Cyclocreatine Phosphate: A Novel Bioenergetic/Anti-Inflammatory Drug That Resuscitates Poorly Functioning Hearts and Protects against Development of Heart Failure.

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-ß, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts.

New Insurance Product Needed for Physicians: Coverage for Sham Peer Review and Hospital Immunity.

This commentary article highlights the need for an insurance product for hospital-employed physicians that provides coverage against sham peer review and a complete defense against wrongful hospital allegations of incompetent, whistleblowing, or disruptive behavior.

Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to a successive stimulus.

Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its sensitivity to the strength of depolarization remains unknown. Also unknown is whether activity history of graded potential changes influence future neuronal activity. In this work with dissociated rat cortical neurons, we found that mild depolarization-mediated by elevated extracellular potassium (K+)-induces a wide array of rapid IEGs and transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, and signaling via calcineurin or mitogen-activated protein kinase. Furthermore, as measured by multiple electrode arrays and calcium imaging, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity via calcium- and N-methyl-d-aspartate receptor-dependent mechanisms. Collectively, this work suggests that a recent history of graded potential changes acutely depress neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during synaptic plasticity processes.

Robotic surgery: would any other (more accurate) name smell as sweet?

The term we use to describe a surgical case that employs robotics influences how experts and laypeople think about this procedure. Robotic surgery is a misnomer because it implies more automation compared to what actually happens. A more realistic description is robot-assisted surgery and this term is likely to help promote more realistic understanding among stakeholders.

Coronary computed tomography angiography following robotic coronary artery bypass grafting surgery: Systematic approach to image analysis and practical considerations.

Standard open chest Coronary Artery Bypass Grafting (CABG) has evolved over last couple of decades. With advancement in minimally invasive procedures, Robotic CABG (RCABG) is still in its evolution phase. There is dearth of experienced surgeons in this complicated field and lack of data to verify it clinical safety. in this review, we intend to describe the utility of Cardiac Computed Tomography Angiography (CCTA) in assessment of graft anatomy and quality, grafting strategy, distal graft anastomosis site evaluation and detection of complications associated with RCABG. CCTA appears to provide valuable information regarding the visualization of grafts, target coronary arteries and other cardiac and non-cardiac structures.

Early and Midterm Clinical Outcomes of Transcatheter Valve-in-Valve Implantation Versus Redo Surgical Aortic Valve Replacement for Aortic Bioprosthetic Valve Degeneration: Two Faces of the Same Medal.

OBJECTIVE: To compare early and midterm outcomes of transcatheter valve-in-valve implantation (ViV-TAVI) and redo surgical aortic valve replacement (re-SAVR) for aortic bioprosthetic valve degeneration. DESIGN: Patients who underwent ViV-TAVI and re-SAVR for aortic bioprosthetic valve degeneration between January 2010 and October 2018 were retrospectively analyzed. Mean follow-up was 3.0 years. SETTING: In-hospital, early, and mid-term outcomes. PARTICIPANTS: Eighty-eight patients were included in the analysis. INTERVENTIONS: Thirty-one patients (37.3%) had ViV-TAVI, and 57 patients (62.7%) had re-SAVR. MEASUREMENTS AND MAIN RESULTS: In the ViV-TAVI group, patients were older (79.1 ± 7.4 v 67.2 ± 14.1, p < 0.01). The total operative time, intubation time, intensive care unit length of stay, total hospital length of stay, inotropes infusion, intubation >24 hours, total amount of chest tube losses, red blood cell transfusions, plasma transfusions, and reoperation for bleeding were significantly higher in the re-SAVR cohort (p < 0.01). There was no difference regarding in-hospital permanent pacemaker implantation (ViV-TAVI = 3.2% v re-SAVR = 8.8%, p = 0.27), patient-prosthesis mismatch (ViV-TAVI = 12 patients [mean 0.53 ± 0.07] and re-SAVR = ten patients [mean 0.56 ± 0.08], p = 0.4), stroke (ViV-TAVI = 3.2% v re-SAVR = 7%, p = 0.43), acute kidney injury (ViV-TAVI = 9.7% v re-SAVR = 15.8%, p = 0.1), and all-cause infections (ViV-TAVI = 0% v re-SAVR = 8.8%, p = 0.02), between the two groups. In-hospital mortality was 0% and 7% for ViV-TAVI and re-SAVR, respectively (p = 0.08). At three-years' follow-up, the incidence of pacemaker implantation was higher in the re-SAVR group (ViV-TAVI = 0 v re-SAVR = 13.4%, p < 0.01). There were no differences in reintervention (ViV-TAVI = 3.8% v re-SAVR = 0%, p = 0.32) and survival (ViV-TAVI = 83.9% v re-SAVR = 93%, p = 0.10) between the two cohorts. CONCLUSIONS: ViV-TAVI is a safe, feasible, and reliable procedure.

