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    Mechanisms of action behind the protective effects of proactive esophageal cooling during radiofrequency catheter ablation in the left atrium
    (Elsevier, 2024-06-20) González-Suárez, Ana
    Proactive esophageal cooling for the purpose of reducing the likelihood of ablation-related esophageal injury resulting from radiofrequency (RF) cardiac ablation procedures is increasingly being used and has been Food and Drug Administration cleared as a protective strategy during left atrial RF ablation for the treatment of atrial fibrillation. In this review, we examine the evidence supporting the use of proactive esophageal cooling and the potential mechanisms of action that reduce the likelihood of atrioesophageal fistula (AEF) formation. Although the pathophysiology behind AEF formation after thermal injury from RF ablation is not well studied, a robust literature on fistula formation in other conditions (eg, Crohn disease, cancer, and trauma) exists and the relationship to AEF formation is investigated in this review. Likewise, we examine the abundant data in the surgical literature on burn and thermal injury progression as well as the acute and chronic mitigating effects of cooling. We discuss the relationship of these data and maladaptive healing mechanisms to the well-recognized postablation pathophysiological effects after RF ablation. Finally, we review additional important considerations such as patient selection, clinical workflow, and implementation strategies for proactive esophageal cooling.
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    Mesenchymal stromal cells from people with osteoporosis are fewer, and defective in both osteogenic and adipogenic capacity
    (Open Exploration, 2024-06-03) Cassidy, Féaron C.; Shortiss, Ciara; Thompson, Kerry; Soriano Arroquia, Ana; Murphy, Colin G.; Kearns, Stephen R.; Curtin, William; Goljanek-Whysal, Katarzyna; O'Brien, Timothy; Coleman, Cynthia M.
    Introduction/Purpose: Osteoporosis is caused by imbalanced bone remodelling homeostasis. It is highly prevalent, especially in post-menopausal women, resulting in high risk of fracture and morbidity. MSCs are osteoblast progenitors, and orchestrate the function of surrounding cells including osteoblasts. Understanding MSC phenotype and function is therefore critical in discerning the aetiology of osteoporosis and developing superior therapies. Currently, adequate long-term therapeutic strategies are not available. Methods: Bioinformatic analysis of RNA-seq data revealed differential expression of genes primarily related to osteogenic differentiation and proliferation, followed by confirmatory in vitro analysis. Results: This study identified novel (P2RY6, AJAP1, ARHGAP32, EPHB6, TEP1, HAUS5, WAVE and Reelin) and previously proposed targets (PRKG1, EFNB2, c-Fos, OXTR, SMOC1, NPR3 and TEP1) for therapeutic intervention in osteoporosis. Functional assessment demonstrated reduced MSC number and osteogenic capacity associated with osteoporosis. Proliferation was not affected but osteoporosis was unexpectedly associated with a reduction in MSC adipogenic differentiation capacity, correlating with donor age. Conclusions: These data indicate specific targets for further studies of future treatments for osteoporosis, including the assessment of modified MSCs as therapeutics. Advances in this area may contribute to reducing fracture-associated morbidity and mortality, and improving quality of life for the 200 million people living with osteoporosis globally.
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    Difference between endocardial and epicardial application of pulsed fields for targeting Epicardial Ganglia: An in-silico modelling study
    (Elsevier, 2024-04-20) Estevez-Laborí, Francisco; O'Brien, Barry; González-Suárez, Ana; Science Foundation Ireland; Ministerio de Ciencia e Innovación; Universidad Internacional de Valencia-VIU
    Background Pulsed Field Ablation (PFA) has recently been proposed as a non-thermal energy to treat atrial fibrillation by selective ablation of ganglionated plexi (GP) embedded in epicardial fat. While some of PFA-technologies use an endocardial approach, others use epicardial access with promising pre-clinical results. However, as each technology uses a different and sometimes proprietary pulse application protocol, the comparation between endocardial vs. epicardial approach is almost impossible in experimental terms. For this reason, our study, based on a computational model, allows a direct comparison of electric field distribution and thermal-side effects of both approaches under equal conditions in terms of electrode design, pulse protocol and anatomical characteristics of the tissues involved. Methods 2D computational models with axial symmetry were built for endocardial and epicardial approaches. Atrial (1.5−2.5 mm) and fat (1−5 mm) thicknesses were varied to simulate a representative sample of what happens during PFA ablation for different applied voltage values (1000, 1500 and 2000 V) and number of pulses (30 and 50). Results The epicardial approach was superior for capturing greater volumes of fat when the applied voltage was increased: 231 mm3/kV with the epicardial approach vs. 182 mm3/kV with the endocardial approach. In relation to collateral damage to the myocardium, the epicardial approach considerably spares the myocardium, unlike what happens with the endocardial approach. Although the epicardial approach caused much more thermal damage in the fat, there is not a significant difference between the approaches in terms of size of thermal damage in the myocardium. Conclusions Our results suggest that epicardial PFA ablation of GPs is more effective than an endocardial approach. The proximity and directionality of the electric field deposited using an epicardial approach are key to ensuring that higher electric field strengths and increased temperatures are obtained within the epicardial fat, thus contributing to selective ablation of the GPs with minimal myocardial damage.
