Citations

ABSTRACT Aging is a prominent risk factor for heart disease, driving pathological cardiac changes such as hypertrophy, fibrosis, and cellular senescence. While BubR1 has been linked to systemic aging in mammalian models, its specific role in regulating cardiac aging remains unclear. Here, we investigated how BubR1 regulates heart aging and its potential contribution to the pathogenesis of cardiac disease, including heart failure. BubR1 insufficiency in mice resulted in marked cardiac hypertrophy, increased fibrosis, and elevated markers of cellular senescence. Transcriptomic profiling revealed widespread disruption in key pathways involved in cardiac function, including ion channel regulation, cytoskeletal organization, and contractile fiber dynamics. Comparative analysis with aged hearts demonstrated shared dysregulated gene networks, linking BubR1 deficiency to age‐related cardiac dysfunction. Additionally, BubR1 hypomorphic hearts mirrored transcriptomic changes observed in end‐stage heart failure patients, and BubR1 protein levels were found to decline with age in the heart and were also significantly reduced in rodent models of heart failure and in heart failure patients. BubR1 reduction in cardiomyocytes in vitro led to an increased expression of markers of heart failure, hypertrophy, and cytoskeletal remodeling, underscoring an essential and direct role of BubR1 in maintaining cardiomyocyte health. Overall, our data suggest that BubR1 deficiency is a feature of cardiac aging and disease in humans, and that sustaining BubR1 expression may offer a potential therapeutic strategy to mitigate age‐associated cardiac decline and improve heart health in the elderly.

Portal hypertension is a key factor in posthepatectomy liver failure (PHLF). While preoperative liver function tests like APRI+ALBI assess liver function, they only partially reflect portal hypertension severity. Elevated von Willebrand factor antigen (vWF-Ag) indicates endothelial dysregulation and correlates with portal hypertension. Combining vWF-Ag with APRI+ALBI may enhance PHLF prediction. A total of 534 patients who underwent liver resection at Mayo Clinic Rochester (2020–2024) were analyzed for PHLF incidence, postoperative morbidity, and 90-day mortality. Predictive probability for PHLF was assessed using receiver operating characteristic analysis and validated in an external Austrian cohort of 283 patients (2008–2017). vWF-Ag was then integrated into the existing APRI+ALBI multivariable model. PHLF grade B/C was reported in 56 patients (10.5%). The 90-day mortality rate was 0.9% (n=5). Using 2 cutoffs (182%, 240%), vWF-Ag was found to be an independent predictive factor for PHLF grade B/C that remained statistically significant upon multivariable analysis. The combination of preoperative APRI+ALBI and vWF-Ag increased the positive predictive value to 27.9% for PHLF grade B/C in the APRI+ALBI high and vWF-Ag high group. Incorporation of vWF-Ag into the established APRI+ALBI-based multivariable model revealed a superior AUC of 0.772 for PHLF risk stratification and was successfully validated in an independent cohort (AUC=0.834). The combination of vWF-Ag with APRI+ALBI demonstrates a favorable predictive potential for PHLF risk assessment. We provide 2 pathways for clinical assessment: (1) a cutoff-based system and (2) a more complex multivariable model that can be calculated in a specifically designed smartphone application.

