Efficacy and Safety of an Upfront RotaTripsy Strategy in the Treatment of De Novo and In-Stent Restenosis Cases.

BACKGROUND: Use of both rotational atherectomy (RA) and intravascular lithotripsy (IVL)-the "RotaTripsy" technique-offers a potentially synergistic calcium-modification strategy that can treat both luminal and abluminal calcification. An upfront RotaTripsy strategy using an undersized burr in large-caliber coronaries also offers the advantage of facilitating IVL catheter passage while being able to undertake the procedure with a 6-Fr system. METHODS: Consecutive patients with heavily calcified lesions on angiographic or intravascular imaging and large target-vessel caliber (≥3 mm) who underwent an upfront RA followed by IVL between July 2021 and January 2022 were included in this study. Study aims were to evaluate periprocedural efficacy and safety. RESULTS: Of the 21 patients included, RotaTripsy was used for treatment of de novo lesions in 12 patients (57%) and for in-stent-restenosis in 9 patients (43%). Seven cases of in-stent restenosis (ISR) involved 2 layers of stents. Mean reference vessel diameter was 3.67 ± 0.46 mm and baseline diameter stenosis was 77.4 ± 11.3%. Average RA burr-to-artery ratio was 0.43 ± 0.05 and IVL balloon-to-artery ratio was 0.93 ± 0.06, with IVL balloon crossing the lesion in all cases following RA. Procedural success was attained in 20 of 21 cases; 1 periprocedural complication (a death related to coronary perforation following stent postdilation) was recorded. CONCLUSIONS: An upfront RotaTripsy strategy is associated with a high degree of procedural success in de novo lesions and ISR cases by facilitating the use of a smaller burr-to-artery ratio and smaller-bore vascular access. Larger studies are required to further evaluate the potential benefits of an upfront RotaTripsy strategy from a safety and cost-benefit perspective.

Ticagrelor or prasugrel versus clopidogrel in patients undergoing percutaneous coronary intervention for chronic coronary syndromes.

BACKGROUND: Potent P2Y12 inhibitors such as ticagrelor and prasugrel are superior to clopidogrel in acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). Whether this benefit extends to a patient population with chronic coronary syndromes (CCS) is unclear. AIMS: We sought to compare the safety and efficacy of prasugrel and ticagrelor versus clopidogrel in patients undergoing PCI for CCS. METHODS: Consecutive patients undergoing PCI for CCS at a tertiary centre between 2014 and 2019 who were discharged on prasugrel or ticagrelor were compared with those on clopidogrel. The primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularisation at 1 year. RESULTS: Overall, 11,508 patients were included in the study (ticagrelor/prasugrel n=2,860 [24.9%], clopidogrel n=8,648 [75.1%]) with an increasing frequency of potent P2Y12 inhibitor use over the study period (ptrend<0.001). Clopidogrel was used more frequently in patients with multimorbid risk factors, whereas anatomical or procedural complexity was associated with ticagrelor/prasugrel use (left main PCI, bifurcation PCI, number of lesions, rotational atherectomy). No difference in the incidence of death or MI was noted across the groups (ticagrelor/prasugrel vs clopidogrel: 2.7% vs 3.1%, adjusted hazard ratio [adjHR] 0.86, 95% confidence interval [CI]: 0.62-1.17; p=0.33) or secondary outcomes including bleeding (adjHR 0.75, 95% CI: 0.46-1.21; p=0.23) on propensity score stratification analysis. Additionally, no difference in the primary outcome was observed across subgroups, including those undergoing complex PCI. CONCLUSIONS: Ticagrelor and prasugrel are increasingly used in patients with CCS undergoing PCI with similar 1-year efficacy and safety when compared to clopidogrel. Whether use of these agents can be beneficial in patients undergoing PCI for CCS with a high thrombotic and low bleeding risk warrants further study.

High dose insulin therapy for inotropic support during veno-arterial extracorporeal membrane oxygenation decannulation: A case report.

RATIONALE: High-dose insulin (HDI) therapy has been used as inotropic support for toxin-induced cardiogenic shock, but literature suggests that it can also be used in non-toxin-induced cardiogenic shock states. Its use has not been reported in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) decannulation. PATIENT CONCERNS: A 56-year-old male presented with progressive dyspnea and lower extremity edema without any reported toxic ingestion. DIAGNOSIS: After left heart catheterization, he was diagnosed with acute biventricular nonischemic cardiac failure that ultimately required VA-ECMO support for 8 days, after which decannulation was planned. INTERVENTIONS: During decannulation, he was initiated on HDI therapy via a 1 U/kg regular insulin bolus with 25 g of dextrose and a 1 U/kg/hr insulin infusion. OUTCOMES: During the decannulation, he was monitored with transesophageal echocardiography. Initially, left ventricular (LV) ejection fraction (EF) was estimated at 10% to 15%. Transesophageal echocardiography after HDI but prior to decannulation showed LVEF 30% to 40%. Transthoracic echocardiography 3.5 hours after HDI bolus and decannulation revealed normal LV systolic function; LVEF 50% to 55%. LESSONS: While multiple interventions occurred during decannulation, HDI therapy may have assisted in transitioning off ECMO support, and HDI should be investigated as an adjunctive option in future decannulations and other non-toxin-induced cardiogenic shock states.

p53 missense mutant G242A subverts natural killer cells in sheltering mouse breast cancer cells against immune rejection.

