Effect of early cryoballoon ablation on atrial fibrillation recurrence-A Danish nationwide register study.

INTRODUCTION: Cryoballoon ablation is a safe and efficient rhythm control strategy in atrial fibrillation (AF) patients. The impact of time from diagnosis to ablation is unclear. The aim of this study was to examine the impact of timing of first-time cryoballoon ablation on AF recurrence in a nationwide cohort of AF patients. METHODS AND RESULTS: From nationwide registers, all AF patients ≥18 years of age who underwent first-time AF cryoballoon ablation in Denmark from 2012 to 2018 were included. The AF patients were stratified by ablation timing: Early group (≤1 year after AF diagnosis), intermediate group (1-3 years after AF diagnosis), and late group (≥3 years after AF diagnosis). By adjusted Cox regression models, the effect of timing on AF recurrence was examined. This study included 1064 AF patients with a median age of 63 years. Most patients were male (66%) and had paroxysmal AF (67%). The 1-year risk of AF recurrence increased from 31% in the early group to 41% and 44% in the intermediate and late group. The hazard ratios (95% confidence intervals) were 1.28 (0.95, 1.74) in the intermediate group and 1.42 (1.09, 1.86) in the late group when compared to the early group. Continuous diagnosis-to-ablation time seemed to have the greatest impact on AF recurrence within the first 2 years. CONCLUSION: In AF patients undergoing cryoballoon ablation, late timing of ablation was associated with a significantly higher AF recurrence rate when compared to early timing of ablation. These findings support early cryoballoon ablation to improve the outcomes after ablation.

Effect of oral semaglutide on energy intake, appetite, control of eating and gastric emptying in adults living with obesity: A randomized controlled trial.

AIM: To investigate the effects of once-daily oral semaglutide 50 mg on energy intake, appetite, control of eating and gastric emptying. METHODS: A clinical pharmacology, double-blind study was conducted in 61 adults with obesity randomized to once-daily oral semaglutide (dose-escalated to 50 mg) or placebo for 20 weeks. Energy intake was measured during an ad libitum lunch, and participant-reported appetite ratings and Control of Eating Questionnaire responses were assessed. Gastric emptying was measured using paracetamol absorption following a standardized breakfast. RESULTS: The relative change from baseline in ad libitum energy intake at week 20 (primary endpoint) was -39.2% points (95% confidence interval -59.0%, -19.4%) with semaglutide compared with placebo. Body weight was reduced by 9.8% with semaglutide and by 1.5% with placebo. Semaglutide reduced hunger, increased fullness and satiety, and was associated with fewer food cravings and better control of eating versus placebo. No statistically significant difference in gastric emptying was observed at week 20. CONCLUSIONS: In participants with obesity, once-daily oral semaglutide 50 mg reduced energy intake, body weight and appetite, and improved control of eating. There was no evidence of delayed gastric emptying at week 20, as measured through paracetamol absorption.

Environmental DNA metabarcoding reveals temporal dynamics but functional stability of arthropod communities in cattle dung.

Terrestrial invertebrates are highly important for the decomposition of dung from large mammals. Mammal dung has been present in many of Earth's ecosystems for millions of years, enabling the evolution of a broad diversity of dung-associated invertebrates that process various components of the dung. Today, large herbivorous mammals are increasingly introduced to ecosystems with the aim of restoring the ecological functions formerly provided by their extinct counterparts. However, we still know little about the ecosystem functions and nutrient flows in these rewilded ecosystems, including the dynamics of dung decomposition. In fact, the succession of insect communities in dung is an area of limited research attention also outside a rewilding context. In this study, we use environmental DNA metabarcoding of dung from rewilded Galloway cattle in an experimental set-up to investigate invertebrate communities and functional dynamics over a time span of 53 days, starting from the time of deposition. We find a strong signal of successional change in community composition, including for the species that are directly dependent on dung as a resource. While several of these species were detected consistently across the sampling period, others appeared confined to either early or late successional stages. We believe that this is indicative of evolutionary adaptation to a highly dynamic resource, with species showing niche partitioning on a temporal scale. However, our results show consistently high species diversity within the functional groups that are directly dependent on dung. Our findings of such redundancy suggest functional stability of the dung-associated invertebrate community, with several species ready to fill vacant niches if other species disappear. Importantly, this might also buffer the ecosystem functions related to dung decomposition against environmental change. Interestingly, alpha diversity peaked after approximately 20-25 days in both meadow and pasture habitats, and did not decrease substantially during the experimental period, probably due to preservation of eDNA in the dung after the disappearance of visiting invertebrates, and from detection of tissue remains and cryptic life stages.

