The Combined Effect of Copper Nanoparticles and Microplastics on Transcripts Involved in Oxidative Stress Pathway in Rainbow Trout (Oncorhynchus Mykiss) Hepatocytes.

Copper nanoparticles (CuNPs) and microplastics (MPs) are two emerging contaminants of freshwater systems. Despite their co-occurrence in many water bodies, the combined effects of CuNPs and MPs on aquatic organisms are not well-investigated. In this study, primary cultures of rainbow trout hepatocytes were exposed to dissolved Cu, CuNPs, MPs, or a combination of MPs and CuNPs for 48 h, and the transcript abundances of oxidative stress-related genes were investigated. Exposure to CuNPs or dissolved Cu resulted in a significant increase in the transcript abundances of two antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD). Exposure to CuNPs also led to an upregulation in the expression of Na+/K+ ATPase alpha 1 subunit (ATP1A1). Microplastics alone or in combination with CuNPs did not have a significant effect on abundances of the target gene transcripts. Overall, our findings suggested acute exposure to CuNPs or dissolved ions may induce oxidative stress in hepatocytes, and the Cu-induced effect on target gene transcripts was not associated with MPs.

Consideration of appropriate clinical applications for cardiac xenotransplantation.

The field of cardiac xenotransplantation has entered an exciting era due to recent advances in the field. Although several hurdles remain, the use of rapidly evolving transgenic technology has the potential to address current allogeneic donor pool constraints and mechanical circulatory system device limitations. The success of xenotransplantation will undoubtedly be dependent on specific patient selection criteria. Defining these particular indications for xenotransplantation is important as we approach the possibility of clinical applications.

The natural history of new-onset heart failure with a severely depressed left ventricular ejection fraction: implications for timing of implantable cardioverter-defibrillator implantation.

BACKGROUND: Guidelines recommend that patients with new-onset systolic heart failure (HF) receive a trial of medical therapy before an implantable cardiac defibrillator (ICD). This strategy allows for improvement of left ventricular ejection fraction (LVEF), thereby avoiding an ICD, but exposes patients to risk of potentially preventable sudden cardiac death during the trial of medical therapy. METHODS: We reviewed a consecutive series of patients with HF of <6 months duration with a severely depressed LVEF (<30%) evaluated in a HF clinic (N = 224). The ICD implantation was delayed with plans to reassess LVEF approximately 6 months after optimization of ß-blockers. Mortality was ascertained by the National Death Index. RESULTS: Follow-up echocardiograms were performed in 115 of the 224 subjects. Of these, 50 (43%) had mildly depressed or normal LVEF at follow-up ("LVEF recovery") such that an ICD was no longer indicated. In a conservative sensitivity analysis (using the entire study cohort, whether or not a follow-up echocardiogram was obtained, as the denominator), 22% of subjects had LVEF recovery. Mortality at 6, 12, and 18 months in the entire cohort was 2.3%, 4.5%, and 6.8%, respectively. Of 87 patients who tolerated target doses of ß-blockers, only 1 (1.1%) died during the first 18 months. CONCLUSION: Patients with new-onset systolic HF have both a good chance of LVEF recovery and low 6-month mortality. Achievement of target ß-blocker dose identifies a very low-risk population. These data support delaying ICD implantation for a trial of medical therapy.

Inhibition of Oocyte Maturation by Malathion and Structurally Related Chemicals in Zebrafish (Danio rerio) After In Vitro and In Vivo Exposure.