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    Proactive esophageal cooling during laser cardiac ablation: A computer modeling study
    (Wiley, 2024-03-04) Gomez Bustamante, Tatiana; Mercado Montoya, Marcela; Berjano, Enrique; González Suárez, Ana; Kulstad, Erik
    Background and Objectives Laser ablation is increasingly used to treat atrial fibrillation (AF). However, atrioesophageal injury remains a potentially serious complication. While proactive esophageal cooling (PEC) reduces esophageal injury during radiofrequency ablation, the effects of PEC during laser ablation have not previously been determined. We aimed to evaluate the protective effects of PEC during laser ablation of AF by means of a theoretical study based on computer modeling. Methods Three-dimensional mathematical models were built for 20 different cases including a fragment of atrial wall (myocardium), epicardial fat (adipose tissue), connective tissue, and esophageal wall. The esophagus was considered with and without PEC. Laser-tissue interaction was modeled using Beer¿Lambert's law, Pennes' Bioheat equation was used to compute the resultant heating, and the Arrhenius equation was used to estimate the fraction of tissue damage (FOD), assuming a threshold of 63% to assess induced necrosis. We modeled laser irradiation power of 8.5¿W over 20¿s. Thermal simulations extended up to 250¿s to account for thermal latency. Results PEC significantly altered the temperature distribution around the cooling device, resulting in lower temperatures (around 22°C less in the esophagus and 9°C in the atrial wall) compared to the case without PEC. This thermal reduction translated into the absence of transmural lesions in the esophagus. The esophagus was thermally damaged only in the cases without PEC and with a distance equal to or shorter than 3.5¿mm between the esophagus and endocardium (inner boundary of the atrial wall). Furthermore, PEC demonstrated minimal impact on the lesion created across the atrial wall, either in terms of maximum temperature or FOD. Conclusions PEC reduces the potential for esophageal injury without degrading the intended cardiac lesions for a variety of different tissue thicknesses. Thermal latency may influence lesion formation during laser ablation and may play a part in any collateral damage.
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    Full torso and limited-domain computer models for epicardial pulsed electric field ablation
    (Elsevier, 2022-05-18) González-Suárez, Ana; Irastorza, Ramiro M.; Deane, Stuart; O'Brien, Barry; O'Halloran, Martin; Elahi, Adnan
    Background and objectives Pulsed Electric Field (PEF) ablation has been proposed as a non-thermal energy to treat atrial fibrillation (AF) by ablation of ganglionated plexi using the epicardial approach. The electric field distribution at the target site (heart) and its surroundings has not yet been assessed previously, using epicardial ablation technique. Our objective was to develop computational models, incorporating the real anatomy of the heart and the patient's torso, to assess the electric field distribution when applying epicardial monopolar PEF. Methods A novel 3D realistic full torso model was built with the multi-electrode ablation device placed on the epicardium and a dispersive pad on the patient's back to evaluate the electric field distribution. The 400 V/cm isoline was used to estimate the â PEF-zoneâ . A 3D limited-domain model was also built including only the region of interest around the ablation device to assess its validity in comparison with the full torso model. Results The electrical field is mainly limited to the target site (PEF-zone with lengths of 25.79 to 29.00 mm, depths of 5.98â 7.02 mm and maximum widths of 8.75â 10.57 mm) and is practically negligible in adjacent organs (
