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Abstract Background Many patients with post COVID-19 condition (PCC) require healthcare services. However, qualitative studies indicate that patients with PCC encounter many barriers to healthcare access. This cross-sectional study aimed to determine how many PCC patients report barriers to healthcare access and which barriers are reported, and to explore differences between subgroups. Methods Data were collected via an online survey from 10,462 adult patients with a confirmed or suspected COVID-19 infection in the Netherlands, who experienced persisting symptoms ≥ 3 months after the initial infection. To study self-perceived barriers, a list of eleven possible barriers was used, covering multiple aspects of healthcare access. Differences between subgroups based on sociodemographic characteristics, medical characteristics, PCC symptoms (fatigue, dyspnoea, cognitive problems, anxiety and depression), and healthcare use (general practitioner, paramedical professional, medical specialist, occupational physician and mental health professional) were studied through multivariable multinomial (0 vs. 1 vs. > 1 barrier) and binomial regression analyses (for each individual barrier). Results A total of 83.2% of respondents reported at least one barrier to healthcare access. Respondents reported a median of 2.0 (IQR = 3.0) barriers. The barriers “I didn’t know who to turn to for help” (50.9%) and “No one with the right knowledge/skills was available” (36.8%) were most frequently reported. Respondents with younger age, higher educational level, not hospitalized during acute COVID-19 infection, longer disease duration, who had more severe PCC symptoms, and who did not consult an occupational physician or paramedical professional, were more likely to report barriers. Analyses per barrier showed that women were more likely to report financial and help-seeking barriers, while men were more likely to report barriers related to availability of care. Hospitalized respondents were less likely to report barriers related to availability of care, but not less likely to report financial or help-seeking barriers. Conclusions This study shows that the majority of patients with PCC experiences barriers to healthcare access. Particular attention should be paid to younger, non-hospitalized patients with a long disease duration and severe PCC symptoms. Efforts to remove barriers should focus not only on improving availability of care, but also on helping patients navigate care pathways.

Abstract Objectives This study aimed to assess the diagnostic management and follow‐up imaging for glioma patients across Belgian hospitals by calculating process indicators. Methods Patients with newly diagnosed glioma in Belgium (2016–2019) were selected from the Belgian Cancer Registry. The National Social Security Number served as unique patient identifier, linking the Registry to vital status and reimbursement data. Nine measurable process related to diagnosis and follow‐up imaging were identified, with reformulations for 7 due to data limitations. For each indicator, technical documentation sheets, containing all required details (rationale, numerator and denominator, target, limitations, benchmarking, subgroup analyses) were developed, reviewed by a multidisciplinary expert panel, and validated in six pilot hospitals. Per indicator, patients were assigned to the most relevant hospital per indicator using allocation algorithms. Results Results for process indicators assessing MRI use in glioma diagnosis and follow‐up aligned with predefined targets (90%), except for early postoperative MRI (48.5% vs. target 90%). Mandatory reporting of the WHO performance status (89.3% vs. target 100%) and performance of full‐spine (43.6% vs. target 90%) and follow‐up MRI (73.5% vs. target 90%) in ependymoma were suboptimal. The largest variability across centers was noted for the indicator on early postoperative MRI. Conclusion This calculation of process indicators identified opportunities for improvement in diagnosis and follow‐up imaging for glioma patients in Belgium. Monitoring indicator results and providing individual feedback reports to the Belgian hospitals invites neuro‐oncology care teams and hospital managements to reflect on their results and to take measures to continuously improve care for glioma.

Summary: Feather bacterial load affects key avian life-history traits such as plumage condition, innate immunity, and reproductive success. Investigating the interplay between life-history traits and feather microbial load is critical for understanding mechanisms of host-microbiome interactions. We hypothesize that spatiotemporal variation associated with migration and molting, body size affecting colonizable body surface area, and preening intensity could shape feather bacterial load. Integrating 16S rDNA-qPCR and flow cytometry, we examined total and viable bacterial loads in the feathers of 316 individuals of 24 Palearctic passerine species. We found that viable bacterial load in feathers was lower in larger species and higher in residents compared to migrants. In contrast, total bacterial load was not explained by any of the life-history traits but varied considerably among species, sampling sites, and years. By pinpointing main drivers of bacterial loads on avian body surfaces, we identify key mechanisms shaping host-microbiome interactions and open alternative research directions.