Background: Cytokine release syndrome (CRS) is a life-threatening systemic inflammatory condition marked by excessive cytokine production, leading to multi-organ dysfunction. It is commonly associated with T-cell-engaging therapies such as chimeric antigen receptor (CAR) T cells, T-cell receptor bispecific molecules, and monoclonal antibodies. Carfilzomib, a proteasome inhibitor, is known to cause a range of adverse effects, primarily hematologic and cardiovascular. However, multiorgan failure grade 5 (fatal), resembling CRS has not been previously reported in association with Carfilzomib. Case Report: A 74-year-old male with relapsed multiple myeloma developed grade 5 multiorgan failure 60 min after the third dose of Carfilzomib, resulting in death within 24 h of symptom onset. The patient tolerated the first doses of Carfilzomib well with only fever and headache developing post infusion. Before the second dose, the patient developed worsening pancytopenia, prompting the discontinuation of Lenalidomide. After the second Carfilzomib infusion, he experienced fever and transient encephalopathy, which resolved with acetaminophen, corticosteroids, and supportive care. However, following the third dose, he rapidly deteriorated—developing fever, tachycardia, hypotension, hypoxia, and encephalopathy. Despite aggressive management with intravenous fluids, broad-spectrum antibiotics, corticosteroids, and tocilizumab, the patient progressed to refractory shock and multi-organ failure, culminating in death within 24 h. A comprehensive infectious workup was negative, ruling out sepsis and suggesting possible Carfilzomib-induced CRS. Conclusion: Grade 5 multiorgan failure with signs and symptoms similar with CRS following Carfilzomib administration is a rare but potentially fatal adverse drug reaction. Further research is needed to better define the risk factors and optimal management strategies for Carfilzomib-induced multiorgan failure and possible CRS.

Transactive response DNA-binding protein of 43 kDa (TDP-43) and tau proteins play critical roles in neurodegenerative diseases, particularly frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). The co-occurrence of TDP-43 and tau pathologies raises questions about their role in disease progression. This review explores the simultaneous presence of tau and TDP-43 co-pathologies, emphasizing their molecular interactions and the resultant neuropathological implications. Additionally, we provide representative examples of their clinical presentations, neuroimaging, and neuropathological findings associated with FTLD-TDP and FTLD-tau, emphasizing the need for a comprehensive understanding of these intertwined pathologies. We analyze various clinical scenarios, including argyrophilic grain disease (AGD), primary age-related tauopathy (PART), and limbic predominant age-related TDP-43 encephalopathy (LATE), to elucidate the complex relationship between these proteinopathies. From the literature, the co-occurrence of tau and TDP-43 is linked to more severe and poorer clinical outcomes compared to isolated pathologies. This review underscores the necessity of considering co-pathologies in the context of FTLD, as they may act as accelerators of cognitive decline. This highlights the importance of integrated approaches in diagnosing and treating neurodegenerative conditions characterized by tau and TDP-43 misfolding. Understanding the interplay between these molecular markers is vital for advancing therapeutic strategies for such disorders.

ABSTRACTIn Functional Magnetic Resonance Imaging (fMRI), the primary contrast is Blood Oxygen Level Dependent (BOLD) signal. Systemic Low Frequency Oscillations (sLFO) are BOLD signals between 0.01 and 0.1 Hz originating from systemic physiological processes. While sLFO signals in the brain have been shown to travel with blood in numerous studies, their behavior in the spinal cord (SC) remains unexplored. This study characterizes the coupling between brain‐sLFO and SC‐sLFO signals. Understanding brain‐SC‐coupling is pivotal for unraveling the vascular continuity of the central nervous system, which plays a crucial role in SC‐injury pathophysiology. BOLD signal extraction involved registering structural masks to fMRI space to obtain average time series from the brain, SC, and superior sagittal sinus. The sLFOs of the time series were cross‐correlated to determine vascular delays and analyzed for band power. It is found that the SC‐sLFO signal comprises two components relative to the brain, showing opposite correlation polarity and varying delays. These findings suggest that highly oxygenated blood arrives at the spinal cord before arriving at the brain, and some component of the brain's venous output circulates to or near to the spinal cord later, likely due to unique arterial and venous pathways connecting the central nervous system. This insight offers a valuable imaging marker for future studies on the effects of SC injury on brain‐SC interconnectivity.

