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Permeability is an important molecular property in drug discovery, as it co-determines pharmacokinetics whenever a drug crosses the phospholipid bilayer, e.g., into the cell, in the gastrointestinal tract, or across the blood-brain barrier. Many methods for the determination of permeability have been developed, including cell line assays (CACO-2 and MDCK), cell-free model systems like parallel artificial membrane permeability assay (PAMPA) mimicking, e.g., gastrointestinal epithelia or the skin, as well as the black lipid membrane (BLM) and submicrometer liposomes. Furthermore, many in silico approaches have been developed for permeability prediction: meta-analysis of publicly available databases for permeability data (MolMeDB and ChEMBL) was performed to establish their usability. Four experimental and two computational methods were evaluated. It was shown that repeatability of the reported permeability measurement is not great even for the same method. For the PAMPA method, two different permeabilities are reported: intrinsic and apparent. They can vary in degrees of magnitude; thus, we suggest being extra cautious using literature data on permeability. When we compared data for the same molecules using different methods, the best agreement was between cell-based methods and between BLM and computational methods. Existence of unstirred water layer (UWL) permeability limits the data agreement between cell-based methods (and apparent PAMPA) with data that are not limited by UWL permeability (computational methods, BLM, intrinsic PAMPA). Therefore, different methods have different limitations. Cell-based methods provide results only in a small range of permeabilities (-8 to -4 in cm/s), and computational methods can predict a wider range of permeabilities beyond physical limitations, but their precision is therefore limited. BLM with liposomes can be used for both fast and slow permeating molecules, but its usage is more complicated than standard transwell techniques. To sum up, when working with in-house measured or published permeability data, we recommend caution in interpreting and combining them.

This study explores the potential of using liposomal electrokinetic chromatography as a ranking method for the rapid and simultaneous evaluation of drug-membrane interactions of a larger group of substances and assessing their sensitivity to tissue-specific parameters, namely pH, temperature, and lipid composition. We used a group of nine model drug substances to manifest how molecules could be classified for the relative sensitivity of drug-membrane interactions to pH and temperature. We observed that increasing the amount of liposomes in the background electrolyte significantly affected the separation kinetics of various active pharmaceutical ingredients, altering their mobility and/or peak shapes. Experiments with liposomes from bovine liver and heart tissue extracts revealed different interactions based on the lipid composition. Canagliflozin, which initially showed no electrophoretic mobility, migrated toward the anode in the presence of negatively charged liposomes. Mobility of positively charged substances, ambroxol and maraviroc, was suppressed by the interactions with liposomes. Their peaks also exhibited significant tailing. The effect on the separation of negatively charged compounds was significantly weaker. A small change in mobility was observed only in the case of deferasirox. We also examined the effect of temperature during separation, and we observed that increased temperature generally enhanced effective mobility due to lower electrolyte viscosity and increased lipid bilayer fluidity. Lastly, we tested the effect of sodium phosphate buffer pH (ranging from 6.0 to 8.0) with 4% liposomes on drug-liposome interactions. However, the effects were complex due to changes in API ionization and liposome surface charge, complicating the distinction between pH effects and liposome presence on API behavior. Our findings emphasize the significance of liposome composition, temperature, and pH in studying the interactions of liposomes with drugs, which is crucial for optimizing liposome-based drug delivery systems., Competing Interests: Declarations. Ethics approval: This study does not contain any studies with human participants or animals performed by any of the authors. Consent for publication: The authors agree with the publication of the manuscript. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Patients with obesity, especially those suffering from obstructive sleep apnea (OSA), are prone to postoperative respiratory hypoxemia. The PRODIGY (prediction of opioid-induced respiratory depression in patients monitored by capnography) Score is used to predict respiratory complications that factor in sleep-disordered breathing. Data on the impact of OSA on the frequency and timing of postoperative desaturation trends after bariatric surgery are lacking., Methods: This cohort study included 195 patients who underwent robotic-assisted bariatric surgery between June 2022 and December 2023. Patients underwent were classified by OSA status (yes/no) and PRODIGY Risk Score (high/intermediate/low). All patients received low or opioid sparing anesthesia and were continuously monitored postoperatively using the Masimo Rad-97 device (Masimo, Irvine, CA, USA). Postoperative monitoring averaged 14.5 hours, including tracking several variables and SpO2 values. We documented desaturations and opioid usage in 2-hour intervals. Patients also underwent 30-day postoperative follow up. Descriptive statistics were analyzed based on OSA status and PRODIGY scores using Student's t-test, ANOVA, and Fisher's Exact Test., Results: Most study patients (57.4%) had OSA, were significantly older, and were predominantly female. Patients with OSA had substantially more prolonged exposure to SpO2 ranges between 80-95% and experienced more frequent desaturation events between 10 and 14 hours after Post-Anesthesia Care Unit (PACU) discharge. Patients with high PRODIGY scores (>15) had significantly more desaturation events compared to intermediate and low-score groups., Conclusions: Postoperative desaturation rates are significantly higher among patients with OSA with high PRODIGY scores, especially in the delayed postoperative period. Continuous extended postoperative monitoring is warranted for these high-risk patients after bariatric surgery.