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    In silico modelling to assess the electrical and thermal disturbance provoked by a metal intracoronary stent during epicardial pulsed electric field ablation
    (MDPI, 2022-12-14) González-Suárez, Ana; Pérez, Juan J.; O’Brien, Barry; Elahi, Adnan
    Background: Pulsed Electric Field (PEF) ablation has been recently proposed to ablate cardiac ganglionic plexi (GP) aimed to treat atrial fibrillation. The effect of metal intracoronary stents in the vicinity of the ablation electrode has not been yet assessed. Methods: A 2D numerical model was developed accounting for the different tissues involved in PEF ablation with an irrigated ablation device. A coronary artery (with and without a metal intracoronary stent) was considered near the ablation source (0.25 and 1 mm separation). The 1000 V/cm threshold was used to estimate the `PEF-zone¿. Results: The presence of the coronary artery (with or without stent) distorts the E-field distribution, creating hot spots (higher E-field values) in the front and rear of the artery, and cold spots (lower E-field values) on the sides of the artery. The value of the E-field inside the coronary artery is very low (~200 V/cm), and almost zero with a metal stent. Despite this distortion, the PEF-zone contour is almost identical with and without artery/stent, remaining almost completely confined within the fat layer in any case. The mentioned hot spots of E-field translate into a moderate temperature increase (
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    Pulsed electric field ablation of epicardial autonomic ganglia: Computer analysis of monopolar electric field across the tissues involved
    (MDPI, 2022-11-27) González-Suárez, Ana; O’Brien, Barry; O’Halloran, Martin; Elahi, Adnan
    Background and objectives: Pulsed Electric Field (PEF) ablation has been proposed as a non-thermal energy to treat atrial fibrillation (AF) by epicardial ablation of ganglionated plexi (GP), which are embedded within epicardial fat. Our objective was to study the distribution of the electric field through the involved tissues (fat, GPs, myocardium and blood) during epicardial PEF ablation. Methods: A two-dimensional model was built considering different tissue layers below the ablation device which consists of an irrigated electrode. The 1000 V/cm threshold was used to estimate the `PEF-zone¿. Results: The PEF-zone was almost 100% circumscribed in the epicardial fat layer, with very little incidence in the myocardium. The presence of the saline on the epicardial fat causes the PEF-zone to spread laterally around the electrode from ~5 mm to ~15 mm, relatively independently of how embedded the electrode is in the saline layer. For a saline layer well spread over the tissue surface and an electrode fully embedded in the saline layer, the PEF-zone width decreases as the fat layer thickens: from ~15 mm for fat thickness of 1 and 2 mm, down to ~10 mm for fat thickness of 5 mm. The presence of a GP in the center of the fat layer hardly affects the size of the PEF-zone, but significantly alters the distribution of the electric field around the GP, resulting in progressively lower values than in the surrounding adipose tissue as the fat layer thickness increased. Conclusions: Our results suggest how some procedural (irrigation) and anatomical parameters (fat thicknesses and presence of GPs) could be relevant in terms of the size of the tissue area affected by pulsed field ablation.
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    Disturbing effect of intra-tissue temperature sensors in pre-clinical experimental studies of radiofrequency cardiac ablation: A computer-based modeling study
    (MDPI, 2023-04-11) Cuenca-Dacal, Luis; Berjano, Enrique; González-Suárez, Ana; Pérez, Juan J.
