement could provide high repeatability with P<15% of 98.8%–99.9% at 12 mGy with IR reconstruction on all four scanners. On scanner A, P<15% were 91.5%–99.9% at the three dose levels and for all three object sizes while the numbers were 93.6%–99.998% on scanner B. P<15% were 96.5%–97.2% for the two deep learning reconstructions and 97.0%–99.97% for the four scan/reconstruction modes on the PCD‐CT.ConclusionThe CHO provided highly repeatable measurements with over 95% probability that a CHO measurement would lie within the ±15% tolerance for most of the dose levels and object sizes on the ACR phantom. The repeatability was maintained when the CHO was applied to images created with a commercial deep learning‐based reconstruction and various scan/reconstruction modes on a PCD‐CT. This study demonstrates that practical implementation of CHO for routine quality control and performance evaluation is feasible.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used diabetes and obesity medications but have been associated with gastrointestinal (GI) adverse events. However, real-world evidence on comparative GI adverse reaction profiles is limited. Objectives: This study aimed to evaluate GI adverse events among GLP-1 RA users and compare semaglutide, dulaglutide, liraglutide, and exenatide safety regarding the GI adverse reaction profile. Methods: This retrospective cross-sectional analysis utilized real-world data on 10,328 adults with diabetes/obesity in the National Institutes of Health All of Us cohort. New GLP-1 RA users were identified, and GI adverse events were examined. Logistic regression determined factors associated with GI adverse events. Results: The mean age of the study population was 61.4 ± 12.6 years, 65.7% were female, 51.3% were White, and they had a high comorbidity burden. Abdominal pain (57.6%) was the most common GI adverse event, followed by constipation (30.4%), diarrhea (32.7%), nausea and vomiting (23.4%), GI bleeding (15.9%), gastroparesis (5.1%), and pancreatitis (3.4%). Dulaglutide and liraglutide had higher rates of abdominal pain, constipation, diarrhea, and nausea and vomiting than semaglutide and exenatide. Liraglutide and exenatide had the highest pancreatitis (4.0% and 3.8%, respectively). Compared to semaglutide, dulaglutide and liraglutide had higher odds of abdominal pain, and nausea and vomiting. They also had higher odds of gastroparesis than semaglutide. No significant differences existed in GI bleeding or pancreatitis risks between the GLP-1 RAs. Conclusions: In this real-world cohort, GI adverse events were common with GLP-1 RAs. Differences in GI safety profiles existed between agents, with exenatide appearing safer than other GLP-1 RAs, except for gastroparesis. These findings can inform GLP-1 RA selection considering GI risk factors. Further studies are needed to evaluate the causal relationship and GLP-1 RA safety with concomitant medication use.

Background: Wrestling is a physically demanding sport with young athletes prone to traumatic shoulder instability and a paucity of data evaluating the results of shoulder instability surgery (SIS). Purpose: To assess reoperation rates, patient-reported outcomes, and return to wrestling (RTW) after SIS in a cohort of competitive wrestlers. Study Design: Case series; Level of evidence, 3. Methods: All competitive wrestlers with a history of shoulder instability and subsequent surgery at a single institution between 1996 and 2020 were identified. All directions of shoulder instability (anterior shoulder instability [ASI], posterior shoulder instability [PSI], and traumatic multidirectional shoulder instability [TMDI]) were analyzed. Exclusions included revision SIS and <2 years of follow-up. Athletes were contacted for determination of complications, RTW, and Western Ontario Shoulder Instability Index scores. Results: Ultimately, 104 wrestlers were included with a mean age at initial instability of 16.9 years (range, 12.0-22.7 years), mean age at surgery of 18.9 years (range, 14.0-29.0 years), and a mean follow-up of 5.2 years (range, 2.0-22.0 years). A total of 58 (55.8%) wrestlers were evaluated after a single shoulder instability event, while 46 (44.2%) sustained multiple events before evaluation. ASI was the most common direction (n = 79; 76.0%), followed by PSI (n = 14; 13.5%) and TMDI (n = 11; 10.6%). Surgical treatment was most commonly an arthroscopic soft tissue stabilization (n = 88; 84.6%), with open soft tissue repair (n = 13; 12.5%) and open bony augmentation (n = 3; 2.9%) performed less frequently. RTW occurred in 57.3% of wrestlers at a mean of 9.8 months. Recurrent instability was the most common complication, occurring in 18 (17.3%) wrestlers. Revision SIS was performed in 15 (14.4%) wrestlers. Across the entire cohort, survivorship rates free from recurrent instability and revision surgery were 90.4% and 92.5% at 2 years, 71.9% and 70.7% at 5 years, and 71.9% and 66.5% at 10 years, respectively. Preoperative recurrent instability was an independent risk factor for postoperative recurrent instability (hazard ratio, 3.8; 95% CI, 1.33-11.03; P = .012). Conclusion: Competitive wrestlers with multiple dislocations before initial clinical evaluation were 3.8 times more likely to experience postoperative recurrent instability. Patients should be counseled that despite SIS, only 57.3% returned to wrestling after surgery.

Article Title: Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis

Mixture analysis is an emerging statistical tool in epidemiological research that seeks to estimate the health effects associated with mixtures of several exposures. This approach acknowledges that individuals experience many simultaneous exposures and it can estimate the relative importance of components in the mixture. Health effects due to mixtures may vary over space driven by to political, demographic, environmental, or other differences. In such cases, estimating a global mixture effect without accounting for spatial variation would induce bias in effect estimates and potentially lower statistical power. To date, no methods have been developed to estimate spatially varying chemical mixture effects. We developed a Bayesian spatially varying mixture model that estimates spatially varying mixture effects and the importance weights of components in the mixture, while adjusting for covariates. We demonstrate the efficacy of the model through a simulation study that varies the number of mixtures (one and two) and spatial pattern (global, one‐dimensional, radial) and magnitude of mixture effects, showing that the model is able to accurately reproduce the spatial pattern of mixture effects across a diverse set of scenarios. Finally, we apply our model to a multi‐center case‐control study of non‐Hodgkin lymphoma (NHL) in Detroit, Iowa, Los Angeles, and Seattle. We identify significant spatially varying positive and inverse associations with NHL for two mixtures of pesticides in Iowa and do not find strong spatial effects at the other three centers. In conclusion, the Bayesian spatially varying mixture model represents a novel method for modeling spatial variation in mixture effects.

Abstract Delivery of therapeutics to solid tumors with high bioavailability remains a challenge and is likely the main contributor to the ineffectiveness of immunotherapy and chemotherapy. Here, a catheter‐directed ionic liquid embolic (ILE) is bioengineered to achieve durable vascular embolization, uniform tissue ablation, and drug delivery in non‐survival and survival porcine models of embolization, outperforming the clinically used embolic agents. To simulate the clinical scenario, rabbit VX2 orthotopic liver tumors are treated showing successful trans‐arterial delivery of Nivolumab and effective tumor ablation. Furthermore, similar results are also observed in human ex vivo tumor tissue as well as significant susceptibility of highly resistant patient‐derived bacteria is seen to ILE, suggesting that ILE can prevent abscess formation in embolized tissue. ILE represents a new class of liquid embolic agents that can treat tumors, improve the delivery of therapeutics, prevent infectious complications, and potentially increase chemo‐ and immunotherapy response in solid tumors.