The Impact of the COVID-19 Pandemic on Cardiac Electrophysiology Training: A Survey Study.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a significant decrease in volume of electrophysiology (EP) procedures. There has been concern that trainees may not achieve the procedural numbers required to graduate as independent electrophysiologists within the usual timeline. We sought to determine the impact of the COVID-19 pandemic on the percentage of clinical cardiac EP (CCEP) fellows in jeopardy of not meeting procedural volume requirements and overall sentiments regarding preparedness of fellows for independent practice. METHODS: We surveyed CCEP fellows and program directors about baseline procedural volumes, curriculum changes due to the pandemic, and attitudes about preparedness for board examinations and independent practice. RESULTS: Ninety-nine fellows and 27 program directors responded to the survey. Ninety-eight percent of responding fellows reported a decrease in procedural volume as a result of the pandemic. Program directors reported an overall decrease in annual number of ablations and device procedures performed by each fellow during the 2019-2020 academic year compared to the preceding year. Despite this, a minority of fellows and program directors reported concerns about meeting Accreditation Council for Graduate Medical Education procedural requirements for devices (9% and 4%, respectively) and ablation (19% and 9%) or preparedness for independent practice after a 2-year fellowship. CONCLUSIONS: The COVID-19 pandemic has resulted in a decrease in procedural volume for CCEP trainees, but the majority of fellows and program directors do not anticipate major barriers to timely graduation. This may change with COVID-19 resurgence and further interruptions in training.

Determinants of regeneration and strength of hamstrings after anterior cruciate ligament reconstruction-fate of hamstring tendon.

BACKGROUND AND AIM: Arthroscopic reconstruction of anterior cruciate ligament (ACL) surgical procedure using hamstring autograft is the most common surgery performed in the arena of sports medicine and arthroscopy. Most studies in literature are ambiguous regarding the fate of hamstrings based on function, regenerative potential, and cross-sectional area (CSA). The aim of this research study is analysis of the fate of hamstring tendons (both semitendinosus and gracilis) during the time course for determinants of regeneration and strength. METHODS: Fifty patients who were operated for unilateral isolated ACL reconstruction from July 2015 to June 2018 were evaluated for the fate of harvested hamstring tendons which included the following: regeneration, cross-sectional area (CSA), strength, and insertion of regenerated hamstrings by isometric torque and isokinetic strength. MRI of knee was performed for both knees concerning the semitendinosus (ST), gracilis (G), Sartorius, biceps femoris, and medial head of gastrocnemius. RESULTS: Eighty-four percent men and 16% women within a mean patient age of 34 ± 4.12 years were evaluated and all 50 (100%) patients demonstrated hamstring regeneration by the MRI measurements at six months and at one year post-ACL reconstruction. The torque of isometric knee flexion measured in 60° was found to be remarkably lower in the ACL-reconstructed lower extremity compared to that of the contralateral limb (87.13 ± 20.18% of BW), at 90° (49.17 ± 15.09% BW), and at 105° (43.91 ± 13.17% BW), respectively (p < 0.01). However, at 30° flexion and 45° flexion, the difference was insignificant (116.48 ± 21.07% BW for 30° and 100.16 ± 25.12% BW for 45°). CONCLUSIONS: It was found that the properties of musculotendinous units of ST and G were significantly transformed after their harvesting for ACL reconstruction and these weaknesses contribute to the flexion deficit of knee in the deeper range of flexion in the operated limb. Therefore, approaches facilitating tendon regeneration and preservation must be warranted.

Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open-label multiple-dose study.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open-label, multi-dose study, 73 subjects were divided into six treatment groups: (1) 55-65 years; (2) 66-75 years; (3) >75 years (dosing for groups 1-3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired-no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0-τ)ss was 112.2 (90% CI; 92.0-136.8) and Cmax,ss was 109.9 (89.6-134.8), Group 3 and 1 of AUC(0-τ),ss was 140.5 (115.9-170.3) and Cmax,ss was 137.8 (112.9-168.2), Group 4 and 1 of AUC(0-τ),ss was 114.2 (90.3-144.4) and Cmax,ss was 120.8 (92.5-157.8), Group 5 and 1 of; AUC(0-τ),ss was 213.0 (153.1-296.3) and Cmax,ss was 123.3 (92.2-164.7) and Group 6 and 1 of AUC(0-τ),ss was 247.4 (197.8-309.6) and Cmax,ss was 95.6 (73.0-125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well-tolerated.

Differential Metabolic Effects of Beta-Blockers: an Updated Systematic Review of Nebivolol.

