Anterior Pathway for Epicardial Left Atrial Appendage Clip Occlusion During Minimally Invasive Atrioventricular Valve Surgery.

The left atrial appendage occlusion (LAAO) by endocardial suture is sometimes inadequate and thrombogenic with uncertain electrical competence. Moreover, epicardial LAAO clip placement through the transverse sinus can be technically challenging during minimally invasive atrioventricular valve surgery. Here, we describe our new endoscopic technique via an anterior access pathway in 5 patients with concomitant atrial fibrillation using an epicardial clip device (AtriClip Pro 1 or AtriClip Pro 2, AtriCure, Mason, OH, USA) for LAAO. The LAAO was successful in all patients without residual perfusion and surgical complications. Epicardial LAAO by clip via the anterior access pathway represents a novel and feasible endoscopic technique for minimally invasive atrioventricular valve surgery.

Splenic rupture and fungal endocarditis in a pediatric patient with invasive fusariosis after allogeneic hematopoietic stem cell transplantation for aplastic anemia: A case report.

Background: Invasive mold infections are a well-known and life-threatening condition after allogeneic hematopoietic stem cell transplantation (HSCT). While Aspergillus species are recognized as predominant pathogens, Fusarium species should also be considered due to their broad environmental distribution and the expected poor outcome of invasive fusariosis. Particularly, splenic rupture as a complication of disseminated disease has not been reported yet. Case presentation: Two weeks after allogeneic HSCT for severe aplastic anemia, a 16-year-old boy presented with painful, erythematous skin nodules affecting the entire integument. As disseminated mycosis was considered, treatment with liposomal amphotericin B and voriconazole (VCZ) was initiated. Invasive fusariosis was diagnosed after histological and previously unpublished polymerase chain reaction-based examination of skin biopsies. Microbiological tests revealed Fusarium solani species. Despite stable neutrophil engraftment and uninterrupted treatment with VCZ, he developed mold disease-associated splenic rupture with hypovolemic shock and fungal endocarditis. The latter induced a cardiac thrombus and subsequent embolic cerebral infarctions with unilateral hemiparesis. Following cardiac surgery, the patient did not regain consciousness because of diffuse cerebral ischemia, and he died on day +92 after HSCT. Conclusion: Invasive fusariosis in immunocompromised patients is a life-threatening condition. Despite antimycotic treatment adapted to antifungal susceptibility testing, the patient reported here developed uncommon manifestations such as splenic rupture and fungal endocarditis.

More Than Fish-Framing Aquatic Animals within Sustainable Food Systems.

Aquatic animals are diverse in terms of species, but also in terms of production systems, the people involved, and the benefits achieved. In this concept piece, we draw on literature to outline how the diversity of aquatic animals, their production, and their consumption all influence their impact within the food system. Built on evidence from an array of reductionist and non-reductionist literature, we suggest that food systems researchers and policymakers adapt current methods and theoretical frameworks to appropriately contextualise aquatic animals in broader food systems. We do this through combining current understandings of food systems theory, value chain, livelihoods, nutritional outcomes, and planetary boundaries thinking. We make several claims around understanding the role of aquatic animals in terms of nutritional output and environmental impacts. We suggest a need to consider: (1) the diversity of species and production methods; (2) variable definitions of an "edible yield"; (3) circular economy principles and the impacts of co-products, and effects beyond nutrient provision; (4) role of aquatic animals in the overall diet; (5) contextual effects of preservation, preparation, cooking, and consumer choices; (6) globalised nature of aquatic animal trade across the value chain; and (7) that aquatic animals are produced from a continuum, rather than a dichotomy, of aquaculture or fisheries. We conclude by proposing a new framework that involves cohesive interdisciplinary discussions around aquatic animal foods and their role in the broader food system.

The Role of Aquaculture and Capture Fisheries in Meeting Food and Nutrition Security: Testing a Nutrition-Sensitive Pond Polyculture Intervention in Rural Zambia.