N -Acetyllactosamine is a common saccharide motif found in various biologically active glycans. This motif usually works as a backbone for additional modifications and thus significantly influences glycan conformational behavior and biological activity. In this work, we have investigated the type-2 N -acetyllactosamine scaffold using the complete series of its monodeoxyfluorinated analogs. These glycomimetics have been studied by molecular mechanics, quantum mechanics, X-ray crystallography, and various NMR techniques, which have provided a comprehensive and complete insight into the role of individual hydroxyl groups in the conformational behavior and lipophilicity of N -acetyllactosamine.

The permeation of small molecules across biological membranes is a crucial process that lies at the heart of life. Permeation is involved not only in the maintenance of homeostasis at the cell level but also in the absorption and biodistribution of pharmacologically active substances throughout the human body. Membranes are formed by phospholipid bilayers that represent an energy barrier for permeating molecules. Crossing this energy barrier is assumed to be a singular event, and permeation has traditionally been described as a first-order kinetic process, proportional only to the concentration gradient of the permeating substance. For a given membrane composition, permeability was believed to be a unique property dependent only on the permeating molecule itself. We provide experimental evidence that this long-held view might not be entirely correct. Liposomes were used in copermeation experiments with a fluorescent probe, where simultaneous permeation of two substances occurred over a single phospholipid bilayer. Using an assay of six commonly prescribed drugs, we have found that the presence of a copermeant can either enhance or suppress the permeation rate of the probe molecule, often more than 2-fold in each direction. This can have significant consequences for the pharmacokinetics and bioavailability of commonly prescribed drugs when used in combination and provide new insight into so-far unexplained drug-drug interactions as well as changing the perspective on how new drug candidates are evaluated and tested.

Imiquimod (IMQ) is an immunostimulating agent used in the treatment of basal cell carcinoma and actinic keratosis. Due to its low solubility and poor skin bioavailability, the dermal formulation of IMQ remains challenging. In analogy to tyre compounds used in Formula 1 racing, we compare four types of nanosystems belonging to three groups: (i) "hard" nanoparticles in the form of IMQ nanocrystals, (ii) "intermediate" nanoparticles in the form of liposomes and lipid nanocapsules, and (iii) "soft" nanoparticles in the form of a nanoemulsion based on oleic acid. The nanoemulsion and nanocrystals were able to incorporate the highest amount of IMQ (at least 2 wt%) compared to liposomes (0.03 wt%) and lipid nanocapsules (0.08 wt%). Regarding size, liposomes, and lipid nanocapsules were rather small (around 40 nm) whereas nanocrystals and nanoemulsion were larger (around 200 nm). All developed nanoformulations showed high efficiency to deliver IMQ into the skin tissue without undesirable subsequent permeation through the skin to acceptor. Especially, the 2 wt% IMQ nanoemulsion accumulated 129 μg/g IMQ in the skin, compared to 34 μg/g of a 5 wt% commercial cream. The effects of the respective nanoparticulate systems were discussed with respect to their possible diffusion kinetics (Brownian motion vs. settling) in the aqueous phase., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Encapsulation into liposomes is a formulation strategy that can improve efficacy and reduce side effects of active pharmaceutical ingredients (APIs) that exhibit poor biodistribution or pharmacokinetics when administered alone. However, many APIs are unsuitable for liposomal formulations intended for parenteral administration due to their inherent physicochemical properties─lipid bilayer permeability and water-lipid equilibrium partitioning coefficient. Too high permeability results in premature leakage from liposomes, while too low permeability means the API is not able to pass across biological barriers. There are several options for solving this issue: (i) change of the lipid bilayer composition, (ii) addition of a permeability enhancer, or (iii) modification of the chemical structure of the API to design a prodrug. The latter approach was taken in the present work, and the effect of small changes in the molecular structure of the API on its permeation rate across a lipidic bilayer was systematically explored utilizing computer simulations. An in silico methodology for prodrug design based on the COSMOperm approach has been proposed and applied to four APIs (abiraterone, cytarabine, 5-fluorouracil, and paliperidone). It is shown that the addition of aliphatic hydrocarbon chains via ester or amide bonds can render the molecule more lipophilic and increase its permeability by approximately 1 order of magnitude for each 2 carbon atoms added, while the formation of fructose adducts can provide a more hydrophilic character to the molecule and reduce its lipid partitioning. While partitioning was found to depend only on the size and type of the added group, permeability was found to depend also on the added group location. Overall, it has been shown that both permeability and lipid partitioning coefficient can be systematically shifted into the desired liposome formulability window by appropriate group contributions to the parental drug. This can significantly increase the portfolio of APIs for which liposome or lipid nanoparticle formulations become feasible.