OR and ICU teams 'running in parallel' at the end of cardiothoracic surgery improves perceptions of handoff safety.

The transfer of a cardiac surgery patient from the operating room (OR) to the intensive care unit (ICU) is both a challenging process and a critical period for outcomes. Information transferred between these two teams-known as the 'handoff'-has been a focus of efforts to improve patient safety. At our institution, staff have poor perceptions of handoff safety, as measured by low positive response rates to questions found in the Agency for Health Care Research and Quality (AHRQ) Hospital Survey on Patient Safety Culture (HSOPS). In this quality improvement project, we developed a novel handoff protocol after cardiac surgery where we invited the ICU nurse and intensivist into the OR to receive a face-to-face handoff from the circulating nurse, observe the final 30 min of the case, and participate in the end-of-case debrief discussions. Our aim was to increase the positive response rates to handoff safety questions to meet or surpass the reported AHRQ national averages. We used plan, do, study, act cycles over the course of 123 surgical cases to test how our handoff protocol was leading to changes in perceptions of safety. After a 10-month period, we achieved our aim for four out of the five HSOPS questions assessing safety of handoff. Our results suggest that having an ICU team 'run in parallel' with the cardiac surgical team positively impacts safety culture.

Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium.

Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, downstream transcriptional events, and many other intracellular responses to depolarization. However, there is enormous variability in these treatments, including durations from seconds to days and concentrations from 3mM to 150 mM KCl. Differential effects of these variable protocols on neuronal activity and transcriptional programs are underexplored. Furthermore, potassium chloride treatments in vitro are criticized for being poor representatives of in vivo phenomena and are questioned for their effects on cell viability. In this review, we discuss the intracellular consequences of elevated extracellular potassium chloride treatment in vitro, the variability of such treatments in the literature, the strengths and limitations of this tool, and relevance of these studies to brain functions and dysfunctions.

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes.

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH-BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH-BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK-ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand-protein docking suggested that 6-OH-BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH-BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH-BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body ß-lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK-ERK signaling, and axonal guidance.

Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion.

Introduction: A critical mechanism of how hypoxia/ischemia causes irreversible myocardial injury is through the exhaustion of adenosine triphosphate (ATP). Cyclocreatine (CCr) and its water-soluble salt Cyclocreatine-Phosphate (CCrP) are potent bioenergetic agents that preserve high levels of ATP during ischemia. Areas covered: CCr and CCrP treatment prior to the onset of ischemia, preserved high levels of ATP in ischemic myocardium, reduced myocardial cell injury, exerted anti-inflammatory and anti-apoptotic activities, and restored contractile function during reperfusion in animal models of acute myocardial infarction (AMI), global cardiac arrest, cardiopulmonary bypass, and heart transplantation. Medline and Embase (1970 - Feb 2019), the WIPO databank (up to Feb 2019); no language restriction. Expert opinion: This review provides the basis for a number of clinical applications of CCrP and CCr to minimize ischemic injury and necrosis. One strategy is to administer CCrP to AMI patients in the pre-hospital phase, as well as during, or after Percutaneous Coronary Intervention (PCI) procedure to potentially achieve protection of the myocardium, reduce infarcted-size, and, thus, limit the progression to heart failure. Another clinical applications are in predictable myocardial ischemia where pretreatment with CCrP would likely improve outcome and quality of life of patients who will undergo cardiopulmonary bypass for coronary revascularization and end-stage heart failure patients scheduled for heart transplantation.

