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Introduction The global COVID-19 vaccine rollout has been impacted by socioeconomic disparities and vaccine hesitancy, but few studies examine reasons for changed attitudes. In Lao People’s Democratic Republic (Lao PDR), a nationwide government-led initiative was developed in response to COVID-19, focused on community health ownership and trust in primary healthcare. The intervention team including health and governance sectors conducted capacity-building workshops with local staff and community representatives and visited villages for vaccination outreach. This study investigates the impact of this intervention on COVID-19 vaccine acceptance in rural communities.Methods Conducted in Xiengkhuang province, Lao PDR, from December 2022 to February 2023, the study employed a sequential mixed-methods research design. Data on vaccinated individuals from 25 villages were collected from 11 primary healthcare units; pre-post analysis was applied. Qualitative data, gathered through interviews and focus group discussions with villagers, village authorities, health staff and local government (n=102) in six villages, underwent inductive thematic analysis.Results First-dose vaccine uptake after the intervention increased significantly (6.9 times). Qualitative analysis identified key reasons for vaccination hesitancy: (1) mistrust due to rumours and past experiences; (2) poor communication and inconsistent messaging and (3) challenges in access for priority groups. Influencing factors during the intervention included (1) effective local-context communication; (2) leveraging existing community structures and influential individuals in a multisectoral approach and (3) increased community motivation through improved satisfaction, ownership and relationships.Conclusion This study highlights the impact and methods of building trust with unreached populations in health interventions, emphasising locally led solutions. Successful reversal of vaccine hesitancy was achieved by addressing root causes and fostering ownership at community and local government levels through a ‘positive approach’. This diverges from conventional supplemental immunisation activities and holds potential for systematically building trust between unreached populations and health systems. Further research could explore the impacts of routine vaccination for sustained improvements in health equity.

Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.

Background and aimsRight phrenic nerve palsy is the most frequent complication of cryoballoon procedures. The SMARTFREEZE™ console (Boston Scientific, St. Paul, MN, USA) has integrated a new tool for diaphragm monitoring—the Diaphragm Movement Sensor; however, it has not been evaluated in clinical practice. We aimed to assess the diagnostic performance of the Diaphragm Movement Sensor based on compound motor action potential data recorded simultaneously.MethodsThirty consecutive patients (mean age 63.2 ± 10.2 years) were included. We simultaneously recorded the compound motor action potential and the Diaphragm Movement Sensor during cryoapplications in the right pulmonary veins. The right phrenic nerve was paced at 60 per minute, 12 V and 2.9 ms. Compound motor action potential monitoring with a 30% decrease cutoff for the diagnosis of phrenic nerve threatening was considered the gold standard. The Diaphragm Movement Sensor decrease threshold was also set at 30%.ResultsConsidering compound motor action potential monitoring, phrenic nerve threatening occurred 11 times (in seven patients) among 84 cryoapplications (13.1%) at the right pulmonary veins. The sensitivity and specificity of the Diaphragm Movement Sensor were, respectively, 33% (95% CI: 7%–70%) and 49% (95% CI: 38%–61%; P

Abstract The Central Andes of Peru are a region of great concern regarding pesticide risk to the health of local communities. Therefore, we conducted an observational study to assess the level of pesticide contamination among Andean people. Analytical chemistry methods were used to measure the concentrations of 170 pesticide-related compounds in hair samples from 50 adult Andean subjects living in rural and urban areas. As part of the study, a questionnaire was administered to the subjects to collect information regarding factors that increase the risk of pesticide exposure. Our results indicate that Andean people are strongly exposed to agrochemicals, being contaminated with a wide array of pesticide-related compounds at high concentration levels. Multivariate analyses and geostatistical modeling identified sociodemographic factors associated with rurality and food origin that increase pesticide exposure risk. The present study represents the first comprehensive investigation of pesticide-related compounds detected in body samples collected from people living in the Central Andes of Peru. Our findings pinpoint an alarming environmental situation that threatens human health in the region and provide a rationale for improving public policies to protect local communities.

Backgroundwhile the duration of dual antiplatelet therapy (DAPT) following coronary angioplasty for chronic coronary syndrome (CCS) recommended by the European Society of Cardiology has decreased over the last decade, little is known about the adherence to those guidelines in clinical practice in France.AimTo analyze the real duration of DAPT post coronary angioplasty in CCS, as well as the factors affecting this duration.MethodsBetween 2014 and 2019, 8.836 percutaneous coronary interventions for CCS from the France-PCI registry were evaluated, with 1 year follow up, after exclusion of patients receiving oral anticoagulants, procedures performed within one year of an acute coronary syndrome, and repeat angioplasty.ResultsPost-percutaneous coronary intervention (PCI) DAPT duration was > 12 months for 53.1% of patients treated for CCS; 30.5% had a DAPT between 7 and 12 months, and 16.4% a DAPT ≤ 6 months. Patients with L-DAPT (>12 months) were at higher ischemic risk [25.0% of DAPT score ≥2 vs. 18.8% DAPT score ≥2 in S&I-DAPT group (≤12 months)]. The most commonly used P2Y12 inhibitor was clopidogrel (82.2%). The prescription of ticagrelor increased over the period.Conclusionspost-PCI DAPT duration in CCS was higher than international recommendations in the France PCI registry between 2014 and 2019. More than half of the angioplasty performed for CCS are followed by a DAPT > 12 months. Ischemic risk assessment influences the duration of DAPT. This risk is probably overestimated nowadays, leading to a prolongation of DAPT beyond the recommended durations, thus increasing the bleeding risk.

Entre las neoplasias malignas más frecuentes del mundo, el carcinoma hepatocelular (CHC) es la segunda causa de muerte relacionada con el cáncer (1). Su incidencia se ha duplicado durante las dos últimas décadas y la mayor carga se produce en los países de ingresos bajos y medianos. Los tumores hepáticos primarios malignos suelen describirse como una patología que afecta principalmente a hombres mayores de 40 años con un hígado cirrótico; rara vez se han registrado en personas más jóvenes y normalmente, en menores de 40, lo más común es el hepatoblastoma.