Objective The objective of this study was to determine the safety profile of methotrexate (MTX) therapy in patients with rheumatoid arthritis Study design This was a cross-sectional observational study. Place and duration of the study The study took place in the Division of Rheumatology, Lady Reading Hospital Peshawar, from May 2020 to August 2021. Methodology A total of 411 patients with rheumatoid arthritis and receiving MTX in the dose of 10-20 mg/week for at least four months were included by consecutive sampling. All patients were followed for four months for the development of cytopenias, deranged liver function tests, renal function tests, fever, and gastrointestinal upsets. Data were recorded on a pro forma. Results There were 237 (57.6%) females and 174 (42.4%) males. The female to male ratio was 1.4: 1. The average age of patients was 43.01 years + 17.1 SD with a range of 18-72 years. Gastrointestinal side effects were the most common, found in 49 patients (11.9%), followed by mucocutaneous side effects in 35 patients (8.5%) and fever (34 patients, 8.3%). Conclusion Every one in three patients developed some adverse effect within six months of methotrexate therapy. Moreover, we conclude that gastrointestinal side effects were the most common side effects seen., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Mustafa et al.)

Yeast glucan particles are porous polysaccharide cell walls extracted from Saccharomyces cerevisiae. Being mildly immunogenic, they are efficiently phagocytosed and have therefore been proposed as possible vehicles for drug delivery. Using curcumin as a model poorly water-soluble drug, a systematic comparison of three different physical loading methods - incipient wetness impregnation, slurry evaporation, and spray drying - was carried out and their influence on the particle morphology, encapsulation efficiency, amorphous drug content and release kinetics was evaluated. It was found that yeast glucan particles can contain up to 30% wt. of curcumin in the amorphous form when prepared by slurry evaporation. The dissolution of curcumin from glucan particles lead to a supersaturated solution in asimilar way as amorphous solid dispersions do, despite the fact that glucan particles themselves do not dissolve. Bi-phasic dissolution tests revealed up to 4-fold acceleration of curcumin dissolution rate from amorphous glucan particles compared to its crystalline form. Crucially, glucan particles were shown to retain the ability to be recognised and phagocytosed even after drug encapsulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: This study blindly evaluated sugammadex compared with neostigmine on length of stay in the postanesthesia care unit (PACU)., Methods: Fifty patients undergoing elective laparoscopic cholecystectomy or abdominal wall hernia repair consented to receive either sugammadex (2 mg/kg) or neostigmine (0.07 mg/kg) for the reversal of rocuronium neuromuscular blockade. Reversal agents were administered during surgical closing, and the train of four was measured until a twitch ratio of T4:T1 ≥ 0.9 was obtained to signify a robust reversal. Postreversal outcomes also were measured during PACU stay. Aldrete scores, pain visual analog scale score, and nausea were measured during the PACU stay., Results: Patients receiving sugammadex experienced a shorter PACU stay at the time of discharge than patients receiving neostigmine, by an average of 12 minutes ( P < 0.05)., Conclusions: Sugammadex patients had a significantly shorter PACU stay.

The sorption of poorly aqueous soluble active pharmaceutical ingredients (API) to mesoporous silica carriers is an increasingly common formulation strategy for dissolution rate enhancement for this challenging group of substances. However, the success of this approach for a particular API depends on an array of factors including the properties of the porous carrier, the loading method, or the attempted mass fraction of the API. At present, there is no established methodology for the rational selection of these parameters. In the present work, we report a systematic comparison of four well-characterised silica carriers and seven APIs loaded by the same solvent evaporation method. In each case, we find the maximum amorphization capacity by x-ray powder diffraction analysis and measure the in vitro drug release kinetics. For a selected case, we also demonstrate the potential for bioavailability enhancement by a permeation essay., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Lipid bilayers are the basic structural components of all living systems, forming the membranes of cells, sub-cellular organelles, and extracellular vesicles. A class of man-made lipidic vesicles called multilobed magnetic liposomes (MMLs) is reported in this work; these MMLs possess a previously unattained combination of features owing to their unique multilobe structure and composition. MMLs consist of a central cluster of lipid-coated magnetic iron oxide nanoparticles that lend them a magnetophoretic velocity comparable to the most efficient living microswimmers. Multiple liposome-like lobes protrude from the central region; these can incorporate both water-soluble and lipid-soluble molecular payloads at high carrying capacity and exchange the incorporated substances with the membranes of both artificial and live cells by the contact diffusion mechanism. The size of MMLs is controllable in the range of 200-800 nm. Their functionality is demonstrated by completing a model mission where MMLs are remotely controlled to collect, transport, and deliver a cargo to live cells.

