The Aortic Team Model for the Management of the Distal Arch, Descending Thoracic and Thoracoabdominal Aorta: Appraisal at 3 Years.

BACKGROUND: This study aimed to assess feasibility, logistical challenges, and clinical outcomes associated with the implementation of an Aortic Team model for the management of distal arch, descending thoracic and thoracoabdominal aortic disease. METHODS: An Aortic Team care pathway was implemented in November 2019. Working as a unit, two cardiac surgeons, two vascular surgeons, an interventional radiologist, a cardiologist, and an anesthesiologist collectively determined care decisions via multispecialty presence at an Aortic Clinic. Cardiac and vascular surgeons operated in tandem for open procedures. Interventional radiology participated alongside cardiac and vascular for endovascular procedures. Cardiology aided in medical therapies for heritable and degenerative disease, and had a lead role for genetics and high-risk pregnancy referrals. The model spanned three hospitals. Clinical outcomes at 3 years were assessed. RESULTS: There were 35 descending thoracic and thoracoabdominal surgeries and 77 thoracic endovascular aortic repairs. Endoarch devices were used in 7 cases (Gore Thoracic Branch Endoprosthesis, 4, Terumo RelayBranch, 3) and an endothoracoabdominal device in 4 cases (Cook Zenith t-branch). The Aortic Clinic acquired 456 patients, with yearly increases (54 patients [year 1], 181 patients [year 2], 221 patients [year 3]). For surgery, mortality was 8.6% (3/35), permanent paralysis 5.7% (2/35), stroke 8.6% (3/35), permanent dialysis 0%, and reinterventions 8.6% (3/35). For endovascular cases, mortality was 3.9% (3/77), permanent paralysis 3.9% (3/77), stroke 5.2% (4/77), permanent dialysis 1.3% (1/77), and reinterventions 16.9% (13/77). CONCLUSION: An Aortic Team model is feasible and ensures all treatment options are considered. Conventional open thoracoabdominal procedures showed acceptable outcomes. Endoarch technology shows early promise.

C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease.

Gaucher disease is a lysosomal storage disease, which happens due to mutations in GBA1/Gba1 that encodes the enzyme termed as lysosomal acid ß-glucosidase. The major function of this enzyme is to catalyze glucosylceramide (GC) into glucose and ceramide. The deficiency of this enzyme and resultant abnormal accumulation of GC cause altered function of several of the innate and adaptive immune cells. For example, augmented infiltration of T cells contributes to the increased production of pro-inflammatory cytokines, (e.g., IFNγ, TNFα, IL6, IL12p40, IL12p70, IL23, and IL17A/F). This leads to tissue damage in a genetic mouse model (Gba19V/-) of Gaucher disease. The cellular mechanism(s) by which increased tissue infiltration of T cells occurs in this disease is not fully understood. Here, we delineate role of the CXCR3 receptor and its exogenous C-X-C motif chemokine ligand 9 (CXCL9) in induction of increased tissue recruitment of CD4+ T and CD8+ T cells in Gaucher disease. Intracellular FACS staining of macrophages (Mϕs) and dendritic cells (DCs) from Gba19V/- mice showed elevated production of CXCL9. Purified CD4+ T cells and the CD8+ T cells from Gba19V/- mice showed increased expression of CXCR3. Ex vivo and in vivo chemotaxis experiments showed CXCL9 involvement in the recruitment of Gba19V/- T cells. Furthermore, antibody blockade of the CXCL9 receptor (CXCR3) on T cells caused marked reduction in CXCL9- mediated chemotaxis of T cells in Gba19V/- mice. These data implicate abnormalities of the CXCL9-CXCR3 axis leading to enhanced tissue recruitment of T cells in Gaucher disease. Such results provide a rationale for blockade of the CXCL9/CXCR3 axis as potential new therapeutic targets for the treatment of inflammation in Gaucher disease.

Iridium-Catalyzed Aza-Spirocyclization of Indole-Tethered Amides: An Interrupted Pictet-Spengler Reaction.

A mild, reductive spirocyclization of indole-linked amides and lactams for the efficient and selective synthesis of aza-spirocyclic indoline products is described. The catalytic reductive activation of tertiary amides or lactams by Vaska's complex with tetramethyldisiloxane as the terminal reductant allowed iminium ion formation, before a diastereoselective 5-endo-trig spirocyclization of the tethered indole moiety was triggered. Terminal reduction affords the aza-spiroindoline products in an overall highly chemoselective and diastereoselective one-pot process.