Epigenetic Effects of Polybrominated Diphenyl Ethers on Human Health.

Disruption of epigenetic regulation by environmental toxins is an emerging area of focus for understanding the latter's impact on human health. Polybrominated diphenyl ethers (PBDEs), one such group of toxins, are an environmentally pervasive class of brominated flame retardants that have been extensively used as coatings on a wide range of consumer products. Their environmental stability, propensity for bioaccumulation, and known links to adverse health effects have evoked extensive research to characterize underlying biological mechanisms of toxicity. Of particular concern is the growing body of evidence correlating human exposure levels to behavioral deficits related to neurodevelopmental disorders. The developing nervous system is particularly sensitive to influence by environmental signals, including dysregulation by toxins. Several major modes of actions have been identified, but a clear understanding of how observed effects relate to negative impacts on human health has not been established. Here, we review the current body of evidence for PBDE-induced epigenetic disruptions, including DNA methylation, chromatin dynamics, and non-coding RNA expression while discussing the potential relationship between PBDEs and neurodevelopmental disorders.

Saving the split: the benefits of VATS thymectomy.

BACKGROUND: With the advent of minimally invasive techniques, the standard approaches to many surgeries have changed. We compared the financial costs and health care outcomes between standard thymectomy via sternotomy and video assisted thoracoscopic surgery (VATS). METHODS: A 3-year review [2010-2012] of the National Inpatient Sample (NIS) was performed. All patients undergoing thymectomy were included. Patients undergoing VATS thymectomy were identified. Outcomes measured were hospital length of stay (LOS), hospital charges, and mortality. Univariate and multivariate analyses were performed to control for demographics and comorbidities. RESULTS: The results of 2,065 patients who underwent thymectomy were analyzed, of which 373 (18.1%) had VATS thymectomy and 1,692 (81.9%) had standard thymectomy. Mean age was 52.8±16, 42.5% were male, and 65.5% were Caucasian. There was a significant interval increase in number of patients undergoing VATS thymectomy (10% in 2010 vs. 19.2% in 2012, P<0.001). Patients undergoing standard thymectomy had longer hospital LOS (6.8±6.6 vs. 3.3d±3.4 d, P<0.001), hospital charges $88,838±$120,892 vs. $57,251±$54,929) and hospital mortality (0.9% vs. 0%, P=0.01). In multivariate analysis, thymectomy via sternotomy was independently associated with increased hospital LOS B =1.6 d, P<0.001) and charges (B = $13,041, P=0.041). CONCLUSIONS: Our study demonstrates decreased hospital length of stay and reduced hospital charges in patients undergoing VATS thymectomy compared to standard thymectomy. Our data demonstrates that the prevalence of VATS thymectomies is increasing, likely related to improved healthcare and financial outcomes.

Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers.

Polybrominated diphenyl ethers (PBDEs) are a pervasive class of brominated flame retardants that are present in the environment at particularly high levels, especially in the United States. Their environmental stability, propensity for bioaccumulation, and known potential for neurotoxicity has evoked interest regarding their effects on the developing nervous system. Exposure to PBDEs has been strongly associated with neurodevelopmental disorders. However, the details of their mechanistic roles in such disorders are incompletely understood. Here, we report the effects of one of the most prevalent congeners, BDE-47, and its hydroxylated metabolites on the maturation and function of embryonic rat cortical neurons. Prolonged exposure to 6OH-BDE-47 produces the strongest effects amongst the parent BDE-47 congener and its tested hydroxylated metabolites. These effects include: i) disruption of transcriptional responses to neuronal activity, ii) dysregulation of multiple genes associated with neurodevelopmental disorders, and intriguingly, iii) altered expression of several subunits of the developmentally-relevant BAF (Brg1-associated factors) chromatin remodeling complex, including the key subunit BAF170. Taken together, our data indicate that persistent exposure to 6OH-BDE-47 may interfere with neurodevelopmental chromatin remodeling mechanisms and gene transcription programs, which in turn are likely to interfere with downstream processes such as synapse development and overall functional maturity of neurons. Results from this study have identified a novel aspect of 6OH-BDE-47 toxicity and open new avenues to explore the effects of a ubiquitous environmental toxin on epigenetic regulation of neuronal maturation and function.