Oogenesis is the process by which a primary oocyte develops into a fertilizable oocyte, making it critical to successful reproduction in fish. In zebrafish (Danio rerio), there are five stages of oogenesis. During the final step (oocyte maturation), the maturation-inducing hormone 17α,20ß-dihydroxy-4-pregnen-3-one (MIH) activates the membrane progestin receptor, inducing germinal vesicle breakdown. Using in vitro assays, it has been shown that anthropogenic stressors can dysregulate MIH-induced oocyte maturation. However, it is unknown whether the in vitro assay is predictive of reproductive performance after in vivo exposure. We demonstrate that a known inhibitor of oocyte maturation, malathion, and a structurally related chemical, dimethoate, inhibit oocyte maturation. However, malaoxon and omethoate, which are metabolites of malathion and dimethoate, did not inhibit oocyte maturation. Malathion and dimethoate inhibited maturation to a similar magnitude when oocytes were exposed for 4 h in vitro or 10 days in vivo, suggesting that the in vitro zebrafish oocyte maturation assay might be predictive of alterations to reproductive performance. However, when adult zebrafish were exposed to malathion for 21 days, there was no alteration in fecundity or fertility in comparison with control fish. Our study supports the oocyte maturation assay as being predictive of the success of in vitro oocyte maturation after in vivo exposure, but it remains unclear whether inhibition of MIH-induced oocyte maturation in vitro correlates to decreases in reproductive performance. Environ Toxicol Chem 2022;41:1381-1389. © 2022 SETAC.

The brominated flame retardant, TBCO, impairs oocyte maturation in zebrafish (Danio rerio).

The brominated flame retardant, 1,2,5,6-tetrabromocyclooctane (TBCO), has been shown to decrease fecundity in Japanese medaka (Oryzias latipes) and there is indirect evidence from analysis of the transcriptome and proteome that this effect might be due to impaired oogenesis. An assay for disruption of oocyte maturation by chemical stressors has not been developed in Japanese medaka. Thus, using zebrafish (Danio rerio) as a model, objectives of the present study were to determine whether exposure to TBCO has effects on maturation of oocytes and to investigate potential mechanisms. Sexually mature female zebrafish were given a diet of 35.3 or 628.8 µg TBCO / g food for 14 days after which, stage IV oocytes were isolated to assess maturation in response to maturation inducing hormone. To explore potential molecular mechanisms, abundances of mRNAs of a suite of genes that regulate oocyte maturation were quantified by use of quantitative real-time PCR, and abundances of microRNAs were determined by use of miRNAseq. Ex vivo maturation of oocytes from fish exposed to TBCO was significantly less than maturation of oocytes from control fish. The percentage of oocytes which matured from control fish and those exposed to low and high TBCO were 89, 71, and 67%, respectively. Among the suite of genes known to regulate oocyte maturation, mRNA abundance of insulin like growth factor-3 was decreased by 1.64- and 3.44-fold in stage IV oocytes from females given the low and high concentrations of TBCO, respectively, compared to the control group. Abundances of microRNAs regulating the expression of proteins that regulate oocyte maturation, including processes related to insulin-like growth factor, were significantly different in stage IV oocytes from fish exposed to TBCO. Overall, results of this study indicated that impaired oocyte maturation might be a mechanism of reduced reproductive performance in TBCO-exposed fish. Results also suggested that effects of TBCO on oocyte maturation might be due to molecular perturbations on insulin-like growth factor signaling and expression of microRNAs.

Dicamba elevates concentrations of S-adenosyl methionine but does not induce oxidative stress or alter DNA methylation in rainbow trout (Oncorhynchus mykiss) hepatocytes.

Dicamba is a benzoic acid herbicide used to target woody and broadleaf weeds in industrial, domestic, and municipal spheres. Because of its widespread use, dicamba is frequently detected in surface waters near sites of application. However, little is known regarding the effects of dicamba on freshwater fishes. In the present study, primary cultures of hepatocytes from rainbow trout (Oncorhynchus mykiss) were exposed to either an environmentally relevant (0.22 or 2.2 µg L-1) or supra-environmental (22 µg L-1) concentration of dicamba for 48 h to investigate if oxidative stress is a mechanism of toxicity. mRNA abundances of genes involved in the response to oxidative stress, levels of lipid peroxidation, and concentrations of glutathione and s-adenosyl methionine (SAM) were quantified. Results indicate that dicamba does not induce oxidative stress. However, exposure to 2.2 µg L-1 of dicamba did cause a 5.24-fold increase in concentrations of SAM. To investigate the mechanisms of increased SAM, effects of dicamba on global and genome-wide DNA methylation were quantified. Dicamba did not cause changes to DNA methylation. Overall, dicamba was not acutely toxic to hepatocytes and did not cause oxidative stress or changes in DNA methylation at environmentally relevant concentrations.

