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To examine the effect of various biologic adjuvants on the polarization of macrophages in an in vitro model for rotator cuff tears. Tissue was harvested from 6 patients undergoing arthroscopic rotator cuff repair. An in vitro model of the supraspinatus and subacromial bursa was created and treated with control, platelet-rich plasma (PRP), autologous activated serum (AAS), or a combination of PRP+AAS. The effect of treatment on macrophage polarization between M1 proinflammatory macrophages or M2 anti-inflammatory macrophages was measured using gene expression, protein expression, flow cytometry, and nitric oxide production. Tendon and bursa treated with PRP, AAS, and PRP+AAS significantly decreased the gene expression of M1 markers interleukin (IL)-12 and tumor necrosis factor-alpha while significantly increasing the expression of M2 markers arginase, IL-10, and transforming growth factor-β (P <.05) compared with treatment with control. Enzyme-linked immunosorbent assay analysis of protein production demonstrated that, compared with control, coculture treated with PRP, AAS, and PRP+AAS significantly decreased markers of M1-macrophages (IL-6, IL-12, and tumor necrosis factor-alpha) while significantly increasing the expression of markers of M2-macrophages (arginase, IL-10, and transforming growth factor-beta) (P <.05). Flow cytometry analysis of surface markers demonstrated that compared with control, tendon and bursa treated with PRP, AAS, and PRP+AAS significantly decreased markers of M1-macrophages (CD80, CD86, CD64, CD16) while significantly increasing the expression of markers of M2-macrophages (CD163 and CD206) (P <.05). Treatment of the coculture with PRP, AAS, and PRP+AAS consistently demonstrated a decrease in nitric oxide production (P <.05) compared with control. AAS and PRP+AAS demonstrated an increased macrophage shift to M2 compared with PRP alone, whereas there was not as uniform of a shift when comparing PRP+AAS with AAS alone. In an in vitro model of rotator cuff tears, the treatment of supraspinatus tendon and subacromial bursa with PRP, AAS, and PRP+AAS demonstrated an increase in markers of anti-inflammatory M2-macrophages and a concomitant decrease in markers of proinflammatory M1-macrophages. AAS and PRP+AAS contributed to a large shift to macrophage polarization to the anti-inflammatory M2 compared with PRP. The mechanism of biologic adjuvant effects on the rotator cuff remains poorly understood. This study suggests that they may contribute to polarization of macrophages for their proinflammatory (M1) state to the anti-inflammatory (M2) state. [ABSTRACT FROM AUTHOR]

Trained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT 7 functional polymorphism. This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo. Compared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT 7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT 7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT 7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production. This novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT 7 mice in a model of allergic airway inflammation. [ABSTRACT FROM AUTHOR]

The CLASP IID randomized trial (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial) demonstrated the safety and effectiveness of the PASCAL system for mitral transcatheter edge-to-edge repair (M-TEER) in patients at prohibitive surgical risk with significant symptomatic degenerative mitral regurgitation (DMR). This study describes the echocardiographic methods and outcomes from the CLASP IID trial and analyzes baseline variables associated with residual mitral regurgitation (MR) ≤1+. An independent echocardiographic core laboratory assessed echocardiographic parameters based on American Society of Echocardiography guidelines focusing on MR mechanism, severity, and feasibility of M-TEER. Factors associated with residual MR ≤1+ were identified using logistic regression. In 180 randomized patients, baseline echocardiographic parameters were well matched between the PASCAL (n = 117) and MitraClip (n = 63) groups, with flail leaflets present in 79.2% of patients. Baseline MR was 4+ in 76.4% and 3+ in 23.6% of patients. All patients achieved MR ≤2+ at discharge. The proportion of patients with MR ≤1+ was similar in both groups at discharge but diverged at 6 months, favoring PASCAL (83.7% vs 71.2%). Overall, patients with a smaller flail gap were significantly more likely to achieve MR ≤1+ at discharge (adjusted OR: 0.70; 95% CI: 0.50-0.99). Patients treated with PASCAL and those with a smaller flail gap were significantly more likely to sustain MR ≤1+ to 6 months (adjusted OR: 2.72 and 0.76; 95% CI: 1.08-6.89 and 0.60-0.98, respectively). The study used DMR-specific echocardiographic methodology for M-TEER reflecting current guidelines and advances in 3-dimensional echocardiography. Treatment with PASCAL and a smaller flail gap were significant factors in sustaining MR ≤1+ to 6 months. Results demonstrate that MR ≤1+ is an achievable benchmark for successful M-TEER. (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID]; NCT03706833) [Display omitted] [ABSTRACT FROM AUTHOR]