Objectives Periodic quality control (QC) testing of ultrasound (US) imaging systems is essential to ensure and maintain image quality and safety. The study aims to analyze QC findings from medical physics annual surveys of modern clinical US systems in a multi‐institutional survey. Methods QC results from annual surveys between 2018 and 2021 were retrospectively collected from 12 medical physicists from 11 institutions or consulting companies (hereafter referred to as sites). QC tests were classified as scanner‐ and transducer‐related tests, where scanner‐related tests also included evaluation of diagnostic workstation display monitors and routine QC programs if applicable. Test methodology and pass/fail criteria were established by each site. QC findings were defined as results requiring follow‐up action by service engineers, vendors, or other personnel. The percentage of annual findings was calculated for each site and averaged across the years of data contributed. Furthermore, findings across all sites were aggregated for an overall analysis. Results QC data from a total of 1069 scanner tests and 4542 transducer tests were collected. The average annual percentage of scanner‐related findings varied from 0 to 40.8% among all sites (first quartile 8.7%, median 18.2%, and third quartile 34.1%), while that of transducer‐related findings ranged between 0.5% and 19.9% (first quartile 3.9%, median 7.2%, and third quartile 14.5%). For scanner‐related tests, the top 3 categories of findings were associated with physical and mechanical integrity (171 findings, 74.7%), quantitative testing of the scanner display monitor (40 findings, 17.5%), and scanner port creating artifacts (10 findings, 4.4%). The top 3 findings for transducers related to uniformity and artifact (227 findings, 79.9%), physical and mechanical integrity (44 findings, 15.5%), and sensitivity in fundamental mode (9 findings, 3.2%). Conclusions Medical physics annual surveys revealed considerable actionable findings of modern US systems, which inform the status of current US QC practices in the United States and may guide future standardization and recommendation of QC tests.

Ketones, which are key biomarkers of fat oxidation, are relevant for metabolic health maintenance and disease development, making continuous monitoring essential. In this study, we introduce a novel colorimetric sensor designed for potential continuous acetone detection in biological fluids. The sensor features a polydimethylsiloxane (PDMS) shell that encapsulates a sensitive and specific liquid-core acetone-sensing probe. The microsphere sensors were characterized by evaluating their size, PDMS shell thickness, colorimetric response, and sensitivity under realistic conditions, including 100% relative humidity (RH) and CO2 interference. The microsphere size and sensor sensitivity can be controlled by modifying the fabrication parameters. Critically, the sensor showed high selectivity for acetone detection, with negligible interference from CO2 concentrations up to 4%. In addition, the sensor displayed good reproducibility (CV < 5%) and stability under realistic storage conditions (over two weeks at 4 °C). Finally, the accuracy of the microsphere sensor was validated against a gold standard gas chromatography-mass spectrometry (GC-MS) method using simulated and real breath samples from healthy individuals and type 1 diabetes patients. The correlation between the microsphere sensor and GC-MS produced a linear fit with a slope of 0.948 and an adjusted R-squared value of 0.954. Therefore, the liquid-core microsphere-based sensor is a promising platform for acetone body fluid analysis.

ABSTRACTThe current study includes 910 patients with systemic mastocytosis (SM) seen at the Mayo Clinic from 1968 to 2024. The primary objective was to examine the prognostic contribution of the International Consensus Classification (ICC), in the context of the Mayo Alliance Prognostic System (MAPS) for SM. World Health Organization classification (WHO‐HAEM5) subcategories included (i) indolent/smoldering SM (ISM/SSM; N = 518), (ii) SM associated with another hematological neoplasm (SM‐AHN; N = 273), with the latter including both myeloid and lymphoid neoplasms, (iii) aggressive SM (ASM; N = 106), and (iv) WHO‐defined mast cell leukemia (MCL; N = 13), which included mast cells with both “mature” and “immature” morphology. The ICC‐defined subcategories were mostly similar with the exception that SM‐AHN was replaced by SM associated with another myeloid neoplasm (SM‐AMN; N = 235) and WHO‐defined MCL was replaced by ICC‐defined MCL (N = 8), which included only those with immature MC morphology. Overall survival (OS) was similar between WHO‐defined MCL (median 1.8 years) vs. SM‐AHN (median 2.3 years; p = 0.3) but significantly different between ICC‐defined MCL (median 0.08 years) vs. SM‐AMN (median 2.0 years; p < 0.01). Significant difference in OS was also apparent between ICC‐defined SM‐AMN and SM associated with lymphoid neoplasm (SM‐ALN; median 8.1 years; HR 3.4; p < 0.01). Multivariable analysis confirmed the inter‐independent prognostic contributions of both ICC‐defined morphologic subcategories and MAPS risk variables, including age > 60 years, anemia, alkaline phosphatase > ULN, and platelet count < 150 × 109/L (p < 0.03 in all instances); the same was not true for WHO‐HAEM5‐defined SM subcategories. The addition of mutational information into the multivariable model resulted in ousting anemia and inclusion of ASXL1 (p < 0.01), SRSF2 (p = 0.01), and NRAS (p = 0.01) mutations as additional risk factors. Classification of SM by ICC is prognostically more accurate, compared to WHO‐HAEM5, and strengthens the prognostic contribution of morphology to current clinical and molecular risk models.

