Citations

Abstract Eosinophil recruitment and accumulation in the lungs of asthmatics is a hallmark feature of asthma. The causative relationship between eosinophils and induced Th2 pulmonary pathologies remains unclear. Our data suggest a novel role for eosinophils as immune modulators that drive Th2-mediated pulmonary pathologies through modulation of dendritic cell function leading to the suppression of Th1/Th17 immune responses. Methods: Eosinophils and ovalbumin (OVA)-pulsed myeloid dendritic cells were adoptively transferred into IL-5-/- (eosinophil-low) or PHIL mice (eosinophil-null) at the time of allergen challenge using an established acute OVA protocol. Allergen-induced pulmonary changes were assessed as changes in lung and lung draining lymph node (LDLN) cells, activation/polarization of T cells, and induced lung histopathologies. Conclusions: We demonstrate that a threshold level of eosinophils must migrate to the lung draining lymph node to promote dendritic cell recruitment and thus activation of antigen-specific memory T cells. Expression of MHC II or CCR7 on eosinophils is not necessary for proliferation of T cells in the LDLN. These lymphatic eosinophils are necessary to suppress Th1/Th17 neutrophilic polarized immune responses initiated by OVA-pulsed dendritic cells during allergen challenge. These results imply an important function for eosinophils in modulating the balance between Th2 and Th1/Th17 pathways in the development of allergic respiratory inflammation.

AbstractEosinophil migration from circulation is controlled, in part, by chemokines through a family of G-protein-coupled chemokine receptors (CCR). Studies of human eosinophils have demonstrated that signaling through CCR3 receptors is a prominent pathway leading to chemotaxis, although several other receptor-ligand interactions also appear to mediate eosinophil recruitment. The availability of genetically unique strains of mice permits a reductionist approach to assess the signaling pathways in experimental models of human disease. However, despite similarities in these pathways between mice and humans, significant species differences exist, complicating the translation of results from animal models to humans. Purified mouse eosinophils were used in this study to investigate the chemokine receptor expression and the activities of 18 chemokines. Mouse eosinophils isolated from IL-5 transgenic mice expressed transcripts encoding the chemokine receptors CCR1, CCR2, CCR3, CCR5, CCR8, CXCR2, and CXCR4, but not CCR4. Mouse eosinophils also migrated in response to human and mouse eotaxin-1 and -2, but not human eotaxin-3. In addition, the induced migration of mouse eosinophils by TARC, MIP-1β, and KC suggests that unidentified receptor-ligand interactions contribute to eosinophil recruitment. It is interesting that the potent chemoattractant of human eosinophils, RANTES, was unable to mediate mouse eosinophil migration. Furthermore, despite the ability of MIP-1α to bind receptors on purified mouse eosinophils, it was only able to induce significant eosinophil migration in a mixed splenocyte population and was unable to induce migration of highly purified eosinophils. Collectively, these observations reveal physiologically relevant distinctions in mechanisms mediating human and mouse eosinophil migration that potentially reflect evolutionary disparities between these species.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

ImportanceAdrenalectomy is the definitive treatment for multiple adrenal abnormalities. Advances in technology and genomics and an improved understanding of adrenal pathophysiology have altered operative techniques and indications.ObjectiveTo develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy.Evidence ReviewA multidisciplinary panel identified and investigated 7 categories of relevant clinical concern to practicing surgeons. Questions were structured in the framework Population, Intervention/Exposure, Comparison, and Outcome, and a guided review of medical literature from PubMed and/or Embase from 1980 to 2021 was performed. Recommendations were developed using Grading of Recommendations, Assessment, Development and Evaluation methodology and were discussed until consensus, and patient advocacy representation was included.FindingsPatients with an adrenal incidentaloma 1 cm or larger should undergo biochemical testing and further imaging characterization. Adrenal protocol computed tomography (CT) should be used to stratify malignancy risk and concern for pheochromocytoma. Routine scheduled follow-up of a nonfunctional adrenal nodule with benign imaging characteristics and unenhanced CT with Hounsfield units less than 10 is not suggested. When unilateral disease is present, laparoscopic adrenalectomy is recommended for patients with primary aldosteronism or autonomous cortisol secretion. Patients with clinical and radiographic findings consistent with adrenocortical carcinoma should be treated at high-volume multidisciplinary centers to optimize outcomes, including, when possible, a complete R0 resection without tumor disruption, which may require en bloc radical resection. Selective or nonselective α blockade can be used to safely prepare patients for surgical resection of paraganglioma/pheochromocytoma. Empirical perioperative glucocorticoid replacement therapy is indicated for patients with overt Cushing syndrome, but for patients with mild autonomous cortisol secretion, postoperative day 1 morning cortisol or cosyntropin stimulation testing can be used to determine the need for glucocorticoid replacement therapy. When patient and tumor variables are appropriate, we recommend minimally invasive adrenalectomy over open adrenalectomy because of improved perioperative morbidity. Minimally invasive adrenalectomy can be achieved either via a retroperitoneal or transperitoneal approach depending on surgeon expertise, as well as tumor and patient characteristics.Conclusions and RelevanceTwenty-six clinically relevant and evidence-based recommendations are provided to assist surgeons with perioperative adrenal care.