To quantify cellular senescence in supraspinatus tendon and subacromial bursa of humans with rotator cuff tears and to investigate the in vitro efficacy of the senolytic dasatinib + quercetin (D+Q) to eliminate senescent cells and alter tenogenic differentiation. Tissue was harvested from 41 patients (mean age, 62 years) undergoing arthroscopic rotator cuff repairs. In part 1 (n = 35), senescence was quantified using immunohistochemistry and gene expression for senescent cell markers (p16 and p21) and the senescence-associated secretory phenotype (SASP) (interleukin [IL] 6, IL-8, matrix metalloproteinase [MMP] 3, monocyte chemoattractant protein [MCP] 1). Senescence was compared between patients <60 and ≥60 years old. In part 2 (n = 6) , an in vitro model of rotator cuff tears was treated with D+Q or control. D+Q, a chemotherapeutic and plant flavanol, respectively, kill senescent cells. Gene expression analysis assessed the ability of D+Q to kill senescent cells and alter markers of tenogenic differentiation. Part 1 revealed an age-dependent significant increase in the relative expression of p21, IL-6, and IL-8 in tendon and p21, p16, IL-6, IL-8, and MMP-3 in bursa (P <.05). A significant increase was seen in immunohistochemical staining of bursa p21 (P =.028). In part 2, D+Q significantly decreased expression of p21, IL-6, and IL-8 in tendon and p21 and IL-8 in bursa (P <.05). Enzyme-linked immunosorbent assay analysis showed decreased release of the SASP (IL-6, MMP-3, MCP-1; P =.002, P =.024, P <.001, respectively). Tendon (P =.022) and bursa (P =.027) treated with D+Q increased the expression of COL1A1. While there was an age-dependent increase in markers of cellular senescence, this relationship was not consistently seen across all markers and tissues. Dasatinib + quercetin had moderate efficacy in decreasing senescence in these tissues and increasing COL1A1 expression. This study reveals that cellular senescence may be a therapeutic target to alter the biological aging of rotator cuffs and identifies D+Q as a potential therapy. [ABSTRACT FROM AUTHOR]

Climate change is allowing fire to expand into previously unburnt ecosystems and regions. While management policies such as fire suppression have significantly altered their frequency and intensity. To prevent future biodiversity/ecosystem services loss, and the large financial burden of wildfires, management plans will be required to adapt to future climate and land use changes. Long-term ecological data offer a unique perspective to assess fire variability under different climate and land-use conditions. In this study, we focus on Killarney National Park, Ireland. An area which today is under threat from an increase in fire activity. Comparing palaeoecological and archaeological records, we reconstruct the past fire dynamic and its impact on the landscape, and evaluate the role of climate vs humans in influencing the natural fire regime over the millennial time-scale. Our results indicate that fire has been present in the landscape since the beginning of the Holocene, with fire in the early Holocene being largely controlled by climate and microsite conditions, and in the late Holocene being increasingly influenced by human activity. The knowledge of past fire regimes can help inform future management in order to protect the semi-natural native woodland. The park's present landscape mosaic, could be preserved by limiting forest encroachment through moderate grazing and burning, while also protecting any fragmented forest from excessive grazing and large/intense fires, via traditional fire management strategies such as fuel load management. However, a fire management strategy should only be implemented following careful consideration of all ecosystem factors and controls. [ABSTRACT FROM AUTHOR]