BackgroundThere is no clear guidance on how to implement opportunistic atrial fibrillation (AF) screening in daily clinical practice.ObjectivesThis study evaluated the perception of general practitioners (GPs) about value and practicalities of implementing screening for AF, focusing on opportunistic single-time point screening with a single-lead electrocardiogram (ECG) device.MethodsA descriptive cross-sectional study was conducted with a survey developed to assess overall perception concerning AF screening, feasibility of opportunistic single-lead ECG screening and implementation requirements and barriers.ResultsA total of 659 responses were collected (36.1% Eastern, 33.4% Western, 12.1% Southern, 10.0% Northern Europe, 8.3% United Kingdom & Ireland). The perceived need for standardized AF screening was rated as 82.7 on a scale from 0 to 100. The vast majority (88.0%) indicated no AF screening program is established in their region. Three out of four GPs (72.1%, lowest in Eastern and Southern Europe) were equipped with a 12-lead ECG, while a single-lead ECG was less common (10.8%, highest in United Kingdom & Ireland). Three in five GPs (59.3%) feel confident ruling out AF on a single-lead ECG strip. Assistance through more education (28.7%) and a tele-healthcare service offering advice on ambiguous tracings (25.2%) would be helpful. Preferred strategies to overcome barriers like insufficient (qualified) staff, included integrating AF screening with other healthcare programs (24.9%) and algorithms to identify patients most suitable for AF screening (24.3%).ConclusionGPs perceive a strong need for a standardized AF screening approach. Additional resources may be required to have it widely adopted into clinical practice.

The mahouts and the elephants of Thongmyxay district in Laos form an original hybrid community composed of humans and an animal species represented by both wild and domestic animals (elephants). We investigated in particular the interactions between mahouts' observation of elephants and their own medicinal practices (human and ethnoveterinary), which have been the subject of two previous publications. Based on this material, supplemented by data collected on the status of domestic village elephants and interviews with four local healers, we discuss here with a multispecies approach combining ethnographic data and ethological knowledge, the modalities of construction and possible exchanges of medicinal knowledge between the two species. Elephants have a status characterised by a double hybridity: wild and domestic on the one hand (with ontological circulations from one state to the other), and animal and human on the other. The part of humanity attributed to the elephants is reflected in particular in the self-agency that is recognised in their ability to heal themselves when they are suffering, which leads to the therapeutic use of their dung by Mahouts. The mahouts include in their ethnoveterinary care of the elephants plants that they see the elephants use when they are ill. The medicinal uses they make of some of these plants in their households are more consistent with their observations of these elephant behaviours than it is with the use of the same items by local healers, suggesting a transfer of medicinal knowledge from elephants to mahouts.Since some of the village elephants in Thongmyxay are still periodically released and come into contact with their wild counterparts, the domestication space forms an interface between humans, wild elephants and the forest, and we discuss conversely the possibility of knowledge transfer from mahouts to village elephants through the ethnoveterinary care they receive.This knowledge which is precious for the health and well-being of people and elephants in Laos is threatened by the reduction of the forest cover sheltering the resources used, and by the relocation of village elephants to tourist centres. Thus, emerges the need to think the conservation of the intangible heritage represented by the knowledge of hybrid communities in terms of interspecific heritage, implying that along with the preservation of the ecosystems that host the resources involved in this knowledge, care must be taken to maintain their access to all the populations (human and animal) that use them.

The mahouts and the elephants of Thongmyxay district in Laos form an original hybrid community composed of humans and an animal species represented by both wild and domestic animals (elephants). We investigated in particular the interactions between mahouts' observation of elephants and their own medicinal practices (human and ethnoveterinary), which have been the subject of two previous publications. Based on this material, supplemented by data collected on the status of domestic village elephants and interviews with four local healers, we discuss here with a multispecies approach combining ethnographic data and ethological knowledge, the modalities of construction and possible exchanges of medicinal knowledge between the two species.Elephants have a status characterised by a double hybridity: wild and domestic on the one hand (with ontological circulations from one state to the other), and animal and human on the other. The part of humanity attributed to the elephants is reflected in particular in the self-agency that is recognised in their ability to heal themselves when they are suffering, which leads to the therapeutic use of their dung by Mahouts. The mahouts include in their ethnoveterinary care of the elephants plants that they see the elephants use when they are ill. The medicinal uses they make of some of these plants in their households are more consistent with their observations of these elephant behaviours than it is with the use of the same items by local healers, suggesting a transfer of medicinal knowledge from elephants to mahouts.Since some of the village elephants in Thongmyxay are still periodically released and come into contact with their wild counterparts, the domestication space forms an interface between humans, wild elephants and the forest, and we discuss conversely the possibility of knowledge transfer from mahouts to village elephants through the ethnoveterinary care they receive.This knowledge which is precious for the health and well-being of people and elephants in Laos is threatened by the reduction of the forest cover sheltering the resources used, and by the relocation of village elephants to tourist centres. Thus, emerges the need to think the conservation of the intangible heritage represented by the knowledge of hybrid communities in terms of interspecific heritage, implying that along with the preservation of the ecosystems that host the resources involved in this knowledge, care must be taken to maintain their access to all the populations (human and animal) that use them.