    Background: Preclinical studies on radiofrequency (RF) cardiac ablation (RFCA) use very small temperature sensors in specific positions in the tissue subjected to RF heating. Despite the sensors¿ small size, the proximity to the ablation electrode and the extremely high thermal gradient around the electrode means that the presence of the temperature sensors could distort the temperatures recorded. Our objective was to assess the thermal impact of intra-tissue temperature sensors during RFCA. Methods: 3D RFCA models were built including different temperature sensors based on fiber optics and T-type thermocouples. Constant power ablation was simulated for 10 s. Results: The results showed that the disturbance caused by the presence of the T-type thermocouples was considerably greater (one order of magnitude) than that caused by the optical fibers. The closer the sensor was to the ablation electrode, the greater the greater the disturbance was and the more it increased with time in sensors more than 3 mm deep. The fiber optic measurements always slightly underestimated (
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    How intramyocardial fat can alter the electric field distribution during Pulsed Field Ablation (PFA): Qualitative findings from computer modeling
    (Public Library of Science, 2023-11-02) Pérez, Juan J.; González-Suárez, Ana
    Even though the preliminary experimental data suggests that cardiac Pulsed Field Ablation (PFA) could be superior to radiofrequency ablation (RFA) in terms of being able to ablate the viable myocardium separated from the catheter by collagen and fat, as yet there is no formal physical-based analysis that describes the process by which fat can affect the electric field distribution. Our objective was thus to determine the electrical impact of intramyocardial fat during PFA by means of computer modeling. Computer models were built considering a PFA 3.5-mm blunt-tip catheter in contact with a 7-mm ventricular wall (with and without a scar) and a 2-mm epicardial fat layer. High voltage was set to obtain delivered currents of 19, 22 and 25 A. An electric field value of 1000 V/cm was considered as the lethal threshold. We found that the presence of fibrotic tissue in the scar seems to have a similar impact on the electric field distribution and lesion size to that of healthy myocardium only. However, intramyocardial fat considerably alters the electrical field distribution and the resulting lesion shape. The electric field tends to peak in zones with fat, even away from the ablation electrode, so that â cold pointsâ (i.e. low electric fields) appear around the fat at the current entry and exit points, while â hot pointsâ (high electric fields) occur in the lateral areas of the fat zones. The results show that intramyocardial fat can alter the electric field distribution and lesion size during PFA due to its much lower electrical conductivity than that of myocardium and fibrotic tissue.
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    Low-frequency electrical conductivity of trabecular bone: Insights from in silico modeling
    (MDPI, 2023-09-23) Cervantes, María José; Basiuk, Lucas O.; González-Suárez, Ana; Carlevaro, C. Manuel; Irastorza, Ramiro M.; María José Cervantes
    Background: The electrical conductivity of trabecular bone at 100 kHz has recently been reported as a good predictor of bone volume fraction. However, quantifying its relationship with free water (or physiological solution) content and the conductivities of its constituents is still difficult. Methods: In this contribution, in silico models inspired by microCT images of trabecular bovine samples were used to build realistic geometries. The finite element method was applied to solve the electrical problem and to robustly fit the conductivity of the constituents to the literature data. The obtained effective electrical conductivity was compared with the Bruggeman three-medium mixture model using a physiological solution, bone marrow and a bone matrix. Results: The values for the physiological solution plus bone marrow (together as one material) and the bone matrix that best captured the bone volume fraction in the two-medium finite element model were ¿ps+bm=298.4 mS/m and ¿b=21.0 mS/m, respectively. Additionally, relatively good results were obtained with the three-medium Bruggeman mixture model, with ¿bm=103 mS/m, ¿b=21.0 mS/m and ¿ps=1200 mS/m. Simple linear relationships between the proportions of constituents depending on bone volume fraction were tested. Degree of anisotropy and fractal dimension do not show detectable changes in effective conductivity. Conclusions: These results provided some useful findings for simulation purposes. First, a higher value for the electrical conductivity of bone marrow has to be used in order to obtain similar values to those of experimental published data. Second, anisotropy is not detectable with conductivity measurements for small trabecular samples (5 mm cube). Finally, the simulations presented here showed relatively good fitting of the Bruggeman mixture model, which would potentially account for the free water content and could rescale the model for whole-bone electrical simulations.
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    Cardioneuroablation using epicardial pulsed field ablation for the treatment of atrial fibrillation
    (MDPI, 2023-05-29) O’Brien, Barry; Reilly, John; Coffey, Ken; González-Suárez, Ana; Quinlan, Leo; van Zyl, Martin
    Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting millions of people worldwide. The cardiac autonomic nervous system (ANS) is widely recognized as playing a key role in both the initiation and propagation of AF. This paper reviews the background and development of a unique cardioneuroablation technique for the modulation of the cardiac ANS as a potential treatment for AF. The treatment uses pulsed electric field energy to selectively electroporate ANS structures on the epicardial surface of the heart. Insights from in vitro studies and electric field models are presented as well as data from both pre-clinical and early clinical studies.
