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Key Points The rat arteriovenous fistula (AVF) model exhibits marked upregulation of p16 Ink4a and p21 Cip1 and multiple markers of senescence. Fisetin, an established vasoprotective senolytic agent, when administered for 3 weeks, increases AVF blood flow and AVF outward remodeling. Heme is shown to be a novel prosenescence metabolite, and when chronically administered, it decreases AVF blood flow. Background Maturational failure of dialysis arteriovenous fistulas (AVFs) not uncommonly occurs and is of considerable and timely importance. Our prior studies demonstrate that senescence, a phenotypic process that promotes vascular and other diseases, occurs in the murine AVF. In this study, we examined whether senescence also occurs in the rat AVF model and the effect of compounds that inhibit or accelerate senescence. Methods The rat AVF was created in the femoral vessels by an end vein-side artery anastomosis. In the AVF, we assessed the expression of critical drivers of senescence, specifically, the cell cycle inhibitors p16 Ink4a and p21 Cip1 , and such indices of a senescence phenotype as senescence-associated β -galactosidase (SA- β -gal) activity, SA- β -gal staining, and a senescence-associated secretory phenotype. We examined the effects of compounds that retard or accelerate senescence on AVF blood flow. Results The AVF evinced upregulation of p16 Ink4a and p21 Cip1 when assessed 3 days after AVF creation. The AVF also demonstrated increased SA- β -gal activity in the artery and vein; staining for SA- β -gal in the AVF artery, anastomosis, and vein; and a prominent senescence-associated secretory phenotype. Fisetin, an established senolytic that is protective in other models of vascular injury, when administered for 3 weeks, increased AVF blood flow and outward remodeling. Hemin, when administered for 3 weeks, decreased AVF blood flow. We demonstrate that hemin is a novel inducer of a senescence phenotype in endothelial cells, as reflected by several senescence indices. However, when administered relatively acutely (for 5 days), hemin increased AVF blood flow by heme oxygenase–dependent mechanisms because the latter was entirely prevented by a competitive inhibitor of heme oxygenase activity. Conclusions The rat AVF exhibits senescence within 3 days of its creation. Chronic administration of a senolytic compound (fisetin) increases AVF blood flow, whereas chronic administration of a prosenescence compound (hemin) decreases AVF blood flow.

Background Genetics may influence symptoms experienced by breast cancer survivors (BCS) by moderating the effects of stress-reducing interventions, including the Mindfulness-Based Stress Reduction (MBSR(BC)) program, to reduce symptom severity. As part of a larger clinical trial, the aim of this study was to evaluate genetic variants as moderators of MBSR(BC) on improvements among BCS in cognitive functioning and symptoms. Methods BCS ( n = 128) were randomized to MBSR(BC) or the Breast Cancer Education Support Program. Objective neuropsychological and subjective measures of cognitive performance, and psychological and physical symptoms were collected at baseline, 6, 12, and 26 weeks. Linear mixed models were implemented to identify MBSR(BC)’s effects over time. A total of 22 single nucleotide polymorphisms (SNPs) from 20 genes known to be related to these symptoms were investigated using genomic DNA. These SNPs were tested as moderators of MBSR(BC) program effects. Results Results showed MBSR(BC) participants experienced significantly greater benefits in cognitive functioning, however, the level of benefit varied based on one’s genetic profile. Effects sizes, consistency across similar measures were investigated. Among 22 candidate SNPs, rs4680 in COMT, rs1800497 in ANKK1, and rs6277 in DRD2 demonstrated the strongest, most consistent positive effects in moderating MBSR(BC)’s impact on cognitive outcomes. Conclusions Although the effects were small, this translational research may potentially identify BCS with genotypes that would be most influenced by the MBSR(BC) program. These results may be used to develop personalized intervention programs tailored to the genetic profile of each breast cancer survivor who received chemotherapy or chemotherapy and radiation. Trial Registration ClinicalTrials.gov, https://www.ClinicalTrials.gov Registration Number: NCT02786797.