Aims: Electrophysiological study (EPS) is recommended in case of new-onset persistent left bundle branch block (NOP-LBBB) after transaortic valve implantation (TAVI) to identify patients at high risk of delayed atrioventricular block (D-AVB). We evaluated the added value of drug challenge, after normal baseline EPS, to predict D-AVB in such patients. Methods: We conducted a comparative single-centre study of two successive periods, during which we used baseline EPS alone (first period) or drug challenge in case of normal baseline EPS (second period), for patients with NOP-LBBB after TAVI. The primary endpoint was a composite of pacemaker use, documented D-AVB, cardiac syncope, sudden death, or delayed pacemaker implantation. Results: Among 736 patients with TAVI implantation between January 2016 and September 2019, 64 with NOP-LBBB were included. During the first period, 4/22 (18.2%) presented with a positive baseline EPS. After a mean (standard deviation [SD]) of 15.6 (8.3) months, 7/22 (31.8%) reached the primary endpoint. During the second period, 19/42 (45.2%) presented with a positive EPS. After a mean (SD) of 12.8 (3.5) months, 8/42 (19.0%) reached the primary endpoint. There was a tendency to increased sensitivity (42.9–87.5%; P = 0.12) and negative predictive value (77.8–95.7%; P = 0.15) of the EPS, respectively during the first to the second period. However, the specificity decreased (93.3–64.7%; P = 0.04). Conclusion: Diagnostic yield improved with drug challenge in case of normal baseline EPS. However, the decrease in specificity led to a high rate of unnecessary pacemaker implantation.

Abstract Background Despite a widespread aversion towards faeces and urine, animal excreta are used in traditional medicine in many countries since centuries, but records are scattered and few therapeutic uses have been accurately documented while in the current context of emerging zoonoses such records may be of major interest. Methodology In this study, we investigated the therapeutic uses that mahouts in Xayaboury province, Lao PDR make of elephant urine and faeces as well as of the brood chamber that beetles (Heliocopris dominus) fashion from elephant dung. Semi-structured interviews were conducted with mahouts on elephant diet, health problems and responses to disease, andwhether they use elephant products. Data were supplemented by interviews with traditional healers. Results Seven respondents reported the use of elephant urine in ethnoveterinary care for elephants and in human medicine in case of diabetes and otitis. 25 respondents reported therapeutic use of elephant faeces (EF) and elephant dung beetle brood chambers. The major indications are gastrointestinal and skin problems. Macerations or decoctions are drunk or used externally as a lotion. The mahouts attribute the therapeutic effectiveness of EFs to their content which includes the remains of many species from the elephant diet which they consider to be medicinal. Discussion The indications of these uses are consistent with pharmacological and clinical studies highlighting the properties of different animals’ urine and faeces and their curative potential tested in vivo. The acknowledgement by the mahouts of medicinal properties of elephant faecal bolus contrasts with the rare justifications of animal material use recorded in zootherapeutic studies, which falls within the symbolic domain. However, numerous studies highlight the preponderant role of the microbiota in physiological processes, raising the hypothesis of a curative action of EF, by rebalancing the user’s microbiota. Conclusion The therapeutic uses of EF preparations despite their possible curative properties are a potential source of zoonotic transmission from elephants to humans. In the current context of globalisation of trade which favours the emergence of zoonoses and in relation with the issue of One Health, it becomes crucial to further document the zootherapeutic practices to prevent emerging diseases. As elephants and local related ethnoethological knowledge are threatened, documenting them is urgent to contribute to their preservation.

We evaluated the age-specific mortality of unselected adult outpatients infected with SARS-CoV-2 treated early in a dedicated COVID-19 day hospital and we assessed whether the use of hydroxychloroquine (HCQ) + azithromycin (AZ) was associated with improved survival in this cohort. A retrospective monocentric cohort study was conducted in the day hospital of our center from March to December 2020 in adults with PCR-proven infection who were treated as outpatients with a standardized protocol. The primary endpoint was 6-week mortality, and secondary endpoints were transfer to the intensive care unit and hospitalization rate. Among 10,429 patients (median age, 45 [IQR 32–57] years; 5597 [53.7%] women), 16 died (0.15%). The infection fatality rate was 0.06% among the 8315 patients treated with HCQ+AZ. No deaths occurred among the 8414 patients younger than 60 years. Older age and male sex were associated with a higher risk of death, ICU transfer, and hospitalization. Treatment with HCQ+AZ (0.17 [0.06–0.48]) was associated with a lower risk of death, independently of age, sex and epidemic period. Meta-analysis evidenced consistency with 4 previous outpatient studies (32,124 patients—Odds ratio 0.31 [0.20–0.47], I2 = 0%). Early ambulatory treatment of COVID-19 with HCQ+AZ as a standard of care is associated with very low mortality, and HCQ+AZ improve COVID-19 survival compared to other regimens.

Summary: Background: Laos is considered highly endemic for persistent infection with hepatitis B virus (HBV). To eliminate this burden, it has gradually implemented universal anti-hepatitis B immunisation of newborns over the past two decades. Methods: Using VIKIA® HBsAg, a rapid test for the qualitative detection of the HBV surface antigen, we conducted between Sep 1st, 2020 and Aug 31st, 2021 the largest prospective prevalence survey ever in Laos. This survey included blood donors (BD, n = 42,277), patients attending care in capital and provincial hospitals (n = 37,347) including attending mothers (n = 20,548), HIV-infected patients (n = 7439, recruited from 2009 to 2020), students from the Health Sciences University (n = 609), and outpatients (n = 350) coming for diagnosis at the Center Infectiology Lao-Christophe Mérieux in Vientiane. In total, 88,022 persons were tested, representing approximately 1.22% of the national population. To reach a reasonable estimate of HBsAg prevalence in Laos, we segmented the population according to three variables, age (≤20 years as a cut-off), sex, and geographical origin. BD values were used to estimate HBsAg prevalence in patients aged

Background Little data are available in women presenting with ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI). We assessed frequency, predictors of VF, and outcomes, with a special focus on women compared with men. Methods and Results Data were analyzed from the FAST‐MI (French Registry of Acute ST‐Elevation or Non‐ST‐Elevation Myocardial Infarction) program, which prospectively included 14 406 patients admitted to French cardiac intensive care units ≤48 hours from AMI onset between 1995 and 2015 (mean age, 66±14 years; 72% men; mean left ventricular ejection fraction, 52±12%; 59% with ST‐segment–elevation myocardial infarction). A total of 359 patients developed VF during AMI, including 81 women (2.0% of 4091 women) and 278 men (2.7% of 10 315 men, P=0.02). ST‐segment–elevation myocardial infarction (odds ratio [OR], 2.29 [95% CI, 1.75–2.99]; P