Objective: To develop an artificial intelligence–based pipeline to assess and triage patient-submitted postoperative wound images. Background: The rise of outpatient surgeries, remote monitoring, and patient-submitted wound images via online portals has contributed to a growing administrative workload on clinicians. Early identification of surgical site infection (SSI) is essential for reducing postoperative morbidity. Methods: Patients ≥18 years old who underwent surgery at 9 affiliated Mayo Clinic hospitals (2019-2022) and were captured by the National Surgical Quality Improvement Program (NSQIP) were included. Eligibility required submission of one image via the patient portal within 30 days after surgery. Images were independently screened in duplicate to determine the presence of an incision. SSI outcomes were obtained from NSQIP. The developed model consisted of 2 stages: incision detection and SSI detection in images with incisions. Four pretrained architectures were evaluated using 10-fold cross-validation, with upsampling and data augmentation to mitigate class imbalance. An end-to-end pipeline, image quality assessment and sensitivity analysis stratified by race were also performed. Results: Among 6060 patients, the median age was 54 years (interquartile range: 40–65), 61.4% (n=3805) were female, and 92.5% (n=5731) identified as White. SSIs were confirmed in 6.2% (n=386) images. Vision Transformer outperformed all others, achieving an incision detection accuracy of 0.94 (area under the curve=0.98) and an SSI detection accuracy of 0.73 (area under the curve=0.81). In addition, it demonstrated strong performance in assessing image quality. Sensitivity analysis revealed comparable performance across racial subgroups. Conclusion: This artificial intelligence pipeline demonstrates promising performance in automating wound image assessment and SSI detection, reducing clinical workload and improving postoperative care.

Abstract Introduction As the field of sexual medicine continues to grow, there has been increasing attention on methodological integrity and rigor of sexual medicine research, including an emphasis on guidelines for quantitative research design and standards for assessing clinical trial outcomes. However, qualitative research (QR) methodology has garnered relatively scant attention in comparison. Objectives To clarify the value of QR and provide recommendations for improving implementation of QR methods in sexual medicine research. Methods A PubMed review was conducted. Expert opinion was based on a process of literature review and expert consensus. Results An essential goal of QR is to describe and explain unknown or insufficiently understood phenomena through detailed investigation of subjective human experience. Results from QR allow for generating hypotheses that may then be tested. More recently, mixed-methods research, ie, research integrating both qualitative and quantitative methods, is being increasingly used across domains of biomedical and health science research. While there remain differences of opinion regarding use of qualitative methodology in sexual medicine, best-practice models of QR underscore the principle of trustworthiness and include ethics and transparency in protocols for data collection and analysis. It is recommended that established QR frameworks for developing a research question are utilized and that consolidated criteria for reporting research results are employed. Furthermore, authors and reviewers need training in both QR methods and qualitative reporting frameworks to be able to adequately report and review this type of research. Specific areas in sexual medicine that would ideally benefit from QR methods are suggested. Conclusion As the field of sexual medicine continues to expand, qualitative methodologies including mixed-methods research, offer significant value for understanding domains of inquiry that have not been thoroughly investigated. To achieve these targets, training of authors and reviewers on QR is needed.