Citations

Abstract Rationale: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and cellular chemical sensor. AhR maintains cellular homeostatsis in respons to endogenous and exogenous organic molecules. Airway smooth muscle (ASM) cells are major structural cells in airway which is involved in characteristic features of asthma such as increased airway wall thickness, airway remodeling and airway hyperresponsiveness. Previously, we found notable expression of AhR in human ASM and its increased expression during inflammation and asthma. However, the mechanisms of enhanced AhR expression in ASM is unknown. Therefore, we examined the role of pro-inflammatory signaling pathways in enhanced AhR expression. Methods: Primary human non-asthmatic and asthmatic ASM cells isolated from surgical lung resections (Mayo IRB approved) were cultured in DMEM-F12 medium supplemented with 10% fetal bovine serum and 1% antibiotic/antimycotic. At ∼80% confluency, cells were serum deprived and treated with TNFα (20 ng/mL), IL13 (50 ng/mL) with or without PI3K/Akt inhibitor (Wortmannin: 50 nM), p38 inhibitor (SB203580: 600 nM), NFkB inhibitor (SN50 20 μM), and AP1 inhibitor (SR11302 10 μM). Subsequently, expression of AhR was determined using RNA sequencing, confocal microscopy, real-time qPCR, and Western blotting. AhR expression in isolated ASM fron lung tissue section was determined using laser capture microdissection (LCM). Moreover, role of AP1 in inducing AhR expression was confirmed using c-JUN (AP1) siRNA transfection in ASM cells. Additionally, binding of AP1 to the AhR promoter region was demonstrated by chromatin-immunoprecipitation (ChIP-qPCR) technique. Results: AhR expression was significantly high in asthmatic ASM cells and tissue than non-asthmatics. Exposure to pro-inflammatory cytokine TNFα increased AhR mRNA and protein expression, whereas IL-13 failed to do so. Furthermore, inhibition of p38 significantly reduced AhR expression whereas PI3K inhibition had no effect, indicating a role for p38 in AhR increased expression. AP1 inhibition significantly downregulated AhR, while NFkB inhibition showed no effect. Similarly, siRNA mediated silencing of c-JUN (AP1) also downregulated AhR, indicating AP1 role in AhR upregulation. Furthermore, transcription factor binding study suggested AhR promoter region has binding site for AP1 and NFkB. Interestingly, ChIP-qPCR study confirmed binding of AP1 at AhR promote region in response to TNFα. Conclusions: Collectively, the current study show that pro-inflammatory cytokine TNFα increases AhR expression through p38-AP1 pathway. The data shows that pro-inflammatory cytokines can regulate AhR expression in ASM, suggesting AhR in ASM has a role in asthma.

Abstract RATIONALE: Research since 2017 has highlighted artificial intelligence (AI)-based technologies to assist in detecting and/or classifying lung nodules on Computed Tomography (CT) scans. However, few have combined detection and classification tasks, and most have required extensive hands-on image manipulation to process the cases, which is both costly and time-consuming. Here, we present a closed loop, fully automated software package, Bronchosolve, which handles cases from scan to result without manual intervention. METHODS: The software package combined pre-processing, analysis, and result generation system including a deep learning convolutional neural network (CNN) for assessment of suspicious pulmonary nodules. Model inputs were full CT cases formatted in Digital Imaging and Communications in Medicine (DICOM), without demographics or clinical variables. Automated steps included 1) automatic selection of the optimal CT series for analysis; 2) normalization and pre-processing of the series; 3) AI-based analysis of the images to both detect and classify suspicious lung lesions; and 4) generation of analysis report. The system was trained using a multi-center dataset of over 2,358 cases of suspicious lung nodules, including cancers and non-cancers. A United States-based, multi-site cohort (n=184) was used for initial algorithm validation where positive cases were defined as biopsy-proven cancer within 1 year, and negatives as negative biopsy or 2+ year negative follow-up. RESULTS: In the validation set, the system achieved a technical completion rate of 100%, automatically for all cases. Median patient age was 62.5 years (interquartile range 58.5 to 66.5 years), 45% were former smokers, 55% were current smokers, and 40% were female. The AI cancer risk (CA-risk) model achieved an area under the receiver-operating-characteristic curve (AUC) of 0.828 [CI: 0.773 – 0.883] in differentiating cancer from non-cancer in cases with known suspicious pulmonary nodules, as confirmed by biopsy, surgery, and/or follow-up. These results were statistically superior to Lung-RADS pAUC of 0.669 [CI: 0.601 – 0.737] and trended better than Brock model AUC of 0.783 [CI: 0.723 – 0.842], Figure 1. At the Youden operating point, model sensitivity was 73.1% [CI: 66.7 – 79.5%], and specificity was 82.5% [CI: 77.0 – 88.0%]. The model's performance was consistent across various CT scanner manufacturers and tested slice thickness. CONCLUSIONS: The closed loop, automated software system, Bronchosolve, consistently processed and analyzed a wide range of CT scans, providing accurate assessment in risk-classifying suspicious lung nodules. This approach has the potential to improve non-invasive assessment of lung nodules eliminating the need for additional user training and time.