Genotype I, the penultimate HBV genotype to date, was granted the status of a bona fide genotype only in the XXIst century after some hesitations. The reason for these hesitations was that genotype I is a complex recombinant virus formed with segments from three original genotypes, A, C, and G. It was estimated that genotype I is responsible for only an infinitesimal fraction (2 spreading from Eastern India to China, inhabited by a little more than 100 million persons belonging primarily to ethnic minorities speaking various types of languages (Tibeto-Burman, Austroasiatic, and Tai-Kadai) who managed to escape the authority of central states during historical times. Genotype I consists of two subtypes: I1, present in China, Laos, Thailand, and Vietnam; and I2, encountered in India, Laos, and Vietnam.

Although very common, the precise mechanisms that explain the symptomatology of neuroendocrine syncope (NES) remain poorly understood. This disease, which can be very incapacitating, manifests itself as a drop in blood pressure secondary to vasodilation and/or extreme slowing of heart rate. As studies continue, the involvement of the adenosinergic system is becoming increasingly evident. Adenosine, which is an ATP derivative, may be involved in a large number of cases. Adenosine acts on G protein-coupled receptors with seven transmembrane domains. A1 and A2A adenosine receptor dysfunction seem to be particularly implicated since the activation leads to severe bradycardia or vasodilation, respectively, two cardinal symptoms of NES. This mini-review aims to shed light on the links between dysfunction of the adenosinergic system and NHS. In particular, signal transduction pathways through the modulation of cAMP production and ion channels in relation to effects on the cardiovascular system are addressed. A better understanding of these mechanisms could guide the pharmacological development of new therapeutic approaches.

BackgroundEither high or low values of adenosine blood level (ABL) can differentiate some forms of neurally mediated syncope (NMS). A rapid method of measurement has recently been developed. The aim of the present study was: (1) to compare ABLs in an unselected population of consecutive patients referred for evaluation of suspected NMS syncope and in healthy controls; and (2) to assess the relative prevalence of low and high adenosine forms among an unselected syncope population.MethodWhole blood was collected after finger puncture, blood being deposit on a blot paper and adenosine concentration was measured by liquid chromatography/mass spectrometry (LC-MS/MS).ResultsAmong 89 control subjects, the median ABL value was 0.54 μM (IQR, 0.46–0.65). The lowest 5% and the upper 95% percentile were 0.40 and 0.80 μM, respectively. Compared with healthy subjects, the 146 patients with syncope showed, on average, a higher median ABL value [0.63 (IQR 0.45–0.73, p = 0.04)] and a larger distribution of values. Low ABL values below the 5th percentile were observed in 28 (19%) patients, and, in five controls, p = 0.003 and high ABL values were observed in 26 (18%) patients and five controls, p = 0.009.ConclusionsABL is different in patients with suspected NMS than in healthy subjects. Patients with low and high adenosine values account for 19% and 18% of the general population. Thus, low and high ABL limits, as defined in this study, may help to define the purinergic profile of unselected subjects with a clinical diagnosis of suspected NMS.

Background and Objectives: Hydroxychloroquine (HCQ) combined with azithromycin (AZM) has been widely administered to patients with COVID-19 despite scientific controversies. In particular, the potential of prolong cardiac repolarization when using this combination has been discussed. Materials and Methods: We report a pragmatic and simple safety approach which we implemented among the first patients treated for COVID-19 in our center in early 2020. Treatment contraindications were the presence of severe structural or electrical heart disease, baseline corrected QT interval (QTc) > 500 ms, hypokalemia, or other drugs prolonging QTc that could not be interrupted. Electrocardiogram and QTc was evaluated at admission and re-evaluated after 48 h of the initial prescription. Results: Among the 424 consecutive adult patients (mean age 46.3 ± 16.1 years; 216 women), 21.5% patients were followed in conventional wards and 78.5% in a day-care unit. A total of 11 patients (2.6%) had contraindications to the HCQ-AZ combination. In the remaining 413 treated patients, there were no arrhythmic events in any patient during the 10-day treatment regimen. QTc was slightly but statistically significantly prolonged by 3.75 ± 25.4 ms after 2 days of treatment (p = 0.003). QTc prolongation was particularly observed in female outpatients 60 ms, and none had QTc > 500 ms. Conclusions: This report does not aim to contribute to knowledge of the efficacy of treating COVID-19 with HCQ-AZ. However, it shows that a simple initial assessment of patient medical history, electrocardiogram (ECG), and kalemia identifies contraindicated patients and enables the safe treatment of COVID-19 patients with HCQ-AZ. QT-prolonging anti-infective drugs can be used safely in acute life-threatening infections, provided that a strict protocol and close collaboration between infectious disease specialists and rhythmologists are applied.

[Display omitted] Atrial fibrillation (AF) is the primary cause of ischaemic stroke and transient ischaemic attack (TIA). AF is associated with a high risk of recurrence, which can be reduced using optimal prevention strategies, mainly anticoagulant therapy. The availability of effective prophylaxis justifies the need for a significant, coordinated and thorough transdisciplinary effort to screen for AF associated with stroke. A recent French national survey, initiated and supported by the Société française neurovasculaire (SFNV) and the Société française de cardiologie (SFC), revealed many shortcomings, such as the absence or inadequacy of telemetry equipment in more than half of stroke units, insufficient and highly variable access to monitoring tools, delays in performing screening tests, heterogeneous access to advanced or connected ambulatory monitoring techniques, and a lack of dedicated human resources. The present scientific document has been prepared on the initiative of the SFNV and the SFC with the aim of helping to address the current shortcomings and gaps, to promote efficient and cost-effective AF detection, and to improve and, where possible, homogenize the quality of practice in AF screening among stroke units and outpatient post-stroke care networks. The working group, composed of cardiologists and vascular neurologists who are experts in the field and are nominated by their peers, reviewed the literature to propose statements, which were discussed in successive cycles, and maintained, either by consensus or by vote, as appropriate. The text was then submitted to the SFNV and SFC board members for review. This scientific statement document argues for the widespread development of patient pathways to enable the most efficient AF screening after stroke. This assessment should be carried out by a multidisciplinary team, including expert cardiologists and vascular neurologists. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mexiletine, an antiarrhythmic agent, can relieve skeletal muscle myotonic symptoms. • In France, mexiletine can be used compassionately for myotonic dystrophy (MD). • An expert group has produced an algorithm for mexiletine use in patients with MD. • Patients with MD need close cardiac monitoring before and during mexiletine use. In France, mexiletine – a class I antiarrhythmic drug – can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy. [ABSTRACT FROM AUTHOR]