Fully acetylated deoxyfluorinated hexosamine analogues and non-fluorinated 3,4,6-tri-O-acylated N-acetyl-hexosamine hemiacetals have previously been shown to display moderate anti-proliferative activity. We prepared a set of deoxyfluorinated GlcNAc and GalNAc hemiacetals that comprised both features: O-acylation at the non-anomeric positions with an acetyl, propionyl and butanoyl group, and deoxyfluorination at selected positions. Determination of the in vitro cytotoxicity towards the MDA-MB-231 breast cancer and HEK-293 cell lines showed that deoxyfluorination enhanced cytotoxicity in most analogues. Increasing the ester alkyl chain length had a variable effect on the cytotoxicity of fluoro analogues, which contrasted with non-fluorinated hemiacetals where butanoyl derivatives had always higher cytotoxicity than acetates. Reaction with 2-phenylethanethiol indicated that the recently described S-glyco-modification is an unlikely cause of cytotoxicity.

Background: Noninvasive monitoring of partial pressure of carbon dioxide can be accomplished indirectly with capnography (P ET CO 2 ) or with transcutaneous carbon dioxide monitoring (P TC CO 2 ). The use of capnography has been shown to offer an advantage over pulse oximetry alone in the early detection of adverse respiratory events when supplemental oxygen is administered. Furthermore, capnography allows for the monitoring of various respiratory measures, including end-tidal carbon dioxide, respiratory rate, tidal volume, and changes in breathing patterns. Transcutaneous CO 2 also closely approximates arterial CO 2 values, but is not as easy to monitor for prolonged periods. The purpose of this study was to examine the usefulness of capnography and of transcutaneous carbon dioxide monitoring in patients recovering from obesity surgery at high risk of developing postoperative obstructive sleep apnea., Methods: In a prospective observational study, 64 bariatric surgery patients at risk of developing obstructive sleep apnea were monitored in the postanesthesia care unit (PACU) with either capnography alone (31 patients) or capnography plus transcutaneous carbon dioxide monitoring (33 additional patients) every 3-5 minutes for the duration of their recovery. Primary endpoints included end-tidal and transcutaneous carbon dioxide, peripheral oxygen saturation, respiratory rate, pain scores, and incidence of adverse respiratory events., Results: Although no adverse pulmonary events were observed, capnography detected several patients who experienced short periods of respiratory apnea while maintaining pulse oximetry readings within normal limits. Transcutaneous values were slow to change and averaged 4.5 ± 5.5 mm Hg (P < .05) higher than corresponding end-tidal measurements., Conclusions: These results indicate the capabilities of both these noninvasive techniques for postoperative monitoring. Capnography acutely monitors changes in respiration, whereas transcutaneous monitoring more accurately reflects arterial CO 2 levels., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Diseases related to a disrupted skin barrier are accompanied by lower levels of ceramides in the stratum corneum (SC) lipid matrix. Delivering ceramides directly into damaged skin is a viable alternative to conventional corticosteroids, but is hindered by their low skin bioavailability and limited nanoformulation ability. Here, we developed stable liposomal systems containing ceramides and other SC lipids, and tested their effectiveness in skin barrier repair. Lipid film hydration and high-pressure homogenization were used to prepare different types of liposomes. To determine the stability, the particle size and polydispersity index were measured. The optimal systems were found to include ceramide 3 and 6, cholesterol and stearic acid, with 10% urea in phosphate-buffered saline as the aqueous phase. The ability of the system to repair chemically-damaged porcine skin was tested. While treatment by a standard lipid suspension reduced the passage of a model permeant only to a limited extent, drug flux through the liposomally-treated skin was much closer to permeation through intact skin. The non-homogenized liposomes were more effective than their homogenized version. These findings were also confirmed by FTIR measurements. This suggests that our approach to liposomal development has considerable potential for the repair of a disrupted skin barrier., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Massive transfusion protocols (MTPs) facilitate the organized delivery of blood components for traumatically injured patients. MTPs vary across institutions, and ratios of blood components can change during clinical management. As a result, significant amounts of components can be wasted. We completed a review of all MTP activations from 2015 to 2018, providing an in-depth analysis of waste in our single Level 1 trauma center. An interdepartmental group analyzed patterns of blood component wastage to guide three quality improvement initiatives. Specifically, we (1) completed a digital timeline for each MTP activation and termination, (2) improved communications between departments, and (3) provided yearly training for all personnel about MTP deployment. The analysis identified an association between delayed MTP deactivations and waste (RR = 1.48, CI 1.19-1.85, p = 0.0005). An overall improvement in waste was seen over the years, but this could not be attributed to increased closed-loop communication as determined by the proportion of non-stop activations (F(124,3) = 0.98, not significant). Delayed MTP deactivations are the primary determinant of blood component waste. Our proactive intervention on communications between groups was not sufficient in reducing the number of delayed deactivations. However, implementing a digital timeline and regular repetitive training yielded a significant reduction in wasted blood components.