Importance Many older adults with advanced cancer never communicate goals of care or treatment preferences to their clinicians, raising the risk that care received will not match their values. Scalable models of care may help surmount this barrier. Objective To test whether a combined patient and clinician intervention increased the rate of advance care planning (ACP) documentation in large health care systems. Design, Setting, and Participants This stepped-wedge cluster randomized clinical trial using an open cohort design included patients aged 65 years or older with advanced cancer seen at oncology clinics in 3 health care systems located in the US South, Midwest, and Mid-Atlantic regions from April 1, 2020, to November 30, 2022. Data collection ended in 2024. Intervention The intervention involved delivering brief evidence-based patient-facing video decision aids available in 25 languages as well as goals-of-care communication training to oncology clinicians. Patients in the control period received usual care. Main Outcomes and Measures The primary outcome was ACP documentation, which included any electronic health record documentation of a goals-of-care conversation, palliative care, hospice, or limitation of life-sustaining treatments, identified via a validated natural language processing program. Analysis was performed on an intention-to-treat basis. Results Twenty-nine practices, comprising 13 800 unique eligible patients with a total of 29 357 repeated measurements, were included (mean [SD] age, 74.5 [6.6] years; 52.3% men [15 344 of 29 357 measurements]). The proportion of patients with ACP documentation was greater in the intervention phase compared with the usual care phase (adjusted rate difference, 6.8% [95% CI, 2.8%-10.8%]; P < .001). ACP documentation in the intervention phase occurred among 3980 of 15 754 patients (25.3%) (goals-of-care conversation, 21.4% [3377 of 15 754]; palliative care, 9.6% [1517 of 15 754]; hospice, 5.4% [847 of 15 754]; and limitation of life-sustaining treatments, 7.2% [1128 of 15 754]). In comparison, ACP documentation in the usual care phase occurred among 2834 of 13 603 patients (20.8%) (goals-of-care conversation, 16.8% [2281 of 13 603]; palliative care, 9.5% [1287 of 13 603]; hospice, 5.3% [724 of 13 603]; and limitation of life-sustaining treatments, 8.4% [1149 of 13 603]). Conclusions and Relevance In this stepped-wedge cluster randomized clinical trial for older adults with advanced cancer, a bundled evidence-based decision aid and communication training intervention increased the proportion of older patients with ACP documentation. This approach offers an innovative paradigm with a clinically meaningful increase in ACP documentation, a widely used quality metric that reflects high-quality patient-centered care delivery. Trial Registration ClinicalTrials.gov Identifier: NCT03609177

AbstractINTRODUCTIONWe compare the stability of phosphorylated tau (p‐tau)217, amyloid beta (Aβ)42, Aβ40, Aβ42/40, and p‐tau217/Aβ42 at different storage temperatures.METHODSTen ethylenediaminetetraacetic acid–plasma sample aliquots stored at frozen, refrigerated, and ambient temperatures were tested at various timepoints up to 30 days. The mean percent change from baseline was calculated.RESULTSAβ42 and Aβ40 concentrations decreased by >15% after 6 hours at ambient temperature and after 24 hours refrigerated, while p‐tau217 remained stable over 72 hours with < 10% deviation from baseline at either storage temperature. The Aβ42/40 ratio remained relatively constant as each analyte concentration decreased concurrently, while the p‐tau217/Aβ42 ratio deviated from baseline over time. All biomarkers were stable up to 30 days frozen.DISCUSSIONDifferences in the stability of Aβ42 and p‐tau217 may lead to altered p‐tau217/Aβ42 ratio results if samples are not handled properly during the pre‐analytical testing phase. Ideally, samples should be frozen promptly and sent to the laboratory frozen.Highlights Plasma phosphorylated tau (p‐tau)217, amyloid beta (Aβ)42, Aβ40, Aβ42/40, and p‐tau217/Aβ42 stability was assessed. P‐tau217 was stable, but Aβ42 and Aβ40 started decreasing by 6 hours at ambient temperature. The analyte stability differences led to falsely increased p‐tau217/Aβ42 ratios. Increases > 15% were seen in p‐tau217/Aβ42 after 6 hours at ambient temperature or 24 hours at 4°C.