Intramyocardial Bone Marrow Stem Cells in Patients Undergoing Cardiac Surgical Revascularization.

BACKGROUND: Bone marrow stromal or stem cells (BMSCs) remain a promising potential therapy for ischemic cardiomyopathy. The primary objective of this study was to evaluate the safety and feasibility of direct intramyocardial injection of autologous BMSCs in patients undergoing transmyocardial revascularization (TMR) or coronary artery bypass graft surgery (CABG). METHODS: A phase I trial was conducted on adult patients who had ischemic heart disease with depressed left ventricular ejection fraction and who were scheduled to undergo TMR or CABG. Autologous BMSCs were expanded for 3 weeks before the scheduled surgery. After completion of surgical revascularization, BMSCs were directly injected into ischemic myocardium. Safety and feasibility of therapy were assessed. Cardiac functional status and changes in quality of life were evaluated at 1 year. RESULTS: A total of 14 patients underwent simultaneous BMSC and surgical revascularization therapy (TMR+BMSCs = 10; CABG+BMSCs = 4). BMSCs were successfully expanded, and no significant complications occurred as a result of the procedure. Regional contractility in the cell-treated areas demonstrated improvement at 12 months compared with baseline (TMR+BMSCs Δ strain: -4.6% ± 2.1%; P = .02; CABG+MSCs Δ strain: -4.2% ± 6.0%; P = .30). Quality of life was enhanced, with substantial reduction in angina scores at 1 year after treatment (TMR+BMSCs: 1.3 ± 1.2; CABG+MSCs: 1.0 ± 1.4). CONCLUSIONS: In this phase I trial, direct intramyocardial injection of autologous BMSCs in conjunction with TMR or CABG was technically feasible and could be performed safely. Preliminary results demonstrate improved cardiac function and quality of life in patients at 1 year after treatment.

Novel Direct Annuloplasty Fastener System for Minimally Invasive Mitral Valve Repair.

The development of less invasive approaches for mitral valve repair remains an important objective, particularly in patients with multiple comorbidities. We describe a novel method to affix a mitral valve annuloplasty ring in a minimally invasive manner. A delivery apparatus for an annuloplasty fastener system was designed. Two channels were created, one for advancing the annuloplasty ring, and another to accommodate the fastener applicator. Custom designed fasteners, either with a helical-shaped screw or a strap-shaped tack structure, were tested. Fasteners were primed within an application device and automatic alignment of fasteners was achieved to allow accurate firing of the fixators securing the ring. The delivery apparatus was constructed to be deployed within a 10 mm trocar through a left atrial approach. Using a cadaveric swine heart model, access to the mitral valve from the left atrium was obtained with insertion of a trocar. The delivery apparatus was accurately directed to the mitral annulus under echocardiographic guidance. Fasteners were placed along the annular plane to secure the annuloplasty ring. Both fastener designs achieved considerable fixation force; the helical-shaped screw was found to have significantly greater fixation force compared to the strap-shaped tack design. The annuloplasty ring remained intact and did not experience any structural deformity during the fixation process. The use of a novel fastener system was successful in deploying and securing a mitral valve annuloplasty ring. These promising results may have further application for minimally invasive mitral valve repairs. Additional evaluation of this procedure with pre-clinical in vivo animal studies is necessary.

A Multidisciplinary Protocol-Driven Approach to Improve Extubation Times After Cardiac Surgery.

