Jenkins, Sarah M.

Abstract Background In 2017, Mayo Clinic Laboratories commenced offering a comprehensive type 1 diabetes mellitus (T1DM) autoantibody (Ab) evaluation including 4 known Abs targeting glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and zinc transporter 8 protein (ZnT8) antigens. Methods The objective of this study was to evaluate real-time data on the frequency and patterns of all 4 Abs stratified by age and sex from 6044 unique consecutive adult and pediatric patients undergoing evaluation for suspected diabetes. Results At least one Ab was found in 3370 (56%) of all samples: 67% of children (aged 0–17), 49% of young adults (aged 18–35), and 41% for both middle-aged (aged 36–55) and older (aged >55) adults (P ≤ 0.0001). GAD65-Abs were the most common in all age groups, followed by ZnT8-Ab in those <36 years, or IAA-Ab in those ≥36. Frequencies of IA2- and ZnT8-Abs drop significantly with increasing age. Clusters of 3 or 4 Abs were more frequently encountered in younger patients (41% of children vs 12% in middle- and 13% in older age groups, P ≤ 0.0001). Conclusions Children undergoing serological evaluation for T1DM were more commonly positive for autoantibodies than older age groups. The frequency of ZnT8- and IA2-Abs decreases, and IAA-Ab frequency increases with increasing age, and clusters of 2 to 4 autoantibodies are more common in children. In clinical practice, comprehensive testing for diabetes autoantibodies resulted in a switch in diagnosis to T1DM for patients previously classified as type 2 diabetes mellitus.

Background: African Americans continue to have suboptimal cardiovascular health (CVH) based on the American Heart Association Life’s Simple 7 (LS7), 7 health-promoting behaviors and biological risk factors (eg, physical activity, blood pressure). Innovative, community-level interventions in partnership with trusted institutions such as African American churches are potential means to improve CVH in this population. Methods: Using a community-based participatory research approach, the FAITH! Trial (Fostering African American Improvement in Total Health) rigorously assessed the feasibility and preliminary efficacy of a refined, community-informed, mobile health intervention (FAITH! App) for promoting CVH among African Americans in faith communities using a cluster randomized controlled trial. Participants from 16 churches in Rochester and Minneapolis-St Paul, MN, were randomized to receive the FAITH! App (immediate intervention) or were assigned to a delayed intervention comparator group. The 10-week intervention core features included culturally relevant and LS7-focused education modules, diet/physical activity self-monitoring, and a group sharing board. Data were collected via electronic surveys and health assessments. Primary outcomes were average change in mean LS7 score (continuous measure of CVH ranging from poor to ideal [0–14 points]) from baseline to 6 months post-intervention (using generalized estimating equations) and app engagement/usability (by the Health Information Technology Usability Evaluation Scale; range, 0–5). Results: Of 85 enrolled participants (randomized to immediate [N=41] and delayed [control] intervention [N=44] groups), 76 and 68 completed surveys/health assessments at baseline and 6 months post-intervention, respectively (80% retention rate with assessments at both baseline and 6-month time points); immediate intervention [N=30] and control [N=38] groups). At baseline, the majority of participants (mean age [SD], 54.2 [12.3] years, 71% female) had <4-year college education level (39/66, 59%) and poor CVH (44% in poor category; mean LS7 score [SD], 6.8 [1.9]). The mean LS7 score of the intervention group increased by 1.9 (SD 1.9) points compared with 0.7 (SD 1.7) point in the control group (both P <0.0001) at 6 months. The estimated difference of this increase between the groups was 1.1 (95% CI, 0.6–1.7; P <0.0001). App engagement/usability was overall high (100% connection to app; >75% completed weekly diet/physical activity tracking; Health Information Technology Usability Evaluation Scale, mean [SD], 4.2 [0.7]). Conclusions: On the basis of preliminary findings, the refined FAITH! App appears to be an efficacious mobile health tool to promote ideal CVH among African Americans. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03777709.