Introduction While uncommon for cesarean delivery, general anesthesia may be patient requested or necessary due to maternal contraindication. Traditionally, opioids are used as a part of the general anesthetic. Because of their associated complications, it is standard to limit opioid use and fetal narcotic exposure during cesarean delivery. We conducted a retrospective study to evaluate the feasibility of multi-modal opioid-free general anesthesia for cesarean delivery. Methods Electronic medical records were obtained for patients receiving general anesthesia for cesarean delivery of live pregnancies through 2017 at our tertiary care facility. Post-operative pain was estimated using a 10-cm visual analogue scale and by calculating postoperative narcotic requirements in milligram morphine equivalents (MME) over three-time periods: during post-anesthesia recovery in the post-anesthesia care unit (PACU), the first 24 hrs after PACU discharge, and 24-48 hrs after PACU discharge. Apgar scores were also obtained to quantify neonatal effects of the general anesthetic. Results Eight of 17 patients (47.06%) received opioid-free anesthesia (OFA), and nine of 17 patients (52.94%) received anesthesia with opioids (OA). No significant difference was found between groups in terms of postoperative mean Visual Analog Scale (VAS) pain score over each time period. Similarly, no significant difference was found between groups in terms of postoperative narcotics requirement at all study points. Apgar scores were not significantly different between the two groups. Conclusion The OFA group displayed equivalent analgesia to the OA group in terms of self-reported VAS pain scores and postoperative MME. A larger prospective study is recommended to fully evaluate OFA for cesarean delivery., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Enten et al.)

Background: Recent studies suggest that left atrial (LA) late gadolinium enhancement (LGE) can quantify the underlying tissue remodeling that harbors atrial fibrillation (AF). However, quantification of LA-LGE requires labor-intensive magnetic resonance imaging acquisition and postprocessing at experienced centers. LA intra-atrial dyssynchrony assessment is an emerging imaging technique that predicts AF recurrence after catheter ablation. We hypothesized that 1) LA intra-atrial dyssynchrony is associated with LA-LGE in patients with AF and 2) LA intra-atrial dyssynchrony is greater in patients with persistent AF than in those with paroxysmal AF., Method: We conducted a cross-sectional study comparing LA intra-atrial dyssynchrony and LA-LGE in 146 patients with a history of AF (60.0 ± 10.0 years, 30.1% nonparoxysmal AF) who underwent pre-AF ablation cardiac magnetic resonance (CMR) in sinus rhythm. Using tissue-tracking CMR, we measured the LA longitudinal strain in two- and four-chamber views. We defined intra-atrial dyssynchrony as the standard deviation (SD) of the time to peak longitudinal strain (SD-TPS, in %) and the SD of the time to the peak pre-atrial contraction strain corrected by the cycle length (SD-TPSpreA, in %). We used the image intensity ratio (IIR) to quantify LA-LGE., Results: Intra-atrial dyssynchrony analysis took 5 ± 9 minutes per case. Multivariable analysis showed that LA intra-atrial dyssynchrony was independently associated with LA-LGE. In addition, LA intra-atrial dyssynchrony was significantly greater in patients with persistent AF than those with paroxysmal AF. In contrast, there was no significant difference in LA-LGE between patients with persistent and paroxysmal AF. LA intra-atrial dyssynchrony showed excellent reproducibility and its analysis was less time-consuming (5 ± 9 minutes) than the LA-LGE (60 ± 20 minutes)., Conclusion: LA Intra-atrial dyssynchrony is a quick and reproducible index that is independently associated with LA-LGE to reflect the underlying tissue remodeling.

Objectives: The purpose of this study was to evaluate the usefulness of intra-atrial dyssynchrony as a marker of underlying left atrial (LA) remodeling to predict recurrence after the first atrial fibrillation (AF) ablation., Background: Catheter ablation for AF remains far from curative with relatively high recurrence rates. One of the causes of recurrence is poor patient selection out of a diverse patient population with different degrees of LA remodeling., Methods: We included 208 patients with a history of AF (59.4 ± 10.0 years of age; 26.0% nonparoxysmal AF) referred for catheter ablation of AF who underwent pre-ablation cardiac magnetic resonance in sinus rhythm. Clinical follow-up was 20 ± 6 months. Using tissue tracking cardiac magnetic resonance, we measured the LA longitudinal strain in each of 12 equal-length segments in 2- and 4-chamber views. We defined intra-atrial dyssynchrony as the standard deviation of the time to the peak longitudinal strain corrected by the cycle length (SD-time to peak strain [TPS], %)., Results: Patients with AF recurrence after ablation (n = 101) had significantly higher SD-TPS than those without (n = 107; 3.9% vs. 2.2%; p < 0.001). Multivariable cox analysis showed that SD-TPS was associated with recurrence after adjusting for clinical risk factors, AF type, LA structure and function, and fibrosis (p < 0.001). Furthermore, receiver-operating characteristics analysis showed SD-TPS improved prediction of recurrence better than clinical risk factors, LA structure and function, and fibrosis., Conclusions: Intra-atrial dyssynchrony during sinus rhythm is an independent predictor of recurrence after the first catheter ablation of paroxysmal or persistent AF. Assessment of intra-atrial dyssynchrony may improve ablation outcomes by refining patient selection., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We present a 40 year old asymptomatic man with mild left main artery narrowing who demonstrated extreme discordance between symptom presentation and ischemic burden i.e. visual (angiographic) and ischemic (functional) mismatch. The use of an appropriately selected screening stress test can lead to an appropriate decision for revascularization, supported by landmark risk assessment documents and revascularization trials., (Published by Elsevier Inc.)