Blood pressure management in hypertensive patients with metabolic abnormalities is challenging, since many of the antihypertensive drugs adversely affect metabolism. Besides effective control of blood pressure in patients with hypertension, third-generation beta-blockers such as nebivolol offer additional benefits for central hemodynamics and neutral or beneficial effects on metabolism. Emerging clinical data suggest that nebivolol also has similar effects on metabolism in obese hypertensive and hypertensive diabetic patients. The present article will provide a systematic analysis of the pathophysiological links among hypertension, insulin resistance, and metabolic syndrome. We will also summarize the available clinical evidence regarding the metabolic effects of beta-blockers in hypertensive patients, with an emphasis on nebivolol. Nebivolol exerts neutral or beneficial effects on insulin sensitivity and lipid metabolism in hypertensive patients, owing to its nitric oxide-mediated vasodilatory and antioxidative properties. Thus, nebivolol could be a favorable therapeutic option for the treatment of hypertension in patients with impaired glucose and lipid metabolism.

Optical Properties of Secondary Organic Aerosol from cis-3-Hexenol and cis-3-Hexenyl Acetate: Effect of Chemical Composition, Humidity, and Phase.

Atmospheric aerosols play an important role in Earth's radiative balance directly, by scattering and absorbing radiation, and indirectly, by acting as cloud condensation nuclei (CCN). Atmospheric aerosol is dominated by secondary organic aerosol (SOA) formed by the oxidation of biogenic volatile organic compounds (BVOCs). Green leaf volatiles (GLVs) are a class of BVOCs that contribute to SOA, yet their role in the Earth's radiative budget is poorly understood. In this work we measured the scattering efficiency (at 450, 525, and 635 nm), absorption efficiency (between 190 and 900 nm), particle phase, bulk chemical properties (O:C, H:C), and molecular-level composition of SOA formed from the ozonolysis of two GLVs: cis-3-hexenol (HXL) and cis-3-hexenyl acetate (CHA). Both HXL and CHA produced SOA that was weakly absorbing, yet CHA-SOA was a more efficient absorber than HXL-SOA. The scatter efficiency of SOA from both systems was wavelength-dependent, with the stronger dependence exhibited by HXL-SOA, likely due to differences in particle size. HXL-SOA formed under both dry (10% RH) and wet (70% RH) conditions had the same bulk chemical properties (O:C), yet significantly different optical properties, which was attributed to differences in molecular-level composition. We have found that SOA derived from green leaf volatiles has the potential to affect the Earth's radiative budget, and also that bulk chemical properties can be insufficient to predict SOA optical properties.

Application of design of experiments for formulation development and mechanistic evaluation of iontophoretic tacrine hydrochloride delivery.

OBJECTIVE: The objective of this investigation is to develop mathematical equation to understand the impact of variables and establish statistical control over transdermal iontophoretic delivery of tacrine hydrochloride. In addition, possibility of using conductivity measurements as a tool of predicting ionic mobility of the participating ions for the application of iontophoretic delivery was explored. METHODS: Central composite design was applied to study effect of independent variables like current strength, buffer molarity, and drug concentration on iontophoretic tacrine permeation flux. Molar conductivity was determined to evaluate electro-migration of tacrine ions with application of Kohlrausch's law. RESULTS: The developed mathematic equation not only reveals drug concentration as the most significant variable regulating tacrine permeation, followed by current strength and buffer molarity, but also is capable to optimize tacrine permeation with respective combination of independent variables to achieve desired therapeutic plasma concentration of tacrine in treatment of Alzheimer's disease. Moreover, relative higher mobility of sodium and chloride ions was observed as compared to estimated tacrine ion mobility. CONCLUSIONS: This investigation utilizes the design of experiment approach and extends the primary understanding of imapct of electronic and formulation variables on the tacrine permeation for the formulation development of iontophoretic tacrine delivery.

Formulation and rheological evaluation of ethosome-loaded carbopol hydrogel for transdermal application.

