Citations

Purpose Diffusion‐weighted imaging allows investigators to identify structural, microstructural, and connectivity‐based differences between subjects, but variability due to session and scanner biases is a challenge. Methods To investigate DWI variability, we present MASiVar, a multisite data set consisting of 319 diffusion scans acquired at 3 T from b = 1000 to 3000 s/mm 2 across 14 healthy adults, 83 healthy children (5 to 8 years), three sites, and four scanners as a publicly available, preprocessed, and de‐identified data set. With the adult data, we demonstrate the capacity of MASiVar to simultaneously quantify the intrasession, intersession, interscanner, and intersubject variability of four common DWI processing approaches: (1) a tensor signal representation, (2) a multi‐compartment neurite orientation dispersion and density model, (3) white‐matter bundle segmentation, and (4) structural connectomics. Respectively, we evaluate region‐wise fractional anisotropy, mean diffusivity, and principal eigenvector; region‐wise CSF volume fraction, intracellular volume fraction, and orientation dispersion index; bundle‐wise shape, volume, fractional anisotropy, and length; and whole connectome correlation and maximized modularity, global efficiency, and characteristic path length. Results We plot the variability in these measures at each level and find that it consistently increases with intrasession to intersession to interscanner to intersubject effects across all processing approaches and that sometimes interscanner variability can approach intersubject variability. Conclusions This study demonstrates the potential of MASiVar to more globally investigate DWI variability across multiple levels and processing approaches simultaneously and suggests harmonization between scanners for multisite analyses should be considered before inference of group differences on subjects.

Abstract Background Despite safety communications from the Food and Drug Administration (FDA) regarding the outbreak of Mycobacterium chimaera infections (MCIs) from contaminated heater-cooler devices, new cases continue to be identified. Methods We retrospectively reviewed confirmed cases of MCI that were managed at Mayo Clinic sites (Arizona, Florida, and Minnesota) from 09/2015 to 01/2021. Clinical histories including prior cardiovascular surgery were recorded. Diagnostic workup including ophthalmologic examination, imaging, and laboratory testing was reviewed. Treatment and survival outcomes on follow-up were obtained. Results Twelve patients with MCI were included. All patients had aortic valve or graft replacement. Five patients had their surgical procedures following the 10/15/2015 FDA safety communication. The mean time from surgery to symptom onset (range) was 32 (13–73) months. Ten of 11 patients who underwent ophthalmologic examination had chorioretinal abnormalities. Three patients who underwent microbial cell-free deoxyribonucleic acid sequencing tested positive for M. chimaera, which was subsequently confirmed with blood culture growth. Echocardiography and positron emission tomography/computed tomography (PET/CT) revealed evidence of prosthetic valve/graft infection in 7/12 (58.3%) and 6/10 (60.0%) of cases, respectively. Seven patients (58.3%) underwent redo cardiovascular surgery. Of these, 1 patient died 2 days postdischarge, 1 experienced spinal osteomyelitis relapse, and another had interval prosthetic valve fluorodeoxyglucose (FDG) uptake on PET/CT suspicious for recurrent infection. Among 4 patients on medical therapy only, 3 expired or transitioned to hospice during follow-up. Conclusions MCI continues to occur despite the FDA communications. Incorporation of ophthalmologic examination and use of advanced tools may improve MCI diagnosis. The mortality in these patients is high even with aggressive surgical/medical management.

Antibiotic use is often the target of interventions in health care organizations that aim to decrease healthcare-associated infections (HAI) such as Clostridioides difficile (CDI); this is particularly important for fluoroquinolones (FQ), which are frequently used in critical care settings. In this study, using a multiple case study research approach, we conduct an in-depth analysis of an intervention aimed at limiting ICU prescriber access to FQ in two ICUs of two hospitals. The data collection and analysis were guided by a human factors engineering approach based on the SEIPS (Systems Engineering Initiative for Patient Safety) model and evidence-based implementation principles. Our results show some differences in the implementation of the FQ intervention between the two ICUs, such as level and method of FQ restriction, and training and communication with physicians and pharmacists. In both ICUs, several organizational learning mechanisms helped to quickly identify problems with the intervention and ensure that changes were made in a just-in-time manner (e.g. just-in-time training, removal of FQ in order set for pneumonia). Despite their organizational differences, both sites developed strategies to successfully implement the FQ intervention.