Different Neuronal Activity Patterns Induce Different Gene Expression Programs.

A vast number of different neuronal activity patterns could each induce a different set of activity-regulated genes. Mapping this coupling between activity pattern and gene induction would allow inference of a neuron's activity-pattern history from its gene expression and improve our understanding of activity-pattern-dependent synaptic plasticity. In genome-scale experiments comparing brief and sustained activity patterns, we reveal that activity-duration history can be inferred from gene expression profiles. Brief activity selectively induces a small subset of the activity-regulated gene program that corresponds to the first of three temporal waves of genes induced by sustained activity. Induction of these first-wave genes is mechanistically distinct from that of the later waves because it requires MAPK/ERK signaling but does not require de novo translation. Thus, the same mechanisms that establish the multi-wave temporal structure of gene induction also enable different gene sets to be induced by different activity durations.

Characterization of a Vesivirus Associated with an Outbreak of Acute Hemorrhagic Gastroenteritis in Domestic Dogs.

Four of eleven affected dogs died despite aggressive treatment during a 2015 focal outbreak of hemorrhagic gastroenteritis following a stay in a pet housing facility. Routine diagnostic investigations failed to identify a specific cause. Virus isolation from fresh necropsy tissues yielded a calicivirus with sequence homology to a vesivirus within the group colloquially known as the vesivirus 2117 strains that were originally identified as contaminants in CHO cell bioreactors. In situ hybridization and reverse transcription-PCR assays of tissues from the four deceased dogs confirmed the presence of canine vesivirus (CaVV) nucleic acids that localized to endothelial cells of arterial and capillary blood vessels. CaVV nucleic acid corresponded to areas of necrosis and hemorrhage primarily in the intestinal tract, but also in the brain of one dog with nonsuppurative meningoencephalitis. This is the first report of an atypical disease association with a putative hypervirulent vesivirus strain in dogs, as all other known strains of CaVV appear to cause nonclinical infections or relatively mild disease. After identification of the CU-296 vesivirus strain from this outbreak, four additional CaVV strains were amplified from unrelated fecal specimens and archived stocks provided by other laboratories. Broader questions include the origins, reservoir(s), and potential for reemergence and spread of these related CaVVs.

A Novel Hemostatic Patch That Stops Bleeding in Cardiovascular and Peripheral Vascular Procedures.

BACKGROUND: Achieving hemostasis during surgery is a common challenge across surgical specialties and procedures, including cardiovascular and peripheral vascular procedures. Although several hemostatic agents are available, they all become less effective as bleeding becomes more vigorous. Veriset™ hemostatic patch is a topical hemostatic agent that has been approved for use on solid organs and in soft tissue. The primary aim of these studies was to assess the safety of Veriset hemostatic patch during cardiovascular and peripheral vascular procedures. METHODS: Adult domestic swine were given intraoperative anticoagulation and systemic antiplatelet therapy, and then underwent a variety of cardiovascular coronary artery bypass graft (CABG anastomosis and aortotomy closure) and peripheral vascular (carotid arteriotomy with patch angioplasty) procedures. Bleeding was identified or created from each anastomotic site and was brisk in many cases. Veriset hemostatic patch, Surgicel(®) Nu-Knit(®) absorbable hemostat, or standard of care treatment was applied topically to the site of bleeding, and time to hemostasis was monitored for each animal. Animals were assessed during and after the surgical procedure to determine the effects of treatment on vessel diameter, clinical laboratory parameters, and host tissue response and/or tissue integration. RESULTS: Application of Veriset hemostatic patch had no effect on vessel diameter, similar to Surgicel Nu-Knit absorbable hemostat and standard of care treatment. Approximately 28 days after application, Veriset hemostatic patch and Surgicel Nu-Knit absorbable hemostat were completely absorbed, with no impact on serum chemistry profiles. Furthermore, Veriset hemostatic patch was as effective or more effective than Surgicel Nu-Knit absorbable hemostat when applied during carotid arteriotomy (30.0 ± 0.0 sec vs. 163.6 ± 86.9 sec, P < 0.001) and CABG anastomosis (91.9 ± 66.0 sec vs. 207.5 ± 159.2 sec, P = 0.053). CONCLUSIONS: Veriset hemostatic patch exhibits similar safety as Surgicel Nu-Knit absorbable hemostat, with effectiveness against cardiovascular and peripheral vascular bleeding. If these preclinical results are confirmed in clinical trials, this highly effective patch with a topical application requiring less than 30 seconds is likely to prove useful in many clinical settings.