OBJECTIVE: To select a suitable ethosome-loaded Carbopol hydrogel formulation, specifically tailored for transdermal application that exhibits (i) plastic flow with yield stress of approximately 50-80 Pa at low polymer concentration, (ii) relatively frequency independent elastic (G') and viscous (G″) properties and (iii) thermal stability. METHODS: Carbopol (C71, C934, C941, C971 or C974) hydrogels were prepared by dispersing Carbopol in distilled water followed neutralization by sodium hydroxide. The effects of Carbopol grade, Carbopol concentration, ethosome addition and temperature on flow (yield stress and viscosity) and viscoelastic (G' and G″) properties of Carbopol hydrogel were evaluated. Based on the aforementioned rheological properties evaluated, suitable ethosome-loaded Carbopol hydrogel was selected. In-vitro permeation studies of diclofenac using rat skin were further conducted on ethosome-loaded Carbopol hydrogel along with diclofenac-loaded ethosomal formulation as control. RESULTS: Based on preliminary screening, C934, C971 and C974 grades were selected and further evaluated for flow and viscoelastic properties. It was observed that ethosome-loaded C974 hydrogel at concentration of 0.50 and 0.75% w/w, respectively, demonstrated acceptable plastic flow with distinct yield stress and a frequency independent G' and G″. Furthermore, the flow and viscoelastic properties were maintained at the 4, 25 and 32 °C. The results from in vitro skin permeation studies indicate that ethosome-loaded C974 hydrogel at 0.5% w/w polymer concentration exhibited similar skin permeation as that of ethosomal formulation. CONCLUSION: The results indicate that suitable rheological properties of C974 could facilitate in achieving desired skin permeation of diclofenac while acting as an efficient carrier system for ethosomal vesicles.

Nucleic acid scavengers inhibit thrombosis without increasing bleeding.

Development of effective, yet safe, antithrombotic agents has been challenging because such agents increase the propensity of patients to bleed. Recently, naturally occurring polyphosphates such as extracellular DNA, RNA, and inorganic polyphosphates have been shown to activate blood coagulation. In this report, we evaluate the anticoagulant and antithrombotic activity of nucleic acid-binding polymers in vitro and in vivo. Such polymers bind to DNA, RNA, and inorganic polyphosphate molecules with high affinity and inhibit RNA- and polyphosphate-induced clotting and the activation of the intrinsic pathway of coagulation in vitro. Moreover, [NH(2)(CH(2))(2)NH(2)](G = 3);dendri PAMAM(NH(2))(32) (PAMAM G-3) prevents thrombosis following carotid artery injury and pulmonary thromboembolism in mice without significantly increasing blood loss from surgically challenged animals. These studies indicate that nucleic acid-binding polymers are able to scavenge effectively prothrombotic nucleic acids and other polyphosphates in vivo and represent a new and potentially safer class of antithrombotic agents.

Diagnosis and Management of Closed Internal Degloving Injuries: The Morel-Lavallée Lesion.

BACKGROUND: Morel-Lavallée (ML) lesions are closed degloving injuries described as posttraumatic subcutaneous fluid collections. They are most commonly seen in the proximal thigh. They can present several days to months after the inciting event. CASE REPORT: A 55-year-old woman with a recent admission for trauma presented to the Emergency Department with increasing swelling and pain in the right thigh for the previous 3 days. Ultrasound of the thigh was negative. Magnetic resonance imaging performed to further evaluate for leg swelling revealed a "Morel-Lavallée lesion" of the thigh that required drainage. The patient recovered completely after the surgery. WHY SHOULD THE EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of these rare lesions because they are often mistaken for tumors or hematomas. Early recognition may avoid subsequent complications and help in obtaining prompt specialist care.

Solubility and dissolution enhancement strategies: current understanding and recent trends.

Identification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.

Quality by design approach for formulation, evaluation and statistical optimization of diclofenac-loaded ethosomes via transdermal route.

The objective of this study was to fabricate and understand ethosomal formulations of diclofenac (DF) for enhanced anti-inflammatory activity using quality by design approach. DF-loaded ethosomal formulations were prepared using 4 × 5 full-factorial design with phosphatidylcholine:cholesterol (PC:CH) ratios ranging between 50:50 and 90:10, and ethanol concentration ranging between 0% and 30% as formulation variables. These formulations were characterized in terms of physicochemical properties and skin permeation kinetics. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation kinetics. The results of multivariate regression analysis illustrated that vesicle size and elasticity of ethosomes were the dominating physicochemical properties affecting skin permeation, and could be suitably controlled by manipulation of formulation variables to optimize the formulation and enhance the skin permeation of DF-loaded ethosomes. The optimized formulation had ethanol concentration of 22.9% and PC:CH ratio of 88.4:11.6, with vesicle size of 144 ± 5 nm, zeta potential of -23.0 ± 3.76 mV, elasticity of 2.48 ± 0.75 and entrapment efficiency of 71 ± 4%. Permeation flux for the optimized formulation was 12.9 ± 1.0 µg/h cm(2), which was significantly higher than the drug-loaded conventional liposome, ethanolic or aqueous solution. The in vivo study indicated that optimized ethosomal hydrogel exhibited enhanced anti-inflammatory activity compared with liposomal and plain drug hydrogel formulations.