Background: Women have a higher rate of adverse events after mitral valve surgery. We sought to evaluate whether outcomes after transcatheter edge-to-edge repair intervention by sex have similar trends to mitral valve surgery. Methods: The primary outcome was 1-year major adverse events defined as a composite of all-cause mortality, stroke, and any bleeding in the overall study cohort. Patients who underwent transcatheter edge-to-edge repair for mitral regurgitation with the MitraClip system in the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy registry were evaluated. Linked administrative claims from the Centers for Medicare and Medicaid Services were used to evaluate 1-year clinical outcomes. Associations between sex and outcomes were evaluated using a multivariable logistic regression model for in-hospital outcomes and Cox model for 1-year outcomes. Results: From November 2013 to March 2017, 5295 patients, 47.6% (n=2523) of whom were female, underwent transcatheter edge-to-edge repair. Females were less likely to have >1 clip implanted ( P <0.001) and had a lower adjusted odds ratio of device success (adjusted odds ratio, 0.78 [95% CI, 0.67–0.90]), driven by lower odds of residual mitral gradient <5 mm Hg (adjusted odds ratio, 0.54 [CI, 0.46–0.63]) when compared with males. At 1-year follow-up, the primary outcome did not differ by sex. Female sex was associated with lower adjusted 1-year risk of all-cause mortality (adjusted hazard ratio, 0.80 [CI, 0.68–0.94]), but the adjusted 1-year risk of stroke and any bleeding did not differ by sex. Conclusions: No difference in composite outcome of all-cause mortality, stroke, and any bleeding was observed between females and males. Adjusted 1-year all-cause mortality was lower in females compared with males.

Focus on residents' role in teaching and learning has become a topic of increasing interest underscored by the responsibility that physicians in training are given as facilitators of medical student rotations, supervisors of peers and patient educators. Studies demonstrate that more developed teaching skills are predictive of increased knowledge base and improved clinical skill. As a coveted competency, development of teaching skill has become an established milestone in residency programs and a requirement by regulatory agencies (ACGME, LCME) that training institutions provide more opportunities for formal Resident‐as‐Teacher programs (RAT). In keeping with the authentic learning curriculum, the Student‐as‐Teacher (SAT) program in the Department of Anatomy, Mayo Clinic offers a structured and formal near‐peer teaching opportunity to third year medical students for advancing teaching skills. The program selects an average of 5–6 applicants to participate in teaching a 7‐week Anatomy block for first year medical students in an apprenticeship‐based model that emphasizes (1) Teamwork, (2) Leadership, (3) Lifelong learning, (4) Communication, (5) Core Knowledge, and (6) Teaching Skills/Professional development through individualized mentoring, structured debriefing, and reflective diaries. The purpose of this study is to assess the effectiveness of the apprenticeship model by measuring changes in the targeted competencies in the context of teaching practice. Teaching assistants (TAs) were asked to reflect and evaluate their pre‐ and post‐teaching experience in SAT program on a visual analog scale (VAS). All 5 TAs voluntarily responded to the survey. De‐identified VAS ratings were converted into numerical data from 1 to 100. Most reported increase in perception was in the area of non‐technical skills development: providing feedback (59.7; P = 0.0009); understanding expectations and teaching skills required in medical education (39.7; P = 0.002); and understanding teamwork in teaching role (33.1; P = 0.025). Additionally, TAs appreciated increased acquisition of technical skills: knowledge in anatomy, embryology and radiology (31.4; P = 007). Thematic analysis of responses generated a list of themes which included “appreciation for learning of non‐technical skills” and “skills in providing feedback”. The role of basic science educators is extended through facilitation of future physician required competencies in early medical education. While improvement of anatomical knowledge is an obvious benefit to medical students, improvement of non‐technical skills is reinforced by opportunity of the near‐peer teaching experience. In a teaching role, non‐technical skills supported through the art of “learning by doing” provides senior medical students with an authentic experience and ability to turn the intangible into the tangible. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