In cardiomyocytes, the KCNQ1/KCNE1 channel complex mediates the slow delayed-rectifier current (IKs), pivotal during the repolarization phase of the ventricular action potential. Mutations in IKs cause long QT syndrome (LQTS), a syndrome with a prolonged QT interval on the ECG, which increases the risk of ventricular arrhythmia and sudden cardiac death. One potential therapeutical intervention for LQTS is based on targeting IKs channels to restore channel function and/or the physiological QT interval. Polyunsaturated fatty acids (PUFAs) are potent activators of KCNQ1 channels and activate IKs channels by binding to two different sites, one in the voltage sensor domain – which shifts the voltage dependence to more negative voltages – and the other in the pore domain – which increases the maximal conductance of the channels (Gmax). However, the mechanism by which PUFAs increase the Gmax of the IKs channels is still poorly understood. In addition, it is unclear why IKs channels have a very small single-channel conductance and a low open probability or whether PUFAs affect any of these properties of IKs channels. Our results suggest that the selectivity filter in KCNQ1 is normally unstable, contributing to the low open probability, and that the PUFA-induced increase in Gmax is caused by a stabilization of the selectivity filter in an open-conductive state.

The inward rectifier potassium channel Kir2.1 (KCNJ2) is an important regulator of resting membrane potential in both excitable and non-excitable cells. The functions of Kir2.1 channels are dependent on their lipid environment, including the availability of PI(4,5)P2, secondary anionic lipids, cholesterol and long-chain fatty acids acyl coenzyme A (LC-CoA). Endocannabinoids are a class of lipids that are naturally expressed in a variety of cells, including cardiac, neuronal, and immune cells. While these lipids are identified as ligands for cannabinoid receptors there is a growing body of evidence that they can directly regulate the function of numerous ion channels independently of CBRs. Here we examine the effects of a panel of endocannabinoids on Kir2.1 function and demonstrate that a subset of endocannabinoids can alter Kir2.1 conductance to varying degrees independently of CBRs. Using computational and Surface plasmon resonance analysis, endocannabinoid regulation of Kir2.1 channels appears to be the result of altered membrane properties, rather than through direct protein-lipid interactions. Furthermore, differences in endocannabinoid effects on Kir4.1 and Kir7.1 channels, indicating that endocannabinoid regulation is not conserved among Kir family members. These findings may have broader implications on the function of cardiac, neuronal and/or immune cells.

Anion exchanger 1 (AE1, band 3) is a major membrane protein of red blood cells and plays a key role in acid-base homeostasis, urine acidification, red blood cell shape regulation, and removal of carbon dioxide during respiration. Though structures of the transmembrane domain (TMD) of three SLC4 transporters, including AE1, have been resolved previously in their outward-facing (OF) state, no mammalian SLC4 structure has been reported in the inward-facing (IF) conformation. Here we present the cryoEM structures of full-length bovine AE1 with its TMD captured in both IF and OF conformations. Remarkably, both IF-IF homodimers and IF-OF heterodimers were detected. The IF structures feature downward movement in the core domain with significant unexpected elongation of TM11. Molecular modeling and structure guided mutagenesis confirmed the functional significance of residues involved in TM11 elongation. Our data provide direct evidence for an elevator-like mechanism of ion transport by an SLC4 family member.