Background African-Americans are underrepresented in mobile health intervention research studies which can perpetuate health inequities and the digital divide. A community-based, user-centered approach to designing mobile health interventions may increase their sociocultural relevance and effectiveness, especially with increased smartphone use during the coronavirus disease 2019 pandemic. We aimed to refine an existing mobile health intervention via a virtual focus group series. Methods African-American community members (n = 15) from churches in Minneapolis-St. Paul and Rochester, Minnesota were enrolled in a virtual (via videoconferencing), three-session focus group series over five months to refine a cardiovascular health-focused mobile health application (FAITH! [Fostering African-American Improvement in Total Health!] App). Participants accessed the app via their smartphones and received a Fitbit synced to the app. Participants engaged with multimedia cardiovascular health-focused education modules, a sharing board for social networking, and diet/physical activity self-monitoring. Participant feedback on app features prompted iterative revisions to the FAITH! App. Primary outcomes were app usability (assessed via Health Information Technology Usability Evaluation Scale range: 0–5) and user satisfaction. Results Participants (mean age [SD]: 56.9 [12.3] years, 86.7% female) attended a mean 2.8 focus groups (80% attended all sessions). The revised FAITH! App exceeded the goal Health Information Technology Usability Evaluation Scale score threshold of ≥4 (mean: 4.39, range: 3.20–4.95). Participants positively rated updated app content, visual appeal, and use of social incentives to maintain engagement. Increasing user control and refinement of the moderated sharing board were identified as areas for future improvement. Conclusions Community-partnered, virtual focus groups can optimize usability and increase participant satisfaction of mobile health lifestyle interventions that aim to promote cardiovascular health in African-Americans.

Objective The objective of this study is to determine the association of proliferation indices and pathologic biomarkers on overall and recurrence/metastasis‐free survival (OS and RMFS) in patients with sinonasal mucosal melanoma (SNMM) and to assess the genetic mutational landscape of SNMM. Methods This is a retrospective cohort study of 45 SNMM patients without neoadjuvant therapy who underwent surgical therapy with curative intent and had tumor tissue available for histopathologic review, molecular analysis, and genetic mutational assessment. The OS and RMFS were assessed for associations with numerous tumor and patient‐related factors. Results Among proliferative indices, higher Ki67 and mitotic rates were associated with worsened OS and RMFS (Ki67: p = 0.0007 and p < 0.0001; mitotic rate: p = 0.005 and p = 0.0009, respectively). The presence of brisk tumor‐infiltrating lymphocytes (TILs) was associated with improved RMFS ( p = 0.007) and the presence of lymphovascular invasion was associated with worsened OS and RMFS ( p = 0.02 and p = 0.04, respectively). Patients with amelanotic tumors were more likely to have higher T‐stage ( p = 0.046), less likely to have brisk TILs ( p = 0.02) and had worsened RMFS ( p = 0.03). Patients on immunotherapy with tumor Ki67 < 40% had better 3‐year OS compared to those with higher Ki67 index ( p = 0.004). Actionable genetic mutations such as BRAF V600E are rare and present in only 1 of 20 patients tested. Conclusion In SNMM patients, pathologic and proliferation markers such as Ki67, mitotic rate and brisk TILs are associated with survival and may be considered in future staging systems. Clinical response to immunotherapy appears to correlate with the Ki67 index. Given the distinct genetic profile of SNMM, targeted therapies against the MAPK kinase pathway have limited utility. Level of Evidence 3 Laryngoscope , 132:2350–2358, 2022

Abstract Background Measurement of cholesterol within lipoprotein subfractions may aid in cardiovascular disease prediction. Simple, homogenous enzymatic assays for the direct measurement of lipoprotein subfractions have been developed to measure small dense low-density lipoprotein cholesterol (sdLDL-C), high-density lipoprotein-3 cholesterol (HDL3-C), and triglyceride-rich lipoprotein (TRL-C) cholesterol. The objective of this study was to determine biological variability for sdLDL-C, HDL3-C, and TRL-C in a healthy reference population to facilitate interpretation of these analytes. Methods Serum samples were collected from 24 healthy subjects (n = 14 female/10 male) daily for 3 days while non-fasting, and daily for 5 days, weekly for 4 weeks, and monthly for 6 months after overnight fasting. sdLDL-C, HDL3-C, and TRL-C cholesterol were measured by homogenous enzymatic assays. Sources of variability (between-subject, within-subject, and analytical) were calculated using random-effects regression models. Reference change value (RCV) and index of individuality (II) for each time period were determined from the variance components. Results Analytic variability (daily, weekly, and monthly CVA) was &lt;3% for each analyte. Monthly within-subject variability (CVI) was 17.1% for sdLDL-C, 7.4% for HDL3-C, and 25.7% for TRL-C. Most of the monthly variation was attributed to between-subject variation for all 3 analytes. Overall RCVs for monthly measurements were 18.1 mg/dL for sdLDL-C, 6.1 mg/dL for HDL3-C, and 16.0 mg/dL for TRL-C. IIs were &lt;0.6 for sdLDL-C and HDL3-C, and 0.81 for TRL-C. Conclusions sdLDL-C, HDL3-C, and TRL-C showed moderate within-subject variability, but high between-subject variability, in a healthy reference population. Given the high individuality of each analyte, population-based reference intervals may be inadequate to detect clinically significant changes.