Cancer cells acquire immunoediting ability to evade immune surveillance and thus escape eradication. It is widely known that mutant proteins encoded from tumor suppressor TP53 exhibit gain-of-function in cancer cells, thereby promoting progression; however, how mutant p53 contributes to the sheltering of cancer cells from host anticancer immunity remains unclear. Herein, we report that murine p53 missense mutation G242A (corresponding to human G245A) suppresses the activation of host natural killer (NK) cells, thereby enabling breast cancer cells to avoid immune assault. We found that serial injection of EMT6 breast cancer cells that carry wild-type (wt) Trp53, like normal fibroblasts, promoted NK activity in mice, while SVTneg2 cells carrying Trp53 G242A+/+ mutation decreased NK cell numbers and increased CD8+ T lymphocyte numbers in spleen. Innate immunity based on NK cells and CD8 T cells was reduced in p53 mutant-carrying transgenic mice (Trp53 R172H/+, corresponding to human R175H/+). Further, upon co-culture with isolated NK cells, EMT6 cells substantively activated NK cells and proliferation thereof, increasing interferon-gamma (IFN-γ) production; however, SVTneg2 cells suppressed NK cell activation. Further mechanistic study elucidated that p53 can modulate expression by cancer cells of Mult-1 and H60a, which are activating and inhibitory ligands for NKG2D receptors of NK cells, respectively, to enhance immune surveillance against cancer. Our findings demonstrate that wt p53 is requisite for NK cell-based immune recognition and elimination of cancerous cells, and perhaps more importantly, that p53 missense mutant presence in cancer cells impairs NK cell-attributable responses, thus veiling cancerous cells from host immunity and enabling cancer progression.

Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation.

Abnormal activation of SETBP1 due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of Hoxa9/Hoxa10/Myb transcription by SETBP1 and its missense mutants is essential for their transforming capability; however, the underlying epigenetic mechanisms remain elusive. We found that both SETBP1 and its missense mutant SETBP1(D/N) directly interact with histone methyltransferase MLL1. Using a combination of ChIP-seq and RNA-seq analysis in primary hematopoietic stem and progenitor cells, we uncovered extensive overlap in their genomic occupancy and their cooperation in activating many oncogenic transcription factor genes including Hoxa9/Hoxa10/Myb and a large group of ribosomal protein genes. Genetic ablation of Mll1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated Setbp1/Setbp1(D/N)-induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in Setbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation.

Single bag high dose intravenous N-acetylcysteine associated with decreased hepatotoxicity compared to triple bag intravenous N-acetylcysteine in high-risk acetaminophen ingestions.

INTRODUCTION: There is controversy that the triple bag intravenous (IV) N-acetylcysteine (NAC) regimen may be underdosing the sickest patients in its current, common usage. We hypothesize that a higher dose IV NAC regimen improves some outcomes. METHODS: We conducted a poison center based retrospective observational study from January 1, 2016 to December 31, 2017 comparing a single bag higher dose IV NAC regimen (150 mg/kg over 1 h, 15 mg/kg/hour) to the triple bag IV NAC regimen (150 mg/kg over 1 h, 12.5 mg/kg/hour for 4 h, 6.25 mg/kg/hour). In a high-risk population of patients with acetaminophen ingestion (defined as multiplication product ≥ 10,000 mg/L IU/L, not acute ingestions receiving NAC within 8 h, and not hepatotoxic on first contact), we evaluated the rate of hepatotoxicity, peak transaminase, and rate of laboratory coagulopathy. RESULTS: 89 patients met the inclusion criteria. 12 of the 23 patients (52%) who received triple bag NAC became hepatotoxic and 10 (43%) became coagulopathic, while only 19 of 66 patients (29%) who received single bag NAC became hepatotoxic and 15 (23%) became coagulopathic; p = .043 and .057, resp. Mean peak transaminase was 4481 IU/L vs 2143 IU/L in those receiving triple bag NAC vs single bag NAC, difference of means 2338 IU/L; p = .026. CONCLUSION: In this exploratory study of a high-risk population of patients with acetaminophen ingestions, the single bag IV NAC regimen was associated with lower peak transaminase and fewer patients becoming hepatotoxic as compared to the triple bag IV NAC regimen.