This study tested the efficacy of a pond polyculture intervention with farming households in northern Zambia. Longitudinal data on fish consumption and the associated nutrient intake of households (N = 57) were collected over a six-month period (September 2019-March 2020). One group of people tested the intervention while another group that practiced monoculture tilapia farming, and a third group that did not practice aquaculture, acted as control groups. A similar quantity of fish was consumed on average; however, the associated nutrient intake differed, based on the quantity and type of species consumed, particularly for those who had access to pelagic small fish from capture fisheries. There was a decrease in fish consumption from December onward due to fisheries management restrictions. The ponds provided access to micronutrient-rich fish during this time. Pond polyculture can act as a complementary source of fish to capture fisheries that are subjected to seasonal controls, as well as to households that farm tilapia. Assessments of how aquatic foods can improve food and nutrition security often separate aquaculture and capture fisheries, failing to account for people who consume fish from diverse sources simultaneously. A nutrition-sensitive approach thus places food and nutrition security, and consumers, at the center of the analysis.

Harnessing the diversity of small-scale actors is key to the future of aquatic food systems.

Small-scale fisheries and aquaculture (SSFA) provide livelihoods for over 100 million people and sustenance for ~1 billion people, particularly in the Global South. Aquatic foods are distributed through diverse supply chains, with the potential to be highly adaptable to stresses and shocks, but face a growing range of threats and adaptive challenges. Contemporary governance assumes homogeneity in SSFA despite the diverse nature of this sector. Here we use SSFA actor profiles to capture the key dimensions and dynamism of SSFA diversity, reviewing contemporary threats and exploring opportunities for the SSFA sector. The heuristic framework can inform adaptive governance actions supporting the diversity and vital roles of SSFA in food systems, and in the health and livelihoods of nutritionally vulnerable people-supporting their viability through appropriate policies whilst fostering equitable and sustainable food systems.

Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3.

BACKGROUND: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). METHODS: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. FINDINGS: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical:SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK-/- mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3. VALIDATION: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature. INTERPRETATION: Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response. FUNDING: German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274.

Synergizing Antegrade Endoscopic with Bridging Vein Harvesting for Improvement of Great Saphenous Vein Graft Quality from the Lower Leg.

Antegrade endoscopic harvesting of autografts for bypass grafting may be an optimal strategy addressing excellent graft quality and reduced post-operative wound complications. This standardized protocol for antegrade endoscopic vein harvesting (EVH) from the lower leg has the potential to be introduced to routine coronary artery bypass grafting (CABG). Patients undergoing CABG surgery are positioned on a surgical table with two additional foam rollers below the extended legs, enabling antegrade EVH from the lower leg. Following minimally invasive surgical access through a bridging vein harvest technique, an endoscopic optical dissector is inserted antegrade into the wound. The main vessel and side branches are dissected under continuous optical control of vein quality status and the working channel. After, an endoscopic optical retractor is inserted with an internal bipolar electrocoagulation device for precise, safe, and tissue-protective interruption of side branches. After release of the vein, the vessel is cut off at the proximal and distal ends under optical control, retrieved from the wound, then cannulated and flushed with heparinized saline. Finally, all side branches of the vein graft are double-clipped. Vascular histology is analyzed in a randomized selection of vein samples. After applying this standardized EVH protocol, the learning curve was shown to be steep, and graft quality was sufficient for coronary artery bypass grafting in every case. There was no conversion to surgical harvesting and low risks for tissue damage and bleeding. Leg positioning and synergizing EVH with bridging vein harvesting improved procedural success and vein graft quality. In our hands, antegrade EVH from the lower leg was feasible, demonstrating straightforward graft dissection as well as adequate macroscopic and microscopic graft quality with preserved endothelial integrity. In conclusion, the introduced technique is safe, shows excellent vein autograft quality, and illustrates feasibility for elective and urgent isolated CABG and combined CABG scenarios.

Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133+ Application After Myocardial Infarction.