Background: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the diagnosis is important for patient management and treatment. This study aimed to identify a panel of immunohistochemical (IHC) markers that aid in the distinction between thymomas and thymic carcinomas in routine practice. Materials and Method: Thymic carcinomas, type A and B3 thymomas, and MNTLS were identified in an institutional database of thymic epithelial tumors (TET) (1963–2021). IHC was performed using antibodies against TdT, Glut-1, CD5, CD117, BAP1, and mTAP. Percent tumor cell staining was recorded (Glut-1, CD5, CD117); loss of expression (BAP1, mTAP) was considered if essentially all tumor cells were negative; TdT was recorded as thymocytes present or absent (including rare thymocytes). Results: 81 specimens included 44 thymomas (25 type A, 11 type B3, 8 MNTLS) and 37 thymic carcinomas (including 24 squamous cell carcinomas). Using BAP1, mTAP, CD117 (cut-off, 10%), and TdT, 88.9% of thymic carcinomas (95.7% of squamous cell carcinomas) and 77.8% of thymomas could be predicted. Glut-1 expression was not found to be useful in that distinction. All tumors that expressed CD5 in ≥50% of tumor cells also expressed CD117 in ≥10% of tumor cells. In four carcinomas with homozygous deletion of CDKN2A, mTAP expression was lost in two squamous cell carcinomas and in a subset of tumor cells of an adenocarcinoma and was preserved in a lymphoepithelial carcinoma. Conclusion: A panel of immunostains including BAP1, mTAP, CD117 (using a cut-off of 10% tumor cell expression), and TdT can be useful in the distinction between thymomas and thymic carcinomas, with only a minority of cases being inconclusive.

Context.— Studies of lungs in patients with COVID-19 have focused on early findings. Objective.— To systematically study histopathologic and imaging features and presence of SARS-CoV-2 RNA in lung tissue from patients in later stages of COVID-19. Design.— Autopsies, explants, surgical lung biopsies, transbronchial biopsies, cryobiopsies, and needle biopsies from patients with COVID-19 whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure were studied. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction for SARS-CoV-2 RNA was performed on lung tissue. Results.— Of 44 specimens (43 patients; median age, 59.3 years; 26 [60.5%] male) features of acute lung injury (ALI) were seen in 39 (88.6%), predominantly organizing pneumonia and diffuse alveolar damage, up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic diffuse alveolar damage (n = 22) and cicatricial organizing pneumonia (n = 12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median, 61.5 days) compared with patients with focal (140 days) or no ALI (130 days) (P = .009). Sixteen (of 20; 80%) SARS-CoV-2 reverse transcription droplet digital polymerase chain reaction tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent computed tomography in patients with consolidation on imaging was shorter (median, 43.0 days) versus in patients without consolidation (87.5 days; P = .02). Reticulations were associated with longer time to computed tomography after COVID-19 onset (median, 82 versus 23.5 days; P = .006). Conclusions.— ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.