Background: Acute pulmonary vein (PV) reconnection predicts atrial fibrillation (AF) recurrence after ablation. Contact-force (CF) sensing catheters improve lesion delivery. We assessed the incidence, timing, location, and lesion characteristics of acute reconnection after PV isolation with CF sensing catheters., Methods: Patients undergoing radiofrequency ablation for AF from October 2016 to February 2017 were studied. Assessment for acute reconnection at 20 and 40 minute intervals was performed in each isolated PV. Additional lesions were applied as needed. Lesion location, contact force, power, duration, impedance, and force-time integral values were compared at sites with and without reconnection., Results: Twenty-two patients (60.6 + 1.8 years; 36.4% female; 27.3% persistent AF; CHA2DS2VASC 1.9 + 0.3) were included. Eighty-eight veins were isolated. Eleven reconnections occurred in 10 patients; 9 occurred by 20 minutes and 2 between 20 - 40 minutes. Most reconnections (6/11) were in the left superior PV. Of 4993 ablation points analyzed, 72 were at acute reconnection sites, and no differences in average contact force (11.4 + 8.1 vs 11.3 + 7.1 gm, p=0.868), power (29.7 + 3.9 vs 29.9 + 4.6 watts, p=0.620), impedance (64.1 + 60 vs 72.5 + 60, p=0.236) and the force time integral (86.9 + 78.8 vs 99.7 + 100 gm/sec, p=0.282) were found., Conclusion: Acute PV reconnection rates using CF sensing catheters are roughly 12.5%, with the majority occurring within 20 minutes. We found no significant differences in characteristics of ablation points in areas of reconnection. Optimum wait periods after isolation to check for acute reconnection may be as brief as 20 minutes.

Focal impulse and rotor mapping (FIRM) involves intracardiac detection and catheter ablation of re-entrant drivers (RDs), some of which may contribute to arrhythmia perpetuation in persistent atrial fibrillation (PsAF). Patient-specific computational models derived from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) has the potential to non-invasively identify all areas of the fibrotic substrate where RDs could potentially be sustained, including locations where RDs may not manifest during mapped AF episodes. The objective of this study was to carry out multi-modal assessment of the arrhythmogenic propensity of the fibrotic substrate in PsAF patients by comparing locations of RD-harboring regions found in simulations and detected by FIRM (RD sim and RD FIRM ) and analyze implications for ablation strategies predicated on targeting RDs. For 11 PsAF patients who underwent pre-procedure LGE-MRI and FIRM-guided ablation, we retrospectively simulated AF in individualized atrial models, with geometry and fibrosis distribution reconstructed from pre-ablation LGE-MRI scans, and identified RD sim sites. Regions harboring RD sim and RD FIRM were compared. RD sim were found in 38 atrial regions (median [inter-quartile range (IQR)] = 4 [3; 4] per model). RD FIRM were identified and subsequently ablated in 24 atrial regions (2 [1; 3] per patient), which was significantly fewer than the number of RD sim -harboring regions in corresponding models ( p < 0.05). Computational modeling predicted RD sim in 20 of 24 (83%) atrial regions identified as RD FIRM -harboring during clinical mapping. In a large number of cases, we uncovered RD sim -harboring regions in which RD FIRM were never observed (18/22 regions that differed between the two modalities; 82%); we termed such cases "latent" RD sim sites. During follow-up (230 [180; 326] days), AF recurrence occurred in 7/11 (64%) individuals. Interestingly, latent RD sim sites were observed in all seven computational models corresponding to patients who experienced recurrent AF (2 [2; 2] per patient); in contrast, latent RD sim sites were only discovered in two of four patients who were free from AF during follow-up (0.5 [0; 1.5] per patient; p < 0.05 vs. patients with AF recurrence). We conclude that substrate-based ablation based on computational modeling could improve outcomes.

