Type A Aortic Dissection After Thoracic Endovascular Aortic Repair for Type B.

Type A aortic dissection (TAAD) has been associated with thoracic endovascular aortic repair (TEVAR) for aortic conditions: dissection and aneurysm. Our purpose was to study a subset of patients who had an initial TEVAR for type B aortic dissection, followed by a TAAD, which was treated by open ascending aortic repair. Over a 6-year period, 171 consecutive patients underwent open ascending aortic repair for TAAD, of whom 21 (12%) had a previous cardiovascular procedure, 17 of which were endovascular.

Superlative performance in cardiovascular surgery.

Achieving excellence in surgery is an ongoing endeavor, gained through experience, observation, and practice. It is difficult to evaluate enterprise excellence, but attempts include the ratings of the Society of Thoracic Surgeons. The surgery team at Baylor University Medical Center has achieved three-star ratings for 9 of the past 10 evaluations for coronary artery bypass.

Discovery of pyrrolo[2,1-][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.

Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1.

Discovery of ()-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain.

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. ()-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) () was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers.

Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain.

Effect of antibiotics on the human microbiome: a systematic review.

Background: Global antibiotic use has been increasing for decades. The gut microbiome, a key contributor to health, can be altered by antibiotics, which have been associated with both short- and long-term effects on the intestinal microbiome. The aim of this study was to summarize the effects of antibiotics on the diversity and composition of the human microbiota at different anatomical sites.

Interhospital failure to rescue after coronary artery bypass grafting.

Objective: We evaluated whether interhospital variation in mortality rates for coronary artery bypass grafting was driven by complications and failure to rescue.

Methods: An observational study was conducted among 83,747 patients undergoing isolated coronary artery bypass grafting between July 2011 and June 2017 across 90 hospitals. Failure to rescue was defined as operative mortality among patients developing complications.

High-quality cardiac surgery through teamwork.

The high-quality cardiothoracic surgery program is primed for mindful effective surgery. The challenge lies in attaining mindful skills and efficiency. Herein is one journey toward high departmental quality over two decades.

Libman-Sacks Endocarditis Involving a Bioprosthesis in the Aortic Valve Position in Systemic Lupus Erythematosus.

Described herein is a 39-year-old man with systemic lupus erythematosus not receiving corticosteroid therapy who developed Libman-Sacks endocarditis causing stenosis of a bioprosthesis in the aortic valve position.

Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase.

PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related protein families remain elusive. Here, we generate isoform-selective PROTACs for the p38 MAPK family using a single warhead (foretinib) and recruited E3 ligase (von Hippel-Lindau).

Major Adverse Renal and Cardiac Events After Coronary Angiography and Cardiac Surgery.

Background: Patients at high risk for having postprocedural complications may receive iodixanol, an iso-osmolar contrast, during coronary angiography to minimize the risk of renal toxicity. For those who also require cardiac surgery, the wait time between angiography and surgery may be a modifiable factor capable of mitigating poor surgical outcomes; however, there have been inconsistent reports regarding the optimal wait time. We sought to determine the effects of wait time between angiography and cardiac surgery, as well as contrast-induced acute kidney injury on the development of major adverse renal and cardiac events (MARCE).

Can use of an administrative database improve accuracy of hospital-reported readmission rates?

Objectives: Readmission rates after cardiac surgery are being used as a quality indicator; they are also being collected by Medicare and are tied to reimbursement. Accurate knowledge of readmission rates may be difficult to achieve because patients may be readmitted to different hospitals. In our area, 81 hospitals share administrative claims data; 28 of these hospitals (from 5 different hospital systems) do cardiac surgery and share Society of Thoracic Surgeons (STS) clinical data.

Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead.

Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded.

Efficacy and effectiveness of on- versus off-pump coronary artery bypass grafting: A meta-analysis of mortality and survival.

Background: Despite many studies comparing on- versus off-pump coronary artery bypass graft (CABG), there is no consensus as to whether one of these techniques offers patients better outcomes.

Methods: We searched PubMed from inception to June 30, 2015, and identified additional studies from bibliographies of meta-analyses and reviews. We identified 42 randomized controlled trials (RCTs) and 31 rigorously adjusted observational studies (controlling for the Society of Thoracic Surgeons-recognized risk factors for mortality) reporting mortality for off-pump versus on-pump CABG at specified time points.

Impact of Accurate 30-Day Status on Operative Mortality: Wanted Dead or Alive, Not Unknown.

Background: Risk-adjusted operative mortality is the most important quality metric in cardiac surgery for determining The Society of Thoracic Surgeons (STS) Composite Score for star ratings. Accurate 30-day status is required to determine STS operative mortality. The goal of this study was to determine the effect of unknown or missing 30-day status on risk-adjusted operative mortality in a regional STS Adult Cardiac Surgery Database cooperative and demonstrate the ability to correct these deficiencies by matching with an administrative database.

Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1.

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities.

Lipoma of the Mitral Valve.

Described herein is a 67-year-old morbidly obese man who had a lipoma excised from his posterior mitral leaflet after it was found by echocardiogram. Findings in 6 other previously reported cases are reviewed.

Comparison of Outcomes of Operative Therapy for Acute Type A Aortic Dissections Provided at High-Volume Versus Low-Volume Medical Centers in North Texas.

Immediate surgery is standard therapy for acute type A aortic dissections (TAAD). Because of its low incidence, many smaller cardiac surgery programs do not routinely perform this procedure because it may negatively affect outcomes. Many high-risk, low-volume (LV) surgical procedures are now preferentially performed in reference centers.

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain.

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL).

Mitral Valve Replacement After Failed Mitral Ring Insertion With or Without Leaflet/Chordal Repair for Pure Mitral Regurgitation.

Mitral repair operations for correction of pure mitral regurgitation (MR) are generally quite successful. Occasionally, however, the reparative procedure incompletely corrects the MR or the MR recurs. From March 1993 to January 2016, twenty nine patients had mitral valve replacement after the initial mitral repair operation, and observations in them were analyzed.