General anaesthesia compared to conscious sedation for first-time atrial fibrillation catheter ablation-a Danish nationwide cohort study.

AIMS: Catheter ablation (CA) is a well-established treatment option for atrial fibrillation (AF), where sedation and analgesia are pivotal for patient comfort and lesion formation. The impact of anaesthesia type on AF recurrence rates remains uncertain. This study aimed to examine AF recurrence rates depending on conscious sedation (CS) vs. general anaesthesia (GA) during CA. METHODS AND RESULTS: Utilizing nationwide data from the Danish healthcare registries, we conducted this cohort study involving adults (≥18 years) undergoing first-time CA for AF between 2010 and 2018. Patients were categorized by anaesthesia type (CS or GA), with the primary endpoint being AF recurrence, defined by a composite endpoint of either antiarrhythmic drug (AAD) prescriptions, AF-related hospital admissions, electrical cardioversions, or AF re-ablation. The impact of anaesthesia type was evaluated using multivariable Cox proportional hazards analysis. The study cohort comprised 7957 (6421 CS and 1536 GA) patients. Persistent AF, hypertension, and heart failure, as well as use of AAD, were more prevalent in the GA group. Cumulative incidences of recurrent AF were higher in the CS group at 1 (46% vs. 37%) and at 5 (68% vs. 63%) years. Multivariate analysis revealed CS as significantly associated with increased risk of AF recurrence at 5-year follow-up [hazard ratio 1.26 (95% confidence interval 1.15-1.38)], consistent across paroxysmal and persistent AF subtypes. CONCLUSION: This nationwide cohort study suggests a higher risk of AF recurrence with CS during CA compared to GA. These results advocate for considering GA as the preferred anaesthesia type for improved CA outcomes.

Understanding the incidence of atrial fibrillation and stroke in hypertrophic cardiomyopathy patients: insights from Danish nationwide registries.

AIMS: The treatment of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) can be challenging since AF aggravates symptoms and increases the risk of stroke. Which factors contribute to the development of AF and stroke in HCM remains unknown. The aim of this study was to determine the incidence of AF and stroke in HCM patients and identify the risk factors. METHODS AND RESULTS: Using Danish national registries, all HCM patients from 2005 to 2018 were included. The association between HCM, incident AF, and stroke was investigated using multivariable Cox proportional hazards analysis. Cumulative incidences were calculated using the Aalen-Johansen estimator. Among the 3367 patients without prevalent AF, 24% reached the endpoint of incident AF with death as a competing risk. Median follow-up time was 4 years. Atrial fibrillation incidence was equal between sexes and increased for patients with ischaemic heart disease [IHD; hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.08-1.63], hypertension (HT) (HR 1.36, 95% CI 1.14-1.67), and obstructive HCM (HR 1.27, 95% CI 1.05-1.52). Seven per cent developed stroke, with no difference detected stratifying for the presence of AF. Sub-analysis revealed that when AF was treated with oral anticoagulants (OACs), stroke was less likely (HR 0.4, 95% CI 0.18-0.86, P = 0.02). However, 34% of patients were not receiving adequate anticoagulation following AF diagnosis. CONCLUSION: Obstructive HCM, HT, and IHD were associated with increased risk of AF. Prevalent AF alone was not predictive of stroke; however, AF patients treated with OAC were significantly less likely to develop stroke, suggesting that this development is driven by the protective effect of OAC. Despite this, 34% of patients did not receive OAC.

A danish healthcare-focused economic evaluation of first-line cryoballoon ablation versus antiarrhythmic drug therapy for the treatment of paroxysmal atrial fibrillation.