AimsPrevious studies have highlighted differences in the risk of periprosthetic fractures (PPFs) in patients undergoing total hip arthroplasty with either a cemented taper slip (TS) stem or a composite beam (CB) stem. This biomechanical study explored the occurrence of PPF around these stems, and the protective effect of adding a 16-gauge prophylactic calcar or diaphyseal wire to the TS stems to increase the resistance to torque as a potential way to prevent these fractures.MethodsA total of 21 TS stems (eight alone, six with calcar wiring, and seven with diaphyseal wiring placed 2 cm distal to the lesser trochanter) and seven CB stems were cemented into standard sawbones. The peak torque at failure was measured using a servohydraulic test machine, and the fracture location was recorded. An a priori power analysis determined that seven specimens per group were needed to detect a 30 Nm difference with 90% power, assuming a 14.8 Nm SD in peak torque between groups. Comparisons were performed using paired t-tests.ResultsCB stems exhibited a significantly higher mean peak torque at failure (205.3 Nm (SD 26.9)) than TS stems (159.5 Nm (SD 17.4); p = 0.012), calcar-wired TS (148.2 Nm (SD 38.6); p = 0.031), and diaphyseal-wired TS (164.9 Nm (SD 21.5); p = 0.027). This study did not demonstrate that wired-TS stems had a higher peak torque at failure than non-wired TS stems. Additionally, calcar wiring was not found to be stronger than diaphyseal wiring (p = 0.400). Four CB fractures occurred distal to the stem, whereas all TS fractures occurred at the mid-stem, simulating a Vancouver type B fracture. Interestingly, adding the diaphyseal wire shifted the fracture location more distally in four of the seven stems (p = 0.070).ConclusionIn this model, CB stems had greater resistance to torque than TS stems, which may explain the lower risk of PPF. Adding calcar or diaphyseal wires to the TS stems resulted in no significant change in peak torque to fracture. CB cemented stems should be considered in patients at high risk of PPF.Cite this article: Bone Joint J 2025;107-B(5 Supple A):32–37.

Background The Woven EndoBridge (WEB) device is a prevalent treatment for intracranial aneurysms. While many studies have assessed the obliteration rate post-WEB embolization, few have focused on long-term outcomes in partially thrombosed aneurysms. Objective To assess whether partially thrombosed aneurysms are at higher risk of recurrence or retreatment following WEB embolization compared with non-thrombosed aneurysms. Methods We evaluated data from 22 academic institutions, focusing on previously untreated cerebral aneurysms treated with the WEB device. Logistic regression was utilized to analyze factors predicting long-term aneurysm obliteration and retreatment necessity. Results Among 1303 patients, 26 presented with a partially thrombosed aneurysm. In the partially thrombosed group, the mean aneurysm maximal diameter was 10.7±4 mm with a neck ratio of 1.99±1.19 mm, larger than in the control group where the mean aneurysm maximal diameter was 6.81±2.37 mm with a neck ratio of 1.64±0.51 mm (P<0.001 for both maximal diameter and neck ratio). At the final follow-up, partially thrombosed aneurysms treated by the WEB device had a 38.5% retreatment rate, compared with 7.0% for non-thrombosed aneurysms (P<0.001). Among partially thrombosed aneurysms, the Raymond-Roy type IIIa/b occlusion rate was higher (38.5% vs 9.9%, P<0.001). On multivariate analysis, partially thrombosed aneurysms compared with non-thrombosed aneurysms had an increased rate of retreatment (OR 3.64, 95% CI 1.28 to 10.1). Conclusion Partially thrombosed aneurysms are associated with a poorer occlusion rate and a higher rate of retreatment following WEB embolization. For partially thrombosed aneurysms, the WEB device appears suboptimal as a first-line treatment, and therefore alternative techniques should be prioritized.

Abstract This multisociety infection prevention guidance document was developed for individuals and organizations that engage in sterilization or high-level disinfection (HLD). It was endorsed by SHEA, APIC, ASGE, IDSA, and SGNA. This guidance is based on a synthesis of published scientific evidence, theoretical rationale, current practices, practical considerations, writing group consensus, and consideration of potential harm when applicable. The supplementary material includes a summary of recommendations. The guidance provides an overview of the Spaulding Classification and considerations around manufacturers’ instructions for use (MIFUs). Its recommendations address: point-of-use treatment prior to sterilization or HLD, preparation of reusable medical devices at the location of processing, sterilization, and immediate use steam sterilization (IUSS), HLD of lumened and non-lumened devices, processing of reusable medical devices used with lubricating or defoaming agents, monitoring for effectiveness of processing, handling of devices after HLD, augments and alternatives to HLD, processing of investigational devices, tracking of reusable medical devices, and approaches to implementation.