Abstract Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising cell therapy in regenerative medicine and for autoimmune/inflammatory diseases. However, a main hurdle for MSCs‐based therapies is the loss of their proliferative potential in vitro. Here we report that glycoprotein A repetitions predominant (GARP) is required for the proliferation and survival of adipose‐derived MSCs (ASCs) via its regulation of transforming growth factor‐β (TGF‐β) activation. Silencing of GARP in human ASCs increased their activation of TGF‐β which augmented the levels of mitochondrial reactive oxygen species (mtROS), resulting in DNA damage, a block in proliferation and apoptosis. Inhibition of TGF‐β signaling reduced the levels of mtROS and DNA damage and restored the ability of GARP−/lowASCs to proliferate. In contrast, overexpression of GARP in ASCs increased their proliferative capacity and rendered them more resistant to etoposide‐induced DNA damage and apoptosis, in a TGF‐β‐dependent manner. In summary, our data show that the presence or absence of GARP on ASCs gives rise to distinct TGF‐β responses with diametrically opposing effects on ASC proliferation and survival.

Background & objectives: In Colombian Amazonia, Uitoto indigenous people use a preparation of Curarea toxicofera (Menispermaceae) to prevent and treat malaria. To open the way for the production of a standardized herbal remedy, we compared the activity of the traditional preparation with laboratory preparations. Methods: People were interviewed on their mode of use and preparation of what is considered the best remedy against fevers in this area. The herbal remedy was prepared according to the healer’s recommendations. The plant was also submitted to continuous distillation and percolation extraction. The preparations were then tested against Plasmodium falciparum, in vitro. Traditional preparation and extract obtained by percolation were tested on Plasmodium berghei infected mice. Chemical profiles were also explored by thin-layer chromatography. Results: Yields of extraction were around 7% in the preparations (percolation was the most efficient). The phytochemical profile showed a mix of steroids, flavonoids and alkaloids qualitatively similar in all preparations. In vitro, the extracts showed inhibitory concentration 50

BackgroundCompound motor action potential (CMAP) monitoring is a common method used to prevent right phrenic nerve palsy during cryoballoon ablation for atrial fibrillation.ObjectiveWe compared recordings simultaneously obtained with surface and hepatic electrodes.MethodsWe included 114 consecutive patients (mean age 61.7 ± 10.9 years) admitted to our department for cryoballoon ablation. CMAP was monitored simultaneously with a hepatic catheter and a modified lead I ECG, whilst right phrenic nerve was paced before (stage 1) and during (stage 2) the right-sided freezes. If phrenic threat was detected with hepatic recordings (CMAP amplitude drop >30%) the application was discontinued with forced deflation.ResultsThe ratio of CMAP/QRS was 4.63 (2.67–9.46) for hepatic and 0.76 (0.55–1.14) for surface (p < 0.0001). Signal coefficients of variation during stage 1 were 3.92% (2.48–6.74) and 4.10% (2.85–5.96) (p = 0.2177), respectively. Uninterpretable signals were more frequent on surface (median 10 vs. 0; p < 0.0001). For the 14 phrenic threats, the CMAP amplitude dropped by 35.61 ± 8.27% on hepatic signal and by 33.42 ± 11.58% concomitantly on surface (p = 0.5417). Our main limitation was to achieve to obtain stable phrenic capture (57%). CMAP monitoring was not reliable because of pacing instability in 15 patients (13.16%). A palsy occurred in 4 patients (3.51%) because cryoapplication was halted too late.ConclusionBoth methods are feasible with the same signal stability and amplitude drop precocity during phrenic threats. Clarity and legibility are significantly better with hepatic recording (sharper signals, less far-field QRS). The two main limitations were pacing instability and delay between 30% CMAP decrease and cryoapplication discontinuation.

Objective: Although atrial fibrillation is a common cardiac arrhythmia in humans, the mechanism that leads to the onset of this condition is poorly elucidated. Adenosine is suspected to be implicated in the trigger of atrial fibrillation (AF) through the activation of its membrane receptors, mainly adenosine receptor (AR) subtypes A1R and A2R. In this study, we compared blood adenosine concentration (BAC), and A1R, A2AR, and A2BR production in right (RA) and left atrium (LA), and on peripheral blood mononuclear cells (PBMCs) in patients with underlying structural heart disease undergoing cardiac surgery with or without peri-operative AF (PeOpAF).Methods: The study group consisted of 39 patients (30 men and 9 women, mean age, range 65 [40–82] years) undergoing cardiac surgery and 20 healthy patients (8 women and 12 men; mean age, range 60 [39–72] years) as controls were included. Among patients, 15 exhibited PeOpAF.Results: Blood adenosine concentration was higher in patients with PeOpAF than others. A2AR and A2BR production was higher in PBMCs of patients compared with controls and was higher in PeOpAF patients than other patients. In LA and RA, the production of A2AR and A2BR was higher in patients with PeOpAF than in other patients. Both A2AR and A2BR production were higher in LA vs. RA. A1R production was unchanged in all situations. Finally, we observed a correlation between A1R, A2AR, and A2BR production evaluated on PBMCs and those evaluated in LA and RA.Conclusions: Perioperative AF was associated with high BAC and high A2AR and A2BR expression, especially in the LA, after cardiac surgery in patients with underlying structural heart disease. Whether these increases the favor in triggering the AF in this patient population needs further investigation.