INTRODUCTION: Three randomised controlled trials (RCTs) have demonstrated that first-line cryoballoon pulmonary vein isolation decreases atrial tachycardia in patients with symptomatic paroxysmal atrial fibrillation (PAF) compared with antiarrhythmic drugs (AADs). The aim of this study was to develop a cost-effectiveness model (CEM) for first-line cryoablation compared with first-line AADs for the treatment of PAF. The model used a Danish healthcare perspective. METHODS: Individual patient-level data from the Cryo-FIRST, STOP AF and EARLY-AF RCTs were used to parameterise the CEM. The model structure consisted of a hybrid decision tree (one-year time horizon) and a Markov model (40-year time horizon, with a three-month cycle length). Health-related quality of life was expressed in quality-adjusted life years (QALYs). Costs and benefits were discounted at 3% per year. Model outcomes were produced using probabilistic sensitivity analysis. RESULTS: First-line cryoablation is dominant, meaning it results in lower costs (-€2,663) and more QALYs (0.18) when compared to first-line AADs. First-line cryoablation also has a 99.96% probability of being cost-effective, at a cost-effectiveness threshold of €23,200 per QALY gained. Regardless of initial treatment, patients were expected to receive ∼ 1.2 ablation procedures over a lifetime horizon. CONCLUSION: First-line cryoablation is both more effective and less costly (i.e. dominant), when compared with AADs for patients with symptomatic PAF in a Danish healthcare system.

Health care services for older people in COVID-19 pandemic times - A Nordic comparison.

OBJECTIVE: To explore the Nordic municipal health and care services' ability to promote principal goals within care for older people during the COVID-19 pandemic. DESIGN AND SETTING: Two surveys were conducted among managers of municipal health care services for older people in Denmark, Finland, Norway and Sweden; the first around 6 months into the pandemic (survey 1), and the second around 12 months later (survey 2). Data were analysed through descriptive statistics, and multiple regression (OLS). SUBJECTS: 1470 (survey 1, 2020) and 745 (survey 2, 2021) managers. 32% in home care, 51% in nursing homes, 17% combined. RESULTS: In all countries the pandemic seems to have had more negative impact on eldercare services' ability to promote an active and social life, than on the ability to promote or enhance older people's mental and physical health. The regression analysis indicates that different factors influence the ability to promote these goals. Managers within nursing homes reported reduced ability to promote mental and physical health and an active social life to a significantly lower degree than managers of home care. The effect of three prevention strategies (lock down, testing, and/or organisational change), were explored. Organisational change (reorganize staff and practice, restrict use of substitutes) tended to impact the units' ability to promote a social life in a positive direction, while lock down (areas, buffets etc) tended to impact both the ability to promote mental/physical health and a social life in a negative direction. CONCLUSION: Measures that can improve opportunities for an active and social life during a pandemic should have high priority, particularily within home care.

It is important to learn from how the COVID-19 outbreak in 2020 affected the municipal health and care services' ability to achieve principal goals within care for older people.The pandemic had a more negative impact on the services' ability to promote an active and social life, than on their ability to promote or enhance mental and physical health.Measures that can improve opportunities for an active and social life during a pandemic situation should have high priority, particularily within home-based care.

Healthcare Professionals' Experiences of Recovery-Oriented Collaboration Between Mental Health Centres and Municipalities: A Qualitative Study.

Collaboration within mental health centres and with municipalities in Western European healthcare has presented challenges due to structural and cultural disparities. The Danish healthcare system faces obstacles that impact mental healthcare services, particularly in cross-sectorial cooperation. Our aim was to investigate healthcare professionals' experiences of recovery-oriented collaboration within a mental healthcare setting across hospitals and municipalities to gather a deeper understanding of this issue. Twenty-four employees were purposively sampled from mental health centres in Copenhagen and focus group interviews were conducted to explore their perceptions of working together. Inductive content analysis was used to analyse the data and identify themes and categories. The participants emphasised challenges in communication and coordination to improve collaboration within across the two sectors. This study can contribute to a greater understanding of collaboration between mental health centres and municipalities. It aims to inspire improvements in communication, coordination, and the optimisation of mental health service delivery across sectors.

Health professionals' perceptions of user involvement in a mental health centre: A critical discourse analysis.