Sustained Improvement in the Performance of Rapid Sequence Intubation Five Years after a Quality Improvement Initiative.

Many quality improvement interventions do not lead to sustained improvement, and the sustainability of healthcare interventions remains understudied. We conducted a time-series analysis to determine whether improvements in the safety of rapid sequence intubation (RSI) in our academic pediatric emergency department were sustained 5 years after a quality improvement initiative. METHODS: There were 3 study periods: baseline (April 2009-March 2010), improvement (July 2012-December 2013), and operational (January 2014-December 2018). All patients undergoing RSI were eligible. We collected data using a structured video review. We compared key processes and outcomes with statistical process control charts. RESULTS: We collected data for 615 of 643 (96%) patient encounters with RSI performed: 114 baseline (12 months), 105 improvement (18 months), and 396 operational (60 months). Key characteristics were similar, including patient age. Statistical process control charts indicated sustained improvement of all 6 key processes and the primary outcome measure (oxyhemoglobin desaturation) throughout the 5-year operational period. CONCLUSIONS: Improvements in RSI safety were sustained 5 years after a successful improvement initiative, with further improvement seen in several key processes. Further research is needed to elucidate the factors contributing to sustainability.

Calcium Carbonate for Elemental Lead Ingestions: Effect of Alkalinization on Elemental Lead Solubility in a Simulated Gastric Environment.

INTRODUCTION: Acute ingestion of elemental lead foreign bodies has resulted in multiple pediatric deaths. Elemental lead is relatively insoluble at alkaline pH. Furthermore, calcium decreases lead absorption by interfering with the lead absorptive receptor. We hypothesize that alkalinization of gastric fluid with an oral calcium-containing agent, such as calcium carbonate, will decrease lead solubility, thus reducing the potential for systemic lead absorption and toxicity. METHODS: This was an in vitro controlled study. One lead sphere (00 buckshot, cast 30 days prior) was randomly placed in each of ten tubes containing 20 mL simulated gastric fluid, with five tubes having 500 mg calcium carbonate added at 20 min and 140 min. We measured the fluid pH and the lead concentrations hourly for 4 h. We compared the median amount of total lead liberated after 4 h between the two groups using the Mann-Whitney U test. RESULTS: The pH of the gastric fluid only tubes remained 1 at every measurement, and the pH of the gastric fluid + calcium carbonate tubes was 6 at every measurement. At hour 4, the total amount of lead liberated in the soluble fraction in the control group vs the calcium carbonate group was 850 vs 12.4 mcg (95% CI for absolute difference: 605-964 mcg; p = 0.0079). CONCLUSIONS: Calcium carbonate antacid alkalinizes gastric fluid pH and dramatically decreases the total amount of solubilized lead by 60-fold. This project lends foundational evidence to a low-cost, widely available, pre-hospital strategy to decrease lead absorption after acute elemental lead ingestions.

Gb3-cSrc complex in glycosphingolipid-enriched microdomains contributes to the expression of p53 mutant protein and cancer drug resistance via ß-catenin-activated RNA methylation.

Glucosylceramide synthase (GCS) is a key enzyme catalyzing ceramide glycosylation to generate glucosylceramide (GlcCer), which in turn serves as the precursor for cells to produce glycosphingolipids (GSLs). In cell membranes, GSLs serve as essential components of GSL-enriched microdomains (GEMs) and mediate membrane functions and cell behaviors. Previous studies showed that ceramide glycosylation correlates with upregulated expression of p53 hotspot mutant R273H and cancer drug resistance. Yet, the underlying mechanisms remain elusive. We report herewith that globotriaosylceramide (Gb3) is associated with cSrc kinase in GEMs and plays a crucial role in modulating expression of p53 R273H mutant and drug resistance. Colon cancer cell lines, either WiDr homozygous for missense-mutated TP53 (R273H+/+) or SW48/TP53-Dox bearing heterozygous TP53 mutant (R273H/+), display drug resistance with increased ceramide glycosylation. Inhibition of GCS with Genz-161 (GENZ 667161) resensitized cells to apoptosis in these p53 mutant-carrying cancer cells. Genz-161 effectively inhibited GCS activity, and substantially suppressed the elevated Gb3 levels seen in GEMs of p53-mutant cells exposed to doxorubicin. Complex formation between Gb3 and cSrc in GEMs to activate ß-catenin was detected in both cultured cells and xenograft tumors. Suppression of ceramide glycosylation significantly decreased Gb3-cSrc in GEMs, ß-catenin, and methyltransferase-like 3 for m6A RNA methylation, thus altering pre-mRNA splicing, resulting in upregulated expression of wild-type p53 protein, but not mutants, in cells carrying p53 R273H. Altogether, increased Gb3-cSrc complex in GEMs of membranes in response to anticancer drug induced cell stress promotes expression of p53 mutant proteins and accordant cancer drug resistance.