Atrial fibrillation (AF) is the most common arrhythmia in the world. Because the key to developing innovative therapies that limit the onset and the progression of AF is to fully understand the underlying molecular mechanisms of AF, the aim of the present narrative review is to report the most recent advances in the potential role of the adenosinergic system in the pathophysiology of AF. After a comprehensive approach describing adenosinergic system signaling and the mechanisms of the initiation and maintenance of AF, we address the interactions of the adenosinergic system’s signaling with AF. Indeed, adenosine release can activate four G-coupled membrane receptors, named A1, A2A, A2B and A3. Activation of the A2A receptors can promote the occurrence of delayed depolarization, while activation of the A1 receptors can shorten the action potential’s duration and induce the resting membrane’s potential hyperpolarization, which promote pulmonary vein firing, stabilize the AF rotors and allow for functional reentry. Moreover, the A2B receptors have been associated with atrial fibrosis homeostasis. Finally, the adenosinergic system can modulate the autonomous nervous system and is associated with AF risk factors. A question remains regarding adenosine release and the adenosine receptors’ activation and whether this would be a cause or consequence of AF.

Mitral valve prolapse (MVP) is a common valvular heart defect with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. Herein, we report a clinical and genetic investigation of a family with bileaflet MVP and a history of syncopes and resuscitated sudden cardiac death. Using family based whole exome sequencing, we identified two missense variants in the SCN5A gene. A rare variant SCN5A:p.Ala572Asp and the well-known functional SCN5A:p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father and sister carried only the SCN5A:p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as the potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and/or SCD history.

Fibromuscular dysplasia (FMD) is a non-inflammatory vascular disease that is characterized by unexplained systemic hypertension occurring in young people, associated with arterial stenosis, aneurysm rupture, intracranial/renal infarction, and stroke. Although the gold standard for the diagnosis remains catheter-angiography, biological markers would be helpful due to the delay from first symptom to diagnosis. Adenosine is an ATP derivative, that may be implicated in FMD pathophysiology. We hypothesized that changes in adenosine blood level (ABL) and production of adenosine receptors may be associated with FMD. Using peripheral blood mononuclear cells, we evaluated A1, A2A, and A2B receptor production by Western blot, in 67 patients (17 men and 50 women, mean (range) age 55 (29–77) years and 40 controls, 10 men and 30 women, mean (range) age 56 (37–70)). ABL was evaluated by liquid chromatography, mass spectrometry. ABL was significantly higher in patients vs. controls, mean (range): 1.7 (0.7–3) µmol/L vs. controls 0.6 (0.4–0.8) µmol/L (+180%) p < 0.001. While A1R and A2AR production did not differ in patients and controls, we found an over-production of A2BR in patients: 1.70 (0.90–2.40; arbitrary units) vs. controls = 1.03 (0.70–1.40), mean + 65% (p < 0.001). A2BR production with a cut off of 1.3 arbitrary units, gives a good sensitivity and specificity for the diagnosis. Production measurement of A2BR on monocytes and ABL could help in the diagnosis, especially in atypical or with poor symptoms.

[Display omitted] • HAVB occurred in 11% of patients with aortic IE. • HAVB was associated with severe biological sepsis. • HAVB was associated with periannular extension of infection. • HAVB was associated with prolonged PR interval at admission. • HAVB represented an additional in-hospital mortality marker. • Most patients implanted with PM were not dependent at long-term follow-up. Aortic valve infective endocarditis may be complicated by high-degree atrioventricular block in up to 10–20% of cases. To assess high-degree atrioventricular block occurrence, contributing factors, prognosis and evolution in patients referred for aortic infective endocarditis. Two hundred and five patients referred for aortic valve infective endocarditis between January 2018 and March 2021 were included in this study. A comprehensive assessment of clinical, electrocardiographic, biological, microbiological and imaging data was conducted, with a follow-up carried out over 1 year. High-degree atrioventricular block occurred in 22 (11%) patients. In univariate analysis, high-degree atrioventricular block was associated with first-degree heart block at admission (odds ratio 3.1; P = 0.015), periannular complication on echocardiography (odds ratio 6.9; P < 0.001) and severe biological inflammatory syndrome, notably C-reactive protein (127 vs 90 mg/L; P = 0.011). In-hospital mortality (12.7%) was higher in patients with high-degree atrioventricular block (odds ratio 4.0; P = 0.011) in univariate analysis. Of the 16 patients implanted with a permanent pacemaker for high-degree atrioventricular block and interrogated, only four (25%) were dependent on the pacing function at 1-year follow-up. High-degree atrioventricular block is associated with high inflammation markers and periannular complications, especially if first-degree heart block is identified at admission. High-degree atrioventricular block is a marker of infectious severity, and tends to raise the in-hospital mortality rate. Systematic assessment of patients admitted for infective endocarditis suspicion, considering these contributing factors, could indicate intensive care unit monitoring or even temporary pacemaker implantation in those at highest risk. [ABSTRACT FROM AUTHOR]