AbstractBackgroundDue to elevated surgical risk, transcatheter mitral valve replacement (TMVR) is used as an alternative for treating failed bioprosthetic valves, annuloplasty repairs and mitral annular calcification (MAC). We report the procedural and longitudinal outcomes for each subtype: Mitral valve‐in‐valve (MVIV), mitral valve‐in‐ring (MViR), and valve‐in‐MAC (ViMAC).MethodsConsecutive patients undergoing TMVR from October 2013 to December 2019 were assessed. Patients at high risk for left ventricular outflow tract obstruction had either alcohol septal ablation or intentional laceration of the anterior leaflet (LAMPOON).ResultsEight‐eight patients underwent TMVR; 38 MViV, 31 MViR, and 19 ViMAC procedures were performed. The median Society of Thoracic Surgery 30‐day predicted risk of mortality was 8.2% (IQR 5.2, 19.9) for all. Sapien 3 (78%) and transseptal access (98%) were utilized in most cases. All‐cause in‐hospital mortality, technical, and procedural success were 8%, 83%, and 66% respectively. Median follow up was 1.4 years (IQR 0.5–2.9 years) and overall survival was 40% at 4 years. Differential survival rates were observed with MViV doing the best, followed by MViR and ViMAC having a <20% survival at 4 years. After adjusting for co‐variates, MViV procedure was the strongest predictor of survival (HR 0.24 [95% CI 0.079–0.7]).ConclusionTMVR is performed in at high‐risk patients with attenuated long‐term survival. MViV has the best success and survival rate, but long‐term survival in MViR and ViMAC is guarded.

AbstractObjective/BackgroundSmall balloon expandable valves have higher echocardiographic transvalvular gradients and rates of prosthesis‐patient mismatch (PPM) compared to larger valves. However, the impact of these echocardiographic findings on clinical outcomes is unknown. We sought to determine the clinical outcomes of 20 mm SAPIEN 3 (S3 BEV) compared to larger S3 BEV in relation to echocardiographic hemodynamics.MethodsUsing the STS/ACC transcatheter valve registry, we performed a propensity‐matched comparison of patients undergoing treatment of native aortic valve stenosis using transfemoral, balloon‐expandable implantation of 20 mm and ≥ 23 mm S3 BEVs. Baseline and procedure characteristics, echocardiographic variables and survival were analyzed. Multivariable logistic regression was used to identify predictors of 1‐year mortality.ResultsAfter propensity matching of the 20 mm and ≥ 23 mm SAPIEN 3 valves, 3,931 pairs with comparable baseline characteristics were identified. Small valves were associated with significantly higher echocardiographic gradients at discharge (15.7 ± 7.1 mmHg vs. 11.7 ± 5.5 mmHg, p < 0.0001) and severe PPM rates (21.5% vs. 9.7%, p < 0.0001). There was no significant difference in 1‐year all‐cause mortality (20 mm: 13.0% vs. ≥23 mm: 12.7%, p = 0.72) or other major adverse event rates and outcomes between the two cohorts. Based on a multivariable analysis, elevated discharge mean gradient (>20 mmHg), severe PPM and the use of 20 mm versus ≥23 mm were not independent predictors of 1‐year mortality.ConclusionSAPIEN 3 20 mm valves were associated with higher echocardiographic gradients, and severe PPM rates compared to larger valves but these factors were not associated with significant differences in 1‐year all‐cause mortality or rehospitalization.

ABSTRACT A MyoD family gene was identified in the ascidian Ciona intestinalis and designated CiMDF (Ciona intestinalisMuscle Determination Factor). Expression of CiMDF was restricted to the muscle cells of the developing embryo and the body-wall muscle of adults. Northern blots showed that two differentially regulated CiMDF transcripts were expressed during development. A 1.8 kb transcript (CiMDFa) appeared first and was gradually replaced by a 2.7 kb transcript (CiMDFb). These transcripts encoded essentially identical MyoD family proteins with the exception of a 68 amino acid C-terminal sequence present in CiMDFb that was absent from CiMDFa. Although both CiMDFa and CiMDFb contained the cysteine-rich/basichelix loop helix domain (Cys-rich/bHLH) present in all MyoD family proteins, only CiMDFb contained the region near the C terminus (Domain III) characteristic of this gene family. Genomic Southern blots showed that C. intestinalis has only one MyoD family gene, suggesting that CiMDFa and CiMDFb result from differential processing of primary transcripts. The existence of two MyoD family proteins that are differentially expressed during ascidian embryogenesis has novel parallels to vertebrate muscle development and may reflect conserved myogenic regulatory mechanisms among chordates.