ObjectiveTo determine work participation, social roles, and empowerment of QFS patients ≥10-year after infection.MethodsQFS patients ≥10-year after acute infection, who were of working age, participated in a cross-sectional survey study. Work participation, fulfilment of social roles, and empowerment outcomes were studied for the total population, as well as for subgroups based on employment type and current work status. Associations between empowerment, work and social roles were examined.Results291 participants were included. Of the 250 participants who had paid work before Q-fever, 80.4% stopped working or worked less hours due to QFS. For each social role, more than half of the participants (56.6-87.8%) spent less time on the role compared to before Q-fever. The median empowerment score was 41.0 (IQR: 37.0-44.0) out of 60. A higher empowerment score was significantly associated with lower odds of performing all social roles less due to QFS (OR = 0.871-0.933; pConclusionWork participation and fulfilment of social roles is generally low in QFS patients. Many of the participants stopped working or are working less hours due to QFS, and most spent less time on social roles compared to before Q-fever. Minor variation was seen in total empowerment scores of participants; however, these slight differences were associated with the fulfilment of social roles, but not work participation. This new insight should be further explored in future studies.

Background Sex differences in atrial fibrillation (AF) are observed in terms of comorbidities, symptoms, therapies received, AF progression and cardiovascular complications.Methods We assessed the differences in prevalence and the determinants of AF progression, as well as the clinical characteristics and quality of life (QoL), between women and men with paroxysmal AF included in the RACE V (Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) study. At baseline, extensive phenotyping was done. To assess AF progression, implantable loop recorder (ILR) monitoring was used throughout follow-up. AF progression was defined as (1) progression to persistent or permanent AF or (2) progression of paroxysmal AF (>3% burden increase).Results 417 patients were included, 179 (43%) of whom were women. Women were older (median 67 years vs 63 years, p

Abstract Background In contrast with macroorganisms, that show well-documented biogeographical patterns in distribution associated with local adaptation of physiology, behavior and life history, strong biogeographical patterns have not been found for microorganisms, raising questions about what determines their biogeography. Thus far, large-scale biogeographical studies have focused on free-living microbes, paying little attention to host-associated microbes, which play essential roles in physiology, behavior and life history of their hosts. Investigating cloacal gut microbiota of closely-related, ecologically similar free-living songbird species (Alaudidae, larks) inhabiting desert, temperate and tropical regions, we explored influences of geographical location and host species on α-diversity, co-occurrence of amplicon sequence variants (ASVs) and genera, differentially abundant and dominant bacterial taxa, and community composition. We also investigated how geographical distance explained differences in gut microbial community composition among larks. Results Geographic location did not explain variation in richness and Shannon diversity of cloacal microbiota in larks. Out of 3798 ASVs and 799 bacterial genera identified, 17 ASVs (

Electrospray ionization (ESI) mass spectrometry is invaluable for studying complex biological systems, and although lipid nanodiscs are a powerful tool for the study of membrane proteins, a lack of clear understanding of the ESI mechanism presents a challenge for spectral interpretation and assignments. Here, the authors study the release behavior of lipid nanodiscs from charged nano-droplets in the ESI process using microsecond atomistic molecular dynamics simulations.

CryoEM structures and computational modeling of bovine anion exchanger 1 in both inward and outward facing conformations reveal an elevator-like mechanism of ion transport by a solute carrier ion transport family 4 member.

Abstract Background Gut microbiotas play a pivotal role in host physiology and behaviour, and may affect host life-history traits such as seasonal variation in host phenotypic state. Generally, seasonal gut microbiota variation is attributed to seasonal diet variation. However, seasonal temperature and day length variation may also drive gut microbiota variation. We investigated summer–winter differences in the gut bacterial community (GBC) in 14 homing pigeons living outdoors under a constant diet by collecting cloacal swabs in both seasons during two years. Because temperature effects may be mediated by host metabolism, we determined basal metabolic rate (BMR) and body mass. Immune competence is influenced by day length and has a close relationship with the GBC, and it may thus be a link between day length and gut microbiota. Therefore, we measured seven innate immune indices. We expected the GBC to show summer–winter differences and to correlate with metabolism and immune indices. Results BMR, body mass, and two immune indices varied seasonally, other host factors did not. The GBC showed differences between seasons and sexes, and correlated with metabolism and immune indices. The most abundant genus (Lachnoclostridium 12, 12%) and associated higher taxa, were more abundant in winter, though not significantly at the phylum level, Firmicutes. Bacteroidetes were more abundant in summer. The Firmicutes:Bacteroidetes ratio tended to be higher in winter. The KEGG ortholog functions for fatty acid biosynthesis and linoleic acid metabolism (PICRUSt2) had increased abundances in winter. Conclusions The GBC of homing pigeons varied seasonally, even under a constant diet. The correlations between immune indices and the GBC did not involve consistently specific immune indices and included only one of the two immune indices that showed seasonal differences, suggesting that immune competence may be an unlikely link between day length and the GBC. The correlations between the GBC and metabolism indices, the higher Firmicutes:Bacteroidetes ratio in winter, and the resemblance of the summer–winter differences in the GBC with the general temperature effects on the GBC in the literature, suggest that temperature partly drove the summer–winter differences in the GBC in homing pigeons.