Abstract Antiplatelet therapy through inhibition of the adenosine diphosphate (ADP)/P2Y12 pathway is commonly used in the treatment of acute coronary syndrome (ACS). Although efficient in preventing platelet activation and thrombus formation, it increases the risk of bleeding complications. In patients with ACS receiving platelet aggregation inhibitors, that is, P2Y12 blockers (n = 923), we investigated the relationship between plasma and platelet‐associated CD40L levels and bleeding events (n = 71). Treatment with P2Y12 inhibitors in patients with ACS did not affect plasma‐soluble CD40L levels, but decreased platelet CD40L surface expression (pCD40L) and platelet‐released CD40L (rCD40L) levels in response to stimulation as compared to healthy controls. In vitro inhibition of the ADP pathway in healthy control platelets reduced both pCD40L and rCD40L levels. In a multivariable analysis, the reduced pCD40L level observed in ACS patients was significantly associated with the risk of bleeding occurrence (adjusted odds ratio = 0.15; 95% confidence interval = 0.034‐0.67). P2Y12 inhibitor‐treated (ticagrelor) mice exhibited a 2.5‐fold increase in tail bleeding duration compared with controls. A significant reduction in bleeding duration was observed on CD40L+/+ but not CD40L−/− platelet infusion. In addition, CD40L blockade in P2Y12 inhibitor–treated blood samples from a healthy human reduced thrombus growth over immobilized collagen under arterial flow. In conclusion, measurement of pCD40L may offer a novel approach to assessing bleeding risk in patients with ACS who are being treated with P2Y12 inhibitors.

The Task Force for the diagnosis and management of syncope of the European Society of Cardiology (ESC)Developed with the special contribution of the European Heart Rhythm Association (EHRA)Endorsed by: European Academy of Neurology (EAN), European Federation of Autonomic Societies (EFAS), European Federation of Internal Medicine (EFIM), European Union Geriatric Medicine Society (EUGMS), European Society of Emergency Medicine (EuSEM)(text is available in electronic version doi:10.15829/1560-4071-2019-7-130-194)

Abstract Background Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018. Methods ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years. Results Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA2DS2-VASc and HAS-BLED mean scores were 3.1 and 2.6, respectively. Overall, 3.3, 14.6 and 82.0% of patients had low (CHA2DS2-VASc = 0), intermediate (CHA2DS2-VASc = 1) and high (CHA2DS2-VASc≥2) risks of stroke, respectively. High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA2DS2-VASc ≥4) comprised 38.4% of the overall population. For 75.1% of patients edoxaban was their first anticoagulant prescription, whilst 16.9% switched from a VKA and 8.0% from another NOAC. A total of 23.4% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg. Overall, 83.8% of patients received an edoxaban dose in line with the criteria outlined in the label. Conclusion Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label. Trial registration NCT02944019; Date of registration: October 24, 2016.

Abstract Background In Lao PDR, the Hmong ethnic group has extensive knowledge about the use of medicinal plants. However, despite the importance of the Hmong pharmacopeia as a primary health care resource, no study has been undertaken to thoroughly document medicinal plant knowledge and its transmission. Objectives of this study are (i) to describe and characterize Hmong pharmacopeia, and (ii) to understand how medicinal plant knowledge is transmitted and spread among Hmong in Lao PDR, in order to assess whether this knowledge base is under threat. Methods In order to describe Hmong pharmacopeia, a total of 14 interlocutors were interviewed in three provinces (Bokeo, Xieng Khouang, and Vientiane), using “walk in the wood” methodology. To gain insight about knowledge transmission, semi-structured interviews were conducted with 28 people. Twenty of them were herbalists. Data analysis was performed using univariate analysis for the description of the pharmacopeia. Medicinal plant knowledge consistency was assessed through use and plant name overlapping. Answers to the semi-structured interview on knowledge transmission were analyzed qualitatively. Results Three hundred thirty-three different medicinal species were collected. The majority of uses attributed to plants were gastrointestinal conditions (22% of total use reports), gynecological conditions and sexually transmitted disease (12%), skin affections (8%), kidney and bladder problems (5%), physical traumas (5%), and aphrodisiac (or male tonics; 5%). Use convergences are more marked in the gynecological sphere, but there is a strong heterogeneity in practices and knowledge. Medicinal plant knowledge transmission is oral, gained from direct experience since childhood, matrilineal, and kept strictly within the family lineage. Apparent limited consensus on uses might stem from the method of knowledge transmission and to the economic value given to medicinal plants. Discussion Use pattern of species from the Hmong pharmacopeia does not appear to be strikingly different from the national Lao pharmacopeia. Differences may lie in the methods and reasons for knowledge transmission. It can be proposed that the economic value given to plants helps in keeping the knowledge alive, and encourages its transmission. Conclusion Hmong traditional medicine is constantly evolving in a dynamic process and aims to respond to health problems faced by the local population. Herbalists appear as health fully fledged actors and should be recognized and valued as such.

Abstract Background Combination of elementary parameters (force, time, power, impedance drop) has been proposed to optimize radiofrequency (RF) delivery. They have been partially validated in clinical studies. Aims The aim of this study was to assess contact‐force (CF) implementation into clinical practice. Methods A 36‐question electronic form was sent to 105 electrophysiologists (EP) including some general questions concerning the practice of catheter atrial fibrillation ablation and items concerning the parameters used for CF‐guided ablation. Results Answers from 98 EP were collected (93% response rate). The CF‐catheters used were Smart Touch, Biosense (52%), Tacticath, Saint‐Jude Medical (12%), or both (27%) and no CF (9%). The power applied on the left atrial (LA) anterior (LAAW) and posterior (LAPW) wall was, respectively, 26‐34 W (for 73% of the EP) and below 25 W (88% of the EP). Forty percent of the Visitag® users mostly used the nominal parameters. Seventy‐five percent of the users did not use automatic display of the impedance drop. For the Tacticath users, 57% used a target value of 400 gs on the LAAW and 300 to 400 gs on the LAPW. Lesion Size Index was exceptionally used. Conclusions The parameters used for CF‐guided ablation are widely variable among the different operators. Further prospective studies are needed to validate the targets for automatic annotation of the RF applications.