OBJECTIVE: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair. DESIGN: Multicentre, double-blinded, randomised placebo controlled trial. SETTING: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015. PARTICIPANTS: Post-infarction patients with chronic ischemia and reduced LVEF (25-50%). INTERVENTIONS: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5-5×106 CD133+. OUTCOME: Primary endpoint was delta (∆) LVEF at 180days (d) compared to baseline measured in MRI. FINDINGS (PRESPECIFIED): Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133+. Efficacy (n=58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p=0.001 (n=58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ∆CD133+vs placebo +2.6%, p=0.4). FINDINGS (POST HOC): Responders (R) classified by ∆LVEF≥5% after 180d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p=0.005) and thrombocytes (p=0.004) in contrast to increased Erythropoeitin (p=0.02), and SH2B3 mRNA expression (p=0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation. INTERPRETATION: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature. TRIAL REGISTRATION: ClinicalTrials.govNCT00950274.

Stem cell registry programme for patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting: what benefits does it derive?

AIMS: Standardization of stem cell therapy requires application of appropriate methods to evaluate safety and efficacy, including long-term pharmacovigilance. To accomplish this objective, a long-term registry programme was installed. METHODS AND RESULTS: We analysed 150 patients with ischemic cardiomyopathy, who received intramyocardial CD133+ bone marrow mononuclear stem cell treatment combined with coronary artery bypass grafting (CABG) or CABG alone. The mortality rate, major adverse cerebral and cardiac events, and functional outcome parameters were evaluated for the time period up to 14 years follow-up. As a result, we have stratified the patient population (96 patients) into responders and non-responders. Furthermore, the analysis of relevant predictors of good response to CD133+ bone marrow mononuclear stem cell treatment was performed. Several positive tendencies related to stem cells transplantation were demonstrated. First, no significant difference in major adverse cardiovascular and cerebral events was observed between stem cell and control group up to 14 years follow-up. Second, an improvement of left ventricle ejection fraction (LVEF) in stem cell group retained for 5 years in contrast with CABG-only group, where no significant changes in LVEF after 2 years were observed. In addition, LVEF under 30% and left ventricle end diastolic diameter above 60 mm were independent predictors of functional response to CD133+ cell therapy. CONCLUSIONS: Participants with overt heart failure benefit most from CABG combined with intramyocardial injection of CD133+ bone marrow mononuclear cell within the group. An improvement LVEF in stem cell group remained for 5 years in contrast with the CABG-only group. The patients, in whom the improvement of both LVEF and LVED was observed, have benefited by increased life expectancy.

Therapeutic progenitor cell application for tissue regeneration: Analyzing the impact of toll-like receptor signaling on c-kit+ cell migration following ischemia-reperfusion injury in vivo.

OBJECTIVES: Toll-like-receptor (TLR) mediated immune response has been shown to regulate myocardial damage following cardiac ischemia-reperfusion (IR). It has not been described conclusively so far whether migration of therapeutically applied progenitor cells following an IR event depends on TLR-signaling. METHODS: In vivo migratory capacity murine c-kit+ cells following IR injury was quantified by intravital fluorescence microscopy, utilizing the mouse cremaster muscle model and analyzing early (rolling) and late (adhesion) c-kit+ cell interaction with the local endothelium. The role of TLR-2 and TLR-4, as well as MyD88 and TRIF was analyzed by applying specific knock-out models. RESULTS: A sequence of 15min ischemia followed by 15min of reperfusion induced firm endothelial c-kit+ cell adhesion (5.6±1.3cells/mm2 in Control vs. 30.2±10.1cells/mm2 in IR, p<0.05). Knock-out of TLR-2 and TLR-4 diminished both IR induced early c-kit+ cell-endothelial cell interactions (67.6±2.3% c-kit+ cell rolling in IR vs. 46.3±4.8% c-kit+ cell rolling in IR-TLR-2-ko vs. 45.3±4.8% c-kit+ cell rolling in IR-TLR-4-ko, p<0.05) as well as firm endothelial c-kit+ cell adhesion (30.2±10.1cells/mm2 in IR vs. 16.3±3.9cells/mm2 in IR-TLR-2-ko vs. 14.5±4.4cells/mm2 in IR-TLR-4-ko, p<0.05). Adaptor protein knock-out resulted in a significantly decreased firm endothelial c-kit+ cell adhesion only in MyD88 knock-out but not in TRIF knock-out (9.2±2.2cells/mm2 in IR-MyD88-ko vs. 30.1±9.9cells/mm2 in IR-WT, p<0.05). CONCLUSION: Artificially applied c-kit+ cells interact with the target organ endothelium following IR injury. This interaction seems to depend on TLR-MyD88 signaling. Therapeutic blockade of TLR signaling for anti-inflammatory purposes might interfere with regenerative cell-based therapy protocols.