Risk of Acute Kidney Injury in Patients Randomized to a Restrictive Versus Liberal Approach to Red Blood Cell Transfusion in Cardiac Surgery: A Substudy Protocol of the Transfusion Requirements in Cardiac Surgery III Noninferiority Trial.

BACKGROUND: When safe to do so, avoiding blood transfusions in cardiac surgery can avoid the risk of transfusion-related infections and other complications while protecting a scarce resource and reducing costs. This protocol describes a kidney substudy of the Transfusion Requirements in Cardiac Surgery III (TRICS-III) trial, a multinational noninferiority randomized controlled trial to determine whether the risk of major clinical outcomes in patients undergoing planned cardiac surgery with cardiopulmonary bypass is no greater with a restrictive versus liberal approach to red blood cell transfusion. OBJECTIVE: The objective of this substudy is to determine whether the risk of acute kidney injury is no greater with a restrictive versus liberal approach to red blood cell transfusion, and whether this holds true in patients with and without preexisting chronic kidney disease. DESIGN AND SETTING: Multinational noninferiority randomized controlled trial conducted in 73 centers in 19 countries (2014-2017). PATIENTS: Patients (~4800) undergoing planned cardiac surgery with cardiopulmonary bypass. MEASUREMENTS: The primary outcome of this substudy is perioperative acute kidney injury, defined as an acute rise in serum creatinine from the preoperative value (obtained in the 30-day period before surgery), where an acute rise is defined as ≥26.5 µmol/L in the first 48 hours after surgery or ≥50% in the first 7 days after surgery. METHODS: We will report the absolute risk difference in acute kidney injury and the 95% confidence interval. We will repeat the primary analysis using alternative definitions of acute kidney injury, including staging definitions, and will examine effect modification by preexisting chronic kidney disease (defined as a preoperative estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). LIMITATIONS: It is not possible to blind patients or providers to the intervention; however, objective measures will be used to assess outcomes, and outcome assessors will be blinded to the intervention assignment. RESULTS: Substudy results will be reported by the year 2018. CONCLUSIONS: This substudy will provide generalizable estimates of the risk of acute kidney injury of a restrictive versus liberal approach to red blood cell transfusion in the presence of anemia during cardiac surgery done with cardiopulmonary bypass. TRIAL REGISTRATION: www.clinicaltrials.gov; clinical trial registration number NCT 02042898.

CONTEXTE: En chirurgie cardiaque, éviter les transfusions sanguines, lorsque sécuritaire, contribue à réduire les risques d'infections transfusionnelles et de complications tout en préservant une ressource rare et en réduisant le coût des soins. Ce protocole décrit une étude secondaire qui examine le volet des risques d'insuffisance rénale aiguë (IRA) de l'étude TRICS-III (Transfusion Requirements in Cardiac Surgery III), un essai de non-infériorité multinational, contrôlé et à répartition aléatoire faisant état des exigences applicables à la transfusion sanguine en chirurgie cardiaque. Notre protocole vise plus particulièrement à déterminer si le risque d'atteintes rénales encouru par les patients subissant une chirurgie de pontages coronarien est plus ou moins grand selon que l'on préconise une approche restrictive ou libérale en matière de transfusion sanguine. OBJECTIF: L'objectif de notre étude est de déterminer si le risque d'IRA est plus ou moins grand selon que l'on préconise une approche restrictive ou libérale à l'égard de la transfusion sanguine; et, si c'est le cas, d'établir si ce risque différentiel perdure selon que le patient était ou non atteint d'insuffisance rénale chronique avant l'intervention. CADRE ET TYPE D'ÉTUDE: L'étude consiste en un essai multinational de non-infériorité, contrôlé et à répartition aléatoire, mené entre 2014 et 2017 au sein de 73 centres répartis dans 19 pays. PATIENTS: L'étude compte environ 4 800 patients ayant subi un pontage coronarien. MESURES: Le principal facteur observé est le développement d'une IRA périopératoire, telle que définie par une hausse marquée du taux de créatinine sérique par rapport à la valeur préopératoire (prélevée dans les 30 jours précédant l'intervention). Nous avons défini une « hausse marquée ¼ par un taux de créatinine atteignant au moins 26,5µmol/L dans les 48 heures postopératoires ou son augmentation d'au moins 50 % à l'intérieur des sept premiers jours. MÉTHODOLOGIE: Nous présenterons le risque différentiel absolu d'IRA dans un intervalle de confiance à 95 %. Nous répéterons l'analyse primaire en alternant les définitions de l'IRA (notamment en fonction des différents stades) et examinerons les éventuelles modifications de l'incidence chez des patients atteints d'une insuffisance rénale préexistante (définie par un DFGe préopératoire à moins de 60 ml/min/1,73 m2). LIMITES DE L'ÉTUDE: Il n'est évidemment pas possible de procéder à l'insu des patients ni des fournisseurs de soins lors de l'intervention. Toutefois, des mesures objectives seront utilisées pour évaluer les résultats, et les évaluateurs ne seront aucunement au courant de la répartition des cas. RÉSULTATS: Les résultats de cette étude secondaire seront présentés d'ici 2018. CONCLUSION: Cette étude secondaire fournira des estimations généralisables du risque de développer une IRA lors d'un pontage coronarien selon que, pour traiter l'anémie, l'approche à l'égard de la transfusion sanguine soit restrictive ou libérale.