The objective of this study was to investigate the engagement between healthcare professionals and users of mental healthcare at the individual level in a mental health hospital. A qualitative research design with purposive sampling was adopted. Five audio-recorded focus group interviews were conducted with nurses and other health professionals at a mental health hospital in Copenhagen and were explored using Fairclough's discourse analysis framework. This study shows how users can be subject to paternalistic control despite the official aim that user involvement be an integral part of the care and treatment offered. As evidenced in discussions by health professionals, the users were involved in plans based on conditions determined by the health professionals who were predominantly focused on treating diseases and enabling the users to live a life independent of professional help. Our results can contribute to dealing with the challenges of incorporating user involvement as an ideology in mental health hospitals.

Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity.

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14+ monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

Interactions of oral permeation enhancers with lipid membranes in simulated intestinal environments.

The oral bioavailability of therapeutic peptides is generally low. To increase peptide transport across the gastrointestinal barrier, permeation enhancers are often used. Despite their widespread use, mechanistic knowledge of permeation enhancers is limited. To address this, we here investigate the interactions of six commonly used permeation enhancers with lipid membranes in simulated intestinal environments. Specifically, we study the interactions of the permeation enhancers sodium caprate, dodecyl maltoside, sodium cholate, sodium dodecyl sulfate, melittin, and penetratin with epithelial cell-like model membranes. To mimic the molecular composition of the real intestinal environment, the experiments are performed with two peptide drugs, salmon calcitonin and desB30 insulin, in fasted-state simulated intestinal fluid. Besides providing a comparison of the membrane interactions of the studied permeation enhancers, our results demonstrate that peptide drugs as well as intestinal-fluid components may substantially change the membrane activity of permeation enhancers. This highlights the importance of testing permeation enhancement in realistic physiological environments and carefully choosing a permeation enhancer for each individual peptide drug.

Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial.

Background: Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk. Methods: This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score < -1.0 at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516. Findings: Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5 kg/m2 (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8 µg/L [95% CI -5.6 to 13.3]; p = 0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3 µg/L versus placebo 62.3 µg/L [95% CI -10.8 to 15.0]; p = 0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4 ng/L [95% CI 25.5-307.3]; p = 0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide group after 52 weeks ((ETD lumbar spine -0.018 g/cm3 [95% CI -0.031 to -0.005]; p = 0.007); ETD total hip -0.020 g/cm2 ([95% CI -0.032 to -0.008]; p = 0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p = 0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD -6.8 kg [95% CI -8.8 to -4.7]; p < 0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported. Interpretation: In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss. Funding: Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.

Efficacy and safety of once weekly semaglutide 2·4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial.

BACKGROUND: Data on the benefits of the once weekly GLP-1 receptor agonist semaglutide 2·4 mg for weight management in people from east Asia are insufficient. The objective of this study was to determine the efficacy and safety of once weekly semaglutide 2·4 mg versus placebo for weight management in a predominantly east Asian adult population. METHODS: This randomised phase 3a, double-blind multicentre controlled trial (STEP 7) recruited participants from 23 hospitals and trial centres in China, Hong Kong, Brazil, and South Korea. Adults with overweight or obesity, with or without type 2 diabetes, were randomly assigned (2:1) to receive a subcutaneous injection of either semaglutide 2·4 mg or placebo once a week for 44 weeks, plus a diet and physical activity intervention. Randomisation was done in blocks of six with an interactive web response system and was stratified by diagnosis of type 2 diabetes. Participants, investigators, and the trial sponsor were masked to treatment allocation until after database lock. Primary endpoints were percentage change in mean bodyweight and proportion of participants having reached a weight reduction of at least 5% of bodyweight from baseline to week 44. Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04251156, and is now complete. FINDINGS: From Dec 8, 2020, to Aug 23, 2022, 448 participants were screened, of whom 375 were randomly assigned to either the semaglutide 2·4 mg group (n=249) or the placebo group (n=126). Estimated mean percentage change in bodyweight from baseline to week 44 was -12·1% (SE 0·5) with semaglutide 2·4 mg versus -3·6% (0·7) with placebo (estimated treatment difference -8·5 percentage points [95% CI -10·2 to -6·8]; p<0·0001). At week 44, the proportion of participants who lost 5% or more of their bodyweight was higher in the semaglutide 2·4 mg group than in the placebo group (203/238 [85%] vs 36/116 [31%]); odds ratio 13·1 (95% CI 7·4-23·1; p<0·0001). Adverse events were reported by 231 (93%) of 249 participants in the semaglutide 2·4 mg group and 108 (86%) of 126 participants in the placebo group, the most common of which were gastrointestinal disorders (168/249, 67% vs 45/126, 36%). INTERPRETATION: The results of this study support the use of semaglutide 2·4 mg for weight management in people of east Asian ethnicity with overweight or obesity and with or without type 2 diabetes. FUNDING: Novo Nordisk. TRANSLATIONS: For the Mandarin, Portuguese and South Korean translations of the abstract see Supplementary Materials section.