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    How far the zone of heat-induced transient block extends beyond the lesion during RF catheter cardiac ablation
    (Taylor and Francis Group, 2023-01-02) Pérez, Juan J.; Berjano, Enrique; González-Suárez, Ana
    Purpose While radiofrequency catheter ablation (RFCA) creates a lesion consisting of the tissue points subjected to lethal heating, the sublethal heating (SH) undergone by the surrounding tissue can cause transient electrophysiological block. The size of the zone of heat-induced transient block (HiTB) has not been quantified to date. Our objective was to use computer modeling to provide an initial estimate. Methods and materials We used previous experimental data together with the Arrhenius damage index (Ω) to fix the Ω values that delineate this zone: a lower limit of 0.1–0.4 and upper limit of 1.0 (lesion boundary). An RFCA computer model was used with different power-duration settings, catheter positions and electrode insertion depths, together with dispersion of the tissue’s electrical and thermal characteristics. Results The HiTB zone extends in depth to a minimum and maximum distance of 0.5 mm and 2 mm beyond the lesion limit, respectively, while its maximum width varies with the energy delivered, extending to a minimum of 0.6 mm and a maximum of 2.5 mm beyond the lesion, reaching 3.5 mm when high energy settings are used (25 W–20s, 500 J). The dispersion of the tissue’s thermal and electrical characteristics affects the size of the HiTB zone by ±0.3 mm in depth and ±0.5 mm in maximum width. Conclusions Our results suggest that the size of the zone of heat-induced transient block during RFCA could extend beyond the lesion limit by a maximum of 2 mm in depth and approximately 2.5 mm in width.
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    Analysis of thermal effects from pulsed field ablation
    (Oxford University Press, 2023-11-09) Mercado Montoya, Marcela; Gomez Bustamante, Tatiana; Kulstad, Erik; Mickelsen, Steven R.; González Suárez, Ana; European Heart Journal, Volume 44, Issue Supplement_2, November 2023, ehad655.381
    Background Pulsed field ablation (PFA) has been described as non-thermal, but abundant data exist in oncology applications [1-3], and growing data are emerging in cardiology [4], highlighting that thermal effects are in fact present with PFA. The particular parameters (such as voltage, pulse gap, pulse number) that most influence the development of thermal energy during PFA are less clear. Purpose We sought to evaluate the thermal effects arising from pulsed field ablation of myocardial and esophageal tissue over a range of typical peak voltage operating conditions. Methods Using a three-dimensional computer model of the left atrium and esophagus, we quantified the thermal effects from PFA applications over a range of peak voltage operating conditions (1 kV, 1.5 kV, and 2 kV). Bipolar electroporation was simulated using one electrode as the anode and the other as a grounded cathode. Far-field and symmetry boundaries were set as electrically insulating. A monophasic waveform with a pulse duration of 100 µs and pause between pulses of 1 s was applied for a total of 50 pulses in a single train. Myocardial thickness was 1.5 mm, esophageal thickness was 2 mm, and the pericardial fat layer was varied between 0.3 and 0.75 mm. Results Minimal temperature rise in the esophagus was seen with 1 kV pulses (corresponding to 13.4 J input). With 1.5 kV and 2 kV peak voltages (corresponding to 32.3 J and 66.2 J), temperature elevations reaching 46.3 °C and > 62 °C were seen, respectively. These elevations occurred after only a single pulse train of 50 pulses, implying that further elevations in temperature would be seen with subsequent applications. Conclusions Thermal effects from PFA depend on total energy deposited, of which peak voltage is an important component. Current commercially available systems appear to have the potential to induce collateral thermal injury, particularly with a thin pericardial fat layer, and with repeated applications of pulsed field energy.