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease.Design Registry based observational study.Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients).Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease.Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07).Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research.

Voltage-gated potassium (KV) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. KV channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore KV channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of KV channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac IKs channel – a tetrameric potassium channel complex formed by KV7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac IKs channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the IKs channel by generating modified aromatic head groups designed to probe cation–pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the IKs channel through cation–pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

BackgroundA subset of patients experience persisting symptoms after an acute COVID-19 infection, referred to as “post COVID-19 condition”. This cross-sectional study aimed to compare symptoms, health-related quality of life (HRQoL), fatigue, mental well-being, and determinants of diminished HRQoL, between patients with post COVID-19 condition categorized by time since acute infection.MethodsWe performed an online survey and analyzed responses of 10,194 adult respondents with a confirmed or suspected COVID-19 infection, who experienced persisting symptoms ≥3 months after the initial infection. The most debilitating symptoms and health outcomes were studied separately for respondents 3–6, 7–9, 10–12, 13–18, 19–24, and >24 months after acute infection.ResultsAt each time period, fatigue, sensory-processing problems, and concentration problems were the most debilitating symptoms reported by respondents, although the proportion of respondents who reported these symptoms differed significantly between time periods. Respondents 3–6 months post-acute infection had the lowest HRQoL (median EQ-5D utility score: 0.59), the highest fatigue level (median score: 110.0) and the highest proportion with a likely depressive disorder (32.4%), whereas respondents 13–18 months post-infection had the highest HRQoL (0.65), the lowest fatigue level (106.0), and the second lowest proportion with a likely depressive disorder (25.0%) (p = 0.000–0.007). Compared to those 13–18 and 19–24 months post-infection, respondents >24 months post-infection had a slightly lower HRQoL (0.60), lower fatigue level (108.0), and lower proportion with a likely depressive disorder (29.2%), although only the differences in HRQoL were statistically significant (p = 0.001–0.010). Younger age, female gender, lower level of education, not having paid work before COVID-19, comorbidity, and not being vaccinated, seemed to be associated with lower HRQoL.ConclusionRegardless of time since infection, respondents considered fatigue, sensory processing problems and concentration problems the most debilitating symptoms. They experienced a low HRQoL and severe fatigue, even more than two years after acute COVID-19 infection. Respondents 3–6 months post-infection had the worst health outcomes, whereas respondents 13–18 months post-infection had the best outcomes, indicating that, at least for a subgroup of patients, health status may improve over time.