Myosin 10 (Myo10) is an unconventional myosin involved in a wide range of cell processes from filopodial formation and extension to spindle orientation during cell division. Among its multiple functional domains, Myo10 contains three IQ motifs that bind calmodulin and specifically calmodulin‐like protein (CLP) as light chains. We have recently shown that CLP expression up‐regulates Myo10, leading to increased Myo10‐dependent cell motility and filopodial extension (R.D. Bennett et al., J. Biol. Chem. 282, 3205–3212, 2007). CLP‐dependent Myo10 up‐regulation occurs without a concomitant increase in Myo10 mRNA. We followed Myo10 degradation in vivo and in vitro and found that CLP does not affect the decay rate of Myo10. Myo10 decayed rapidly with a half‐life of about 2.5 hours indicating that this myosin participates in signaling processes. Using an in vitro transcription/translation system we determined that CLP increased Myo10 heavy chain translation, resulting in a higher relative accumulation of Myo10 in the presence than in the absence of CLP. Taken together, our data suggest that CLP functions to increase translation of Myo10 possibly by acting as a chaperone for the emerging Myo10 heavy chain protein. Supported in part by the Mayo Graduate School and grant BCTR‐0201979 from the Susan G. Komen Breast Cancer Foundation.

Significance Statement Renal artery stenosis (RAS) engenders stenotic-kidney ischemia, dysfunction, and injury, but whether these are mediated by cellular senescence has not been elucidated. INK-ATTAC transgenic mice, high-resolution imaging, and unbiased single-cell RNA sequencing of murine kidneys demonstrated cellular senescence as an important mechanism of progressive injury to epithelial/stromal cells within poststenotic kidneys. Both p16-specific and broad quercetin/dasatinib interventions to blunt senescence improved renal function and structure, underscoring the central role of senescence in the pathogenesis. Furthermore, this mechanism was conserved in human subjects with RAS. These observations reveal new mechanisms that contribute to the pathogenesis of chronic ischemic renal injury, and support the development of senolytic therapy to reduce senescent cell burden and delay renal injury. Background Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. Methods Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function ( in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. Results Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16 Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 ( Cdkn1a ) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. Conclusions Maladaptive tubular cell senescence, involving upregulated p16 ( Cdkn2a ), p19 ( Cdkn2d ), and p21 ( Cdkn1a ) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

8031 Background: New orally administered anticancer treatments have launched in recent years, promising gains in survival and quality of life, but with high prices.Financial difficulties encountered over the course of cancer diagnosis and treatment is a growing concern. These difficulties include inability to pay for basic necessities, presence of medical debt, and high out of pocket burdens relative to income. The primary objective of this study was to estimate the proportion of patients with multiple myeloma (MM) who experience financial difficulties in the past 12 months.Methods: Data collection entailed a comprehensive, theoretically grounded telephone survey and companion medical chart abstraction. Subjects included individuals with a current diagnosis of MM whose current or recent treatment included pharmaceutical-based care and who were not enrolled in a treatment-based trial. Practices eligible to recruit respondents included 44 NCORP affiliates of the Alliance. 14 geographically diverse NCORP affiliates participated between 11/2019 and 6/2020. The primary endpoint of the study was the proportion of subjects who reported financial difficulty in the past 12 months, as measured by the EORTC QLQ-C30 item #28. This proportion and 95% Wilson score confidence interval were estimated for all MM patients who responded to the financial difficulty question ((# reported financial difficulty)/(total # in that category who answered the question)). NCI Central IRB approved this study. Results: 393 subjects were recruited. 304 subjects completed the survey (77.4% response rate). Mean age was 67.5 years (SD 9.8), 143 (46.4%) were female, 24 (7.8%) self-reported race as ‘Black or African American’, 82 (26.6%) reported insured by government insurance Medicare only, 116 (38.2%) reported highest education as high school or below, and 94 (30.5%) reported high income. Mean time from diagnosis to survey enrollment was 3.6 years (SD 4.5). 292 (95.1%) were currently receiving treatment and 192 (62.5%) reported currently receiving a pre-defined ‘expensive’ oral pharmaceutical-based cancer treatment. 20.2% (95% CI:16.1%, 25.0%) reported financial difficulties. Conclusions: This is the first national study to systematically assess the prevalence of financial difficulties and its correlates among MM patients. Approximately 1 in 5 surveyed patients reported financial difficulties. Results of this study aim to inform efforts to improve financial navigation and resources for cancer patients.