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    Impact of ultra-short pauses between stacked lesions with and without active esophageal cooling
    (Oxford University Press, 2023-05-24) Mercado Montoya, Marcela; Gomez Bustamante, Tatiana; Berjano, Enrique; Mickelsen, Steven R.; Hernandez Arango, Pablo; González Suárez, Ana; Schieber, Jay; Kulstad, Erik; Daniels, James D.; EP Europace, Volume 25, Issue Supplement_1, June 2023, euad122.717
    Background Placing lesions at the same point (stacking lesions) in the left atrium during radiofrequency (RF) ablation can increase the risk of collateral injury. The use of active esophageal cooling has been shown to significantly reduce the risk of thermal injury to the esophagus, but stacking of lesions may overcome these protective effects. Longer pauses between lesions may reduce this risk, but the effect of very short pauses has not been previously quantified. Purpose To examine the impact of ultra-short pauses between stacked lesions with and without active esophageal cooling. Methods Using a computational model of the left atrium, we measured the effect of RF ablation in the left atrium on injury formation in the esophagus. Models with and without active esophageal cooling, using a dedicated esophageal cooling device, were created. Using a power of 50 W for 10 s, with up to 3 sequential lesions placed in the same location, we used the Arrhenius equation to quantify the fraction of damage (FOD) in the esophageal wall. The time between lesions was set to as short as 1 s, and results were compared to prior studies using longer pauses of up to 20 s. To account for thermal latency, measures of esophageal damage were taken both immediately after RF ablation, and again 90 s afterwards. Results With active cooling in place, esophageal injury was eliminated with active esophageal cooling after the first lesion placement, but reached 21% transmurality without cooling. Lesion transmurality increased after each lesion due to thermal latency, but active esophageal cooling prevented this effect when only one lesion was placed. Subsequent lesions resulted in esophageal injury when placed in the same location. After 3 lesions with 1 s pauses between each, esophageal injury transmurality reached 91% without cooling in place, and 22% with active cooling in place (Figure 1). In contrast, analysis of the intended lesions in the atrial wall demonstrated minimal effects from cooling (Figure 2). Conclusions Active esophageal cooling significantly reduces esophageal injury from RF ablation, but placing additional lesions at the same point can overcome the heat extraction capacity of a dedicated cooling device. Decreased time between lesions exacerbates this risk, with an ultra-short pause of one second posing the greatest risk.
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    Epicardial pulsed field ablation of ganglionated plexi: Computational and pre-clinical evaluation of a bipolar sub-xiphoid catheter for the treatment of atrial fibrillation
    (MDPI, 2023-12-24) O’Brien, Barry; Reilly, John; Coffey, Ken; González-Suárez, Ana; Buchta, Piotr; Buszman, Piotr P.; Lukasik, Karolina; Tri, Jason; van Zyl, Martin; Asirvatham, Samuel; Science Foundation Ireland
    Epicardial pulsed field ablation (PFA) of ganglionated plexi (GPs) is being explored as a potential treatment for atrial fibrillation. Initial work using open-chest access with a monopolar ablation device has been completed. This study describes the early development work for a device that can be used with subxiphoid access and deliver bipolar ablation pulses. Electric field computational models have been used for the initial guidance on pulse parameters. An in vivo assessment of these ablation parameters has been performed in an open-chest canine study, while subxiphoid access and navigation of the device has been demonstrated in a porcine model. Results from this acute study have demonstrated the promising potential of this approach.
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    The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD)
    (Oxford University Press, 2023-05-15) Allen, Nicholas M.; O’Rahelly, Mark; Eymard, Bruno; Chouchane, Mondher; Hahn, Andreas; Kearns, Gerry; Kim, Dae-Seong; Byun, Shin Yun; Nguyen, Cam-Tu Emilie; Schara-Schmidt, Ulrike; Kölbel, Heike; Marina, Adela Della; Schneider-Gold, Christiane; Roefke, Kathryn; Thieme, Andrea; Van den Bergh, Peter; Avalos, Gloria; Álvarez-Velasco, Rodrigo; Natera-de Benito, Daniel; Cheng, Man Hin Mark; Chan, Wing Ki; Wan, Hoi Shan; Thomas, Mary Ann; Borch, Lauren; Lauzon, Julie; Kornblum, Cornelia; Reimann, Jens; Mueller, Andreas; Kuntzer, Thierry; Norwood, Fiona; Ramdas, Sithara; Jacobson, Leslie W.; Jie, Xiaobo; Fernandez-Garcia, Miguel A.; Wraige, Elizabeth; Lim, Ming; Lin, Jean Pierre; Claeys, Kristl G.; Aktas, Selma; Oskoui, Maryam; Hacohen, Yael; Masud, Ameneh; Leite, M Isabel; Palace, Jacqueline; De Vivo, Darryl; Vincent, Angela; Jungbluth, Heinz
    In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose ‘fetal acetylcholine receptor antibody-related disorders’ (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.