• Utilizing technology to promote learning in Gen Z students is generally effective. • A trial with first semester ADN students describes unexpected challenges. • Recommendations made to utilize the same process successfully in other settings. Nursing schools throughout the country are faced with many challenges. Nursing faculty numbers are dwindling and current student traits are changing, affecting the way they learn and comprehend. Nursing faculty must be able to provide rigorous and effective clinical learning opportunities that are effective for today's nursing student. In an effort to meet this goal, faculty implemented an innovative educational intervention allowing the students to record their first semester skills evaluations for instructor viewing instead of performing face-to-face. Students were allowed practice time and given a rubric and concrete instructions on recording their videos that would include teamwork, civility, integrity, and accountability. The students required a stair-step method approach as some had difficulty grasping the entire process. There were a variety of challenges for both students and faculty that caused tremendous amounts of anxiety and frustration. In theory, this innovation aligned with literature review findings and Earl's Model, but going forward, would recommend this process for more advanced nursing students, who were not in their first semester of nursing school. [ABSTRACT FROM AUTHOR]

Subscapularis failure is a troublesome complication following anatomic total shoulder arthroplasty (aTSA). Commonly discarded during aTSA, the long head of the biceps tendon (LHBT) may offer an efficient and cheap autograft for the augmentation of the subscapularis repair during aTSA. The purpose of this study was to biomechanically compare a standard subscapularis peel repair to 2 methods of subscapularis peel repair augmented with LHBT. 18 human cadaveric shoulders (61 ± 9 years of age) were used in this study. Shoulders were randomly assigned to biomechanically compare subscapularis peel repair with (1) traditional single-row repair, (2) single row with horizontal LHBT augmentation, or (3) single row with V-shaped LHBT augmentation. Shoulders underwent biomechanical testing on a servohydraulic testing system to compare cyclic displacement, load to failure, and stiffness. There were no significant differences in the cyclic displacement between the 3 techniques in the superior, middle, or inferior portion of the subscapularis repair (P >.05). The horizontal (436.7 ± 113.3 N; P =.011) and V-shape (563.3 ± 101.0 N; P <.001) repair demonstrated significantly greater load to failure compared with traditional repair (344.4 ± 82.4 N). The V-shape repair had significantly greater load to failure compared to the horizontal repair (P <.001). The horizontal (61.6 ± 8.4 N/mm; P <.001) and the V-shape (62.8 ± 6.1; P <.001) repairs demonstrated significantly greater stiffness compared to the traditional repair (47.6 ± 6.2 N). There was no significant difference in the stiffness of the horizontal and V-shape repairs (P =.770). Subscapularis peel repair augmentation with LHBT autograft following aTSA confers greater time zero load to failure and stiffness when compared to a standard subscapularis peel repair. [ABSTRACT FROM AUTHOR]

The mechanism through which emotional states impact learning is not yet fully understood. Through the lens of cognitive load theory, this study examines the relationship between emotional valence and learning during an algebra-based mathematics task and explores cognitive load as a potential mechanism through which emotions impact learning. Using structural equation modelling and path analysis of Australian Year 7 and 8 Secondary School students completing an algebraic learning task, we test a hypothesised model whereby extraneous cognitive load mediates the relationship between positive emotions, painful emotions, and learning. This model was tested against an alternative model with emotions mediating the relationship between extraneous cognitive load and learning. Results demonstrate that extraneous cognitive load mediates the relationship between painful emotions and learning. Alternatively, positive emotions were related to learning but not mediated by extraneous cognitive load. Implications of these findings for teachers and educators are also discussed. • Individual differences in students' emotional states can influence their learning. • Extraneous cognitive load is an intervening variable between painful emotions and learning. • Painful emotions may hinder learning by impeding students' ability to manage extraneous cognitive load. • Positive emotions directly relate to learning, but this path is not mediated by extraneous cognitive load. [ABSTRACT FROM AUTHOR]