Influence of electronic and formulation variables on transdermal iontophoresis of tacrine hydrochloride.

Freshly excised rat skin and side-by-side permeation cells were used to study the effect of electronic and formulation variables on transdermal iontophoretic delivery of tacrine. Current strength at 0.1-0.3 mA was observed to be the driving force resulting in tacrine permation flux of 30.3-366.6 µg/cm(2)/h. Depot formation of tacrine and altered skin permeability resulted in post iontophoretic flux even after termination of applied current. Increase in the duration of current application did not show significant difference in tacrine permeation flux upto 6 h. Tacrine permeation was directly proportional to tacrine concentration upto 10 mg/ml but further increase in concentration (upto 20 mg/ml) exhibited permeation flux plateau. Buffer molarity had an inverse relationship on permeation flux and the presence of co-ions in formulation exhibited reduced permeation flux. Permeation flux decreased when pH of formulation was successively increased from 7.0 to 10.0 suggesting electromigration of tacrine. Alternate buffer systems including HEPES and Tris showed improved tacrine permeation due to their larger ion size compared to phosphate buffer ions. The results of this study show that transdermal tacrine permeation can be controlled by electronic and formulation variables which would be useful for the development of transdermal iontophoretic delivery of tacrine for the treatment of Alzehimer's disease.

Inhibition of proliferation and migration of stricture fibroblasts by epithelial cell-conditioned media.

INTRODUCTION: Urethral stricture is characterized by urethral lumen narrowing due to fibrosis. Urethroplasty of the urethral stricture involves excision of scar, and may be followed by reconstruction of the urethra using split-thickness skin, buccal mucosa, urethral mucosa or, more recently, tissue-engineered grafts. The stricture wound healing process after urethroplasty is known to be mediated by an interaction between keratinocyte and fibroblasts; however, the underlying mechanisms are not studied in detail yet. We investigated the influence of epithelial cell-conditioned medium (ECCM) (obtained from confluent penile skin, buccal mucosa and urethral cell cultures) on the proliferation and migration of stricture fibroblasts using an in vitro scratch assay. MATERIALS AND METHODS: ECCM was collected from confluent primary epithelial cell cultures of three different human biopsies (penile skin, buccal mucosa and urethral mucosa), whereas stricture fibroblasts were isolated from human urethral stricture biopsies. The effect of ECCM on stricture fibroblasts' proliferation and migration into the scratch was observed using a standard in vitro scratch assay over a period of 3 days. Four experiments were performed independently using four stricture fibroblasts from four patients and ECCM was collected from 12 different patients' primary cell cultures. RESULTS: ECCM from primary epithelial cells cultures obtained from penile skin, buccal mucosa and urethra inhibited stricture fibroblasts' proliferation and migration in the in vitro scratch assay. CONCLUSION: These results demonstrate the ability of ECCM to inhibit the proliferation and migration of stricture fibroblasts and present it as an effective adjunct in urethroplasty, which may influence stricture wound healing and inhibit the recurrence of stricture.

Soft ionization chemical analysis of secondary organic aerosol from green leaf volatiles emitted by turf grass.

Globally, biogenic volatile organic compound (BVOC) emissions contribute 90% of the overall VOC emissions. Green leaf volatiles (GLVs) are an important component of plant-derived BVOCs, including cis-3-hexenylacetate (CHA) and cis-3-hexen-1-ol (HXL), which are emitted by cut grass. In this study we describe secondary organic aerosol (SOA) formation from the ozonolysis of dominant GLVs, their mixtures and grass clippings. Near-infrared laser desorption/ionization aerosol mass spectrometry (NIR-LDI-AMS) was used for chemical analysis of the aerosol. The chemical profile of SOA generated from grass clippings was correlated with that from chemical standards of CHA and HXL. We found that SOA derived from HXL most closely approximated SOA from turf grass, in spite of the approximately 5× lower emission rate of HXL as compared to CHA. Ozonolysis of HXL results in formation of low volatility, higher molecular weight compounds, such as oligomers, and formation of ester-type linkages. This is in contrast to CHA, where the hydroperoxide channel is the dominant oxidation pathway, as oligomer formation is inhibited by the acetate functionality.

Multidisciplinary Management of Opioid Use-Related Infective Endocarditis: Treatment, QTc Values, and Cardiac Arrests due to Ventricular Fibrillation.