Human osteoclasts in vitro are dose dependently both inhibited and stimulated by cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC).

Legalized use of cannabis for medical or recreational use is becoming more and more common. With respect to potential side-effects on bone health only few clinical trials have been conducted - and with opposing results. Therefore, it seems that there is a need for more knowledge on the potential effects of cannabinoids on human bone cells. We studied the effect of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) (dose range from 0.3 to 30 µM) on human osteoclasts in mono- as well as in co-cultures with human osteoblast lineage cells. We have used CD14+ monocytes from anonymous blood donors to differentiate into osteoclasts, and human osteoblast lineage cells from outgrowths of human trabecular bone. Our results show that THC and CBD have dose-dependent effects on both human osteoclast fusion and bone resorption. In the lower dose ranges of THC and CBD, osteoclast fusion was unaffected while bone resorption was increased. At higher doses, both osteoclast fusion and bone resorption were inhibited. In co-cultures, both osteoclastic bone resorption and alkaline phosphatase activity of the osteoblast lineage cells were inhibited. Finally, we observed that the cannabinoid receptor CNR2 is more highly expressed than CNR1 in CD14+ monocytes and pre-osteoclasts, but also that differentiation to osteoclasts was coupled to a reduced expression of CNR2, in particular. Interestingly, under co-culture conditions, we only detected the expression of CNR2 but not CNR1 for both osteoclast as well as osteoblast lineage nuclei. In line with the existing literature on the effect of cannabinoids on bone cells, our current study shows both stimulatory and inhibitory effects. This highlights that potential unfavorable effects of cannabinoids on bone cells and bone health is a complex matter. The contradictory and lacking documentation for such potential unfavorable effects on bone health as well as other potential effects, should be taken into consideration when considering the use of cannabinoids for both medical and recreational use.

Two decades of SVT ablation in Denmark: a trend towards higher age, more comorbidity, and less prior use of antiarrhythmic and rate-limiting pharmacotherapy-a nationwide registry-based Danish study.

BACKGROUND AND AIMS: Trends in patient selection and use of pharmacotherapy prior to catheter ablation (CA) for supraventricular tachycardia (SVT) are not well described. This study examined temporal trends in patients undergoing first-time CA for regular SVT, including atrioventricular nodal re-entry tachycardia (AVNRT), accessory pathways (APs), and ectopic atrial tachycardia (EAT) on a nationwide scale in Denmark in the period 2001-2018. METHODS AND RESULTS: Using Danish Nationwide registers, 9959 patients treated with first-time CA for SVT between 2001 and 2018 were identified, of which 6023 (61%) received CA for AVNRT, 2829 (28%) for AP, and 1107 (11%) for EAT. Median age was 55, 42, and 55 in the AVNRT, APs, and EAT group, respectively. The number of patients receiving CA increased from 1195 between 2001 and 2003 to 1914 between 2016 and 2018. The percentage of patients with a CHA2DS2-VASc score ≥ 2 increased in all patient groups. The number of patients who underwent CA with no prior use of antiarrhythmic- or rate limiting medicine increased significantly, though prior use of beta-blockers increased for AVNRT patients. Use of verapamil decreased in all three SVT groups (P < 0.05). Use of amiodarone and class 1C antiarrhythmics remained low, with the highest usage among EAT patients. CONCLUSION: Between 2001 and 2018, CA was increasingly performed in patients with SVT, primarily AVNRT- and EAT patients. The burden of comorbidities increased. Patients undergoing CA without prior antiarrhythmic- or rate-limiting drug therapy increased significantly. Use of beta-blockers increased and remained the most widely used drug.

Resistance towards and biotransformation of a Pseudomonas-produced secondary metabolite during community invasion.