BACKGROUND: Prolonged intubation after cardiac surgery is associated with significant morbidity. A fast-track extubation protocol primarily driven by bedside providers was instituted for all postoperative cardiac surgery patients to facilitate safe and expeditious extubation. METHODS: A retrospective review of 1,581 cardiac surgery patients over an 8-year period was performed. Before 2011, nonprotocolized standard perioperative management was utilized (n = 807). From 2011 onward, a fast-track extubation (FTE) protocol directed by bedside providers was instituted (n = 774). Postoperatively, patients were placed on pressure-regulated volume control and titrated down to minimal support to maintain peripheral capillary oxygen saturation greater than 94%. For patients deemed ready for weaning (no evidence of hypoxia, hemodynamic instability, and so forth), a 30-minute continuous positive airway pressure trial was performed. Patients meeting all neurologic, respiratory, and cardiovascular criteria were extubated. The impact of the FTE algorithm on timely extubation, clinical outcomes, and safety was assessed. RESULTS: Baseline preoperative and intraoperative characteristics were similar between pre-FTE and FTE groups. Before instituting the FTE protocol, the rate of early extubation (less than 6 hours) was 43.7%, and increased to 64.1% during the FTE era (p < 0.001). Median time to extubation was also found to be significantly decreased: 295 minutes (interquartile range: 288) versus 385 minutes (interquartile range: 362, p = 0.041). There was no statistically significant difference in reintubation rates or 30-day mortality. CONCLUSIONS: The institution of a bedside provider-directed FTE pathway reduced overall intubation times and increased the rate of early extubation, without an increase in reintubation or mortality. This program-wide multidisciplinary approach appears to promote safe and expeditious extubation of cardiac surgery patients.

Real-time magnetic resonance imaging-guided transcatheter aortic valve replacement.

OBJECTIVES: To demonstrate the feasibility of Real-time magnetic resonance imaging (rtMRI) guided transcatheter aortic valve replacement (TAVR) with an active guidewire and an MRI compatible valve delivery catheter system in a swine model. METHODS: The CoreValve system was minimally modified to be MRI-compatible by replacing the stainless steel components with fluoroplastic resin and high-density polyethylene components. Eight swine weighing 60-90 kg underwent rtMRI-guided TAVR with an active guidewire through a left subclavian approach. RESULTS: Two imaging planes (long-axis view and short-axis view) were used simultaneously for real-time imaging during implantation. Successful deployment was performed without rapid ventricular pacing or cardiopulmonary bypass. Postdeployment images were acquired to evaluate the final valve position in addition to valvular and cardiac function. CONCLUSIONS: Our results show that the CoreValve can be easily and effectively deployed through a left subclavian approach using rtMRI guidance, a minimally modified valve delivery catheter system, and an active guidewire. This method allows superior visualization before deployment, thereby allowing placement of the valve with pinpoint accuracy. rtMRI has the added benefit of the ability to perform immediate postprocedural functional assessment, while eliminating the morbidity associated with radiation exposure, rapid ventricular pacing, contrast media renal toxicity, and a more invasive procedure. Use of a commercially available device brings this rtMRI-guided approach closer to clinical reality.

Robot-assisted real-time magnetic resonance image-guided transcatheter aortic valve replacement.

BACKGROUND: Real-time magnetic resonance imaging (rtMRI)-guided transcatheter aortic valve replacement (TAVR) offers improved visualization, real-time imaging, and pinpoint accuracy with device delivery. Unfortunately, performing a TAVR in a MRI scanner can be a difficult task owing to limited space and an awkward working environment. Our solution was to design a MRI-compatible robot-assisted device to insert and deploy a self-expanding valve from a remote computer console. We present our preliminary results in a swine model. METHODS: We used an MRI-compatible robotic arm and developed a valve delivery module. A 12-mm trocar was inserted in the apex of the heart via a subxiphoid incision. The delivery device and nitinol stented prosthesis were mounted on the robot. Two continuous real-time imaging planes provided a virtual real-time 3-dimensional reconstruction. The valve was deployed remotely by the surgeon via a graphic user interface. RESULTS: In this acute nonsurvival study, 8 swine underwent robot-assisted rtMRI TAVR for evaluation of feasibility. Device deployment took a mean of 61 ± 5 seconds. Postdeployment necropsy was performed to confirm correlations between imaging and actual valve positions. CONCLUSIONS: These results demonstrate the feasibility of robotic-assisted TAVR using rtMRI guidance. This approach may eliminate some of the challenges of performing a procedure while working inside of an MRI scanner, and may improve the success of TAVR. It provides superior visualization during the insertion process, pinpoint accuracy of deployment, and, potentially, communication between the imaging device and the robotic module to prevent incorrect or misaligned deployment.

Robotic-assisted real-time MRI-guided TAVR: from system deployment to in vivo experiment in swine model.