(1) Background: The opioid epidemic has led to an increase in cardiac surgery for infective endocarditis (IE-CS) related to injection use of opioids (OUD) and other substances and a call for a coordinated approach to initiate substance use disorder treatment, including medication for OUD (MOUD), during IE-CS hospitalizations. We sought to determine the effects of the initiation of a multi-disciplinary endocarditis evaluation team (MEET) on MOUD use, electrocardiographic QTc measurements and cardiac arrests due to ventricular fibrillation (VF) in patients with OUD. (2) Methods and Results: A historical group undergoing IE-CS at Yale-New Haven Hospital prior to MEET initiation, Group I (43 episodes of IE-CS, 38 patients) was compared to 24 patients undergoing IE-CS after MEET involvement (Group II). Compared to Group l, Group II patients were more likely to receive MOUD (41.9 vs. 95.8%, p < 0.0001), predominantly methadone (41.9 vs. 79.2%, p = 0.0035) at discharge. Both groups had similar QTcs: approximately 30% of reviewed electrocardiograms had QTcs ≥ 470 ms and 17%, QTcs ≥ 500 ms. Cardiac arrests due to VF were not uncommon: Group I: 9.3% vs. Group II: 8.3%, p = 0.8914. Half occurred in the 1-2 months after surgery and were contributed to by pacemaker malfunction/ management and half were related to opioid use. (3) Conclusions: MEET was associated with increased MOUD (predominantly methadone) use during IE-CS hospitalizations without an increase in QTc prolongation or cardiac arrest due to VF compared to Group I, but events occurred in both groups. These arrests were associated with pacemaker issues or a return to opioid use. Robust follow-up of IE-CS patients is essential, as is further research to clarify the longer-term effects of MEET on outcomes.

Abernethy malformation: A comprehensive review.

Abernethy malformation is a rare condition in which portomesenteric blood bypasses the liver and drains into the systemic vein through a partial or complete shunt. It is categorised into two types on the basis of the shunt pattern between the portal vein and systemic vein. Abernethy malformation is associated with multiple congenital anomalies and acquired complications. A detailed understanding of anatomy and embryology is a prerequisite to interpret the imaging findings. Computed tomography and magnetic resonance angiography can delineate the shunt anatomy and evaluate the concomitant malformations. It is essential to differentiate Abernethy malformation from intrahepatic portosystemic shunts and acquired extrahepatic portosystemic shunts. Mild metabolic abnormalities are treated with dietary modifications and medical therapy. Definitive treatment is done in symptomatic patients. Generally, type I Abernethy patients undergo liver transplantation, and type II undergo shunt occlusion by surgery or transcatheter coiling.

Platelets: linking hemostasis and cancer.

Platelets are the main cellular component in blood responsible for maintaining the integrity of the cardiovascular system via hemostasis. Platelet dysfunction contributes to a wide range of obvious pathological conditions, such as bleeding or thrombosis, but normal platelet function is also linked to diseases not immediately associated with hemostasis or thrombosis, such as cancer. Since the description of Trousseau syndrome in 1865, various experimental and clinical studies have detailed the interaction of platelets with primary tumors and circulating metastatic tumor cells. Observations have suggested that platelets not only augment the growth of primary tumors via angiogenesis but endow tumor cells physical and mechanical support to evade the immune system and extravasate to secondary organs, the basis of metastatic disease. Many laboratory and animal studies have identified specific targets for antiplatelet therapy that may be advantageous as adjuncts to existing cancer treatments. In this review, we summarize important platelet properties that influence tumorigenesis, including primary tumor growth and metastasis at the molecular level. The studies provide a link between the well-studied paradigms of platelet hemostasis and tumorigenesis.

Spray desorption collection: an alternative to swabbing for pharmaceutical cleaning validation.

Spray Desorption Collection (SDC) allows for much larger areas of surfaces to be sampled compared to traditional swabbing techniques, providing a valuable pre-concentration advantage. Closely related to desorption electrospray ionization (DESI), analytes from the sample surface are collected onto a selected collection surface, which in a second step can be analyzed directly. Here we demonstrate the application of SDC as a large surface area sampling tool coupled with paper spray MS (PS-MS) and demonstrate its capabilities for cleaning validation of pharmaceutical equipment for both acidic and basic active ingredients from an aluminium surface.

Isolated right subclavian artery with interrupted aortic arch, ventricular septal defect and bilateral patent ductus arteriosus: a rare congenital anomaly.

Isolation of the left subclavian artery or its anomalous origin from the pulmonary artery has been documented in several cases, especially in association with a right-sided aortic arch. However, similar anomaly involving the right subclavian artery has been less frequently reported. Isolated right subclavian artery in association with interrupted aortic arch (IAA) is extremely rare, and only three cases have been reported so far. Here, we have presented yet another case of isolated right subclavian artery associated with ventricular septal defect, type B IAA and bilateral patent ductus arteriosus.