Aims: We sought to evaluate the relationship between left atrial (LA) mechanical dyssynchrony and history of stroke or transient ischaemic attack (TIA) in patients with atrial fibrillation (AF). We hypothesized that mechanical dyssynchrony of the LA is associated with history of stroke/TIA independent of LA function and Cardiac failure, Hypertension, Age, Diabetes, Stroke/transient ischaemic attack (TIA), VAscular disease, and Sex category (CHA2DS2-VASc) score in patients with AF., Methods and Results: We conducted a cross-sectional study of 246 patients with a history of AF (59 ± 10 years, 29% female, 26% non-paroxysmal AF) referred for catheter ablation to treat drug-refractory AF who underwent preablation cardiac magnetic resonance (CMR) in sinus rhythm. Using tissue-tracking CMR, we measured the LA longitudinal strain and strain rate in each of 12 equal-length segments in two- and four-chamber views. We defined indices of LA mechanical dyssynchrony, including the standard deviation of the time to the peak longitudinal strain (SD-TPS). Patients with a prior history of stroke or TIA (n = 23) had significantly higher SD-TPS than those without (n = 223) (39.9 vs. 23.4 ms, P < 0.001). Multivariable analysis showed that SD-TPS was associated with stroke/TIA after adjusting for the CHA2DS2-VASc score, LA minimum index volume, and the peak LA longitudinal strain (P < 0.001). The receiver-operating characteristics curve showed that SD-TPS identified patients with stroke/TIA more accurately than CHA2DS2-VASc score alone (c-statistics: 0.82 vs. 0.75, P < 0.001)., Conclusion: Higher mechanical dyssynchrony of the LA during sinus rhythm is associated with a history of stroke/TIA in patients with AF.

Background: The extent of left atrial (LA) baseline low-voltage areas (LVA-B), which may be a surrogate for fibrosis, is associated with recurrent atrial fibrillation (AF) after ablation. This study aimed to assess the relationship between the extent of LVA-B isolated by ablation (LVA-I) and AF recurrence., Methods: The study cohort included 159 consecutive patients with drug-refractory AF who underwent an initial AF ablation with LA voltage mapping during sinus rhythm. The extent of LVA-B was quantified while excluding the pulmonary veins, LA appendage, and mitral valve area. LVA-I was quantified as the percentage of LVA-B encircled by pulmonary vein isolation. Surveillance and symptom-prompted electrocardiograms, Holter monitors, and event monitors were used to document atrial arrhythmia recurrence for a median follow-up of 712 days (1.95 years)., Results: Of 159 patients, 72% were men and 27% had persistent AF. The mean number of sampled bipolar voltage points was 119 ± 56. The mean LA surface area was 102.3 ± 37.3 cm 2 , and the mean LVA-B was 1.9 ± 3.8 cm 2 . The mean LVA-I was 51.05% ± 36.8% of LVA-B. In the multivariable Cox proportional hazards model adjusted for LA volume, CHA 2 DS 2 -VASc (Congestive Heart Failure, Hypertension, Age [≥ 75 years], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 years], Sex [Female] score), LVA-B, and AF type, LVA-I was inversely associated with recurrent atrial arrhythmia after the blanking period (hazard ratio, 0.42/percent LVA isolated; P = 0.037)., Conclusions: The extent of LVA-I is independently associated with freedom from atrial arrhythmias after AF ablation, supporting ongoing efforts to target low LA voltage areas and other fibrosis indicators to improve ablation outcomes., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The utility of rotor ablation using commercially available systems as an adjunct to pulmonary vein isolation (PVI) is controversial. Variable results may stem from heterogeneous practice patterns. We investigated whether a prespecified protocol to determine temperospatial rotor stability improved acute and intermediate outcomes following rotor ablation., Hypothesis: Protocolized rotor mapping and ablation, with prespecified metrics to determine temporal rotor stability prior to ablation, will improve short- and long-term PVI/rotor ablation outcomes., Methods: Patients undergoing PVI plus rotor ablation at Johns Hopkins during 2015 were included. The first cohort underwent rotor mapping and ablation at the operator's discretion, whereas the second cohort underwent protocolized rotor mapping, with ablation limited to temperospatially stable rotors. Both cohorts underwent PVI. Acute results (rotor elimination, atrial fibrillation [AF] termination), procedural data, and 1-year outcomes were assessed., Results: Twenty-seven patients underwent ablation (mean age, 64.4 ± 9 years, male 81.5%, persistent AF 85.2%, long-standing persistent AF 14.8%, mean AF duration 4.4 ± 4 years, repeat cases 51.8%, and mean LA size 4.6 ± 0.8 cm). In the protocolized cohort, rotors were reproducible in 83% (10/12) of cases in at least 1 chamber. Acute rhythm change was achieved in 8/27 (29.6%) patients. Sinus rhythm on presentation (62.5% vs 15.8%, P = 0.03) and higher total targeted rotors (3.8 ± 1.7 vs 2.5 ± 1.0, P = 0.02) predicted acute change. At 12 months, freedom from AF/atrial tachycardia was achieved in 5/15 (33.3%) patients in the first cohort and 5/11 patients in the protocolized cohort (45.5%; P = 0.53 for comparison)., Conclusions: Acute and intermediate results did not change with protocolized mapping designed to identify temperospatially stable rotors. Outcomes at 12 months were similar in both groups., (© 2017 Wiley Periodicals, Inc.)