Single Coil Implantable Cardioverter Defibrillator Leads in Patients With Hypertrophic Cardiomyopathy.

Patients with hypertrophic cardiomyopathy (HC) may require higher energies to terminate ventricular fibrillation (VF); thus, dual coil defibrillation leads are often implanted. However, single coil leads may be preferred in young patients. All patients with HCM implanted with a transvenous ICD from years 2000 to 2014 were included. Of 249 patients, 223 underwent VF testing including 150 with a dual coil lead and 73 a single coil. Patients tested with dual coil compared with single coil had lower successful VF energies (15.7 ± 6.1 joule to 20.2 ± 7.9 joule (p <0.0001)). Adequate safety margin for defibrillation was noted in 97.3% of patients. Notably, 6 (4 with single coil leads) had inadequate safety margins (defined as ≥10 joule). Three of these 6 patients required replacement of a single coil lead with a dual coil lead. The remaining 3 underwent waveform tilt alteration, higher energy ICD, or removal of the can from the shock vector. There were no clinical or implant predictors of inadequate safety margins. In follow-up of 16 ± 30 months (range 0 to 170), there were 24 arrhythmias including 13 VF, all successfully terminated. In conclusion, in HC patients undergoing ICD implantation, single coil leads can provide adequate safety margins. In conclusion, defibrillation testing should be considered in all HC patients undergoing ICD implantation, and should be performed in those undergoing implantation with a single coil lead.

Cardiac rehabilitation in older adults: New options.

Cardiac rehabilitation (CR) is an important component in the continuum of care for patients with cardiovascular diseases, including the older population. Benefits of CR which include mortality benefit, decreased hospitalizations, increased functional capacity all extend to an older population. In Medicare beneficiaries which represent an older population, utilization of CR continues to remain low despite evidence that suggests lower hospitalization rates, Medicare costs, and improved symptoms. Given poor referral rates, enrollment rates, and completion rates, a call for new strategies has been made by all major societies. However, several barriers exist. Newer models of CR constructed to overcome these barriers are reviewed below. Some of these new strategies include alternative site CR or home-based CR and the utilization of technology.

Rubusoside-assisted solubilization of poorly soluble C6-Ceramide for a pilot pharmacokinetic study.

Although C6-Ceramide has attracted much attention as a possible tumor suppressor, the delivery of C6-Ceramide is still challenging due to its inherent hydrophobicity and insolubility. In this study we explored the use of a natural compound rubusoside (RUB) as a solubilizer to enhance the solubility of a fluorescence-labeled C6-Ceramide (NBD C6-Ceramide) and to characterize its pharmacokinetics and tissue distribution in an animal model. RUB significantly enhanced the solubility of NBD C6-Ceramide by forming nanomicelles, and efficiently delivered NBD C6-Ceramide in rats by oral and intravenous administration. RUB loaded 1.96 % of NBD C6-Ceramide in the nanomicelles and solubilized it to a concentration of 3.6 mg/mL in water. NBD C6-Ceramide in nanomicelles remained stable in aqueous solutions, allowing intravenous administration without the use of any organic solvents or surfactants. After oral administration, NBD C6-Ceramide rapidly rose to peak plasma concentrations within the first 90 min, distributed to tissues, and remained in vivo for more than 24 h. Tissular levels of NBD C6-Ceramide from high to low were associated with heart, lung, cerebellum, testicle, spleen, liver, kidney, and brain. Altogether, our study demonstrated that RUB-assisted nanomicelles can serve as an efficient and convenient delivery system for short-chain C6-Ceramide and enable in vivo evaluation of potential new cancer treatments.

Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity.

A 33-year-old male presented to the emergency department with a chief complaint of abdominal pain after taking #50 500 mg acetaminophen tablets over the preceding two days. He was tachycardic and tachypneic, and the initial labs were notable for acetaminophen level, 337 mg/L; AST, 137 IU/L; ALT, 194 IU/L; ABG pH, 7.24; and lactate, 4.1 mmol/L. The patient was started on IV N-Acetylcysteine (NAC) as well as given a single dose of 15 mg/kg fomepizole. The patient did remarkably well, with a peak AST of 198 IU/L, peak ALT of 301 IU/L, and peak INR of 3.1. Biochemical and animal data support fomepizole having hepatoprotective effects in acetaminophen poisoning. To our knowledge, this is the first human case of an intentional dual NAC/fomepizole regimen for severe acetaminophen toxicity.