Introduction: Estimating body fat content has shown to better predict adiposity-related cardiovascular risk than the commonly used body mass index (BMI). The white-light 3D Body Volume Index Scanner (BVI) is a non-invasive device normally used in the clothing industry to asses body shapes and sizes. We assessed the hypothesis that volume obtained by BVI is comparable to the volume obtained by air displacement plethysmography (BodPod) (COSMED Concord, CA, USA) and thus capable of assessing body fat mass using the bicompartmental principles of body composition. Methods: We compared BVI to BodPod, a validated bicompartmental method to assess body fat percent that uses pressure/volume relationships in isothermal conditions to estimate body volume. Volume is then used to calculate body density (BD) applying the formula density= Body mass/Volume. Body fat mass percentage is then calculated using the Siri formula (4.95/BD – 4.50) х 100. Subjects were members of the Mayo Clinic Dan Abraham Healthy Living Center undergoing a wellness evaluation. Measurements from both devices were obtained the same day. A prediction model for total BodPod volume was developed using linear regression based on 80% of the observations (N=971), as follows: Predicted BodPod Volume (L) = 9.498 + 0.805*(BVI volume, L) - 0.0411*(Age, years) - 3.295*(Male=0, Female=1) + 0.0554*(BVI volume, L)*(Male=0, Female=1) + 0.0282*(Age, years)*(Male=0, Female=1). Predictions for BodPod volume based on the estimated model were then calculated for the remaining 20% (N=243) and compared to the volume measured by the BodPod. Results: Mean (SEM) age was 41.5(0.41) years, 39.4% were men, weight 81.6(0.67) kg, BMI was 27.8 (0.20) kg/m2. Average difference between volume measured by BodPod- predicted volume by BVI was 0.0 L, median: -0.4 L, IQR: -1.8 L to 1.5 L. Average difference between Body fat % measured - predicted was -1%, median: -2.7%, IQR: -13.2 to 9.9, R2 = 0.9845 (Figure 1-A, B). Conclusion: Body fat mass can be estimated using volume measurements obtained by a white- light 3D body scanner (Figure 1-A).

Abstract Aims In heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling. Methods and results Large PV were banded (PVH, n = 10) or not (Sham, n = 9) in piglets. At sacrifice, PV and PA were perfusion labelled for vessel-specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry. Pulmonary vascular resistance [Wood Units; 8.6 (95% confidence interval: 6.3, 12.3) vs. 2.0 (1.7, 2.3)] and PA [19.9 (standard error of mean, 1.1) vs. 10.3 (1.1)] and PV [14.2 (1.2) vs. 7.6 (1.1)] wall thickness/external diameter (%) were increased in PVH (P &lt; 0.05 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 vs. 161), altered canonical pathways (17 vs. 3), and predicted upstream regulators (PUSR; 22 vs. 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mammalian target of rapamycin signalling with dysregulated growth. In PV, there was also activation of Rho/Rho-kinase signalling with decreased actin cytoskeletal signalling and altered tight and adherens junctions, ephrin B, and caveolae-mediated endocytosis signalling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (transforming growth factor-beta) suggested endothelial to mesenchymal transition in PV. Findings were similar in human autopsy specimens. Conclusion These findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH.

AbstractBackgroundCeramides are bioactive lipid species that mediate numerous cell-signaling events. Elevated plasma ceramides concentration constitutes a risk factor for several pathologies. Multiple studies have affirmed the plasma concentrations of 4 specific ceramides (Cer16:0, Cer18:0, Cer24:0, and Cer24:1) can predict cardiovascular disease risk. Furthermore, these ceramides can be altered by many lipid-lowering therapies. Understanding the biological variability within an individual, and within a population, will further inform the clinical use of plasma ceramides as a biomarker. In this study, we aimed to define the intra- and interbiological variability of ceramides in a healthy reference population in a weekly and monthly manner.MethodsFasting plasma from 24 healthy adults was collected daily (5 days), weekly (4 weeks), and monthly (7 months). Ceramide concentrations were measured with liquid chromatography–mass spectrometry (LC–MS). For analysis, we used random-effects regression models to estimate variance components.ResultsThe analytical variability was smaller compared to the biological variability overall. The greatest variation reported was between-subject variation for all ceramide species. The critical difference-reference change value (RCV) for within-subject variations monthly were 0.07 mcmol/L (Cer16:0), 0.04 mcmol/L (Cer18:0), 1.09 mcmol/L (Cer24:0), and 0.27 mcmol/L (Cer24:1). The index of individuality (IOI) of ceramides were 0.82 (Cer16:0), 0.96 (Cer18:0), 1.06 (Cer24:0), and 0.89 (Cer24:1). The most consistent ceramide species was Cer18:0 with the lowest within- and between-subject critical differences in weekly and monthly measurements.ConclusionsOverall, this study demonstrates that the variability of ceramide concentrations at different time points is minimal within individuals, allowing a single draw to be sufficient at least in a yearly time frame.