PURPOSE: Real-time magnetic resonance imaging (rtMRI) guidance provides significant advantages during transcatheter aortic valve replacement (TAVR) as it provides superior real-time visualization and accurate device delivery tracking. However, performing a TAVR within an MRI scanner remains difficult due to a constrained procedural environment. To address these concerns, a magnetic resonance (MR)-compatible robotic system to assist in TAVR deployments was developed. This study evaluates the technical design and interface considerations of an MR-compatible robotic-assisted TAVR system with the purpose of demonstrating that such a system can be developed and executed safely and precisely in a preclinical model. METHODS: An MR-compatible robotic surgical assistant system was built for TAVR deployment. This system integrates a 5-degrees of freedom (DoF) robotic arm with a 3-DoF robotic valve delivery module. A user interface system was designed for procedural planning and real-time intraoperative manipulation of the robot. The robotic device was constructed of plastic materials, pneumatic actuators, and fiber-optical encoders. RESULTS: The mechanical profile and MR compatibility of the robotic system were evaluated. The system-level error based on a phantom model was 1.14 ± 0.33 mm. A self-expanding prosthesis was successfully deployed in eight Yorkshire swine under rtMRI guidance. Post-deployment imaging and necropsy confirmed placement of the stent within 3 mm of the aortic valve annulus. CONCLUSIONS: These phantom and in vivo studies demonstrate the feasibility and advantages of robotic-assisted TAVR under rtMRI guidance. This robotic system increases the precision of valve deployments, diminishes environmental constraints, and improves the overall success of TAVR.

Experience with an adult alcohol withdrawal syndrome practice guideline in internal medicine patients.

STUDY OBJECTIVE: To standardize treatment of alcohol withdrawal syndrome (AWS) in internal medicine patients using an adult AWS practice guideline with a symptom-triggered management approach. DESIGN: Prospective interventional (pilot group) and retrospective (control group). SETTING: University teaching hospital. PATIENTS: Thirty-two internal medicine patients identified as being at risk for AWS and treated according to the AWS practice guideline who were compared with 49 internal medicine patients managed with nonstandardized approaches. INTERVENTION: Patients in the pilot group were assessed using the AWS type indicator. They received lorazepam, clonidine, or haloperidol, based on AWS type indicator assessment and adult AWS practice guideline criteria. MEASUREMENTS AND MAIN RESULTS: Data collected and analyzed were drugs administered to control AWS symptoms, use of sitters and physical restraints, length of hospital stay, and discharge from hospital receiving tapered drug therapy. Pilot patients received 46.6% less benzodiazepine (p=0.001), 20% more clonidine (p=0.01), and 18.2% more haloperidol (p=0.002) than control patients. No drug therapy was required in 19% of pilot patients compared with 2% of controls (p=0.01). Significantly more control (71.4%) than pilot patients (18.8%) were discharged with tapered benzodiazepine therapy (p

Hospitalists and improved cost savings in patients with bacterial pneumonia at a state level.

OBJECTIVES: In the hospitalist literature, most studies have focused on outcomes related to cost savings for individual hospital systems. This study sought to determine if hospitalists could improve cost savings at a state level. METHODS: This is a retrospective analysis of a statewide database for inpatients in 2002 with bacterial pneumonia. The primary outcomes measured were mean length of stay (LOS) and mean charges per patient between hospitalists and nonhospitalists. The secondary outcome measured was percentage of patients by severity of illness between the groups. RESULTS: The difference of LOS in the moderate illness category was 4.9 days for hospitalists and 5.2 for nonhospitalists (P = 0.04). The major illness category was 7.4 and 8 (P = 0.03), and the extreme illness category was 10.6 and 12.9 (P = 0.02). The difference of mean charges per patient in the major category were dollars 20,950 and dollars 23,259 (P = 0.03) and dollars 42,045 and dollars 56,867, respectively (P = 0.002), in the extreme category. Patients in the major/extreme categories of illness accounted for 41% of hospitalist patients versus 32% of nonhospitalist patients (P < 0.001). CONCLUSIONS: Hospitalists have shorter LOS, lower charges per patient, and admit a larger proportion of high acuity patients at a state level.