Abstract Background In a diverse microbial world immune function of animals is essential. Diverse microbial environments may contribute to extensive variation in immunological phenotypes of vertebrates, among and within species and individuals. As maternal effects benefit offspring development and survival, whether females use cues about their microbial environment to prime offspring immune function is unclear. To provide microbial environmental context to maternal effects, we asked if the bacterial diversity of the living environment of female zebra finches Taeniopygia guttata shapes maternal effects on egg immune function. We manipulated environmental bacterial diversity of birds and tested if females increased immunological investment in eggs in an environment with high bacterial diversity (untreated soil) versus low (gamma-sterilized soil). We quantified lysozyme and ovotransferrin in egg albumen and IgY in egg yolk and in female blood, and we used 16S rRNA gene sequencing to profile maternal cloacal and eggshell microbiotas. Results We found a maternal effect on egg IgY concentration that reflected environmental microbial diversity: females who experienced high diversity deposited more IgY in their eggs, but only if maternal plasma IgY levels were relatively high. We found no effects on lysozyme and ovotransferrin concentrations in albumen. Moreover, we uncovered that variation in egg immune traits could be significantly attributed to differences among females: for IgY concentration in yolk repeatability R = 0.80; for lysozyme concentration in albumen R = 0.27. Furthermore, a partial least squares path model (PLS-PM) linking immune parameters of females and eggs, which included maternal and eggshell microbiota structures and female body condition, recapitulated the treatment-dependent yolk IgY response. The PLS-PM additionally suggested that the microbiota and physical condition of females contributed to shaping maternal effects on egg immune function, and that (non-specific) innate egg immunity was prioritized in the environment with low bacterial diversity. Conclusions The microbial environment of birds can shape maternal effects on egg immune function. Since immunological priming of eggs benefits offspring, we highlight that non-genetic maternal effects on yolk IgY levels based on cues from the parental microbial environment may prove important for offspring to thrive in the microbial environment that they are expected to face.

Summary: Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardiovascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel KV7.1/KCNE1, which is the most frequently mutated ion channel in LQTS. Methods: We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts. Findings: We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate KV7.1/KCNE1. Using the endocannabinoid ARA-S as a prototype, we show that the effect is not dependent on the KCNE1 subunit or the phosphorylation state of the channel. In guinea pig hearts, ARA-S was found to reverse the E4031-prolonged action potential duration and QT interval. Interpretation: We consider the endocannabinoids as an interesting class of hKV7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts. Funding: ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing.

Abstract Background Age and comorbidities increase COVID-19 related in-hospital mortality risk, but the extent by which comorbidities mediate the impact of age remains unknown. Methods In this multicenter retrospective cohort study with data from 45 Dutch hospitals, 4806 proven COVID-19 patients hospitalized in Dutch hospitals (between February and July 2020) from the CAPACITY-COVID registry were included (age 69[58–77]years, 64% men). The primary outcome was defined as a combination of in-hospital mortality or discharge with palliative care. Logistic regression analysis was performed to analyze the associations between sex, age, and comorbidities with the primary outcome. The effect of comorbidities on the relation of age with the primary outcome was evaluated using mediation analysis. Results In-hospital COVID-19 related mortality occurred in 1108 (23%) patients, 836 (76%) were aged ≥70 years (70+). Both age 70+ and female sex were univariably associated with outcome (odds ratio [OR]4.68, 95%confidence interval [4.02–5.45], OR0.68[0.59–0.79], respectively;both p

The family Alaudidae, larks, comprises 93–100 species (depending on taxonomy) that are widely distributed across Africa and Eurasia, with single species extending their ranges to North and northernmost South America and Australia. A decade-old molecular phylogeny, comprising ∼80% of the species, revealed multiple cases of parallel evolution and large variation in rates of morphological evolution, which had misled taxonomists into creating many non-monophyletic genera. Here, we reconstruct the phylogeny of the larks, using a dataset covering one mitochondrial and 16 nuclear loci and comprising all except one of the currently recognised species as well as several recently proposed new species (in total 133 taxa; not all loci available for all species). We provide additional support using genome-wide markers to infer a genus-level phylogeny based on near-complete generic sampling (in total 51 samples of 44 taxa across 40 species). Our results confirm the previous findings of rampant morphological convergence and divergence, and reveal new cases of paraphyletic genera. We propose a new subfamily classification, and also that the genus Mirafra is divided into four genera to produce a more balanced generic classification of the Alaudidae. Our study supports recently proposed species splits as well as some recent lumps, while also questioning some of the latter. This comprehensive phylogeny will form an important basis for future studies, such as comparative studies of lark natural history, ecology, evolution and conservation.

Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning aspects. The macro and micro-scale mechanical properties, as determined by rheology and micro-indentation, revealed the local heterogeneity of the ECM. When growing CCAOs in decellularized lung and lymph nodes genes related to metastatic processes, including epithelial-to-mesenchymal transition and cancer stem cell plasticity, were significantly influenced by the ECM in an organ-specific manner. Furthermore, CCAOs exhibit significant differences in migration and proliferation dynamics dependent on the original patient tumor and donor of the target organ. In conclusion, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. Convergence of CCAOs with the ECM of its metastatic organs provide a new platform for mechanistic study of cancer metastasis.

Objectives Pulmonary vein isolation (PVI) is widely accepted as an effective and safe treatment for symptomatic atrial fibrillation (AF). However, data on sex-related differences and associations with clinical outcome and safety of PVI with cryoballoon ablation are limited. We sought to compare sexrelated efficacy and safety of cryoballoon ablation and identify sex-related associations with clinical outcomes.Methods and results We included 650 consecutive patients with AF undergoing PVI with cryoballoon ablation at our institution between 2013 and 2017. The efficacy outcome was the first documented recurrence (>30 s) of AF, atrial flutter or atrial tachycardia (AF/AT) or repeat ablation during follow-up, after a 90-day blanking period. The safety outcome was the incidence of periprocedural complications. Mean age of the population was 58±10, and 210 (32.3%) patients were women. Women were older, had a higher body mass index, had more renal dysfunction and less coronary artery disease as compared with men. The rate of AF/AT recurrence was similar between women and men at 12-month follow-up (27.6% vs 24.8%, p=0.445). The incidence of periprocedural complications was higher in women (12.9% vs 4.6%; p

IntroductionPulsed field ablation (PFA) was recently introduced for the treatment of symptomatic atrial fibrillation (AF) with the claim of selectively ablating the myocardium while sparing surrounding tissues. We present our initial experience with a PFA catheter for pulmonary vein isolation (PVI) and describe procedural findings and peri-procedural safety of the first 100 patients.Materials and methodsWe investigated 100 patients treated for symptomatic AF using the FARAWAVE PFA catheter (Farapulse, Menlo Park, CA, USA) between July 2021 and March 2022. Procedure workflow and electrophysiological findings at the time of ablation, peri-procedural complications, and operator learning curves are described.ResultsThe mean age of patients was 62.9 ± 9.4 years, 62% were male subjects and 80% had paroxysmal AF. The median CHA2DS2-VASc score was 1.5 (IQR: 1.0–2.0) and the mean left atrial volume index was 35.7 ± 9.6 ml/m2. In 88 (88%) patients, PVI alone was performed and in 12 (12%) patients additional ablation of the posterior wall was performed. 3D-electroanatomic mapping was performed in 18 (18%) patients. Procedures without mapping lasted for 52.3 ± 16.6 min. The mean number of applications per pulmonary vein (PV) was 8.1 ± 0.6. In all patients (100%), all PVs were confirmed to be isolated. The learning curves of the two operators who performed > 20 procedures showed a negligible variation of performance over time and practice did not significantly predict procedure time [Operator 1 (senior): R2 = 0.034, p = 0.35; Operator 2 (junior): R2 = 0.004, p = 0.73]. There was no difference between the procedure times between senior and junior operators (Operator 1: 46.9 ± 9.7 min vs. Operator 2: 45.9 ± 9.9 min; p = 0.73). The only complications observed were two cases of bleeding at the site of percutaneous access.ConclusionOur initial experience shows that use of the PFA catheter for pulmonary vein isolation (PVI) is safe, fast, and easy to learn.

The lipid regulation of mammalian ion channel function has emerged as a fundamental mechanism in the control of electrical signalling and transport specificity. Here, the authors combine molecular dynamics simulations, mutagenesis, and electrophysiology to provide mechanistic insights into how lipophilic molecules alter gating kinetics and K+ currents of hERG1.