  • Publication
    Immunomodulatory function of licensed human bone marrow mesenchymal stromal cell-derived apoptotic bodies
    (Elsevier, 2023-10-23) Wang, Jiemin; Donohoe, Ellen; Canning, Aoife; Moosavizadeh, Seyedmohammad; Buckley, Fiona; Brennan, Meadhbh Á.; Ryan, Aideen E.; Ritter, Thomas; China Scholarship Council; Science Foundation Ireland; Engineering and Physical Sciences Research Council; European Regional Development Fund; Horizon 2020; College of Medicine, Nursing and Health Sciences, University of Galway
    Background Mesenchymal stromal cells (MSCs) show great potential for immunomodulatory and anti-inflammatory treatments. Clinical trials have been performed for the treatment of Type 1 diabetes, graft-versus-host disease and organ transplantation, which offer a promise of MSCs as an immunomodulatory therapy. Nevertheless, their unstable efficacy and immunogenicity concerns present challenges to clinical translation. It has emerged that the MSC-derived secretome, which includes secreted proteins, exosomes, apoptotic bodies (ABs) and other macromolecules, may have similar therapeutic effects to parent MSCs. Among all of the components of the MSC-derived secretome, most interest thus far has been garnered by exosomes for their therapeutic potential. However, since MSCs were reported to undergo apoptosis after in vivo transplantation and release ABs, we speculated as to whether ABs have immunomodulatory effects. In this study, cytokine licensing was used to enhance the immunomodulatory potency of MSCs and ABs derived from licensed MSCs in vitro were isolated to explore their immunomodulatory effects as an effective non-viable cell therapy. Results IFN-γ and IFN-γ/TGF-β1 licensing enhanced the immunomodulatory effect of MSCs on T cell proliferation. Further, TGF-β1 and IFN-γ licensing strengthened the immunomodulatory effect of MSC on reducing the TNF-α and IL-1β expression by M1 macrophage-like THP-1 cells. Additionally, we discovered the immunomodulatory effect mediated by MSC-derived apoptotic bodies. Licensing impacted the uptake of ABs by recipient immune cells and importantly altered their phenotypes. Conclusion ABs derived from IFN-γ/TGF-β1-licensed apoptotic MSCs significantly inhibited T cell proliferation, induced more regulatory T cells, and maintained immunomodulatory T cells but reduced pro-inflammatory T cells.
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    Artificial cornea: Past, current, and future directions
    (Frontiers Media, 2021-11-12) Holland, Gráinne; Pandit, Abhay; Sánchez-Abella, Laura; Haiek, Andrea; Loinaz, Iraida; Dupin, Damien; Gonzalez, Maria; Larra, Eva; Bidaguren, Aritz; Lagali, Neil; Moloney, Elizabeth B.; Ritter, Thomas; Horizon 2020; Science Foundation Ireland; European Regional Development Fund
    Corneal diseases are a leading cause of blindness with an estimated 10 million patients diagnosed with bilateral corneal blindness worldwide. Corneal transplantation is highly successful in low-risk patients with corneal blindness but often fails those with high-risk indications such as recurrent or chronic inflammatory disorders, history of glaucoma and herpetic infections, and those with neovascularisation of the host bed. Moreover, the need for donor corneas greatly exceeds the supply, especially in disadvantaged countries. Therefore, artificial and bio-mimetic corneas have been investigated for patients with indications that result in keratoplasty failure. Two long-lasting keratoprostheses with different indications, the Boston type-1 keratoprostheses and osteo-odonto-keratoprostheses have been adapted to minimise complications that have arisen over time. However, both utilise either autologous tissue or an allograft cornea to increase biointegration. To step away from the need for donor material, synthetic keratoprostheses with soft skirts have been introduced to increase biointegration between the device and native tissue. The AlphaCor¿, a synthetic polymer (PHEMA) hydrogel, addressed certain complications of the previous versions of keratoprostheses but resulted in stromal melting and optic deposition. Efforts are being made towards creating synthetic keratoprostheses that emulate native corneas by the inclusion of biomolecules that support enhanced biointegration of the implant while reducing stromal melting and optic deposition. The field continues to shift towards more advanced bioengineering approaches to form replacement corneas. Certain biomolecules such as collagen are being investigated to create corneal substitutes, which can be used as the basis for bio-inks in 3D corneal bioprinting. Alternatively, decellularised corneas from mammalian sources have shown potential in replicating both the corneal composition and fibril architecture. This review will discuss the limitations of keratoplasty, milestones in the history of artificial corneal development, advancements in current artificial corneas, and future possibilities in this field.