Clinical outcomes of conventional surgery versus MitraClip® therapy for moderate to severe symptomatic mitral valve regurgitation in the elderly population: an institutional experience.

BACKGROUND: The aim of this study was to compare treatment of moderate to severe symptomatic mitral regurgitation (MR) with either conventional surgery or the mitral valve edge-to-edge device (MitraClip®) in very elderly patients. The newly introduced MitraClip device has demonstrated promising acute results in treating this patient cohort. Also noteworthy is the fact that patients who otherwise would have been denied surgery are increasingly referred for treatment with the MitraClip device. We sought to review our institutional experience, comparing outcomes in both surgical and MitraClip arms of treatment in the elderly population with symptomatic MR. METHODS: From October 2008 through October 2014, 136 consecutive patients aged ≥ 80 with moderate to severe symptomatic MR were scheduled for either conventional surgery or MitraClip intervention. 56 patients ≥ 80 were operated for symptomatic MR and 80 patients ≥ 80 were treated with the mitraClip device. Patients suitable for this study were identified from our hospital database. Patients ≥80 with moderate/severe symptomatic MR treated with either conventional surgery or the MitraClip device were eligible for our analysis. We compared the surgical patient cohort with the mitraClip patient cohort after eliminating patients that did not meet our inclusion criteria. Forty-two patients were identified from the conventional cohort who were then compared with 42 patients from the mitraClip cohort. Forty-two patients (50%) underwent mitral valve repair or replacement (40.5% functional MR, 59.5% organic/mixed MR) and 42 patients (50%) underwent MitraClip intervention (50% functional MR, 50% organic/mixed MR). Associated procedures in the conventional surgical group were myocardial revascularization 38%, pulmonary vein ablation 23.8%, left atrial appendage resection 52.4% and PFO occlusion 11.9%. RESULTS: Patients who underwent MitraClip treatment were though slightly older but the differences did not attain statistical significance (mean, 82.2 ± 1.65 vs 81.7 ± 1.35 years, p = 0,100), had lower LVEF (mean, 47.6 ± 14.2 vs 53.4 ± 14.3, p = 0.072), lower logistic EuroScore II (mean, 11.3 ± 5.63 vs 12.1 ± 10.6, p = 0.655) but higher STS risk score (mean, 11.8 ± 6.7 vs 8.1 ± 5.6, p = 0.008) respectively compared to surgical patients. Procedural success was 100% vs 96% in surgery and MitraClip groups respectively. Thirty -day mortality was 7.1% vs 4.8% (p = 1.000) in surgery and MitraClip group respectively. Residual postoperative MR ≥2 at discharge was present in none of the patients treated surgically, whereas this was the case in 10 (23.8%) patients treated with the MitraClip device. At 1 year a cumulative number of four (9.52%) patients died in the surgical group vs 9 (21.4%) patients who died in the MitraClip group. CONCLUSIONS: Elderly patients presenting with moderate to severe symptomatic MR may either be treated by conventional surgery or with the MitraClip device with acceptable acute outcomes. The decision for treatment with the MitraClip device should not depend on age alone rather on cumulative risk of conventional surgery. Concomitant cardiac pathologies, often times treated simultaneously during surgery for symptomatic MR may be omitted, if patients are scheduled outright to MitraClip treatment. The effect of concomitant cardiac pathologies left untreated at the time of interventional mitral valve repair on outcome after MitraClip therapy remain widely unknown.