The role of antagonistic secondary metabolites produced by Pseudomonas protegens in suppression of soil-borne phytopathogens has been clearly documented. However, their contribution to the ability of P. protegens to establish in soil and rhizosphere microbiomes remains less clear. Here, we use a four-species synthetic community (SynCom) in which individual members are sensitive towards key P. protegens antimicrobial metabolites (DAPG, pyoluteorin, and orfamide A) to determine how antibiotic production contributes to P. protegens community invasion and to identify community traits that counteract the antimicrobial effects. We show that P. protegens readily invades and alters the SynCom composition over time, and that P. protegens establishment requires production of DAPG and pyoluteorin. An orfamide A-deficient mutant of P. protegens invades the community as efficiently as wildtype, and both cause similar perturbations to community composition. Here, we identify the microbial interactions underlying the absence of an orfamide A mediated impact on the otherwise antibiotic-sensitive SynCom member, and show that the cyclic lipopeptide is inactivated and degraded by the combined action of Rhodococcus globerulus D757 and Stenotrophomonas indicatrix D763. Altogether, the demonstration that the synthetic community constrains P. protegens invasion by detoxifying its antibiotics may provide a mechanistic explanation to inconsistencies in biocontrol effectiveness in situ.

Tuning the double lipidation of salmon calcitonin to introduce a pore-like membrane translocation mechanism.

A widespread strategy to increase the transport of therapeutic peptides across cellular membranes has been to attach lipid moieties to the peptide backbone (lipidation) to enhance their intrinsic membrane interaction. Efforts in vitro and in vivo investigating the correlation between lipidation characteristics and peptide membrane translocation efficiency have traditionally relied on end-point read-out assays and trial-and-error-based optimization strategies. Consequently, the molecular details of how therapeutic peptide lipidation affects it's membrane permeation and translocation mechanisms remain unresolved. Here we employed salmon calcitonin as a model therapeutic peptide and synthesized nine double lipidated analogs with varying lipid chain lengths. We used single giant unilamellar vesicle (GUV) calcein influx time-lapse fluorescence microscopy to determine how tuning the lipidation length can lead to an All-or-None GUV filling mechanism, indicative of a peptide mediated pore formation. Finally, we used a GUVs-containing-inner-GUVs assay to demonstrate that only peptide analogs capable of inducing pore formation show efficient membrane translocation. Our data provided the first mechanistic details on how therapeutic peptide lipidation affects their membrane perturbation mechanism and demonstrated that fine-tuning lipidation parameters could induce an intrinsic pore-forming capability. These insights and the microscopy based workflow introduced for investigating structure-function relations could be pivotal for optimizing future peptide design strategies.

Lower Recurrence Rates of Atrial Fibrillation and MACE Events After Early Compared to Late Ablation: A Danish Nationwide Register Study.

BACKGROUND: Guidelines recommend prioritizing treatment with antiarrhythmic drugs before referral of patients with atrial fibrillation to ablation, delaying a potential subsequent ablation. However, delaying ablation may affect ablation outcomes. We sought to investigate the impact of duration from diagnosis to ablation on the risk of atrial fibrillation recurrence and adverse events. METHODS AND RESULTS: Using Danish nationwide registries, all patients with first-time ablation for atrial fibrillation were identified and included from 2010 to 2018. Patients were divided into 4 groups by diagnosis-to-ablation time: <1.0 year (early ablation), 1.0 to 1.9 years, 2.0 to 2.9 years, and >2.9 years (late ablation). The primary end point was atrial fibrillation recurrence after the 90-day blanking period, defined by admission for atrial fibrillation, cardioversions, use of antiarrhythmic drugs, or repeat atrial fibrillation ablations. The secondary end point was a composite end point of heart failure, ischemic stroke, or death, and each event individually. The study cohort consisted of 7705 patients. The 5-year cumulative incidence of atrial fibrillation recurrence in the 4 groups was 42.9%, 54.8%, 55.9%, and 58.4%, respectively. Hazard ratios were 1.20 (95% CI, 1.07-1.35), 1.29 (95% CI, 1.13-1.47), and 1.40 (95% CI, 1.28-1.53), respectively, with the early ablation group as reference. The hazard ratio for the combined secondary end point was 1.22 (95% CI, 1.04-1.44) in the late ablation group compared with the early ablation group. CONCLUSIONS: In patients undergoing ablation for atrial fibrillation, early ablation was associated with a significantly lower risk of atrial fibrillation recurrence. Furthermore, the associated risk of heart failure, ischemic stroke, or death was significantly lower in early-compared with late-ablation patients.