Anatomic teaching has long informed surgical knowledge, experience, and skills. One tool for teaching that emerged during the Renaissance was the fugitive anatomic sheet, which used flap layers to reveal different levels of anatomy. In 1538, Vogtherr introduced the first fugitive sheets, which included illustrations of male and female figures with a torso paper flap that, when lifted, revealed the internal organs in a cartoonish style. The popularity of these anatomic fugitive sheets spurred an increase in small print-and-sale workshops. In 1543, Vesalius included fugitive anatomic sheets in his books Fabrica and Epitome , containing large paper flapped models that could be created by cutting out and gluing images of human internal anatomy onto a base layer. Students could tack these manikins up to a nearby wall during dissection. Significant collaboration between Vesalius and his publisher occurred to coordinate the integration of large foldable sheets featuring the cutout models into his works. Vesalius's groundbreaking discoveries, his use of the most advanced printing techniques, and his innovative teaching style are fundamental aspects of the legacy of medical education. This article shows these remarkable fugitive anatomic sheets from the original publications of Fabrica and Epitome together for the first time. It explores the innovative concepts and applications of Vesalius's unique printings.

Background: Previous data suggested that the outcomes for liver-alone transplant recipients following transjugular intrahepatic portosystemic shunt (TIPS) insertion were comparable to those without TIPS. This study investigates the association between TIPS and outcomes among simultaneous liver–kidney (SLK) recipients in the United States. Methods: Utilizing the Scientific Registry for Transplant Recipients (SRTR) standard analysis file from 2003 to 2022, we examined 9717 adult SLK recipients, among whom 858 had undergone TIPS before transplantation. Kaplan–Meier curves were generated to assess recipient and death-censored liver and kidney graft survival. Mixed-effects Cox proportional hazard models were employed to analyze the association between TIPS and the outcomes of interest, where the transplant center was treated as a random effect. The models were adjusted for recipient age, sex, MELD score, diabetes, duration of listing, induction, steroid maintenance, hepatitis C status, donor age, donor sex, cold ischemia time, local vs. shipped organs, and allocation era. Results: Overall, the two groups were comparable, with minor differences. Notably, the median liver waiting time was significantly longer in the TIPS group compared to the non-TIPS group (4.1 vs. 2 months, p < 0.001). One-year rejection rates for liver and kidney allografts did not differ significantly between groups. Univariable Cox regression analyses demonstrated no association between TIPS and worse outcomes for recipient, liver, and kidney survival (p = 0.65, p = 0.22, and p = 0.54, respectively). TIPS did not emerge as a predictor of recipient or death-censored liver or kidney graft survival in multivariable models. Conclusion: In this extensive national cohort of SLK transplant recipients, pre-transplant TIPS was not linked to adverse outcomes for recipients or their allografts.

BACKGROUND: Distinguishing between unilateral and bilateral primary aldosteronism, a major cause of secondary hypertension, is crucial due to different treatment approaches. While adrenal venous sampling is the gold standard, its invasiveness, limited availability, and often difficult interpretation pose challenges. This study explores the utility of circulating microRNAs (miRNAs) and machine learning in distinguishing between unilateral and bilateral forms of primary aldosteronism. METHODS: MiRNA profiling was conducted on plasma samples from 18 patients with primary aldosteronism taken during adrenal venous sampling on an Illumina MiSeq platform. Bioinformatics and machine learning identified 9 miRNAs for validation by reverse transcription real-time quantitative polymerase chain reaction. Validation was performed on a cohort consisting of 108 patients with known subdifferentiation. A 30-patient subset of the validation cohort involved both adrenal venous sampling and peripheral, the rest only peripheral samples. A neural network model was used for feature selection and comparison between adrenal venous sampling and peripheral samples, while a deep-learning model was used for classification. RESULTS: Our model identified 10 miRNA combinations achieving >85% accuracy in distinguishing unilateral primary aldosteronism and bilateral adrenal hyperplasia on a 30-sample subset, while also confirming the suitability of peripheral samples for analysis. The best model, involving 6 miRNAs, achieved an area under curve of 87.1%. Deep learning resulted in 100% accuracy on the subset and 90.9% sensitivity and 81.8% specificity on all 108 samples, with an area under curve of 86.7%. CONCLUSIONS: Machine learning analysis of circulating miRNAs offers a minimally invasive alternative for primary aldosteronism lateralization. Early identification of bilateral adrenal hyperplasia could expedite treatment initiation without the need for further localization, benefiting both patients and health care providers.