Objectives: This study assessed trends in transesophageal echocardiography (TEE) use, rate of left atrial appendage (LAA) thrombus detection, and incidence of periprocedural cerebrovascular accident (CVA) since transitioning to a strategy of uninterrupted warfarin or briefly interrupted novel oral anticoagulant therapy in 2010., Background: TEE is routinely performed before ablation for atrial fibrillation (AF) to ensure absence of LAA thrombus., Methods: Patients with AF ablation presenting between January 2010 and September 2015 at Johns Hopkins Hospital were enrolled in an AF ablation registry; TEE and ablation outcomes were retrospectively analyzed. Presence of LAA thrombus, dense spontaneous echo contrast (SEC), or patent foramen ovale (PFO) were recorded. CVA incidence from procedure onset to 30 days post-procedure was evaluated using electronic medical record review., Results: Pre-procedure TEE was performed in 646 of 1,224 AF ablation cases (52.8%). There was a decline in pre-procedure TEE use from 86% in 2010 to 42% in 2015 (p < 0.001). CVA incidence was 4/1,224 (0.33%) cases, and did not change during the study period. TEE findings included LAA thrombus (n = 6; 0.93%), PFO (n = 23; 3.6%), and dense spontaneous echo contrast (n = 99; 15.3%). Both SEC and LAA thrombus were associated with persistent AF, higher CHA 2 DS 2 VASC score, increased LA size, reduced LAA flow velocity, and decreased left ventricular ejection fraction. PFO was not associated with prior AF ablation, and SEC was not associated with increased CVA incidence., Conclusions: CVA is a rare complication of AF ablation in patients with minimally interrupted anticoagulation. Pre-ablation TEE may be reasonably avoided in patients without high-risk features., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Complications from catheter ablation for atrial fibrillation (AF) are well described. Changing aspects of AF ablation including patient populations referred, institutional experience, and emerging catheter and pharmacological options may impact complication rates. We assessed procedural complication trends in AF ablation patients from 2003–2015 to identify what factors affect adverse event rates., Methods and Results: We evaluated consecutively enrolled patients undergoing initial AF ablation from 2003 through 2015. Statistical analyses were performed to identify predictors of increased risk for major complications, which were defined as death, stroke, atrio-oesophageal fistula, phrenic nerve injury, cardiovascular events requiring blood transfusions or procedural interventions, or non-cardiovascular events requiring intervention. A total of 1475 patients (mean age 59.5 ± 10.5, 82% male) were evaluated. Major complications occurred in 3.9% (n = 58) of cases, including vascular access-site haematoma (1.3%), cardiac tamponade (1.1%), and cerebrovascular accident (CVA) (0.9%). Univariate analysis revealed increased risk of complications associated with hypertension (P = 0.048), CHA2DS2VASc score ≥1 (P = 0.015), and early institutional experience (P = 0.003). Populations with higher CHA2DS2VASc scores underwent AF ablation more frequently over time (P < 0.001). Novel catheters and anticoagulants did not appreciably affect complication rates. Multivariate analysis adjusting for hypertension, CHA2DS2VASc score, and institutional experience showed that higher CHA2DS2VASc score and early institutional experience were independent predictors of adverse events., Conclusion: Patient characteristics reflected in CHA2DS2VASc scoring and early institutional experience predict increased complication rates following AF ablation. Despite more patients with higher CHA2DS2VASc scores undergoing AF ablation, complication rates fell over time as institutional experience increased.

Background: The classic method of mesh fixation in laparoscopic ventral hernia repair is transfascial sutures with tacks. This method has been associated with low recurrence rates, but yields significant morbidity from pain and bleeding. Fibrin glue has been used successfully in inguinal hernia repair with decreased incidence of chronic pain without an increase in recurrence rates, but its utility for laparoscopic ventral hernia repair is unknown. Our aim is to evaluate the efficacy of fibrin glue for laparoscopic mesh fixation to the anterior abdominal wall compared with other fixation methods., Methods: Four different laparoscopic mesh fixation methods were randomly assigned to midline positions along the abdominal wall of 12 female pigs and compared: (1) fibrin glue only (GO), (2) transfascial sutures with tacks (ST), (3) fibrin glue with tacks (GT), and (4) tacks only (TO). At 4 weeks post implantation, tensile strength, adhesions, migration, contraction, and buckling/folding were assessed using Kruskal-Wallis one-way analysis by ranks test., Results: There were no significant differences in tensile strength, adhesions or buckling/folding among the four fixation methods. A significant increase in mean migration (3.3 vs. 0.0 mm, p = 0.03) and percentage contraction (28% vs. 14%, p = 0.02) were identified in the GO group when compared with ST (see Table 3)., Conclusions: Mesh fixation using fibrin glue has comparable tensile strength and adhesion rate to sutures with tacks in the swine model. Increased contraction and migration rates associated with fibrin glue alone may be an issue and warrants further study. On the other hand, the GT group showed similar biomechanical characteristics to the other groups and may represent a reasonable alternative to the use of transfascial sutures.