Temporal trends in mortality, heart failure hospitalisation, and stroke in heart failure patients with and without atrial fibrillation: a nationwide study from 1997-2018 on 152,059 patients.

AIMS: We aimed to investigate temporal trends in all-cause mortality, heart failure (HF) hospitalisation, and stroke from 1997 to 2018 in patients diagnosed with both HF and atrial fibrillation (AF). METHODS AND RESULTS: From Danish nationwide registers, we identified 152 059 patients with new-onset HF between 1997 and 2018. Patients were grouped according to year of new-onset HF and AF-status: Prevalent AF (n = 34 734), New-onset AF (n = 12 691), and No AF (n = 104 634). Median age decreased from 76 to 73 years between 1997 and 2018. The proportion of patients with prevalent or new-onset AF increased from 24.7% (n = 9256) to 35.8% (n = 14 970). Five-year risk of all-cause mortality went from 69.1% (CI: 67.9%-70.2%) to 51.3% (CI: 49.9%-52.7%), 62.3% (CI: 60.5%-64.4%) to 43.0% (CI: 40.5%-45.5%), and 61.9% (CI: 61.3%-62.4%) to 36.7% (CI: 35.9%-37.6%) for the Prevalent AF, New-onset AF and No AF-group, respectively. Minimal changes were observed in the risk of HF-hospitalisation. Five-year stroke risk decreased from 8.5% (CI: 7.8%-9.1%) to 5.0% (CI: 4.4%-5.5%) for the prevalent AF group, 8.2% (CI: 7.2%-9.2%) to 4.6% (CI: 3.7%-5.5%) for new-onset AF, and 6.3% (CI: 6.1%-6.6%) to 4.9% (CI: 4.6%-5.3%) for the No AF group. Simultaneously, anticoagulant therapy increased for patients with prevalent (from 42.7% to 93.1%) and new-onset AF (from 41.9% to 92.5%). CONCLUSION: From 1997 to 2018, we observed an increase in patients with HF and co-existing AF. Mortality decreased for all patients, regardless of AF-status. Anticoagulation therapy increased, and stroke risk for patients with AF was reduced to a similar level as patients without AF in 2013-2018.

Trends in percutaneous left atrial appendage occlusion and 1-year mortality 2013-2021: A nationwide observational study.

BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) is increasingly used for stroke prevention in patients with atrial fibrillation and anticoagulant-related complications. Yet, real-life studies evaluating changes in patient characteristics and indications for LAAO remain scarce. METHODS: To evaluate changes in patient characteristics and indications for LAAO defined as 2-year history of intracerebral bleeding, any ischemic stroke/systemic embolism (SE), any non-intracerebral bleeding, other indication, and 1-year mortality. All patients undergoing percutaneous LAAO in Denmark from 2013 to 2021 were stratified into the following year groups: 2013-2015, 2016-2018, and 2019-2021. RESULTS: In total, 1465 patients underwent LAAO. Age remained stable (2013-2015: 74 years versus 2019-2021: 75 years). Patients' comorbidity burden declined, exemplified by CHA2DS2-VASc ≥4 and HAS-BLED ≥3 decreased from 56.7% and 63.7% in 2013-2015 to 40.3% and 45.8% in 2019-2021. Indications for LAAO changed over time with other indication comprising 44.7% in 2019-2021; up from 26.9% in 2013-2015. Conversely, fewer patients had an indication of any ischemic stroke/SE (2013-2015: 30.8% vs 2019-2021: 20.3%) or any non-intracerebral bleeding (2013-2015: 29.4% vs 2019-2021: 23.4%). 1-year mortality was 11.3% for any non-intracerebral bleeding and 6.2% for other indication. CONCLUSION: The LAAO patient-profile has changed considerably. Age remained stable, while comorbidity burden decreased during the period 2013-2021. LAAO is increasingly used in patients with no clinical event history and mortality differs according to indication. Selection of patients to LAAO should be done carefully, and contemporary real-life studies investigating clinical practice could add important insights.