Abstract Background Radiotherapy of breast cancer can be associated with dermatitis. Grade ≥ 2 radiation dermatitis can be painful and impair the patients’ quality of life. To reduce the risk of this complication, patients have to perform skin care several times each day. This may require a considerable level of compliance. This randomized DAI-BREAC trial investigates whether a mobile application reminding the patients four times per day to perform skin care (reminder app) will contribute to reduction of grade ≥ 2 radiation dermatitis. Methods This multinational, randomized, active-controlled, parallel-group, multicenter trial compares standard skin care supported by a reminder app (Arm A) versus standard skin care alone (Arm B) regarding grade ≥ 2 radiation dermatitis in patients receiving adjuvant radiotherapy for breast cancer. The effect of the app will be considered clinically relevant, if the rate of grade ≥ 2 radiation dermatitis is reduced from 25.4% (rate identified in a preceding study) to 15%. A total of 134 patients per arm including drop-outs are required. Secondary aims include pain (visual analogue scale), patient satisfaction with the app (questionnaire), impact of the app on the use of health technology (questionnaire), and benefit from support (coaching) by staff members regarding the use of the app (questionnaire). Discussion If reminder app contributes to a decrease of grade ≥ 2 radiation dermatitis in patients irradiated for breast cancer, it will likely become a useful instrument for these patients. Trial registration: clinicaltrials.gov (NCT06483477; URL: https://clinicaltrials.gov/show/NCT06483477). Registered on 1st of July, 2024. First patient is planned to be included in September 2024.

Background: Recent literature demonstrated a 24-hour reduction in vancomycin duration of therapy (DOT) for skin and soft tissue infections (SSTIs) with a negative methicillin-resistant staphylococcus aureus (MRSA) nasal screening versus a positive nasal screening. Objective of this study was to investigate vancomycin DOT in patients with SSTIs who received MRSA nasal polymerase chain reaction (PCR) screening versus those who did not receive MRSA nasal PCR screening. Methods: A retrospective, multi-center, cohort study was completed in admitted adult patients on vancomycin for SSTI from 01/01/2020 to 09/30/2022. Hospital policy permits any clinician to order a MRSA nasal PCR screening test for various indications, including SSTIs, pneumonia and sepsis. Results: One-hundred-fifty-one patients were included, of which 71 had MRSA nasal PCR screening tests obtained, and 80 did not. The median vancomycin DOT in patients with MRSA nasal PCR screening tests was 19.9 versus 36.7 hours ( P = .014) in patients without screening tests. Conclusion: Patients with SSTIs who receive MRSA nasal PCR screening tests have a shortened vancomycin DOT. These results contribute to current data in support of the efficacy and clinical utility of obtaining MRSA nasal PCR screening tests for SSTIs.

AbstractINTRODUCTIONPrimary age‐related tauopathy (PART) is characterized by neurofibrillary tangles and minimal β‐amyloid deposition, diagnosed postmortem. This study investigates 18F‐flortaucipir (FTP) PET imaging for antemortem PART diagnosis.METHODSWe analyzed FTP PET scans from 50 autopsy‐confirmed PART and 13 control subjects. Temporal lobe uptake was assessed both qualitatively and quantitatively. Demographic and clinicopathological characteristics and voxel‐level uptake using SPM12 were compared between FTP‐positive and FTP‐negative cases. Intra‐reader reproducibility was evaluated with Krippendorff's alpha.RESULTSMinimal/mild and moderate FTP uptake was seen in 32% of PART cases and 62% of controls, primarily in the left inferior temporal lobe. No demographic or clinicopathological differences were found between FTP‐positive and FTP‐negative cases. High intra‐reader reproducibility (α = 0.83) was noted.DISCUSSIONFTP PET imaging did not show a specific uptake pattern for PART diagnosis, indicating that in vivo PART identification using FTP PET is challenging. Similar uptake in controls suggests non‐specific uptake in PART.Highlights 18F‐flortaucipir (FTP) PET scans were analyzed for diagnosing PART antemortem. 32% of PART cases had minimal/mild FTP uptake in the left inferior temporal lobe. Similar to PART FTP uptake was found in 62% of control subjects. No specific uptake pattern was found, challenging in vivo PART diagnosis.