Conventional Surgery for Early and Late Symptomatic Mitral Valve Stenosis After MitraClip® Intervention: An Institutional Experience With Four Consecutive Patients.

BACKGROUND: Surgical mitral valve repair is the gold standard for treatment of mitral regurgitation. Recently, the transcatheter treatment of mitral regurgitation with the MitraClip® device (Abbot Vascular Structural Heart, Menlo Park, CA) has demonstrated promising results in treating patients not amenable for surgical correction of mitral valve regurgitation. Most patients reported in the literature requiring surgical bailout after MitraClip treatment presented with residual or recurrent mitral valve regurgitation. Mitral valve stenosis after MitraClip treatment has been rarely reported. METHODS: From February 2010 to December 2014, four patients out of 165 patients who underwent MitraClip therapy developed symptomatic mitral valve stenosis (2.4%) and needed surgical correction. Data of the four patients were reviewed retrospectively. Follow-up data were obtained from each patient's general practitioner/cardiologist by phone calls and facsimile and were complete in all patients. RESULTS: All four patients were treated with ≥ 2 MitraClip (MC) devices during their initial presentation. All four patients underwent MV replacement with a tissue valve. The postoperative course was uneventful and there was no 30-day mortality. At 6-month follow-up, all patients were alive and in NYHA class I-III. CONCLUSION: Placement of multiple clip devices may lead to slightly elevated transmitral gradients. This may not necessarily interpret into symptomatic mitral stenosis. However, in some cases this is possible. Caution should be exercised at this phase of the learning curve of the percutaneous MC treatment, especially in use of multiple MC devices.

Spray- and laser-assisted biomaterial processing for fast and efficient autologous cell-plus-matrix tissue engineering.

At present, intensive investigation aims at the creation of optimal valvular prostheses. We introduced and tested the applicability and functionality of two advanced cell-plus-matrix seeding technologies, spray-assisted bioprocessing (SaBP) and laser-assisted bioprocessing (LaBP), for autologous tissue engineering (TE) of bioresorbable artificial grafts. For SaBP, human mesenchymal stem cells (HMSCs), umbilical cord vein endothelial cells (HUVECs) and fibrin were simultaneously spray-administered on poly(ε-caprolactone) (PCL) substrates. For LaBP, HUVECs and HMSCs were separately laser-printed in stripes, followed by fibrin sealing. Three-leaflet valves were manufactured following TE of electrospun PCL tissue equivalents. Grafts were monitored in vitro under static and dynamic conditions in bioreactors. SaBP and LaBP resulted in TE of grafts with homogeneous cell distribution and accurate cell pattern, respectively. The engineered valves demonstrated immediate sufficient performance, complete cell coating, proliferation, engraftment, HUVEC-mediated invasion, HMSC differentiation and extracellular matrix deposition. SaBP revealed higher efficiency, with at least 12-fold shorter processing time than the applied LaBP set-up. LaBP realized coating with higher cell density and minimal cell-scaffold distance. Fibrin and PCL stability remain issues for improvement. The introduced TE technologies resulted in complete valvular cell-plus-matrix coating, excellent engraftment and HMSCs differentiation. SaBP might have potential for intraoperative table-side TE considering the procedural duration and ease of implementation. LaBP might accelerate engraftment with precise patterns.

Awake extracorporeal membrane oxygenation (ECMO) as bridge to recovery after left main coronary artery occlusion: a promising concept of haemodynamic support in cardiogenic shock.

Cardiogenic shock following acute myocardial infarction is associated with high mortality rate. Different management concepts including fluid management, inotropic support, intra aortic balloon counterpulsation (IABP) and extracorporeal membrane oxygenation (ECMO) mainly in mechanically ventilated patients have been used as cornerstones of management. However, success rates have been disappointing. Few reports suggested that ECMO when performed under circumvention of mechanical ventilation, may offer some survival benefits. We herein present our experience with the use of veno-arterial ECMO as bridge to recovery in an awake and spontaneously breathing patient after left main coronary artery occlusion complicated by cardiogenic shock.