Introduction: The Mayo Clinic Cardiac Intensive Care Unit Admission Risk Score (M-CARS) has been shown to predict hospital mortality in the CICU population better than conventional critical care scoring models. We tested the hypothesis that M-CARS could similarly be used to predict one-year mortality. Methods: We retrospectively reviewed adult CICU patients admitted from 2007 to 2018. M-CARS was calculated using admission data. Groups were compared using Wilcoxon test for continuous variables and chi-squared test for categorical variables. Results: This study included 12428 unique patients with a mean age of 67 ± 15 years (37% females), of whom 11279 (90.8%) survived hospitalization and 2839 patients (22.8%) died within 1 year of admission. The 1-year survival decreased incrementally as a function of increasing M-CARS ( Figure 1A , p<0.0001), and all components of M-CARS were significant predictors of 1-year mortality (p<0.001). 1690 hospital survivors (15.0%) died within 1 year. The 1-year survival decreased incrementally as a function of increasing M-CARS for scores <3 (all p<0.001); however, there was no further adverse 1-year survival for patients with M-CARS ≥3 ( Figure 1B, p=0.99). M-CARS components associated with 1-year mortality among hospital survivors included blood urea nitrogen, red blood cell distribution width, Braden score, and respiratory failure (all p<0.001), while cardiac arrest, cardiogenic shock, and anion gap were not. Conclusions: M-CARS accurately predicts 1-year mortality among CICU admissions, with a plateau effects at high M-CARS scores ≥3. Significant predictors of 1-year mortality among CICU survivors include frailty markers rather than admission severity.

Introduction: Mycobacterium Chimaera (MC) infections following cardiovascular surgery are challenging to diagnose given their insidious presentation. We therefore reviewed the various imaging modalities used to diagnose these infections at Mayo Clinic. Methods: Cases from 01/01/2010-06/01/2020 were identified using electronic medical records. Demographics and clinical history were collected. Imaging studies, including transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), positron emission tomography / computed tomography (PET/CT), cardiac CT (CCT), and cardiac magnetic resonance (CMR) were reviewed. Results: A total of 7 patients (85.7% male) were found. 6 underwent aortic valve replacement and 1 received an aortic composite valve conduit. Surgical dates ranged from 01/2010-12/2018. Mean age at presentation was 63.3 years. Mean time from surgery to symptom onset was 28.0 months. All patients underwent TTE and TEE; prosthetic valve endocarditis was identified in 6 cases between both, while CMR established the diagnosis in 1 case. TTE showed prosthetic valve obstruction in 2 cases and an anterior pseudoaneurysm in 1 case. TEE findings included thickened prosthesis and/or vegetations (n=5), thickened posterior root (n=4), and root abscess (n=3). Among the 3 patients who underwent PET/CT, 2 demonstrated increased fluorodeoxyglucose (FDG) uptake around the aortic prosthesis; in addition, 1 had elevated FDG uptake in the myocardium suggesting myocarditis. 1 patient did not have aortic prosthesis FDG uptake. In the 2 patients who had CCT, 1 showed a pseudoaneurysm that prompted suspicion for endocarditis, and the other revealed a fluid collection adjacent to the aortic valve conduit. 2 patients underwent CMR; 1 had aortic prosthesis thickening and patchy areas of myocardial delayed enhancement suspicious for myocarditis, whereas the other showed vegetation and an aortic root abscess. Conclusion: TTE plus TEE successfully identified MC prosthetic valve endocarditis in most cases with TEE having higher specificity. Advanced imaging techniques are helpful to support the diagnosis and assess for myocardial and/or aortic involvement. Combining these modalities is therefore crucial in unveiling this elusive organism.

Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.