Unilateral robotic hybrid mini-maze: a novel experimental approach.

BACKGROUND: A complete Cox maze IV procedure is difficult to accomplish using current endoscopic and minimally invasive techniques. These techniques are hampered by inability to adequately dissect the posterior structures of the heart and place all necessary lesions. We present a novel approach, using robotic technology, that achieves placement of all the lesions of the complete maze procedure. METHODS: In three cadaveric human models, the technical feasibility of using robotic instruments through the right chest to dissect the posterior structures of the heart and place all Cox maze lesions was performed. RESULTS: The entire posterior aspect of the heart was dissected in the cadaveric model facilitating successful placement of all Cox maze IV lesions with robotic assistance through minimally invasive incisions. CONCLUSION: The robotic Cox maze IV procedure through the novel right thoracic approach is feasible. This obviates the need for sternotomy and avoids the associated morbidity of the conventional Cox-maze procedure.

Simulation trainer for practicing emergent open thoracotomy procedures.

BACKGROUND: An emergent open thoracotomy (OT) is a high-risk, low-frequency procedure uniquely suited for simulation training. We developed a cost-effective Cardiothoracic (CT) Surgery trainer and assessed its potential for improving technical and interprofessional skills during an emergent simulated OT. MATERIALS AND METHODS: We modified a commercially available mannequin torso with artificial tissue models to create a custom CT Surgery trainer. The trainer's feasibility for simulating emergent OT was tested using a multidisciplinary CT team in three consecutive in situ simulations. Five discretely observable milestones were identified as requisite steps in carrying out an emergent OT; namely (1) diagnosis and declaration of a code situation, (2) arrival of the code cart, (3) arrival of the thoracotomy tray, (4) initiation of the thoracotomy incision, and (5) defibrillation of a simulated heart. The time required for a team to achieve each discrete step was measured by an independent observer over the course of each OT simulation trial and compared. RESULTS: Over the course of the three OT simulation trials conducted in the coronary care unit, there was an average reduction of 29.5% (P < 0.05) in the times required to achieve the five critical milestones. The time required to complete the whole OT procedure improved by 7 min and 31 s from the initial to the final trial-an overall improvement of 40%. CONCLUSIONS: In our preliminary evaluation, the CT Surgery trainer appears to be useful for improving team performance during a simulated emergent bedside OT in the coronary care unit.

Robotic Left Ventricular Assist Device Implantation Using Left Thoracotomy Approach in Patients with Previous Sternotomies.

Left ventricular assist devices (LVADs) are commonly used as either a bridge-to-transplant or a destination therapy. The traditional approach for LVAD implantation is via median sternotomy, but many candidates for this procedure have a history of failed cardiac surgeries and previous sternotomy. Redo sternotomy increases the risk of heart surgery, particularly in the setting of advanced heart failure. Robotics facilitates a less invasive approach to LVAD implantation that circumvents some of the morbidity associated with a redo sternotomy. We compared the outcomes of all patients at our institution who underwent LVAD implantation via either a traditional sternotomy or using robotic assistance. The robotic cohort showed reduced resource utilization including length of hospital stay and use of blood products. As the appropriate candidates become elucidated, robotic assistance may improve the safety and cost-effectiveness of reoperative LVAD surgery.