Midterm results of endovascular stent grafts in the proximal aortic arch (zone 0): an imaging perspective.

BACKGROUND: Endovascular options to repair the arch and ascending aorta are rapidly evolving. Little is known about the durability of endovascular devices deployed at this location. This report describes a single-centre experience with the novel application of thoracic endovascular aortic repair (TEVAR) by examining clinical and radiological outcomes. METHODS: A retrospective review was performed for a cohort of patients undergoing TEVAR of the arch or ascending aorta, or both, at a single centre from November 2008-July 2012. RESULTS: Sixteen patients were included in the study, with mean imaging follow-up of 38 months (range, 15-72 months). Two complications at the proximal landing zone in the ascending aorta were identified: 1 endoleak and 1 infolding identified at 3 and 24 months postoperatively, respectively. Clinically, both these complications were attributed to the bird-beak configuration at the proximal landing zone site. At up to 72 months of follow-up, there were no cases of retrograde dissection of the native sinus of Valsalva. There were no cases of stent graft migration, graft fracture, open surgical reintervention for aortic pathologic conditions, or late mortality. CONCLUSIONS: Early outcomes suggest that the current generation of thoracic aortic endografts can be placed in the complex anatomy of the ascending aorta and aortic arch without a high incidence of early graft fracture or migration. Future endeavors will need to focus on techniques to achieve optimal apposition with the curves of the ascending aorta. These findings are important as indications for endovascular aortic therapies expand to address proximal aortic pathologic conditions.

Iridium-catalyzed reductive nitro-Mannich cyclization.

A new chemoselective reductive nitro-Mannich cyclization reaction sequence of nitroalkyl-tethered lactams has been developed. Relying on the rapid and chemoselective iridium(I)-catalyzed reduction of lactams to the corresponding enamine, subsequent nitro-Mannich cyclization of tethered nitroalkyl functionality provides direct access to important alkaloid natural-product-like structures in yields up to 81 % and in diastereoselectivities that are typically good to excellent. An in-depth understanding of the reaction mechanism has been gained through NMR studies and characterization of reaction intermediates. The new methodology has been applied to the total synthesis of (±)-epi-epiquinamide in four steps.

Thoracic aortic frontier: review of current applications and directions of thoracic endovascular aortic repair (TEVAR).

Thoracic endovascular aortic repair, a minimally invasive technique is replacing the maximally invasive gold standard of thoracotomy and replacement of the descending thoracic aorta. With experience, indications have expanded to encroach on the arch and even ascending aorta. This review highlights the current state of technology, discusses controversies, and takes the perspective of a forward-thinking review to describe novel, innovative techniques that might make the entire thoracic aorta amenable to minimally invasive repair.

Gold and BINOL-phosphoric acid catalyzed enantioselective hydroamination/N-sulfonyliminium cyclization cascade.

A highly enantioselective hydroamination/N-sulfonyliminium cyclization cascade is reported using a combination of gold(I) and chiral phosphoric acid catalysts. An initial 5-exo-dig hydroamination and a subsequent phosphoric acid catalyzed cyclization process provide access to complex sulfonamide scaffolds in excellent yield and high enantiocontrol. The method can be extended to lactam derivatives, with excellent yields and enantiomeric excesses of up to 93% ee.