The evaluation of suspected coronary artery disease (CAD) in the medical community is challenging. Patients with suspected coronary chronic syndrome (CCS) are referred by the medical community to be assessed by specialists for the performance of noninvasive tests that have high rates of false positives and false negatives. While troponins are the gold standard for evaluate myocardial injuries, there is no biomarker to assess myocardial ischemia in patient populations with negative electrocardiography or without an increase in troponin level. A2A adenosine receptors control the coronary blood flow through its vasodilating properties. It has been shown that patients with CAD have a lower A2AR expression on peripheral blood mononuclear cells, suggesting a link between A2AR production and the severity of CAD. Herein, we present a new and innovative method of inhibition ELISA for A2AR in the plasma of patients who permit the evaluation of the amount of soluble A2AR. For this analysis, the total study sample was 54, including 31 patients with CAD with stenosis > 50% and a significant fractional flow reserve (FFR < 0.8) (Group 1) and 23 patients with normal or non-obstructive coronary arteries (stenosis < 50% and nonsignificant FFR > 0.8) (Group 2). The % inhibition (which is linked to the presence of soluble receptors) with the plasma of patients with FFR < 0.8 was significantly lower than that of patients with FFR > 0.8 (median [range]: 68% [20.7–86.9] vs. 83% [67–88.4]; p < 0.001). The ROC curve indicated a good sensitivity/specificity ratio with a cut off of 72.5% and an area under the curve of 0.87. In conclusion, a rapid ELISA to assess soluble A2AR in the plasma shows promise to screen patients suspected of having CAD.

Atrial fibrillation (AF) is still a major cause of disease morbidity and mortality, making its early diagnosis desirable and urging researchers to develop efficient methods devoted to automatic AF detection. Till now, the analysis of Holter-ECG recordings remains the gold-standard technique to screen AF. This is usually achieved by studying either RR interval time series analysis, P-wave detection or combinations of both morphological characteristics. After extraction and selection of meaningful features, each of the AF detection methods might be conducted through univariate and multivariate data analysis. Many of these automatic techniques have been proposed over the last years. This work presents an overview of research studies of AF detection based on RR interval time series. The aim of this paper is to provide the scientific community and newcomers to the field of AF screening with a resource that presents introductory concepts, clinical features, and a literature review that describes the techniques that are mostly followed when RR interval time series are used for accurate detection of AF.

Adenosine is a ubiquitous nucleoside that is implicated in the occurrence of clinical manifestations of neuro-humoral syncope (NHS). NHS is characterized by a drop in blood pressure due to vasodepression together with cardio inhibition. These manifestations are often preceded by prodromes such as headaches, abdominal pain, feeling of discomfort or sweating. There is evidence that adenosine is implicated in NHS. Adenosine acts via four subtypes of receptors, named A1 (A1R), A2A (A2AR), A2B (A2BR) and A3 (A3R) receptors, with all subtypes belonging to G protein membrane receptors. The main effects of adenosine on the cardiovascular system occurs via the modulation of potassium ion channels (IK Ado, K ATP), voltage-gate calcium channels and via cAMP production inhibition (A1R and A3R) or, conversely, through the increased production of cAMP (A2A/BR) in target cells. However, it turns out that adenosine, via the activation of A1R, leads to bradycardia, sinus arrest or atrioventricular block, while the activation of A2AR leads to vasodilation; these same manifestations are found during episodes of syncope. The use of adenosine receptor antagonists, such as theophylline or caffeine, should be useful in the treatment of some forms of NHS. The aim of this review was to summarize the main data regarding the link between the adenosinergic system and NHS and the possible consequences on NHS treatment by means of adenosine receptor antagonists.

While the concept of a receptor reserve (spare receptors) is old, their presence on human cells as an adaptive mechanism in cardiovascular disease is a new suggestion. The presence of spare receptors is suspected when the activation of a weak fraction of receptors leads to maximal biological effects, in other words, when the half-maximal effective concentration (EC50) for a biological effect (cAMP production, for example) is lower than the affinity (KD) of the ligand for a receptor. Adenosine is an ATP derivative that strongly impacts the cardiovascular system via its four membrane receptors, named A1R, A2AR, A2BR, and A3R, with the A1R being more particularly involved in heart rhythm, while the A2AR controls vasodilation. After a general description of the tools necessary to explore the presence of spare receptors, this review focuses on the consequences of the presence of spare adenosine receptors in cardiovascular physiopathology. Finally, the role of the adenosinergic system in the long-term potentiation and its possible consequences on the physiopathology are also mentioned.

Background The incidence of conduction abnormalities requiring permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) with early and later generation prostheses remains debated. Methods and Results Based on the administrative hospital‐discharge database, we collected information for all patients treated with TAVR between 2010 and 2019 in France. We compared the incidence of PPI after TAVR according to the type and generation of valve implanted. A total of 49 201 patients with aortic stenosis treated with TAVR using the balloon‐expandable (BE) Edwards SAPIEN valve (early Sapien XT and latest Sapien 3) or the self‐expanding (SE) Medtronic CoreValve (early CoreValve and latest Evolut R) were found in the database. Mean (SD) follow‐up was 1.2 (1.5 years) (median [interquartile range] 0.6 [0.1–2.0] years). PPI after the procedure was reported in 13 289 patients, among whom 11 010 (22.4%) had implantation during the first 30 days. In multivariable analysis, using early BE TAVR as reference, adjusted odds ratio (95% CI) for PPI during the first 30 days was 0.88 (0.81–0.95) for latest BE TAVR, 1.40 (1.27–1.55) for early SE TAVR, and 1.17 (1.07–1.27) for latest SE TAVR. Compared with early BE TAVR, the adjusted hazard ratio for PPI during the whole follow‐up was 1.01 (0.95–1.08) for latest BE TAVR, 1.30 (1.21–1.40) for early SE TAVR, and 1.25 (1.18–1.34) for latest SE TAVR. Conclusions In patients with aortic stenosis treated with TAVR, our systematic analysis at a nationwide level found higher rates of PPI than previously reported. BE technology was independently associated with lower incidence rates of PPI both at the acute and chronic phases than SE technology. Recent generations of TAVR were not independently associated with different rates of PPI than early generations during the overall follow‐up.