  • Publication
    A longitudinal survey of antibiotic-resistant enterobacterales in the Irish environment, 2019–2020
    (Elsevier, 2022-03-17) Hooban, Brigid; Fitzhenry, Kelly; O'Connor, Louise; Miliotis, Georgios; Joyce, Aoife; Chueiri, Alexandra; Farrell, Maeve Louise; DeLappe, Niall; Tuohy, Alma; Cormican, Martin; Morris, Dearbháile; Environmental Protection Agency; Health Service Executive; Horizon 2020
    The natural environment represents a complex reservoir of antibiotic-resistant bacteria as a consequence of different wastewater discharges including anthropogenic and agricultural. Therefore, the aim of this study was to examine sewage and waters across Ireland for the presence of antibiotic-resistant Enterobacterales. Samples were collected from the West, East and South of Ireland. Two periods of sampling took place between July 2019 and November 2020, during which 118 water (30 L) and 36 sewage samples (200 mL) were collected. Waters were filtered using the CapE method, followed by enrichment and culturing. Sewage samples were directly cultured on selective agars. Isolates were identified by MALDI-TOF and antibiotic susceptibility testing was performed in accordance with EUCAST criteria. Selected isolates were examined for blaCTX-M, blaVIM, blaIMP, blaOXA-48, blaNDM, and blaKPC by real time PCR and whole genome sequencing (n = 146). A total of 419 Enterobacterales (348 water, 71 sewage) were isolated from all samples. Hospital sewage isolates displayed the highest percentage resistance to many beta-lactam and aminoglycoside antibiotics. Extended-spectrum beta-lactamase-producers were identified in 78% of water and 50% of sewage samples. One or more carbapenemase-producing Enterobacterales were identified at 23 individual sampling sites (18 water, 5 sewage). This included the detection of blaOXA-48 (n = 18), blaNDM (n = 14), blaKPC (n = 4) and blaOXA-484 (n = 1). All NDM-producing isolates harbored the ble-MBL bleomycin resistance gene. Commonly detected sequence types included Klebsiella ST323, ST17, and ST405 as well as E. coli ST131, ST38 and ST10. Core genome MLST comparisons detected identical E. coli isolates from wastewater treatment plant (WWTP) influent and nursing home sewage, and the surrounding waters. Similarly, one Klebsiella pneumoniae isolated from WWTP influent and the surrounding estuarine water were identical. These results highlight the need for regular monitoring of the aquatic environment for the presence of antibiotic-resistant organisms to adequately inform public health policies.
  • Publication
    Experience-based learning: how a crisis solution informed fundamental change in a clinical education curriculum
    (Wiley, 2021-11-28) Costello, Maria; Cantillon, Peter; Geoghegan, Rosemary; Byrne, Dara; Lowery, Aoife; Walsh, Sinead M.
    Background Clinical education represents the most important formative period in undergraduate medical education. It is often criticised as haphazard and inefficient. Experience-based learning (ExBL) is a novel clinical education design that utilises practices of support, learner participation and real patient learning to enhance students' development of vital professional capabilities. We introduced ExBL to address the challenges of a 50% reduction in clinical placement time that arose during the COVID-19 pandemic. Approach Final year medical students were assimilated into clinical teams as co-workers to facilitate learning through participation rather than observation. Placement education was supported by an integrated case-based learning and high-fidelity simulation program. Real patient learning in workplace contexts was supported by a network of clinician mentors. Evaluation A qualitative evaluation revealed that granting students co-worker status strongly supported participatory learning and professional identity formation. Furthermore, the triangulation of placements with cognitive coaching and high-fidelity simulation greatly enhanced skills development and students' sense of readiness for practice. Implications Utilisation of ExBL significantly enhanced the quality of informal learning on clinical placements despite the reduced clinical placement time. In addition, the integration of cognitive coaching with simulation opportunities meant students were better prepared for meaningful participation as members of clinical teams. The introduction of ExBL increased the workload of clinical teachers. Moreover, favouring learning through participatory experience reduced exposure to more traditional formal bedside teaching encounters. Despite these challenges, we have adopted an ExBL model created in a crisis as our core educational design for our final year clinical programme.